Endocrine-Disrupting Effects of Salicylate Preservatives on Neurosteroidogenesis: Targeting 5α-Reductase Type 1.

Salicylate preservatives are widely used in consumer products and pharmaceuticals. This study investigates their potential endocrine-disrupting effects on neurosteroidogenesis, focusing on 5α-reductase type 1 (SRD5A1). We evaluated the effects of 13 salicylates on human SRD5A1 using SF126 glioblastoma cell microsomes and rat brain microsomes, examining dihydrotestosterone production in SF126 cells. Results revealed a hierarchy of inhibitory potency against human SRD5A1, with methyl salicylate (IC50, 71.93 µM) to menthyl salicylate (2.41 µM), indicating increasing potency. Kinetic analysis indicates their mixed/noncompetitive inhibitions. In SF126 cells, all salicylates at 100 µM significantly reduced dihydrotestosterone production. Rat SRD5A1 showed reduced sensitivity, with menthyl salicylate as the most potent inhibitor (IC50, 17.12 µM). Docking analysis suggests salicylates bind to the reduced nicotinamide adenine dinucleotide phosphate site of both human and rat SRD5A1. Bivariate correlation analysis highlights the influence of LogP, molecular weight, carbon number in the alcohol moiety, and pKa on inhibitory potency. 3D-QSAR revealed the importance of hydrophobic aromatic regions in SRD5A1 binding. This study delineates the inhibitory effects of salicylates and binding mechanisms on human and rat SRD5A1, providing insights into their impact on neurosteroid production.

FePt/MnO2@PEG Nanoparticles as Multifunctional Radiosensitizers for Enhancing Ferroptosis and Alleviating Hypoxia in Osteosarcoma Therapy.

Radiotherapy (RT) is a widely used cancer treatment, and the use of metal-based nanoradiotherapy sensitizers has demonstrated promise in enhancing its efficacy. However, achieving effective accumulation of these sensitizers within tumors and overcoming resistance induced by the hypoxic tumor microenvironment remain challenging issues. In this study, we developed FePt/MnO2@PEG nanoparticles with multiple radiosensitizing mechanisms, including high-atomic-number element-mediated radiation capture, catalase-mimicking oxygenation, and GSH depletion-induced ferroptosis. Both in vitro and in vivo experiments were conducted to validate the radiosensitizing mechanisms and therapeutic efficacy of FePt/MnO2@PEG. In conclusion, this study presents a novel and clinically relevant strategy and establishes a safe and effective combination radiotherapy approach for cancer treatment. These findings hold significant potential for improving radiotherapy outcomes and advancing the field of nanomedicine in cancer therapy.

Physical activity modifies the association between atherogenic index of plasma and prediabetes and diabetes: A cross-sectional analysis.

BACKGROUND: Although research has explored the association between atherogenic index of plasma (AIP) and prediabetes and diabetes, there is still not sufficient available evidence the role of physical activity (PA) in this relationship. Our purpose is to examine the complex connections between AIP, PA, and prediabetes and diabetes in a young and middle-aged population. METHODS: This study included 2220 individuals from the general population, aged 20-60 years. AIP was calculated from the logarithm of the triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio. PA was assessed depending to the American Heart Association (AHA) criteria and categorized into medium-high and low PA levels. We used binary logistic regression to explore associations and subsequently performed sensitivity and subgroup analyses. RESULTS: The 2220 participants had a mean age of 38 years, with a mean AIP of -0.1185, and a prediabetes and diabetes prevalence of 7.2%. After adjusting for auxiliary variables, AIP was positively correlated with prediabetes and diabetes (odds ratio [OR]: 3.447, 95% confidence interval [CI]: 1.829-6.497). In the low PA population, the prevalence of prediabetes and diabetes raised significantly with higher AIP (OR: 3.678, 95% CI: 1.819-7.434). This association was not meaningful in the medium to high PA population (OR: 1.925, 95% CI: 0.411-9.007). Joint and sensitivity analyze results also showed agreement. Restricted cubic spline identified a linear relationship between AIP and the prevalence of prediabetes and diabetes. Notably, the prevalence significantly increases when AIP values exceed -0.16 (p for linearity <0.05). The findings revealed heterogeneity across subgroups stratified by sex and age. CONCLUSIONS: PA may modify the link as regards AIP with prediabetes and diabetes in young and middle-aged populations. Adherence to PA prevents the adverse effects of abnormal glucose metabolism caused by dyslipidemia, particularly in women.

The role of vitreous cortex remnants in secondary macular hole formation and spontaneous closure following vitrectomy for rhegmatogenous retinal detachment.

BACKGROUND: Macular hole (MH) formation after rhegmatogenous retinal detachment (RRD) surgery is rare, and in most cases, additional surgical procedures are required to repair MH. Spontaneous closure of the MH is even rarer. In this study, we aimed to report a series of cases of spontaneous closure of the secondary MH and provide a review of the literature. METHODS: We retrospectively collected the cases of secondary MH formation following vitrectomy in RRD patients followed by spontaneous closure. Ophthalmological data at presentation and during follow-up were collected and analyzed. RESULTS: We reported a total of three RRD patients aged 31,67,12 years, including two females and one male. The three patients underwent pars plana vitrectomy (PPV) with either silicone oil tamponade or air tamponade. Optical coherence tomography (OCT) revealed a second full-thickness MH formation with remnant vitreous cortex bridging in the macular region during early follow-up. Observations of the cases revealed subsequent remnant vitreous cortex traction remission and spontaneous closure of MH during follow-up, although with subsequent thin macular and abnormal macular structure. CONCLUSION: The progression of secondary MH formation in the cases may be related to vitreomacular traction (VMT) by the posterior vitreous cortex remnant after PPV, and the release of VMT may help the spontaneous closure of the MH after PPV for RRD.

Inhibition of human and rat placental 3ß-hydroxysteroid dehydrogenases by bisphenol A analogues depends on their hydrophobicity: In silico docking analysis.

Bisphenol A (BPA) and its analogues are widely used industrial chemicals. Placental 3ß-hydroxysteroid dehydrogenases (3ß-HSDs) catalyse the conversion of pregnenolone to progesterone. However, the potency of BPA analogues in inhibiting 3ß-HSDs activity remains unclear. We investigated the inhibitory effect of 10 BPA analogues on 3ß-HSDs activity using an in vitro assay and performed the structure-activity relationship and in silico docking analysis. BPH was the most potent inhibitor of human 3ß-HSD1, with an IC50 value of 0.95 µM. BPFL, BPG, DABPA, BPAP, BPZ, DMBPA, and BPB also inhibited human 3ß-HSD1 activity, albeit with lower potency. BPG was the most potent inhibitor of rat 3ß-HSD4, with an IC50 value of 1.14 µM. BPAP, BPFL, BPG, BPH, BPZ, DABPA, and DMBPA are mixed inhibitors of human 3ß-HSD1 and they significantly inhibited human JAr cells to secrete progesterone. The LogP values were inversely correlated with the inhibitory effects. Docking analysis showed that most BPA analogues bind to steroid-binding site of both 3ß-HSDs. A pharmacophore containing hydrogen bond donor and hydrophobic region was generated for predicting the inhibitory strength of BPA analogues. In conclusion, this study demonstrates that some BPA analogues are potent inhibitors of 3ß-HSDs and lipophilicity determines the inhibitory potency.

Low-temperature magnetic properties of theS= 1/2 kagomé antiferromagnet YCo3(OH)6.55Br2.45.

We report the synthesis, crystal structure, magnetization and specific heat studies of YCo3(OH)6.55Br2.45single crystal. YCo3(OH)6.55Br2.45crystallizes in trigonal structure, in which Co2+ions form a perfect kagomé lattice. The magnetic susceptibility reveals successive magnetic transitions at 6.5 and 7.8 K and the Curie-Weiss fitting demonstrates that YCo3(OH)6.55Br2.45has strong antiferromagnetic coupling and pronounced magnetic frustration effect. Specific heat data suggest that low-Tmagnetic transitions are attributed to antiferromagnetic ordering of Co2+ions and the magnetic entropy points to effective 1/2 spin in the system. These results indicate that an unusual magnetic ordering state with effective spin-1/2 is realized in kagomé lattice system YCo3(OH)6.55Br2.45.

NL13, a novel curcumin analogue and polo like kinase 4 inhibitor, induces cell cycle arrest and apoptosis in prostate cancer models.

BACKGROUND AND PURPOSE: Prostate cancer remains a major public health burden worldwide. Polo like kinase 4 (PLK4) has emerged as a promising therapeutic target in prostate cancer due to its key roles in cell cycle regulation and tumour progression. This study aims to develop and characterize the novel curcumin analogue NL13 as a potential therapeutic agent and PLK4 inhibitor against prostate cancer. EXPERIMENTAL APPROACH: NL13 was synthesized and its effects were evaluated in prostate cancer cells and mouse xenograft models. Kinome screening and molecular modelling identified PLK4 as the primary target. Antiproliferative and proapoptotic mechanisms were explored via cell cycle, apoptosis, gene and protein analyses. KEY RESULTS: Compared with curcumin, NL13 exhibited much greater potency in inhibiting PC3 (IC50, 3.51 µM vs. 35.45 µM) and DU145 (IC50, 2.53 µM vs. 29.35 µM) prostate cancer cells viability and PLK4 kinase activity (2.32 µM vs. 246.88 µM). NL13 induced G2/M cell cycle arrest through CCNB1/CDK1 down-regulation and triggered apoptosis via caspase-9/caspase-3 cleavage. These effects were mediated by PLK4 inhibition, which led to the inactivation of the AKT signalling pathway. In mice, NL13 significantly inhibited tumour growth and modulated molecular markers consistent with in vitro findings, including decreased p-AKT and increased cleaved caspase-9/3. CONCLUSION AND IMPLICATIONS: NL13, a novel PLK4-targeted curcumin analogue, exerts promising anticancer properties against prostate cancer by disrupting the PLK4-AKT-CCNB1/CDK1 and apoptosis pathways. NL13 represents a promising new agent for prostate cancer therapy.

Extremely Large Anomalous Hall Conductivity and Unusual Axial Diamagnetism in a Quasi-1D Dirac Material La3MgBi5.

Anomalous Hall effect (AHE), one of the most important electronic transport phenomena, generally appears in ferromagnetic materials but is rare in materials without magnetic elements. Here, a study of La3MgBi5 is presented, whose band structure carries multitype Dirac fermions. Although magnetic elements are absent in La3MgBi5, the signals of AHE can be observed. In particular, the anomalous Hall conductivity is extremely large, reaching 42,356 Ω-1 cm-1 with an anomalous Hall angle of 8.8%, the largest one that has been observed in the current AHE systems. The AHE is suggested to originate from the combination of skew scattering and Berry curvature. Another unique property discovered in La3MgBi5 is the axial diamagnetism. The diamagnetism is significantly enhanced and dominates the magnetization in the axial directions, which is the result of the restricted motion of the Dirac fermion at the Fermi level. These findings not only establish La3MgBi5 as a suitable platform to study AHE and quantum transport but also indicate the great potential of 315-type Bi-based materials for exploring novel physical properties.

A Novel Melanin-Targeted 18F-PFPN Positron Emission Tomography Imaging for Diagnosing Ocular and Orbital Melanoma.

OBJECTIVE: 18F-N-(2-(Diethylamino)ethyl)-5-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy) picolinamide (18F-PFPN) is a novel positron emission tomography (PET) probe designed to specifically targets melanin. This study aimed to evaluate the diagnostic feasibility of 18F-PFPN in patients with ocular or orbital melanoma. MATERIALS AND METHODS: Three patients with pathologically confirmed ocular or orbital melanoma (one male, two females; age 41-59 years) were retrospectively reviewed. Each patient underwent comprehensive 18F-PFPN and 18F-fluorodeoxyglucose (18F-FDG) PET scans. The maximum standardized uptake value (SUVmax) of the lesion and the interference caused by background tissue were compared between 18F-PFPN and 18F-FDG PET imaging. In addition, the effect of intrinsic pigments in the uvea and retina on the interpretation of the results was examined. The contralateral non-tumorous eye of each patient served as a control. RESULTS: All primary tumors (3/3) were detected using 18F-PFPN PET, while only two primary tumors were detected using 18F-FDG PET. Within each lesion, the SUVmax of 18F-PFPN was 2.6 to 8.3 times higher than that of 18F-FDG. Regarding the quality of PET imaging, the physiological uptake of 18F-FDG PET in the brain and periocular tissues limited the imaging of tumors. However, 18F-PFPN PET minimized this interference. Notably, intrinsic pigments in the uvea and retina did not cause abnormal concentrations of 18F-PFPN, as no anomalous uptake of 18F-PFPN was detected in the healthy contralateral eyes. CONCLUSION: Compared to 18F-FDG, 18F-PFPN demonstrated higher detection rates for ocular and orbital melanomas with minimal interference from surrounding tissues. This suggests that 18F-PFPN could be a promising clinical diagnostic tool for distinguishing malignant melanoma from benign pigmentation in ocular and orbital melanomas.

Triclosan inhibits testosterone biosynthesis in adult rats via inducing m6A methylation-mediated autophagy.

Triclosan is a potent antibacterial compound widely used in everyday products. Whether triclosan affects Leydig cell function in adult male rats remains unknown. In this study, 0, 50, 100, or 200 mg/kg/day triclosan was gavaged to Sprague-Dawley male rats from 56 to 63 days postpartum. Triclosan significantly reduced serum testosterone levels at ≥ 50 mg/kg/day via downregulating the expression of Leydig cell gene Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, and Hsd17b3 and regulatory transcription factor Nr3c2 at 100-200 mg/kg. Further analysis showed that triclosan markedly increased autophagy as shown by increasing LC3II and BECN1 and decreasing SQSTM1. The mRNA m6A modification analysis revealed that triclosan significantly downregulated Fto expression at 200 mg/kg while upregulating Ythdf1 expression at 100 and 200 mg/kg, leading to methylation of Becn1 mRNA as shown by MeRIP assay. Triclosan significantly inhibited testosterone output in rat R2C Leydig cells at ≥ 5 µM via downregulating Fto and upregulating Ythdf1. SiRNA Ythdf1 knockdown can reverse triclosan-mediated mitophagy in R2C cells, thereby reversing the reduction of testosterone output. In summary, triclosan caused Becn1 m6A methylation by downregulating Fto and upregulating Ythdf1, which accelerated Becn1 translation, thus leading to the occurrence of autophagy and the decrease of testosterone biosynthesis.

Carbon-chain length determines the binding affinity and inhibitory strength of per- and polyfluoroalkyl substances on human and rat steroid 5α-reductase 1 activity.

Per- and polyfluoroalkyl substances (PFAS) are widely used synthetic chemicals that persist in the environment and bioaccumulate in animals and humans. There is growing evidence that PFAS exposure adversely impacts neurodevelopment and neurological health. Steroid 5α-reductase 1 (SRD5A1) plays a key role in neurosteroidogenesis by catalyzing the conversion of testosterone or pregnenolone to neuroactive steroids, which influence neural development, cognition, mood, and behavior. This study investigated the inhibitory strength and binding interactions of 18 PFAS on human and rat SRD5A1 activity using enzyme assays, molecular docking, and structure-activity relationship analysis. Results revealed that C9-C14 PFAS carboxylic acid at 100 µM significantly inhibited human SRD5A1, with IC50 values ranged from 10.99 µM (C11) to 105.01 µM (C14), and only one PFAS sulfonic acid (C8S) significantly inhibited human SRD5A1 activity, with IC50 value of 8.15 µM. For rat SRD5A1, C9-C14 PFAS inhibited rat SRD5A1, showing the similar trend, depending on carbon number of the carbon chain. PFAS inhibit human and rat SRD5A1 in a carbon chain length-dependent manner, with optimal inhibition around C11. Kinetic studies indicated PFAS acted through mixed inhibition. Molecular docking revealed PFAS bind to the domain between NADPH and testosterone binding site of both SRD5A1 enzymes. Inhibitory potency correlated with physicochemical properties like carbon number of the carbon chain. These findings suggest PFAS may disrupt neurosteroid synthesis and provide insight into structure-based inhibition of SRD5A1.

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.

Anomalous Hall effect and magnetic transition in the kagome material YbMn6Sn6.

We investigate the magnetic and transport properties of a kagome magnet YbMn6Sn6. We have grown YbMn6Sn6single crystals having a HfFe6Ge6type structure with ordered Yb and Sn atoms, which is different from the distorted structure previously reported. The single crystal undergoes a ferromagnetic phase transition around 300 K and a ferrimagnetic transition at approximately 30 K, and the magnetic transition at low temperature may be correlated to the ordered Yb sublattice. Negative magnetoresistance has been observed at high temperatures, while the positive magnetoresistance appears at 5 K when the current is oriented out of kagome plane. We observe a large anisotropic anomalous Hall effect with the intrinsic Hall contribution of 141 Ω-1cm-1forσzxintand 32 Ω-1cm-1forσxyint, respectively. These values are similar to those in YMn6Sn6with the same anisotropy. The magnetic transition and anomalous Hall behavior in YbMn6Sn6highlights the influence of the ordered Yb atoms and rare earth elements on its magnetic and transport properties.

Single-cell RNA-seq reveals T cell exhaustion and immune response landscape in osteosarcoma.

Background: T cell exhaustion in the tumor microenvironment has been demonstrated as a substantial contributor to tumor immunosuppression and progression. However, the correlation between T cell exhaustion and osteosarcoma (OS) remains unclear. Methods: In our present study, single-cell RNA-seq data for OS from the GEO database was analysed to identify CD8+ T cells and discern CD8+ T cell subsets objectively. Subgroup differentiation trajectory was then used to pinpoint genes altered in response to T cell exhaustion. Subsequently, six machine learning algorithms were applied to develop a prognostic model linked with T cell exhaustion. This model was subsequently validated in the TARGETs and Meta cohorts. Finally, we examined disparities in immune cell infiltration, immune checkpoints, immune-related pathways, and the efficacy of immunotherapy between high and low TEX score groups. Results: The findings unveiled differential exhaustion in CD8+ T cells within the OS microenvironment. Three genes related to T cell exhaustion (RAD23A, SAC3D1, PSIP1) were identified and employed to formulate a T cell exhaustion model. This model exhibited robust predictive capabilities for OS prognosis, with patients in the low TEX score group demonstrating a more favorable prognosis, increased immune cell infiltration, and heightened responsiveness to treatment compared to those in the high TEX score group. Conclusion: In summary, our research elucidates the role of T cell exhaustion in the immunotherapy and progression of OS, the prognostic model constructed based on T cell exhaustion-related genes holds promise as a potential method for prognostication in the management and treatment of OS patients.

Halogenated bisphenol A derivatives potently inhibit human and rat 11ß-hydroxysteroid dehydrogenase 1: Structure-activity relationship and molecular docking.

Chlorinated bisphenol A (BPA) derivatives are formed during chlorination process of drinking water, whereas bisphenol S (BPS) and brominated BPA and BPS (TBBPA and TBBPS) were synthesized for many industrial uses such as fire retardants. However, the effect of halogenated BPA and BPS derivatives on glucocorticoid metabolizing enzyme 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) remains unclear. The inhibitory effects of 6 BPA derivatives in the inhibition of human and rat 11ß-HSD1 were investigated. The potencies for inhibition on human 11ß-HSD1 were TBBPA (IC50, 3.87 µM) = monochloro BPA (MCBPA, 4.08 µM) = trichloro BPA (TrCBPA, 4.41 µM) > tetrachloro BPA (TCBPA, 9.75 µM) > TBBPS (>100 µM) = BPS (>100 µM), and those for rat 11ß-HSD1 were TrCBPA (IC50, 2.76 µM) = MCBPA (3.75 µM) > TBBPA (39.58 µM) > TCBPA = TBBPS = BPS. All these BPA derivatives are mixed/competitive inhibitors of both human and rat enzymes. Molecular docking studies predict that MCBPA, TrCBPA, TCBPA, and TBBPA all bind to the active site of human 11ß-HSD1, forming hydrogen bonds with catalytic residue Ser170 except TCBPA. Regression of the lowest binding energy with IC50 values revealed a significant inverse linear regression. In conclusion, halogenated BPA derivatives are mostly potent inhibitors of human and rat 11ß-HSD1, and there is structure-dependent inhibition.

Perfluorotetradecanoic acid exposure to adult male rats stimulates corticosterone biosynthesis but inhibits aldosterone production.

Perfluorotetradecanoic acid (PFTeDA) is a novel perfluoroalkyl substance that ubiquitously exists in the environment. However, whether PFTeDA affects adrenal cortex function remains unclear. Male Sprague-Dawley rats (age of 60 days) were daily administered with PFTeDA (0, 1, 5, and 10 mg/kg body weight) through gavage for 28 days. PFTeDA did not change body and adrenal gland weights. PFTeDA markedly elevated serum corticosterone level at 10 mg/kg but lowering serum aldosterone level at this dosage without influencing serum adrenocorticotropic hormone level. PFTeDA thickened zona fasciculata without affecting zona glomerulosa. PFTeDA remarkably upregulated the expression of corticosterone biosynthetic genes (Mc2r, Scarb1, Star, Cyp21, Cyp11b1, and Hsd11b1) and their proteins, whereas downregulating aldosterone biosynthetic enzyme Cyp11b2 and its protein, thereby distinctly altering their serum levels. PFTeDA markedly downregulated the expression of antioxidant genes (Sod1 and Sod2) and their proteins at 10 mg/kg. PFTeDA significantly decreased SIRT1/PGC1α and AMPK signaling while stimulating AKT1/mTOR signaling. Corticosterone significantly inhibited testosterone production by adult Leydig cells at >0.1 µM in vitro; however aldosterone significantly stimulated testosterone production at 0.1 nM. In conclusion, exposure to PFTeDA at male rat adulthood causes corticosterone excess and aldosterone deficiency via SIRT1/PGC1α, AMPK, and AKT1/mTOR signals, which in turn additively leads to testosterone deficiency.

Are physically disabled people at high risk of coronary heart disease among disabled population - Evidence from 7.5-year retrospective cohort study.

OBJECTIVES: Previous cross-sectional studies suggested that people with physical disabilities (one of the subgroups of disabled people) are associated with an increased risk of cardiovascular diseases (CVD) than healthy peers. However, a longitudinal cohort of disabled people exhibited a different trend, in which the study populations were similar in health inequalities. We aimed to examine whether physical disability was associated with an increased risk of coronary heart disease (CHD) among disabled people. STUDY DESIGN AND SETTING: This retrospective cohort study from the Shanghai Health Examination Program included a total of 6419 disabled adults (50.77 [9.88] age) with complete electronic health records and were free of CHD at baseline (2012) were followed-up for a 7.5-year period until 2019. The physical disability and non-physical disability subgroups were characterized based on the Disability Classification and Grading Standard (GB/T 26341-2010). Multivariable Cox regression analyses were used to evaluate adjusted hazard ratios (HR) for subsequent CHD, while Kaplan-Meier curves was used to assess the proportional hazards assumption. We conducted subgroup analyses based on gender, levels of disability, and baseline blood pressure. RESULTS: Kaplan-Meier analysis revealed a higher incidence of CHD in the physical disability group compared to the non-physical disability group during the 7.5-year follow-up period (P < 0.05). Subjects with physical disabilities exhibited an increased risk for subsequent CHD occurrence (HR: 1.12; 95% CI: 1.03-1.31), compared to the non-physical subgroup after adjustments for confounders. The sensitivity analysis conducted on subgroups according to gender and disability severity indicated that moderate physical disability and female physical disability were associated with a higher prevalence of CHD, which was confirmed by multi-adjusted regression analysis. The spline curves of BP and CHD indicated that the physical disability group displayed lower SBP and DBP thresholds of 120 mmHg and SBP, respectively. CONCLUSION: Within the disabled population, individuals with physical disability are at higher risk of developing CHD, and it is plausible that their optimal BP threshold for CHD prevention may need to be set at a lower level. Further research is essential to investigate BP management among individuals with physical disabilities and its influence on cardiovascular-related adverse events.

Comparison of structure-activity relationship for bisphenol analogs in the inhibition of gonadal 3ß-hydroxysteroid dehydrogenases among human, rat, and mouse.

Bisphenol A (BPA) is a widely used plastic material and its potential endocrine disrupting effect has restricted its use and increasing use of BPA alternatives has raised health concerns. However, the effect of bisphenol alternatives on steroidogenesis remains unclear. The objective of this study was to compare inhibitory potencies of 10 BPA alternatives in the inhibition of gonadal 3ß-hydroxysteroid dehydrogenase (3ß-HSD) in three species (human, rat and mouse). The inhibitory potency for human 3ß-HSD2, rat 3ß-HSD1, and mouse 3ß-HSD6 ranged from bisphenol FL (IC50, 3.32 µM for human, 5.19 µM for rat, and 3.26 µM for mouse) to bisphenol E, F, and thiodiphenol (ineffective at 100 µM). Most BPA alternatives were mixed inhibitors of gonadal 3ß-HSD and they dose-dependently inhibited progesterone formation in KGN cells. Molecular docking analysis showed that all BPA analogs bind to steroid and NAD+ active sites. Lipophilicity of BPA alternatives was inversely correlated with IC50 values. In conclusion, BPA alternatives mostly can inhibit gonadal 3ß-HSDs and lipophilicity determines their inhibitory strength.

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.

Observation of the possible magnetic correction above the Curie temperature in Cr2Si2Te6 single crystals.

Intrinsic magnetic semiconductors hold great promise in the fields of fundamental magnetization and spintronics. One such semiconductor is Cr2Si2Ti6 (CST), a quasi two-dimensional (2D) magnetic semiconductor with potential applications in future magnetic devices. However, the origin of ferromagnetism in CST remains a mystery. To investigate this, ac/dc susceptibility and electronic spin resonance (ESR) measurements were conducted. Based on ac susceptibility scaling, the critical temperature (TC) for the ferromagnetic (FM) to paramagnetic (PM) phase transition was found to be ∼32.5 K, with a critical exponent of δ = 6.7 from the critical isotherm, ß + γ = 1.72 from the temperature dependence of the crossover line, and γ = 1.43 from the temperature dependence of susceptibility along the same line. All critical exponents were found to be consistent with the dc magnetization scaling method. However, above and below TC, the origin of magnetism cannot be explained by a single theory. To explore the origin of abnormal magnetic critical behavior, ESR measurements were performed. Below T* ∼ 130 K, the ESR measurements revealed that the resonance field width (ΔH) tends to increase and decrease for the applied magnetic field H parallel and perpendicular to the c axis, respectively, indicating the onset of magnetic interaction even in the PM state. Meanwhile, the deviation from Curie-Weiss behavior below T* also confirmed the occurrence of magnetic correlation above the TC in CST. These observations suggest that the competition and cooperation among the direct and indirect interactions, the structural distortion and the van der Waals interaction at high temperature should be considered to investigate the origin of anomalous magnetism in CST. The present results provide valuable insights into the nature of ferromagnetism in 2D magnetic semiconductors.