miR-92b-3p protects retinal tissues against DNA damage and apoptosis by targeting BTG2 in experimental myopia.

BACKGROUND: Myopia is one of the eye diseases that can damage the vision of young people. This study aimed to explore the protective role of miR-92b-3p against DNA damage and apoptosis in retinal tissues of negative lens-induced myopic (LIM) guinea pigs by targeting BTG2. METHODS: Biometric measurements of ocular parameters, flash electroretinogram (FERG), and retinal thickness (RT) were performed after miR-92b-3p intravitreal injection in LIM guinea pigs. The apoptotic rate was detected by Annexin V-FITC/PI double staining, and the change in mitochondrial membrane potential was measured by JC-1 staining. Retinal apoptosis and expression of p53, BTG2, and CDK2 were explored by TdT-mediated dUTP-biotin nick labeling (TUNEL) and immunofluorescence staining assays, respectively. BTG2 and its upstream and downstream molecules at gene and protein levels in retinal tissues were measured by real-time quantitative PCR (qPCR) and Western blotting. RESULTS: Compared with normal controls (NC), the ocular axial length of LIM guinea pig significantly increased, whereas refraction decreased. Meanwhile, dMax-a and -b wave amplitudes of ERG declined, retinal thickness was decreased, the number of apoptotic cells and apoptotic rate in LIM eyes was exaggerated, and the mitochondrial membrane potential significantly decreased. In addition, results of qPCR and Western blot assays showed that the expression levels of p53, BTG2, CDK2, and BAX in LIM guinea pigs were higher than the levels of the NC group, whereas the BCL-2 expression level was decreased. By contrast, the miR-92b-3p intravitreal injection in LIM guinea pigs could significantly inhibit axial elongation, alleviate DNA damage and apoptosis, and thus protect guinea pigs against myopia. CONCLUSION: In conclusion, p53 and BTG2 were activated in the retinal tissue of myopic guinea pigs, and the activated BTG2 could elevate the expression of CDK2 and BAX, and attenuate the expression of BCL-2, which in turn promote apoptosis and eventually lead to retinal thinning and impaired visual function in myopic guinea pigs. The miR-92b-3p intravitreal injection can attenuate the elongation of ocular length and retinal thickness, and inhibit the CDK2, BAX, and p53 expression by targeting BTG2, thereby ameliorating DNA damage and apoptosis in LIM guinea pigs and protecting ocular tissues.

Elevated retinal fibrosis in experimental myopia is involved in the activation of the PI3K/AKT/ERK signaling pathway.

OBJECTIVE: This study aimed to investigate the regulatory role of the PI3K/AKT/ERK signaling pathway in retinal fibrosis in -6.0 diopter (D) lens-induced myopic (LIM) guinea pigs. METHODS: Biological measurements of eye tissues were performed on guinea pigs to obtain their refraction, axial length, retinal thickness, physiological function, and fundus retinal status. In addition, Masson staining and immunohistochemical (IHC) assay were further done to explore the changes in retinal morphology after myopic induction. Meanwhile, hydroxyproline (HYP) content was measured to evaluate the degree of retinal fibrosis. Moreover, the levels of the PI3K/AKT/ERK signaling pathway and fibrosis-related molecules in retinal tissues including matrix metalloproteinase 2(MMP2), collagen type I (Collagen I), and α-smooth muscle actin (α-SMA) were detected by real-time quantitative PCR (qPCR) and Western blot. RESULTS: The LIM guinea pigs showed a significant myopic shift in refractive error and an increase in axial length compared with those of the normal control (NC) group. Masson staining, hydroxyproline content determination, and IHC showed an increase in retinal fibrosis. After myopic induction, qPCR and western blot analyses showed that phosphatidylinositol-3-kinase catalytic subunit α (PIK3CA), protein kinase B (AKT), extracellular regulated protein kinase 1/2 (ERK1/2), MMP2, Collagen I, and α-SMA were consistently elevated in the LIM group than those in the NC group. CONCLUSION: The PI3K/AKT/ERK signaling pathway was activated in the retinal tissues of myopic guinea pigs, which exaggerated fibrotic lesions and reduced retinal thickness, ultimately leading to retinal physiological dysfunctions in myopic guinea pigs.

Significance of FNAC, BRAF mutation, and intraoperative frozen section in surgical decision-making of thyroid nodules.

BACKGROUND: A preoperative method is desired to discriminate benign from malignant thyroid nodules. This retrospective study evaluated the diagnostic performance of BRAF (B-Raf proto-oncogene) mutation (BRAFV600E ) positivity and fine-needle aspiration cytology (FNAC) relative to intraoperative frozen section pathology. METHODS: Patients underwent preoperative FNAC of thyroid nodules. Cytology specimens were classified according to the Bethesda System for Reporting Thyroid Cytopathology (BSRTC), and analyzed for BRAFV600E using an amplification-refractory mutation system (ARMS). Thyroid tissue was surgically removed and frozen sections processed for histology. The sensitivities and specificities of each analysis were compared, alone and in combination. RESULTS: Among 346 patients, 333/358 FNACs (93%) showed malignant nodules; 322 (93%) patients received a pathological diagnosis of papillary thyroid carcinoma (PTC). The sensitivity and specificity of BSRTC VI for malignancy was the highest among the BSRTC categories. Compared with FNAC, the BRAFV600E analysis had significantly higher sensitivity and specificity. The diagnostic efficacy of frozen section pathology was significantly higher than that of either BSRTC category or BRAFV600E analysis alone. Combining methods variably improved diagnostic performance. BRAFV600E was not associated with capsule infiltration, neurovascular infiltration, mono- or multifocal PTC, lymph node metastasis, or clinical stage. CONCLUSION: The diagnostic performance of preoperative BRAFV600E determination was better than that of the BSRTC-FNAC category; combining both improved sensitivity and specificity. Patients with positive malignancy scores from both should be recommended for surgery; those with negative scores require close monitoring. Surgical treatment should include comprehensive intraoperative frozen section assessment. BRAF mutations cannot indicate aggressive treatment.

Enhanced Apoptosis in Choroidal Tissues in Lens-Induced Myopia Guinea Pigs by Activating the RASA1 Signaling Pathway.

Purpose: This study aimed to explore the role of the RAS p21 protein activator 1 (RASA1) signaling pathway in apoptosis in choroid tissues from guinea pigs with negative lens-induced myopia (LIM). Methods: Biometric measurements were performed to examine refractive status, ocular parameters, and choroidal thickness (ChT) after myopia induction. The choroidal morphology was observed by hematoxylin and eosin (H&E) staining and TUNEL assay. The expression of the RASA1 signaling pathway at the mRNA and protein levels in choroidal tissues was measured by real-time quantitative PCR (qPCR) and western blot assays. Results: Compared with the normal control (NC) group, the ocular length of the guinea pigs in LIM increased remarkably, as did the myopic refraction. ChT decreased after myopia induction. H&E staining showed that the thickness and laxity of the choroidal tissues in LIM were strikingly reduced. The number of apoptotic cells in the LIM eyes was increased. Moreover, qPCR and western blot assays showed that the expression levels of both RASA1 and BCL-2-associated agonist of cell death (BAD) were higher in the LIM group than in the NC group, whereas the expression level of B-cell lymphoma 2 (BCL-2) was decreased after 2 weeks of experimental myopia. However, the trend of RASA1, BAD, and BCL-2 expression was reversed after 4 weeks of experimental myopia compared with levels after 2 weeks of experimental myopia. Conclusions: Results showed that the RASA1 signaling pathway is activated in choroid tissues in myopic guinea pigs. Activated RASA1 signaling induces high BAD expression and low BCL-2 expression, which in turn promotes apoptosis and ultimately causes ChT thinning in myopic guinea pigs.

Strong Electronic Orbit Coupling between Cobalt and Single-Atom Praseodymium for Boosted Nitrous Oxide Decomposition on Co3O4 Catalyst.

Nitrous oxide (N2O) has gained increasing attention as an important noncarbon dioxide greenhouse gas, and catalytic decomposition is an effective method of reducing its emissions. Here, Co3O4 was synthesized by the sol-gel method and single-atom Pr was confined in its matrix to improve the N2O decomposition performance. It was observed that the reaction rate varied in a volcano-like pattern with the amount of doped Pr. A N2O decomposition reaction rate 5-7.5 times greater than that of pure Co3O4 is achieved on the catalyst with a Pr/Co molar ratio of 0.06:1, and further Pr doping reduced the activity due to PrOx cluster formation. Combined with X-ray photoelectron spectroscopy, X-ray absorption fine structure, density functional theory and in situ near-ambient pressure X-ray photoelectron spectroscopy, it was demonstrated that the single-atom doped Pr in Co3O4 generates the "Pr 4f-O 2p-Co 3d" network, which redistributes the electrons in Co3O4 lattice and increases the t2g electrons at the tetracoordinated Co2+ sites. This coupling between the Pr 4f orbit and Co2+ 3d orbit triggers the formation of a 4f-3d electronic ladder, which accelerates the electron transfer from Co2+ to the 3π* antibonding orbital of N2O, thus contributing to the N-O bond cleavage. Moreover, the energy barrier for each elementary reaction in the decomposition process of N2O is reduced, especially for O2 desorption. Our work provides a theoretical grounding and reference for designing atomically modified catalysts for N2O decomposition.

Retraction: MicroRNA-497 inhibits thyroid cancer tumor growth and invasion by suppressing BDNF.

[This retracts the article DOI: 10.18632/oncotarget.13747.].

Interaction Mechanism for Simultaneous Elimination of Nitrogen Oxides and Toluene over the Bifunctional CeO2-TiO2 Mixed Oxide Catalyst.

Simultaneous catalytic elimination of nitrogen oxides (NOx, x = 1 and 2) and volatile organic compounds (VOCs) is of great importance for environmental preservation in China. In this work, the interactions of simultaneous removal of NOx and methylbenzene (PhCH3) were investigated on a CeO2-TiO2 mixed oxide catalyst, which demonstrated excellent bifunctional removal efficiencies for the two pollutants. The results indicated that NOx positively promotes PhCH3 oxidation, while NH3 negatively inhibits through competitive adsorption with PhCH3. The underlying mechanism is that a pseudo PhCH3-SCR reaction happened in this process is parallel to NH3-SCR. Combined with in situ diffuse reflectance infrared Fourier transform spectroscopy and quasi in situ X-ray photoelectron spectroscopy, the interaction mechanism between NOx and PhCH3 is proposed. Specifically, NOx is adsorbed on the catalyst surface to produce nitrate species, which reacts with the carboxylate generated during PhCH3 oxidation to form organic nitrogen intermediates that create N2 and CO2 in the following reactions. In the reaction process, the superoxide (O2-) generated by O2 activation on the catalyst surface is an important species for the propelling of oxidation reaction. This work could provide guidelines for the design of state-of-the-art catalysts for simultaneous catalytic removal of NOx and VOCs.

Non-invasive detection and complementary diagnosis of liver metastases via chemokine receptor 4 imaging.

Noninvasive detection of early-stage liver metastases from different primary cancers is a pressing unmet medical need. The lack of both molecular biomarkers and the sensitive imaging methodology makes the detection challenging. In this study, we observed the elevated expression of chemokine receptor 4 (CXCR4) in uveal melanoma (UM) patient liver tissues, and high CXCR4 expression in liver metastases of UM murine models, regardless of the expression levels in the primary tumors. Based on these findings, we identified CXCR4 as an imaging biomarker and exploited a CXCR4-targeted MRI contrast agent ProCA32.CXCR4 for molecular MRI imaging. ProCA32.CXCR4 has strong CXCR4 binding affinity, high metal selectivity, and r1 and r2 relaxivities, which enables the sensitive detection of liver micrometastases. The MRI imaging capacity for detecting liver metastases was demonstrated in three UM models and one ovarian cancer model. The imaging results were validated by histological and immunohistochemical analysis. ProCA32.CXCR4 has strong potential clinical application for non-invasive diagnosis of liver metastases.

Early-Life Exposure to Famine and Risk of Metabolic Associated Fatty Liver Disease in Chinese Adults.

BACKGROUND: Early-life exposure to the Chinese famine has been related to the risk of obesity, type 2 diabetes, and nonalcoholic fatty liver disease later in life. Nevertheless, the long-term impact of famine exposure on metabolic associated fatty liver disease (MAFLD), a recently proposed term to describe liver disease associated with known metabolic dysfunction, remains unknown. The aim of our study was to explore the relationship between early famine exposure and MAFLD in adulthood. METHODS: A total of 26,821 participants (10,994 men, 15,827 women) were recruited from a cohort study of Chinese adults in Shanghai. We categorized participants into four famine exposure subgroups based on the birth year as nonexposed (1963-1967), fetal-exposed (1959-1962), childhood-exposed (1949-1958), and adolescence-exposed (1941-1948). MAFLD was defined as liver steatosis detected by ultrasound plus one of the following three criteria: overweight/obesity, type 2 diabetes, or evidence of metabolic dysregulation. Multivariable logistic regression models were performed to examine the association between famine exposure and MAFLD. RESULTS: The mean ± standard deviation age of the participants was 60.8 ± 6.8 years. The age-adjusted prevalence of MAFLD was 38.3, 40.8, 40.1, and 36.5% for the nonexposed, fetal-exposed, childhood-exposed, and adolescence-exposed subgroups, respectively. Compared with nonexposed participants, fetal-exposed participants showed an increased risk of adulthood MAFLD (OR = 1.10, 95% CI 1.00-1.21). The significant association between fetal famine exposure and MAFLD was observed in women (OR = 1.22, 95% CI 1.08-1.37), but not in men (OR = 0.88, 95% CI 0.75-1.03). In age-balanced analyses combining pre-famine and post-famine births as the reference, women exposed to famine in the fetal stage still had an increased risk of MAFLD (OR = 1.15, 95% CI 1.05-1.26). CONCLUSIONS: Prenatal exposure to famine showed a sex-specific association with the risk of MAFLD in adulthood.

Halogen bonding in differently charged complexes: basic profile, essential interaction terms and intrinsic σ-hole.

Studies on halogen bonds (XB) between organohalogens and their acceptors in crystal structures revealed that the XB donor and acceptor could be differently charged, making it difficult to understand the nature of the interaction, especially the negatively charged donor's electrophilicity and positively charged acceptor's nucleophilicity. In this paper, 9 XB systems mimicking all possibly charged halogen bonding interactions were designed and explored computationally. The results revealed that all XBs could be stable, with binding energies after removing background interaction as strong as -1.2, -3.4, and -8.3 kcal mol-1 for Cl, Br, and I involved XBs respectively. Orbital and dispersion interactions are found to be always attractive while unidirectional intermolecular electron transfer from a XB acceptor to a XB donor occurs in all XB complexes. These observations could be attributed to the intrinsic σ-hole of the XB donor and the intrinsic electronic properties of the XB acceptor regardless of their charge states. Intramolecular charge redistribution inside both the donor and the acceptor is found to be system-dependent but always leads to a more stable XB. Accordingly, this study demonstrates that the orbital-based origin of halogen bonds could successfully interpret the complicated behaviour of differently charged XB complexes, while electrostatic interaction may dramatically change the overall bonding strength. The results should further promote the application of halogens in all related areas.

Prevalence of tobacco related chronic diseases and its role in smoking cessation among smokers in a rural area of Shanghai, China: a cross sectional study.

BACKGROUND: Tobacco smoking is a recognized risk factor for many chronic diseases and previous study evidences have indicated that smokers receive smoking cessation service after the diagnosis of chronic diseases increases successful rate in quitting. But the prevalence of tobacco related chronic diseases (TCD) among smokers, as well as the role of TCD diagnosis in smoking cessation is still unclear in China. METHODS: From June 2016 to December 2017, we sampled 36, 698 residents aged over 18 years by a three stage sampling in Songjiang district, Shanghai. We conducted a cross-sectional study to understand the prevalence of TCD among smokers, and the role of TCD diagnosis in smoking cessation among ex-smokers as well as the smoking cessation attempt among current smokers. RESULTS: Over all, the prevalence of current smoking is 19.78% (48.36% for male and 0.22% for female). 15.93% of smokers have stopped smoking successfully (1, 376/8, 636). The prevalence of ten selected TCDs among smokers range from 0.63% (Chronic Obstructive Pulmonary Disease, COPD) to 36.31% (hypertension). All of 1, 376 ex-smokers had at least one kind of TCD, and 52.33% of them stop smoking after the diagnosis of TCD, the time interval between TCD diagnosis and smoking cessation ranges from 0 to 65 years, with a median of 9 years. Smokers with TCD had higher prevalence of quit smoking, and current smokers with TCD had higher smoking cessation attempt proportion. CONCLUSIONS: The prevalence of current smoking is still very high among male residents in rural area of Shanghai, and the occurrence of TCD even non-lethal one could provide an opportunity for doctors to assist the smoking cessation among smokers.

Design, Synthesis and Pharmacological Evaluation of Novel Hsp90N-terminal Inhibitors Without Induction of Heat Shock Response.

Heat shock protein 90 (Hsp90) is a potential oncogenic target. However, Hsp90 inhibitors in clinical trial induce heat shock response, resulting in drug resistance and inefficiency. In this study, we designed and synthesized a series of novel triazine derivatives (A1-26, B1-13, C1-23) as Hsp90 inhibitors. Compound A14 directly bound to Hsp90 in a different manner from traditional Hsp90 inhibitors, and degraded client proteins, but did not induce the concomitant activation of Hsp72. Importantly, A14 exhibited the most potent anti-proliferation ability by inducing autophagy, with the IC50 values of 0.1 µM and 0.4 µM in A549 and SK-BR-3 cell lines, respectively. The in  vivo study demonstrated that A14 could induce autophagy and degrade Hsp90 client proteins in tumor tissues, and exhibit anti-tumor activity in A549 lung cancer xenografts. Therefore, the compound A14 with potent antitumor activity and unique pharmacological characteristics is a novel Hsp90 inhibitor for developing anticancer agent without heat shock response.

Improving the accuracy of predicting protein-ligand binding-free energy with semiempirical quantum chemistry charge.

Aim: It is a challenge to predict binding-free energy (ΔG) accurately. Methodology/results: For accurate ΔG prediction, a new strategy combining solvated interaction energy (SIE) or molecular mechanics/generalized Born surface area (MM/GBSA) approach with the Coulson charge of both protein and ligand calculated by semiempirical quantum mechanics (SQM), named SIE-SQMPC or MM/GBSA-SQMPC approach, was developed and tested on 50 protein-ligand complexes. Both approaches achieved higher correlation (R2) between experimental and predicted ΔG than that with Amber-ff03 charge, even for ligands with highly different scaffolds. But, SIE-SQMPC is computationally much faster than MM/GBSA-SQMPC. Conclusion: SIE-SQMPC provided an effective alternative to predict ΔG of protein-ligand binding (R2 = 0.66-0.94 for SIE-AM1; R2 = 0.59-0.98 for SIE-PM7), which has the potential of high-throughput processing for molecular docking and drug design.

Exploring binding mechanisms of VEGFR2 with three drugs lenvatinib, sorafenib, and sunitinib by molecular dynamics simulation and free energy calculation.

Lenvatinib (LEN), sorafenib (SOR), and sunitinib (SUN) are drugs targeting vascular endothelial growth factor receptor 2 (VEGFR2). Despite sharing similar chemical structures and bioactivities, LEN and SOR bind to different functional states of VEGFR2, viz. DFG-in and DFG-out state, respectively. SUN binds to the DFG-out state of VEGFR2 just like SOR but with less potency. Thus, detail binding mechanisms between VEGFR2 and these drugs, especially dynamic interaction, are valuable for future drug design. In the present work, molecular dynamics simulation, essential dynamic analysis, and molecular mechanics/generalized born surface area were performed to these VEGFR2-drugs systems. Rank of calculated binding affinities is in accordance with the experimental data. The binding free energy calculation suggests that van der Waals interaction plays a vital role in the binding. Per-residue free energy decomposition indicates that residues L840, V848, A866, E885, L889, V899, V916, F918, C919, L1035, C1045, D1046, and F1047 play an important role in the binding between VEGFR2 and LEN/SOR. While residues L840, V848, E917, F918, C919, G922, L1035, and F1047 contribute the major hydrophobic interaction for SUN binding to the receptor. Our results also reveal that residue E885/D1046 plays a vital role in binding via forming hydrogen bonds with drugs.

Gossypol inhibits 5α-reductase 1 and 3α-hydroxysteroid dehydrogenase: Its possible use for the treatment of prostate cancer.

Gossypol is a yellow polyphenol isolated from cotton seeds. It has the antitumor activity and it is being tested to treat prostate cancer. However, its underlying mechanisms are still not well understood. The present study investigated the inhibitory effects of gossypol acetate on rat 5α-reductase 1, 3α-hydroxysteroid dehydrogenase, and retinol dehydrogenase 2 for androgen metabolism. Rat 5α-reductase 1, 3α-hydroxysteroid dehydrogenase, and retinol dehydrogenase 2 were expressed in COS-1 cells. Immature Leydig cells that contain these enzymes were isolated from 35-day-old male Sprague Dawley rats. The potency and mode of action of gossypol acetate to inhibit these enzymes in both enzyme-expressed preparations and immature Leydig cells were examined. Molecular docking study of gossypol on the crystal structure of 3α-hydroxysteroid dehydrogenase was performed. Gossypol acetate inhibited 5α-reductase 1 and 3α-hydroxysteroid dehydrogenase with IC50 values of 3.33 ±â€¯0.07 and 0.52 ±â€¯0.06 × 10-6 M in the expressed enzymes as well as 8.512 ±â€¯0.079 and 1.032 ±â€¯0.068 × 10-6 M in intact rat immature Leydig cells, respectively. Gossypol acetate inhibited rat 5α-reductase 1 in a noncompetitive mode and 3α-hydroxysteroid dehydrogenase in a mixed mode when steroid substrates were supplied. Gossypol acetate weakly inhibited retinol dehydrogenase 2 with IC50 value over 1 × 10-4 M. Molecular docking analysis showed that gossypol partially bound to the steroid-binding site of the crystal structure of rat 3α-hydroxysteroid dehydrogenase. Gossypol acetate is a potent inhibitor of rat 5α-reductase 1 and 3α-hydroxysteroid dehydrogenase, possibly inhibiting the formation of androgen in the prostate cancer cells.

MoS2 nanotubes loaded with TiO2 nanoparticles for enhanced electrocatalytic hydrogen evolution.

Efficient and stable non-precious metal catalysts composed of earth-abundant elements are crucial to the hydrogen evolution reaction (HER) in high-energy conversion efficiency. Herein, TiO2/MoS2-NTs catalyst, in which the MoS2 nanotubes were loaded with TiO2 nanoparticles, have been synthesized via a facile solvothermal and hydrothermal method. The as-prepared TiO2/MoS2-NTs electrocatalyst demonstrated enhanced electrocatalytic hydrogen evolution performance compared with MoS2-NTs. Electrochemical measurements reveal the overpotential and Tafel slope of as-prepared TiO2/MoS2-NTs are -0.21 V and 42 mV dec-1. The HER improvement is proposed to be attributed to the increased edge sites results from the interfaces and synergic effect between TiO2 nanoparticles and MoS2 nanotubes.

Smoking cessation mutually facilitates alcohol drinking cessation among tobacco and alcohol co-users: A cross-sectional study in a rural area of Shanghai, China.

INTRODUCTION: Tobacco smoking and alcohol drinking are strongly paired behaviours, affecting millions of people worldwide. Studies in western countries demonstrate that alcohol use among smokers makes it harder to quit smoking, and addressing alcohol use is particularly important for smoking cessation, but the evidence is limited in China. We conducted a cross-sectional study to understand the prevalence of smoking, drinking, as well as tobacco and alcohol co-use, and to explore how smoking cessation mutually facilitates drinking cessation among tobacco and alcohol co-users. METHODS: During 2016 and 2017, we sampled 36698 participants aged >18 years in Songjiang district, Shanghai. A questionnaire was designed to collect data, and participants were classified into non-smokers and smokers (current and former smokers), as well as non-alcohol drinkers and alcohol drinkers (current and former alcohol drinkers). SAS software was applied to analyse the differences by weighted logistic regressions. RESULTS: The prevalence of tobacco smoking, alcohol drinking, and tobacco and alcohol co-use was 23.53%, 13.52% and 9.85%, respectively. Smoking cessation prevalence was 15.93%, which was higher than drinking cessation prevalence (8.22%). Tobacco and alcohol co-users had a higher prevalence of smoking cessation (16.95%) than participants who were only smokers (15.20%) and had higher prevalence of alcohol drinking cessation (8.71%) than residents who were only drinkers (6.91%). Tobacco and alcohol co-users who stopped alcohol drinking were much more likely to stop smoking than those who still drank alcohol (OR=8.83; 95% CI: 6.91-11.28) or those who only smoked (OR=7.51; 95% CI: 5.93-9.52). CONCLUSIONS: Drinking cessation prevalence was lower than that of smoking cessation, and drinking cessation could mutually facilitate smoking cessation among tobacco and alcohol co-users. Tobacco smoking cessation programs could incorporate alcohol drinking cessation measures to achieve higher public health benefits.

4-Bromodiphenyl ether delays pubertal Leydig cell development in rats.

Polybrominated diphenyl ethers are a class of brominated flame retardants that are potential endocrine disruptors. 4-Bromodiphenyl ether (BDE-3) is the most abundant photodegradation product of higher polybrominated diphenyl ethers. However, whether BDE-3 affects Leydig cell development during puberty is still unknown. The objective of this study was to explore effects of BDE-3 on the pubertal development of rat Leydig cells. Male Sprague Dawley rats (35 days of age) were gavaged daily with BDE-3 (0, 50, 100, and 200 mg/kg body weight/day) for 21 days. BDE-3 decreased serum testosterone levels (1.099 ±â€¯0.412 ng/ml at a dose of 200 mg/kg BDE-3 when compared to the control level (2.402 ±â€¯0.184 ng/ml, mean ±â€¯S.E.). BDE-3 decreased Leydig cell size and cytoplasmic size at a dose of 200 mg/kg, decreased Lhcgr, Star, Dhh, and Sox9 mRNA levels at ≥ 100 mg/kg and Scarb1, Cyp11a1, Hsd17b3, and Fshr at 200 mg/kg. BED-3 also decreased the phosphorylation of AKT1, AKT2, ERK1/2, and AMPK at 100 or 200 mg/kg. BDE-3 in vitro induced ROS generation, inhibited androgen production, down-regulated Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Srd5a1, and Akr1c14 expression in immature Leydig cells after 24-h treatment. In conclusion, the current study indicates that BDE-3 disrupts Leydig cell development via suppressing AKT, ERK1/2, and AMPK phosphorylation and inducing ROS generation.

Platelet-derived growth factor BB stimulates differentiation of rat immature Leydig cells.

Platelet-derived growth factor (PDGF) is one family of growth factors that regulate cell growth and differentiation. Rat Leydig cells express PDGF-ß receptor (PDGFRB) during pubertal development. However, the mechanism of PDGF in the regulation of Leydig cell development is unclear. In the present study, rat immature Leydig cells were isolated from the testes of 35-day-old Sprague-Dawley rats and treated with 1 and 10 ng/mL of PDGF-BB. After 24 h of treatment, these cells were harvested for genomics profiling and the medium steroids were measured. 1 and 10 ng/mL PDGF-BB significantly increased androgen production by rat immature Leydig cells. Genomics profiling analysis showed that the expression levels of steroidogenic acute regulatory protein (Star) were increased by 2-fold. Further analysis showed that Fos expression level was increased 2- and 5-fold by 1 and 10 ng/mL PDGF-BB, respectively. In conclusion, PDGF-BB stimulated the differentiation of rat immature Leydig cells via regulating Star.

Combined Virtual Screening and Substructure Search for Discovery of Novel FABP4 Inhibitors.

Fatty acid-binding protein 4 (FABP4, AFABP) is a potential drug target for diabetes and atherosclerosis. In this study, a series of novel FABP4 inhibitors were discovered through combining virtual screening and substructure search. Seventeen compounds exhibited FABP4 inhibitory activities with IC50 < 10 µM, among which 11 compounds showed high selectivity against FABP3. The best compound 36b displayed an IC50 value of 1.5 µM. Molecular docking and point mutation studies revealed that Gln95, Arg126, and Tyr128 play key roles for these compounds binding with FABP4. Interestingly, Gln95 seems to be essential for conformation stability of FABP4. The new scaffolds of these compounds and their interaction mechanisms binding with FABP4 should provide an important clue for the further development of novel FABP4 inhibitors.