Cognitive impairment in cerebral small vessel disease induced by hypertension

Hypertension is a primary risk factor for the progression of cognitive impairment caused by cerebral small vessel disease,the most common cerebrovascular disease.Howeve r,the causal relationship between hypertension and cerebral small vessel disease remains unclear.Hypertension has substantial negative impacts on brain health and is recognized as a risk factor for cerebrovascular disease.Chronic hypertension and lifestyle factors are associated with risks for stro ke and dementia,and cerebral small vessel disease can cause dementia and stroke.Hypertension is the main driver of cerebral small vessel disease,which changes the structure and function of cerebral vessels via various mechanisms and leads to lacunar infarction,leukoaraiosis,white matter lesions,and intracerebral hemorrhage,ultimately res ulting in cognitive decline and demonstrating that the brain is the to rget organ of hypertension.This review updates our understanding of the pathogenesis of hypertensioninduced cerebral small vessel disease and the res ulting changes in brain structure and function and declines in cognitive ability.We also discuss drugs to treat cerebral small vessel disease and cognitive impairment.

Outcomes of surgical correction of Peyronie’s disease with plaque excision and grafting: Comparison of testicular tunica vaginalis graft versus bovine pericardium graft

Objective:Peyronie’s disease(PD)is an abnormal wound healing in the penile tunica albuginea.After fibrotic plaque excision,different graft materials have been used to repair the defects,but the optimal graft remains unknown.This study aimed to compare the functional outcomes of testicular tunica vaginalis grafts and bovine pericardium grafts in patients with severe PD.Methods:A retrospective comparative study was conducted on 33 PD patients undergoing partial plaque excision and grafting from September 2015 to May 2021.The patients were divided into two groups depending on the type of graft used.For 15 patients in Group B,testicular tunica vaginalis grafts were used to repair the defect,while for 18 patients in Group A,bovine pericardium grafts were used.Data of the patient’s age,comorbidities,sexual function,penile curvature,postoperative complications,need for further treatment,change in penile length,and satisfaction were gathered and compared between the groups.Sexual function was evaluated using the 5-item version of the International Index of Erectile Function(IIEF-5),and a functional less than 20-degree penile curvature after surgery was considered a successful intervention.Results:There was no difference in age,comorbidities,degree of curvature,perioperative IIEF-5,operative time,plaque size,or complication rates.After surgery,a statistically significant improvement in curvature degree(p<0.05)and satisfactory penile appearance(p<0.05)were seen in both groups without any superiority between the two groups(p=0.423 and p=0.840,respectively).With a 30-month follow-up,the IIEF-5 was consistent in both groups,with no statistical significance between the groups(p=0.492).The main change in penile length during the operation was increased and still positive in the last follow-up in both groups without statistical significance(p=0.255 and p=0.101,respectively).Conclusion:Partial plaque excision and corporoplasty with both testicular tunica vaginalis or bovine pericardium grafts are equally effective in treating males with clinically significant PD.

Storage time affects the level and diagnostic efficacy of plasma biomarkers for neurodegenerative diseases

Several promising plasma biomarker proteins,such as amyloid-β(Aβ),tau,neurofilament light chain,and glial fibrillary acidic protein,are widely used for the diagnosis of neurodegenerative diseases.However,little is known about the long-term stability of these biomarker proteins in plasma samples stored at-80°C.We aimed to explore how storage time would affect the diagnostic accuracy of these biomarkers using a large cohort.Plasma samples from 229 cognitively unimpaired individuals,encompassing healthy controls and those experiencing subjective cognitive decline,as well as 99 patients with cognitive impairment,comprising those with mild cognitive impairment and dementia,were acquired from the Sino Longitudinal Study on Cognitive Decline project.These samples were stored at-80°C for up to 6 years before being used in this study.Our results showed that plasma levels of Aβ42,Aβ40,neurofilament light chain,and glial fibrillary acidic protein were not significantly correlated with sample storage time.However,the level of total tau showed a negative correlation with sample storage time.Notably,in individuals without cognitive impairment,plasma levels of total protein and tau phosphorylated protein threonine 181(p-tau181)also showed a negative correlation with sample storage time.This was not observed in individuals with cognitive impairment.Consequently,we speculate that the diagnostic accuracy of plasma p-tau181 and the p-tau181 to total tau ratio may be influenced by sample storage time.Therefore,caution is advised when using these plasma biomarkers for the identification of neurodegenerative diseases,such as Alzheimer's disease.Furthermore,in cohort studies,it is important to consider the impact of storage time on the overall results.

Unraveling brain aging through the lens of oral microbiota

The oral cavity is a complex physiological community encompassing a wide range of microorganisms.Dysbiosis of oral microbiota can lead to various oral infectious diseases,such as periodontitis and tooth decay,and even affect systemic health,including brain aging and neurodegenerative diseases.Recent studies have highlighted how oral microbes might be involved in brain aging and neurodegeneration,indicating potential avenues for intervention strategies.In this review,we summarize clinical evidence demonstrating a link between oral microbes/oral infectious diseases and brain aging/neurodegenerative diseases,and dissect potential mechanisms by which oral microbes contribute to brain aging and neurodegeneration.We also highlight advances in therapeutic development grounded in the realm of oral microbes,with the goal of advancing brain health and promoting healthy aging.

The burden and long-term trends of breast cancer by different menopausal status in China

Background: The burden of breast cancer in women of different menopausal status has not been assessed in China previously. We aim to evaluate and project the burden of breast cancer in different menopausal status in China. Methods: The incidence and mortality of breast cancer were estimated using the data of 554 cancer registries in 2017 and the trends of incidence and mortality of 112 cancer registries from 2010 to 2017. Data from 22 continued cancer registries from 2000 to 2017 were applied for long-term trend projection to 2030 using the Bayesian age- period-cohort model. Menopausal status was stratified by age, with premenopause defined as chronological age < 45 years, perimenopause defined as 45-54 years, and postmenopause defined as ≥ 55 years. Results: Approximately 352,300 incident cases and 74,200 deaths of breast cancer occurred in China in 2020, contributing to 2.6 million disability-adjusted life years (DALYs). Perimenopausal women had the highest inci- dence, prevalence, and DALYs rates, with the rates being 100.3 per 100,000, 819.2 per 100,000 and 723.1 per 100,000 persons. While postmenopausal women had the highest mortality rates (25.5 per 100,000 persons). From 2000 to 2017, the largest increase in incidence and mortality for breast cancer was observed in postmenopausal women with an average annual percentage change (AAPC) of 5.6% and 2.94%. The number of breast cancer cases and deaths will increase to 452,000 and 98,800 in 2030, resulting in 3.2 million DALYs. Conclusions: The burden of breast cancer is rapidly increasing in China and varies among different menopausal status. Specific prevention and control strategies for women in different menopausal status will be more helpful in reducing the rapidly growing trends of breast cancer.

Epidemiological and clinical features,treatment status,and economic burden of traumatic spinal cord injury in China:a hospital-based retrospective study

Traumatic spinal cord injury is potentially catastrophic and can lead to permanent disability or even death.China has the largest population of patients with traumatic spinal cord injury.Previous studies of traumatic spinal cord injury in China have mostly been regional in scope;national-level studies have been rare.To the best of our knowledge,no national-level study of treatment status and economic burden has been performed.This retrospective study aimed to examine the epidemiological and clinical features,treatment status,and economic burden of traumatic spinal cord injury in China at the national level.We included 13,465 traumatic spinal cord injury patients who were injured between January 2013 and December 2018 and treated in 30 hospitals in 11 provinces/municipalities representing all geographical divisions of China.Patient epidemiological and clinical features,treatment status,and total and daily costs were recorded.Trends in the percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department and cost of care were assessed by annual percentage change using the Joinpoint Regression Program.The percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department did not significantly change overall(annual percentage change,-0.5%and 2.1%,respectively).A total of 10,053(74.7%)patients underwent surgery.Only 2.8%of patients who underwent surgery did so within 24 hours of injury.A total of 2005(14.9%)patients were treated with high-dose(≥500 mg)methylprednisolone sodium succinate/methylprednisolone(MPSS/MP);615(4.6%)received it within 8 hours.The total cost for acute traumatic spinal cord injury decreased over the study period(-4.7%),while daily cost did not significantly change(1.0%increase).Our findings indicate that public health initiatives should aim at improving hospitals’ability to complete early surgery within 24 hours,which is associated with improved sensorimotor recovery,increasing the awareness rate of clinical guidelines related to high-dose MPSS/MP to reduce the use of the treatment with insufficient evidence.

Ethical concerns in aging research:perspectives of global frontline researchers

This study investigated the ethical landscape of aging research amid the increasing global focus on extending the human lifespan and health span.Our global survey of 180 researchers across 38 jurisdictions revealed divergent perceptions of aging,a consensus regarding the feasibility of delaying aging,and multiple perspectives regarding lifespan extension.The present findings underscore a paradigm shift toward inclusive and ethically sound research,emphasizing the need for an approach that strikes a balance between basic and clinical research.In addition,this study highlighted key ethical concerns in aging research,including the effects of misleading advertising,potential inequality in access to aging interventions,and risks pertaining to the extrapolation of research findings from lower-model organisms to humans.The insights presented in this paper call for an integrated approach for overcoming the complex ethical and societal challenges in aging research to ensure responsible and equitable advancements in this burgeoning field.

Publication characteristics and visualized analysis of research about liver sinusoidal endothelial cells

Background and aims:Through visual analysis of related literature,the main research direction and hot spots of liver sinusoidal endothelial cells(LSECs)in recent 24 years were explored.Methods:This study used bibliometric analysis with CiteSpace,VOSviewer,Biblioshiny and online analytic tool bibliometric.com to provide a quantitative analysis,hot spot mining,and commentary of articles published in the field of LSECs research.The relevant literature in the Web of Science Core Collection(WOSCC)was searched from 2000 to 2023.The publications with topics or titles or keywords containing LSECs were included into this study.The countries,organizations,journals,authors,and keywords of the publications were summarized and analyzed.Results:This study included 3,747 publications from 14,132 authors belonging to 389 institutions in 61 countries/regions and published in 150 journals,with 156,309 citations.The United States contributed most(1,150)to the publications.The most productive institution was the University of Sydney.Hepatology accounts for the most output(293,7.8%),European authors had a widespread cooperation.The most productive author was Adam DH with 68 papers.Immunological function of LSECs is research hot spot.Conclusion:This study highlights key trends based on a large dataset of the most influential publications about LSECs research over a 24-year period.It provides important clues and ideas for researchers focusing in this area and facilitates future liver disease mechanism,understanding,and treatment.

5-hydroxymethyl-2-furfural prolongs survival and inhibits oxidative stress in a mouse model of forebrain ischemia

In the present study, we hypothesized that 5-hydroxymethyl-2-furfural could attenuate ischemic brain damage by reducing oxidative injury. Thus, mice were subjected to bilateral common carotid artery occlusion to establish a model of permanent forebrain ischemia. The mice were intraperitoneally injected with 5-hydroxymethyl-2-furfura130 minutes before ischemia or 5 minutes after ischemia. The survival time of mice injected with 5-hydroxymethyl-2-furfural was longer compared with untreated mice. The mice subjected to ischemia for 30 minutes and reperfusion for 5 minutes were intraperitoneally injected with 5-hydroxymethyl-2-furfural 5 minutes prior to reperfusion, which increased superoxide dismutase content and reduced malondialdehyde content, similar to the effects of Edaravone, a hydroxyl radical scavenger used for the treatment of stroke. These findings indicate that intraperitoneal injection of 5-hydroxymethyl-2-furfural can prolong the survival of mice with permanent forebrain ischemia. This outcome may be mediated by its antioxidative effects.

Design feasibility of gamma camera without collimator based on specific arrangement of the detectors

In gamma camera and single-photon emission computerized tomography, the collimator removes most photons. Here, a gamma camera without collimator utilizes a specific arrangement of detectors. Instead of bending beams(like a lens) or directing beams(by parallel hole collimator), changes are created in detectors' field of view(FOV), so that each detector's FOV looks different from others. Simulation proved this theory, with 98 detectors(2 cm 9 1.41 cm) arranged in a zigzag manner for Monte Carlo simulation. A radioactive source with energy of140 ke V was situated on the detectors' faces. Sixty projections, each 3(0 –179) apart, were simulated by Monte Carlo N-Particle(MCNP) 4C code, rotating detectors around a radioactive point. The band containing the radioactive source is clearly visible in each projection.Counts obtained after simulation in different projections were reconstructed, and point source location emerged correctly. Simulation of gamma camera with zigzag arrangement of detectors and MCNP-4C code demonstrated that one could string the space and determine radioactive source by image reconstruction without using collimators, solely through these special detectors' distribution.

Effects of tetrahydroxystilbene glucoside in Parkinson′s disease mice model induced by MPTP

OBJECTIVE To observe effects of tetrahydroxystilbene glucoside(TSG)on behavior,content of dopamine and its metabolites in striatum of Parkinson′s disease(PD)model mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)injection.METHODS Mice were randomly divided into control group,model group,TSG low dose(60mg·kg-1)and high dose(120mg·kg-1)groups.The behavior changes of mice were observed by pole test,rotarod test and spontaneous movement test.The tyrosine hydroxylase(TH)positive cells were detected by immunohistochemical method.The content of dopamine(DA)and its metabolites in striatum were determined by HPLC-ECD.RESULTS MPTP model mice showed behavior deficit.The number of TH positive neurons in substantia nigra,the content of dopamine and its metabolites in striatum in model mice decreased significantly compared with control group.TSG ameliorated mice behavior,increased the number of TH positive neurons in the substantia nigra about 18.8%,and elevated the content of dopamine in striatum about 34.5% compared with model mice.CONCLUSION TSG protected dopaminergic neurons against MPTP-induced damage,and may become a candidate drug for prevention and treatment of Parkinson′s disease.

Effect of cornel iridoid glycoside on experimental autoimmune encephalomyelitis attenuation through JAK/STAT signaling pathway,at least partially

OBJECTIVE In order to investigate whether cornel iridoid glycoside(CIG),the main component extracted from Cornus officinalis,can treat demyelinating diseases of the central nervous system(CNS)such as multiple sclerosis(MS).METHODS CIG(30,60 and 120mg·kg-1)or vehicle was intragastrically administered once daily to rats,starting immediately after purified myelin basic protein(MBP)68-86 peptides immunization until day 20 post immunization(p.i.).Histopathological staining,enzyme-linked immunosorbent assay,biochemical methods and Western blotting approaches were used to evaluate the disease incidence and severity,neuroinflammatory and neurotrophic response in the CNS.RESULTS Neurological deficit and proportion of incidence seen in EAE rats were significantly reduced by CIG treatment in a dose-dependent manner.Histopathological staining showed that CIG treatment alleviated demyelination and inflammatory infiltration,increased the number of oligodendrocytes,enhanced the expression of brain-derived neurotrophic factor(BDNF).Production of proinflammatory molecules such as interleukin-1β(IL-1β),tumour necrosis factor-αand interferon-γwere also inhibited by CIG administration.CIG could ameliorate phosphorylation of STAT1,STAT3 and JAK1 as well as IL-6/IL-6 Rexpression,which involved in immune response and inflammation.CONCLUSION Our results demonstrated that CIG may ameliorate EAE rats through down-regulation of JAK/STAT signaling pathway.This study gave new insight into the novel regulatory mechanism of CIG and highlight novel therapeutic targets and a potential therapeutic agent for the treatment of MS.

A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes

Aging increases the risk ofliver diseases and systemic susceptibility to aging-related diseases.However,cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely characterized.Here,we constructed the first single-nucleus transcriptomic landscape of primate liver aging,in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell-cell interactions between hepatocytes and niche cells.Upon in-depth dissection of this rich dataset,we identifed impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during aging.In particular,hyperactivated sterol regulatory element-binding protein(SREBP)signaling was a hallmark of the aged liver,and consequently,forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes,manifesting as impaired detoxification and accelerated cellular senescence.This study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.

Single-nucleus transcriptomics uncovers a geroprotective role of YAP in primate gingival aging

Aging has a profound impact on the gingiva and significantly increases its susceptibility to periodontitis,a worldwide prevalent inflammatory disease.However,a systematic characterization and comprehensive understanding of the regulatory mechanism underlying gingival aging is still lacking.Here,we systematically dissected the phenotypic characteristics of gingiva during aging in primates and constructed the first single-nucleus transcriptomic landscape of gingival aging,by which a panel of cell type-specific signatures were elucidated.Epithelial cells were identified as the most affected cell types by aging in the gingiva.Further analyses pinpointed the crucial role of YAP in epithelial self-renew and homeostasis,which declined during aging in epithelial cells,especially in basal cells.The decline of YAP activity during aging was confrmed in the human gingival tissues,and downregulation of YAP in human primary gingival keratinocytes recapitulated the major phenotypic defects observed in the aged primate gingiva while overexpression of YAP showed rejuvenation effects.Our work provides an in-depth understanding of gingival aging and serves as a rich resource for developing novel strategies to combat aging-associated gingival diseases,with the ultimate goal of advancing periodontal health and promoting healthy aging.

Degeneration Directory:a multi-omics web resource for degenerative diseases

Background of database.Organ degeneration refers to the gradual decline in organ function and structure deterioration that occurs during aging,which represents the greatest risk factor for various degenerative diseases,including cardiovascular diseases,neurodegenerative diseases,and osteoarthritis,etc.(Aging Biomarker et al.,2023;Becker et al.,2018;Cai et al.,2022).

Identification of FOXO1 as a geroprotector in human synovium through single-nucleus transcriptomic profiling

The synovium,a thin layer of tissue that is adjacent to the joints and secretes synovial fluid,undergoes changes in aging that contribute to intense shoulder pain and other joint diseases.However,the mechanism underlying human synovial aging remains poorly characterized.Here,we generated a comprehensive transcriptomic profile of synovial cells present in the subacromial synovium from young and aged individuals.By delineating aging-related transcriptomic changes across different cell types and their associated regulatory networks,we identified two subsets of mesenchymal stromal cells(MSCs)in human synovium,which are lining and sublining MSCs,and found that angiogenesis and fibrosis-associated genes were upregulated whereas genes associated with cell adhesion and cartilage development were downregulated in aged MSCs.Moreover,the specific cell-cell communications in aged synovium mirrors that of aging-related inflammation and tissue remodeling,including vascular hyperplasia and tissue fibrosis.In particular,we identified forkhead box O1(FOXO1)as one of the major regulons for aging differentially expressed genes(DEGs)in synovial MSCs,and validated its downregulation in both lining and sublining MSC populations of the aged synovium.In human FOXO1-depleted MSCs derived from human embryonic stem cells,we recapitulated the senescent phenotype observed in the subacromial synovium of aged donors.These data indicate an important role of FOXO1 in the regulation of human synovial aging.Overall,our study improves our understanding of synovial aging during joint degeneration,thereby informing the development of novel intervention strategies aimed at rejuvenating the aged joint.

Human ESC-derived vascular cells promote vascular regeneration in a HIF-1α dependent manner

Hypoxia-inducible factor(HIF-1α),a core transcription factor responding to changes in cellular oxygen levels,is closely associated with a wide range of physiological and pathological conditions.However,its differential impacts on vascular cell types and molecular programs modulating human vascular homeostasis and regeneration remain largely elusive.Here,we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells and directed differentiation to generate HIF-ia-deficient human vascular cells including vascular endothelial cells,vascular smooth muscle cells,and mesenchymal stem cells(MsCs),as a platform for discovering cell type-specific hypox-ia-induced response mechanisms.Through comparative molecular profiling across cell types under normoxic and hypoxic conditions,we provide insight into the indispensable role of HIF-1αin the promotion of ischemic vascular regeneration.We found human MSCs to be the vascular cell type most susceptible to HIF-1a deficiency,and that transcriptional inactivation of ANKZF1,an effector of HIF-1a,impaired pro-angiogenic processes.Altogether,our findings deepen the understanding of HIF-ia in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.

Aging hallmarks of the primate ovary revealed by spatiotemporal transcriptomics

The ovary is indispensable for female reproduction,and its age-dependent functional decline is the primary cause of infertility.However,the molecular basis of ovarian aging in higher vertebrates remains poorly understood.Herein,we apply spatiotemporal transcriptomics to benchmark architecture organization as well as cellular and molecular determinants in young primate ovaries and compare these to aged primate ovaries.From a global view,somatic cells within the non-follicle region undergo more pronounced transcriptional fluctuation relative to those in the follicle region,likely constituting a hostile microenvironment that facilitates ovarian aging.Further,we uncovered that inflammation,the senescent-associated secretory phenotype,senescence,and fibrosis are the likely primary contributors to ovarian aging(PCOA).Of note,we identified spatial co-localization between a PCOA-featured spot and an unappreciated MT2(Metallothionein 2)highly expressing spot(MT2^(high))characterized by high levels of inflammation,potentially serving as an aging hotspot in the primate ovary.Moreover,with advanced age,a subpopulation of MT2^(high)accumulates,likely disseminating and amplifying the senescent signal outward.Our study establishes the first primate spatiotemporal transcriptomic atlas,advancing our understanding of mechanistic determinants underpinning primate ovarian aging and unraveling potential biomarkers and therapeutic targets for aging and age-associated human ovarian disorders.

CRISPR-based screening identifies XPO7 as a positive regulatorof senescence

Dear Editor,Cells enter senescence,or irreversible growth arrest,when exposed to stressors such as DNA damage,epigenetic alterations and chronic inflammation(Zhao and Chen,2022).In aging and aging-related diseases,senescent cells are known to accumulate across tissues and organs(Sun et al.,2022;Lopez-Otin et al.,2023).

A single-nucleus transcriptomic atlas of primate testicular aging reveals exhaustion of the spermatogonial stem cell reservoir and loss of Sertoli cell homeostasis

The testis is pivotal for male reproduction,and its progressive functional decline in aging is associated with infertility.However,the regulatory mechanism underlying primate testicular aging remains largely elusive.Here,we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing a single-nucleus transcriptomic atlas.Gene-expression patterns along the spermatogenesis trajectory revealed molecular programs associated with attrition of spermatogonial stem cell reservoir,disturbed meiosis and impaired spermiogenesis along the sequential continuum.Remarkably,Sertoli cell was identified as the cell type most susceptible to aging,given its deeply perturbed age-associated transcriptional profiles.Concomitantly,downregulation of the transcription factor Wilms'Tumor 1(WTi),essential for Sertoli cell homeostasis,was associated with accelerated cellular senescence,disrupted tight junctions,and a compromised cell identity signature,which altogether may help create a hostile microenvironment for spermatogenesis.Collectively,our study depicts in-depth transcriptomic traits of non-human primate(NHP)testicular aging at single-cell resolution,providing potential diagnostic biomarkers and targets for therapeutic interventions against testicular aging and age-related male reproductive diseases.