ß-Caryophyllene Confers Cardioprotection by Scavenging Radicals and Blocking Ferroptosis.

Ferroptosis is a form of regulated cell death triggered by iron-dependent lipid peroxidation and has been associated with heart diseases. However, there are currently no approved drugs that specifically inhibit ferroptosis in clinical practice, which largely limits the translational potential of this novel target. Here, we demonstrated that ß-caryophyllene (BCP; 150 µM), a natural dietary cannabinoid, protects cardiomyocytes against ferroptotic cell death induced by cysteine deprivation or glutathione peroxidase 4 (GPX4) inactivation. Moreover, BCP preserved the mitochondrial morphology and function during ferroptosis induction. Unexpectedly, BCP supported ferroptosis resistance independent of canonical antiferroptotic pathways. Our results further suggested that BCP may terminate radical chain reactions through interactions with molecular oxygen, which also explains why its oxidation derivative failed to suppress ferroptosis. Finally, oral BCP administration (50 mg/kg, daily) significantly alleviated doxorubicin (15 mg/kg, single i.p. injection)-induced cardiac ferroptosis and cardiomyopathy in mice. In conclusion, our data revealed the role of BCP as a natural antiferroptotic compound and suggest pharmacological modification based on BCP as a promising therapeutic strategy for treating ferroptosis-associated heart disorders.

Identification of Isoliensinine as a Ferroptosis Suppressor with Iron-Chelating Activity.

Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of lipid peroxides. The high involvement of ferroptosis in diverse human diseases highlights the need for the identification of new chemotypes with anti-ferroptotic activity. Here, we performed a natural product library screening in HT1080 fibrosarcoma cells and identified licochalcone A (LA), isoeugenyl acetate (ISA), and isoliensinine (ISL) as suppressors of either RSL3- or IKE-induced ferroptosis. Mechanistically, ferroptosis resistance conferred by these compounds is mainly through GPX4/NRF2-independent mechanisms. Among them, only ISL could effectively rescue ferroptosis induced by FINO2, which is a stable oxidant of ferrous iron, suggesting that ISL may have the properties of an iron chelator. Consistent with the hypothesis, both computational tools and X-ray photoelectron spectroscopy supported the binding between ISL and iron ions. And ISL greatly inhibited excessive iron-dependent ferroptotic cell death through limiting intracellular iron accumulation. Furthermore, its iron chelator activity also protected mice from organ injury in an acute iron overload model. In conclusion, this study provided valuable insights for developing effective anti-ferroptosis agents from natural products, which represent a potential therapeutic strategy for treating ferroptosis-associated organ damage.

Gallic Acid Attenuates Sepsis-Induced Liver Injury through C/EBPß-Dependent MAPK Signaling Pathway.

SCOPE: Liver injury is a major complication associated with sepsis. Together with others, the study has shown that gallic acid (GA) exerts anti-inflammatory and antioxidant effects in vivo. However, the role of GA in sepsis-mediated hepatic impairment and the underlying mechanisms remains to be elucidated. METHODS AND RESULTS: C57BL/6J mice are pretreated with saline or GA and subjected to sham or cecal ligation and puncture (CLP). The pathological alterations are assessed by hematoxylin and eosin staining as well as immunohistochemical staining. RNA sequencing is employed to analyze hepatic transcriptome modifications. The study finds that GA supplementation significantly ameliorates CLP-induced mortality, liver dysfunction, and inflammation. RNA sequencing reveals that 1324 genes are markedly differentially regulated in livers of saline- or GA-treated sham or CLP mice. Gene ontology analysis demonstrates that the differentially expressed genes regulated by GA are predominantly correlated with the immune system process, oxidation-reduction process, and inflammatory response. Furthermore, mitogen-activated protein kinase (MAPK) signaling is localized in the center of the GA-mediated pathway network. Notably, activation of MAPK by C16-PAF significantly blocks GA-mediated protective effects on hepatic injury, inflammation, as well as CCAAT/enhancer-binding protein-ß (C/EBPß) dependent extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-κB (NF-κB) signaling. CONCLUSION: Therefore, this study indicates that GA may offer a promising therapeutic opportunity for sepsis-associated liver injury.

Serum Uric Acid Levels and Their Association with Renal Function Decline and Kidney Disease Progression in Middle-Aged and Elderly Populations: A Retrospective Cohort Study.

Objective: To evaluate the associations between serum uric acid (SUA) levels and estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD), with a focus on gender differences, and variations among women pre-and post-menopausal stages. Design: A retrospective cohort study. Setting: A large community-based survey was conducted every two years from 2010 to 2018 in Hangzhou, Zhejiang Province, Southeastern China. Participants: 10,218 participants (40 years or above) without CKD at baseline who underwent three physical examinations were enrolled. CKD was defined as an eGFR of less than 60 mL/min/1.73m2. Methods: Participants with SUA levels were divided into four groups (Q1-Q4) based on baseline SUA quartiles. The Q1 was the reference. By stratifying participants by gender, the relationships between SUA levels and eGFR were investigated using the generalized additive mixture model. The associations of SUA and the risk of incident CKD were examined using multivariate logistic regression models in the generalized estimating equation. Results: After adjusting for confounding variables, a nonlinear association between SUA and eGFR was observed in females, while an approximately linear relationship was observed in males, suggesting that elevated SUA levels are associated with renal function decline. Furthermore, the highest quartile of SUA was associated with a 2.16-fold (95% CI: 1.31-3.58) increased risk of CKD in males and a 2.76-fold (95% CI: 1.59-4.78) increased risk in females, compared with the lowest quartile. And the spline curves demonstrated a U-shaped pattern, suggesting a potential threshold effect of SUA on the risk of CKD. Additionally, Subgroup analyses revealed significant associations between elevated SUA levels with CKD in postmenopausal women, but not in premenopausal women. Conclusion: Elevated SUA levels are associated with an increased risk of CKD development and renal function decline in middle-aged and elderly individuals, particularly in postmenopausal women.

Associations of serum uric acid with cardiovascular disease risk factors: a retrospective cohort study in southeastern China.

OBJECTIVE: To evaluate the associations between serum uric acid (SUA) levels and cardiovascular disease (CVD) risk factors, focusing on potential sex-specific differences. DESIGN: A retrospective cohort study. SETTING: A large community-based survey was conducted every two years from 2010 to 2018 in Hangzhou, Zhejiang Province, outheastern China. PARTICIPANTS: 6119 participants aged 40 years and above who underwent at least three times of physical examinations were enrolled. METHODS: Participants were categorised into four groups (Q1-Q4) based on baseline SUA quartiles within the normal range, with hyperuricaemia (HUA) as the fifth group. The Q1 was the reference. By stratifying participants by gender, the relationships between SUA levels and systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose (FBG) and total cholesterol (TC) were investigated using linear regression models in the generalised estimating equation. Additionally, the associations of elevated SUA levels and HUA with hypertension, hyperglycaemia and dyslipidaemia were correspondingly examined using multivariate logistic regression models. RESULTS: After adjusting for confounding variables, we found positive associations between SUA levels and SBP, DBP, FBG and TC in women, and with TC in men (p<0.01). Likewise, elevated SUA quartiles and HUA were linked to increased dyslipidaemia risk in both sexes, and increased hyperglycaemia risk only in women, with HRs (95% CI) of 1.64 (1.05 to 2.55) and 2.37 (1.47 to 3.81) in the Q4 and HUA group, respectively. Women with HUA had higher hypertension risk (HR=1.45, 95% CI 1.21 to 1.73), while no such association was observed in men. Stratified analyses revealed significant associations between elevated SUA levels and CVD risk factors in postmenopausal and non-obese women. CONCLUSIONS: Elevated SUA levels increase the risk of dyslipidaemia in both sexes. SUA levels within normal range and HUA are positively associated with hyperglycaemia and hypertension in postmenopausal women, but not in men.

Effect of low-glycemic index diet advice on pregnant outcomes in women with elevated risk of gestational diabetes mellitus: A meta-analysis of randomized controlled trails.

BACKGROUND AND AIMS: The beneficial effect of low-glycemic index (GI) diet on gestational diabetes mellitus (GDM) has been suggested in many observational studies; however, results from intervention trials remain inconsistent. This study aims to estimate the effect of interventions with low-GI dietary advice on pregnant outcomes in women with elevated risk of GDM. DESIGN: PubMed, Web of Science, Embase, and Cochrane Library databases were searched for randomized clinical trials (RCTs) through March 2022. Studies reporting the effect of low-GI diet advice intervention on maternal and fetal outcomes in pregnant women with increased risks of GDM were included. Random or fixed effects model was used to calculate combined treatment effects. Publication bias was assessed via Begg's and Egger's tests and funnel plot inspection. RESULTS: Nine RCTs recruiting 3416 participants were included. Low-GI diet advice did not modulate the risk of GDM. Compared with control diets, low-GI diet advice significantly reduced gestational weight gain (GWG) (weighted mean differences, WMD = -0.93 kg, 95% CI: -1.31, -0.55; p < 0.001; n = 7) and the risk of premature birth (RR = 0.55, 95% CI: 0.35, 0.88; p = 0.012; n = 5). In subgroup analyses, the effect of low-GI diet interventions on premature birth was significant only in women with BMI higher than 30 kg/m2 (RR = 0.28, 95% CI: 0.10, 0.77, p = 0.014; n = 3); the significant effect on GWG was not altered by stratification of BMI and the type of GDM risk factors. No significant changes in other maternal and newborn outcomes were found. CONCLUSIONS: Low-GI diet advice interventions during pregnancy decreased GWG and the risk of premature birth in women with elevated GDM risk; however, the interventions did not significantly prevent GDM development in these women.

A meta-analysis and systematic review of randomized clinical trials on the effect of coffee consumption on heart rate.

CONTEXT: Resting heart rate (HR) is increasingly recognized as an indicator of disease and overall morbidity and mortality. Whether chronic coffee consumption affects resting HR is an important consideration for individual consumers as well as from a public health perspective. OBJECTIVE: A meta-analysis of randomized controlled trials (RCTs) was conducted to examine the effectiveness of coffee consumption on resting HR. DATA SOURCES: Original RCTs assessing the effect of coffee consumption on resting HR and published prior to March 2023 were identified by searching online databases, including PubMed, Web of Science, and Cochrane Library databases. DATA EXTRACTION AND ANALYSIS: Data searches and extraction and risk-of-bias assessments were performed according to the Cochrane guidelines, and the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for systematic reviews were followed. Data on study characteristics, type, and amount of coffee and net change and measurement resting HR were extracted. A random-effects or a fixed-effects model was used to estimate the pooled effect sizes. Homogeneity was determined with the Cochran Q test, and publication bias was assessed through Begg's test, Egger's test, and funnel plots. RESULTS: A total of 6 RCTs with 11 intervention trials or arms involving 485 individuals were included. The participants were generally healthy, although some had hypertension, hypercholesterolemia, or were overweight. The trial duration ranged from 2 weeks to 24 weeks. The overall pooled analysis showed that coffee consumption resulted in a negligible increase in resting HR of 0.40 beats per minute (95% CI: -0.78 to 1.57; P = 0.506), which was statistically insignificant. Subgroup analysis of all specified categories was consistent with the overall analysis. No heterogeneity was observed among included trials (I2 = 0.0%, P = 0.756). CONCLUSION: The results of the present meta-analysis study demonstrate that daily coffee consumption of 3 to 6 cups for a period of 2 to 24 weeks has no statistically significant effect on resting HR.

3,5,6-Trichloro-2-pyridinol confirms ototoxicity in mouse cochlear organotypic cultures and induces cytotoxicity in HEI-OC1 cells.

The metabolite of organophosphate pesticide chlorpyrifos (CPF), 3,5,6-Trichloro-2-pyridinol (TCP), is persistent and mobile toxic substance in soil and water environments, exhibiting cytotoxic, genotoxic, and neurotoxic properties. However, little is known about its effects on the peripheral auditory system. Herein, we investigated the effects of TCP exposure on mouse postnatal day 3 (P3) cochlear culture and an auditory cell line HEI-OC1 to elucidate the underlying molecular mechanisms of ototoxicity. The damage of TCP to outer hair cells (OHC) and support cells (SC) was observed in a dose and time-dependent manner. OHC and SC were a significant loss from basal to apical turn of the cochlea under exposure over 800 µM TCP for 96 h. As TCP concentrations increased, cell viability was reduced whereas reactive oxygen species (ROS) generation, apoptotic cells, and the extent of DNA damage were increased, accordingly. TCP-induced phosphorylation of the p38 and JNK MAPK are the downstream effectors of ROS. The antioxidant agent, N-acetylcysteine (NAC), could reverse TCP-mediated intracellular ROS generation, inhibit the expressive level of cleaved-caspase 3 and block phosphorylation of p38/JNK. Overall, this is the first demonstration of TCP damaging to peripheral sensory HCs and SC in organotypic cultures from the postnatal cochlea. Data also showed that TCP exposure induced oxidase stress, cell apoptosis and DNA damage in the HEI-OC1 cells. These findings serve as an important reference for assessing the risk of TCP exposure.

Malic Enzyme 1 as a Novel Anti-Ferroptotic Regulator in Hepatic Ischemia/Reperfusion Injury.

Ferroptosis has been linked to the pathogenesis of hepatic injury induced by ischemia/reperfusion (I/R). However, the mechanistic basis remains unclear. In this study, by using a mouse model of hepatic I/R injury, it is observed that glutathione (GSH) and cysteine depletion are associated with deficiency of the reducing power of nicotinamide adenine dinucleotide phosphate (NADPH). Genes involved in maintaining NADPH homeostasis are screened, and it is identified that I/R-induced hepatic ferroptosis is significantly associated with reduced expression and activity of NADP+ -dependent malic enzyme 1 (Me1). Mice with hepatocyte-specific Me1 gene deletion exhibit aggravated ferroptosis and liver injury under I/R treatment; while supplementation with L-malate, the substrate of ME1, restores NADPH and GSH levels and eventually inhibits I/R-induced hepatic ferroptosis and injury. A mechanistic study further reveals that downregulation of hepatic Me1 expression is largely mediated by the phosphatase and tensin homologue (PTEN)-dependent suppression of the mechanistic target of rapamycin/sterol regulatory element-binding protein 1 (mTOR/SREBP1) signaling pathway in hepatic I/R model. Finally, PTEN inhibitor, mTOR activator, or SREBP1 over-expression all increase hepatic NADPH, block ferroptosis, and protect liver against I/R injury. Taken together, the findings suggest that targeting ME1 may provide new therapeutic opportunities for I/R injury and other ferroptosis-related hepatic conditions.

AQP9 (Aquaporin 9) Determines Arsenic Uptake and Tolerance in Human Hepatocellular Carcinoma Cells In Vitro.

Arsenic-based therapeutic strategies, even though promising for acute promyelocytic leukemia (APL), are limited by arsenic-related toxic effect and resistance with unknown mechanisms. The purpose of this study is to better understand the different sensitivities of hepatocellular carcinoma cells to arsenic and its mechanism. Arsenic-sensitive liver cancer cell line (HepG2) and arsenic-resistant HepG2 (AsHepG2) cells are employed to study the role of aquaporin 9 (AQP9) in arsenic uptake and tolerance. The half-maximal inhibitory concentration (IC50) value of arsenic in AsHepG2 cells (15.59 ± 1.36 µM) is significantly higher than that in HepG2 cells (7.33 ± 0.93 µM; p= 0.0288). We demonstrated that, with the treatment of sodium arsenite (NaAsO2), arsenic was accumulated at a significantly lower level in AsHepG2 cells in comparison with HepG2 cells (p= 0.00549). Further, arsenic level in AsHepG2 cells reaches a plateau after six hours of treatment, whereas arsenic continues to increase in HepG2 cells during the entire experimental period. Mechanistic study showed that the expression of AQP9 is decreased in a dose-dependent manner in AsHepG2 cells, but no significant difference in HepG2 cells. Furthermore, NaAsO2 dramatically increases AQP9 and p38 phosphorylation, which may partially regulate arsenic sensitivity in both cell lines. In conclusion, the expression and phosphorylation of AQP9 regulated by p38 kinase are involved in the arsenic uptake, thus regulating cellular arsenic sensitivity.

[Association between the diet balance index-based dietary quality and cognitive function among Zhejiang population aged 40 years and older].

OBJECTIVE: To evaluation the dietary quality of Zhejiang population aged 40 years and older using the Dietary Balance Index(DBI) and to analyze the association between dietary quality and cognitive function. METHODS: The dietary information was collected with the help of questionnaire survey, a 3-day dietary recall and household condiment weighing method from Zhejiang participants of the 2018 wave of the China Health and Nutrition Survey aged 40 years and older, and the food and energy intakes were calculated. The cognitive function was assessed by the Mini Mental Status Examination. Dietary quality was evaluated using the DBI method. A multivariate Logistic regression model was used to examine the association between dietary quality and the risk of cognitive impairment. RESULTS: Among 640 participants aged 40 years and older, 14.2% had cognitive impairment. Univariate analysis showed that those with cognitive impairment had higher cereal(P=0.001), particularly, higher rice and products intake(P<0.001), as well as higher egg intake(P=0.008) than those with normal cognitive function; while the intake of soybean and its product(P=0.025) was lower. Those with cognitive impairment had higher DBI score of cereal(P=0.006) and high bound score(HBS)(P=0.028)than those with normal cognitive function. After adjustment for possible confounding factors, Logistic regression showed that moderated and severe over-consumption was positively associated with cognitive impairment(OR=2.486, 95% CI 1.130-5.470, P=0.024). CONCLUSION: Over-consumption may increase the risk of cognitive impairment among aged Zhejiang population, and should be used to prevent or reduce cognitive decline by improving the quality of the diet through a reasonable dietary mix.

Childcare burden and psychological distress among elderly people involved in grandparenting: A study on local and migrant grandparents in Hangzhou, China.

Grandparenting is known to impact psychological health in older people. However, the extent to which the effect is altered by migration-related and sociodemographic determinants is less clear. Therefore, we conducted this cross-sectional study to investigate whether the association between grandparenting and psychological distress differs between rural-urban migrants and local older adults from May to September 2019. A total of 373 rural-urban migrants and 602 local older adults involved in grandparenting in Hangzhou completed measurements assessing sociodemographic characteristics, childcare burden and psychological distress. In total, 22.2% of the grandparents reported psychological distress. Rural-urban migrant grandparents had a lower socioeconomic status (SES), a higher childcare burden (23.6 ± 9.2 vs. 20.7 ± 9.5, p < 0.001) and higher levels of psychological distress (29.8% vs. 17.4%, p < 0.001) than local grandparents. Childcare burden and pressure from adult children were the most significant predictors for psychological distress in both groups (ps < 0.05). Psychological distress was also significantly associated with self-rated health status (ß = -0.276, p = 0.033) and willingness to participate in grandparenting (ß = -0.659, p = 0.024) in migrant grandparents but associated with female gender (ß = 0.346, p = 0.022), caring for children at night (ß = 0.424, p = 0.011), conflict with adult children (ß = 0.432, p < 0.001) and annual income (ß = -0.237, p < 0.001) in local grandparents. Migrant status showed a statistically significant moderating effect between childcare burden and psychological distress. These results may be of assistance in comprehensively understanding the social determinants of mental health of grandparents involved in grandparenting.

Iron status and mental disorders: A Mendelian randomization study.

Background: Mental disorders account for an enormous global burden of disease, and has been associated with disturbed iron metabolism in observational studies. However, such associations are inconsistent and may be attributable to confounding from environmental factors. This study uses a two-sample Mendelian randomization (MR) analysis to investigate whether there is any causal effect of systemic iron status on risk of 24 specific mental disorders. Methods: Genetic variants with concordant relations to 4 biomarkers of iron status (serum iron, ferritin, transferrin saturation, and transferrin) were obtained from a genome-wide association study performed by the Genetics of Iron Status (GIS) consortium. Summary-level data for mental disorders were obtained from the UK Biobank. An inverse-variance weighted (IVW) approach was used for the main analysis, and the simple median, weighted median and MR-Egger methods were used in sensitivity analyses. Results: Genetically predicted serum iron, ferritin, and transferrin saturation were positively associated with depression and psychogenic disorder, and inversely associated with gender identity disorders. A higher transferrin, indicative of lower iron status, was also associated with increased risk of gender identity disorders and decreased risk of psychogenic disorder. Results were broadly consistent when using multiple sensitivity analyses to account for potential genetic pleiotropy. Conclusion: Our findings offer a novel insight into mental health, highlighting a detrimental effect of higher iron status on depression and psychogenic disorder as well as a potential protective role on risk of gender identity disorders. Further studies regarding the underlying mechanisms are warranted for updating preventative strategies.

Perceived uncertainty stress and its predictors among residents in China during the COVID-19 pandemic.

The prevalence of and risk factors for uncertainty stress among residents during the COVID-19 pandemic remain unclear. An online cross-sectional survey was conducted to explore and identify the risk factors for high perceived uncertainty stress among the general public in China during the COVID-19 outbreak. Information about the respondents' socioeconomic characteristics, knowledge of and attitudes towards COVID-19, perceived uncertainty stress, social capital, anxiety, and depressive symptoms was collected and analysed. Among the 1205 respondents, 45.3% (546) reported a high level of uncertainty stress. Multiple linear regression analysis indicated that anxiety (ß=3.871,P<0.001) and depression symptoms (ß=2.458, P<0.001), family residence (in towns or rural areas) (ß=0.947, P<0.001), lack of support for local epidemic control strategies (ß=1.253, P<0.001), worry about the pandemic (ß=1.191, P<0.001), and symptoms of weakness among family members (ß=1.525, P=0.002) were positively associated with perceived uncertainty stress. Cognitive social capital (ß=-0.883, P<0.001) and social networks (ß=-0.726, P<0.001) were negatively, but social participation (ß=0.714, P<0.001) was positively associated with perceived uncertainty stress. Our findings identify factors associated with a higher level of uncertainty stress and should be helpful in the consideration of effective policies and interventions for uncertainty stress during the initial phases of public health emergencies.

Anthocyanin-rich blueberry extracts and anthocyanin metabolite protocatechuic acid promote autophagy-lysosomal pathway and alleviate neurons damage in in vivo and in vitro models of Alzheimer's disease.

OBJECTIVES: As the global aging phenomenon intensifies, the incidence of Alzheimer's disease (AD) is gradually increasing. Diet appears to be an effective way to prevent and delay the progression of AD. Previous studies have found that cognitive impairment and neuronal damage were effectively alleviated by blueberry extract (BBE) in AD mice, but its mechanism is still unclear. The aims of this study were to detect the main anthocyanins of BBE; then to verify the protective effects of anthocyanin-rich BBE on hippocampal neurons and the promotion of autophagy; and finally to investigate the main protective effects and mechanisms of protocatechuic acid (PCA), a major metabolite of BBE, for promoting autophagy and thus playing a neuroprotective role. METHODS: APP/PS1 mice were given 150 mg/kg BBE daily for 16 wk. Morphology of neurons was observed and autophagy-related proteins were detected. RESULTS: Neuron damage in morphology was reduced and the expression of autophagy-related proteins in APP/PS1 mice were promoted after BBE treatment. In vitro, Aß25-35-induced cytotoxicity, including decreased neuron viability and increased levels of lactate dehydrogenase and reactive oxygen species, was effectively reversed by PCA. Furthermore, by adding autophagy inducers rapamycin and autophagy inhibitors Bafilomycin A1, it was verified that degradation of autophagosomes was upregulated and autophagy was promoted by PCA. CONCLUSION: This study elucidated the mechanism of BBE for reducing neuronal damage by promoting neuronal autophagy and proved PCA may be the main bioactive metabolite of BBE for neuroprotective effects, providing a basis for dietary intervention in AD.

Combination of Lutein and DHA Alleviate H2O2 Induced Cytotoxicity in PC12 Cells by Regulating the MAPK Pathway.

Docosahexaenoic acid (DHA) and lutein are important nutrients for brain health. Whether there were synergistic effects of DHA and lutein on the protection against neuronal cell damage induced by oxidative stress remained unclear. The present study was designed to investigate the synergistic effects of DHA and lutein against hydrogen peroxide (H2O2)-induced oxidative challenge in PC12 cells. PC12 cells were divided into different groups and received H2O2 (80 µM), lutein (20 µM)+H2O2 (80 µM), DHA (25 µM)+H2O2 (80 µM), and lutein (20 µM)+DHA (25 µM)+H2O2 (80 µM), respectively. The results indicated that pre-treatment of cells with lutein, DHA and DHA+lutein could significantly antagonize the H2O2-mediated growth inhibition and morphological changes in PC12 cells (p<0.05). Molecularlevel studies indicated that the DHA+lutein combination can significantly inhibit the mRNA expression of AMAD10 and BAX. Furthermore, Western blot analysis demonstrated that DHA+lutein synergistically inhibits the phosphorylation of JNK1/2. The results of the present study suggest that DHA and lutein in combination may be utilized as potent antioxidative compounds, with potential preventative or palliative effects on age-related neurodegenerative diseases.

Causal association of childhood obesity with cancer risk in adulthood: A Mendelian randomization study.

In observational studies of children and adolescents, higher body weight has been associated with distinct disease outcomes, including cancer, in adulthood. Therefore, we performed a two-sample Mendelian randomization (MR) study to evaluate the causal effect of childhood obesity on long-term cancer risk. Single-nucleotide polymorphisms associated with higher childhood body mass index (BMI) from large-scale genome-wide association studies were used as genetic instruments. Summary-level data for 24 site-specific cancers were obtained from UK Biobank. We found that a 1-SD increase in childhood BMI (kg/m2 ) was significantly associated with a 60% increase in risk of pancreatic cancer (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.12-2.28; P < 0.01) and a 47% increase in risk of esophageal cancer (OR: 1.47; 95% CI: 1.09-1.97; P < 0.01) in adults. In contrast, there was an inverse association of genetic predisposition to childhood obesity with throat (OR: 0.46; 95% CI: 0.27-0.79; P < 0.01) and breast cancer (OR: 0.77; 95% CI: 0.64-0.94; P < 0.01) in adult life. For the other 20 cancers studied, no statistically significant association was observed. Our MR analyses found causal effects of childhood obesity on several cancers. Maintaining a healthy weight should be emphasized during childhood and adolescence to prevent cancer risk later in life.

The effects of vitamin D supplementation on glycemic control and maternal-neonatal outcomes in women with established gestational diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND & AIMS: Gestational Diabetes Mellitus (GDM) is associated with a well-documented range of adverse pregnancy outcomes. The present meta-analysis was conducted to evaluate the effects of vitamin D supplementation on glycemic control and maternal-neonatal outcomes in women with established GDM. METHODS: Published literature was retrieved and screened from PubMed, Embase, Web of Science, CNKI (China National Knowledge Infrastructure), Wanfang, and Cochrane Center Register of Controlled Trails up to May 2020. RCTs of vitamin D supplementation on pregnant women with GDM were included. RESULTS: 19 RCTs (1550 participants) were eligible for meta-analyses. Overall, vitamin D supplementation significantly reduced serum fasting plasma glucose (FPG) (MD: -10.20 mg/dL, 95%CI: -13.43 to -6.96), insulin concentration (MD: -5.02 µIU/mL, 95%CI: -6.83 to -3.20) and the homeostasis model assessment of insulin resistance (HOMA-IR) (MD:-1.06, 95%CI: -1.40 to -0.72) in women with GDM. In addition, vitamin D supplementation in pregnant women with GDM significantly reduced adverse maternal outcomes including cesarean section (RR: 0.75, 95%CI: 0.63 to 0.89), maternal hospitalization (RR: 0.13, 95%CI: 0.02 to 0.98) and postpartum hemorrhage (RR: 0.47, 95%CI: 0.22 to 1.00). Several adverse neonatal complications including neonatal hyperbilirubinemia (RR: 0.47, 95%CI: 0.33 to 0.67), giant children (RR: 0.58, 95%CI: 0.38 to 0.89), polyhydramnios (RR: 0.42, 95% CI: 0.24 to 0.72), fetal distress (RR: 0.46, 95%CI: 0.24 to 0.90) and premature delivery (RR: 0.43, 95% CI: 0.26 to 0.72) were also significantly reduced. CONCLUSIONS: This meta-analysis suggested that supplementation of GDM women with vitamin D may lead to an improvement in glycemic control and reduction of adverse maternal-neonatal outcomes.

Environmental Risk Factors for Nonsyndromic Cleft Lip and/or Cleft Palate in Xinjiang Province, China: A Multiethnic Study.

OBJECTIVE: To determine the risk factors of the occurrence of nonsyndromic cleft lip and/or cleft palate (NSCL/P) in Xinjiang Province, China. DESIGN: The study included 359 patients of NSCL/P and 310 controls. Information about sociodemographic characteristics, lifestyle behaviors, negative life events, possible environmental hazards exposures, and use of supplementations were collected from cases and controls. Both t test and χ2 tests were used for group comparisons. Multivariable logistic regression was used to estimate the independent associations between environmental risk factors and the presence of NSCL/P. The receiver operating characteristic curve was used to establish the predictive variables for the occurrence of NSCL/P. RESULTS: The results showed that maternal pesticide exposure (odds ratio [OR] = 11.40, 95%CI: 5.40-24.10), antibiotic drugs use (OR = 1.32, 95%CI: 1.14-1.53), paternal smoking (OR = 3.30, 95%CI: 1.87-5.83), threatened abortion (OR = 12.2, 95%CI: 3.29-45.25) were associated with increased risk of NSCL/P in offspring. In contrast, maternal moderate (OR = 0.43, 95%CI: 0.20-0.92) and middle physical workload (OR = 0.48, 95%CI: 0.0.23-0.97), vitamin-B complex supplementations (OR = 0.11, 95%CI: 0.03-0.41), calcium and iron (OR = 0.27, 95%CI: 0.08-0.90) supplementations were associated with reduced risk of NSCL/P in offspring. These variables together explain nearly 60% of the variation of occurrence of NSCL/P. CONCLUSION: These findings from our study may help to develop primary prevention strategies for NSCL/P in Xinjiang.