Advanced biological ageing predicts future risk for neurological diagnoses and clinical examination findings.

Age is a dominant risk factor for some of the most common neurological diseases. Biological ageing encompasses interindividual variation in the rate of ageing and can be calculated from clinical biomarkers or DNA methylation data amongst other approaches. Here, we tested the hypothesis that a biological age greater than one's chronological age affects the risk of future neurological diagnosis and the development of abnormal signs on clinical examination. We analysed data from the Swedish Adoption/Twin Study of Aging (SATSA): a cohort with 3175 assessments of 802 individuals followed-up over several decades. Six measures of biological ageing were generated: two physiological ages (created from bedside clinical measurements and standard blood tests) and four blood methylation age measures. Their effects on future stroke, dementia or Parkinson's disease diagnosis, or development of abnormal clinical signs, were determined using survival analysis, with and without stratification by twin pairs. Older physiological ages were associated with ischaemic stroke risk; for example one standard deviation advancement in baseline PhenoAgePhys or KDMAgePhys residual increased future ischaemic stroke risk by 29.2% [hazard ratio (HR): 1.29, 95% confidence interval (CI) 1.06-1.58, P = 0.012] and 42.9% (HR 1.43, CI 1.18-1.73, P = 3.1 × 10-4), respectively. In contrast, older methylation ages were more predictive of future dementia risk, which was increased by 29.7% (HR 1.30, CI 1.07-1.57, P = 0.007) per standard deviation advancement in HorvathAgeMeth. Older physiological ages were also positively associated with future development of abnormal patellar or pupillary reflexes, and the loss of normal gait. Measures of biological ageing can predict clinically relevant pathology of the nervous system independent of chronological age. This may help to explain variability in disease risk between individuals of the same age and strengthens the case for trials of geroprotective interventions for people with neurological disorders.

Exploration and structure-activity relationship research of benzenesulfonamide derivatives as potent TRPV4 inhibitors for treating acute lung injury.

RN-9893, a TRPV4 antagonist identified by Renovis Inc., showcased notable inhibition of TRPV4 channels. This research involved synthesizing and evaluating three series of RN-9893 analogues for their TRPV4 inhibitory efficacy. Notably, compounds 1b and 1f displayed a 2.9 to 4.5-fold increase in inhibitory potency against TRPV4 (IC50 = 0.71 ± 0.21 µM and 0.46 ± 0.08 µM, respectively) in vitro, in comparison to RN-9893 (IC50 = 2.07 ± 0.90 µM). Both compounds also significantly outperformed RN-9893 in TRPV4 current inhibition rates (87.6 % and 83.2 % at 10 µM, against RN-9893's 49.4 %). For the first time, these RN-9893 analogues were profiled in an in vivo mouse model, where intraperitoneal injections of 1b or 1f at 10 mg/kg notably mitigated symptoms of acute lung injury induced by lipopolysaccharide (LPS). These outcomes indicate that compounds 1b and 1f are promising candidates for acute lung injury treatment.

Preliminary Validation of Measures of Experienced, Perceived, and Internalized Stigma Among Adults Who Are d/Deaf or Hard of Hearing in the United States and Ghana.

OBJECTIVES: In this article, we examine the psychometric performance of 3 scales measuring experienced, perceived, and internalized d/Deaf or hard of hearing (d/DHH) stigma among adult (18 and older) populations of individuals who are d/DHH, including those who have been d/DHH since before they developed language (lifelong) and those who became d/DHH after they developed language (acquired) in the United States and Ghana. DESIGN: The preliminary validation study took place in the Greater Accra and Eastern regions of Ghana and across the United States. In the United States, all data were collected online via self-administered surveys in English. In Ghana, trained interviewers who are d/DHH and fluent in Ghanaian Sign Language conducted interviews with participants who are lifelong d/DHH using a video survey. Ghanaian participants with acquired d/DHH status were surveyed by trained hearing interviewers. We calculated polychoric correlation matrices between the measures to remove redundant and unrelated items and used exploratory factor analysis to create the final scales. We also tested the association between the factor scores and a simple summing method for calculating the scale. RESULTS: The study sample included people who have been d/DHH since before they developed language (Ghana: n = 171, United States n = 100) and people who became d/DHH after they developed language (Ghana: n = 174, United States: n = 219). The final experienced, perceived, and internalized scales included six, seven, and five items, respectively. All three scales performed well as unidimensional measures across all four samples. Across the four samples, the experienced, perceived, and internalized stigma scales yielded ordinal αs ranging from 0.725 to 0.947, 0.856 to 0.935, and 0.856 to 0.935, respectively. It would be acceptable to operationalize all stigma scales as sum-of-item scores. CONCLUSIONS: The scales performed well and appear to provide a valid means of measuring different types of stigma among diverse groups of people who are d/DHH. Future work should refine and validate these scales in additional contexts.

Occupational inhalable agents constitute major risk factors for rheumatoid arthritis, particularly in the context of genetic predisposition and smoking.

OBJECTIVES: To assess the effects of occupational inhalable exposures on rheumatoid arthritis (RA) development and their interactions with smoking and RA-risk genes, stratifying by presence of anticitrullinated protein antibodies (ACPA). METHODS: Data came from the Swedish Epidemiological Investigation of RA, consisting of 4033 incident RA cases and 6485 matched controls. Occupational histories were retrieved, combining with a Swedish national job-exposure matrix, to estimate exposure to 32 inhalable agents. Genetic data were used to define Genetic Risk Score (GRS) or carrying any copy of human leucocyte antigen class II shared epitope (HLA-SE) alleles. Associations were identified with unconditional logistical regression models. Attributable proportion due to interaction was estimated to evaluate presence of interaction. RESULTS: Exposure to any occupational inhalable agents was associated with increased risk for ACPA-positive RA (OR 1.25, 95% CI 1.12 to 1.38). The risk increased as number of exposed agents increased (Ptrend<0.001) or duration of exposure elongated (Ptrend<0.001). When jointly considering exposure to any occupational inhalable agents, smoking and high GRS, a markedly elevated risk for ACPA-positive RA was observed among the triple-exposed group compared with those not exposed to any (OR 18.22, 95% CI 11.77 to 28.19). Significant interactions were found between occupational inhalable agents and smoking/genetic factors (high GRS or HLA-SE) in ACPA-positive RA. CONCLUSIONS: Occupational inhalable agents could act as important environmental triggers in RA development and interact with smoking and RA-risk genes leading to excessive risk for ACPA-positive RA. Future studies are warranted to assess preventive strategies aimed at reducing occupational hazards and smoking, especially among those who are genetically vulnerable.

Absorption, metabolism and excretion of 14C-emvododstat following repeat daily oral dose administration in human volunteers using a combination of microtracer radioactivity and high radioactivity doses.

Emvododstat is a potent inhibitor of dihydroorotate dehydrogenase and is now in clinical development for the treatment of COVID-19 and acute myeloid leukemia. Since the metabolism and pharmacokinetics of emvododstat in humans is time­dependent, a repeat dose study design using a combination of microtracer radioactivity and high radioactivity doses was employed to evaluate the metabolism and excretion of emvododstat near steady state. Seven healthy male subjects each received 16 mg/0.3 µCi 14C-emvododstat daily oral doses for 6 days followed by a 16 mg/100 µCi high radioactivity oral dose on Day 7. Following the last 16 mg/0.3 µCi 14C­emvododstat dose on Day 6, total radioactivity in plasma peaked at 6 h post-dose. Following a high radioactivity oral dose (16 mg/100 µCi) of 14C-emvododstat on Day 7, both whole blood and plasma radioactivity peaked at 6 h, rapidly declined from 6 h to 36 h post-dose, and decreased slowly thereafter with measurable radioactivity at 240 h post-dose. The mean cumulative recovery of the administered dose was 6.0% in urine and 19.9% in feces by 240 h post-dose, and the mean extrapolated recovery to infinity was 37.3% in urine and 56.6% in feces. Similar metabolite profiles were observed after repeat daily microtracer radioactivity oral dosing on Day 6 and after a high radioactivity oral dose on Day 7. Emvododstat was the most abundant circulating component, M443 and O-desmethyl emvododstat glucuronide were the major circulating metabolites; M474 was the most abundant metabolite in urine, while O­desmethyl emvododstat was the most abundant metabolite in feces. Significance Statement This study provides a complete set of the absorption, metabolism and excretion data of emvododstat, a potent inhibitor of dihydroorotate dehydrogenase, at close to steady state in healthy human subjects. Resolution of challenges due to slow metabolism and elimination of a lipophilic compound highlighted in this study can be achieved by repeat daily microtracer radioactivity oral dosing followed by a high radioactivity oral dosing at therapeutically relevant doses.

Repurposing antidiabetic drugs for rheumatoid arthritis: results from a two-sample Mendelian randomization study.

Despite increasing therapeutic options to treat rheumatoid arthritis (RA), many patients fail to reach treatment targets. The use of antidiabetic drugs like thiazolidinediones has been associated with lower RA risk. We aimed to explore the repurposing potential of antidiabetic drugs in RA prevention by assessing associations between genetic variation in antidiabetic drug target genes and RA using Mendelian randomization (MR). A two-sample MR design was used to estimate the association between the antidiabetic drug and RA risk using summary statistics from genome-wide association studies (GWAS). We selected independent genetic variants from the gene(s) that encode the target protein(s) of the investigated antidiabetic drug as instruments. We extracted the associations of instruments with blood glucose concentration and RA from the UK Biobank and a GWAS meta-analysis of clinically diagnosed RA, respectively. The effect of genetic variation in the drug target(s) on RA risk was estimated by the Wald ratio test or inverse-variance weighted method. Insulin and its analogues, thiazolidinediones, and sulfonylureas had valid genetic instruments (n = 1, 1, and 2, respectively). Genetic variation in thiazolidinedione target (gene: PPARG) was inversely associated with RA risk (odds ratio [OR] 0.38 per 0.1mmol/L glucose lowering, 95% confidence interval [CI] 0.20-0.73). Corresponding ORs (95%CIs) were 0.83 (0.44-1.55) for genetic variation in the targets of insulin and its analogues (gene: INSR), and 1.12 (0.83, 1.49) 1.25 (0.78-2.00) for genetic variation in the sulfonylurea targets (gene: ABCC8 and KCNJ11). In conclusion, genetic variation in the thiazolidinedione target is associated with a lower RA risk. The underlying mechanisms warrant further exploration.

The Orco gene involved in recognition of host plant volatiles and sex pheromone in the chive maggot Bradysia odoriphaga.

The insect olfactory recognition system plays a crucial role in the feeding and reproductive behaviors of insects. The odorant receptor co-receptor (Orco), as an obligatory chaperone, is critical for odorant recognition by way of forming heteromeric complexes with conventional odorant receptors (ORs). To investigate the biological functions of Orco in perceiving host plant volatiles and sex pheromone, the Orco gene was identified from the chive maggot Bradysia odoriphaga transcriptome data. Multiple sequence alignment reveals that BodoOrco exhibits an extremely high sequence identity with Orcos from other dipteran insects. The expression of BodoOrco is significantly higher in adults than in larvae and pupae, and the BodoOrco gene is primarily expressed in the antennae of both sexes. Furthermore, the Y-tube assay indicated that knockdown of BodoOrco leads to significant reductions in B. odoriphaga adults' response to all tested host plant volatiles. The dsOrco-treated unmated male adults show less attraction to unmated females and responded slowly compared with dsGFP control group. These results indicated that BodoOrco is involved in recognition of sex pheromone and host plant volatiles in B. odoriphaga and has the potential to be used as a target for the design of novel active compounds for developing ecofriendly pest control strategies.

Recent Advances in Drug Discovery Toxicology.

Major advances in scientific discovery and insights that stem from the development and use of new techniques and models can bring remarkable progress to conventional toxicology. Although animal testing is still considered as the "gold standard" in traditional toxicity testing, there is a necessity for shift from animal testing to alternative methods regarding the drug safety testing owing to the emerging state-of-art techniques and the proposal of 3Rs (replace, reduce, and refine) towards animal welfare. This review describes some recent research methods in drug discovery toxicology, including in vitro cell and organ-on-a-chip, imaging systems, model organisms (C. elegans, Danio rerio, and Drosophila melanogaster), and toxicogenomics in modern toxicology testing.

A genome-wide cross-trait analysis identifies shared loci and causal relationships of type 2 diabetes and glycaemic traits with polycystic ovary syndrome.

AIMS/HYPOTHESIS: The link underlying abnormal glucose metabolism, type 2 diabetes and polycystic ovary syndrome (PCOS) that is independent of BMI remains unclear in observational studies. We aimed to clarify this association using a genome-wide cross-trait approach. METHODS: Summary statistics from the hitherto largest genome-wide association studies conducted for type 2 diabetes, type 2 diabetes mellitus adjusted for BMI (T2DMadjBMI), fasting glucose, fasting insulin, 2h glucose after an oral glucose challenge (all adjusted for BMI), HbA1c and PCOS, all in populations of European ancestry, were used. We quantified overall and local genetic correlations, identified pleiotropic loci and expression-trait associations, and made causal inferences across traits. RESULTS: A positive overall genetic correlation between type 2 diabetes and PCOS was observed, largely influenced by BMI (rg=0.31, p=1.63×10-8) but also independent of BMI (T2DMadjBMI-PCOS: rg=0.12, p=0.03). Sixteen pleiotropic loci affecting type 2 diabetes, glycaemic traits and PCOS were identified, suggesting mechanisms of association that are independent of BMI. Two shared expression-trait associations were found for type 2 diabetes/T2DMadjBMI and PCOS targeting tissues of the cardiovascular, exocrine/endocrine and digestive systems. A putative causal effect of fasting insulin adjusted for BMI and type 2 diabetes on PCOS was demonstrated. CONCLUSIONS/INTERPRETATION: We found a genetic link underlying type 2 diabetes, glycaemic traits and PCOS, driven by both biological pleiotropy and causal mediation, some of which is independent of BMI. Our findings highlight the importance of controlling fasting insulin levels to mitigate the risk of PCOS, as well as screening for and long-term monitoring of type 2 diabetes in all women with PCOS, irrespective of BMI.

P-block atom modified Sn(200) surface as a promising electrocatalyst for two-electron CO2 reduction: a first-principles study.

Low activity and poor product selectivity of CO2 reduction have seriously hampered its further practical application. Introducing p-block atoms to the catalyst is regarded as a promising strategy due to the versatility of p orbitals and diversity of p-block elements. Here, we systematically studied the influence of p-block atom X (X = C, N, O, S, and Se) on CO2 catalytic properties on a Sn(200) surface by first-principles calculation. Our work shows that all the p-block atoms are relative stable with Ef in the range of -5.11 to -3.59 eV. Further calculation demonstrates that the diversity of the p-block atoms results in unique CO2 electrocatalytic activity and product selectivity. Interestingly, the p-block C atom shows bi-functional activity to form two-electron products HCOOH and CO, with the corresponding energy barriers remarkably low at about 0.19 eV and 0.28 eV. In particular, the p-block S(Se) atom appears to have striking HCOOH selectivity, with the energy barrier to form HCOOH only a quarter of that to form the CO product. This unusual behavior is mainly attributed to the adsorption strength and frontier orbital interaction between the p-block atom and intermediates. These findings can effectively provide a valuable insight into the design of highly efficient CO2 electrocatalyst.

Associations of health-risk behaviors with mental health among Chinese children.

The study aimed to investigate the individual and combined association of health-risk behaviors with mental health among Chinese children. A cross-sectional study was conducted in Wuhan, China, from May to June 2018. Participants self-reported the information on physical activity (PA), screen time (ST), fruit and vegetable (FV) intake, and sleep duration. Mental health, including depression, social anxiety and self-esteem, was assessed using standard questionnaires. A total of 1296 children (704 males and 592 females) aged 9.2 ± 0.4 years were included in the present study. The prevalence of low PA, high ST, low FV intake, and inadequate sleep duration was 45.6%, 18.0%, 69.7%, and 64.7%, respectively. Overall, significant associations were found between individual health-risk behavior and increased risks of mental health. Furthermore, children with three or four health-risk behaviors showed significantly increased risks of anxiety (OR: 3.18, 95%CI: 1.63-6.21), depression (OR: 4.55, 95%CI: 2.28-9.09) and low self-esteem (OR: 3.59, 95%CI: 2.20-5.88) compared with those without health-risk behavior. Results of this study revealed a high prevalence of health-risk behaviors among Chinese children. Furthermore, the clustering of health-risk behavior was associated with significantly increased risks of mental health in this population. Considering these findings, it is important to perform early interventions to reduce children's health-risk behavior and prevent mental health problems.

Pathogenic variants of ATG4D in infertile men with non-obstructive azoospermia identified using whole-exome sequencing.

Non-obstructive azoospermia (NOA) is the most severe form of male infertility, and it is primarily associated with genetic defects. We performed whole-exome sequencing of 236 patients with NOA and identified a homozygous pathogenic variant of autophagy-related 4D cysteine peptidase (ATG4D) in two siblings from a consanguineous family and compound heterozygous pathogenic variants of ATG4D in two sporadic cases. The expression of LC3B, a regulator of autophagic activity, was significantly decreased, and the apoptosis rate of spermatogenic cells in testicular tissues was increased. Transfection of GC-2spd cells with a ATG4D mutant plasmid (Flag-Atg4dmut ) significantly decreased the expression level of Lc3b and increased the rate of apoptosis. Moreover, a pathogenic variant in X-linked ATG4A and compound heterozygous pathogenic variants of ATG4B were identified in one patient each. All novel variants were segregated by disease phenotype and were predicted to be pathogenic. Our findings revealed that autophagy-related cysteine peptidase family genes may play crucial roles in human spermatogenesis and identified ATG4D as a novel candidate gene for male infertility due to NOA.

Circulating Lipoprotein Lipids, Apolipoproteins and Ischemic Stroke.

OBJECTIVE: We conducted a Mendelian randomization (MR) study to disentangle the comparative effects of lipids and apolipoproteins on ischemic stroke. METHODS: Single-nucleotide polymorphisms associated with low- and high-density lipoprotein (LDL and HDL) cholesterol, triglycerides, and apolipoprotein A-I and B (apoA-I and apoB) at the level of genomewide significance (p < 5 × 10-8 ) in the UK Biobank were used as instrumental variables. Summary-level data for ischemic stroke and its subtypes were obtained from the MEGASTROKE consortium with 514,791 individuals (60,341 ischemic stroke cases, and 454,450 non-cases). RESULTS: Increased levels of apoB, LDL cholesterol, and triglycerides were associated with higher risk of any ischemic stroke, large artery stroke, and small vessel stroke in the main and sensitivity univariable MR analyses. In multivariable MR analysis including apoB, LDL cholesterol, and triglycerides in the same model, apoB retained a robust effect (p < 0.05), whereas the estimate for LDL cholesterol was reversed, and that for triglycerides largely attenuated. Decreased levels of apoA-I and HDL cholesterol were robustly associated with increased risk of any ischemic stroke, large artery stroke, and small vessel stroke in all univariable MR analyses, but the association for apoA-I was attenuated to the null after mutual adjustment. INTERPRETATION: The present MR study reveals that apoB is the predominant trait that accounts for the etiological basis of apoB, LDL cholesterol, and triglycerides in relation to ischemic stroke, in particular large artery and small vessel stroke. Whether HDL cholesterol exerts a protective effect on ischemic stroke independent of apoA-I needs further investigation. ANN NEUROL 2020;88:1229-1236.

Major depressive disorder and cardiometabolic diseases: a bidirectional Mendelian randomisation study.

AIMS/HYPOTHESIS: Observational studies have shown a bidirectional association between major depressive disorder (MDD) and cardiometabolic diseases. We conducted a two-sample bidirectional Mendelian randomisation (MR) study to assess the causal associations of MDD with type 2 diabetes, coronary artery disease (CAD) and heart failure and vice versa. METHODS: We extracted summary-level data for MDD, type 2 diabetes, CAD and heart failure from corresponding published large genome-wide association studies of individuals mainly of European-descent. In total, 96 SNPs for MDD, 202 SNPs for type 2 diabetes, 44 SNPs for CAD and 12 SNPs for heart failure were proposed as instrumental variables at the genome-wide significance level (p < 5 × 10-8). The random-effects inverse-variance weighted method was used for the main analyses. RESULTS: Genetic liability to MDD was significantly associated with type 2 diabetes and CAD at the Bonferroni-corrected significance level. The ORs of type 2 diabetes and CAD were respectively 1.26 (95% CI 1.10, 1.43; p = 6 × 10-4) and 1.16 (95% CI 1.05, 1.29; p = 0.0047) per one-unit increase in loge odds of MDD. There was a suggestive association between MDD and heart failure (OR 1.11 [95% CI 1.01, 1.21]; p = 0.033). We found limited evidence supporting causal effects of cardiometabolic diseases on MDD risk in the reverse MR analyses. CONCLUSIONS/INTERPRETATION: The present study strengthened the evidence that MDD is a potential risk factor for type 2 diabetes and CAD. Whether MDD is causally related to heart failure needs further study. DATA AVAILABILITY: All data included in this study were uploaded as supplements and are also publicly available through published GWASs and open GWAS datasets (UK Biobank, 23andMe and Psychiatric Genomics: https://datashare.is.ed.ac.uk/handle/10283/3203; DIAGRAM: http://diagram-consortium.org/downloads.html; CARDIoGRAMplusCD4: www.cardiogramplusc4d.org/; HERMES: http://www.kp4cd.org/datasets/mi). Graphical abstract.

Association of Adverse Childhood Experiences with Health Risk Behaviors Among College Students in Zambia.

BACKGROUND: Adverse childhood experiences (ACEs) have been linked to long-term health outcomes, while the impact of such experience has not been investigated among Zambian youth. This study examined the associations of ACEs with individual and clusters of health risk behavior among college students in Zambia. METHOD: A total of 624 college students participated in this cross-sectional study. A self-administered questionnaire was used to collect information on their ACEs and health risk behaviors. RESULTS: There were 58.3% (364) reporting some forms of ACEs, with 27.6% (172), 16.3% (102), and 14.4% (90) being exposed to 1, 2, and ≥ 3 ACEs, respectively. The prevalence of health risk behaviors ranged from 6.0 to 34.2%. Overall, ACEs were associated with increased risk of smoking, binge drinking, suicide attempt, risky sexual behaviors, and illicit drug use. Logistic regression suggested that participants with ≥ 3 ACEs (OR, 3.62; 95% CI, 2.14-6.13) were more likely to engage in the unhealthy cluster, characterized by the presence of any health risk behavior, than those without ACE. CONCLUSION: ACEs were associated with individual and clustering of health risk behaviors among Zambia college students. Our study suggests that early intervention is needed to prevent long-term adverse health consequences in this population.

Synthesis and biological evaluation of (3/4-(pyrimidin-2-ylamino)benzoyl)-based hydrazine-1-carboxamide/carbothioamide derivatives as novel RXRα antagonists.

Abnormal alterations in the expression and biological function of retinoid X receptor alpha (RXRα) have a key role in the development of cancer. Potential modulators of RXRα as anticancer agents are explored in growing numbers of studies. A series of (4/3-(pyrimidin-2-ylamino)benzoyl)hydrazine-1-carboxamide/carbothioamide derivatives are synthesised and evaluated for anticancer activity as RXRα antagonists in this study. Among all synthesised compounds, 6A shows strong antagonist activity (half maximal effective concentration (EC50) = 1.68 ± 0.22 µM), potent anti-proliferative activity against human cancer cell lines HepG2 and A549 cells (50% inhibition of cell viability (IC50) values < 10 µM), and low cytotoxic property in normal cells such as LO2 and MRC-5 cells (IC50 values > 100 µM). Further bioassays indicate that 6A inhibits 9-cis-RA-induced activity in a dose-dependent manner, and selectively binds to RXRα-=LΒD with submicromolar affinity (Kd = 1.20 × 10-7 M). 6A induces time-and dose-dependent cleavage of poly ADP-ribose polymerase, and significantly stimulates caspase-3 activity, leading to RXRα-dependent apoptosis. Finally, molecular docking studies predict the binding modes for RXRα-LBD and 6A.

Synthesis, biological activities, and docking studies of d-pantolactone derivatives as novel FAS inhibitors.

A novel series of fatty acid synthase (FAS) inhibitors with D-(-)-pantolactone moiety and potential utility for the treatment of obesity were designed, synthesized and characterized, in which the structure of compound 3k was further confirmed by single X-ray diffraction. The mouse FAS inhibitory activity of synthesized compounds was evaluated. Major synthesized compounds (except 3g, 3i, 3k, 3l, and 3n) exhibited moderate FAS inhibitory properties with IC50 values in the range of 13.68 ±â€¯1.52-33.19 ±â€¯1.39 µM, reference inhibitor C75 has IC50 value of 13.86 ±â€¯2.79 µM. Eight compounds (3c, 3d, 3e, 3f, 3j, 3m, 3q and 3r) also displayed inhibitory effect on lipid accumulation in human HepG2 cells. Additionally, the molecular docking study revealed that compound 3m having good inhibition activity against FAS and lipid accumulation also showed promising binding affinities with hFAS, while its binding model with hFAS (PDB ID: 4PIV) was different from that of reference compound C75.

Cigarette smoking as a risk factor for type 2 diabetes in women compared with men: a systematic review and meta-analysis of prospective cohort studies.

BACKGROUND: Few studies have investigated the effect of smoking on type 2 diabetes in women compared with men, even though several epidemiological studies provided a clear picture of the risk among the entire population. METHODS: We systematically searched PubMed and Embase up to August 2017 for prospective studies that were stratified by sex with measures of the relative risk (RR) for type 2 diabetes and current smoking compared with non-smoking. The sex-specific RRs and their ratios (RRRs), comparing women with man, were pooled using random-effects models. RESULTS: Seventeen articles were identified including 20 prospective cohorts with 5 077 289 participants and 223 084 incident cases of type 2 diabetes. The pooled RRR suggested a similar risk of type 2 diabetes associated with smoking in women compared with men (RRR: 0.98, 95% confidence interval [CI]: 0.96-1.01). Furthermore, no significant sex difference in the RR was found between former smokers and those who had never smoked (RRR: 0.98, 95% CI: 0.92-1.04). CONCLUSIONS: The findings of this meta-analysis indicate that female smokers had similar risk of type 2 diabetes with male smokers.

Two New Cytotoxic Compounds from a Deep-Sea Penicillum citreonigrum XT20-134.

Penicillum citreonigrum XT20-134 (MCCC 3A00956) is a fungus with cytotoxic activity, derived from deep-sea sediment. Five new compounds, adeninylpyrenocine (1), 2-hydroxyl-3-pyrenocine-thio propanoic acid (2), ozazino-cyclo-(2,3-dihydroxyl-trp-tyr) (3), 5,5-dichloro-1-(3,5-dimethoxyphenyl)-1,4-dihydroxypentan-2-one (4), and 2,3,4-trihydroxybutyl cinnamate (5), together with 19 known compounds (6-24), were isolated from an ethyl acetate (EtOAc) extract of its fermentation. The structures of the new compounds were comprehensively characterized by high-resolution electrospray ionization-mass spectrometry (HR-ESI-MS), 1D and 2D nuclear magnetic resonance (NMR). All isolates were evaluated for their cytotoxic activities. The heteroatom-containing new compounds 2 and 4 showed potent cytotoxicity to the human hepatoma tumor cell Bel7402 with IC50 values of 7.63 ± 1.46, 13.14 ± 1.41 µM and the human fibrosarcoma tumor cell HT1080 with IC50 values of 10.22 ± 1.32, 16.53 ± 1.67 µM, respectively.

Association between fruit and vegetable intake and the risk of hypertension among Chinese adults: a longitudinal study.

PURPOSE: Fruit and vegetable intake has been inversely associated with the risk of hypertension; however, there is inconsistent evidence on the long-term association. Given this gap in the literature, it is necessary to identify evidence from large prospective studies, especially in China, where insufficient evidence exists. Thus, we examined the association of fruit and vegetable intake with incident hypertension in Chinese adults. METHODS: We conducted analyses among 5659 Chinese adults aged 18-64 years, free of cardiovascular disease, cancer, and hypertension in the 2006 wave of the China Health and Nutrition Survey. Fruit and vegetable intake was assessed using consecutive 24-h recalls. Incident hypertension was identified from the 2011 wave of the survey. RESULTS: A total of 866 participants developed incident hypertension. The relative risks (RRs) and 95% confidence intervals (CIs) of hypertension were 0.74 (0.55-0.99), 0.65 (0.48-0.88), 0.68 (0.50-0.92), and 0.73 (0.53-0.99) comparing each quintile group of fruit and vegetable intake with the lowest quintile group. These associations attenuated for the change of intake but remained significant for the fourth quintile, of which the RR (95% CI) was 0.65 (0.47-0.89). The magnitude of association was stronger among those who were younger, female, overweight and had prehypertension. When examined separately, fruit intake was more strongly and significantly associated with lowering BP than vegetable intake. Adding body mass index to the models attenuated all associations. CONCLUSIONS: Greater long-term intake and increased intake of fruit and vegetables may reduce the risk of developing hypertension in Chinese adults.