Bisphenol H exposure disrupts Leydig cell function in adult rats via oxidative stress-mediated m6A modifications: Implications for reproductive toxicity.

Bisphenol H (BPH) has emerged as a potential alternative to bisphenol A (BPA), which has been curtailed for use due to concerns over its reproductive and endocrine toxicity. This study investigates whether BPH exerts antiandrogenic effects by impairing Leydig cell function, a critical component in testosterone production. We administered orally BPH to adult male rats at doses of 0, 1, 10, and 100 mg/kg/day for 7 days. Notably, BPH treatment resulted in a dose-dependent reduction in testicular testosterone levels, with significant decreases observed at ≥ 1 mg/kg/day. Additionally, BPH affected the expression of key genes involved in steroidogenesis and cholesterol metabolism, including Nr5a1, Nr3c4, Lhcgr, Scarb1, and Star, at higher doses (10 and/or 100 mg/kg/day). The study also revealed alterations in antioxidant gene expression (Sod2 and Cat) and modulation of m6A-related genes (Ythdf1-3 and Foxo3) and their proteins. Through MeRIP-qPCR analysis, we identified increased m6A modifications in Scarb1 and Star genes following BPH exposure. In vitro experiments with primary Leydig cells confirmed that BPH enhanced oxidative stress and diminished testosterone production, which were partially mitigated by antioxidant vitamin E supplementation and Ythdf3 knockdown. Meanwhile, simultaneous administration of BPH and vitamin E to primary Leydig cells partially counteracted BPH-induced alterations in the Ythdf3 expression. Our findings underscore a novel mechanism by which BPH disrupts Leydig cell function through the oxidative stress-m6A modification-autophagy pathway, raising concerns about its potential reproductive toxicity.

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.

Comparative efficacy and safety of tenofovir amibufenamide vs tenofovir alafenamide in the initial 48-week treatment of high viral load chronic hepatitis B: A single-centre retrospective study.

BACKGROUND/AIM: Tenofovir amibufenamide (TMF) employs innovative ProTide technology and a methylation strategy to enhance the lipid solubility and plasma stability of the amide bond, providing advantages over tenofovir alafenamide (TAF). Despite promising Phase III clinical trial results demonstrating its antiviral efficacy, real-world data on TMF remains scarce. This study evaluates the antiviral efficacy and safety of TMF compared to TAF as the initial treatment in patients with high viral loads of chronic hepatitis B (CHB). METHODS: We retrospectively collected clinical data from March 1 2022 to June 30 2022 for highly viremic CHB patients who received either TMF (n = 58) or TAF (n = 32) as their initial monotherapy at Beijing YouAn Hospital. To understand the efficacy and safety of TMF over 48 weeks, we compared the virological response rates and HBeAg/HBsAg serological clearance rates between TMF and TAF groups. Also, the changes in serum creatinine, eGFR and serum lipid levels were assessed. RESULTS: Baseline median HBV DNA levels were 7.85 (6.89, 8.36) IgIU/ml for TMF and 7.44 (6.89, 8.03) IgIU/ml for TAF. Median ALT levels were 102.0 (56.0, 210.0) U/L for TMF and 195.0 (73.5, 371.0) U/L for TAF, with HBeAg positivity rates of 70.7% and 75.0%, respectively. At 48 weeks, virological response rates (HBV DNA <10 IU/ml) were 43.5% (20/46) for TMF and 42.9% (12/28) for TAF (p = 1.000). ALT normalization rates were 87.9% for TMF and 90.6% for TAF (p = .969), and HBeAg serological clearance rates were 21.1% and 18.2%, respectively (p = 1.000). No patients achieved HBsAg clearance. Compared with the baseline, LDL-C levels increased, while eGFR decreased, with no significant differences in serum creatinine, triglycerides and total cholesterol levels noted at week 48 for both TMF and TAF groups. CONCLUSION: TMF demonstrates comparable antiviral efficacy to TAF when used as initial therapy in highly viremic CHB patients, with similar impacts on renal function and lipid profiles.

Bimetallic MOFs-Derived Metal Oxides Co3O4/SnO2 Microspheres for Ultrahigh Response n-Butanol Gas Sensors.

The construction of p-n heterojunctions is expected to be one of the effective means to improve gas sensitivity. In this research, p-n heterojunctions are successfully constructed by metal oxides derived from metal-organic frameworks (MOFs). MOFs-derived bimetallic Co3O4/SnO2 microspheres are prepared by precipitation. Gas-sensing performance shows that the Co3O4/SnO2 sensor exhibits an extremely high response (Ra/Rg = 641) to 20 ppm of n-butanol at 200 °C, which is 19 times that of pristine SnO2. It can detect n-butanol gas at low concentrations, has good selectivity to alcohol gas, and reduces the interference of benzene gas. The improved gas sensitivity can be attributed to the formation of a stable heterojunction between Co3O4 and SnO2, resulting in a greater resistance change of Co3O4/SnO2. Co3O4/SnO2 inherits the characteristic of high specific surface area of MOFs, which provides abundant sites for the reaction of the target gas and oxygen molecules. Finally, the gas-sensing mechanism of the Co3O4/SnO2-based sensor is discussed in detail.

Human and rat gonadal 3ß-hydroxysteroid dehydrogenases are suppressed by dithiocarbamate fungicides via interacting with cysteine residues.

Dithiocarbamates have been widely used in various industrial applications, such as insecticides (ferbam) or drug (disulfiram). This study explored the inhibitory effects of dithiocarbamates on human and rat gonadal 3ß-hydroxysteroid dehydrogenases (3ß-HSD) and investigated the structure-activity relationship and mechanistic insights. The inhibitory activity of six dithiocarbamates and thiourea on the conversion of pregnenolone to progesterone was evaluated using human KGN cell and rat testicular microsomes, with subsequent progesterone measurement using HPLC-MS/MS. The study found that among the tested compounds disulfiram, ferbam, and thiram exhibited significant inhibitory activity against human 3ß-HSD2 and rat 3ß-HSD1, with ferbam demonstrating the highest potency. The mode of action for these compounds was characterized, showing mixed inhibition for human 3ß-HSD2 and mixed/noncompetitive inhibition for rat 3ß-HSD1. Additionally, it was observed that dithiothreitol dose-dependently reversed the inhibitory effects of dithiocarbamates on both human and rat gonadal 3ß-HSD enzymes. The study also delved into the penetration of these dithiocarbamates through the human KGN cell membrane and their impact on progesterone production, highlighting their potency in inhibiting human 3ß-HSD2. Furthermore, bivariate correlation analysis revealed a positive correlation of LogP (lipophilicity) with IC50 values for both enzymes. Docking analysis indicated that dithiocarbamates bind to NAD+ and steroid-binding sites, with some interactions with cysteine residues. In conclusion, this study provides valuable insights into the structure-activity relationship and mechanistic aspects of dithiocarbamates as inhibitors of human and rat gonadal 3ß-HSDs, suggesting that these compounds likely exert their inhibitory effects through binding to cysteine residues.

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.

Selective CO2 Electroreduction to Multi-Carbon Products on Organic-Functionalized CuO Nanoparticles by Local Micro-Environment Modulation.

Surface functionalization of Cu-based catalysts has demonstrated promising potential for enhancing the electrochemical CO2 reduction reaction (CO2RR) toward multi-carbon (C2+) products, primarily by suppressing the parasitic hydrogen evolution reaction and facilitating a localized CO2/CO concentration at the electrode. Building upon this approach, we developed surface-functionalized catalysts with exceptional activity and selectivity for electrocatalytic CO2RR to C2+ in a neutral electrolyte. Employing CuO nanoparticles coated with hexaethynylbenzene organic molecules (HEB-CuO NPs), a remarkable C2+ Faradaic efficiency of nearly 90% was achieved at an unprecedented current density of 300 mA cm-2, and a high FE (> 80%) was maintained at a wide range of current densities (100-600 mA cm-2) in neutral environments using a flow cell. Furthermore, in a membrane electrode assembly (MEA) electrolyzer, 86.14% FEC2+ was achieved at a partial current density of 387.6 mA cm-2 while maintaining continuous operation for over 50 h at a current density of 200 mA cm-2. In-situ spectroscopy studies and molecular dynamics simulations reveal that reducing the coverage of coordinated K⋅H2O water increased the probability of intermediate reactants (CO) interacting with the surface, thereby promoting efficient C-C coupling and enhancing the yield of C2+ products. This advancement offers significant potential for optimizing local micro-environments for sustainable and highly efficient C2+ production.

Food additive salicylates inhibit human and rat placental 3ß-hydroxysteroid dehydrogenase: 3D-QSAR and in silico analysis.

The use of salicylates as flavoring agents in food and beverages is common, but their potential to disrupt the endocrine system remains unclear. Human placental 3ß-hydroxysteroid dehydrogenase 1 (h3ß-HSD1) plays a role in progesterone synthesis and is the potential target. This study evaluated the inhibition of 13 salicylates on h3ß-HSD1, structure-activity relationship (SAR) and compared with rat placental homolog r3ß-HSD4. Salicylates inhibited h3ß-HSD1, depending on carbon chain number in the alcohol moiety and the IC50 values for hexyl, ethylhexyl, homomenthyl, and menthyl salicylates were 53.27, 15.78, 2.35, and 2.31 µM, as mixed inhibitors, respectively, while methyl to benzyl salicylates were ineffective at 100 µM. Interestingly, only hexyl salicylate inhibited r3ß-HSD4 with IC50 of 31.05 µM. Bivariate analysis revealed a negative correlation between IC50 and hydrophobicity (LogP), molecular weight, heavy atoms, and carbon number in the alcohol moiety against h3ß-HSD1. Docking analysis demonstrated that these salicylates bind to cofactor binding sites or between the steroid and cofactor binding sites. Additionally, 3D-QSAR showed distinct binding via hydrogen bond donors and hydrophobic regions. In conclusion, the inhibition of h3ß-HSD1 by salicylates appears to be dependent on factors such as LogP, molecular weight, heavy atoms, and carbon-chain length and there is species-dependent inhibition sensitivity.

Compressive strain in Cu catalysts: Enhancing generation of C2+ products in electrochemical CO2 reduction.

Elastic strain in Cu catalysts enhances their selectivity for the electrochemical CO2 reduction reaction (eCO2RR), particularly toward the formation of multicarbon (C2+) products. However, the reasons for this selectivity and the effect of catalyst precursors have not yet been clarified. Hence, we employed a redox strategy to induce strain on the surface of Cu nanocrystals. Oxidative transformation was employed to convert Cu nanocrystals to CuxO nanocrystals; these were subsequently electrochemically reduced to form Cu catalysts, while maintaining their compressive strain. Using a flow cell configuration, a current density of 1 A/cm2 and Faradaic efficiency exceeding 80% were realized for the C2+ products. The selectivity ratio of C2+/C1 was also remarkable at 9.9, surpassing that observed for the Cu catalyst under tensile strain by approximately 7.6 times. In-situ Raman and infrared spectroscopy revealed a decrease in the coverage of K+ ion-hydrated water (K·H2O) on the compressively strained Cu catalysts, consistent with molecular dynamics simulations and density functional theory calculations. Finite element method simulations confirmed that reducing the coverage of coordinated K·H2O water increased the probability of intermediate reactants interacting with the surface, thereby promoting efficient C-C coupling and enhancing the yield of C2+ products. These findings provide valuable insights into targeted design strategies for Cu catalysts used in the eCO2RR.

Inhibitory effects of parabens on human and rat 17ß-hydroxysteroid dehydrogenase 1: Mechanisms of action and impact on hormone synthesis.

Parabens are commonly used preservatives in cosmetics, food, and pharmaceutical products. The objective of this study was to examine the effect of nine parabens on human and rat 17ß-hydroxysteroid dehydrogenase 1 (17ß-HSD1) in human placental and rat ovarian cytosols, as well as on estradiol synthesis in BeWo cells. The results showed that the IC50 values for these compounds varied from methylparaben with the weakest inhibition (106.42 µM) to hexylparaben with the strongest inhibition (2.05 µM) on human 17ß-HSD1. Mode action analysis revealed that these compounds acted as mixed inhibitors. For rats, the IC50 values ranged from the weakest inhibition for methylparaben (no inhibition at 100 µM) to the most potent inhibition for hexylparaben (0.87 µM), and they functioned as mixed inhibitors. Docking analysis indicated that parabens bind to the region bridging the NADPH and steroid binding sites of human 17ß-HSD1 and the NADPH binding site of rat 17ß-HSD1. Bivariate correlation analysis demonstrated negative correlations between LogP, molecular weight, heavy atoms, and apolar desolvation energy, and the IC50 values of these compounds. In conclusion, this study identified the inhibitory effects of parabens and their binding mechanisms on human and rat 17ß-HSD1, as well as their impact on hormone synthesis.

Unveiling the Promoting Mechanism of H2 Activation on CuFeOx Catalyst for Low-Temperature CO Oxidation.

The effect of H2 activation on the performance of CuFeOx catalyst for low-temperature CO oxidation was investigated. The characterizations of XRD, XPS, H2-TPR, O2-TPD, and in situ DRIFTS were employed to establish the relationship between physicochemical property and catalytic activity. The results showed that the CuFeOx catalyst activated with H2 at 100 °C displayed higher performance, which achieved 99.6% CO conversion at 175 °C. In addition, the H2 activation promoted the generation of Fe2+ species, and more oxygen vacancy could be formation with higher concentration of Oα species, which improved the migration rate of oxygen species in the reaction process. Furthermore, the reducibility of the catalyst was enhanced significantly, which increased the low-temperature activity. Moreover, the in situ DRIFTS experiments revealed that the reaction pathway of CO oxidation followed MvK mechanism at low temperature (<175 °C), and both MvK and L-H mechanism was involved at high temperature. The Cu+-CO and carbonate species were the main reactive intermediates, and the H2 activation increased the concentration of Cu+ species and accelerated the decomposition carbonate species, thus improving the catalytic performance effectively.

A novel selenium analog of HDACi-based twin drug induces apoptosis and cell cycle arrest via CDC25A to improve prostate cancer therapy.

Cancer therapy has moved from single agents to more mechanism-based targeted approaches. In recent years, the combination of HDAC inhibitors and other anticancer chemicals has produced exciting progress in cancer treatment. Herein, we developed a novel prodrug via the ligation of dichloroacetate to selenium-containing potent HDAC inhibitors. The effect and mechanism of this compound in the treatment of prostate cancer were also studied. Methods: The concerned prodrug SeSA-DCA was designed and synthesized under mild conditions. This compound's preclinical studies, including the pharmacokinetics, cell toxicity, and anti-tumor effect on prostate cancer cell lines, were thoroughly investigated, and its possible synergistic mechanism was also explored and discussed. Results: SeSA-DCA showed good stability in physiological conditions and could be rapidly decomposed into DCA and selenium analog of SAHA (SeSAHA) in the tumor microenvironment. CCK-8 experiments identified that SeSA-DCA could effectively inhibit the proliferation of a variety of tumor cell lines, especially in prostate cancer. In further studies, we found that SeSA-DCA could also inhibit the metastasis of prostate cancer cell lines and promote cell apoptosis. At the animal level, oral administration of SeSA-DCA led to significant tumor regression without obvious toxicity. Moreover, as a bimolecular coupling compound, SeSA-DCA exhibited vastly superior efficacy than the mixture with equimolar SeSAHA and DCA both in vitro and in vivo. Our findings provide an important theoretical basis for clinical prostate cancer treatment. Conclusions: Our in vivo and in vitro results showed that SeSA-DCA is a highly effective anti-tumor compound for PCa. It can effectively induce cell cycle arrest and growth suppression and inhibit the migration and metastasis of PCa cell lines compared with monotherapy. SeSA-DCA's ability to decrease the growth of xenografts is a little better than that of docetaxel without any apparent signs of toxicity. Our findings provide an important theoretical basis for clinical prostate cancer treatment.

Tailoring local electron density and molecular oxygen activation behavior via potassium/halogen co-tuned graphitic carbon nitride for enhanced photocatalytic activity.

Graphite carbon nitride (g-C3N4) is a promising photocatalyst,but its inadequate reactive sites, weak visible light responsiveness, and sluggish separation of photogenerated carriers hamperthe improvement of photodegradation efficiency. In this work, potassium (K) and halogen atoms co-modified g-C3N4 photocatalysts (CN-KX, X = F, Cl, Br, I) were constructed to adjust the electrical and band structure for enhanced generation of reactive oxygen species. Through an integration of theoretical calculation and experimental exploration, the doping sites of halogen atoms as well as the evolution of crystal, band, and electronic structures were investigated. The results show that a covalent bond is formed between the F atom and the C atom, substitution of the N atom occurs with a Cl atom, and doping of Br, I, or K atoms takes place at the interstitial site. CN-KX photocatalysts exhibits lower band gap, faster photogenerated electron migration, and enhanced photocatalytic activity. Specifically, the CN-KI photocatalyst exhibits the highest photodegradation efficiency because of its smaller interplanar spacing, formation of the midgap state, and adjustable local electron density. Equally, the doping of I atom not only provides a stable adsorption site for oxygen (O2) but also facilitates electron transfer, promoting the production of superoxide radicals (O2-) and contributing to the process of photodegradation.

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.

Structure-activity relationship and mechanistic study of organotins as inhibitors of human, pig, and rat gonadal 3ß-hydroxysteroid dehydrogenases.

Organotins have been widely used in various industrial applications. This study investigated the structure-activity relationship as inhibitors of human, pig, and rat gonadal 3ß-hydroxysteroid dehydrogenases (3ß-HSD). Human KGN cell, pig, and rat testis microsomes were utilized to assess the inhibitory effects of 18 organotins on the conversion of pregnenolone to progesterone. Among them, diphenyltin, triethyltin, and triphenyltin exhibited significant inhibitory activity against human 3ß-HSD2 with IC50 values of 114.79, 106.98, and 5.40 µM, respectively. For pig 3ß-HSD, dipropyltin, diphenyltin, triethyltin, tributyltin, and triphenyltin demonstrated inhibitory effects with IC50 values of 172.00, 100.19, 87.00, 5.75, and 1.65 µM, respectively. Similarly, for rat 3ß-HSD1, dipropyltin, diphenyltin, triethyltin, tributyltin, and triphenyltin displayed inhibitory activity with IC50 values of 81.35, 43.56, 55.55, 4.09, and 0.035 µM, respectively. They were mixed inhibitors of pig and rat 3ß-HSD, while triphenyltin was identified as a competitive inhibitor of human 3ß-HSD2. The mechanism underlying the inhibition of organotins on 3ß-HSD was explored, revealing that they may disrupt the enzyme activity by binding to cysteine residues in the catalytic sites. This proposition was supported by the observation that the addition of dithiothreitol reversed the inhibition caused by all organotins except for triethyltin, which was partially reversed. In conclusion, this study provides valuable insights into the structure-activity relationship of organotins as inhibitors of human, pig, and rat gonadal 3ß-HSD. The mechanistic investigation suggests that these compounds likely exert their inhibitory effects through binding to cysteine residues in the catalytic sites.

pH-Universal Electrocatalytic CO2 Reduction with Ampere-Level Current Density on Doping-Engineered Bismuth Sulfide.

The practical application of the electrocatalytic CO2 reduction reaction (CO2RR) to form formic acid fuel is hindered by the limited activation of CO2 molecules and the lack of universal feasibility across different pH levels. Herein, we report a doping-engineered bismuth sulfide pre-catalyst (BiS-1) that S is partially retained after electrochemical reconstruction into metallic Bi for CO2RR to formate/formic acid with ultrahigh performance across a wide pH range. The best BiS-1 maintains a Faraday efficiency (FE) of ~95 % at 2000 mA cm-2 in a flow cell under neutral and alkaline solutions. Furthermore, the BiS-1 catalyst shows unprecedentedly high FE (~95 %) with current densities from 100 to 1300 mA cm-2 under acidic solutions. Notably, the current density can reach 700 mA cm-2 while maintaining a FE of above 90 % in a membrane electrode assembly electrolyzer and operate stably for 150 h at 200 mA cm-2. In situ spectra and density functional theory calculations reveals that the S doping modulates the electronic structure of Bi and effectively promotes the formation of the HCOO* intermediate for formate/formic acid generation. This work develops the efficient and stable electrocatalysts for sustainable formate/formic acid production.

Curcuminoid PBPD induces cuproptosis and endoplasmic reticulum stress in cervical cancer via the Notch1/RBP-J/NRF2/FDX1 pathway.

Curcumin has been shown to have antitumor properties, but its low potency and bioavailability has limited its clinical application. We designed a novel curcuminoid, [1-propyl-3,5-bis(2-bromobenzylidene)-4-piperidinone] (PBPD), which has higher antitumor strength and improves bioavailability. Cell counting kit-8 was used to detect cell activity. Transwell assay was used to detect cell invasion and migration ability. Western blot and quantitative polymerase chain reaction were used to detect protein levels and their messenger RNA expression. Immunofluorescence was used to detect the protein location. PBPD significantly inhibited the proliferation of cervical cancer cells, with an IC50 value of 4.16 µM for Hela cells and 3.78 µM for SiHa cells, leading to the induction of cuproptosis. Transcriptome sequencing analysis revealed that PBPD significantly inhibited the Notch1/Recombination Signal Binding Protein for Immunoglobulin kappa J Region (RBP-J) and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathways while upregulating ferredoxin 1 (FDX1) expression. Knockdown of Notch1 or RBP-J significantly inhibited NRF2 expression and upregulated FDX1 expression, leading to the inhibition of nicotinamide adenine dinucleotide phosphate activity and the induction of oxidative stress, which in turn activated endoplasmic reticulum stress and induced cell death. The overexpression of Notch1 or RBP-J resulted in the enrichment of RBP-J within the NRF2 promoter region, thereby stimulating NRF2 transcription. NRF2 knockdown resulted in increase in FDX1 expression, leading to cuproptosis. In addition, PBPD inhibited the acidification of tumor niche and reduced cell metabolism to inhibit cervical cancer cell invasion and migration. In conclusion, PBPD significantly inhibits the proliferation, invasion, and migration of cervical cancer cells and may be a novel potential drug candidate for treatment of cervical cancer.

Conductive MXene/Polymer Composites for Transparent Flexible Supercapacitors.

Transparent flexible energy storage devices are limited by the trade-off among flexibility, transparency, and charge storage capability of their electrode materials. Conductive polymers are intrinsically flexible, but limited by small capacitance. Pseudocapacitive MXene provides high capacitance, yet their opaque and brittle nature hinders their flexibility and transparency. Herein, the development of synergistically interacting conductive polymer Ti3C2Tx MXene/PEDOT:PSS composites is reported for transparent flexible all-solid-state supercapacitors, with an outstanding areal capacitance of 3.1 mF cm-2, a high optical transparency of 61.6%, and excellent flexibility and durability. The high capacitance and high transparency of the devices stem from the uniform and thorough blending of PEDOT:PSS and Ti3C2Tx, which is associated with the formation of O─H…O H-bonds in the composites. The conductive MXene/polymer composite electrodes demonstrate a rational means to achieve high-capacity, transparent and flexible supercapacitors in an easy and scalable manner.

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.

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.