Publications -- Kunlin Jin

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/21595

This collection is limited to articles published under the terms of a creative commons license or other open access publishing agreement since 2016. It is not intended as a complete list of the author's works.

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Pericyte Dysfunction Contributes to Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats
(Aging and Disease, 2023-08-24) Lin, Siyang; Landon, Benjamin; Zhang, Hongxia; Jin, Kunlin
Vascular cognitive impairment (VCI) encompasses cognitive disorders associated with cerebrovascular disease, often manifesting as white matter lesions (WMLs), irrespective of precise triggers. The integrity of white matter is essential for neural communication and cognitive function maintenance. Persistent cerebral hypoperfusion-induced WMLs are now acknowledged as a key driver of VCI and dementia, though their exact formation mechanism remains unclear. Recent studies link pericyte dysfunction to diverse brain disorders like Alzheimer disease. However, the exact pathological connection between pericyte dysfunction and cognitive impairment in VCI remains unexplored. In this study, we aimed to examine whether pericyte dysfunction could impact WMLs and cognitive impairment in a rat VCI model. Using a rat model of chronic cerebral hypoperfusion-induced VCI through two-vessel occlusion (2VO), we verified that 2VO induced both WMLs and cognitive impairment. Notably, the number of pericytes in the brain was significantly altered after 2VO. Furthermore, we observed significantly increased capillary constrictions at pericyte bodies in the brains of 2VO-induced rats compared to sham-operated rats, accompanied by reduced cerebral blood flow (CBF). To tackle this issue, we administered CGS21680, a specific adenosine A2A subtype receptor agonist, intranasally twice a day for 7 days. We found that rats treated with CGS21680 exhibited a significant increase in CBF at 7 and 14 days after 2VO, compared to the vehicle group. Moreover, capillary lumens beneath pericytes also increased after the CGS21680 treatment. Importantly, the treatment led to substantial improvements in WMLs and cognitive impairment compared to the vehicle group. Our findings suggest a critical role of pericyte dysfunction in WMLs and cognitive impairment within the rat VCI model. This insight contributes to our understanding of pathogenesis and offers prospects for targeted intervention in VCI.
Healthy Human Fecal Microbiota Transplantation into Mice Attenuates MPTP-Induced Neurotoxicity via AMPK/SOD2 Pathway
(Aging and Disease, 2023-05-18) Xie, Zhencao; Zhang, Mahui; Luo, Yuqi; Jin, Dana; Guo, Xingfang; Yang, Wanlin; Zheng, Jialing; Zhang, Hongfei; Zhang, Lu; Deng, Chao; Zheng, Wenhua; Tan, Eng-King; Jin, Kunlin; Zhu, Shuzhen; Wang, Qing
Increasing evidence has shown that gut dysbacteriosis may play a crucial role in neuroinflammation in Parkinson's disease (PD). However, the specific mechanisms that link gut microbiota to PD remain unexplored. Given the critical roles of blood-brain barrier (BBB) dysfunction and mitochondrial dysfunction in the development of PD, we aimed to evaluate the interactions among the gut microbiota, BBB, and mitochondrial resistance to oxidation and inflammation in PD. We investigated the effects of fecal microbiota transplantation (FMT) on the physiopathology of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. The aim was to explore the role of fecal microbiota from PD patients and healthy human controls in neuroinflammation, BBB components, and mitochondrial antioxidative capacity via the AMPK/SOD2 pathway. Compared to control mice, MPTP-treated mice exhibited elevated levels of Desulfovibrio, whereas mice given FMT from PD patients exhibited enriched levels of Akkermansia and mice given FMT from healthy humans showed no significant alterations in gut microbiota. Strikingly, FMT from PD patients to MPTP-treated mice significantly aggravated motor impairments, dopaminergic neurodegeneration, nigrostriatal glial activation and colonic inflammation, and inhibited the AMPK/SOD2 signaling pathway. However, FMT from healthy human controls greatly improved the aforementioned MPTP-caused effects. Surprisingly, the MPTP-treated mice displayed a significant loss in nigrostriatal pericytes, which was restored by FMT from healthy human controls. Our findings demonstrate that FMT from healthy human controls can correct gut dysbacteriosis and ameliorate neurodegeneration in the MPTP-induced PD mouse model by suppressing microgliosis and astrogliosis, ameliorating mitochondrial impairments via the AMPK/SOD2 pathway, and restoring the loss of nigrostriatal pericytes and BBB integrity. These findings raise the possibility that the alteration in the human gut microbiota may be a risk factor for PD and provide evidence for potential application of FMT in PD preclinical treatment.
NeuroD4 converts glioblastoma cells into neuron-like cells through the SLC7A11-GSH-GPX4 antioxidant axis
(Springer Nature, 2023-08-16) Wang, Hao; Zhao, Peiqi; Zhang, Ying; Chen, Zhen; Bao, Han; Qian, Wenqi; Wu, Jian; Xing, Zhenqiu; Hu, Xiaowei; Jin, Kunlin; Zhuge, Qichuan; Yang, Jianjing
Cell fate and proliferation ability can be transformed through reprogramming technology. Reprogramming glioblastoma cells into neuron-like cells holds great promise for glioblastoma treatment, as it induces their terminal differentiation. NeuroD4 (Neuronal Differentiation 4) is a crucial transcription factor in neuronal development and has the potential to convert astrocytes into functional neurons. In this study, we exclusively employed NeuroD4 to reprogram glioblastoma cells into neuron-like cells. In vivo, the reprogrammed glioblastoma cells demonstrated terminal differentiation, inhibited proliferation, and exited the cell cycle. Additionally, NeuroD4 virus-infected xenografts exhibited smaller sizes compared to the GFP group, and tumor-bearing mice in the GFP+NeuroD4 group experienced prolonged survival. Mechanistically, NeuroD4 overexpression significantly reduced the expression of SLC7A11 and Glutathione peroxidase 4 (GPX4). The ferroptosis inhibitor ferrostatin-1 effectively blocked the NeuroD4-mediated process of neuron reprogramming in glioblastoma. To summarize, our study demonstrates that NeuroD4 overexpression can reprogram glioblastoma cells into neuron-like cells through the SLC7A11-GSH-GPX4 signaling pathway, thus offering a potential novel therapeutic approach for glioblastoma.
Mitochondria and Neurodegenerative Diseases: A New Hotspot
(Aging and Disease, 2023-05-10) Li, Ang; Cao, Shuqin; Jin, Kunlin; Su, Huanxing
Growing evidence suggests that the prevalence of neurodegenerative diseases (NDs) is on the rise with the aged population with substantially overlapping clinical and pathological features. The journal "Aging & Disease" portals are always responsive to publishing cutting-edge research on age-related neurodegeneration. Even though outstanding progress has recently been made in understanding NDs, the underlying mechanisms involved in neuronal degeneration are yet to be deciphered and addressed. There is credible evidence showing multiple links between mitochondria and NDs, gradually becoming the hotspot in mechanistic or drug development research. The editorial aims to reflect on and discuss some interesting and unique results from the papers published in "Aging & Disease" during the past three years (2020 - 2022).
Aging During the Pandemic: Untangling the Complexities of COVID-19 and Geriatric Care
(JKL International, 2023-05-16) Su, Kaimeng; Jin, Kunlin
The COVID-19 pandemic has posed unprecedented challenges to the global healthcare system, with the elderly population being particularly vulnerable. This comprehensive review synthesizes the findings from publications in "Aging and Disease", highlighting the unique challenges older adults encountered during the pandemic and providing solutions thereof. These studies provide invaluable insights into the elderly population's vulnerabilities and needs during the COVID-19 pandemic. The susceptibility to the virus in older individuals remains debatable, and research on the clinical picture of COVID-19 in older populations has yielded insights into clinical features, molecular mechanisms, and potential therapeutic strategies. This review intends to shed light on the need of sustaining physical and mental well-being among older adults during the periods of lockdown by extensively exploring these concerns and emphasizing the need for targeted interventions and support systems for this population. Ultimately, the findings of these studies contribute to developing more effective and comprehensive approaches to managing and mitigating the risks posed by the pandemic to the elderly.
A Reliable Nonhuman Primate Model of Ischemic Stroke with Reproducible Infarct Size and Long-term Sensorimotor Deficits
(Aging and Disease, 2023-02-24) Lin, Xiao; Wang, Hua; Huang, Shengwei; Chen, Lefu; Yang, Su; Zhao, Peiqi; Lin, Zhongxiao; Yang, Jianjing; Ruan, Linhui; Ni, Haoqi; Wang, Kankai; Wen, Min; Jin, Kunlin; Zhuge, Qichuan
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 (FeCl(3)) onto the MCA-M1 segment through a cranial window in the cynomolgus monkeys. We found that FeCl(3) 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 FeCl(3)-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.
QEEG Signatures are Associated with Nonmotor Dysfunctions in Parkinson's Disease and Atypical Parkinsonism: An Integrative Analysis
(Aging and Disease, 2023-02-24) Liu, Hailing; Huang, Zifeng; Deng, Bin; Chang, Zihan; Yang, Xiaohua; Guo, Xinfang; Yuan, Feilan; Yang, Qin; Wang, Liming; Zou, Haiqiang; Li, Mengyan; Zhu, Zhaohua; Jin, Kunlin; Wang, Qing
Parkinson's disease (PD) and atypical parkinsonism (AP), including progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), share similar nonmotor symptoms. Quantitative electroencephalography (QEEG) can be used to examine the nonmotor symptoms. This study aimed to characterize the patterns of QEEG and functional connectivity (FC) that differentiate PD from PSP or MSA, and explore the correlation between the differential QEEG indices and nonmotor dysfunctions in PD and AP. We enrolled 52 patients with PD, 31 with MSA, 22 with PSP, and 50 age-matched health controls to compare QEEG indices among specific brain regions. One-way analysis of variance was applied to assess QEEG indices between groups; Spearman's correlations were used to examine the relationship between QEEG indices and nonmotor symptoms scale (NMSS) and mini-mental state examination (MMSE). FCs using weighted phase lag index were compared between patients with PD and those with MSA/PSP. Patients with PSP revealed higher scores on the NMSS and lower MMSE scores than those with PD and MSA, with similar disease duration. The delta and theta powers revealed a significant increase in PSP, followed by PD and MSA. Patients with PD presented a significantly lower slow-to-fast ratio than those with PSP in the frontal region, while patients with PD presented significantly higher EEG-slowing indices than patients with MSA. The frontal slow-to-fast ratio showed a negative correlation with MMSE scores in patients with PD and PSP, and a positive correlation with NMSS in the perception and mood domain in patients with PSP but not in those with PD. Compared to PD, MSA presented enhanced FC in theta and delta bands in the posterior region, while PSP revealed decreased FC in the delta band within the frontal-temporal cortex. These findings suggest that QEEG might be a useful tool for evaluating the nonmotor dysfunctions in PD and AP. Our QEEG results suggested that with similar disease duration, the cortical neurodegenerative process was likely exacerbated in patients with PSP, followed by those with PD, and lastly in patients with MSA.
Editorial: The NLRP3 inflammasome-mediated neuroinflammation and its related mitochondrial impairment in neurodegeneration
(Frontiers Media S.A., 2023-01-31) Deng, Chao; Cai, Xiang; Wang, Qing; Jin, Kunlin
Traditional Chinese Medicine and Western Medicine Share Similar Philosophical Approaches to Fight COVID-19
(JKL International, 2021-08-01) Zhao, Fangfang; Yang, Zhenhong; Wang, Ningqun; Jin, Kunlin; Luo, Yumin
Though disciplines in the same field, modern medicine (Western medicine) and traditional medicine (Traditional Chinese medicine, TCM) have been viewed as two distinct and divergent fields of medicine and thus differ greatly in their ways of diagnosing, treating, and preventing disease. In brief, Western medicine is primarily an evidence (laboratory)-based science, whereas TCM is more of a healing art based on the theory of Yin and Yang and the five elements in the human body. Therefore, whether TCM and Western medicine could use similar philosophical approaches to treat disease remains unclear. It is well-known that vitamin D enhances immune function and reduces the spread of some viruses. Indeed, recent evidence shows that the blood calcium level is strongly associated with COVID-19 severity, and vitamin D supplementation has shown favorable effects in viral infections. According to TCM theory, the pathogenesis of COVID-19 is closely associated with cold-dampness, an etiological factor in TCM. Cold-dampness could be attenuated by sun exposure and Wenyang herbs, both of which can restore the vitamin D level in the blood in Western medicine. Therefore, TCM and Western medicine could share similar philosophical methods to fight COVID-19 and understanding their philosophical theories could achieve the maximum benefits for treatment of COVID-19 and other diseases.
Transplantation of ACE2(-) Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia
(JKL International, 2020-03-09) Leng, Zikuan; Zhu, Rongjia; Hou, Wei; Feng, Yingmei; Yang, Yanlei; Han, Qin; Shan, Guangliang; Meng, Fanyan; Du, Dongshu; Wang, Shihua; Fan, Junfen; Wang, Wenjing; Deng, Luchan; Shi, Hongbo; Li, Hongjun; Hu, Zhongjie; Zhang, Fengchun; Gao, Jinming; Liu, Hongjian; Li, Xiaoxia; Zhao, Yangyang; Yin, Kan; He, Xijing; Gao, Zhengchao; Wang, Yibin; Yang, Bo; Jin, Ronghua; Stambler, Ilia; Lim, Lee Wei; Su, Huanxing; Moskalev, Alexey; Cano, Antonio; Chakrabarti, Sasanka; Min, Kyung-Jin; Ellison-Hughes, Georgina; Caruso, Calogero; Jin, Kunlin; Zhao, Robert Chunhua
A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs could cure or significantly improve the functional outcomes of seven patients without observed adverse effects. The pulmonary function and symptoms of these seven patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. After treatment, the peripheral lymphocytes were increased, the C-reactive protein decreased, and the overactivated cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells disappeared in 3-6 days. In addition, a group of CD14+CD11c+CD11b(mid) regulatory DC cell population dramatically increased. Meanwhile, the level of TNF-alpha was significantly decreased, while IL-10 increased in MSC treatment group compared to the placebo control group. Furthermore, the gene expression profile showed MSCs were ACE2(-) and TMPRSS2(-) which indicated MSCs are free from COVID-19 infection. Thus, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.
The Prognostic Value of Serum Cytokines in Patients with Acute Ischemic Stroke
(JKL International, 2019-06-01) Li, Xianmei; Lin, Siyang; Chen, Xiaoli; Huang, Wensi; Li, Qian; Zhang, Hongxia; Chen, Xudong; Yang, Shaohua; Jin, Kunlin; Shao, Bei
The inflammatory response is an unavoidable process and contributes to the destruction of cerebral tissue during the acute ischemic stroke (AIS) phase and has not been addressed fully to date. Insightful understanding of correlation of inflammatory mediators and stroke outcome may provide new biomarkers or therapeutic approaches for ischemic stroke. Here, we prospectively recruited 180 first-ever AIS patients within 72 hrs after stroke onset. We used the National Institutes of Health Stroke Scale (NIHSS) to quantify stroke severity and modified Rankin scale (mRS) to assess the 3-month outcome for AIS patients. Initially, we screened 35 cytokines, chemokines, and growth factors in sera from 75 AIS patients and control subjects. Cytokines that were of interest were further investigated in the 180 AIS patients and 14 heathy controls. We found that IL-1RA, IL-1beta, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-13, IL-15, EGF, G-CSF, Flt-3L, GM-CSF and Fractalkine levels were significantly decreased in severe stroke patients. In particular, IL-1beta, IL-4, IL-5, IL-7, IL-9, IL-10, IL-15, G-CSF and GM-CSF were significantly reduced in AIS patients with poor outcome, compared to those with good prognosis. IL-6 was notably higher in the poor outcome group. Only IL-9 level decreased in the large infarct volume group. After adjusting for confounders, we found that IL-5 was an independent protective factor for prognosis in AIS patients with an adjusted OR of 0.042 (P = 0.007), whereas IL-6 was an independent risk predictor for AIS patients with an adjusted OR of 1.293 (P = 0.003). Our study suggests the levels of serum cytokines are related to stroke severity, short-term prognosis and cerebral infarct volume in AIS patients.
Recent Progress in Vascular Aging: Mechanisms and Its Role in Age-related Diseases
(JKL International, 2017-07-21) Xu, Xianglai; Wang, Brian; Ren, Changhong; Hu, Jiangnan; Greenberg, David A.; Chen, Tianxiang; Xie, Liping; Jin, Kunlin
As with many age-related diseases including vascular dysfunction, age is considered an independent and crucial risk factor. Complicated alterations of structure and function in the vasculature are linked with aging hence, understanding the underlying mechanisms of age-induced vascular pathophysiological changes holds possibilities for developing clinical diagnostic methods and new therapeutic strategies. Here, we discuss the underlying molecular mediators that could be involved in vascular aging, e.g., the renin-angiotensin system and pro-inflammatory factors, metalloproteinases, calpain-1, monocyte chemoattractant protein-1 (MCP-1) and TGFbeta-1 as well as the potential roles of testosterone and estrogen. We then relate all of these to clinical manifestations such as vascular dementia and stroke in addition to reviewing the existing clinical measurements and potential interventions for age-related vascular dysfunction.
Of Cross-immunity, Herd Immunity and Country-specific Plans: Experiences from COVID-19 in India
(JKL International, 2020-12-01) Chakrabarti, Sankha Shubhra; Kaur, Upinder; Singh, Anup; Chakrabarti, Suddhachitta; Krishnatreya, Manigreeva; Agrawal, Bimal Kumar; Mittal, Amit; Singh, Amit; Khanna, Rahul; Gambhir, Indrajeet Singh; Jin, Kunlin; Chakrabarti, Sasanka
India has witnessed a high number of COVID-19 cases, but mortality has been quite low, and most cases have been asymptomatic or mild. In early April, we had hypothesized a low COVID-19 mortality in India, based on the concept of cross-immunity. The presence of cross-immunity is presumed to lead to a milder course of disease and allow the time necessary for the development of adaptive immunity by the body to eliminate the virus. Evidence supporting our hypothesis has started showing up. Multiple studies have shown the generation of different T cell subsets and B cells responding to epitopes of viral proteins, especially of the spike protein, as a part of adaptive immunity against SARS-CoV-2. Cross-reactive T-cells have been demonstrated in patients who have been previously exposed to endemic coronaviruses. The interplay of cross-immunity and herd immunity is apparent in the COVID-19 scenario in India from the presence of a large number of asymptomatic or mild cases, a low infection-fatality ratio and a generally flat curve of percentage positivity of cases with respect to total testing, both in periods of strict lock-down and step-wise unlocking. It seems that cross-immunity resulted in faster generation of herd immunity. Although the initial restrictive measures such as lockdown prevented the rapid spread of the outbreak, further extension of such measures and overly expensive ones such as enhanced testing in India will result in a huge burden on the health economics as well as the society. Hence, we propose a restructuring of the health services and approach to COVID-19. The restructured health services should move away from indiscriminate testing, isolation and quarantine, and instead, the emphasis should be on improving facilities for testing and management of only critical COVID cases and the replacement of complete lockdowns by the selective isolation and quarantine of susceptible persons such as the aged and those with co-morbidities. In the process of describing India-specific plans, we emphasize why the development of country-specific plans for tackling epidemics is important, instead of adopting a "one policy fits all" approach.
The Pathogenetic Dilemma of Post-COVID-19 Mucormycosis in India
(JKL International, 2022-02-01) Chakrabarti, Sankha Shubhra; Kaur, Upinder; Aggarwal, Sushil Kumar; Kanakan, Ahalya; Saini, Adesh; Agrawal, Bimal Kumar; Jin, Kunlin; Chakrabarti, Sasanka
There has been a surge of mucormycosis cases in India in the wake of the second wave of COVID-19 with more than 40000 cases reported. Mucormycosis in patients of COVID-19 in India is at variance to other countries where Aspergillus, Pneumocystis, and Candida have been reported to be the major secondary fungal pathogens. We discuss the probable causes of the mucormycosis epidemic in India. Whereas dysglycaemia and inappropriate steroid use have been widely suggested as tentative reasons, we explore other biological, iatrogenic, and environmental factors. The likelihood of a two-hit pathogenesis remains strong. We propose that COVID-19 itself provides the predisposition to invasive mucormycosis (first hit), through upregulation of GRP78 and downregulation of spleen tyrosine kinase involved in anti-fungal defense, as also through inhibition of CD8+ T-cell mediated immunity. The other iatrogenic and environmental factors may provide the second hit which may have resulted in the surge.
SDF-1/CXCR7 Chemokine Signaling is Induced in the Peri-Infarct Regions in Patients with Ischemic Stroke
(JKL International, 2018-04-01) Zhang, Yu; Zhang, Hongxia; Lin, Siyang; Chen, Xudong; Yao, Yu; Mao, XiaoOu; Shao, Bei; Zhuge, Qichuan; Jin, Kunlin
Stromal-derived factor-1 (SDF-1, also known as CXCL12) and its receptors CXCR4 and CXCR7 play important roles in brain repair after ischemic stroke, as SDF-1/ CXCR4/CXCR7 chemokine signaling is critical for recruiting stem cells to sites of ischemic injury. Upregulation of SDF-1/CXCR4/CXCR7 chemokine signaling in the ischemic regions has been well-documented in the animal models of ischemic stroke, but not in human ischemic brain. Here, we found that protein expression of SDF-1 and CXCR7, but not CXCR4, were significantly increased in the cortical peri-infarct regions (penumbra) after ischemic stroke in human, compared with adjacent normal tissues and control subjects. Double-label fluorescence immunohistochemistry shows that SDF-1 and CXCR4 proteins were expressed in neuronal cells and astrocytes in the normal brain tissue and peri-infarct regions. CXCR7 protein was also observed in neuronal cells and astrocytes in the normal cortical regions, but predominantly in astrocytes in the penumbra of ischemic brain. Our data suggest that ischemic stroke in human leads to an increase in the expression of SDF-1 and CXCR7, but not CXCR4, in the peri-infarct cerebral cortex. Our findings suggest that chemokine SFD-1 is expressed not only in animal models of stroke, but also in the human brain after an ischemic injury. In addition, unlike animals, CXCR7 may be the primary receptor of SDF-1 in human stroke brain.
Rapidly Progressive Dementia with Asymmetric Rigidity Following ChAdOx1 nCoV-19 Vaccination
(JKL International, 2022-06-01) Chakrabarti, Sankha Shubhra; Tiwari, Ashutosh; Jaiswal, Sumit; Kaur, Upinder; Kumar, Ishan; Mittal, Amit; Singh, Anup; Jin, Kunlin; Chakrabarti, Sasanka
Peripheral Circulating Exosomal miRNAs Potentially Contribute to the Regulation of Molecular Signaling Networks in Aging
(MDPI, 2020-03-11) Zhang, Hongxia; Jin, Kunlin
People are living longer than ever. Consequently, they have a greater chance for developing a functional impairment or aging-related disease, such as a neurodegenerative disease, later in life. Thus, it is important to identify and understand mechanisms underlying aging as well as the potential for rejuvenation. Therefore, we used next-generation sequencing to identify differentially expressed microRNAs (miRNAs) in serum exosomes isolated from young (three-month-old) and old (22-month-old) rats and then used bioinformatics to explore candidate genes and aging-related pathways. We identified 2844 mRNAs and 68 miRNAs that were differentially expressed with age. TargetScan revealed that 19 of these miRNAs are predicated to target the 766 mRNAs. Pathways analysis revealed signaling components targeted by these miRNAs: mTOR, AMPK, eNOS, IGF, PTEN, p53, integrins, and growth hormone. In addition, the most frequently predicted target genes regulated by these miRNAs were EIF4EBP1, insulin receptor, PDK1, PTEN, paxillin, and IGF-1 receptor. These signaling pathways and target genes may play critical roles in regulating aging and lifespan, thereby validating our analysis. Understanding the causes of aging and the underlying mechanisms may lead to interventions that could reverse certain aging processes and slow development of aging-related diseases.
Key Signaling Pathways in Aging and Potential Interventions for Healthy Aging
(MDPI, 2021-03-16) Yu, Mengdi; Zhang, Hongxia; Wang, Brian; Zhang, Yinuo; Zheng, Xiaoying; Shao, Bei; Zhuge, Qichuan; Jin, Kunlin
Aging is a fundamental biological process accompanied by a general decline in tissue function. Indeed, as the lifespan increases, age-related dysfunction, such as cognitive impairment or dementia, will become a growing public health issue. Aging is also a great risk factor for many age-related diseases. Nowadays, people want not only to live longer but also healthier. Therefore, there is a critical need in understanding the underlying cellular and molecular mechanisms regulating aging that will allow us to modify the aging process for healthy aging and alleviate age-related disease. Here, we reviewed the recent breakthroughs in the mechanistic understanding of biological aging, focusing on the adenosine monophosphate-activated kinase (AMPK), Sirtuin 1 (SIRT1) and mammalian target of rapamycin (mTOR) pathways, which are currently considered critical for aging. We also discussed how these proteins and pathways may potentially interact with each other to regulate aging. We further described how the knowledge of these pathways may lead to new interventions for antiaging and against age-related disease.
A Microcirculatory Theory of Aging
(JKL International, 2019-06-01) Jin, Kunlin
Aging is the progressive decline of physiological functions necessary for survival and reproduction. In gaining a better understanding of the inevitable aging process, the hope is to preserve, promote, or delay healthy aging through the treatment of common age-associated diseases. Although there are theories that try to explain the aging process, none of them seem to fully satisfy. Microcirculation describes blood flow through the capillaries in the circulatory system. The main functions of the microcirculation are the delivery of oxgen and nutrients and the removal of CO2, metabolic debris, and toxins. The microcirculatory impairment or dysfunction over time will result in the accumulation of toxic products and CO2 and loss of nutrition supplementation and O2 in corresponding tissue systems or internal organs, which eventually affect normal tissue and organ functions, leading to aging. Therefore, I propose a microcirculatory theory of aging: aging is the process of continuous impairment of microcirculation in the body.
Nur77 exacerbates PC12 cellular injury in vitro by aggravating mitochondrial impairment and endoplasmic reticulum stress
(Springer Nature, 2016-09-29) Gao, Huimin; Chen, Zhaoyu; Fu, Yongmei; Yang, Xiaoyan; Weng, Ruihui; Wang, Rui; Lu, Jianjun; Pan, Mengqiu; Jin, Kunlin; McElroy, Chris; Tang, Beisha; Xia, Ying; Wang, Qing
The nuclear orphan receptor, Nur77 plays important roles in neuroimflammation, apoptosis, and dopaminergic neurodegeneration. We conducted a further mechanistic investigation into the association of Nur77 with cell death. Cytosporone B (Csn-B), an agonist for Nur77, and Nur77 knockdown were adopted in the 6-hydroxydopamine (OHDA)-lesioned PC12 cells to investigate the mechanisms underlying Nur77-mediated injury. The 6-OHDA incubation caused Nur77 translocation from the nucleus to cytosol and Endoplasm reticulum (ER) and induced co-localization of Tom20/Nur77 and Protein Disulfide Isomerase (PDI)/Nur77. Nur77 activation further decreased cell viability, aggravated intracellular LDH release, intracellular Ca(2+), ROS levels, apoptosis, ER tress and, mitochondrial transmembrane potential (DeltaPsim) decline. In addition, Nur77 activation significantly enhanced the efficiency of autophagy as indicated by an up-regulation of Beclin-1/LC-3 and downregulation of p62, and aggravated mitochondrial dysfunctions and ER stress as shown by increased HSP60/Cytochrome C (Cyt C) and CHOP-ATF3 levels respectively. These changes could be partially reversed by Nur77 knockdown. Moreover, Nur77 activation upregulated PINK1 and downregulated Parkin levels. We conclude that Nur77 exacerbates PC12 cell death at least partially by aggravating the mitochondrial impairment and ER stress and enhancing autophagy. We propose that Nur77 is likely a critical target in the PD therapy.

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