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.

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.

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.

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.

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.

Differential effects of sleep deprivation on behavior and microglia in a brain-region-specific manner in young and aged male mice.

Microglia, resident immune cells in the central nervous system, constantly monitor the state of the surrounding brain activity. The animal model induced by sleep deprivation (SD) is widely used to study the pathophysiological mechanisms of insomnia and bipolar disorder. However, it remains unclear whether SD affects behaviors in young and aged male mice and microglia in various brain regions. In this study, we confirmed brain region-specific changes in microglial density and morphology in the accumbens nucleus (Acb), amygdala (AMY), cerebellum (Cb), corpus callosum (cc), caudate putamen, hippocampus (HIP), hypothalamus (HYP), medial prefrontal cortex (mPFC), and thalamus (TH) of young mice. In addition, the density of microglia in old mice was higher than that in young mice. Compared with young mice, old mice showed a markedly increased microglial size, decreased total length of microglial processes, and decreased maximum length. Importantly, we found that 48-h SD decreased microglial density and morphology in old mice, whereas SD increased microglial density and morphology in most observed brain regions in young mice. SD-induced hyperactivity was observed only in young mice but not in old mice. Moreover, microglial density (HIP, AMY, mPFC, CPu) was significantly positively correlated with behaviors in SD- and vehicle-treated young mice. Contrarily, negative correlations were shown between the microglial density (cc, Cb, TH, HYP, Acb, AMY) and behaviors in vehicle-treated young and old mice. These results suggest that SD dysregulates the homeostatic state of microglia in a region- and age-dependent manner. Microglia may be involved in regulating age-related behavioral responses to SD.

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.

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.

Cutting Weights of Deep Learning Models for Heart Sound Classification: Introducing a Knowledge Distillation Approach.

Cardiovascular diseases (CVDs) are the number one cause of death worldwide. In recent years, intelligent auxiliary diagnosis of CVDs based on computer audition has become a popular research field, and intelligent diagnosis technology is increasingly mature. Neural networks used to monitor CVDs are becoming more complex, requiring more computing power and memory, and are difficult to deploy in wearable devices. This paper proposes a lightweight model for classifying heart sounds based on knowledge distillation, which can be deployed in wearable devices to monitor the heart sounds of wearers. The network model is designed based on Convolutional Neural Networks (CNNs). Model performance is evaluated by extracting Mel Frequency Cepstral Coefficients (MFCCs) features from the PhysioNet/CinC Challenge 2016 dataset. The experimental results show that knowledge distillation can improve a lightweight network's accuracy, and our model performs well on the test set. Especially, when the knowledge distillation temperature is 7 and the weight α is 0.1, the accuracy is 88.5 %, the recall is 83.8 %, and the specificity is 93.6 %.Clinical relevance- A lightweight model of heart sound classification based on knowledge distillation can be deployed on various hardware devices for timely monitoring and feedback of the physical condition of patients with CVDs for timely provision of medical advice. When the model is deployed on the medical instruments of the hospital, the condition of severe and hospitalised patients can be timely fed back and clinical treatment advice can be provided to the clinicians.

One-dimensional carbon based nanoreactor fabrication by electrospinning for sustainable catalysis.

An efficient and economical electrocatalyst as kinetic support is key to electrochemical reactions. For this reason, chemists have been working to investigate the basic changing of chemical principles when the system is confined in limited space with nanometer-scale dimensions or sub-microliter volumes. Inspired by biological research, the design and construction of a closed reaction environment, namely the reactor, has attracted more and more interest in chemistry, biology, and materials science. In particular, nanoreactors became a high-profile rising star and different types of nanoreactors have been fabricated. Compared with the traditional particle nanoreactor, the one-dimensional (1D) carbon-based nanoreactor prepared by the electrospinning process has better electrolyte diffusion, charge transfer capabilities, and outstanding catalytic activity and selectivity than the traditional particle catalyst which has great application potential in various electrochemical catalytic reactions.

Distinct inhibitory strength of bisphenol A analogues on human and rat 11ß-hydroxysteroid dehydrogenase 1: 3D quantitative structure-activity relationship and in silico molecular docking analysis.

Bisphenol A (BPA) analogues are developed to replace BPA usage. However, their effects on 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) are largely unknown. The inhibitory effects of BPA and 10 BPA analogues with the substituents on the bridge moiety on human and rat 11ß-HSD1 were explored in human and rat liver microsomes. The strength of inhibiting human 11ß-HSD1 was bisphenol FL (IC50, 3.87 µM) > bisphenol Z (6.86 µM) > bisphenol AF (9.42 µM) > bisphenol C (16.14 µM) > bisphenol AP (32.14 µM) = bisphenol B (32.34 µM) > 4,4'-thiodiphenol (67.35 µM) > BPA (297.35 µM) > other BPA analogues (ineffective at 100 µM). The strength of inhibiting rat 11ß-HSD1 was bisphenol Z (IC50, 14.44 µM) > 4,4'-thiodiphenol (19.01 µM) > bisphenol B (20.13 µM) > bisphenol F (22.10 µM) > bisphenol E (33.04 µM) > bisphenol AF (49.67 µM) > bisphenol C > (56.97 µM) > bisphenol AP (62.71 µM) >bisphenol FL (96.31 µM) > other BPA analogues (ineffective at 100 µM). Bisphenol A, AF, AP, B, C, F, FL, Z, and 4,4'-thiodiphenol bind to the active sites of human and rat 11ß-HSD1. Regression of LogP and molecular weight with IC50 values revealed distinct inhibitory pattern (negative correlation for human 11ß-HSD1 vs. positive correlation for rat enzyme). Regression of the lowest binding energy with IC50 values revealed a significant positive regression. 3D QSAR pharmacophore analysis showed one hydrogen bond acceptor and two hydrogen bond donors for human 11ß-HSD1. In conclusion, most BPA analogues are more potent inhibitors of human and rat 11ß-HSD1 enzymes and there is structure-dependent and species-dependent inhibition.

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.

Exposure to 4-nonylphenol compromises Leydig cell development in pubertal male mice.

Exposure to 4-nonyl phenol (4-NP) on Leydig cell (LC) development and function remains poorly understood. We explored the effects of 4-NP on LC development and elucidate the underlying mechanisms. Male (28-day-old) mice received orally 4-NP (0.125, 0.25, and 0.5 mg/kg/day) for 28 days. We found that 4-NP at ≥ 0.125 mg/kg markedly compromised serum testosterone levels and LC numbers. Gene and protein expression analysis demonstrated downregulation of key genes and their proteins involved in LC steroidogenesis, including Star, Cyp11a1, Cyp17a1, Hsd17b3, Hsd3b6, and Scarb1. Furthermore, exposure to 4-NP induced oxidative stress, as evidenced by elevated reactive oxygen species (ROS) and malondialdehyde (MDA), as well as reduced superoxide dismutase 1/2 and catalase (CAT). Apoptosis was also observed in LCs following exposure to 4-NP, as shown by an increased BAX/BCL2 ratio and caspase-3. A TM3 mouse LC line further confirmed that 4-NP induced ROS and the expression of apoptosis-related genes and proteins. In conclusion, this study demonstrates that 4-NP exposure compromises LC development through multiple mechanisms.

Prevalence and associated risk factors for chronic kidney disease in the elderly physically disabled population in Shanghai, China: a cross-sectional study.

BACKGROUND: The global prevalence of chronic kidney disease (CKD) in the general population is relatively clear. Our previous study showed that elderly individuals who are physically disabled are more likely to experience kidney function impairment, and the main purpose of this study was to determine the prevalence and risk factors associated with CKD in elderly patients with physical disabilities. METHODS: A total of 2679 elderly individuals with physical disabilities from the 2018 Shanghai Disability Health Survey were screened to calculate the prevalence of CKD. Multiple logistic regression was performed to identify the factors associated with CKD. Detailed subgroup analyses of disability level were also conducted. RESULTS: We confirmed CKD in 287 of 2679 (10.7%) participants. Female sex, age, history of hypertension, red blood cell count, albumin, urea, and uric acid (UA) were independently correlated with CKD. Age and UA abnormalities were common risk factors for different levels of disabilities. CONCLUSION: The prevalence of CKD is higher in the mild level of older physically handicapped individuals. Age and the level of UA should also be considered in this population. The preventive strategies for patients with two levels of elderly disability should have different focuses.

Bisphenol analogues inhibit human and rat 17ß-hydroxysteroid dehydrogenase 1: 3D-quantitative structure-activity relationship (3D-QSAR) and in silico docking analysis.

Bisphenols, estrogenic endocrine-disrupting chemicals, disrupt at least one of three endocrine pathways (estrogen, androgen, and thyroid). 17ß-Hydroxysteroid dehydrogenase 1 (17ß-HSD1) is a steroidogenic enzyme that catalyzes the activation of estradiol from estrone in human placenta and rat ovary. However, whether bisphenols inhibit 17ß-HSD1 and the mode of action remains unclear. This study we screened 17 bisphenols for inhibiting human 17ß-HSD1 in placental microsomes and rat 17ß-HSD1 in ovarian microsomes and determined 3D-quantitative structure-activity relationship (3D-QSAR) and mode of action. We observed some bisphenols with substituents were found to significantly inhibit both human and rat 17ß-HSD1 with the most potent inhibition on human enzyme by bisphenol H (IC50 = 0.90 µM) when compared to bisphenol A (IC50 = 113.38 µM). Rat enzyme was less sensitive to the inhibition of bisphenols than human enzyme with bisphenol H (IC50 = 32.94 µM) for rat enzyme. We observed an inverse correlation between IC50 and hydrophobicity (expressed as Log P). Docking analysis showed that they bound steroid-binding site of 17ß-HSD1. The 3D-QSAR models demonstrated that hydrophobic region, hydrophobic aromatic, ring aromatic, and hydrogen bond acceptor are key factors for the inhibition of steroid synthesis activity of 17ß-HSD1.

Adsorption of levofloxacin by ultraviolet aging microplastics.

Microplastics can combine with pollutants such as antibiotics and pose a threat to the environment and organisms. At the same time, the inevitable aging behavior of microplastics in the actual environment leads to changes in their physical and chemical properties, and thus changes the reaction mechanism between microplastics and other pollutants. In this study, we used three common microplastics PE/PS/PA to study the adsorption behavior of levofloxacin hydrochloride. Ultraviolet aging method was used to simulate the aging process of levofloxacin hydrochloride under sunlight, and compared with that of before aging. The results showed that the order of adsorption capacity was PS-UV > PA-UV > PE-UV > PA > PS > PE. Aging behavior can significantly enhance the adsorption capacity of microplastics to pollutants. Both Langmuir and Freundlich models can be used to fit the isothermal adsorption process well, indicating that the adsorption process was not a simple monolayer adsorption, but also a multi-molecular layer adsorption. The experiments showed that the adsorption process was affected by various mechanisms, including π-π conjugation, hydrogen bond, ion exchange and electrostatic interaction. This study elucidated the interaction mechanism between microplastics and levofloxacin hydrochloride, which has important significance for future control of microplastics and antibiotic pollution.

Erythrocyte ENT1-AMPD3 Axis is an Essential Purinergic Hypoxia Sensor and Energy Regulator Combating CKD in a Mouse Model.

SIGNIFICANCE STATEMENT: Hypoxia drives kidney damage and progression of CKD. Although erythrocytes respond rapidly to hypoxia, their role and the specific molecules sensing and responding to hypoxia in CKD remain unclear. In this study, we demonstrated in a mouse model that erythrocyte ENT1-AMPD3 is a master energy regulator of the intracellular purinergic hypoxic compensatory response that promotes rapid energy supply from extracellular adenosine, eAMPK-dependent metabolic reprogramming, and O 2 delivery, which combat renal hypoxia and progression of CKD. ENT1-AMPD3-AMPK-BPGM comprise a group of circulating erythroid-specific biomarkers, providing early diagnostic and novel therapeutic targets for CKD. BACKGROUND: Hypoxia drives kidney damage and progression of CKD. Although erythrocytes respond rapidly to hypoxia, their role and the specific molecules sensing and responding to hypoxia in CKD remain unclear. METHODS: Mice with an erythrocyte-specific deficiency in equilibrative nucleoside transporter 1 ( eEnt1-/- ) and a global deficiency in AMP deaminase 3 ( Ampd3-/- ) were generated to define their function in two independent CKD models, including angiotensin II (Ang II) infusion and unilateral ureteral obstruction (UUO). Unbiased metabolomics, isotopic adenosine flux, and various biochemical and cell culture analyses coupled with genetic studies were performed. Translational studies in patients with CKD and cultured human erythrocytes examined the role of ENT1 and AMPD3 in erythrocyte function and metabolism. RESULTS: eEnt1-/- mice display severe renal hypoxia, kidney damage, and fibrosis in both CKD models. The loss of eENT1-mediated adenosine uptake reduces intracellular AMP and thus abolishes the activation of AMPK α and bisphosphoglycerate mutase (BPGM). This results in reduced 2,3-bisphosphoglycerate and glutathione, leading to overwhelming oxidative stress in eEnt1-/- mice. Excess reactive oxygen species (ROS) activates AMPD3, resulting in metabolic reprogramming and reduced O 2 delivery, leading to severe renal hypoxia in eEnt1-/- mice. By contrast, genetic ablation of AMPD3 preserves the erythrocyte adenine nucleotide pool, inducing AMPK-BPGM activation, O 2 delivery, and antioxidative stress capacity, which protect against Ang II-induced renal hypoxia, damage, and CKD progression. Translational studies recapitulated the findings in mice. CONCLUSION: eENT1-AMPD3, two highly enriched erythrocyte purinergic components that sense hypoxia, promote eAMPK-BPGM-dependent metabolic reprogramming, O 2 delivery, energy supply, and antioxidative stress capacity, which mitigates renal hypoxia and CKD progression.