[Research progress on the biological effects of HIF-1α on follicle development and ovulation].

Hypoxia inducible factor-1α (HIF-1α), as a hypoxia inducible factor, affects women's reproductive function by regulating the development and excretion of follicles. HIF-1α induces glycolysis and autophagy in the granule cells by promoting oocyte development, regulating the secretion of related angiogenic factors, and improving follicle maturity. In addition, HIF-1α promotes the process of luteinization of follicular vesicles, maintains luteal function, and finally completes physiological luteal atrophy through cumulative oxidative stress. Dysfunction of HIF-1α will cause a series of pathological consequences, such as angiogenesis defect, energy metabolism abnormality, excessive oxidative stress and dysregulated autophagy and apoptosis, resulting in ovulation problem and infertility. This article summarizes the previous studies on the regulation of follicle development and excretion and maintenance of luteal function and structural atrophy by HIF-1α. We also describe the effective intervention mechanism of related drugs or bioactive ingredients on follicular dysplasia and ovulation disorders through HIF-1α, in order to provide a systematic and in-depth insights for solving ovulation disorder infertility.

SERPINA5 promotes tumour cell proliferation by modulating the PI3K/AKT/mTOR signalling pathway in gastric cancer.

SERPINA5 belongs to the serine protease inhibitor superfamily and has been reported to be lowly expressed in a variety of malignancies. However, few report of SERPINA5 in gastric cancer has been found. The purpose of this study was to determine the role of SERPINA5 in GC and to investigate potential tumorigenic mechanisms. We performed qPCR to determine the level of SERPINA5 expression in GC. We used public databases to evaluate whether SERPINA5 could be utilized to predict overall survival and disease-free survival in GC patients. We also knocked down the expression of SERPINA5 and evaluated its effect on cell proliferation and migration. Furthermore, we explored the signal pathways and regulatory mechanisms related to SERPINA5 functions. According to our findings, SERPINA5 was shown to exhibit high expression in GC. Notably, SERPINA5 was prognostic in GC with high expression being unfavourable. SERPINA5 was further observed to promote GC tumorigenesis by modulating GC cell proliferation ability. Mechanically, SERPINA5 could inhibit CBL to regulate the PI3K/AKT/mTOR signalling pathway, thereby promoting GC carcinogenesis progression. These results highlight the important role of SERPINA5 in GC cell proliferation and suggest that SERPINA5 could be a novel target for GC treatment and a predictor for GC prognosis.

Chronic stress inhibits testosterone synthesis in Leydig cells through mitochondrial damage via Atp5a1.

Stress is one of the leading causes of male infertility, but its exact function in testosterone synthesis has scarcely been reported. We found that adult male rats show a decrease in bodyweight, genital index and serum testosterone level after continual chronic stress for 21 days. Two-dimensional gel electrophoresis (2-DE) and MALDI-TOF-MS analysis identified 10 differentially expressed proteins in stressed rats compared with controls. A strong protein interaction network was found to be centred on Atp5a1 among these proteins. Atp5a1 expression significantly decreased in Leydig cells after chronic stress. Transfection of Atp5a1 siRNAs decreased StAR, CYP11A1, and 17ß-HSD expression by damaging the structure of mitochondria in TM3 cells. This study confirmed that chronic stress plays an important role in testosterone synthesis by regulating Atp5a1 expression in Leydig cells.

LGR6 Acts as an Oncogene and Induces Proliferation and Migration of Gastric Cancer Cells.

Leucine rich repeat containing G protein-coupled receptor 6 (LGR6) belongs to the G protein-coupled receptor family, and it exhibits up-regulated expression in various types of human cancer. However, there are few reports of LGR6 contributing to gastric cancer (GC). Herein, we investigated the function of LGR6 and associated tumorigenic mechanisms in GC. LGR6 expression in GC was analyzed in the cancer genome atlas (TCGA) dataset and further confirmed in GC cell lines and fifteen paired tissue samples via quantitative real-time polymerase chain reaction (qRT-PCR). LGR6 expression was knocked down via small interfering RNA (siRNA), after which the impacts of silencing LGR6 on cell function were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT), cell colony formation, wound-healing, and cell cycle assays. Western blot was performed to explore signaling pathways and regulatory mechanisms associated with LGR6 function. In this study, we showed that LGR6 was at higher levels in GC cell lines and gastric adenocarcinoma tissues. We found that silencing LGR6 in MKN-45 and BGC-823 cells inhibited cell proliferation and migration ability, which accompanied with an obvious regulation of MMP-9, ß-catenin, CCNA2, CDK-2, and ERK1/2. In conclusion, this study demonstrated that LGR6 could act as an oncogene and may be a therapeutic target in GC.

Single-cell transcriptome profiling implicates the psychological stress-induced disruption of spermatogenesis.

Male infertility has emerged as a global issue, partly attributed to psychological stress. However, the cellular and molecular mechanisms underlying the adverse effects of psychological stress on male reproductive function remain elusive. We created a psychologically stressed model using terrified-sound and profiled the testes from stressed and control rats using single-cell RNA sequencing. Comparative and comprehensive transcriptome analyses of 11,744 testicular cells depicted the cellular landscape of spermatogenesis and revealed significant molecular alterations of spermatogenesis suffering from psychological stress. At the cellular level, stressed rats exhibited delayed spermatogenesis at the spermatogonia and pachytene phases, resulting in reduced sperm production. Additionally, psychological stress rewired cellular interactions among germ cells, negatively impacting reproductive development. Molecularly, we observed the down-regulation of anti-oxidation-related genes and up-regulation of genes promoting reactive oxygen species (ROS) generation in the stress group. These alterations led to elevated ROS levels in testes, affecting the expression of key regulators such as ATF2 and STAR, which caused reproductive damage through apoptosis or inhibition of testosterone synthesis. Overall, our study aimed to uncover the cellular and molecular mechanisms by which psychological stress disrupts spermatogenesis, offering insights into the mechanisms of psychological stress-induced male infertility in other species and promises in potential therapeutic targets.

The efficacy and safety of Bazi Bushen Capsule in treating premature aging: A randomized, double blind, multicenter, placebo-controlled clinical trial.

PURPOSE: It is unclear whether traditional Chinese patent medicines can resist premature aging. This prospective study investigated the effects of Bazi Bushen Capsule (BZBS) which is a traditional Chinese patent medicine for tonifying the kidney essence on premature senility symptoms and quality of life, telomerase activity and telomere length. STUDY DESIGN AND METHODS: It was a parallel, multicenter, double-blind, randomized, and placebo-controlled trial. Subjects (n = 530) aged 30-78 years were randomized to receive BZBS or placebo capsules 12 weeks. The primary outcome was the clinical feature of change in kidney deficiency for aging evaluation scale (CFCKD-AES) and tilburg frailty indicator (TFI). The secondary outcomes were SF-36, serum sex hormone level, five times sit-to-stand time (FTSST), 6MWT, motor function test-grip strength, balance test, walking speed, muscle mass measurement, telomerase and telomere length. RESULTS: After 12 weeks of treatment, the CFCKD-AES and TFI scores in the BZBS group decreased by 13.79 and 1.50 respectively (6.42 and 0.58 in the placebo group, respectively); The SF-36 in the BZBS group increased by 98.38 (23.79 in the placebo group). The FTSST, motor function test grip strength, balance test, walking speed, and muscle mass in the elderly subgroup were all improved in the BZBS group. The telomerase content in the BZBS group increased by 150.04 ng/ml compared to the placebo group. The fever led one patient in the placebo group to discontinue the trial. One patient in the placebo group withdrew from the trial due to pregnancy. None of the serious AEs led to treatment discontinuation, and 3 AEs (1.14%) were assessed as related to BZBS by the primary investigator. CONCLUSIONS: BZBS can improve premature aging symptoms, frailty scores, and quality of life, as well as improve FTSST, motor function: grip strength, balance test, walking speed, and muscle mass in elderly subgroups of patients, and enhance telomerase activity, but it is not significantly associated with increasing telomere length which is important for healthy aging. TRIAL REGISTRY: https://www.chictr.org.cn/showproj.html?proj=166181.

The effect of serum calcium on the association of depression with infertility among U.S. women.

This study aimed to explored the association between depressive symptoms and infertility among U.S. women, and the effect of serum calcium on this association. We used data from the National Health and Nutrition Examination Survey (2013-2018), relating to women aged 20-45 years. Depressive symptoms were determined using the nine-item Patient Health Questionnaire (PHQ-9 scores ≥10), and interview data were used to identify self-reported infertility. Of 2708 women (mean age: 32.7 ± 7.5 years), 274 were depressed and 12.0 % self-reported being "ever-infertile." Depressive symptoms were associated with infertility in multivariable logistic regression (OR, 1.62; 95 % CI, 1.11-2.38). Depressive symptoms were associated with infertility among participants who were obese (OR, 1.68; 95 % CI, 1.03-2.74), had not received psychological counseling (OR, 1.60; 95 % CI, 1.03-2.50), were antidepressant users (OR 3.22; 95 % CI, 1.15-9.00), and had high serum calcium levels (OR, 2.05; 95 % CI, 1.25-3.35). A significant interaction between serum calcium and depression was observed for infertility (P = .038, interaction likelihood ratio test). In sensitivity analyses, the association between depressive symptoms and infertility remained after excluding women aged ≥35 years (OR, 1.87; 95 % CI, 1.08-3.23), lowering the cut-off for PHQ-9 scores (≥5) (OR, 1.48; 95 % CI, 1.12-1.96), excluding women with some gynecological diseases (OR, 1.63; 95 % CI, 1.07-2.49), and using inverse probability of treatment weighting (OR, 1.64; 95 % CI, 1.17-2.31). Conclusion: Our findings indicate that depression is associated with infertility among U.S. women and serum calcium may have an effect on the association. Interventions such as serum calcium reduction, weight management and psychosocial counseling for infertility treatment in individuals with depression may be integrated into routine clinical practice. Additionally, more caution could be exercised when using antidepressants.

Proteome analysis reveals novel serum biomarkers for Henoch-Schönlein purpura in Chinese children.

PURPOSE: Henoch-Schönlein purpura (HSP) is diagnosed based on characteristic skin changes. This study aimed to identify the serum biomarkers of HSP in children. EXPERIMENTAL DESIGN: We performed proteomic analysis of serum samples from 38 paired pre- and posttherapy HSP patients and 22 healthy controls using a combination of magnetic bead-based weak cation exchange and MALDI-TOF MS. ClinProTools was used to screen the differential peaks. Then, LC-ESI-MS/MS was performed to identify the proteins. ELISA was used to verify the expression of whole protein in the serum of 92 HSP patients, 14 peptic ulcer disease (PUD) patients and 38 healthy controls, which were prospectively collected. Finally, logistic regression analysis was performed to analyze the diagnostic value of the above predictors and existing clinical indicators. RESULTS: Seven potential HSP serum biomarker peaks (m/z:1228.95, m/z:1781.22, m/z:1468.43, m/z:1619.53, m/z:1868.41, m/z:1694.05, m/z:1743.25) with higher expression in the pretherapy group and one peak (m/z:1947.41) with lower expression in the pretherapy group were all identified as peptide regions of albumin (ALB), complement C4-A precursor (C4A), tubulin beta chain (TUBB), isoform 1 of fibrinogen alpha chain (FGA), and ezrin (EZR). The expression of identified proteins was validated by ELISA. Multivariate logistic regression analysis showed that serum C4A EZR and ALB were independent risk factors for HSP, serum C4A and lgA were independent risk factors for HSPN, and serum D-dimer was an independent risk factor for abdominal HSP. CONCLUSIONS AND CLINICAL RELEVANCE: These findings revealed the specific etiology of HSP from the perspective of serum proteomics. The identified proteins might serve as potential biomarkers for HSP and HSPN diagnoses. SIGNIFICANCE: Henoch-Schönlein purpura (HSP) is the most common systemic vasculitis in children, and its diagnosis depends primarily on characteristic skin changes. Early diagnosis of non-rash patients is difficult, especially for abdominal and renal types (Henoch-Schönlein purpura nephritis, HSPN). HSPN has poor outcomes, is diagnosed based on urinary protein and/or haematuria, and cannot be detected early in HSP. Patients with an earlier diagnosis of HSPN appear to have better renal outcomes. Our plasma proteomic analysis of HSP in children revealed that HSP patients could be distinguished from healthy controls and peptic ulcer disease patients using complement C4-A precursor (C4A), ezrin, and albumin. C4A and IgA could distinguish HSPN from HSP in the early stages, and D-dimer was a sensitive index used to distinguish abdominal HSP; identifying these biomarkers could promote the early diagnosis of HSP, especially pediatric HSPN and abdominal HSP, thereby improving precision therapy.

A terrified-sound stress causes cognitive impairment in female mice by impairing neuronal plasticity.

Stress is an important environmental factor affecting mental health that cannot be ignored. Moreover, due to the great physiological differences between males and females, the effects of stress may vary by sex. Previous studies have shown that terrified-sound stress, meaning exposed mice to the recorded vocalizations in response to the electric shock by their kind to induce psychological stress, can cause cognitive impairment in male. In the study, we investigated the effects of the terrified-sound stress on adult female mice. METHODS: 32 adults female C57BL/6 mice were randomly divided into control (n = 16) and stress group (n = 16). Sucrose preference test (SPT)was carried out to evaluate the depressive-like behavior. Using Open field test (OFT) to evaluate locomotor and exploratory alterations in mice. Spatial learning and memory ability were measured in Morris Water maze test (MWM), Golgi staining and western blotting showed dendritic remodeling after stress. In addition, serum hormone quantifications were performed by ELISA. RESULTS: we found the sucrose preference of stress group was significantly decreased (p < 0.05) compared with control group; the escape latency of the stress group was significantly prolonged (p < 0.05), the total swimming distance and the number of target crossings(p < 0.05) were significantly increased (p < 0.05) in MWM; Endocrine hormone, Testosterone (T) (p < 0.05), GnRH (p < 0.05), FSH and LH levels was decreased; Golgi staining and western blotting showed a significant decrease in dendritic arborization, spine density and synaptic plasticity related proteins PSD95 and BDNF in the stress group. CONCLUSION: Terrified-sound stress induced depressive-like behaviors, locomotor and exploratory alterations. And impaired cognitive by altering dendritic remodeling and the expression of synaptic plasticity-related proteins. However, females are resilient to terrified-sound stress from a hormonal point of view.

Roll eccentricity extraction and compensation based on MPSO-WTD and ITD.

To meet the high thickness accuracy requirements in cold-rolling processes, a roll eccentricity signal extraction method based on modified particle swarm optimization and wavelet threshold denoising (MPSO-WTD) with intrinsic time-scale decomposition (ITD) is proposed. The strong denoising ability of the wavelet is combined with the decomposition and recognition attributes of ITD for non-stationary signals. Periodic disturbances in strip thickness caused by roll eccentricity are actively compensated. First, the wavelet is used to denoise the signal and the MPSO algorithm is applied to determine a rational threshold and improve the calculation efficiency. Then, the denoised signal is decomposed into proper rotational components (PRCs) using the ITD method, and an appropriate PRC component representing the eccentricity signal is extracted. Finally, the eccentricity compensation signal is applied in the automatic gauge control (AGC) system of the cold rolling mill. During the rolling process, the rolling speed is not constant and will directly affect the frequency of the roll eccentricity signal. To solve this problem, an encoder is installed at the end of the roll and the compensation frequency of the roller eccentricity signal is determined in the roller eccentricity compensation system according to the pulse number output. The results of simulations and experiments show that roll eccentricity signals extracted using the proposed method can effectively remove the influence of interference signals. An average improvement of 62.3% in the roll eccentricity compensation effect was achieved under the stable rolling condition in the finishing rolling stage.

Association between testosterone levels and bone mineral density in females aged 40-60 years from NHANES 2011-2016.

Growing evidence indicates that testosterone is a conspicuous marker for assessing male bone mineral density (BMD). However, research regarding testosterone levels and BMD is sparse and controversial for females. Hence, we aimed to investigate the association between testosterone levels and BMD among adult females aged 40-60 years in the United States. In this cross-sectional study, all participants were part of the National Health and Nutrition Examination Survey (2011-2016). A weighted general linear model was used to estimate the association between testosterone levels and lumbar BMD. Age, race, income level, education level, body mass index (BMI), blood urea nitrogen (BUN) level, serum uric acid (UA) level, serum calcium (Ca) level, serum phosphorus (P) level, the use of oral contraceptive pills, the use of hormone replacement therapy (HRT), smoking status, drinking status, and the use of corticosteroids were adjusted using a weighted multiple regression model. Subgroup analyses were performed using the same regression model. We included 2198 female participants in the study, and testosterone levels were positively associated with lumbar BMD after adjusting for all the covariates (ß = 1.12, 95% CI 0.31, 1.93). In subgroup analyses, the associations in the fourth quartile of testosterone levels were stronger for the participants aged 40-50 years old (quartile 4, ß = 42.92, 95% CI 7.53, 78.30 vs. quartile 1) and 50 to 60-year-old (quartile 4, ß = 32.41, 95% CI 0.14, 64.69 vs. quartile 1). Similar results were found in other subgroups, including subgroups for race (Non-Hispanic Black, Other), income level (income ≤ 1.3, income > 3.5), education level (college or higher), BMI > 25 kg/m2, BUN levels ≤ 20 mg/dL, UA levels ≤ 6 mg/dL, Ca levels ≤ 10.1 mg/dL, P levels ≤ 5 mg/dL, drinking status, never smoker, never taking birth control pills, and HRT user. There was no interaction among the covariates in the association between lumbar BMD and testosterone levels (P for interaction > 0.05). In US adult females aged 40-60 years, the testosterone level was a positive predictor of the lumbar BMD after adjusting for covariates.

Pt3R5G inhibits colon cancer cell proliferation through inducing ferroptosis by down-regulating SLC7A11.

AIMS: Colon cancer (CC) is a prevalent malignancy worldwide and is one of the most easily altered cancers by dietary regulation. Petunidin 3-O-[rhamnopyranosyl-(trans-p-coumaroyl)]-5-O-(ß-D-glucopyranoside) (Pt3R5G) isolated and purified from Lycium ruthenicum Murray, which exhibits highly efficient antioxidant activity and specific anticancer effects, is the flavonoids compound. We aimed to study the effect of Pt3R5G on CC cells and elucidate the potential underlying mechanisms. MAIN METHODS: Cell proliferation was measured by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and colony formation assays. Cell cycle, cell apoptosis and reactive oxygen species (ROS) analysis were performed by flow cytometry. RNA-sequencing was performed to elucidate the potential underlying mechanisms. The lipid peroxidation level of cells was detected by malondialdehyde (MDA) assay. The mitochondrial morphology of cells was inspected using a transmission electron microscope. Additionally, we overexpressed SLC7A11 to perform rescue experiments. In vivo, xenograft mice assay was performed to verify the effect of Pt3R5G on the growth of colon cancer. KEY FINDINGS: Pt3R5G reduced the cell activity by blocking the cell cycle in G0/G1 phase, inducing the apoptosis and ferroptosis in RKO cells. The overexpressed of SLC7A11, a significantly down-regulated expression gene caused by Pt3R5G, rescued the cell proliferation inhibition and ferroptosis process. Furthermore, Pt3R5G inhibited tumor growth in nude mice. Our study suggests that Pt3R5G inhibits RKO cell proliferation through mainly reducing ferroptosis by down-regulated SLC7A11. SIGNIFICANCE: As a potential therapeutic drug, Pt3R5G showed efficient anticancer activity through a variety of pathways.