Short-term effects of temperature-related indices on emergency ambulance dispatches due to mental and behavioral disorders in Shenzhen, China.

Introduction: The precise associations between temperature-related indices and mental and behavioral disorders (MBDs) have yet to be fully elucidated. Our study aims to ascertain the most effective temperature-related index and assess its immediate impact on emergency ambulance dispatches (EADs) due to MBDs in Shenzhen, China. Methods: EADs data and meteorological data from January 1, 2013, to December 31, 2020, in Shenzhen were collected. Distributed lag non-linear models (DLNMs) were utilized to examine the non-linear and lagged effects of temperature-related indices on EADs due to MBDs. The Quasi Akaike Information criterion (QAIC) was used to determine the optimal index after standardizing temperature-related indices. After adjusting for confounding factors in the model, we estimated the immediate and cumulative effects of temperature on EADs due to MBDs. Results: The analysis of short-term temperature effects on EADs due to MBDs revealed Humidex as the most suitable index. Referring to the optimal Humidex (3.2th percentile, 12.00°C), we observed a significant effect of Humidex over the threshold (34.6th percentile, 26.80°C) on EADs due to MBDs at lag 0-5. The cumulative relative risks for high temperature (90th percentile, 41.90°C) and extreme high temperature (99th percentile, 44.20°C) at lag 0-5 were 1.318 (95% CI: 1.159-1.499) and 1.338 (95% CI: 1.153-1.553), respectively. No significant cold effect was observed on EADs due to MBDs. Conclusion: High Humidex was associated with more EADs due to MBDs in subtropical regions. Health authorities should implement effective measures to raise public awareness of risks related to high temperature and protect vulnerable populations.

Prenatal diethylhexylphthalate exposure disturbs adult Leydig cell function via epigenetic downregulation of METTL4 expression in male rats.

Prenatal exposure to diethylhexyl phthalate (DEHP) has been linked with a decline in testosterone levels in adult male rats, but the underlying mechanism remains unclear. We investigated the potential epigenetic regulation, particularly focusing on N6-methyladenosine (m6A) modification, as a possible mechanism. Dams were gavaged with DEHP (0, 10, 100, and 750 mg/kg/day) from gestational day 14 to day 21. The male offspring were examined at the age of 56 days. Prenatal DEHP administration at 750 mg/kg/day caused a decline in testosterone concentrations, an elevation in follicle-stimulating hormone, a downregulated expression of CYP11A1 HSD3B2, without affecting Leydig cell numbers. Interestingly, Methyltransferase Like 4 (METTL4), an m6A methyltransferase, was downregulated, while there were no changes in METTL3 and METTL14. Moreover, CYP11A1 showed m6A reduction in response to prenatal DEHP exposure. Additionally, METTL4 expression increased postnatally, peaking in adulthood. Knockdown of METTL4 resulted in the downregulation of CYP11A1 and HSD3B2 and an increase in SCARB1 expression. Furthermore, the increase in autophagy protection in adult Leydig cells induced by prenatal DEHP exposure was not affected by 3-methyladenosine (3MA) treatment, indicating a potential protective role of autophagy in response to DEHP exposure. In conclusion, prenatal DEHP exposure reduces testosterone by downregulating CYP11A1 and HSD3B2 via m6A epigenetic regulation and induction of autophagy protection in adult Leydig cells as a response to DEHP exposure.

Deoxynivalenol Inhibits Progenitor Leydig Cell Development by Stimulating Mitochondrial Fission in Rats.

Deoxynivalenol (DON) is a common food contaminant that can impair male reproductive function. This study investigated the effects and mechanisms of DON exposure on progenitor Leydig cell (PLC) development in prepubertal male rats. Rats were orally administrated DON (0-4 mg/kg) from postnatal days 21-28. DON increased PLC proliferation but inhibited PLC maturation and function, including reducing testosterone levels and downregulating biomarkers like HSD11B1 and INSL3 at ≥2 mg/kg. DON also stimulated mitochondrial fission via upregulating DRP1 and FIS1 protein levels and increased oxidative stress by reducing antioxidant capacity (including NRF2, SOD1, SOD2, and CAT) in PLCs in vivo. In vitro, DON (2-4 µM) inhibited PLC androgen biosynthesis, increased reactive oxygen species production and protein levels of DRP1, FIS1, MFF, and pAMPK, decreased mitochondrial membrane potential and MFN1 protein levels, and caused mitochondrial fragmentation. The mitochondrial fission inhibitor mdivi-1 attenuated DON-induced impairments in PLCs. DON inhibited PLC steroidogenesis, increased oxidative stress, perturbed mitochondrial homeostasis, and impaired maturation. In conclusion, DON disrupts PLC development in prepubertal rats by stimulating mitochondrial fission.

Linear semantic transformation for semi-supervised medical image segmentation.

Medical image segmentation is a focus research and foundation in developing intelligent medical systems. Recently, deep learning for medical image segmentation has become a standard process and succeeded significantly, promoting the development of reconstruction, and surgical planning of disease diagnosis. However, semantic learning is often inefficient owing to the lack of supervision of feature maps, resulting in that high-quality segmentation models always rely on numerous and accurate data annotations. Learning robust semantic representation in latent spaces remains a challenge. In this paper, we propose a novel semi-supervised learning framework to learn vital attributes in medical images, which constructs generalized representation from diverse semantics to realize medical image segmentation. We first build a self-supervised learning part that achieves context recovery by reconstructing space and intensity of medical images, which conduct semantic representation for feature maps. Subsequently, we combine semantic-rich feature maps and utilize simple linear semantic transformation to convert them into image segmentation. The proposed framework was tested using five medical segmentation datasets. Quantitative assessments indicate the highest scores of our method on IXI (73.78%), ScaF (47.50%), COVID-19-Seg (50.72%), PC-Seg (65.06%), and Brain-MR (72.63%) datasets. Finally, we compared our method with the latest semi-supervised learning methods and obtained 77.15% and 75.22% DSC values, respectively, ranking first on two representative datasets. The experimental results not only proved that the proposed linear semantic transformation was effectively applied to medical image segmentation, but also presented its simplicity and ease-of-use to pursue robust segmentation in semi-supervised learning. Our code is now open at: https://github.com/QingYunA/Linear-Semantic-Transformation-for-Semi-Supervised-Medical-Image-Segmentation.

Butorphanol inhibits androgen biosynthesis and metabolism in rat immature Leydig cells in vitro.

Butorphanol is a synthetic opioid analgesic medication that is primarily used for the management of pain. Butorphanol may have an inhibitory effect on androgen biosynthesis and metabolism in rat immature Leydig cells. The objective of this study was to investigate the influence of butorphanol on androgen secretion by rat Leydig cells isolated from the 35-day-old male rats. Rat Leydig cells were cultured with 0.5-50 µM butorphanol for 3 h in vitro. Butorphanol at 5 and 50 µM significantly inhibited androgen secretion in immature Leydig cells. At 50 µM, butorphanol also blocked the effects of luteinizing hormone (LH) and 8bromo-cAMP-stimulated androgen secretion and 22R-hydroxycholesterol- and pregnenolone-mediated androgen production. Further analysis of the results showed that butorphanol downregulated the expression of genes involved in androgen production, including Lhcgr (LH receptor), Cyp11a1 (cholesterol side-chain cleavage enzyme), Srd5a1 (5α-reductase 1), and Akr1c14 (3α-hydroxysteroid dehydrogenase). Additionally, butorphanol directly inhibited HSD3B1 (3ß-hydroxysteroid dehydrogenase 1) and SRD5A1 activity. In conclusion, butorphanol may have side effects of inhibiting androgen biosynthesis and metabolism in Leydig cells.

Structure-activity relationship and docking analysis of nature flavonoids as inhibitors of human and rat gonadal 3ß-hydroxysteroid dehydrogenases for therapeutic purposes.

The potential inhibitory effects of flavonoids on gonadal steroid biosynthesis have gained attention due to their widespread presence in natural plant sources. Specifically, our study focused on evaluating the inhibitory efficacy of these compounds on human 3ß-hydroxysteroid dehydrogenase 2 (h3ß-HSD2) and rat homolog r3ß-HSD1, enzymes responsible for the conversion of pregnenolone to progesterone. Through our investigations, we observed that the potency of flavonoids was silymarin (IC50, 1.31 µM) > luteolin (4.63 µM) > tectorigenin > (5.86 µM), and rutin (44.12 µM) in inhibiting human KGN cell microsomal h3ß-HSD2. Similarly, the potency of flavonoids was silymarin (9.50 µM) > luteolin (11.49 µM) > tectorigenin (14.06 µM), and rutin (145.71 µM) in inhibiting rat testicular r3ß-HSD1. Silymarin, luteolin, and tectorigenin acted as mixed inhibitors of both human and rat 3ß-HSDs. Luteolin and tectorigenin were able to penetrate human KGN cells to inhibit progesterone secretion. Furthermore, docking analysis and structure-activity relationship analysis highlighted the importance of hydrogen bond formation for the inhibitory efficacy of these compounds against h3ß-HSD2 and r3ß-HSD1. Overall, this study demonstrates that silymarin exhibits the most potent inhibition of human and rat gonadal 3ß-HSDs, and significant SAR differences exist among the tested compounds.

Enhanced inhibition of human and rat aromatase activity by benzene ring substitutions in bisphenol A: QSAR structure-activity relationship and in silico docking analysis.

Bisphenol A (BPA) is a widely used plastic material, but its potential endocrine disrupting effect has restricted its use. The BPA alternatives have raised concerns. This study aimed to compare inhibitory potencies of 11 BPA analogues on human and rat placental aromatase (CYP19A1). The inhibitory potency on human CYP19A1 ranged from bisphenol H (IC50, 0.93 µM) to tetramethyl BPA and tetrabromobisphenol S (ineffective at 100 µM) when compared to BPA (IC50, 73.48 µM). Most of them were mixed/competitive inhibitors and inhibited estradiol production in human BeWo cells. Molecular docking analysis showed all BPA analogues bind to steroid active site or in between steroid and heme of CYP19A1 and form a hydrogen bond with catalytic residue Met374. Pharmacophore analysis showed that there were 4 hydrophobic regions for BPA analogues, with bisphenol H occupying 4 regions. Bivariate correlation analysis showed that LogP (lipophilicity) and LogS (water solubility) of BPA analogues were correlated with their IC50 values. Computerized drug metabolism and pharmacokinetics analysis showed that bisphenol H, tetrabromobisphenol A, and tetrachlorobisphenol A had low solubility, which might explain their weaker inhibition on estradiol production on BeWo cells. In conclusion, BPA analogues mostly can inhibit CYP19A1 and the lipophilicity determines their inhibitory strength.

The impact of tetrachlorobisphenol A exposure during puberty: Altered Leydig cell development and induced endoplasmic reticulum stress in male mice.

Tetrachlorobisphenol A (TCBPA), a halogenated flame retardant and endocrine disruptor, has been detected in human urine and serum. While previous research has shown its impact on the reproductive system, investigations into its mechanisms during puberty remain limited. This study aims to explore the effects of TCBPA on Leydig cells in adolescent mice and potential underlying mechanisms. Male C57 mice of age 28 days were gavaged with 50, 100, and 200 mg/kg/day for 28 days. TCBPA did not alter body weight and testis weight but lowered testosterone levels at 100 and 200 mg/kg and reduced sperm count in the epididymis at 200 mg/kg. TCBPA lowered Leydig cell number at 200 mg/kg while it downregulated key Leydig cell gene (Lhcgr, Scarb1, Cyp11a1, Cyp17a1, Hsd3b6, Hsd17b3 and Insl3) as low as 50 mg/kg. Further study indicated that TCBPA induced reactive oxygen species and caused endoplasmic reticulum stress. In vitro study in TM3 mouse Leydig cells showed that TCBPA indeed induced reactive oxygen species and caused endoplasmic reticulum stress at 75 µM and inhibited testosterone production at this concentration and addition of antioxidant tocopherol can reverse it. These discoveries provide new insights and references for a deeper understanding of the toxic mechanisms of TCBPA on Leydig cells during puberty.

Arbutin inhibits androgen biosynthesis by rat immature Leydig cells in vitro.

Arbutin, a widely used skin lightening agent, has raised concerns regarding its potential side effects. In this study, we investigated the impact of arbutin on Leydig cell function using an in vitro model. We measured medium androgen levels, as well as the gene and protein expression related to Leydig cell steroidogenesis. Rat immature Leydig cells from age of 35 days were exposed to arbutin at concentrations ranging from 0.5 to 50 µM for a duration of 3 hrs. Following treatment, we observed a significant inhibition of androgen secretion by Leydig cells at both the 5 and 50 µM concentrations of arbutin. Furthermore, at a concentration of 50 µM, arbutin effectively blocked the stimulatory effects of luteinizing hormone (LH) and 8Br-cAMP on androgen secretion. Subsequent analysis revealed that arbutin downregulated the expression of crucial genes involved in androgen production, including Lhcgr, Hsd3b1, Cyp17a1, and Srd5a1. In silico computer program analysis predicted that arbutin exhibits good absorption, possesses a long elimination half-life, and may have other potential toxicity such as hepatoxicity. Taken together, our results demonstrate that arbutin negatively influences Leydig cell function and androgen production, potentially impacting male reproductive health.

Preference for human papillomavirus vaccine type and vaccination strategy among parents of school-age girls in Guangdong province, China.

In China, the human papillomavirus (HPV) vaccination coverage among age-eligible girls is rather low, and parent's attitude often plays a determinant role in their girls' HPV vaccination. To accelerate HPV vaccination coverage, several cities and Guangdong province in China offered different HPV vaccine types with different reimbursement methods. In April 2022, we conducted a province-wide survey to investigate parents of children aged 9-15 in Guangdong province, and analyzed factors associated with their preference for HPV vaccine type and vaccination strategy. Of the 4,967 surveyed respondents, 2,610 (58.1%) have not yet vaccinated their children. Among these parents, 67.9% preferred to vaccinate their children with the nine-valent vaccine, while only 8.1% preferred the quadrivalent vaccine and 7.4% preferred the bivalent vaccine. More parents preferred fixed subsidies with free choices of HPV vaccine type over the domestic bivalent vaccine provided by the government (58.1% vs. 39.3%). The multinomial logistic regression showed that parents' relationship with children, educational level, household income, and vaccination status were significantly associated with parents' preference for HPV vaccine type. Parent's relationship with children, workplace, household income, vaccination status, and age of children, were significantly associated with parents' preference for HPV vaccination strategy. Our findings suggest that policymakers may consider adjusting the current vaccination strategy by offering more vaccination choices. More health education on HPV vaccine and vaccination should also be provided to parents of age-eligible girls. Future research should examine which HPV vaccination strategy is more effective in promoting HPV vaccine uptakes in China.

Association between thermal stress and cardiovascular mortality in the subtropics.

Hazardous thermal conditions resulting from climate change may play a role in cardiovascular disease development. We chose the Universal Thermal Climate Index (UTCI) as the exposure metric to evaluate the relationship between thermal conditions and cardiovascular mortality in Shenzhen, China. We applied quasi-Poisson regression non-linear distributed lag models to evaluate the exposure-response associations. The findings suggest that cardiovascular mortality risks were significantly increased under heat and cold stress, and the adverse effects of cold stress were stronger than heat stress. Referencing the 50th percentile of UTCI (25.4°C), the cumulative risk of cardiovascular mortality was 75% (RRlag0-21 =1.75, 95%CI: 1.32, 2.32) higher in the 1st percentile (3.5°C), and 40% (RRlag0-21=1.40, 95%CI: 1.09, 1.80) higher in the 99th percentile (34.1°C). We observed that individuals older than 65 years were more vulnerable to both cold and heat stress, and females were identified as more susceptible to heat stress than males. Moreover, increased mortality risks of hypertensive disease and cerebrovascular disease were observed under cold stress, while heat stress was related to higher risks of mortality for hypertensive disease and ischemic heart disease. We also observed a stronger relationship between cold stress and ischemic heart disease mortality during the cold season, as well as a significant impact of heat stress on cerebrovascular disease mortality in the warm season when compared to the analysis of the entire year. These results confirm the significant relationship between thermal stress and cardiovascular mortality, with age and sex as potential effect modifiers of this association. Providing affordable air conditioning equipment, increasing the amount of vegetation, and establishing comprehensive early warning systems that take human thermoregulation into account could all help to safeguard the well-being of the public, particularly vulnerable populations, in the event of future extreme weather.

Temporal and spatial distributions, source identification, and health risk assessment of polycyclic aromatic hydrocarbons in PM2.5 from 2016 to 2021 in Shenzhen, China.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous contaminants in the atmosphere that have drawn intense attention due to their carcinogenicity and mutagenicity. In this work, 1424 air samples were collected between January 2016 and December 2021 in three areas of Shenzhen, China to determine the concentrations of PM2.5 and PAHs and their spatiotemporal variation. Human health risks due to the daily intake and uptake of PAHs and the resulting incremental lifetime cancer risk (ILCR) were also evaluated. PAHs were detected frequently in the samples at concentrations between 0.28 and 32.7 ng/m3 (median: 1.04 ng/m3). PM2.5 and PAH concentrations decreased from 2016 to 2021, and the Yantian area had lower median concentrations of PM2.5 (23.0 µg/m3) and PAHs (0.02 ng/m3) than the Longgang and Nanshan areas. The concentrations of PM2.5 and PAHs were significantly higher in winter than in summer. Analysis of diagnostic ratios indicated that petroleum combustion was the dominant source of airborne PAHs in Shenzhen. The estimated daily intake (EDI) and uptake (EDU) of PAHs by local residents decreased gradually with increasing age, indicating that infants are at particular risk of PAH exposure. However, the incremental lifetime cancer risks (ILCRs) were below the threshold value of 10-6, indicating that inhalation exposure to PAHs posed a negligible carcinogenic risk to Shenzhen residents. While promising, these results may underestimate actual PAH exposure levels, so further analysis of health risks due to PAHs in Shenzhen is needed.

Knowledge, Attitude, and Practice towards Influenza Vaccination among Older Adults in Southern China during the COVID-19 Pandemic.

Influenza is prevalent globally, leading to severe morbidity and mortality. During the pandemic, knowledge, attitude, and practice (KAP) towards influenza virus and vaccination were less investigated among southern Chinese older adults. A cross-sectional study was conducted through the structured questionnaire among community healthcare centers in selected districts in Shenzhen, southern China from September to October 2021. KAP towards influenza virus and vaccination were analyzed. A multivariable logistic regression model was used to identify associated factors. Among 975 participants, 55.6% were reported to have received influenza vaccination ever, and 46.6% had taken influenza vaccination in 2020 during the pandemic. Only one-fifth of participants knew severe comorbidities happen among severe influenza cases. A total of 88.3% thought older adults should have influenza vaccination. COVID-19 vaccination history was associated with receiving influenza vaccination (OR 1.92, 95% CI 1.32-2.80). People with a high-level income had better KAP towards influenza virus and vaccination. COVID-19 vaccination history was associated with the positive actions of influenza vaccination during the pandemic. Efforts should be made to promote the free influenza vaccination program widely and launch health education events on influenza and its vaccination regularly to improve KAP among older adults.

Bisphenol S stimulates Leydig cell proliferation but inhibits differentiation in pubertal male rats through multiple mechanisms.

Bisphenol S (BPS) is a novel bisphenol A (BPA) analogue, a ubiquitous environmental pollutant that disrupts male reproductive system. Whether BPS affects Leydig cell maturation in male puberty remains unclear. Male Sprague-Dawley rats (age of 35 days) were daily gavaged to 0, 1, 10, 100, and 200 mg/kg/day from postnatal days 35-56. BPS at 1-10 mg/kg/day and higher doses markedly reduced serum testosterone and progesterone levels but it at 200 mg/kg/day significantly increased estradiol level. BPS at 100 and 200 mg/kg/day significantly elevated serum luteinizing hormone (LH) levels. BPS at 1-10 mg/kg/day and higher doses significantly reduced inhibin A and inhibin B levels. BPS at 100 and 200 mg/kg/day markedly increased CYP11A1+ Leydig cell number, but did not affect HSD11B1+ (a mature Leydig cell marker) cell number. BPS at 10 mg/kg/day and higher doses significantly downregulated the expression of Cyp11a1 and at 100 and 200 mg/kg/d significantly lowered Cyp17a1, Hsd11b1, and Nr5a1 in the testes. BPS at 100 and/or 200 mg/kg/day significantly elevated Lhb in the pituitary. BPS at 100 and 200 mg/kg/day significantly increased the phosphorylation of AKT1, AKT2, and CREB without affecting total AKT1, AKT2, and CREB levels. BPS at 1-100 µM significantly suppressed testosterone production and induced proliferation of primary immature Leydig cells after 24 h of treatment and these actions were reversed by estrogen receptor α antagonist, ICI 182780, and partially reversed by vitamin E. BPS at 0.1-10 µM significantly increased oxidative stress of Leydig cells in vitro. BPS also directly inhibited 17ß-hydroxysteroid dehydrogenase 3 activity at 10-100 µM. In conclusion, BPS causes hypergonadotropic androgen deficiency in male rats during pubertal exposure via activating ESR1 and inducing ROS in immature Leydig cells and directly inhibiting 17ß-hydroxysteroid dehydrogenase 3 activity.

The role of platelet-derived growth factor BB signaling pathway in the regulation of stem and progenitor Leydig cell proliferation and steroidogenesis in male rats.

Platelet-derived growth factor BB (BB) regulates cell proliferation and function. However, the roles of BB on proliferation and function of Leydig stem (LSCs) and progenitor cells (LPCs) and the underlying signaling pathways remain unclear. This study aimed to analyze the roles of PI3K and MAPK pathways in the regulation of proliferation-related and steroidogenesis-related gene expression in rat LSCs/LPCs. In this experiment, BB receptor antagonist, tyrosine kinase inhibitor IV (PKI), the PI3K inhibitor, LY294002, and the MEK inhibitor, U0126, were used to measure the effects of these pathways on the expression of cell cycle-related genes (Ccnd1 and Cdkn1b) and steroidogenesis-related genes (Star, Cyp11a1, Hsd3b1, Cyp17a1, and Srd5a1), as well as Leydig cell maturation gene Pdgfra [1]. These results showed that BB (10 ng/mL)-stimulated EdU-incorporation into LSCs and BB-mediated inhibition on its differentiation was mediated through the activation of its receptor, PDGFRB, as well as MAPK and PI3K pathways. The results of LPC experiment also showed that LY294002 and U0126 decreased BB (10 ng/mL)-upregulated Ccnd1 expression while only U0126 reversed BB (10 ng/mL)-downregulated Cdkn1b expression. U0126 significantly reversed BB (10 ng/mL)-mediated downregulation of Cyp11a1, Hsd3b1, and Cyp17a1 expression. On the other hand, LY294002 reversed the expression of Cyp17a1 and Abca1. In conclusion, BB-mediated induction of proliferation and suppression of steroidogenesis of LSCs/LPCs are dependent on the activation of both MAPK and PI3K pathways, which show distinct regulation of gene expression.

Inhibition of Resveratrol Analogs on Human and Rat 3ß-Hydroxysteroid Dehydrogenases: Structure-Activity Relationship and Docking Analysis.

Resveratrol and its analogs are phytochemicals. Human 3ß-hydroxysteroid dehydrogenase 1 (3ß-HSD1) synthesizes steroid hormones for normal pregnancy or promoting cancer metastasis. Whether they inhibit 3ß-HSD1 remains unclear. In this study, the inhibitory potency, mode of action, structure-activity relationship, and docking parameters of resveratrol and its analogs on 3ß-HSD1 and rat homolog 3ß-HSD4 were analyzed. The inhibitory potency of these chemicals on human 3ß-HSD1 was 4,4'-dihydroxystilbene (IC50, 3.68 µM) > pinostilbene (8.07 µM) > pinosylvin (10.60 µM) > lunularin (26.84 µM) > resveratrol (30.20 µM) > dihydroresveratrol (>100 µM) = oxyresveratrol (>100 µM) > dihydropinosylvin (ineffective at 100 µM). Resveratrol analogs and metabolites are mixed or competitive inhibitors of human 3ß-HSD1. Resveratrol and 4,4'-dihydroxystilbene inhibited progesterone secretion by human JAr cells at ≥1 µM. Resveratrol (IC50, 32.09 µM) and pinosylvin (34.71 µM) significantly inhibited rat placental 3ß-HSD4 activity. Docking analysis shows that resveratrol analogs and metabolites bind the steroid-binding sites of human 3ß-HSD1 and rat 3ß-HSD4 and interact with the catalytic residues Ser125/Thr125 and Tyr155. The negative correlation of LogP and IC50 values for human 3ß-HSD1 indicates that lipophilicity of chemicals plays a critical role in the inhibitory effect of chemicals. In conclusion, 4,4'-dihydroxystilbene, pinostilbene, and pinosylvin effectively inhibit human 3ß-HSD1 depending on their lipophilicity, thereby acting as potential therapeutic agents.

Deletion of Calhm2 alleviates MPTP-induced Parkinson's disease pathology by inhibiting EFHD2-STAT3 signaling in microglia.

Background: Neuroinflammation is involved in the development of Parkinson's disease (PD). Calhm2 plays an important role in the development of microglial inflammation, but whether Calhm2 is involved in PD and its regulatory mechanisms are unclear. Methods: To study the role of Calhm2 in the development of PD, we utilized conventional Calhm2 knockout mice, microglial Calhm2 knockout mice and neuronal Calhm2 knockout mice, and established the MPTP-induced PD mice model. Moreover, a series of methods including behavioral test, immunohistochemistry, immunofluorescence, real-time polymerase chain reaction, western blot, mass spectrometry analysis and co-immunoprecipitation were utilized to study the regulatory mechanisms. Results: We found that both conventional Calhm2 knockout and microglial Calhm2 knockout significantly reduced dopaminergic neuronal loss, and decreased microglial numbers, thereby improving locomotor performance in PD model mice. Mechanistically, we found that Calhm2 interacted with EFhd2 and regulated downstream STAT3 signaling in microglia. Knockdown of Calhm2 or EFhd2 both inhibited downstream STAT3 signaling and inflammatory cytokine levels in microglia. Conclusion: We demonstrate the important role of Calhm2 in microglial activation and the pathology of PD, thus providing a potential therapeutic target for microglia-mediated neuroinflammation-related diseases.

Ciliary neurotrophic factor stimulates stem/progenitor Leydig cell proliferation but inhibits differentiation into its lineage in rats.

BACKGROUND: Ciliary neurotrophic factor is a member of the interleukin-6 family of cytokines. Ciliary neurotrophic factor drives many cells for their development. However, its effects on Leydig cell development remain unclear. METHODS: In the current study, we used three-dimensional seminiferous tubule culture system to induce the proliferation and differentiation of tubule-associated stem Leydig cells and primary progenitor Leydig cells culture to address the effects of ciliary neurotrophic factor. RESULTS: We found that ciliary neurotrophic factor stimulated the proliferation of stem Leydig cells but inhibited their development into the Leydig cell lineage. The ciliary neurotrophic factor-mediated effects can be reversed by signal transducer and activator 3 inhibitor S3I-201 and phosphatidylinositol 3-kinase inhibitor wortmannin, indicating that ciliary neurotrophic factor acts via signal transducer and activator 3-phosphatidylinositol 3-kinase signaling pathways to increase stem/progenitor Leydig cell proliferation. Ciliary neurotrophic factor at 1 and 10 ng/mL significantly decreased androgen production by progenitor Leydig cells. Microarray analysis of ciliary neurotrophic factor-treated progenitor Leydig cells showed that ciliary neurotrophic factor blocked steroidogenic pathways by downregulating Scarb1, Star, and Hsd3b1, possibly by downregulating the transcription factor Nr5a1 expression. CONCLUSION: Ciliary neurotrophic factor stimulates proliferation but blocks the differentiation of stem/progenitor Leydig cells.

COVID-19 vaccine uptake, reasons, and associated factors among older adults in Shenzhen, China.

Evidence is limited on the actual uptake of the coronavirus disease 2019 (COVID-19) vaccine among older adults, especially those with chronic diseases, during the pandemic. To examine COVID-19 vaccine uptake, reasons, and associated factor among older adults, a cross-sectional survey was conducted between September 24 and October 20, 2021 among older adults aged 60 and above in Shenzhen, China. Logistic regression analysis was used to examine associations of COVID-19 vaccine uptake with sociodemographic characteristics, pneumonia vaccination history, and participation in health education activities among older adults and among those with chronic diseases. Of the 951 participants, 82.8% reported being vaccinated against COVID-19 during the study period, but this proportion was relatively lower among adults aged 80 and above (62.7%) and those with chronic diseases (77.9%). The top-rated reasons for not being vaccinated included doctors not recommending it due to underlying diseases (34.1%), not being ready for it (18.3%), and failure to make an appointment (9.1%). General older adults who were aged below 70, had a high school and above education, were permanent residents of Shenzhen, were with good health and had pneumonia vaccination history were more likely to take the COVID-19 vaccination. Yet, among older adults with chronic diseases, other than age and permanent residency status, health status was the only significant indicator of COVID-19 vaccine uptake. Our study added to evidence that health condition is the critical barrier to the actual uptake of the COVID-19 vaccine among Chinese older adults, especially those aged 80 and above and those with chronic diseases.

Bergapten alleviates depression-like behavior by inhibiting cyclooxygenase 2 activity and NF-κB/MAPK signaling pathway in microglia.

Major depressive disorder (MDD) is a common psychiatric disorder that severely affects human life and health. However, the pathological mechanism of MDD is unclear, and effective treatment strategies are urgently needed. Microglia-mediated neuroinflammation is closely associated with the pathophysiology of depression. Bergapten (BG) is a natural pharmaceutical monomer with anti-inflammatory effects; however, its role in neuroinflammation and depression remains unclear. In this study, we employed a lipopolysaccharide (LPS) injection-induced acute depression mouse model, and found that treatment with BG significantly alleviated LPS-induced depression-like behavior in mice. BG administration largely decreased the increase in microglial numbers and rescued the microglial morphological changes induced by LPS injection. Furthermore, transcriptomic changes revealed a protective role of BG in the hippocampus of mice. Mechanistically, we found that BG directly inhibited cyclooxygenase 2 (COX2) activity, and suppressed nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways in microglia. Together, these results highlight the important role of BG in microglial activation, neuroinflammation, and depression-like behavior, thus providing a new candidate drug for depression treatment.