Using human brown and beige adipocytes to develop new therapies for type 2 diabetes

 

Stephen Dalton

 

School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong

 

Abstract： Most patients with type 2 diabetes (T2D) take some form of medication, but these focus on controlling hyperglycemia, using drugs that have common or overlapping mechanisms of action. These medications often have undesirable side effects and have only incremental efficacy in reducing hemoglobin A1C levels. This is often compounded by the need for dual and triple-drug therapies in conjunction with injectable insulin, and reduced efficacy over time. Insulin resistance and resulting hyperglycemia that develops in T2D is associated with increased, system­ic inflammation that contributes to a broad range of clinical complications. There­fore, the efficacy of drugs that solely regulate glucose homeostasis as a mechanism of action is limited. This establishes a need to develop new approaches for the treatment of T2D.

      Human brown adipose tissue (hBAT) regulates metabolic homeostasis and energy expenditure by impacting the clearance of circulating glucose and triglycerides. A second aspect of this involves the secretion of ‘adipokines⁵, lipoprotein complex­es, and vesicles by BAs that impact inflammation and systemic metabolic regula­tion. These BA-associated functions restrict the development of T2D at the meta­bolic level and minimize disease complications. Animal model studies show that transplantation of BAT from healthy individuals reverses T2D and a broad range of associated complications. In humans, increased BAT activity improves insulin-sen­sitivity in type 2 diabetics and improves the clinical status of individuals with co-morbidities. Patients with T2D typically have limited amounts of brown adipo­cytes, leading to the proposal that increasing the mass of BAT depots would be a viable therapeutic strategy. A major impediment preventing the development of such a therapy has been the unavailability of a transplantable cell source. This presentation will discuss our approach to solving this challenge, using pluripotent stem cells as a technology platform.

Decline of hippocampal TRF2 during aging triggers ATM-dependent memory impairment

 

Marco Raffaeli¹, Jing Ye²,³, Franck Oury⁴ and Eric Gilson¹，²,³,⁵

 

1. Universite Cote d'Azur, Inserm, CNRS, IRCAN, Nice, France.
2. Department of Geriatrics, Medical center on Aging of Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
3. International Laboratory in Hematology, Cancer, Aging and Hematology, Pole Sino-Franqais de Recherches en Sciences du Vivant et Genomique, RuiJin Hospital, Shang­hai Jiao Tong University School of Medicine/CNRS/INSERM/University Cote d'Azur, Shang­hai, China.

4INEM, Necker hospital, Pais, France

⁵ Department of medical genetics, CHU, Nice, France.

 

Abstract

The physiological changes in the brain during normal aging (i.e., without overt pathology) are characterized by a progressive decline in neuronal homeostasis and cognitive functions. Among the regions of the brain most affected by aging is the hippocampus, which controls memory and learning. Our understanding of how the hippocampus ages is still at its infancy. We report that the level of the key telomere-capping protein TRF2 declines in the hippocampi of mice during aging. Next, we modulated the level of TRF2 in hippocampal neurons by stereotactically injecting AAV9 preparations. In young hippocampi, TRF2 was required for episodic and contextual memory and restoration of the TRF2 level in the hippocampi of old mice restored their memory capacity to that of young mice. In the hippocampus, TRF2 suppressed unwanted ATM activation and modulated the expression of genes involved in synaptic plasticity. Therefore, an age-dependent TRF2-ATM axis controls memory performance. The deleterious effect of TRF2 on memory capacity during aging suggests novel strategies for interventions to delay, prevent or revert age-associated memory loss.

Rehabilitation of Age-Related Cognitive Impairment

 

Gong Weijun

Beijing Rehabilitation Hospital and Rehabilitation Medicine School affiliated with Capital Medical University

 

Abstract

In China, the proportion of the population over 65 years old was 6.96% in the year 2000, which increased to 13.5% in 2020, reaching a total number of 191 million. Cognitive impairment is a significant aspect that affects individual activities of daily living and quality of life, thus age-related cognitive impairment is gaining increasing attention from experts in the field of rehabilitation medicine.

Rehabilitation therapy has been validated as safe and effective through evidence-based medicine. Both cognitive training, motor training, cognitive-motor dual-task training, and neuromodulation techniques such as transcranial magnetic stimulation have all demonstrated favorable clinical outcomes and evidence-based support. Further research indicates that these methods can achieve improvements in age-related cognitive impairment through pathways like oxidative stress, synaptic plasticity, chronic inflammation, epigenetics, and so on.

Novel Longevity Compounds in the Context of Cellular Senescence

 

Perinur Bozaykut

 

Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydinlar Universityi

 

Abstract

Chronological aging is a predominant risk factor for various human diseases. While numerous pharmacological, dietary, and genetic interventions are known to target the aging process and age-related diseases, the underlying principles of these interventions remain elusive. Given the complex nature of aging, our primary objective is to analyze the transcriptomes of established longevity interventions to characterize perturbations in gene expression profiles. The identification of common longevity-related signatures facilitates the prediction of novel com­pounds with longevity-promoting properties.

    To experimentally validate these predicted compounds, UM-HET3 mice are subjected to diets with candidate drugs. Furthermore, we employ progeria cells, an accelerated senescence model, to investigate the effects of these compounds at the cellular level. Cellular senescence, a fundamental mechanism in the develop­ment of age-related diseases, has spurred the emergence of senotherapeutic drugs, some of which are already undergoing clinical trials. Following the confir­mation of senescent cells through the use of specific biomarkers, we assess the potential of candidate molecules as senotherapeutic agents when applied to these senescent cells.

This study aims to uncover promising new drug candidates for various aging-relat­ed phenotypes, including cellular senescence, with potential implications for the development of interventions against age-related diseases.

Acknowledgement： This study is supported by The Scientific and Technological Research Council of Turkey (TUBITAK) with grant number 121S705.

Title: In Vivo Imaging of Early Vascular Degeneration in Age-related Cognitive Decline

 

Yulin Ge

 

Department of Radiology, New York University (NYU) Grossman School of Medicine

 

Abstract

Age-related vascular degenerative changes ultimately result in vascular dysfunc­tion. This dysfunction can be attributed to various morphological or structural alterations, such as vessel tortuosity, shrinkage, endothelial dysfunction, and increased blood-brain barrier (BBB) permeability. Detecting these early vascular structural changes in live brains has historically been challenging, despite strong indications from histopathology studies suggesting their pathogenic role in cogni­tive decline. Our recent research, employing high-resolution 7T MRI with ultrasmall superparamagnetic iron oxide (USPIO) contrast agent, has revealed age-related vascular degeneration in early adulthood that intensifies with age in healthy volun­teers. These findings may play a significant pathogenic role in age-related neuro­degeneration and dementia. Notable changes encompass small arterial tortuosity alterations (with vessel diameters ranging from 50-100 卩m) and vascular degenera­tion in the choroid plexus, accompanied by decreased blood perfusion, starting as early as 30 years of age. Furthermore, we have identified correlations between these vascular changes and structural atrophic changes that occur during brain aging. This presentation will delve into the pathophysiological mechanisms under­lying neurovascular changes associated with aging, as well as explore imaging techniques for both qualitative and quantitative analyses of these changes. Research in this direction carries significant implications for understanding the vascular contributions to cognitive impairment and dementia (VCID), as well as for the development of therapeutic strategies aimed at early prevention.

Linking healthy longevity with robust immune function in a long-lived mouse model

 

Abbe N. de Vallejo, PhD

 

University of Pittsburgh School of Medicine

 

Abstract

Chronologic aging is associated with progressive losses in various physiologic functions. Yet, significant proportions of elderly populations are living inde­pendently in the community well beyond their 7th-8th decades of life and exhibit various clinical criteria of healthy or successful longevity. A scientific challenge therefore is to unravel biological processes that promote physiologic homeostasis in old age despite well recognized age-related functional deterioration(s). Along these lines, considerable bodies of evidence have demonstrated that mice with targeted deletion of pregnancy-associated plasma protein A (PAPPA) represents a model of healthy longevity. In addition to its extended lifespan of up to 40% com­pared to its wildtype (WT) littermates, PAPPA-/- mice have significant reductions in mid-life and end-of-life pathologies including resistance to spontaneous tumors and aortitis normally induced by high fat diet. We have shown that such favorable health phenotypes of old PAPPA-/- mice is associated with the retention of their thymi, which normally involves age. This thymic retention maintains large popula­tions of diverse T cells throughout life. In this presentation, we will discuss various experimental platforms we adopted to explore the biological relevance of thymic retention. Experiments were designed to test the hypothesis that healthy longevity is tightly linked to thymus-specific retention of PAPPA that underlie robust T cell mediated immunity as well as intact innate immune defense.

Title: Multi-modal Transformers for Aging Research and Target Discovery

 

Alex Zhavoronkov, PhD

 

The founder and CEO of Insilico Medicine Adjunct professor of artificial intelligence Buck Institute for Research on Aging.

California, USA

 

Abstract

Transformers are popular neural network architectures combining self-attention context modeling and various pre-training approaches that often achieve state-of-the-art performance on multiple diverse tasks primarily involving under­standing and generating natural language. Multi-modal transformers extend regu­lar transformers to handle multiple data modalities like text, images, and video. They model relationships between modalities through cross-attention mecha­nisms. Multi-modal transformers have advantages in leveraging complementary information across modalities and learning aligned representations for stronger generalization. In 2022, Insilico Medicine developed the first multi-modal trans­former titled Precious1GPT trained on transcriptomic and methylation as well as the accompanying metadata to perform multiple tasks including biological age and disease prediction and therapeutic target identification. In this talk we will discuss the applications of Precious1GPT and other generative tools to drug discovery and provide the roadmap for muti-modal GPTs trained on a variety of modalities of data for drug discovery and aging research.

Small molecules effects on organ-specific cell senescence

 

Patrizia Anna d'Alessio, MD, PhD

 

CEO AISA Therapeutics

Faculty of Medicine University Paris Rene Descartes - Necker Hospital Paris INSERM University Paris Sud-11 - Paul Brousse Hospital Villejuif - France

 

Abstract

t some point we have been confronted by some odd results that we could not make sense of. How was it that a small molecule, d-Limonene, able to reverse cell senescence in endothelial cells in vitro, was dramatically healing psoriasis patients skin lesions? Sure enough, pre-clinical studies had shown anti-inflammatory effects of this compound via a possible inhibition of the NF-园 B pathway in fibro­blasts in vitro. Tissue repair and cytokine inhibition had been proven in a rat colitis model, and a specific in vitro model on enterocytes showed gut barrier repair capacity at specific concentrations. In a murine dermatitis model, the same small molecule applied topically, apart from dramatic wound healing, yielded important inhibition of neo vascularsation. A first in human study on a population of seniors had shown the same capacities of the compound orally administered as diet supplement yet extended to the improvement of more parameters (grip test, microbiota reshuffling, cardio-metabolic markers).

Indeed, when it comes to the etio-pathogenesis of intermediate psoriasis or atopic dermatitis (AD), the leaky gut syndrome is always mentioned, installed or ampli­fied following a stressful episode. The brain, which elicits responses to stress via endocrine and neuro-humoral regulations, is largely mirrored in the skin, in partic­ular around hair follicles, as well as in the rich neuronal component of the gut. As for the vascular compartment, it has been observed that oxidative or cytokine stress is able to induce premature senescence in endothelial cells. Moreover, repeated, and non-resolving inflammatory responses involved in the generation of cell senescence in vitro, translate into an augmented expression of adhesion mole­cules such as I CAM-1, VCAM-1, PECAM-1, E- and P-selectins, notably allowing for increased leukocyte diapedesis and the maintenance of tissular chronic inflamma­tion. Concomitantly, senescent cells display an increased actin polymerization generating “stress fibers” limiting their plasticity and inducing the transcription of pro-inflammatory genes. in vitro. The pro-inflammatory cytokines activate the NF-园 B pathway in endothelial cells, and this can be inhibited by the small mole­cule d-Limonene. Furthermore, similar to cytochalasin-D, but without cell toxicity, d-Limonene significantly interferes with actin polymerization leading to reverse F-actin fibers into G-actin monomers, changing the degree of tension operating in the cell, greatly modulating gene expression activation.

Small molecules can be synthetic or natural and they display excellent nontoxic anti-inflammatory effects simulating the effects of biologics. Monoterpenes are small molecules and the pro-drug d-Limonene (currently used in the household and cosmetic industry) but discovered by our team of chemobotanists bio-guided selection in a healing plant of the rain forest at the border of Vietnam and China, is equally present in citrus fruit peels. As for its wound healing and barrier repairing activity, it seems to act via its metabolite perillyl alcohol (POH). Because of the behavioral changes in orally administered d-Limonene animals in pre-clinical stud­ies, our pre-clinical work also addressed a functional Observation Battery (FOB) of stress responses in rodents. It indeed showed an important motivational increase able to induce animal stress resilience following d-Limonene feeding but inde­pendently from the POH effects, that revealed being dependent from an enhanced dopamine release. Indeed, in animal models as well as in human studies, this monoterpene decreases systemic levels of such pro-inflammatory cytokines as TNF-区 and IL-6. Altogether on behalf of d-Limonene-induced modifications of cellular physical and biological parameters, we concluded an anti-senescence effect on the endothelial cells. Before naming and patenting these monoterpens as AISA (Anti-Inflammatory-Senescence Actives) the experimental model was repli­cated in all available species and human organ specific endothelial cells. Although at the time (2015) we thought that skin endothelial senescence was due to the consequences of the generalized corticoid activation in response to stressors, and its consequent chronic inflammation all over the body, recent reports show that there is a precise link between skin endothelial cell senescence and the trigger of cutaneous auto immune diseases (Marco Quarta from Rubedo ref.) but also, even­tually of wound healing (De Maria - Campisi paper). Also, at the time, it was not known that senescent subtypes have different SASPs (Joao F Passos ref.).

Although it remains to grasp the mechanisms connecting the rare and heteroge­neous phenomena of cell senescence to skin pathologies, waved into a conundrum of gut-brain-skin functions, it appears to be essential for the maintenance of youthfulness. The anti-inflammatory action of monoterpenes, restoring the gut barrier function with a wound healing effect, through its metabolite, could thus possibly be considered to contribute in innovative early interventions for the primary prevention of aging. Nutraceutical supplements are not only supplements. they involve peripheral “brains” as well as the brain and act on a plurality of condi­tions allowing to help reversing the senescent phenotype where it hurts most, in the gut, in the brain and in the skin.

 

NRG1 Signaling Defines a Niche for Epidermal Progenitors in Wound Healing

 

Guo-He Tan, Ph.D.

 

Director of Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education,

Director of Guangxi Key Laboratory of Brain Science, & Institute of Neuroscience, Dean of School of Basic Medical Sciences, & Center for Translational Medicine, Guangxi Medical University

E-mail: tanguohe@gxmu.edu.cn

 

Abstract

Skin injury rely on epidermal stem and progenitor cells for regeneration; however, the specific signaling pathways regulating epidermal progenitor cells to partici­pate in wound healing remain elusive. Here, we identified an underlying molecular mechanism that regulate this process and contribute to wound healing, involving neuregulin1 (NRG1) and its tyrosine kinase receptor, ErbB4. Skin injury induced marked upregulation of NRG1 in perineural sensory neurons and increases its release the into the wound edge, which could promote re-epithelization following injury. Pharmacological or genetic inactivation of ErbB4 receptor delayed epitheli- alization in wound healing. Further cellular and molecular experiments indicated that NRG1 promotes wound healing mainly through the ErbB4 receptor on epider­mal progenitor cells within the cutaneous wound edge, in a time-dependent manner. Thus, these findings disclosed a novel mechanism underlying wound repair, providing a promising strategy for promoting wound healing by neuron-epi­dermis communication.

Keywords

Neuregulin1; peripheral nerves; wound healing; epidermal progenitor cells

Repurposing cyclosporine A as a neuroprotective drug for Parkinson's disease: pre-clinical studies

 

Sasanka Chakrabarti¹, Sukhpal Singh¹, Upasana Ganguly¹ and Sankha Shubhra Chakrabarti²

 

1. Department of Biochemistry and Central Research Cell, M M Institute of Medical Sciences & Research, Maharishi Markandeshwar (Deemed to be) University, Mullana-Ambala, India.
2. Department of Geriatric Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

 

Abstract

The identification of neuroprotective drugs for Parkinson's disease (PD), the second most common neurodegenerative disorder in the elderly, has remained elusive despite intensive research. In our lab, we observed that in SH-SY5Y cells (catecholaminergic human neuroblastoma cell line), multiple stressors such as dopamine (DA), ferric ammonium citrate, erastin and rotenone could cause mito­chondrial dysfunction, oxidative stress, an accumulation of a-synuclein and finally neural cell death. Further, the knock-down of a-synuclein expression prevented both mitochondrial dysfunction and cell death in such models of neurodegenera­tion. Interestingly, in these models cyclosporine A, a well-known inhibitor of mito­chondrial permeability transition pore (mPTP), also prevented cell death and mito­chondrial dysfunction without affecting the accumulation of a-synuclein. These results have implications in PD because mitochondrial dysfunction, oxidative stress and a-synuclein accumulation are integral components of the pathogenesis of this disorder. Thus, based on these results we hypothesized that cyclosporine A could function as a neuroprotective molecule in PD-neurodegeneration by preventing the deleterious action of a-synuclein on mitochondria through the involvement of mPTP. To test this hypothesis, we developed a PD model in Wistar rats by daily administration of rotenone (1.5 mg / kg body-weight, i.p. injection) for 8 days and then investigated if oral administration of cyclosporine A (10 mg / kg body-weight starting 7 days prior to the start of the rotenone injection and continuing for 8 more days along with the rotenone-treatment). Our results clearly showed that rotenone-induced motor disability and dopaminergic neurodegener­ation in substantia nigra and striatum could be markedly ameliorated by cyclospo­rine A in PD rat models. Further, the loss of transmembrane potential and ATP synthesis and the increased production of reactive oxygen species (ROS) in isolat­ed mitochondria from the midbrain of rotenone-treated rats were remarkably prevented by oral cyclosporine A treatment. However, the rotenone induced accu­mulation of a-synuclein in the substantia nigra was not affected by cyclosporine A. Thus, the results from the animal studies are in conformity with those from cell-based experiments. Additionally, cyclosporine A conspicuously prevented pro-inflammatory response in the midbrain of rotenone-treated rats. These results have prompted us to plan out a pilot clinical trial with cyclosporine A in early cases of PD.

Keywords: Mitochondria, Alpha-synuclein, Cyclosporine A, Parkinson's disease

 

Targeting senescence to rejuvenate the aged heart

 

Georgina M. Ellison-Hughes

 

School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, Guy's campus, King's College London, London, UK.

 

Abstract

Senescent cells have emerged as bona fide drivers of ageing and age-related cardiovascular disease, with senescent cells accumulating in the aged heart and following damage/injury. We and others have shown that eliminating senescent cells using senolytics (Navitoclax, Dasatanib+Quercetin) or genetic (using INK-AT - TAC+AP mice) clearance of senescent cells in aged mice alleviated detrimental features of cardiac ageing, including myocardial dysfunction, hypertrophy and fibrosis, and induced cardiomyocyte renewal and replacement. Senescent cells and their SASP present a promising therapeutic target to rejuvenate the heart's reparative potential.

Recent data from my lab shows that co-culture of human senescent cells with human iPSC-derived cardiomyocytes (iPSC-CMs) and cardiac microvascular endo­thelial cells (HMVECs) led to decreased survival and proliferation. Moreover, endo­thelial cells showed impaired tube formation and migration. D+Q senolytics, by eliminating senescent cells in the co-culture, improved human iPSC-CM and HMVEC survival and proliferation, and improved endothelial cell migration and tube formation. The mechanism of action supports the secretion of a SASP by senescent cells (especially IL-6, IL-8), which was abrogated with D+Q treatment. Next, we investigated the effects of D+Q senolytics in an in vivo model of takosubo cardiomyopathy (broken heart syndrome) simulated through excessive doses of synthetic catecholamine, Isoproterenol (ISO), administered to aged mice. Results showed that aged mice treated with senolytics before ISO had improved cardiac function, attenuated fibrosis and hypertrophy and increased number of EdU+ cardiomyocytes, compared to aged mice who did not receive senolytics before ISO. In conclusion, senescent cell removal by D+Q senolytics rejuvenated the reparative potential of the heart.

The Hyperoxic-Hypoxic Paradox: Unraveling its Potential in Regenerative Medicine

 

Shai Efrati, MD

 

Sagol Center for Hyperbaric Medicine and Research, Shamir (Assaf-Harofeh) Medical

Center, Israel

School of Medicine and Sagol School of Neuroscience, Tel-Aviv University, Israel

 

Abstract

Hyperbaric Oxygen Therapy (HBOT) allows individuals to inhale 100% oxygen under pressures exceeding one atmosphere absolute (1 ATA). This elevates the amount of oxygen dissolved in body tissues. While historically, HBOT was predomi­nantly used for treating chronic non-healing wounds, its application has seen a paradigm shift.

Emerging evidence underscores HBOT's regenerative capabilities. The synergetic effects of hyperoxia and hyperbaric pressure significantly enhance tissue oxygen­ation. This process activates oxygen and pressure-sensitive genes, bolstering mito­chondrial metabolism while offering anti-apoptotic and anti-inflammatory bene­fits. Impressively, these genes also stimulate stem cell proliferation and elevate the levels of endothelial progenitor cells (EPCs) and angiogenesis factors, fostering improved blood flow in ischemic areas. Recent studies further suggest HBOT's potential in promoting brain regeneration and neuroplasticity.

A striking observation is the Hyperoxic-Hypoxic Paradox, where the intermittent oxygen surge mimics several cellular mechanisms typically associated with hypox­ia, but without its detrimental effects. Such HHP exposures influence HIF-1 levels, matrix metalloproteinases (MMP) activity, and VEGF. Besides promoting angiogen­esis, HBOT tempers the inflammatory response in endothelial cells, as evidenced by reduced TNF-alpha mediation, thus catalyzing vascular recovery. Comprehen­sive animal and human studies have illuminated HBOT's positive impact on mito­chondrial functionality and associated metabolism.

In this lecture, we aim to elucidate the physiological intricacies of the "Hyperox­ic-Hypoxic Paradox" and shed light on the accumulating data concerning brain injuries, age-associated functional decline, and cardio-muscular performance.

Recognizing degenerative aging as a medical condition to enable longevity interventions: research methodology,
education and policy

 

Ilia Stambler, PhD

 

Department of Science, Technology and Society, Bar-Ilan Unviersity, Israel

Vetek (Seniority) Association - the Movement for Longevity and Quality of Life, Israel Intenrational Society on Aging and Disesae (ISOAD), US

 

Abstract

The anti-aging, longevity medicine or geroscience-based approach to health research and health care aims to treat degenerative aging processes as the main underlying causes and risk factors of chronic diseases. This approach is poised to significantly improve healthy longevity and solve urgent challenges of the aging population. Yet, a major obstacle to implementing this approach is the deficit of agreed evidence-based criteria for the evaluation of the aging process, in order not only to predict aging health trajectory, but also to evaluate the efficacy and safety of anti-aging therapies. A further crucial obstacle is the deficit of massive and effective educational and policy-making frameworks that would enable evidence-based and accessible longevity intervnetions. This presentation will discuss some of the methodological, educational and policy challenges of longevi­ty interventions, potential ways toward their solution and initiatives toward their implementation.

A Glimpse on Stem Cell and Organ Aging: the Common & Distinct Mechanisms

 

Zhenyu Ju

 

Dean of the Institute of Aging and Regenerative Medicine, Jinan University

 

Abstract

Stem cell aging and organ dysfunction in the elderly underlie the onset and devel­opment of aging and age-related diseases. Common and distinct mechanisms drive the age-related (patho-)physiological changes, thus it is crucial to holistically recognize and understand the differences among these factors for a better inter­vention of the aging process. Here we have investigated the causes of aging in representative tissues and organs with high-/low-turnover rate, and identified several important targets and mechanisms related to telomere and protein homeostasis, immunometabolic remodeling, and epigenetic changes, during aging.

By elucidating that the m5C modification of TERC regulates telomerase activity, and the Dcaf11-Zscan4-Kap1-mediated ALT mechanism, respectively, we identified telomerase-dependent and independent mechanisms that regulate age-associat­ed homeostasis. We also identified the role of the deacetylase SIRT6 and the E3 ligase TRIM31 in HSC aging, followed by the elucidation of the roles of CHOP and EVA1a in stem cell aging and regeneration. The metabolic regulation of the PGC1a-NAD+ axis has been demonstrated in many important target organs such as heart, brain and liver, paving the way for the development of anti-aging therapeu­tic strategies. In the context of chronic inflammation, we have found that cGAS deficiency promotes inflammation and accelerates cardiac aging.

Moreover, intervention studies targeting these specific candidates showed a great promise to realize healthy aging. MDL-800, a specific SIRT6 agonist, successfully attenuated hematopoietic stem cell aging and inflammaging in the aging mouse cohort. The NAD+ precursor B-NMN, which effectively improved the function of vital organs such as brain, intestine, and heart in late life. In addition, LINE1 inhibi­tors significantly attenuated SASP secretion and thereby ameliorating the inflam­matory phenotype in CMML mouse models.

Together, we elucidate the common and distinct mechanisms that drive stem cell and organ aging. These studies provide new insights for mechanistic studies of aging and age-related diseases.

 

Rejuvenation of peripheral immune cells by bone marrow transplantation attenuates Alzheimer⁹ s disease-like pathol-
ogies and behavioral deficits in an APP/PS1 mouse model

 

Yan-Jiang Wang, MD., PhD.

Professor Wang is the Director of the Department of Neurology at Daping Hospital, Third Military Medical University, China.

 

Abstract

Immunosenescence is known to contribute to systematic ageing and plays a role in the pathogenesis of Alzheimer's disease (AD). Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenat­ed through young bone marrow transplantation (BMT). Single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) revealed that young BMT reversed the expression of ageing- and AD-related genes in multiple cell types within PBMCs. Additionally, analysis of the plasma proteome demonstrated a decrease in circulating senescence-associated secretory phenotype (SASP) proteins following young BMT. Notably, young BMT resulted in a significant reduc­tion in both central and peripheral AB levels, leading to a decrease in cerebral AB plaque burden, neuronal degeneration, neuroinflammation, and improvement in behavioural deficits in aged APP/PS1 mice. These beneficial effects were associat­ed with an enhanced AB clearance capacity of peripheral monocytes. In conclu­sion, our study provides evidence that immune system rejuvenation can effectively mitigate AD-like pathologies and cognitive deficits, representing a promising ther­apeutic approach for AD.

Strategy research and mechanism of ovarian cell homeostasis/activation state balance to maintain fertility

 

Yang Yu

 

The Clinical Stem Cell Research Center of Peking University Third Hospital

 

Abstract

The ovary is one of the important tissues and organs for the maintenance of female fertility. It receives the signal regulation of hypothalamic-pituitary and performs the physiological functions such as follicle growth, maturation and ovulation. However, as women age, hormones and other signals are regulated abnormally, resulting in reduced ovarian function, ovulation disorders, reduced oocyte quality, and decreased fertility. The balance of ovarian homeostasis is the key to maintain­ing ovarian function. Previous studies have shown that in addition to granulosa cells and oocytes, which are closely related to fertility, there are also macrophages, natural killer cells, vascular endothelial cells and other cell types in the ovary. These cells interact with each other to promote the normal development of follicles through a variety of ways, for instance, immune regulation and nutrient transport. Nevertheless, with the imbalance of internal ovarian environmental homeostasis and the disorder of gene expression of various types of cells caused by aging, these ovarian cells how maintain their homeostasis and activation transi­tions, how to stabilize the connection between materials and information between cells, and how to achieve cell self-renewal and self-repair needs to be clarified. By analyzing the regulatory factors of ovarian cell homeostasis/activation states, we can provide theoretical support for the existing therapies such as stem cell to improve ovarian function, and explore new approaches.

Anti-infective Drug Discovery and Biosynthesis from Mi­croorganisms Derived from Special Environments.

 

Jianhua

 

School of Pharmaceutical Sciences, Shandong University

 

Abstract

Infectious diseases constitute a leading cause of death worldwide and continue to improve in their lethality as drug resistance continues to become more wide­spread. This concern, coupled with revelations about as yet, untapped sources of molecular diversity, has spurred intense efforts to discover new drug candidates with novel structures/modes of action able to circumvent or ablate bacterial mech­anisms of drug resistance. Within this context, the underexplored ecosystems (marine-, desert-, traditional Chinese Medicine-derived), have emerged as an excit­ing resource for novel anti-infective natural products discovery. Deciphering and engineering the biosynthetic pathway governing natural product biosynthesis provides an effective strategy to modify natural products. I will discuss examples on discovery, genetic engineering of anti-infective natural products as promising drug leads from mainly marine derived microorganisms

Repopulation and replacement: the philosophy of microglia

 

Bo Peng

 

Institute for Translational Brain Research, Fudan University, Shanghai, China

 

Abstract

Microglia undergo turnover (including cell death and regeneration) throughout the lifespan. Newborn microglia rapidly replenish the whole brain after selective elimi­nation of most microglia (>99%) in adult mice. The origin of these repopulated microglia has been hotly debated. We investigated the origin of repopulated microglia and demonstrated that all repopulated microglia were derived from the proliferation of the few surviving microglia (<1%). To dissect functions of aged microglia excluding the influence from other aged brain cells, we utilized 3-round depletion-repopulation (3xDR) to accelerate microglial turnover without directly affecting other brain cells. By this model, we achieved aged-like microglia in non-aged brains and confirmed that aged-like microglia per se contribute to cogni­tive decline.

Dysfunctions of gene-deficient microglia contribute to the development and progression of multiple CNS diseases. Microglia replacement by nonself cells has been proposed to treat microglia-associated disorders. However, some attempts have failed due to low replacement efficiency, such as with the traditional bone marrow transplantation approach. Based on our understanding in microglial repopulation, we develop three efficient strategies for microglia replacement with diverse application scenarios, which potentially opens up a window on treating microglia-associated CNS disorders.

On the other hand, if microglial debris is not removed in a timely manner, accumu­lated debris may influence CNS function. Clearance of microglial debris is crucial for CNS homeostasis. However, underlying mechanisms remain obscure. We find that although microglia can phagocytose microglial debris in vitro, the territo­ry-dependent competition hinders the microglia-to-microglial debris engulfment in vivo. In contrast, microglial debris is mainly phagocytosed by astrocytes in the brain, facilitated by C4b opsonization and degraded by noncanonical autophagy. Together, we elucidated mechanisms of microglia turnover and developed novel therapeutic approaches for neurological disorders.

 

Reversal Translation Research in Psychopharmacology

 

Hu Ji

 

School of Life science and Technology, ShanghaiTech University, Shanghai, China

 

Abstract

1 in every 8 people, or 970 million people around the world were living with a psychiatric disorder. However, medication for psychiatric disorders has not been updated for 50 years, partly because of a lack of knowledge about the etiology of mental illness, which makes translational research inefficient. We are applying a reverse-translational approach to gain insight into the neurobiological mecha­nisms underlying human psychiatric disorders and the effects of pharmacological treatments. We have found that atypical antipsychotics antagonize GABAA recep­tors in the ventral tegmental area GABA neurons to relieve psychotic behaviors. Also, we reported that propofol actively and directly binds to the dopamine trans­porter (DAT), but not the serotonin transporter, which contributes to the rapid relief of anhedonia.

Making biological ageing clocks actionable

 

Dr. Jan Gruber

 

Yale-NUS College, Science Division, National University of Singapore, Department of Biochemistry, 117608 Singapore

 

Abstract

Current strategies for managing population ageing are often disease-centric and reactive rather than focusing on holistic, organismal aging. Biological age (BA) clocks can be used to inform risk stratification by predicting future all-cause mor­tality. However current BA clocks typically do not pinpoint aging mechanisms, making it difficult to intervene clinically. To generate actionable BA clocks, we developed and validated a clinical aging clock that identifies signatures associated with healthy and unhealthy aging trajectories. We identify proactive interventions using existing drugs as a way to normalize BA and reduce future mortality risk asso­ciated with BA acceleration. Our approach shows that BA clocks can be used to identify and modulate biological process (es) that drive the shift from healthy func­tioning toward aging and the eventual manifestations of age-related disease(s).

Loss of Insulin Signaling in Microglia Exacerbates AD-like Neuropathology: Can We Call it Type 3 Diabetes?

 

Wenqiang Chen¹, and C. Ronald Kahn¹*

 

¹Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Depart­ment of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

 

Abstract

Insulin controls peripheral energy metabolism and plays a key role in the regula­tion of mood and cognition. Dysregulated brain insulin signaling has been impli­cated in cognitive disorders including Alzheimer's disease (AD), which is growingly being suggested as Type 3 diabetes. Although epidemiological studies have suggested that AD is closely associated with insulin resistance and type 2 diabetes (T2D), litter is known on how brain insulin resistance contributes to the comorbidi­ty of T2D and AD. To understand insulin signaling in microglia, the brain resident immune cells, we created mice with microglia-specific insulin receptor knockout (MGIRKO) and found that these mice exhibited behavioral deficits and mild system­ic metabolism impairment. Using RiboTag, we profiled microglia-specific ribo­some-bounded mRNA and identified microglial IRKO-impaired biological path­ways, including innate immune and metabolism pathways. We validated that loss of microglial insulin signaling resulted in metabolic reprogramming and impaired uptake of AB in vitro. Further, we crossed MGIRKO mice with an AD mouse model to create a new mouse model MGIRKO/5xFAD, to study disease comorbidity. Using whole-brain CLARITY, we found that by age 6 mo, these mice exhibited greater levels of AB plaque and hallmarks of neuroinflammation. Thus, our results support that insulin signaling in microglia plays a key role in brain immune and metabolism to regulate AD pathogenesis, highlighting the potential importance of targeting insulin signaling in microglia for new therapeutics for patients with diabetes and AD.

Global burden and cross-country inequalities in urinary tumors from 1990 to 2019 and predicted changes to 2040

 

Dechao Feng¹，², *, &, Zhouting Tuo³, *, Ruicheng Wu¹，*, Dengxiong Li¹，*, Jie Wang¹

^Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

²Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China

³Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China

 

Abstract

Objective: To analyze the global burden of disease (GBD) and cross-country inequalities in urinary tumors from 1990 to 2019 and predict their changes to 2040. Methods: All statistical analyses and visualization were conducted using R software (V.4.2.1).

Results: In 2019, the Age-standardized rate (ASR) rates of disability-adjusted life-years (DALYs) for bladder cancer (BCa), kidney cancer (KCa), prostate cancer (PCa) and testicular cancer (TCa) have significant differences among 204 countries and territories, with different age and sex distribution of global DALYs rate (Fig.1-2). The most significant DALYs rate was mainly distributed at aged old group for BCa, KCa and PCa while focused on young group for TCa. The global burden of disease of BCa, KCa, PCa is mainly focused on countries with higher sociodemographic development levels. The slope index of inequality increased for BCa, KCa, PCa from 1990 to 2019 while the relative concentration decreased for RCa, PCa and TCa (Fig. 3). From 2020 to 2040, the cases of these four cancers are predicted to be increas­ing but only TCa shows a similar trend for the global ASR of DALYs (Fig. 4).

Conclusions: In this study, we observed strong heterogeneities in the ASR of DALYs across all countries, as well as in age and sex distribution of global DALYs rate for four urinary cancers. Countries with higher sociodemographic development levels shouldered disproportionately higher burden of BCa, KCa and PCa, and the magni­tude of this sociodemographic development level-related inequalities aggravated over time.

 

 

Aging, circadian rhythm and cancer: current research actuality from a bibliometric analysis

 

Dechao Feng¹，2，*, &, Yuhan Xiao¹，*, Jie Wang¹，*, Dengxiong Li¹，*, Ruicheng Wu¹，Zhouting Tuo³

 

^Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu 610041, China

2Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, P.R. China

³Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.

 

Abstract

Aging and circadian rhythms have been connected for decades, but their molecu­lar interaction has remained unknown, especially for cancers. In this situation, we summarized the current research actuality and problems in this field using biblio­metric analysis. Publications in the PubMed and Web of Science databases were retrieved from the beginning of the database to August 25, 2023. Citespace v6.2.R4, VOSviewer and pajek were used to analyze and visualize the data. Overall, there is a rising trend in the publication volume regarding aging and circadian rhythms in the field of cancer. Researchers from USA, Germany, Italy, China and England have greater studies than others. Top three publication institutions are University of California System, UDICE-French Research Universities and University of Texas System. Current research hotspots include oxidative stress, breast cancer, mela­tonin, cell cycle, calorie restriction, prostate cancer and NF-KB. In conclusion, current findings show that aging and circadian rhythm gain an increasing attention in cancer research and oxidative stress might play a vital role during these process (Fig. 1).

Clinical Significance and Molecular Mechanism of TRA2A Involved in The Induction of Ischemic Reperfusion Injury

 

Ruize Sun, Jue Wang

 

Department of Neurology, Shengjing Hospital, Affiliated Hospital of China Medical University

 

Abstract

Ischemic stroke is currently one of the major causes of death and disability throughout the world and a health problem that needs to be urgently addressed by the current healthcare system. Ischemic stroke is caused by blockage of cerebral arteries through the generation of emboli or in situ thrombi, disrupting cerebral blood flow and oxygen supply, leading to irreversible neuronal damage and a range of pathological responses. Prompt revascularization therapy allows rapid re-establishment of cerebral blood circulation and is currently the only effec­tive clinical treatment. However, not all patients benefit from revascularization. While restoring blood and oxygen supply to brain tissue, revascularization can exacerbate the inflammatory response, further contributing to cerebral isch- emia/reperfusion (I/R).The pathogenesis of I/R is unclear, but its occurrence is followed by disruption of the cerebral microenvironmental homeostasis and a destructive cascade of reactions in arterial walls, which induces arteriolar endo­thelial dysfunction, which in turn leading to death in approximately 15.3% of revas­cularized patients. Thus, attenuating I/R-induced endothelial cell dysfunction is the key to maximizing the therapeutic benefit of ischemic stroke patients, and it is also a bottleneck in current clinical research and treatment. Thus, we aimed to find the key target of I/R. Transformer2-a (TRA2A), a homologue of Transformer2 (TRA2) located at 7p15.3, is predominantly centralized in the nucleus in mammals and plays an important role in the splicing regulation of precursor mRNAs. Recently, researchers have identified TRA2A as a possible hypoxia-associated gene in gastro­intestinal tumors, and its expression level was up-regulated in oxygen sugar depri- vation/reoxygenation-treated human vascular smooth muscle cells. Meanwhile, TRA2A is also highly expressed in neurodegenerative diseases, suggesting that TRA2A may play a malignant biological behavior in neurological disorders. PCDHAC2 is one of the vertebrate-specific adhesion protein-like neural cell adhe­sion molecules, which is highly expressed in serotonergic neurons, and is neces­sary for the diffusion of serotonin across different brain regions. Meanwhile, the proadhesin PCDHAC2 is also one of the precursor proteins of cadherin. Cadherin is a major component mediating homophilic cell adhesion, especially vascular endo­thelial adhesion protein (Cadherin 5, CDHN5) plays an important role in the normal functioning of endothelial cells, and abnormal alteration of its expression may lead to endothelial dysfunction and further disrupt the integrity of the blood-brain barrier.

Methods： Researchers selected patients with first acute ischemic stroke (AIS) as study subjects and healthy medical examiners in the same period as control group, then used enzyme-linked immunosorbent assay (ELISA) to detect the expression levels of serum TRA2A and VCAM-1, and statistically analyzed the differences between the two groups in terms of general clinical information and serum TRA2A levels. C57BL mice were used for middle cerebral artery occlusion/reperfusion (MCAO/R) to establish an animal model of ischemic stroke, and human cerebral microvascular endothelial cells were treated with oxygen-glucose depriva- tion/reperfusion (OGD/R) to imitate a cellular model of ischemic stroke. SiRNA TRA2A was injected into the lateral ventricles of mice and the severity of brain damage after MCAO/R was assessed by 2,3,5-triphenyltetrazolium chloride staining and Evans blue staining before and after the interference, and OGD/R-induced cellular damage was assessed by Cell Counting Kit-8. Immunoprecipitation of proteins in OGD2/R2-induced human brain microvascular endothelial cells that may interact with TRA2A, and mass spectrometry analysis of SDS-Page gels made from this protein were used to obtain a spectrum of proteins that may interact with TRA2A and to further look for genes related to brain endothelial function. The expression of PCDHAC 2 and Cadherin 5 (CDHN5) was detected by real-time quanti­tative PCR (qRT-PCR) and Western blotting in vivo and in vitro, and the expression of CDHN5 was detected by immunofluorescence staining in vivo and in vitro.

Results： In this study, we found for the first time that TRA2A expression was elevat­ed in patients with acute cerebral ischemia-reperfusion injury and was closely associated with brain endothelial cells. In accordance with the established inclu­sion and exclusion criteria, 87 individuals were finally enrolled in the stroke patients' group (SP) and 26 in the control people group (CP). Serum TRA2A levels were significantly higher in the SP than in the CP (P < 0.0001). The results of univari­ate analysis showed that homocysteine (HCY) (p < 0.0001), history of hypertension (p = 0.04), history of diabetes mellitus (p = 0.015), NIHSS score levels (p <0.0001), TRA2A level (p < 0.0001) and VCAM1 level (p < 0.0001) were significantly higher in the SP compared with the CP. After multiple Logistic regression analysis, the NIHSS score levels remained statistically different from serum TRA2A (r=0.2430, p=0.0242) and VCAM1 (r=0.2479, p=0.0214) levels in the SP. Further analysis of the ROC curves showed that serum TRA2A can sensitively and specifically diagnose stroke (area under the curve, 0.9846; 95% CI, 0.9648- 1.0000; p < 0.0001; specificity, 96.77%; sensitivity, 97.70%.). TRA2A is an independent risk factor for stroke (OR=1.123, p=0.028). In the mice MCAO/R model, TRA2A expression was upregulated with cere­bral infarct volume. Interference with TRA2A expression in MCAO/R resulted in a reduction in cerebral infarct volume, and blood-brain barrier disruption was reduced with TRA2A downregulation. Mass spectrometry assay analysis detected TRA2A binding to PCDHAC2, which was further verified in the MCAO/R, where suppression of TRA2A expression was followed by downregulation of PCDHAC2 and CDHN5 expression. In the OGD/R cell model, TRA2A expression was significantly upregulated and was highest at OGD2/R2. Interference with TRA2A resulted in a synchronized decrease in PCDHAC2 and CDHN5 expression. Further inhibition of PCDHAC2 expression resulted in downregulation of CDHN5 expression, while TRA2A expression was not significantly changed. Finally, further PCDHAC2 overex­pression in cells with inhibited TRA2A expression reversed the down-regulation of CDHN5 and improvement of blood-brain barrier function by TRA2A. This suggests that PCDHAC2 is a key downstream target of TRA2A involved in the regulation of I/R, which exacerbates endothelial dysfunction in cerebral ischemia-reperfusion injury through the TRA2A/PCDHAC2/CDHN5 axis.

Conclusion:

1. For the first time, TRA2A was found to be upregulated in patients with cerebral ischemia/reperfusion, and it is an independent risk factor for the diagnosis of isch­emic stroke.
2. In I/R, TRA2A induced cerebrovascular dysfunction and blood-brain barrier disruption further aggravated the burden of ischemic stroke.
3. TRA2A exacerbates BBB dysfunction in cerebral ischemia-reperfusion injury through the TRA2A/PCDHAC2/CDHN5 axis.

Keywords： TRA2A; ischemia/reperfusion; blood-brain-barrier dysfunction.

Promoting Neurite Outgrowth and Neural Stem Cell Migration Using Engineered Electrospun Nanofibers

 

Tong Wu¹，2, *

 

1Qingdao Medical College, Qingdao University, Qingdao 266071, China.

²Shandong Key Laboratory of Medical and Health Textile Material, Qingdao 266071, China. tongwu24@163.com

 

Abstract

 Scaffolds integrated with topological cues and biological effectors have attracted widespread attention in neural tissue engineering because of their capability of promoting neurite growth and accelerating cell migration. Among others, the electrospinning technique provides a versatile and effective strategy to fabricate scaffolds suitable for nerve repair, which can achieve expected compo­nents, secondary structures, as well as fiber alignments by adjusting the electro­spinning parameters or post treatments.

Here we report the development of a class of nanofibrous scaffolds that can enhance the outgrowth and extension of neurites as well as neural stem cell migration owing to the guidance from topological cues and biolog­ical effectors. The decoration of secondary structures (i.e., nanoscale protrusions or grooves; electrosprayed microparticles) on electrospun fibers or fiber yarns can be obtained. Then, bioactive proteins and growth factors can be coated on or encapsulated in the fiber materials to construct the functionalized nerve guidance conduits (NGCs).

 We showed that the uniaxially aligned PCL/SiO2 nanofibers promoted the neurite outgrowth of SH-SY5Y cells. After coating Gal-1, the neurite length extending from SH-SY5Y cells was further increased. We also observed that the migration of neural stem cells from the neurospheres was significantly acceler­ated along the direction from central toward the peripheral areas on the radially aligned PCL/SiO2/Gal-1 nanofibers. Further, we designed and fabricated a class of uniaxially aligned nanofiber yarns welded with electrosprayed microparticles to guide the directional growth of axons and the migration of neural stem cells. The microparticles were further modified by loading nerve growth factors in the core and then deposited on the nanofiber yarns. Owing to the synthetic effects provided by the physical and biological signals, the migration of neural stem cells was significantly accelerated. Taken together, such nanofibers decorated with topo­graphical and biochemical cues would have great potential in nerve repair and related applications involving neurite extension and stem cell migration.

Conclusions: Nanofiber scaffolds modified with different signals are important for regulating cell migration and promoting axonal growth in neural tissue engineering. In particular, aligned nanofibers or nanofiber yarns can provide the primary direction for cell migration and neurite extension. Then, an appropriate modifica­tion of protrusions (i.e., SiO2 nanoparticles or electrosprayed microparticles) or nanoscale grooves can serve as secondary structures on the fiber surfaces to provide contact guidance for axonal growth and the migration of NSCs. This enhancement can be further boosted by loading NGF in the core of microparticles and sustainable releasing it into the surrounding microenvironment. Such combi­nation will promote the axonal extension and cell migration more effectively than blank fibers or yarns. The uniaxially aligned nanofiber yarns decorated with SiO2 nanoparticles or NGF-loaded microparticles can be further manufactured to construct the NGCs. In this way, the fiber yarns together with the release of NGF can mimic the nerve fiber bundles and the regenerative microenvironment to guide axon extension for passing through the gap at the injury site. Taken together, such class of materials provide promising alternatives for use in neural tissue engineer­ing and related applications involving manipulating axonal extension and cell migration..

Self-support programme improves activies of daily living in dementia population: Results from a 1-year
quasi-experimental design

 

Wang Feng*, huang Xiaoqiong*, Chen Yangkun*, Zhu Xiaodong¹, Wu Xiaojun², Zhang Kaihang* , Weng Hanyu*

 

*Department of Neurology, Dongguan People's Hospital,523058 1Nursing Department of Dongguan People's Hospital,523058

²Department of Rehabilitation Medicine, Puji Branch of Dongguan People's Hospital,523058

 

Abstract

Aims To evaluate the effectiveness of self-support program in OAH.

Methods A parallel-group quasi-experimental study was conducted in OAH with an intervention period lasting for one year. One hundred and sixteen participants were collected, of these, 60 patients were recruited to intervention group (IG) and 56 patients were recruited to control group (CG). The IG received a self-support program, based on geriatric medicine, nursing, rehabilitation and so on. The CG accepted a standard usual care.And the outcomes were measured by Functional measure(FIM), Quality of life-Alzheimer disease(QOL-AD), Zarit Caregiver Burden Interview(ZBI) and Activity of Daily Life(ADL) .All the outcomes were measured at baseline, 3 months, 6 months and 12 months. A generalized estimating equations model was used to compare the differential changes in outcomes at 3 months, 6 months and 12 months with respect to baseline between 2 groups.

Results:Participants in intervention group had a significantly greater increment in the FIM score at T2, T3 with respect to T0 than those in control group [T2 Mean difference=17.27, 95%CI (5.07,29.47), P=0.006; T3 Mean difference =17.84, 95%CI(5.56, 30.17), P=0.004〕. Regarding to ADL score, there present a significantly increment in intervention group at T1,T2,T3 with respect to T0 than those in control group [T1 Mean difference=19.60, 95%CI(9.81,29.39), P=0.000; T2 Mean difference =19.83, 95%CI(9.48,30.19), P=0.000; T3 Mean difference =19.04, 95%CI(8.80,29.39), P=0.000〕.As for QOLAD, participants in intervention group showed a obviously rise at T1,T2,T3 with respect to T0 than those in control group [T1 Mean difference=4.26, 95%CI(2.04,6.47), P=0.000; T2 Mean difference=5.55, 95%CI(2.92, 8.17), P=0.000;T3 Mean difference=4.71, 95%CI(2.23,7.19), P= 0.00〕.

Conclusions:The results provide some positive evidence on Self-support programme for promoting dementia population independently. The covariates at the baseline in favor of the intervention group,the results might be overrated.The generality of the results might be limited.

 

Title： The Chemokine CCL17 is a Novel Therapeutic Target for Cardiovascular Aging

 

Yang Zhang¹，²，#, Xiaoqiang Tang³，# Zeyuan Wang¹，#, Lun Wang¹,Zhangwei Chen², Ju-Ying Qian², Zhuang Tian¹*, Shu-Yang Zhang¹*

 

¹Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China;

²Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, 200032, China;

³Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610041, China.

 

Abstract

Circulating proteomic signatures are closely associated with aging and age-related vascular diseases, but drugs targeting circulating proteins are not available. Circulating cytokines and chemokines are essential immune compo­nents and regulate cardiovascular homeostasis and aging. Modulating these factors is a potential strategy for treating cardiovascular aging.

 An ongoing community-based cohort of Shunyi exploring the risk factors for cardio-cerebro-vascular and age-related diseases was used to analyzed the relationship between C-C motif chemokine ligand 17 (CCL17) and vascular stiffness marker brachial-ankle pulse wave velocity (baPWV). Then, the natural aging and angiotensin II (Ang II)-induced vascular aging models were used for further experi­ments. Vascular arterial stiffness, constriction-relaxation dysfunction, and aortic remodeling, fibrosis, cell senescence, and senescence-associated secretory phenotype, elastin fiber breakage, coupled with reprogrammed immune microen­vironment were measured in our study.

 The population study demonstrated that circulating CCL17 level increased with age and correlated with baPWV. Subsequent animal experiments further revealed that Ccll7-KO significantly repressed cardiovascular aging. We found that Ccl17 knockout alleviated aging and Ang II-induced vascular arterial stiffness, constriction- relaxation dysfunction, pathological vascular remodeling, fibrosis, and senescence- associated secretory phenotypes (SASPs), accompanied by the plasticity and differentiation of T cell subsets. Furthermore, the therapeutic administration of an anti-CCL17 neutralizing antibody inhibited Ang II-induced pathological vascular remodeling.

 Our findings reveal that chemokine CCL17 is identifiable as a novel therapeutic target in age-related vascular homeostasis by reprogramming immune microenvironment

 

The gliosis stiffness affects neural stem cell lineage choice via Piezos in ischemic stroke mice

 

Description:

Background: Transplanted stem cells prefer astrogenesis after brain injury, which limit its therapeutic efficiency. Mechanical signal from environment affects stem cells lineage choice. Glial cells, mainly astrocytes, activate and alter the stiffness of the peri-infarct area after ischemic stroke. However, the effect of post-stroke gliosis stiffness on exogenous neural stem cells (NSCs) and its underlying mechanism is unclear.

Keyword set:

Piezos; gliosis stiffness; NSC transplant;

Complete Blood Cell Count in the Prediction of Functional Outcome after Ischemic Stroke: A Mendelian Randomization Study

 

Tong Shen¹, Ping Liu¹, Yumin Luo¹，²*

^Institute of Cerebrovascular Diseases Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China

²Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China

 

Abstract

Background： Complete blood cell count (CBC) is the most common and readily available laboratory test in clinical practice. Previous research has demonstrated a correlation between neutrophil-to-lymphocyte ratio and stroke prognosis, but the relationship between other indices in CBC and stroke prognosis has not been fully explored. In this study, we aim to explore the causal relationship between the indicators of CBC and 3 months modified Rankin Scale (mRS) score after ischemic stroke with Mendelian randomization (MR) analysis.

Methods: Twenty-two indicators in CBC test were included as exposure traits in this study.

Genetic variants associated with exposures were obtained from the UK Biobank database (n=350,475) and outcome data from the Genetic of Ischemic Stroke Func­tional Outcome (GISCOME) network (n=6,021). We implemented two-sample bi-di­rectional MR and multivariable MR to evaluate the causal relationship between blood traits and 3 months mRS score after ischemic stroke and performed clinical cohort validation (n=233) based on the results of the MR analysis.

Results: In univariable MR, platelet distribution width (PDW) was found causally associated with poor functional outcome (3 months mRS score > 2) after ischemic stroke (odds ratio [OR]=1.20, [95% CI, 1.00-1.44], p=0.047). Further multivariable MR indicated that after eliminating interactions, all four platelet-related indicators showed significant causal relationship with poor functional outcome (platelet count, p= 0.031; platelet crit, p= 0.029; mean platelet volume, p= 0.028; PDW, p= 0.048). In cohort study, we found that 2 extreme quartiles showed higher risk of poor functional outcome (crude OR= 1.76, [95% CI, 1.03-3], p= 0.039; adjusted OR=2.69, [95% CI, 1.15-6.3], p=0.022) and 3 months mortality (crude OR= 5.19, [95% CI, 1.7-15.85], p= 0.004; adjusted OR= 4.49, [95% CI, 1.34-15.05], p=0.015) than middle quartiles.

Conclusion: MR study suggested that platelet-related indicators, especially platelet distribution width, may be used as potential auxiliary method for early prediction of long-term functional outcome after ischemic stroke. Further investigation is required to elaborate the role of platelet in stroke prognosis.

Keywords: Mendelian randomization; complete blood cell count; ischemic stroke; functional outcome

 

Multilevel regulation of NF-kB signaling by NSD2 sup­presses Kras-driven pancreatic tumorigenesis

 

Wenxin Feng¹，²#, Ningning Niu³#, Jing Xue³*, Li Li¹，²*

1. State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineer­ing, Shanghai Jiao Tong University, Shanghai, China.
2. School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
3. State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, Shanghai
4. Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China

 

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer with a dismal overall prognosis. NSD2 is an H3K36-specific di-methyltransferase which has been reported to play a crucial role in promoting tumorigenesis. Here, we demonstrate that NSD2 acts as a putative tumor suppressor in Kras-driven pancre­atic tumorigenesis. Low level of NSD2 indicates aggressive feature of PDAC. NSD2 restrains the mice from inflammation and Kras-induced ductal metaplasia, while NSD2 loss facilitates pancreatic tumorigenesis. Mechanistically, NSD2-mediated H3K36me2 promotes the expression of IkBq, which inhibits the phosphorylation of p65 and NF-kB nuclear translocation. More importantly, NSD2 interacts with the DNA binding domain of p65, attenuating NF-kB transcriptional activity. Further­more, inhibition of NF-kB signaling relieves the symptoms of Nsd2-deficient mice. Together, our study reveals the important tumor suppressor role of NSD2 and multiple mechanisms by which NSD2 suppresses both p65 phosphorylation and downstream transcriptional activity during pancreatic tumorigenesis. This study contributes to understanding the pathogenesis of pancreatic tumorigenesis and identifies a novel negative regulator of NF-kB signaling.

 

Shenfu Tang ameliorates BBB impairment in mice with cerebral ischemia by regulating fatty acid oxidation

 

Wei Zhang1,2,3#, Yu Yangl#, Changhong Ren2,3, Jun Xu2,3, Xiaodan Wul, Yong Yang1*

¹School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China ²Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Capital Medical University, Beijing 100053, China

³Center of Stroke, Beijing Institute for Brain Disorder, Capital Medical University, Beijing 100053, China

* Correspondence should be addressed to Yong Yang, MD; E-mail:yymark@aliyun.com; Professor of School of Chinese Medicine, Beijing University of Chines Medicine, Beijing 100029, China;

 

Abstract

Ischemic stroke (IS) remains one of the most serious threats to human life. Early blood-brain barrier (BBB) damage is the cause of parenchymal cell damage. Repair of the structure and function of the BBB is beneficial for the treatment of IS. The traditional prescription Shenfu Tang (SFT) has a long history in the treatment of cardiovascular and cerebrovascular diseases, however, the effect of SFT on the BBB disruption and underlying mechanisms remains largely unknown. To address these issues, in vitro models of BBB were established with bEnd.3 cells. We found that SFT reduced the leakage of the fluorescent probe FITC-dextran and increased the expression of tight junction in the BBB model in vitro. Furthermore, to investi­gate the BBB protective effects of SFT in vivo, we constructed an ischemic stroke model in mice and found that SFT treatment reduced IgG leakage, up-regulated the expression of tight junction proteins Claudin-5, Occludin, and ZO-1. Further mech­anism study showed that fatty acid oxidation (FAO) of vascular endothelial cells is involved in the protection of the BBB after cerebral ischemic stroke, and SFT regu­lates FAO to protect BBB. In addition, we found the effect of SFT was stronger than that of Chinese ginseng and aconite alone. We concluded that SFT could amelio­rate the BBB dysfunction by regulating FAO involving vascular endothelial cells after IS. At the same time, the prescription is more effective than single traditional Chinese medicine.

Key words: Shenfu Tang, Blood-Brain Barrier，Fatty acid oxidation

 

Azoramide prevents MPP+-induced dopaminergic neuronal death via upregulating ER chaperone BiP expression

 

Nana Ai, Danni Wang, Cheong-Meng Chong*

Institute of Chinese Medical Sciences, University of Macau, Macao, China *Corresponding author: cmchong@um.edu.mo

 

Abstract

Progressive death of dopaminergic (DA) neurons is the main cause of Parkinson's disease (PD). PD has become a global health problem, reducing the quality of life of the elderly. Current drug treatments and surgeries can only relieve PD symptoms but cannot reduce the death of DA neurons in patients. Therefore, there is an urgent need to find a new candidate drug for the treatment of PD. Here, we studied the neuroprotective effects on PD and mechanisms of Azoramide. Azoramide is a new small molecule compound targeting ER stress, which was originally developed for the treatment of diabetes. In this study, pre-treatment with Azoramide was found to suppress mitochondria-targeting neurotoxin MPP+-induced DA neuronal death and locomotor defects in zebrafish larvae. Further study showed that pre-treatment with Azoramide significantly attenuated MPP+-induced SH-SY5Y cell death by reducing aberrant changes in nuclear morphology, mitochondrial mem­brane potential, intracellular reactive oxygen species, and apoptotic biomarkers. The mechanistic study revealed that Azoramide was able to up-regulate the expression of ER chaperone BiP and thereby prevented MPP+-induced BiP decrease. Furthermore, pre-treatment with Azoramide failed to suppress MPP+-in- duced cytotoxicity in the presence of the BiP inhibitor HA15. Taken together, these results suggested that Azoramide is a potential neuroprotectant with pro-survival effects against MPP+-induced cell death through up-regulating BiP expression.

 

Lycorine protects motor neurons against TDP-43 proteinopathy in animal models with amyotrophic lateral sclerosis

 

Jing Wen, Huanxing Su*

Institute of Chinese Medical Sciences, University of Macau, Macao, China *Corresponding author: huanxingsu@um.edu.mo

 

Abstract

Amyotrophic lateral sclerosis (ALS), is a progressive neuromuscular disease char­acterized by selective degeneration of both upper (brain) and lower (spinal cord) motor neurons, which leads to muscle weakness and atrophy and eventually death due to respiratory paralysis within 2-5 years after disease onset. Currently, there is no cure for ALS, and no effective treatments are available. There is an urgent need to develop effective drugs. Aggregation of the TAR-DNA binding protein (TDP)-43 is a common pathological feature present in nearly 97% cases of amyotrophic lateral sclerosis (ALS) patients, making it an attractive target for pathogenic studies and drug screening. We aim to find compounds that reduce TDP-43A315T and further improve disease progression in ALS. Here, we constructed a cell screening model and screened nearly 10,000 compounds through high-throughput screening. Then cells, worms and mouse models were constructed to verify the effectiveness of the drug and study the mechanism. We finally identified a naturally occurring alkaloid -lycorine, significantly downregulated the expression of TDP-43A315T in a cellular model. We further demonstrate that lycorine inhibits the synthesis of TDP-43A315T and promotes the clearance of the mutant protein through the ubiquitin-protea- some system (UPS). Importantly, treatment of lycorine significantly attenuates TDP-43 proteinopathy and improves functional recovery in transgenic C. elegans and mice expressing TDP-43A315T. These findings suggest that lycorine is a prom­ising lead compound that has therapeutic potential for ALS.

Schizophrenia-Like Behaviors Arising from Dysregulated Proline Metabolism Are Associated with Altered Neuronal Morphology and Function in Mice with Hippocampal PRODH Deficiency

 

Yuxiao Yao¹, Weiping Han²*, Dajiang Qin¹*

¹ Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guang­dong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510799, China

²Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore

 

ABSTRACT:

Despite decades of research being conducted to understand what physiological deficits in the brain are an underlying basis of psychiatric diseases like schizophre­nia, it has remained difficult to establish a direct causal relationship between neuronal dysfunction and specific behavioral phenotypes. Moreover, it remains unclear how metabolic processes, including amino acid metabolism, affect neuro­nal function and consequently modulate animal behaviors. PRODH, which catalyz­es the first step of proline degradation, has been reported as a susceptibility gene for schizophrenia. It has consistently been shown that PRODH knockout mice exhibit schizophrenia-like behaviors. However, whether the loss of PRODH directly impacts neuronal function or whether such neuronal deficits are linked to schizo­phrenia-like behaviors has not yet been examined. Herein, we first ascertained that dysregulated proline metabolism in humans is associated with schizophrenia. We then found that PRODH was highly expressed in the oreins layer of the mouse dorsal hippocampus. By using AAV- mediated shRNA, we depleted PRODH expres­sion in the mouse dorsal hippocampus and subsequently observed hyperactivity and impairments in the social behaviors, learning, and memory of these mice. Furthermore, the loss of PRODH led to altered neuronal morphology and function both in vivo and in vitro. Our study demonstrates that schizophrenia-like behaviors may arise from dysregulated proline metabolism due to the loss of PRODH and are associated with altered neuronal morphology and function in mice.

Changes in Plasma Fibrinolysis and Neutrophil Activation-Related Proteins in Patients with Massive Cerebral Infarction after Reperfusion Therapy and their Relationship with Brain Herniation

 

Yuyou Huang¹, Feng Yan¹² , Weibi Chen¹, Linlin Fan¹, Ziping Han¹², Lingzhi Li¹², Yan Zhang¹*, Yumin Luo¹²*

¹ Department of Neurology and Cerebrovascular Diseases Research, Xuanwu Hospital of Capital Medical University, Beijing, China.

²Beijing Geriatric Medical Research Center and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China.

 

Abstract

Objective: Acute ischemic stroke is a major cause of death and disability, especially in China. Reperfusion therapy is the most effective treatment, but it fails in about 50% of cases, leading to complications like cerebral edema and poor outcomes. This study aimed to investigate the relationship between changes in plasma fibri­nolytic protein expression, neutrophil activation markers, and brain herniation in patients with massive cerebral infarction (MCI) after reperfusion therapy.

Methods: The study enrolled MCI patients admitted to a neurology intensive care unit. Blood samples were collected on different days after stroke onset, and the expression of fibrinolysis-related proteins and neutrophil activation markers was measured using ELISA kits.

Results: This study discovered a negative correlation between plasma cFn and plasma MPO expression on the day of stroke onset, as well as a negative correlation between plasma uPAR and plasma VCAM expression on different days. Additional­ly, patients who underwent reperfusion therapy had higher white blood cell count, neutrophil count, and NLR values compared to those without therapy. Among the patients who underwent reperfusion therapy, MCI patients had significantly higher expression of MPO and NE in plasma compared to those without therapy, while the expression of ICAM-1 and VCAM showed an increase that was not statistically signif­icant. The plasma expression of uPAR in patients with brain herniation was slightly lower than in patients without brain herniation, however, the difference was not statistically significant.

Conclusion： Changes in plasma fibrinolysis-related proteins may mediate the migration and adhesion of neutrophils. Patients with brain herniation have lower expression of fibrinolysis-related proteins and upregulation of neutrophil adhe­sion factors, which may contribute to the migration and adhesion of neutrophils and be a partial cause of brain herniation.

AAV-PHP.eB mediated bFGF gene therapy promotes functional recovery at subacute stage after ischemic stroke

 

Rubing Shi

Biology in School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.

 

Abstract

Background： AAV-PHP.eB has been shown to penetrate blood-brain barrier and targets neurons with a higher efficiency than other AAV vectors by non-invasive systematic administration. However, its tropism in cerebrovascular diseases remain unknown. Here, we aim to explore the tropism shift of AAV-PHP.eB in ischemic stroke and investi­gate the efficacy of AAV-PHP.eB-bFGF gene therapy in promoting functional recovery after ischemic stroke.

Methods： Total 63 adult C57BL6/J mice were divided randomly into stroke group and normal group. We established transient middle cerebral artery occlusion model to mimic stroke, and injected AAV-PHP.eB intravenously at a dosage of 1.0E11 v.g./mouse to mice at 14 days before stroke (pre-stroke group) or at 1 day after stroke (post-stroke group). At 14 and 28 days after stroke, we collected brain slices and performed immu­nostaining of brain resident cell marker to examine tropism. Behavioral tests were performed to evaluate overall neurological function. By labeling edU, the efficacy of AAV-PHP.eB-bFGF on proliferation were examined by co-staining with DCX and CD31.

Results: Compared to normal group, the neuronal tropism of AAV-PHP.eB dropped sharply in stroke groups(p<0.05), while astrocytic targeting increased significant- ly(p<0.01). In post-stroke group, we identified a strong endothelial targeting compared to other groups(p<0.01). Furthermore, AAV-PHP.eB-bFGF promoted the overall neuro­behavior outcomes compared to the stroke-control group, in which the pre-stroke administration led to an earlier improvement. The immunostaining results indicated pre-stroke administration promotes an earlier neurogenesis while only post-stroke intervention led to angiogenesis in the peri-infarct area.

Conclusion: Ischemic stroke altered the tropism of AAV-PHP.eB in mouse brain with an increase in endothelial cells and astrocytes. AAV-PHP.eB mediated bFGF gene therapy therefore showed sufficient as well as distinct beneficial effects to the neural recovery at subacute stage of ischemic stroke.

Keyword set: gene therapy; ischemic stroke; AAV-PHP.eB

 

Mechanisms of A20/TNFAIP3 and C/EBPP in aggravating brain injury induced by acute ischemic stroke

 

Wang Rongliang¹，², Yang Zhenhong¹，², Luo Yumin¹²³*

1. Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, Beijing, China
2. Beijing Geriatric Medical Research Center and National Clinical Research Center for Geriatric Disorders, Beijing, China
3. Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China *Corresponding author: No. 45 Changchun Street, Xicheng District, Beijing.

 

Abstract

Recent studies have reported that the ubiquitin-modifying enzyme A20/TNFAIP3 can inhibit neuroinflammation in AD patients and reduce complement-mediated C/EBPB-dependent neuronal death by degrading the transcription factor CCAAT/enhancer-binding protein B (C/EBPB). However, to date, there have been no reports on the interaction between A20/TNFAIP3 and C/EBPB in brain tissue, and their role in post-ischemic inflammatory responses. Our preliminary study found that the plasma C/EBPB level in patients with acute ischemic stroke can improve the predictive efficacy of clinical prognostic model, and C/EBPB mRNA was signifi­cantly increased in peripheral blood neutrophils from acute ischemic stroke patients than that in healthy adults. Therefore, clarifying the key mechanisms of A20/TNFAIP3 and C/EBPB in the inflammatory response of acute ischemic stroke is very important for the development of targeted drugs to improve stroke prognosis. In this study, adult male C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAO) model and reperfusion (I/R) injury. Mice were randomly divided into 3 groups: Sham operation group (Sham), model group (MCAO+NC), and C/EBP B siRNA group (MCAO+C/EBPB siRNA). The C/EBPB siRNA (Lenti-C/EBPB-shRNA) or negative control was administered by right intracerebroventricular (ICV) injections to interfere with the expression of C/EBPB 3 days before MCAO surgery. Modified neurological severity scores (mNSS) were used to evaluate the motor, balance, sensory and reflex function, cerebral infarct volume was evaluated by 2, 3, 5-triph- enyltetrazolium chloride (TTC) staining, western blot and immunoprecipitation were used to detect the expression of A20/TNFAIP3 and C/EBPB, and the interac­tion between A20/TNFAIP3 and C/EBPB, ELISA was used to detect the expression of inflammatory cytokines (IL-1B, IL-6, TNF-a) in mouse brain tissue 7 days after I/R. The results showed that 7 days after cerebral ischemia in mice, compared with the Sham group, the expression of A20/TNFAIP3 in the brain tissue of MCAO+NC group mice was significantly reduced, the expression of C/EBPB was significantly increased, accompanied by a rapid increase in the expression of IL-1B, IL-6, and TNF-a. Immunoprecipitation results showed that the A20/TNFAIP3 and C/EBPB have an interaction in brain tissue 3 days after I/R, but the A20/TNFAIP3-C/EBPB complex almost disappeared 7 days after I/R. Compared with the MCAO+NC mice, the neurological function of MCAO+C/EBPB siRNA mice showed significantly improvement, and the cerebral infarct volume markedly decreased 7 days after I/R, indicating that C/EBPB can aggravate brain injury after ischemia.

In summary, our study shows that the expression of A20/TNFAIP3 decreases and the expression of C/EBPB increases after cerebral ischemia, leading to severe inflammatory responses and thereby aggravating brain damage in mice with acute ischemic stroke. This study initially elucidates the interaction between A20/TN- FAIP3 and C/EBPB after cerebral ischemia, providing a scientific basis for subse­quent drug development.

 

Revealing intrinsic heterogeneity in axon regeneration

 

Zhen-Ge Luo

Professor, Executive Dean, School of Life Science and Technology, ShanghaiTech University, Shanghai, China

 

Abstract

Injuries to the adult mammalian CNS typically lead to irreversible damage and bring many health problems to society and the ability for axon regeneration after injury declines during aging. In the mammalian peripheral nervous system (PNS) or the lower vertebrate central nervous system (CNS), most neurons can regener­ate strongly after axotomy, while the neurons in the mammalian CNS possess a weak regenerative ability. It is generally believed that the lack of endogenous regeneration ability and the presence of exogenous environmental inhibitory factors are the main reasons for the failure of CNS axon regeneration. The intrinsic regeneration capability is highly heterogenous across species, positions, cell types, and even individual cells of the same cell type, but the molecular mecha­nisms remain unclear. We have assumed that individual cells of the same cell type in similar environments may also exhibit different regeneration abilities, and anal­ysis of this heterogeneity may provide a new angle to understand molecular mech­anisms for the cellular states—regeneration competent or not. In this talk, I will introduce our efforts in the identification of transcripts that exhibited differential expression between spinal motor neurons (spMNs) with low and high regenerative abilities, and demonstrate their roles in neuronal regeneration using various model systems. The comparative studies at single-cell resolution have shown promising potential in the identification of therapeutic targets for promoting regeneration of injured neuron

Deficiency of the histone methyltransferase SETD2 reduces intestinal stem cell proliferation

 

Rebiguli Aji, Li Li

Med-X Research Institute, Shanghai Jiao Tong University, 1954 Hua Shan Road, 200030, China. E-mail addresses:

 

Abstract

The aetiology of inflammatory bowel disease (IBD) is a multifactorial interplay between environment and heredity . Epigenetic regulation disorder is important in IBD. SETD2, a histone methyltransferase that mediates the trimethylation of histone H3 at lysine 36 , is frequently mutated in IBD which have a high risk of developing colorectal cancer. However, the function of the histone methyltransfer­ase SETD2 in intestinal stem cell (ISC) in the pathogenesis of IBD remains elusive. Here, we found that loss of Setd2 in ISC aggravates dextran sodium sulfate (DSS) -induced colitis in mice. Lgr5-eGFP-IRES-CreERT2;SETD2f/f mice lost weight rapid­ly, showed blood in stool and loose stools and showed significant decrease in length of colon. Mechanistically, we found that loss of SETD2 reduces ISC prolifera­tion. SETD2 KO led to more ISCs arrested at the G1 phase. Smart-seq RNA sequenc­ing using RNA from Lgr5-eGFP-IRES-CreERT2;SETD2f/f and Lgr5-eG- FP-IRES-CreERT2 ISCs revealed that the global transcriptome was changed dramatically in Lgr5-eGFP-IRES-CreERT2;SETD2f/f ISCs compared to Lgr5-eG- FP-IRES-CreERT2 ISCs, indicating a significant function of SETD2 in ISCs. Gene Ontology (GO) term analysis indicated that there was a significant enrichment of genes linked to cell cycle. Together, our findings provide valuable clues on the development of basic research on IBD.

The Loss of NSD2 Aggravates Colonic Inflammation

 

Yue Xu¹，², Chunxiao Ma¹，² , Li Li ¹>², Weiqiang Gao¹，²

1. State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineer­ing, Shanghai Jiao Tong University, Shanghai, 200127, China.
2. School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.

 

Abstract

Inflammatory bowel disease (IBD) is a complex and relapsing inflammatory disease of the gastrointestinal tract, and patients with IBD exhibit a higher risk of developing colorectal cancer (CRC). Epithelial barrier dysfunction is one of the major causes of IBD in which epigenetic modulation is pivotal. The histone H3K36 dimethyltransferase NSD2 is closely related to tumorigenesis including CRC. How­ever, its role as an epigenetic modifier in IBD remains largely unexplored. Herein, we found that NSD2 plays a pivotal role in IBD. The expression of NSD2 became decreased in IBD patients and DSS-treated colitis mice. Meanwhile, Nsd2Vil-KO mice showed increased susceptibility to DSS-induced colitis, accompanied by more severe epithelial barrier disruption and remarkably increased intestinal permeability. Together, our results demonstrated that the loss of NSD2 aggravates colonic inflammation.

Study on mechanism of cerebral vascular morphological changes caused by chronic cerebral hypoperfusion

 

Meng Geng¹，², Changhong Ren¹, Jun Xu², Yaoming Xu², Wenbo Zhao¹*, Xunming Ji¹

^Institute of Hypoxia Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China, ²Inner Mongolia Medical University, Inner Mongolia 010110, China

 

Abstract

Aging is the largest risk factor for neurodegenerative diseases and is often associat­ed with changes in the morphology of brain vessels. Cellular senescence, a process that imposes permanent proliferative arrest on cells in response to various stress­ors, has emerged as a potentially important contributor to aging and age-related diseases, and is an attractive target for therapeutic development. Over the past half century, a great deal of information has been gained about the aging of cultured cells. However, little is known about aging in living organisms, largely due to technical limitations in the identification and characterization of senescent cells in tissues and organs. With the development of science and technology, previous basic studies using techniques such as continuous two-photon tomography and thin layer microscopy have found that changes in cerebral vascular morphology during normal aging may be the result of various complex age-related diseases, among which chronic cerebral hyponyfusion may be one of several factors affect­ing cerebral vascular morphology during normal aging. The purpose of this study was to investigate the mechanism of cerebral vascular morphological changes caused by chronic cerebral hypoperfusion, and to further clarify the relationship between cerebral vascular morphological changes and chronic cerebral hypoper­fusion during normal aging.

Key word^ vascular aging,chronic cerebral hypoperfusion^ cerebral vascular mor­phological changes

Remote ischemic conditioning facilitates remyelination after stroke via exosome mediated cholesterol metabolism

 

Wantong Yu¹, Changhong Ren¹, Chen Gao¹, Wei Zhang¹, Wenjie Shi¹, Ning Li¹, Jun Xu¹, Xunming Ji¹,²*

^Department of Neurology and Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Capital Medical University Beijing, China;

²Center of Stroke, Beijing Institute for Brain Disorder, Capital Medical University，Beijing, China;

 

Abstract

Background: Remote ischemic conditioning (RIC) has shown potential in promoting recovery after ischemic stroke. However, the underlying mechanisms of post-stroke repair responses to RIC have not been systematically studied. The aim of this study was to characterize the effects of chronic RIC on experimental stroke in mice and the humoral mechanism underlying the beneficial effect.

Methods: A mouse model of ischemic stroke was established by middle cerebral artery occlusion (MCAO). Repeated RIC was performed during the 28 days after reperfusion. Behavioral tests and histological analysis were conducted in multiple time points. Exosome release inhibitor GW4869 was used to examine the effect of exosomes on RIC induced remyelination. Proteomics analysis of serum exosome were performed in RIC treated and control group.

Results: RIC significantly improved behavioral outcomes and increased remyelin­ation after ischemic stroke. Blocking exosomes biogenesis mitigated the beneficial effects of RIC on white matter regeneration. Mechanistically, RIC induced exosomal APOA1 acted through ABCA1 receptors on microglia to enhance myelin debris clearance and cholesterol transportation, consequently enhancing remyelination and white matter repair.

Conclusion: These findings indicate that RIC promotes post-stroke remyelination through the regulation of cholesterol metabolism by exosomal APOA1.

 

Abdominal aortic occlusion and the inflammatory effects in heart and brain

 

Jun Xu^1&, Meng Geng^1&, Linhui Qin¹, Feng-Yong Liu³*, Yuchuan Ding⁴, Changhong Ren¹*, Xunming Ji¹*,

¹Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Capital Medical University, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, 100053, China

³Department of Interventional Radiology, Senior Department of Oncology, Fifth Medical Center of PLA General Hospital, Beijing, China

⁴Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA

 

Abstract

Abdominal aortic occlusion (AAO) is a double-edged sword that can assist in clini­cal surgery, but also causes ischemia/reperfusion (I/R) injury to distant organs. The heart and brain are the most important organs in the human body. In this study, we aimed to investigate whether AAO induced I/R injury to the cardiac and neurologic tissue, and how the length of ischemic time in AAO influences ROS production and inflammatory marker levels in the heart, brain, and serum. We randomly divided 60 male C57BL/6 mice into either sham group or AAO group. The AAO group was further subdivided into 1-, 2-, 3-, and 4-hours groups of aortic occlusion times. The infrarenal abdominal aorta was clamped for 1-4 hours before reperfused for 24 hours. Then serum, hippocampus, and left ventricle tissue samples were taken for biochemical and histopathological analyses. We found that AAO-induced I/R injury had no effect on cell necrosis, cell apoptosis, or reactive oxygen species (ROS) production. However, compared to sham group, the levels of malondialdehyde (MDA) and lactate dehydrogenase (LDH) increased in serum and hippocampus of AAO groups. Superoxide dismutase (SOD) and total antioxidant capacity (TAC) decreased in the serum, hippocampus, and left ventricle. In the serum, AAO increased the level of inducible nitric oxide synthase (iNOS) and decreased the levels of anti-inflammatory factors (such as arginase-1), transforming growth factor-区区 1 (TGF-园 1), interleukin 4 (IL-4), and interleukin 10 (IL-10). In the hippo­campus, AAO increased the levels of tumor necrosis factor (TNF-a), interleukin 邛 (IL-13), interleukin 6 (IL-6), IL-4, and IL-6, and decreased the level of TGF-园 1. In the left ventricle, AAO increased the level of iNOS and decreased the levels of TGF-园 1, IL-4 and IL-10. In conclusions, AAO did not induce cell necrosis or apoptosis in cardiac or neurologic tissue, but it can cause inflammation in the serum, brain, and heart.

Keywords: abdominal aorta occlusion, ischemia/reperfusion, brain injury, heart injury, oxidative stress, inflammation.

 

Neurotoxic Astrocytes Exacerbate Blood-Brain Barrier Disruption in Hemorrhagic Stroke via Matrix Metalloprotease 3

 

Chang Liu¹, Shiyu Deng¹, Shiyi Zhou¹, Yiyan Guo¹, Tongtong Xu¹, Zhijun Zhang¹, Jixian Wang²*, Guo-Yuan Yang¹* and Yaohui Tang¹* ¹Shanghai Jiao Tong University Affiliated Sixth People's Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China

²Department of Rehabilitation Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 197 Ruijin Er Road, Shanghai, 200025, China

 

Abstract

 Neurotoxic astrocytes are induced in a variety of neurological diseases and damage neurons and oligodendrocytes, but their effect on blood-brain barrier (BBB) during hemorrhagic stroke remains unknown.

Aim: To investigate the effect and mechanism of neurotoxic astrocytes on BBB function in mice after hemorrhagic stroke.

Method: Adult male C57BL/6 mice (n=80) underwent collagenase-induced intrace­rebral hemorrhage. Neurotoxic or neuroprotective astrocytes were identified by immunostaining of C3d/GFAP or S100a10/GFAP. PLX5622 or F70101C-A was used to delete microglia or macrophages in mice, respectively. Neurotoxic astrocytes were induced in vitro with IL-1a, TNFa, and C1q. bEnd.3 cells were cultured with neuro­toxic astrocyte-conditioned medium. RNA sequencing was further conducted to determine the mechanism of neurotoxic astrocytes-induced BBB disruption.

Results/Conclusions: The percentage of C3d+/GFAP+ astrocytes increased while the percentage of S100a10+/GFAP+ astrocytes decreased from day 1 to day 14 after hemorrhagic stroke (p<0.01). More than 60% of astrocytes wrapped surround the damaged microvessels were C3d+ subtype on day 3 after hemorrhagic stroke. Furthermore, the neurotoxic astrocytes were induced by residential microglia but not infiltrated macrophages. In vitro experiments showed that neurotoxic astro­cyte-conditioned medium disrupted BBB integrity. BBB disruption related gene matrix metalloproteinase 3 (MMP3) was highly upregulated in the neurotoxic astro­cytes (p<0.01). Finally, inhibiting MMP3 reduced BBB disruption in vitro, and knockout MMP3 in astrocytes also reduced BBB disruption and improved neuro­logical outcomes in hemorrhagic stroke mice (p<0.01). Our study demonstrated that neurotoxic astrocytes exacerbated BBB disruption through MMP3, which opens a new avenue for the treatment of BBB disruption related neurological diseases.

Keywords: Neurotoxic astrocytes; Hemorrhagic stroke; Blood-brain barrier; Matrix metalloproteinase 3

 

Hypoxic Conditioning: A Potential Perioperative Strategy to Reduce Abdominal Aortic Occlusion-Related Injury in
Mouse Proximal and Distal Organs

 

Changhong Ren ^1&, Ning Li^1&, Jun Xu^1&, Linhui Qin¹, Kunlin Jin², Fengyong Liu³, Xunming Ji¹*

¹Beijing Key Laboratory of Hypoxia Conditioning Translational Medicine, Xuanwu Hospital, Capital Medical University, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, 100053, China

² Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA

³Department of Interventional Radiology, Senior Department of Oncology, Fifth Medical Center of PLA General Hospital, Beijing, China

 

Abstract

This study aimed to investigate the impact of abdominal aortic occlusion (AAO)- induced injury on the kidney, lower limb muscles, heart, and brain in mice, and the potential protective effects of hypoxic postconditioning (HyC). The experimental design employed an abdominal aortic occlusion (AAO) model, and involved three groups of mice: sham, AAO, and AAO+HyC. Ten minutes after the AAO model, mice were subjected to hypoxic treatment lowering oxygen concentration to 5% within 45 minutes, and then returned to a normal oxygen environment. Blood biochemi­cal indexes related to kidney function, heart injury and liver function were detect­ed by Biochemical analyses kits. Hematoxylin- eosin (HE) stain was used to for Histopathological examinations, and Quantibody Mouse Array was used for detect apoptosis and inflammation-related protein expression. HyC improved biochemi­cal indices of renal and heat function in the blood. Histopathological examinations showed that HyC mitigated pathological damage to proximal organs (kidneys and lower limb muscles), distal organs (heart and brain), and reduced inflammatory cell infiltration. Expression of apoptosis- and inflammation-related proteins in brain and heart tissues were also evaluated. HyC significantly increased cellular inhibitor of apoptosis 2 (cIAP2) in the brain and Bcl-2 and insulin-like growth factor 2 (IGF-2) in the heart. Additionally, HyC regulated the expression of several inflam­mation-related factors in both brain and heart tissues. Although further investiga­tion is needed, particularly in human subjects, this study highlights the potential of HyC as a promising therapeutic strategy for reducing AAO-associated organ damage.

Key words: Abdominal aortic occlusion; Hypoxic conditioning; Inflammation; Apoptosis;

 

Single-Cell Landscape Reveals Cellular Specific and Activity in the AAO Mouse Hippocampus

 

Linhui Qin^1&, Ling Kui²&,Yanming Jiao^2&, Jun Xu¹, Ning Li¹, Fang Tong¹, Feng-Yong Liu³, Xunming Ji¹*, Changhong Ren¹*

¹ Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Capital Medical University, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, 100053, China

²Department of Neurology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen 518054, China

³Department of Interventional Radiology, Senior Department of Oncology, Fifth Medical Center of PLA General Hospital, Beijing, China

 

ABSTRACT

Abdominal aortic occlusion (AAO)-induced ischemia/reperfusion (I/R) injury (AAIRI) is a serious condition associated with limited treatment options. Under­standing the roles of specific cell subsets in the onset and progression of AAIRI has been challenging due to the cellular heterogeneity within the affected tissues. In this study, we utilized single-cell RNA sequencing (scRNA-seq) to comprehensively characterize the cellular populations in a mouse model of AAIRI.

By subjecting mice to abdominal aortic ischemia and reperfusion, we identified 7 principal clusters of cells within the affected tissues, each displaying cell-type-spe­cific gene expression patterns. Furthermore, we delineated specific subpopula­tions of cells and elucidated their functional roles in various pathways relevant to AAIRI. Notably, the induction AAIRI resulted in the upregulation of previously unre­ported cell type-specific genes.

Of particular interest, we observed a remarkable diversity in the differentiation of Astrocyte, with 7 distinct subtypes emerging after the onset of AAIRI. Additionally, we identified potential trajectory branches within the subsets of monocytes/mac- rophages, shedding light on their response to injury. Furthermore, our analysis revealed distinct subclusters within hippocampus, endothelial, oligodendrocytes, oligodendrocytes precursor cells, and microglia cells in the context of AAIRI.

In summary, our scRNA-seq analysis provided unprecedented insights into the precise transcriptional changes occurring at the single-cell level during neuroin­flammation triggered by AAIRI. This approach opens up new avenues for investigat­ing the underlying mechanisms of the disease and identifying cell-subtype-specific molecules that may serve as potential targets for therapeutic interventions in AAIRI.

Keywords: Abdominal aortic occlusion, Hippocampus, Single-cell RNA sequencing, Cellular specific, Cellular activity,

 

Dihydroergotamine protect against ischemic stroke through modulating microglial/macrophage polarization and inhibiting inflammation in mice

 

Yangmin Zheng¹，², Yue Hu¹，², Feng Yan¹，², Rongliang Wang¹，², Zhen Tao¹，², Junfen Fan¹，², Ziping Han¹，², Haiping Zhao¹，², Ping Liu³, Wei Zhuang⁴*, Yumin Luo¹，²*

^Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, Beijing, China;

²Beijing Geriatric Medical Research Center and Beijing Key Laboratory of 1Translational Medicine for Cerebrovascular Diseases, Beijing, China;

³Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China; ⁴Department of Pharmacy Xuanwu Hospital of Capital Medical University, Beijing, China;

 

Abstract

Objectives: The search for drugs that can protect brain tissue and reduce nerve damage has been a research hotspot in acute ischemic stroke. We aim to investi­gate the potential protective effect of dihydroergotamine on ischemic stroke and its mechanism.

Methods: C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO), intraperitoneal administrated with dihydroergotamine at 10mg/kg/day for 14 days. The adhesive removal test and beam walking test were conducted at 1, 3, 5, 7, 10 and 14 days after MCAO operation. Further, the mechanism of dihydroer­gotamine regulating microglia/macrophage polarization and inflammation partici­pating in ischemic stroke protection was studied by ELISA measurements, immu­nofluorescence staining and western blotting.

Results: In this study, from the perspective of drug repurposing strategy, it was found that dihydroergotamine can inhibit oxygen-glucose deprivation damage to neurons, significantly improve cell survival rate, and may have a protective effect on ischemic nerve injury. Dihydroergotamine can significantly improve the neural function score, reduced brain injury severity, and improved survival rates in mice. Finally, we found that dihydroergotamine has a protective effect on ischemic nerve injury by reducing the expression of TNF-a and IL-邛 in ischemic brain tissue of mice, inhibiting the polarization of microglia/macrophage to M1 and promoting the polarization of microglia/macrophage to M2.

Conclusion: Dihydroergotamine, as a first-line treatment for migraine, this study is the first to show its protective effect against ischemic nerve injury in vitro and in vivo.

Keywords: Dihydroergotamine, Drug repurposing, Inflammation, Microglia/macro­phage polarization, Ischemic stroke,

 

 

Neurotoxic Astrocytes Exacerbate Blood-Brain Barrier Disruption in Hemorrhagic Stroke via Matrix Metalloprotease 3

 

Chang Liu and Guo-Yuan Yang

Department of Biomedical Engineering, Shanghai Jiao Tong University.

 

Abstract:

Background： Neurotoxic astrocytes are induced in a variety of neurological diseas­es and damage neurons and oligodendrocytes, but their effect on blood-brain barrier (BBB) during hemorrhagic stroke remains unknown.

Aim: To investigate the effect and mechanism of neurotoxic astrocytes on BBB function in mice after hemorrhagic stroke.

Method: Adult male C57BL/6 mice (n=80) underwent collagenase-induced intrace­rebral hemorrhage. Neurotoxic or neuroprotective astrocytes were identified by immunostaining of C3d/GFAP or S100a10/GFAP. PLX5622 or F70101C-A was used to delete microglia or macrophages in mice, respectively. Neurotoxic astrocytes were induced in vitro with IL-1a, TNFa, and C1q. bEnd.3 cells were cultured with neuro­toxic astrocyte-conditioned medium. RNA sequencing was further conducted to determine the mechanism of neurotoxic astrocytes-induced BBB disruption.

Results/Conclusions: The percentage of C3d+/GFAP+ astrocytes increased while the percentage of S100a10+/GFAP+ astrocytes decreased from day 1 to day 14 after hemorrhagic stroke (p<0.01). More than 60% of astrocytes wrapped surround the damaged microvessels were C3d+ subtype at day 3 after hemorrhagic stroke. Furthermore, the neurotoxic astrocytes were induced by residential microglia but not infiltrated macrophages. In vitro experiments showed that neurotoxic astro­cyte-conditioned medium disrupted BBB integrity. BBB disruption related gene matrix metalloproteinase 3 (MMP3) was highly upregulated in the neurotoxic astro­cytes (p<0.01). Finally, inhibiting MMP3 reduced BBB disruption in vitro, and knockout MMP3 in astrocytes also reduced BBB disruption and improved neuro­logical outcomes in hemorrhagic stroke mice (p<0.01). Our study demonstrated that neurotoxic astrocytes exacerbated BBB disruption through MMP3, which opens a new avenue for the treatment of BBB disruption related neurological diseases.

Keywords: Neurotoxic astrocytes; Hemorrhagic stroke; Blood-brain barrier; Matrix metalloproteinase 3

 

 

Remote ischemic conditioning facilitates remyelination after stroke via exosome mediated cholesterol metabolism

 

Wantong Yu¹, Changhong Ren¹, Chen Gao¹, Wei Zhang¹, Wenjie Shi¹, Ning Li¹, Jun Xu1, Xunming Ji¹,²*

1. Department of Neurology and Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Capital Medical University Beijing, China;
2. Center of Stroke, Beijing Institute for Brain Disorder, Capital Medical University，Beijing, China;

 

Abstract

Background: Remote ischemic conditioning (RIC) has shown potential in promoting recovery after ischemic stroke. However, the underlying mechanisms of post-stroke repair responses to RIC have not been systematically studied. The aim of this study was to characterize the effects of chronic RIC on experimental stroke in mice and the humoral mechanism underlying the beneficial effect.

Methods: A mouse model of ischemic stroke was established by middle cerebral artery occlusion (MCAO). Repeated RIC was performed during the 28 days after reperfusion. Behavioral tests and histological analysis were conducted in multiple time points. Exosome release inhibitor GW4869 was used to examine the effect of exosomes on RIC induced remyelination. Proteomics analysis of serum exosome were performed in RIC treated and control group.

Results: RIC significantly improved behavioral outcomes and increased remyelin­ation after ischemic stroke. Blocking exosomes biogenesis mitigated the beneficial effects of RIC on white matter regeneration. Mechanistically, RIC induced exosomal APOA1 acted through ABCA1 receptors on microglia to enhance myelin debris clearance and cholesterol transportation, consequently enhancing remyelination and white matter repair.

Conclusion: These findings indicate that RIC promotes post-stroke remyelination through the regulation of cholesterol metabolism by exosomal APOA1.

Key words: Ischemic stroke, Remote ischemic conditioning, White matter repair, APOA1

 

Hsa-circRNA-101141-hsa-miRNA-181d axis in peripheral neutrophils might participate in the pathogenesis of Intracranial Atherosclerotic Stenosis by acting on cytoskeleton organization

 

Ziping Han, Zixian Xie, Yumin Luo

 

ABSTRACT

Background： Expression profiles and clinical significance of circular RNAs (circRNAs) in patients with intracranial atherosclerotic stenosis (ICAS) have not been investigated yet.

Methods: A circRNA microarray was used to identify differentially expressed circRNAs (DEcircRNAs) in the peripheral neutrophils of patients with ICAS. The expressions of upregulated hsa-circRNA-087631 and hsa-circRNA-101141 and downregulated hsa-circRNA-100914 and hsa-circRNA-001082 were verified using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Addition­ally, we compared the expression of those four DEcircRNAs before endovascular treatment (pre-E) and 24 h after endovascular treatment (post-E) and between patients with adverse- and severe adverse effects (AE/SAE) and those without. Their area under the curve (AUC) from receiver operating characteristic (ROC) curve was calculated as well. Bioinformatic analyses of DEcircRNAs host genes and target genes in DEcircRNA-miRNA-mRNA regulatory network were further performed.

Results: Total 70 circRNAs were found to be differentially expressed in patients with ICAS; of these, 7 were upregulated and 63 were downregulated. qRT-PCR-based validation results of the four DEcircRNAs corresponded with the microarray data. The upregulated hsa-circRNA-087631 and hsa-circRNA-101141 were significantly downregulated 24 h post-E; moreover, they were significantly increased in patients with perioperative AE/SAE compared to those without AE/SAE. ROC analysis further supported their potential to be exploited as diagnostic biomarkers for ICAS. The validated DEcircRNA-miRNA-mRNA regulatory network and further bioinfor­matic analysis supported the core roles of and hsa-circRNA-101141 in regulating target genes mainly related to actin or microtubule-based process.

Conclusions: DEcircRNAs in peripheral neutrophils could serve as biomarkers for the diagnostic and adverse effect prediction in ICAS patients receiving endovascu­lar treatment. Moreover, these DEcircRNAs, especially hsa-circRNA-101141-hsa-miR- NA-181d axis, might participate in the pathogenesis of ICAS by acting on actin or microtubule-based cytoskeleton organization processes in neutrophils.

 

Molecular mechanisms of Aging with the anti-aging strategies

 

Yumeng Li¹, Shujin Wang², Xutong Tian³, Xin Wu¹

¹Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China.

² Institute of Life Sciences, Chongqing Medical University, Chongqing, China.

³The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan Universi­ty of Science and Technology, Luoyang, P. R. China.

 

Abstract

Aging is a complex and multifaceted integrated process involving a variety of inter­related molecular mechanisms and cellular systems. Phenotypically, the biological aging process is accompanied by gradual loss of cellular functions and systemic deterioration of multiple tissues, which result in susceptibility to aging-related diseases. Currently, a growing body of evidence suggests that aging was closely associated with telomere attrition, DNA damage, mitochondrial dysfunction, loss of NAD+ levels, disabled macro-autophagy, stem cell exhaustion, inflammation, loss of protein balance, deregulated nutrient-sensing, altered intercellular commu­nication and dysbiosis. These age-related abnormalities may be alleviated by some intervention strategies, such as calorie restriction, improved sleep quality and enhanced physical activity, as well as targeted longevity genes. In this review, we summarized the key historical progress that scientists had explored the import­ant causes of aging and anti-aging strategies in the last decades, so as to provide readers with further understandings toward the reversibility of aging phenotypes and developing novel and reasonable anti-aging treatment strategies.

Keywords: Aging; Triggers of aging; Anti-aging strategies

 

T-LAK cell-originated protein kinase (TOPK): a cell proliferation marker associated with the prognosis of acute
ischemic stroke (Paid)

 

Lingzhi Li¹，², Ziping Han¹, Tong Shen¹, Zhenhong Yang¹, Junfen Fan¹, Rongliang Wang¹, Yangmin Zheng¹, Haiping Zhao¹, Yumin Luo¹，³ institute of Cerebrovascular Diseases Research and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China.

²Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310020, China.

³Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China.

 

Abstract

Background and purpose: T-LAK cell-originated protein kinase (TOPK) plays a crucial role in neuroprotection against cerebral ischemia. We aimed to determine the association between the TOPK level and the clinical outcome of acute ischemic stroke (AIS).

Methods: The plasma TOPK protein level was detected in 330 AIS patients' samples in our biobank (https://www.clinicaltrials.gov; unique identifier: NCT03577093); the mRNA level of neutrophilic TOPK was detected by reverse transcription-poly- merase chain reaction in a subset of 124 AIS patients' samples in the biobank. The primary outcome was the excellent outcome defined as mRS 0-1 at 3 months or equal to mRS prestroke. Univariate and multivariate logistic regression analysis were adopted to evaluate the association between TOPK levels and the outcome of AIS patients.

Results: Among 330 AIS patients, plasma TOPK concentrations (128.2 [54.7, 620.9] vs 67.7 [45.3, 338.1], pg/mL, p = 0.010) differed significantly between patients pres­ent with an excellent outcome or not at 3 months. Plasma TOPK N 69.95 pg/ml (OR = 2.282 [1.462-3.560], p < 0.001; adjusted OR = 2.918 [1.741-4.889], p < 0.001) inde­pendently predict the excellent functional outcome at 3 months. In the subgroup of patients received rtPA treatment, patients with TOPK N 69.95 pg/ml (OR = 2.990 [1.356-6.592], p = 0.007; adjusted OR = 3.435 [1.315-8.972], p = 0.012) also predicted the excellent functional outcome after rtPA treatment. Addition of plasma TOPK to clinical predictors of the excellent outcome after AIS and the outcome after rtPA treatment improved reclassification as well as discrimination. TOPK mRNA level significantly elevated in the neutrophils of AIS patients compared with that of controls (p = 0.024). In the neutrophils of 124 AIS patients, TOPK mRNA was nega­tively correlated with neutrophil count (p = -0.37, p < 0.001) as well as NLR (p = -0.28, p < 0.001), and was higher in the older patients than in young patients (0.73 [0.64, 0.95] vs 0.49 [0.33, 0.76], p = 0.030). Neutrophilic TOPK mRNA level (0.62 [0.36, 0.95] vs 0.58 [0.37, 0.85], p = 0.531) did not differ significantly between patients with excellent outcome or not. No significant predictive value of neutro­philic TOPK mRNA level observed for excellent outcome.

Conclusions：Higher plasma TOPK protein level is associated with the better outcome of AIS, and plasma TOPK possesses prognostic value of the excellent outcome of AIS. The role of neutrophilic TOPK in AIS warrants to be determined in further investigation.

Keywords: T-LAK cell-originated protein kinase; acute ischemic stroke; neutrophil; outcome.

Astrocytic MEGF10- and MERTK-mediated myelin phagocytosis differentially affects white matter repair in mice after chronic cerebral hypoperfusion

 

Tongtong Xu, Yaohui Tang

 

Background： Chronic cerebral hypoperfusion (CCH) causes white matter injury and leads to vascular cognitive impairment and dementia. After CCH, astrocytes are activated and engulf myelin. However, the effect of astrocyte-mediated myelin engulfment on white matter injury and cognitive impairment is unclear.

Aim: To explore the effect and mechanism of astrocyte-mediated myelin phagocy­tosis on white matter injury and cognitive impairment in mice after CCH.

Methods: Astrocyte-specific MEGF10 or MERTK knockout mice were subjected to CCH mouse model of bilateral common carotid artery stenosis (BCAS). White matter injury was evaluated by Luxol fast blue (LFB) staining and transmission electron microscope (TEM). Myelin phagocytosis was assessed by immunostaining, TEM and pHrodo dye. 8-arm maze test and novel object recognition were conduct­ed to determine neurobehavioral outcomes. RNA sequencing was performed for further mechanistic study.

Results: Astrocytes in the corpus callosum were activated and engulfed myelin via MEGF10 and MERTK, two important phagocytic receptors. Conditional knockout of MEGF10 or MERTK in astrocytes reduced astrocyte-mediated myelin engulfment compared with control group in vitro and in vivo. Interestingly, LFB staining and TEM data showed that knockout of MEGF10 in astrocytes alleviated white matter injury while knockout of MERTK in astrocytes aggravated white matter injury after BCAS. Astrocytic MEGF10 knockout mice showed better working memory and exploration tendency, but conditional knockout of MERTK in astrocytes worsened cognitive function, suggesting MEGF10 and MERTK play opposite roles in white matter injury after CCH. Mechanistically, RNA sequencing revealed that knockout of MEGF10 in astrocytes reduced cell cycle-related pathway and proliferation of astrocytes, further reduced astrogliosis and the secretion of remyelination inhibi­tors such as CSPG. However, knockout of MERTK in astrocytes increased cell adhe­sion molecules and MHC class II molecules, which are responsible for initiating inflammatory responses. Together, our findings suggest that astrocytic MEGF10- and MERTK-mediated myelin phagocytosis distinctively contributed to white matter injury in mice after BCAS via different mechanisms.

Conclusion: Our study demonstrated that astrocytic MEGF10- and MERTK-mediated myelin phagocytosis distinctively contributed to white matter injury in mice after BCAS via different mechanisms, suggesting novel therapeutic targets for treating CCH.

Keywords： Myelin phagocytosis, White matter repair, Chronic cerebral hypoperfu­sion

Knowledge Focus

Research

 

 

Metal-Organic Framework-based Biohybrid Nanoassemblies for Biomedical Applications

 

Liangcan He*

School of Medicine and Health, Key Laboratory of Micro-systems and Micro-structures Manufacturing (Ministry of Education), Harbin Institute of Technology, Harbin 150001, China Zhengzhou Research Institute, Harbin Institute of Technology, Zhengzhou, 450046, China Email: liangcanhe@hit.edu.cn

 

Abstract

DeNanotechnology has made remarkable progress in manipulating nanoparticles (NPs) with precise control over their properties. This work presents a novel DNA-mediated assembly strategy to enhance the localization of erbium-based nanoparticles (ErNPs) on bimetal-organic framework (CPM) nanohybrids (ECPM) at tumor sites, leading to improved imaging and therapeutic efficacy. The ECPM nanohybrids exhibit a virus-like structure, with CPM as the core and ErNPs as the outer layer. The surface of ECPM is modified with pH-responsive i-motif DNA strands, which undergo quadruplex structure formation in the acidic tumor micro­environment. This self-assembly process triggers the formation of NP clusters within the tumor region. The ErNPs within these clusters emit visible photons upon excitation, which are harnessed by porphyrin ligands in CPM for NIR-induced pho­todynamic therapy. Importantly, the integration of CPM does not compromise the down-converted NIR-II emission, enabling dual imaging and therapeutic capabili­ties. One of the challenges in cancer therapy is the presence of GSH, which can reduce the effectiveness of ROS-mediated therapies. To address this, the CPM com­ponent in ECPM can deplete intracellular GSH levels, enhancing oxidative stress for improved photodynamic therapy. The responsive self-assembly of ECPM enables selective accumulation within tumors, resulting in enhanced NIR-II imaging and therapeutic effects compared to dispersed ECPM systems. In summary, the DNA-mediated assembly strategy utilizing ECPM nanohybrids holds promise for improving tumor localization, imaging, and therapeutic outcomes. The pH-respon- sive self-assembly of ECPM allows for selective tumor accumulation, while the integration of CPM enables dual imaging and therapeutic functionalities. These findings showcase the potential of nanomaterial assembly strategies for advanced applications in nanomedicine.

 

LCP1 knockdown in monocyte-derived macrophages: mitigating ischemic brain injury and shaping immune cell signaling and metabolism

 

Yan Wang 1，2*#, Qianqian Yin ^1#, Decao Yang 1, Haojie Jin ³, Yang Yao 2, Jibing Song⁴, Cuiying Liu ⁵, Yu Nie ⁶, Baohui Xu , Lixiang Xue 1, Xun- ming Ji ⁸*, Xiaoyuan Chen ⁹*, Heng Zhao ⁸*

^Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.

2Department of Neurosurgery, Stanford University School of Medicine, 1201 Welch Road, MSLS Building, Stanford, USA.

³The Key Laboratory for Silviculture and Conservation of Ministry of Education, The College of forestry, Beijing Forestry University, Beijing, China

⁴College of Chemistry, Beijing University of Chemical Technology, China.

⁵School of Nursing, Capital Medical University, Beijing, China.

⁶Fuwai Hospital, National Centre for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China.

⁷Department of Surgery, Stanford University School of Medicine, 1201 Welch Road, MSLS Building, Stanford, USA.

⁸Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China. ⁹Department of Diagnostic Radiology, Nanomedicine Translational Research Program, NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

 

ABSTRACT

Rationale: Ischemic stroke poses a significant health burden with limited treatment options. Lymphocyte Cytosolic Protein 1 (LCP1) facilitates cell migration and immune responses by aiding in actin polymerization, cytoskeletal rearrangements, and phagocytosis. We have demonstrated that the long non-coding RNA (lncRNA) Maclpil silencing in monocyte-derived macrophages (MoDMs) led to LCP1 inhibi­tion, reducing ischemic brain damage. However, the role of LCP1 of MoDMs in isch­emic stroke remains unknown.

Methods and Results: We investigated the impact of LCP1 on ischemic brain injury and immune cell signaling and metabolism. We found that knockdown of LCP1 in MoDMs demonstrated robust protection against ischemic infarction and improved neurological behaviors in mice. Utilizing the high-dimensional CyTOF technique, we showed that LCP1 knockdown in MoDMs resulted in reduction in neuroinflam­mation and attenuated lymphopenia or stroke-induced immunodepression. It also showed altered immune cell signaling by modulating the phosphorylation levels of key kinases and transcription factors, including p-PLCg2, p-ERK1/2, p-EGFR, p-AKT, and p4E-BP1 as well as transcription factors like p-STAT1, p-STAT3, and p-STAT4. Further bioinformatic analysis indicated that Akt and EGFR are particularly involved in fatty acid metabolism and glycolysis. Indeed, single-cell sequencing analysis confirmed that enrichment of fatty acid and glycolysis metabolism in Lcp1high monocytes/macrophages. Furthermore, Lcp1high cells exhibited enhanced oxidative phosphorylation, chemotaxis, migration, and ATP biosynthesis pathways. In vitro experiments confirmed the role of LCP1 in regulating mitochon­drial function and fatty acid uptake.

Conclusions： These findings contribute to a deeper understanding of LCP1 in the context of ischemic stroke and provide valuable insights into potential therapeutic strategies targeting LCP1 and metabolic pathways, aiming to attenuating neuroin­flammation and immunodepression.

Keywords： Stroke, Monocytes, Macrophages, Lipid metabolism, Neuroinflamma­tion, immunodepression

Multifunctional metallopolyphenol nanoparticles target mitochondria to delay Intervertebral disc degeneration through NOD-like receptor-mediated anti-proptosis effect

 

Aimin Wu^a1* Hao Zhoua，¹, Qiuping Qian^b，1, Qizhu Chen^a，1, Chenyu Wu^a>1 Linjie Chen^a, Zhiguang Zhang^a, Tao Chen^a, Ouqiang Wu^a, Yuxin Jin^a, Xinzhou Wang^a, Zhenyu Guo^a, Xiangyang Wang^a, Jones Mor- gan^c, Pooyan Makvandi^d*, Yunlong Zhou¹³，*,

^a Department of Orthopaedics, Key Laboratory of Structural Malformations in Children of Zhejiang Province，Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China.

^b Zhejiang Engineering Research Center for Tissue Repair Materials, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, 325000, China

^c Spine Unit, The Royal Orthopaedic Hospital, Bristol Road South, Northfield, Birmingham, B31 2AP, United Kingdom.

^d Institute for Bioengineering, School of Engineering, The University of Edinburgh, Edin­burgh, EH9 3FB, United Kingdom.

* Corresponding author. Aimin Wu aiminwu@163.com

Department of Orthopaedics, Key Laboratory of Orthopaedics of Zhejiang Province, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.

 

Abstract

Intervertebral disc degeneration (IVDD) is a significant contributor to low back pain. which is mainly characterized by the excessive generation of reactive oxygen species and inflammation-induced protrusion. Unfortunately, there are currently no simply specific molecules or materials available to effectively delay IVDD. In this study, we explored the potential of utilizing epigallocatechin gallate (EGCG), a natural polyphenolic compound with antioxidant and anti-protrusion properties, to develop a multifunctional nanoparticle network (PG@Cu). A designed penta­peptide fixed on PG@Cu nanoparticles via a Schiff base (C=N) bond to endow metal polyphenol particles with multifunctionality (PG@Cu-FP). The PG@Cu-FP exhibit­ed enhanced escape from lysosomal capture, enabling efficient targeting of mito­chondria to scavenge excess reactive oxygen species and inhibit the onset of protrusion, thus delaying IVDD. The scavenging activity against reactive oxygen species is derived from the polyphenol-based structures within the nanoparticles. Moreover, the proptosis is effectively blocked by inhibiting gasdermin (GSDM- D)-mediated pore formation and membrane rupture. PG@Cu-FP successfully reduces the activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome by inhibiting the oligomerization of GSDMD, leading to reduced expression of Nod-like receptors (NLR). This multifaceted approach demonstrates a higher efficiency in inhibiting proptosis. Importantly, PG@Cu-FP exhibits low cytotoxicity, high biocompatibility, and slows down the degradation of the extracellular matrix (ECM), thereby main­taining ECM stability. Experimental results confirm that PG@Cu-FP preserves disc height, retains water content, and preserves tissue structure. These findings high­light the potential of PG@Cu-FP in improving IVDD and provide novel insights for future research in IVDD treatments

Myoferlin assists in P-STAT3 translocation in glioblastoma

 

Peiqi Zhao, Qichuan Zhuge

Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China Emails: zhaopeiqi1007@163.com; qc.zhuge@wmu.edu.cn;

 

Abstract:

Glioblastoma (GBM), which has a poor prognosis and high mortality, is the most prevalent primary brain malignant tumor. There is currently no effective treatment for GBM patients. Myoferlin (MYOF) is a type II membrane protein of the Ferlin family, involved in many essential physiological functions of the cell membrane. Here, we aim to investigate the function and mechanism of MYOF in the progres­sion of GBM and simultaneously to explore its value as a diagnostic and therapeu­tic target. Our results indicate that MYOF knockdown suppresses cancer cell prolif­eration and migration in vitro and in vivo via preventing phospho-STAT3 from entering the nucleus.

 

Roxadustat-preconditioned bone marrow stromal cells for ischemic stroke rats

 

Su Yang, Qichuan Zhuge

Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China Email: yang- su@wmu.edu.cn; qc.zhuge@wmu.edu.cn;

 

Background： Mesenchymal stem cell (MSC) transplantation has developed into an encouraging strategy for stroke treatment, while the harsh microenvironment including hypoxia, inflammatory cascade, and formation of reactive oxygen species (ROS) results in poor survival and engraftment of BMSCs after transplanta­tion.

Aims： Evaluate whether pretreatment of HIF-1a activator Roxadustat (FG-4592) could promote the survival rate of grafted BMSCs and improve neurological func­tion deficits in ischemia rats.

Methods and Results: We found FG-4592 promoted autophagy level to inhibit OGD-induced apoptosis through HIF-1a/BNIP3 pathway. GFP and Ki67 double staining showed an improved survival rate of BMSCs in the FG-4592 group, whereas infarct volume and neurobehavioral score verified its enhanced neurological recovery activity simultaneously. NeuN and Iba-1 fluorescence staining showed improved neural survival and decreased microglial activation, along with decreased IL-邛，IL-6, and TNF-a levels through the TLR-4/NF-kB pathway.

Conclusions: FG-4592 pretreated BMSCs improve neurological function recovery after stroke and are likely to be a promising strategy for stroke management.

Keywords Autophagy, Bone marrow stromal cells, HIF-1a/ BNIP3 signal pathway, Stroke

 

A Reliable Nonhuman Primate Model of Ischemic Stroke

 

Xiao Lin¹, Kunlin Jin², Qichuan Zhuge¹

¹Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, First Affiliated Hospital of Wenzhou Medical University; Wenzhou, China.

²Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA

 

 

Abstract:

A nonhuman primate model of ischemic stroke is considered as an ideal preclinical model to replicate various aspects of human stroke because of their similarity to humans in genetics, neuroanatomy, physiology, and immunology. However, it remains challenging to produce a reliable and reproducible stroke model in non­human primates due to high mortality and variable outcomes. Here, we developed a focal cerebral ischemic model induced by topical application of 50% ferric chlo­ride (FeCl3) onto the MCA-M1 segment through a cranial window in the cynomol- gus monkeys. We found that FeCl3 rapidly produced a stable intraarterial throm­bus that caused complete occlusion of the MCA, leading to the quick decrease of the regional cerebral blood flow in 10 min. A typical cortical infarct was detected 24 hours by magnetic resonance imaging (MRI) and was stable at least for 1 month after surgery. The sensorimotor deficit assessed by nonhuman primate stroke scale was observed at 1 day and up to 3 months after ischemic stroke. No sponta­neous revascularization or autolysis of thrombus was observed, and vital signs were not affected. All operated cynomolgus monkeys survived. Our data suggested that FeCl3-induced stroke in nonhuman primates was a replicable and reliable model that is necessary for the correct prediction of the relevance of experimental therapeutic approaches in human beings.

Keywords: ferric chloride, cynomolgus macaque, nonhuman primate, ischemic stroke, middle cerebral artery

 

Phillygenin treat ischemic stroke through inhibiting PTP1B to elevate the phosphorylation levels of FGFR1

 

Meiling Bai Juan Feng Jue wang*

Department of Neurology, Shengjing Hospital, China Medical University

 

Aims： Phillygenin is the most important component of forsythia. Much research found out that the various active components of forsythia play protective role in central nervous system through regulating oxidative stress, anti-inflammation etc. This study aims at exploring the therapeutic function of phillygenin in ischemic stroke. Methods: We used the methods of network pharmacology to analyze the chemical components in forsythia and chose phillygenin as the as a representative component to map the association between component and protein targets. We used C57BL wild-type mice to construct MCAO model, gave continuous gavage administration at 12mg/kg, 24mg/kg and 36mg/kg doses after 24h reperfusion, and the effect of mouse weight and behavioral scores and the TTC staining obser­vation on cerebral infarction area were recorded. The phosphorylated IGF1R, EGFR, MAPK14, MET, FGFR1 levels on western blotting. Verification of changes in target location and number by immunofluorescence of mouse brain tissue.

Results: The selected drug targets include FGFR1, and phillygenin binds to FGFR1 weakly, while phillygenin has lower binding energy to PTP1B, meaning that philly­genin may selectively inhibit PTP1B activity and have little effect on FGFR1. The phosphorylation level of phosphorylated FGFR1 increased abviously, and the level of TNF-a and IL-6 decreased. Phillygenin inhibits the activity of PTP1B, which is a phosphatase, thereby reducing its dephosphorylation of FGFR1.

Conclusions: Phillygenin may inhibit the expression of PTP1B, reduce its dephos­phorylation of FGFR1, increase the phosphorylation level of FGFR1 to treat isch­emic stroke.

Keywords phillygenin, ischemic stroke, FGFR1, traditional Chinese medicine treat­ment

 

SETD2-Mediated H3K36 Trimethylation Regulates Chromatin Remodeling to Determine the Fate of Lgr5+ Intestinal Stem Cells

 

Ziyi Wang¹，², Li Li ¹>², Wei-Qiang Gao¹，²

1. State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine and School of Biomedical Engineer­ing, Shanghai Jiao Tong University, Shanghai, 200127, China.
2. School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.

 

Abstract:

Lgr5+ ISCs maintain intestinal homeostasis and promote regeneration through self-renewal and differentiation throughout life, which is commonly regulated by epigenetic modifications. Setd2 is a histone H3 lysine 36 (H3K36) trimethyltransfer­ase that plays an important role in regulating embryonic stem cell differentiation. However, whether and how Setd2 regulates the fate of intestinal stem cells (ISCs) remains unclear. In this study, we used Setd2f/f; Lgr5Cre mice models and found that H3K36me3 deficiency greatly reduced the number of Lgr5+ ISCs in mice. An integrated multi-omics analysis using Cleavage Under Targets and Tagmentation (CUT&Tag-seq) and switching mechanism at 5, end of the RNA transcript sequenc­ing (Smart-seq) revealed the correlation between Setd2-mediated H3K36me3 and other histone modifications, which established a potential chromatin remodeling model. Setd2 loss resulted in a significantly enrichment of genes linked to lipid-mediated signaling and chromosome assembly. Together, our studies high­light that Setd2 regulates the fate of Lgr5+ intestinal stem cells through histone modifications in epigenetic regulation.

Lipofuscin Accumulation is Associated with Systemic Inflammation

 

Qingting Yu¹, Yanzhuo Yang¹, Kairang Yang¹, Zuisu Yang¹, Falei Yuan¹*

^Department of Pharmacy, School of Food and Pharmacy, Zhejiang Ocean University, Zhoushan, China

 

Objectives: Lipofuscin accumulation is a hallmark of the aging brain, characterized by age-dependent autofluorescence (AF). However, the underlying mechanism that induces AF remains unknown. This study aims to determine the cause(s) of this phenomenon.

Methods: We examined the endogenous expression pattern of AF in mice at varying ages. To induce AF, a single intraperitoneal injection of lipopolysaccharide (LPS) was administered. Immunofluorescence staining for neurons, glia, and vascular cells was conducted to detect the presence of AF. To eliminate the possibility of LPS-induced artifacts, Prussian blue staining and blood IgG staining were performed. Senescent cells were confirmed through SA-B-Gal staining.

Results: AF was observed in the mouse brain as early as 3 months of age. In the cortex, AF was evident in the lysosomes of neurons, astrocytes, microglia, oligo­dendrocyte lineage cells, and endothelial cells, and its prevalence increased with age. Administration of LPS resulted in a rapid and pronounced induction of brain AF in the lysosomes of neurons, astrocytes, microglia, oligodendrocyte lineage cells, and endothelial cells, mirroring the normal aging process. Intriguingly, peri­cytes and smooth muscle cells (SMCs) in the brains of young, aged, or LPS-injected mice exhibited no AF. Notably, the LPS treatment did not induce vascular leakage, blood clots, or SA-B-Gal.

Conclusions: These findings suggest that AF in the brain may be linked to the innate immune response against Gram-negative bacterial infections.

Brain control of medullary hematopoiesis underlines aging associated immunosuppression

 

Meng Jia¹#, Shihe Jiang¹#, Wenyan He¹, Kaibin Shi1,Yingying Chang², Fu-Dong Shi¹, Wei-Na Jin¹*

Centers for Neurological Disease and Neuroimmunology, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China

²The Third Affiliated Hospital of Zhengzhou University, No. 7 Kangfu front ST, Zhengzhou, Henan, China

 

Abstract:

Senescence of hematopoietic stem cells (HSCs) is associated with suppressed immune response of elderly people which could lead to severe pathogen infection such as influenza and COVID-19. It has been verified that adrenergic nerve degener­ation in bone marrow could lead to senescence phenotype of the hematopoietic stem cell niche, revealing that neural signals would directly control HSCs senes­cence. Here we show that neurons in the paraventricular nucleus (PVN) that express corticotropin-releasing hormone (CRH) project to bone marrow (BM) and these BM projecting neurons were over-activated in old mice. Pharmacogenetic inhibition of these CRH neurons in the PVN rescues B cell lineage development suppression in the bone marrow of old mice. Conversely, activation of these CRH neurons in the PVN of young mice leads to HSC senescence phenotype. Our study indicates the neural control mechanism of the central nerves system (CNS) towards senescence of hematopoiesis and provides new therapeutic strategy to reverse the suppressed immune response of elderly people.

Abstract topic: paraventricular nucleus,bone marrow,hematopoietic stem cells, B cell lineage development

 

Predictive value of potential no-reflow markers for futile recanalization with endovascular stroke therapy

 

Shuangfeng Huang¹，², Jiali Xu³, Wenbo Zhao¹, Haiqing Song¹, Qing- feng Ma¹, Xunming Ji¹,⁴, Sijie Li¹**

1. Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
2. Emergency Department, Xuan Wu Hospital, Capital Medical University, 100053, China. ³Department of Rehabilitation Medicine, Beijing Shijitan Hospital affiliated to Capital Medical University, Beijing,100038, China

⁴Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospi­tal, Capital Medical University, Beijing, 100053, China.

 

Abstract:

Objective: Our study aimed to explore the additional predictive value of potential no-reflow markers for predicting futile recanalization in AIS patients who achieved full recanalization.

Methods: 173 AIS patients who received endovascular therapy and obtained a Mod­ified Thrombolysis in Cerebral Infarction scale of 3 were included in the study. Clin­ical and demographic variables and potential no-reflow markers were analyzed in univariate and multivariate analyses to determine predictors of poor 3-month neurologic outcomes. A basic predictive model was constructed, and the addition­al predictive value of no-reflow markers was evaluated using area under curve (AUC) analysis, integrated discrimination improvement (IDI) and categorized reclassification improvement (NRI).

Results: The basic model, which included clinical variables had an AUC of 0.868 (95%CI, 0.814-0.923). Potential no-reflow markers including contrast extravasation (OR, 4.321; 95% CI, 1.794-10.405; p=0.001), neutrophil-to-lymphocyte ratio (OR, 1.095; 95% CI, 1.009-1.188, p=0.030), D-dimer (OR, 1.134; 95%CI, 1.017-1.266; p=0.024) were added to the basic model to create a comprehensive model. Incor­poration of no-reflow markers greatly improved the predictive performance of the basic model (AUC, 0.901 (95% CI, 0.855-0.947); IDI, 8.86% (95% CI, 4.34%-13.39%), p<0.001; NRI, 18.38% (95% CI, 3.53%-33.23%), p=0.015).

Conclusions: Inclusion of no-reflow markers could greatly improve the predictive performance of the clinical variable basic model to earlier identify AIS patients with mTICI scores of 3 at high-risk for suffering futile recanalization.

Keywords: acute ischemic stroke; no-reflow phenomenon; D-dimer, contrast extravasation; neutrophil-to-lymphocyte ratio

Stroke-Heart Syndrome: Current Progress and Future Outlook

 

Lanjing Wang¹, Shuangfeng Huang¹, Wenbo Zhao¹，², Changhong Ren²,³, Yumin Luo¹, Xunming Ji¹,², Sijie Li¹,²,⁴*

1. Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China
2. Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 100069, China.
3. Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine, Xuanwu Hospi­tal, Capital Medical University, Beijing, 100053, China
4. Department of Emergency, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China

 

Abstract

Stroke can cause cardiac complications such as arrhythmia, myocardial injury, and cardiac dysfunction, which has received widespread attention and the concept of stroke-heart syndrome (SHS) has been proposed. Cardiac alterations are reported to peak within 72 hours after stroke onset. Moreover, stroke can also confer long-term effects on cardiac function. The post-stroke cardiac complications seriously affect the prognosis and are the second most common cause of death in stroke patients. It is increasingly recognized that SHS are not only the result of traditional vascular risk factors, but also more potential mechanisms that are not yet fully understood. Accumulating clinical and experimental evidences under­score the role of central autonomic network dysregulation and inflammation as the pillars of pathophysiological mechanisms of SHS. In view of this, the assess­ment of post-stroke cardiac dysautonomia is necessary. At the moment, the formu­lation of treatment strategies of SHS is a vital but knotty task. Accordingly, this means that it is important to find potential key mediators and signaling pathways of SHS, which plays a part in identifying therapeutic targets. The therapy targeting pathophysiological mechanisms may be promising approaches, and future well-designed trials are needed to verify the true clinical value. This comprehen­sive and up-to-date review may provide valuable clues for the future research.

 

The loss of NSD2 impairs liver regeneration

 

Wei Zhang¹ , Li Li¹

¹ School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.

 

Abstract:

Hepatocytes could be damaged by various factors such as surgical operation, alco­hol, virus and chemicals, which leads to a decrease in liver mass. To maintain homeostasis, the liver has a unique capability to recover its original mass. Paradox­ically, chronically dysregulated of repair causes defective recovery of healthy liver parenchyma and ultimately results in cirrhosis and liver cancer. NSD2 is a histone methyltransferase that targets histone 3 lysine 36 (H3K36). Abnormal expression of NSD2 correlates with various diseases. However, the effect of NSD2 during liver regeneration remains poorly understood. Herein, we found that NSD2 plays an important role in liver regeneration. The expression of NSD2 in hepatocytes increases during liver regeneration. Liver-specific deletion of NSD2 in mice impairs liver regeneration,suggesting that NSD2 might be a promising target for therapeu­tic applications in liver transplantation.

 

A Mendelian randomisation study: clonal haemopoiesis of indeterminatepotential is associated with the development of gestational diabetes mellitus

 

Yingying Chang¹, Ting Pan¹, Wei-Na Jin¹*

¹ The Third Affiliated Hospital of Zhengzhou University, No. 7 Kangfu front ST, Zhengzhou, Henan,China

 

Abstract：

The age-related presence of clonal haemopoiesis of indeterminatepotential (CHIP) has been shown to increase the risk of cardiovascular disease (CVD) and diabetes, and this has been found in some mothers and their offspring.However, the relationship between CHIP and adverse pregnancy outcomes, including gestation­al diabetes, is unclear.

Methods: A two-sample Mendelian randomisation study based on the largest avail­able genome-wide association study (GWAS) of the IEU open GWASproject and the FinnGen database was conducted to determine whether adverse pregnancy outcomes including gestational diabetes mellitus are causally associated with clonal haemopoiesis of undetermined potential. Various sensitivity analyses were performed to support the results.

Results: A significant causal relationship was found between CHIP and gestational diabetes mellitus (IRR,1.17;95%CI, 1.07-1.36).ConclusionsThe results of this Men­delian randomisationstudy support a causal relationship between clonal haemo­poiesis of undetermined potential and gestational diabetes. The results of this study provide insights into potential therapeutic interventions for gestational diabetes.

Key words: CHIP;age-related clonal hematopoiesis;clonal hematopoiesis of inde­terminate potential; somatic mutations;GDM.