Targeting dysregulated phago-/auto-lysosomes in Sertoli cells to ameliorate late-onset hypogonadism.

Age-related changes in testicular function can impact health and well-being. The mechanisms underlying age-related testicular dysfunction, such as late-onset hypogonadism (LOH), remain incompletely understood. Using single-cell RNA sequencing on human testes with LOH, we delineated Sertoli cells (SCs) as pivotal metabolic coordinators within the testicular microenvironment. In particular, lysosomal acidity probing revealed compromised degradative capacity in aged SCs, hindering autophagy and phagocytic flux. Consequently, SCs accumulated metabolites, including cholesterol, and have increased inflammatory gene expression; thus, we termed these cells as phago-/auto-lysosomal deregulated SCs. Exposure to a high-fat diet-induced phago-/auto-lysosomal dysregulated-like SCs, recapitulating LOH features in mice. Notably, efferent ductular injection and systemic TRPML1 agonist administration restored lysosomal function, normalizing testosterone deficiency and associated abnormalities in high-fat diet-induced LOH mice. Our findings underscore the central role of SCs in testis aging, presenting a promising therapeutic avenue for LOH.

Effect and threshold of PM2.5 on population mortality in a highly polluted area: a study on applicability of standards.

For assessing the effect and threshold of PM2.5 on mortality in highly polluted areas and further studying the standard applicability, daily data on meteorological factors, air pollutants, and mortality were obtained in Jinan, China, from 2011 to 2017. A generalized additive model (GAM) and a distributed lag non-linear model (DLNM) were employed to assess the nonlinearity and the hysteresis of associations. We further explored the breakpoints to evaluate the existence of the threshold. The correlation between mortality and PM2.5 was nonlinear. The impact of average PM2.5 on non-accidental mortality (RR = 1.11; 95% CI = 1.06, 1.16), cardiovascular disease (CVD) mortality (RR = 1.17; 95% CI = 1.10, 1.24), and respiratory disease (RD) mortality (RR = 1.17; 95% CI = 1.10, 1.24) reached the highest in the current day (lag 0). The excess risks of PM2.5 at secondary standard level to non-accidental, CVD, and RD mortality are 8.79% (95% CI = 3.84, 13.98), 14.41% (95% CI = 7.79, 21.43), 15.35% (95% CI = 1.76, 30.74), respectively. The saturation points exist in highly polluted areas. Above the saturation points of 247 µg/m3 for non-accidental mortality, 245 µg/m3 for CVD mortality, and 250 µg/m3 for RD mortality, the model of all three relationships presented a harvesting effect. This study underscores the necessity of the ongoing efforts of reducing particulate air pollution and the adjustment of the standards in seriously polluted areas to adapt to regional conditions. At the same time, for highly polluted areas, it is advocated to strengthen personal protection to decrease the saturation point and control the concentration of pollutants as much as possible, which will substantially save more cost that benefits the public.

The association between high ambient air pollution exposure and respiratory health of young children: A cross sectional study in Jinan, China.

There is growing concern about health effects of high air pollution in less-developed countries. Children represent a population at increased risk for air pollution-related respiratory conditions. This study investigated the relationship between high ambient air pollution exposure and respiratory health of young schoolchildren. From 2014 to 2016 in Jinan, China, 2532 primary school children in grades three to five from two different schools with different levels of air pollution were included in the study. Levels of ambient air pollution exposure including PM10, PM2.5, NO2, SO2, CO and O3 were measured continuously at the two schools. A questionnaire about children's respiratory health was conducted every year. Among them, about 150 randomly selected children also performed lung function tests two times a year at the beginning of November and middle of December. Annual average exposure levels of PM2.5 (66.8-79.1 vs 90.0-107.7 µg/m3), PM10 (129.5-177.3 vs 198.1-218.6 µg/m3), NO2 (45.3-53.2 vs 45.0-56.2 µg/m3), SO2 (29.8-56.5 vs 40.5-80.3 µg/m3), CO (1.3-1.5 vs 1.4-1.7 mg/m3) and O3 (84.8-120.2 vs 61.1-128.1 µg/m3) in the heavy pollution primary school were significantly higher than the light one. The higher air pollution exposure was related to increased prevalence of respiratory diseases of young children in the last year, especially allergic rhinitis. The increased odds of lung function impairment associated with exposure to higher air pollution, could be up to 171.5% (aOR = 2.715; 95% CI = 1.915-3.849) for PEF < 75% predicted in 2014. However, after short-term exposure for 1.5 month or a week, paired comparison for parameters of the same child showed different results. The association between high ambient air pollution exposure and respiratory health of young children is closely related to exposure time and dose and may be fluctuate and complex.

[Correlationship between congenital heart disease and polymorphism of MTHFR gene].

OBJECTIVE: To investigate the association between genetic variations in methylenetetrahydrofolate reductase MTHFR and the risk of congenital heart disease. METHODS: Conducted a case-control study, calculated the sample size by formulas. The sample including 150 isolated CHD cases and 150 controls comparable with the patients in age and sex. They were genotyped for detecting MTHFR C677T, A1298C, G1793A polymorphisms by polymerase chain reaction and restriction fragment length polymorphism analysis (PCR-RFLP) methods. RESULTS: For the 677, compared with wild CC genotype, heterozygosity CT increased the risk of CHD (OR = 2.249, 95% CI 1.305-3.877, P = 0.003), the homozygous mutant genotype TT was associated with the risk of CHD significantly (OR = 3.121, 95% CI 1.612-6.043, P = 0.001). Compared with the wild allete, mutant allete increased the risk of CHD by 1.813 (95% CI 1.310-2.508, P = 0.000). For the 1298, Compared with wild AA genotype, heterozygosity AC increased the risk of CHD (OR = 2.177, 95% CI 1.183-4.077, P = 0.011). The mutant allete C increased the risk of CHD by 2.017 (95% CI 1.128-3.604, P = 0.016). For the 1793, The proportion of the heterozygote GA and homozygote AA had no statistical differences in the two groups (P = 0.145), also the mutant allete and wild allete (P = 0.158). There were joint effects of MTHFR C677T and MTHFR A1298C, MTHFR A1298C and MTHFR G1793A. CONCLUSION: Genetic polymorphisms in MTHFR C677T and MTHFR A1298C might contribute to the risk of developing CHD, joint effects were found of MTHFR C677T and MTHFR A1298C, MTHFR A1298C and MTHFR G1793A.

Characterization of circulating microRNA expression in patients with a ventricular septal defect.

OBJECTIVES: Ventricular septal defect (VSD), one of the most common types of congenital heart disease (CHD), results from a combination of environmental and genetic factors. Recent studies demonstrated that microRNAs (miRNAs) are involved in development of CHD. This study was to characterize the expression of miRNAs that might be involved in the development or reflect the consequences of VSD. METHODS: MiRNA microarray analysis and reverse transcription-polymerase chain reaction (RT-PCR) were employed to determine the miRNA expression profile from 3 patients with VSD and 3 VSD-free controls. 3 target gene databases were employed to predict the target genes of differentially expressed miRNAs. miRNAs that were generally consensus across the three databases were selected and then independently validated using real time PCR in plasma samples from 20 VSD patients and 15 VSD-free controls. Target genes of validated 8 miRNAs were predicted using bioinformatic methods. RESULTS: 36 differentially expressed miRNAs were found in the patients with VSD and the VSD-free controls. Compared with VSD-free controls, expression of 15 miRNAs were up-regulated and 21 miRNAs were downregulated in the VSD group. 15 miRNAs were selected based on database analysis results and expression levels of 8 miRNAs were validated. The results of the real time PCR were consistent with those of the microarray analysis. Gene ontology analysis indicated that the top target genes were mainly related to cardiac right ventricle morphogenesis. NOTCH1, HAND1, ZFPM2, and GATA3 were predicted as targets of hsa-let-7e-5p, hsa-miR-222-3p and hsa-miR-433. CONCLUSION: We report for the first time the circulating miRNA profile for patients with VSD and showed that 7 miRNAs were downregulated and 1 upregulated when matched to VSD-free controls. Analysis revealed target genes involved in cardiac development were probably regulated by these miRNAs.