Insulin-like growth factor 2 (IGF2) is a critical endocrine mediator implicated in male reproductive physiology. To investigate the correlation between IGF2 protein levels and various aspects of male infertility, specifically focusing on sperm quality, inflammation, and DNA damage, a cohort of 320 male participants was recruited from the Women's Hospital, Zhejiang University School of Medicine (Hangzhou, China) between 1 st January 2024 and 1 st March 2024. The relationship between IGF2 protein concentrations and sperm parameters was assessed, and Spearman correlation and linear regression analysis were employed to evaluate the independent associations between IGF2 protein levels and risk factors for infertility. Enzyme-linked immunosorbent assay (ELISA) was used to measure IGF2 protein levels in seminal plasma, alongside markers of inflammation (tumor necrosis factor-alpha [TNF-α] and interleukin-1β [IL-1β]). The relationship between seminal plasma IGF2 protein levels and DNA damage marker phosphorylated histone H2AX (γ-H2AX) was also explored. Our findings reveal that IGF2 protein expression decreased notably in patients with asthenospermia and teratospermia. Correlation analysis revealed nuanced associations between IGF2 protein levels and specific sperm parameters, and low IGF2 protein concentrations correlated with increased inflammation and DNA damage in sperm. The observed correlations between IGF2 protein levels and specific sperm parameters, along with its connection to inflammation and DNA damage, underscore the importance of IGF2 in the broader context of male reproductive health. These findings lay the groundwork for future research and potential therapeutic interventions targeting IGF2-related pathways to enhance male fertility.
Humans ; Male ; Insulin-Like Growth Factor II/metabolism* ; Infertility, Male/genetics* ; DNA Damage ; Adult ; Inflammation/metabolism* ; Spermatozoa/metabolism* ; Semen Analysis ; Semen/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Histones/metabolism* ; Interleukin-1beta/metabolism*

BACKGROUND: Early control of low-density lipoprotein cholesterol (LDL-C) is crucial for reducing the progress of cardiovascular disease. However, its additional role to the risk of primary osteoporosis in men with coronary heart disease was inconclusive. Our study aims to determine the association of LDL-C and its trajectories for osteoporosis risk in the middle-aged and aged men of China. METHODS: The retrospective cohort study of 1546 men aged 69.74 ± 11.30 years conducted in Beijing, China from 2015 to 2022. And the incidence of primary osteoporosis was annually recorded. LDL-C trajectories were further identified by latent class growth model using repeated measurements of LDL-C. The association of baseline LDL-C for osteoporosis was estimated using hazard ratio (HR) with 95% CI in Cox proportional hazard model, while mean level and trajectories of LDL-C for osteoporosis were evaluated using odds ratio (OR) with 95% CI in logistic regression model. RESULTS: During the median 6.2-year follow-up period, 70 men developed primary osteoporosis. The higher level of baseline LDL-C (HR = 1.539, 95% CI: 1.012-2.342) and mean LDL-C (OR = 2.190, 95% CI: 1.443-3.324) were associated with higher risk of osteoporosis in men with coronary heart disease after adjusted for covariates. Compared with those in the LDL-C trajectory of low-stable decrease, participants with medium-fluctuant trajectory, whose longitudinal LDL-C started with a medium LDL-C level and appeared an increase and then decrease, were negatively associated with osteoporosis risk (OR = 2.451, 95% CI: 1.152-5.216). And participants with initially high LDL-C level and then a rapid decrease demonstrated a tendency towards reduced risk (OR = 0.718, 95% CI: 0.212-2.437). CONCLUSIONS Elevated LDL-C level and its long-term fluctuation may increase the risk of primary osteoporosis in men. Early controlling a stable level of LDL-C is also essential for bone health.

Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over 9 years. The most common adverse events (AEs) within 2 months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.
Humans ; Leukodystrophy, Metachromatic/genetics* ; Pilot Projects ; Genetic Therapy/methods* ; Hematopoietic Stem Cell Transplantation ; Male ; Follow-Up Studies ; Female ; Lentivirus/genetics* ; Child ; Child, Preschool ; Hematopoietic Stem Cells/metabolism* ; Cerebroside-Sulfatase/metabolism* ; Adolescent

This study investigates the pharmacokinetics and metabolic characteristics of three marine-derived piericidins as potential drug leads for kidney disease: piericidin A (PA) and its two glycosides (GPAs), glucopiericidin A (GPA) and 13-hydroxyglucopiericidin A (13-OH-GPA). The research aims to facilitate lead selection and optimization for developing a viable preclinical candidate. Rapid absorption of PA and GPAs in mice was observed, characterized by short half-lives and low bioavailability. Glycosides and hydroxyl groups significantly enhanced the absorption rate (13-OH-GPA > GPA > PA). PA and GPAs exhibited metabolic instability in liver microsomes due to Cytochrome P450 enzymes (CYPs) and uridine diphosphoglucuronosyl transferases (UGTs). Glucuronidation emerged as the primary metabolic pathway, with UGT1A7, UGT1A8, UGT1A9, and UGT1A10 demonstrating high elimination rates (30%-70%) for PA and GPAs. This rapid glucuronidation may contribute to the low bioavailability of GPAs. Despite its low bioavailability (2.69%), 13-OH-GPA showed higher kidney distribution (19.8%) compared to PA (10.0%) and GPA (7.3%), suggesting enhanced biological efficacy in kidney diseases. Modifying the C-13 hydroxyl group appears to be a promising approach to improve bioavailability. In conclusion, this study provides valuable metabolic insights for the development and optimization of marine-derived piericidins as potential drug leads for kidney disease.
Animals ; Male ; Mice ; Aquatic Organisms/chemistry* ; Biological Availability ; Cytochrome P-450 Enzyme System/metabolism* ; Glucuronosyltransferase/metabolism* ; Microsomes, Liver/metabolism* ; Molecular Structure ; Biological Products/pharmacokinetics* ; Pyridines/pharmacokinetics*

OBJECTIVE: To identify prognostic genes associated with lysosome-dependent cell death (LDCD) in patients with gastric cancer (GC). METHODS: Differentially expressed genes (DEGs) were identified using The Cancer Genome Atlas - Stomach Adenocarcinoma. Weighted gene co-expression network analysis was performed to identify the key module genes associated with LDCD score. Candidate genes were identified by DEGs and key module genes. Univariate Cox regression analysis, and least absolute shrinkage and selection operator regression and multivariate Cox regression analyses were performed for the selection of prognostic genes, and risk module was established. Subsequently, key cells were identified in the single-cell dataset (GSE183904), and prognostic gene expression was analyzed. Cell proliferation and migration were assessed using the Cell Counting Kit-8 assay and the wound healing assay. RESULTS: A total of 4,465 DEGs, 95 candidate genes, and 4 prognostic genes, including C19orf59, BATF2, TNFAIP2, and TNFSF18, were identified in the analysis. Receiver operating characteristic curves indicated the excellent predictive power of the risk model. Three key cell types (B cells, chief cells, and endothelial/pericyte cells) were identified in the GSE183904 dataset. C19orf59 and TNFAIP2 exhibited predominant expression in macrophage species, whereas TNFAIP2 evolved over time in endothelial/pericyte cells and chief cells. Functional experiments confirmed that interfering with C19orf59 inhibited proliferation and migration in GC cells. CONCLUSION C19orf59, BATF2, TNFAIP2, and TNFSF18 are prognostic genes associated with LDCD in GC. Furthermore, the risk model established in this study showed robust predictive power.
Stomach Neoplasms/pathology* ; Humans ; Prognosis ; Lysosomes/physiology* ; RNA-Seq ; Cell Death ; Single-Cell Analysis ; Gene Expression Regulation, Neoplastic ; Cell Proliferation ; Single-Cell Gene Expression Analysis

2-(4-Methylthiazol-5-yl) ethyl nitrate hydrochloride (W1302) is a nitro containing derivative of clomethiazole, which is a novel neuroprotective agent with both carbon monoxide (NO) donor and weak γ-aminobutyric acid type A (GABA_A) receptor allosteric regulatory excitatory effect. The current study used a rat model of transient middle cerebral arteryocclusion (tMCAO) brain injury to evaluate the therapeutic effect of W1302 on ischemic stroke and explore its potential mechanisms of action. This experiment has been reviewed and approved by the Laboratory Animal Management and Use Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences (ethical review forms No. 620, 632, 5013). The results showed that gavage administration of 1, 3, and 10 mg·kg^-1 of W1302 can significantly reduce the volume of cerebral infarction in rats with ischemia for 2 h and reperfusion for 24 h, and the therapeutic effect was better than that of 200 mg·kg^-1 of DL-3n-butylphthalide. W1302 significantly increased NO levels in blood and brain tissue. It increased cerebral blood flow and brain adenosine triphosphate (ATP) content after reperfusion, as well as, inhibited the expressions of inflammatory factors tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in brain tissue. The time window of W1302 was between 120-180 min after ischemia. These research results demonstrated that W1302 could increase NO release, dilate blood vessels, and increase cerebral blood flow, improve energy supply to brain tissue and increase ATP levels, and inhibit neuro-inflammation, which playing the protective roles in tMCAO stroke model rats. This provides theoretical support for the clinical application of W1302 in the treatment of ischemic stroke.

Drug therapy is a common method to cure diseases and relieve symptoms.The value of patient-reported outcome(PRO)in evaluating the effect of drug therapy has been increasingly paid attention.The PRO scale is a standardized questionnaire,which can scientifically evaluate the experiences and subjective effects of drug use from a patient-centered perspective,and help patients and clinicians make more reasonable medication decisions.By reviewing and sorting out relevant global literature,this paper found that the content of the PRO scales relevant to drug therapy focused on five fields:"medication satisfaction""medication adherence""drug treatment burden""medication-related quality of life"and"adverse drug reactions".This paper described the basic information,measurement characteristics and application of common scales in recent years respectively,and summarized and analyzed the problems and enlightenment of scale development,aiming to provide theoretical reference for the selection,application and development of PRO scales.

Objectives:To establish a comprehensive system of Cardiovascular Academic Performance Evaluation(CAPE)and rank global TOP100 medical institutions in the fields of cardiovascular diseases(CVD). Methods:CVD-related terms were extracted from Medical Subject Headings(MeSH),Embase thesaurus(EMtrees)and International Classification of Diseases(ICD)by CVD-related professionals,as well as by librarians and information professionals.Terminology databases(named as Fuwai Subject Headings)were established,and nine sub-disciplines were proposed,including ischemic heart diseases,hypertension,vascular diseases,arrhythmia,pulmonary vascular diseases,heart failure,congenital heart diseases,cardiomyopathy,and valvular heart diseases.The mapping patterns of sub-discipline,cardiovascular terminology and entry terms were pre-defined.The CVD-related research literature published from January 1,2016 to December 31,2022 were retrieved from Web of Science,PubMed and Scopus.Based on this,metadata were fused and duplicates were excluded.Fuwai Subject Headings were searched and matched into four respects for each literature,including subject words,titles,keywords,and abstracts,which was used to generate an information table of"Position—CVD terminology—Frequency",and to calculate CVD correlation scores and sub-discipline scores.We standardized the names of medical institutions and scholars,and make a ranking system for CAPE based on original articles with strong cardiovascular correlation(correlation score≥4).When evaluating the science and technological performance for Chinese hospitals in cardiovascular diseases,National Natural Science Foundation Projects,authorized invention patents,prize achievements,research platforms,and registered data of drug clinical trials in Center for Drug Evaluation(CDE)were considered besides research papers. Results:During 2016 and 2022,1 545 103 CVD research literatures were found worldwide.After excluding meeting abstracts,books,biographies,news,videos,audio texts,retracted publications,and corrections,1 178 019 CVD research literatures were further evaluated.518 058 literatures were indexed as"strongly correlated to CVD"using Fuwai Subject Headings.Besides papers,other data sources were also collected,including 11 143 CVD-related Natural Science Foundation Projects,19 382 CVD-related effective authorized invention patents,103 CVD-related national prize achievements,24 CVD-related national research platforms,and 2 084 CDE registered data of CVD-related drug clinical trials.Research teams from nine sub-disciplines reviewed and validated research literature in respective fields,and classification rules of corresponding sub-disciplines were created and improved based on their opinions.Finally,eleven individual indexes were chosen to construct CAPE system for ranking global TOP100 medical institutions in overall CVD field and TOP30 in nine sub-disciplines.From 2016 to 2022,the number of cardiovascular disease research papers published by Chinese institutes has increased by 123.5%,with a total of approximately 76.8 thousands papers published(about 30 papers per day on average),ranked the second under the United States(approximately 114.1 thousands papers).However,the proportion of papers published by the Chinese Journal Citation Reports(JCR)and the Chinese Academy of Sciences only ranked eighth in the world.In the comprehensive academic performance of original cardiovascular research papers in global hospitals from 2020 to 2022,only two Chinese medical institutions ranked in the TOP20 as evaluated by CAPE system. Conclusions:Based on multi-source data from 2016 to 2022,CAPE initiated to establish a cardiovascular academic performance evaluation system.

Objective:To describe and analyze suicide risk of patients with schizophrenia,major depressive disorder,and bipolar disorder.Methods:A total of 2 016 patients with schizophrenia,903 patients with major de-pressive disorder,and 381 patients with bipolar disorder from inpatients,clinics,or communities who met the diag-nostic criteria of the Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition were recruited.All patients were interviewed by psychiatrists using the Mini International Neuropsychiatric Interview to diagnose mental disor-ders and assess suicide risk,as well as Clinical-Rated Dimensions of Psychosis Symptom Severity(CRDPSS)to as-sess symptoms.Differences and risk factors of suicide risk among three types of mental disorders were explored u-sing multivariate logistic regression analysis.Results:In the past one month,37 patients with schizophrenia(1.8％),516 patients with major depressive disorder(57.1％),and 102 patients with bipolar disorder(26.8％)had suicide risk.Compared with patients with schizophrenia,suicide risk in patients with major depressive disorder(OR=36.50)and bipolar disorder(OR=20.10)increased.Female(OR=1.87),smoking(OR=1.76),family history of suicide(OR=5.09),higher score of CRDPSS hallucination(OR=1.80),and higher score of CRDPSS depression(OR=1.54)were risk factors of suicide risk of patients.Conclusions:Suicide risk of patients with ma-jor depressive disorder and bipolar disorder is higher than that of patients with schizophrenia.In clinical practice,it is important to regularly assess suicide risk of patients.Patients who experience symptoms of hallucination and de-pression should be paid more attention to.

Objective:To describe demographic,clinical and physiological characteristics,treatment between first-episode major depressive disorder(MDD)and relapse MDD,and to explore characteristics of relapse MDD.Methods:Totally 858 patients who met the diagnostic criteria for depression of the Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition(DSM-5),were included by using the Mini International Neuropsychiatric Interview(MINI),Clinician-Rated Dimensions of Psychosis Symptom Severity,and Hamilton Depression Scale etc.Among them,529(58.6％)were first-episode depression and 329(36.0％)were relapsed.The differences of demographic characteristics,clinical and physiological characteristics,treatment were compared byx2test and Kruskal-Wallis rank sum test.Multivariate logistic regression was used to explore the characteristics of MDD recur-rence.Results:Compared to first-episode MDD,relapse MDD had more comorbidity(OR=2.11,95％CI:1.00-4.44),more days out of role(OR=1.26,95％CI:1.01-1.56),more history of using psychiatric drug more than one month(OR=1.41,95％CI:1.02-1.97)and electroconvulsive therapy(OR=3.23,95％CI:1.42-7.36),and higher waist-hip ratio(OR=33.88,95％CI:2.88-399.32).Conclusion:Relapse MDD has positive as-sociation with comorbidity of mental disorders,out of role,and higher waist-hip ratio.