Ambient particulate matter exposure plus chronic ethanol ingestion exacerbates hepatic fibrosis by triggering the mitochondrial ROS-ferroptosis signaling pathway in mice.

BACKGROUND: Chronic ethanol ingestion causes persistent oxidative stresses in the liver, leading to hepatic injury and fibrosis, but the underlying mechanisms remain unclear. Recently, ambient particulate matter (PM) has been confirmed to aggravate high-fat diet-induced liver fibrosis by enhancing oxidative stress. Thus, we hypothesized that oxidative stress induced by ambient PM exposure increases the severity of liver fibrosis caused by ethanol ingestion. METHODS AND RESULTS: C57BL/6 mice were subjected to ambient PM inhalation, ethanol ingestion or ambient PM-plus-ethanol ingestion for 12 weeks. Oxidative stress, mitochondrial reactive oxygen species (MtROS), liver fibrosis and ferroptosis indicators in the liver were evaluated. In vitro, oxidative stress, MtROS, ferroptosis indicators, profibrotic molecules and fibrosis markers in hepatic stellate (LX-2) cells were also determined. We found that ethanol ingestion markedly elevated hepatic oxidative stress and MtROS levels, triggered hepatic ferroptosis, and induced liver fibrosis, along with upregulation of the profibrotic molecule TGF-ß1 and fibrosis marker collagen-I, in mice. Moreover, the combination of ambient PM and ethanol accelerated these adverse effects. Importantly, the combination of PM exposure and ethanol ingestion had a synergistic effect on these changes. In vitro, LX-2 cells activated with PM2.5 alone or combined with ethanol showed upregulation of TGF-ß1 and collagen-I. In addition, the levels of MtROS, the oxidative stress marker 4-hydroxynonenal (4-HNE) and ferroptosis-related proteins and the GSH/GSSG ratio were significantly increased in PM2.5 plus ethanol-treated LX-2 cells. After pretreatment with a MtROS scavenger (Mito-TEMPO), we found that Mito-TEMPO treatment inhibited ferroptosis and oxidative stress in PM2.5 plus ethanol-treated LX-2 cells. Furthermore, a specific ferroptosis inhibitor (Fer-1) decreased the levels of ferroptosis-related proteins and profibrotic molecules in activated LX-2 cells co-exposed to PM2.5 and ethanol. CONCLUSION: In this study, we revealed that ambient PM exposure induced profibrotic effects and that combined exposure to ambient PM and chronic ethanol ingestion exacerbated hepatic fibrosis, which may trigger ferroptosis by increasing MtROS, thereby activating hepatic stellate cells.

Ambient particulate matter exposure plus a high-fat diet exacerbate renal injury by activating the NLRP3 inflammasome and TGF-ß1/Smad2 signaling pathway in mice.

BACKGROUND: Chronic kidney disease (CKD) is a public health problem of which the prevalence is increasing worldwide. Several studies have reported that ambient particulate matter (PM) causes kidney injury, which may be related to the risk of CKD. However, the underlying molecular mechanisms have not been fully clarified. In addition, whether a high-fat diet (HFD) could exacerbate ambient PM-induced nephrotoxicity has not been evaluated. This study aimed to investigate the combined effect of ambient PM and a HFD on renal injury. METHODS AND RESULTS: Male C57BL/6 J mice were fed either a normal diet or a HFD and exposed to filtered air (FA) or particulate matter (PM) for 18 weeks. In the present study, we observed that renal function changed (serum blood urea nitrogen and serum creatinine), and exposure to PM and a HFD caused a synergistic effect on renal injury. Histopathological analysis showed that PM exposure induced renal fibrosis in mice, and combined exposure to PM and a HFD exacerbated these adverse effects. Moreover, ambient PM exposure activated the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome and increased the inflammatory response, as indicated by the increases in interleukin-1ß, interleukin-6 and tumor necrosis factor-α in the serum and kidney, as well as the upregulation of specific renal fibrosis-related markers (transforming growth factor-ß1 and p-Smad2) in the kidney tissues of mice. Furthermore, combined exposure to PM and a HFD augmented these changes in the kidney. In vitro, inhibition of the NLRP3 inflammasome by MCC950 (an inhibitor of NLRP3) reduced the levels of proinflammatory cytokines and the expression of transforming growth factor-ß1 and p-Smad2 in HK-2 cells. CONCLUSION: Taken together, our data indicated that PM exposure caused renal inflammation and induced profibrotic effects on the kidney, and combined exposure to ambient PM and a HFD exacerbated renal injury, which may involve activation of the NLRP3 inflammasome and the TGF-ß1/Smad2 signaling pathway.

Effect of flavonoid intake on circulating levels of adiponectin and leptin: A systematic review and meta-analysis of randomized controlled clinical trials.

This meta-analysis of randomized controlled trials (RCTs) was conducted to explore the effects of flavonoid intake on adiponectin and leptin levels. The PubMed, EMBASE, and Cochrane Library databases were searched on March 1, 2021. Random-effects, subgroup, sensitivity, and meta-regression analyses were conducted on 40 publications. Flavonoid intake significantly increased circulating adiponectin (0.54 µg/ml, 95% CI [0.20, 0.88], p = .002; I2  = 86.4%) and significantly reduced leptin levels (weighted mean difference: -0.79 ng/ml, 95% CI [-1.33, -0.25], p = .004; I2  = 87.7%). Subgroup analysis demonstrated that flavonoid intervention produced a significant elevation in adiponectin levels only in studies that lasted more than 12 weeks, conducted in Asian regions, were parallel-designed, involved obese or overweight participants and participants with type 2 diabetes mellitus (T2DM) or cardiovascular diseases, used tea catechins, and used a dietary supplement intervention. A significantly negative effect on leptin levels was observed in studies conducted in Asian countries, with healthy participants and participants with T2DM, used whole food interventions, and involved participants with lower baseline leptin levels. In conclusion, flavonoid intake significantly increased circulating adiponectin and decreased leptin levels; however, study heterogeneity was very high. Future well-designed trials are required to address heterogeneous study designs and clarify the efficacy of plants in regulating adiponectin and leptin levels.

Blood biomarker levels of methylation capacity in autism spectrum disorder: a systematic review and meta-analysis.

OBJECTIVE: To compare the peripheral blood levels of methionine (Met), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and the SAM/SAH ratio (the most core and predictive indices of cellular methylation ability) between patients with autism spectrum disorder (ASD) and control subjects. METHODS: PubMed, Embase, PsycINFO, Web of Science, and Cochrane Library were searched from inception to August 2, 2019, without language restriction. The random-effects model was used to summarize effect sizes. RESULTS: We retrieved 1,493 records, of which 22 studies met inclusion criteria. Our overall analyses revealed that individuals with ASD had significantly decreased levels of Met (22 studies; Hedges' g = -0.62; 95% confidence interval [CI]: -0.89, -0.35), SAM (8 studies; Hedges' g = -0.60; 95% CI: -0.86, -0.34), and the SAM/SAH ratio (8 studies; Hedges' g = -0.98; 95% CI: -1.30, -0.66) and significantly increased levels of SAH (8 studies; Hedges' g = 0.69; 95% CI: 0.43, 0.94). The findings of the overall analyses were quite stable after being verified by sensitivity analyses and in agreement with the corresponding outcomes of subgroup analyses. Additionally, our results from meta-analytic techniques confirmed that the effect estimates of this meta-analysis did not originate from publication bias. CONCLUSION: Individuals with ASD have substantially aberrant peripheral blood levels of Met, SAM, SAH, and the SAM/SAH ratio, which supports the association between impaired methylation capacity and ASD. Therefore, further investigations into these indices as potential biomarkers for diagnosis and therapeutic targets of ASD are warranted.

Mild-to-moderate iodine deficiency in a sample of pregnant women and salt iodine concentration from Zhejiang province, China.

Since 2011, Zhejiang province has eliminated iodine deficiency disorders (IDD) in its populations. Following this achievement, a new revised iodine concentration in iodised salt was implemented in Zhejiang in 2012. However, the re-emergence of iodine deficiency has been reported in pregnant women. Therefore, the aim of this study was to assess household salt iodine concentration and iodine status of pregnant women in Zhejiang province, China. We conducted a cross-sectional study between April 2018 and August 2018 in Quzhou, Zhejiang province. Pregnant women aged ≥ 18 years who did not have a history of thyroid disease were recruited into the study. They were asked to complete socio-demographic questionnaires including a food frequency questionnaire (FFQ). In addition, a spot urine sample and a household table salt sample were also provided by each participant. A total of 625 pregnant women agreed to participate. The overall median urinary iodine concentration (UIC) was 130 µg/L, indicating mild-to-moderate iodine deficiency in pregnant women. The coverage of iodised salt was 85.2%, and of these, the rate of adequately iodised salt was 98.1%. In conclusion, our results confirmed the re-emergence of iodine deficiency in pregnant women as reported by other studies conducted in Zhejiang province. Therefore, urgent public health actions are needed to improve iodine status of pregnant women in order to prevent the adverse consequences of IDD on the neurodevelopment of foetus.

Resveratrol alleviates chronic "real-world" ambient particulate matter-induced lung inflammation and fibrosis by inhibiting NLRP3 inflammasome activation in mice.

BACKGROUND: Inhalation of fine particulate matter (PM2.5) induces the occurrence of lung inflammation and fibrosis, but its molecular mechanism remains unclear. Resveratrol (RES) is known to have anti-inflammatory properties in many pulmonary diseases. Here, we aimed to investigate the effect of long-term "real-world" ambient PM exposure on lung inflammation and fibrosis and further explore the protective effect and mechanism of RES. METHODS AND RESULTS: RES (50 and 100 mg/kg.bw) was administered to C57BL/6J mice that were exposed to ambient PM for 5 months. The control group breathed filtered air without RES, and the PM group was exposed to PM without RES. The inflammatory cytokine levels in bronchoalveolar lavage fluid (BALF) and lung fibrosis were evaluated by enzyme-linked immune sorbent assay (ELISA) kits and Masson's trichrome staining. The real-time PCR and Western blot analysis were used to determine the signal pathway. In vivo, PM exposure markedly elevated the levels of inflammatory cytokines and TGF-ß1 in BALF, induced lung fibrosis. Meanwhile, PM exposure triggered autophagy process and activated the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome in lung. Also, RES treatment abolished PM-induced lung inflammation and fibrosis, and inhibited autophagic process and NLRP3 inflammasome activation. In vitro, PM2.5-induced cytotoxicity in BEAS-2B cells dose-dependently. Besides, RES alleviated PM2.5-induced cytotoxicity, inhibited autophagic process and NLRP3 inflammasome activity and decreased IL-1ß production in BEAS-2B cells. CONCLUSION: Long-term PM exposure induced lung inflammation and fibrosis, and RES intervention alleviated these adverse effects via inhibiting autophagy-related NLRP3 inflammasome activation.

TCDD promoted EMT of hFPECs via AhR, which involved the activation of EGFR/ERK signaling.

One critical step of second palatal fusion is the newly formed medial epithelia seam (MES) disintegration, which involves apoptosis, epithelial to mesenchymal transition (EMT), and cell migration. Although the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produces cleft palate at high rates, little is known about the effects of TCDD exposure on the fate of palatal epithelial cells. By using primary epithelial cells isolated from human fetal palatal shelves (hFPECs), we show that TCDD increased cell proliferation and EMT, as demonstrated by increased the epithelial markers (E-cadherin and cytokeratin14) and enhanced the mesenchymal markers (vimentin and fibronectin), but had no effect on cell migration and apoptosis. TCDD exposure led to a dose-dependent increase in Slug protein expression. Coimmunoprecipitation revealed that TCDD promoted AhR to form a protein complex with Slug. ChIP assay confirmed that TCDD exposure recruited AhR to the xenobiotic responsive element of Slug promoter. Knockdown of AhR by siRNA remarkably weakened TCDD-induced binding of AhR to the XRE promoter of slug, thereby suppressed TCDD-induced vimentin. Further experiment showed that TCDD stimulated EGFR phosphorylation did not influence the TGFß3/Smad signaling; whereas TCDD increased phosphorylation of ERK1/2 and p38 with no effect on activation of JNK. By using varieties of inhibitors, we confirmed that TCDD promoted proliferation and EMT of hFPECs via activation of EGFR/ERK pathway. These data make a novel contribution to the molecular mechanism of cleft palate by TCDD.

Effect of TCDD on the fate of epithelial cells isolated from human fetal palatal shelves (hFPECs).

Cleft palate is caused by the failure of palatal midline epithelial cells to disintegrate, which is necessary for palatal mesenchymal confluence. Although 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure is linked to cleft palate at a high rate, the mechanism remains to be elucidated. The present study was designed to determine the effects of TCDD on the fate of epithelial cell isolated from human fetal palatal shelves (hFPECs). We demonstrate that TCDD increased cell proliferation and promoted the progression of cells from G1 to S phase as well as increased the number of cells entering the G2/M phase. We found that TCDD has no measurable effect on apoptosis of hFPECs. The protein level assays revealed that TCDD increased cyclin-dependent kinases 4 (cdk4), cyclin D1, cyclin E and p21 (Waf1/Cip1) but not cdk2, bcl-2, cyclin B1 and cyclin A. Furthermore, TCDD activated PI3K/AKT signaling, and the PI3K inhibitor, LY294002, partially abrogated TCDD-induced cell proliferation and gene modulations. TCDD treatment increased CYP1A1 mRNA and protein levels, which indicated the activation of AhR signaling. Knockdown of the AhR with siRNA suppressed TCDD-induced cell proliferation and PI3K/AKT signaling activation. Taken together, these data demonstrated that TCDD is able to promote growth of hFPECs through AhR-dependent activation of the PI3K/AKT pathway, which may account for the underlying mechanism by which TCDD causes a failure of palatal fusion.

Quercetin alleviates PM2.5-induced chronic lung injury in mice by targeting ferroptosis.

Background: PM2.5 is a well-known harmful air pollutant that can lead to acute exacerbation and aggravation of respiratory diseases. Although ferroptosis is involves in the pathological process of pulmonary disease, the potential mechanism of ferroptosis in PM2.5-caused lung inflammation and fibrosis need to be further clarified. Quercetin is a phenolic compound that can inhibit ferroptosis in various diseases. Hence, this study explores the role of ferroptosis in lung injury induced by PM2.5 in order to further elucidate the beneficial effect of quercetin and its underlying mechanism. Methods: C57BL/6J mice were treated with either saline or PM2.5 by intratracheal instillation 20 times (once every two days). Additionally, PM2.5-treated mice were supplemented with two doses of quercetin. Lung injury, lipid peroxidation, iron content and ferroptosis marker protein expression and the Nrf2 signaling pathway were evaluated. In vitro, cell experiments were applied to verify the mechanisms underlying the links between Nrf2 signaling pathway activation and ferroptosis as well as between ferroptosis and inflammation. Results: In vivo, PM2.5 increased lung inflammation and caused lung fibrosis and increased lipid peroxidation contents, iron contents and ferroptosis markers in lung tissues; these effects were significantly reversed by quercetin. Additionally, quercetin upregulated the nuclear Nrf2 expression and downregulated Keap1 expression in lung tissues of PM2.5-exposed mice. Quercetin decreased lipid peroxidation products, iron contents and ferroptosis levels and increased the nuclear translocation of Nrf2 and the degradation of Keap1 in PM2.5-exposed BEAS-2B cells. Moreover, we found that quercetin and dimethyl fumarate markedly decreased lipid peroxidation production and ferroptosis by activating the Nrf2-Keap1 pathway in PM2.5-exposed cells. Furthermore, quercetin reduced inflammatory cytokines and TGF-ß1 in PM2.5-exposed cells. Conclusion: Our data suggested that Nrf2 is involved in ferroptosis in PM2.5-induced lung injury, and quercetin can alleviate these adverse effects via activating Nrf2-Keap1 signaling pathway.

Does preconception paternal exposure to a physiologically relevant level of bisphenol A alter spatial memory in an adult rat?

Bisphenol A (BPA) is a ubiquitous environmental endocrine disrupting compound (EDC); public health concerns have been fueled by findings that maternal BPA exposure can change sex differences in the brain and in some behaviors. We investigated whether a physiologically relevant dose of BPA ingested by male rats before conception would affect spatial memory and hippocampal acetylcholinesterase (AchE) in their adult offspring. Twenty-two 60-day-old male rats (F0) received either a BPA diet (50 µg/kg/day) or vehicle alone for 10 weeks before being mated with non-exposed females. The paternal rats and their forty adult offspring's (F1) behaviors were then examined in the Morris Water Maze (MWM) and their AchE activities in the hippocampus were evaluated. BPA exposure led to spatial memory deficits along with decreased AchE activities in the hippocampus (p = 0.01) in adult F0 rats. This paternal exposure also induced impairment in spatial memory acquisition in both sexes while retention only in females in F1 rats, as well as abolished sex differences in the hippocampus AchE. Overall, these data provide new evidence that paternal BPA exposure, at a "safe" dose, may induce transgenerational alterations in spatial memory in a sex-specific manner.

Resveratrol reversed ambient particulate matter exposure-perturbed oscillations of hepatic glucose metabolism by regulating SIRT1 in mice.

Much evidence has shown that ambient particulate matter (PM) exposure is associated with abnormal glucose metabolism, but the underlying mechanism has not yet been fully characterized. Circadian disruption has adverse effects on glucose metabolism. In this study, we investigated the effects of long-term ambient PM exposure on the hepatic circadian clock and the expression rhythm of genes associated with hepatic glucose metabolism in mice. C57BL/6 mice were exposed to filtered air (FA), ambient PM, or ambient PM plus resveratrol (RES). After 15 weeks (12 h per day, 7 days per week) of exposure, glucose homeostasis, the rhythmic expression of clock genes, and genes associated with hepatic glucose metabolism were determined. Our results found that PM exposure induced glucose metabolism disorder and perturbed the rhythmic mRNA expression of core clock genes and their target genes involved in hepatic glucose metabolism. Mechanistic investigations demonstrated that ambient PM exposure markedly altered the expression patterns of BMAL1, clock, and SIRT1 in vivo. Simultaneously, we demonstrated that RES (an activator of SIRT1) changed the expression pattern of SIRT1, thereby reversing the rhythm misalignment of BMAL1 and clock and hepatic glucose metabolism disorder induced by ambient PM exposure. In addition, PM2.5 exposure perturbed the rhythmic protein expression of BMAL1, clock, and SIRT1 in L-02 cells. Simultaneously, we demonstrated that RES restored the SIRT1 circadian rhythm, which reversed the rhythm misalignment of BMAL1 and clock in L-02 cells induced by PM2.5 exposure. Taken together, our results suggested that long-term ambient PM exposure perturbed the hepatic core circadian clock rhythm and caused glucose metabolism disorder, which could be reversed by RES supplementation. Our study offers a potential application of RES for combating circadian misalignment-related metabolic diseases.

Epigallocatechin gallate alleviates high-fat diet-induced hepatic lipotoxicity by targeting mitochondrial ROS-mediated ferroptosis.

Background: Non-alcoholic fatty liver disease (NAFLD) is a chronic advanced liver disease that is highly related to metabolic disorders and induced by a high-fat diet (HFD). Recently, epigallocatechin gallate (EGCG) has been regarded as a protective bioactive polyphenol in green tea that has the ability to protect against non-alcoholic fatty liver disease, but the molecular mechanism remains poorly deciphered. Ferroptosis plays a vital role in the progression of non-alcoholic fatty liver disease, but experimental evidence of ferroptosis inhibition by epigallocatechin gallate is limited. Hence, our study aimed to investigate the effect and mechanisms of epigallocatechin gallate on hepatic ferroptosis to mitigate hepatic injury in high-fat diet-fed mice. Methods: Fifty male C57BL/6 mice were fed either a standard chow diet (SCD), a high-fat diet, or a high-fat diet and administered epigallocatechin gallate or ferrostatin-1 (a ferroptosis-specific inhibitor) for 12 weeks. Liver injury, lipid accumulation, hepatic steatosis, oxidative stress, iron overload, and ferroptosis marker proteins were examined. In vitro, steatotic L-02 cells were used to explore the underlying mechanism. Results: In our research, we found that epigallocatechin gallate notably alleviated liver injury and lipid accumulation, oxidative stress, hepatic steatosis, decreased iron overload and inhibited ferroptosis in a high-fat diet-induced murine model of non-alcoholic fatty liver disease. In vitro experiments, using ferrostatin-1 and a mitochondrial reactive oxygen species (MtROS) scavenger (Mito-TEMPO), we found that epigallocatechin gallate remarkably alleviated oxidative stress and inhibited ferroptosis by reducing the level of mitochondrial reactive oxygen species in steatotic L-02 cells. Conclusion: Taken together, our results revealed that epigallocatechin gallate may exert protective effects on hepatic lipotoxicity by inhibiting mitochondrial reactive oxygen species-mediated hepatic ferroptosis. Findings from our study provide new insight into prevention and treatment strategies for non-alcoholic fatty liver disease pathological processes.

Targeting Mitochondrial ROS-Mediated Ferroptosis by Quercetin Alleviates High-Fat Diet-Induced Hepatic Lipotoxicity.

Background: The protective effect of quercetin on nonalcoholic fatty liver disease (NAFLD) has been reported, but its mechanism remains poorly understood. Recently, quercetin was reported to be capable of inhibiting ferroptosis, which is a recognized type of regulated cell death. Moreover, hepatic ferroptosis plays an important role in the progression of NAFLD, but experimental evidence is limited. Hence, our study aimed to investigate the effect of quercetin on hepatic ferroptosis in high-fat diet (HFD)-induced NAFLD and further elucidate the underlying molecular mechanism. Methods: C57BL/6J mice were fed either a normal diet (ND), an HFD, or an HFD supplemented with quercetin for 12 weeks. Hepatic lipid peroxidation, steatosis, ferroptosis and iron overload were examined. In vitro, steatotic L-02 cells was used to study the potential mechanism. Results: We found that the HFD caused lipid peroxidation, lipid accumulation and ferroptosis in the liver, which were rescued by quercetin supplementation. Consistent with the in vivo results, quercetin alleviated lipid droplet accumulation and reduced the levels of lipid reactive oxygen species (ROS) and ferroptosis in steatotic L-02 cells. Using a mitochondrial ROS (MtROS) scavenger (Mito-TEMPO) and ferroptosis specific inhibitor (Fer-1), we found that quercetin remarkably alleviated lipid droplet accumulation and lipid peroxidation by reducing MtROS-mediated ferroptosis in steatotic L-02 cells. Conclusion: Our data showed that HFD consumption induced lipid accumulation and triggered ferroptosis in liver, ultimately leading to hepatic lipotoxicity, which can be alleviated by quercetin. Findings from this study provide new insight into the mechanism by which quercetin can be used for the prevention and treatment of NAFLD.

Quercetin improves the adipose inflammatory response and insulin signaling to reduce "real-world" particulate matter-induced insulin resistance.

Numerous epidemiological data and experimental studies support a strong link between fine particulate matter (less than 2.5 mm in aerodynamic diameter, PM2.5) exposure and the development of insulin resistance/type 2 diabetes mellitus (T2DM). Quercetin (Que), a flavonoid compound with anti-inflammatory effects, has been confirmed to improve glucose metabolic disorders in rodents and humans. In this study, we investigated the underlying mechanisms of particulate matter (PM)-induced glucose metabolic disorder and subsequently examined the protective effect and mechanism of quercetin supplementation. Male C57BL/6 mice in the control group and PM group were exposed to ambient filtered air (FA) or PM (6 h/day, 7 days/week) for 18 weeks. Mice in the Que group were exposed to PM for 18 weeks and administered Que (50 or 100 mg/kg bw). Glucose tolerance, insulin sensitivity, and systemic and visceral white adipose tissue (vWAT) inflammatory responses were measured. The expression of proteins involved in insulin signal transduction in vWAT was assessed. Chronic PM exposure caused systemic and vWAT inflammation characterized by an increase in serum IL-6 and TNF-α levels and increased vWAT macrophage filtration, triggering NLRP3 inflammasome activation, impairing the classic glucose metabolism signal in vWAT, and inducing whole-body insulin resistance. Moreover, Que administration significantly alleviated systemic and vWAT inflammation, abolished NLRP3 inflammasome activation, and improved signaling abnormalities characteristic of insulin resistance in vWAT and adipocytes. Based on these findings, chronic PM exposure activated the NLRP3 inflammasome and subsequently caused systemic and WAT inflammation and impaired insulin signaling in vWAT and adipocytes. Most importantly, Que administration inhibited NLRP3 inflammasome-mediated inflammation and insulin signaling in vWAT to improve these adverse effects.

Resveratrol improves cardiac function and left ventricular fibrosis after myocardial infarction in rats by inhibiting NLRP3 inflammasome activity and the TGF-ß1/SMAD2 signaling pathway.

BACKGROUND: Several studies have shown that resveratrol (RES), a naturally occurring polyphenol found in many plants, is beneficial for preventing cardiovascular diseases. However, the mechanism underlying the RES-mediated protection against myocardial infarction has not yet been revealed entirely. In this study, we investigated the protective effects of RES on cardiac function in a rat model of acute myocardial infarction (AMI) and the related underlying mechanisms. METHODS: Male Sprague-Dawley rats were randomly divided into four groups: Sham (sham operation), Sham-RES, AMI (AMI induction), and AMI-RES. The rat AMI model was established by the permanent ligation of left anterior descending coronary artery method. The rats in the RES-treated groups were gavaged with RES (50 mg/kg/day) daily for 45 days after the Sham operation or AMI induction; rats in the Sham and AMI groups were gavaged with deionized water. Cardiac function was evaluated by echocardiography. Atrial interstitial fibrosis was assessed by hematoxylin-eosin or Masson's trichrome staining. Real-time PCR and western blotting analyses were performed to examine the levels of signaling pathway components. RESULTS: RES supplementation decreased the inflammatory cytokine levels, improved the cardiac function, and ameliorated atrial interstitial fibrosis in the rats with AMI. Furthermore, RES supplementation inhibited NLRP3 inflammasome activity, decreased the TGF-ß1 production, and downregulated the p-SMAD2/SMAD2 expression in the heart. CONCLUSION: RES shows notable cardioprotective effects in a rat model of AMI; the possible mechanisms underlying these effects may involve the improvement of cardiac function and atrial interstitial fibrosis via the RES-mediated suppression of NLRP3 inflammasome activity and inhibition of the TGF-ß1/SMAD2 signaling pathway in the heart.

Blood homocysteine levels in children with autism spectrum disorder: An updated systematic review and meta-analysis.

Results of studies on peripheral blood levels of homocysteine (Hcy) in children with autism spectrum disorder (ASD) are inconsistent, and conclusions from two previous meta-analyses on this subject published in 2012 are already outdated. Therefore, we conducted an updated systematic review and meta-analysis to quantitatively summarize the peripheral blood Hcy data in children with ASD compared with healthy controls (HC). We searched PubMed, EMBASE, PsycINFO, PsycARTICLES, Web of Science, and Cochrane Library databases from inception to September 2019 for eligible studies, with no language restriction. Using random-effects model, we computed summary statistics. Thirty-one studies (3304 participants including 1641 cases) were included. The pooled results showed that the peripheral blood Hcy levels were significantly elevated in children with ASD when compared to HC (Hedges's g = 0.56, 95% CI = 0.36 to 0.76, P < 0.001). By sensitivity analyses, we confirmed that our results were quite robust. Additionally, no publication bias was observed in this meta-analysis. In conclusion, our study support the association of increased circulating Hcy levels with ASD in children, and the involvement of Hcy in the occurrence of ASD. However, in view of the significant between-study heterogeneity, the conclusions should be interpreted cautiously and more investigation is required.

Association of physical activity with chronic kidney disease: a systematic review and dose-response meta-analysis.

BACKGROUND: The relationship between physical activity (PA) and chronic kidney disease (CKD) risk was inconsistent. We therefore conducted a systematic review and dose-response meta-analysis to comprehensively evaluate the association of PA and CKD. RESULTS: A total of 14 studies from 13 articles with 353,975 participants were included. By comparing the highest vs. the lowest level of PA, we found that PA was inversely associated with CKD risk (odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.91-0.98). Seven studies from 6 articles were included in dose-response analysis. Restricted cubic splines showed no evidence of a nonlinear dose-response relationship of PA and CKD risk (Pnonlinearity = 0.135). The risk of CKD was reduced by 2% (OR = 0.98, 95% CI = 0.96-1.00) with each 10 metabolic equivalent h/week increment of PA. CONCLUSIONS: The findings demonstrated that the higher level of PA might have a protective effect against the risk of CKD. METHODS: Electronic databases PubMed and Embase were searched up to March 11, 2020. Observational studies investigated the relationship between PA and CKD risk with estimated effects (relative risk, hazard ratio, or OR) with 95 % CI among adults were included.

Prediction of hypertension, hyperglycemia and dyslipidemia from retinal fundus photographs via deep learning: A cross-sectional study of chronic diseases in central China.

Retinal fundus photography provides a non-invasive approach for identifying early microcirculatory alterations of chronic diseases prior to the onset of overt clinical complications. Here, we developed neural network models to predict hypertension, hyperglycemia, dyslipidemia, and a range of risk factors from retinal fundus images obtained from a cross-sectional study of chronic diseases in rural areas of Xinxiang County, Henan, in central China. 1222 high-quality retinal images and over 50 measurements of anthropometry and biochemical parameters were generated from 625 subjects. The models in this study achieved an area under the ROC curve (AUC) of 0.880 in predicting hyperglycemia, of 0.766 in predicting hypertension, and of 0.703 in predicting dyslipidemia. In addition, these models can predict with AUC>0.7 several blood test erythrocyte parameters, including hematocrit (HCT), mean corpuscular hemoglobin concentration (MCHC), and a cluster of cardiovascular disease (CVD) risk factors. Taken together, deep learning approaches are feasible for predicting hypertension, dyslipidemia, diabetes, and risks of other chronic diseases.

Maternal n-3 PUFAs deficiency during pregnancy inhibits neural progenitor cell proliferation in fetal rat cerebral cortex.

The aim of this study was to evaluate the in vivo impacts of maternal n-3 polyunsaturated fatty acids (PUFAs) deficiency during pregnancy on the proliferation of neural progenitor cells (NPCs) in the developing cerebral cortex of fetal rats. Our results showed that about 5 weeks of maternal dietary n-3 PUFAs deprivation resulted in a substantial n-3 PUFA deficiency in fetal rat cerebral cortex. Importantly, by two survival schemes and two quantitative methods, we found that maternal intake of n-3 PUFAs deficient diet during the gestation significantly inhibited the proliferation of NPCs in fetal rat cerebral cortex. Moreover, the decreased cortical NPCs proliferation induced by nutritional n-3 PUFAs restriction did not originate from the increased NPCs apoptosis. Finally, our observations indicated that the down-regulation of cyclin E protein might be involved in the inhibitory effects of maternal n-3 PUFAs deficient diet on the proliferation of cortical NPCs. These findings highlight the importance of maternal intake of appropriate n-3 PUFAs and deepen our understanding of the exact effects of n-3 PUFAs on mammalian brain development.

Maternal multivitamin supplementation is associated with a reduced risk of autism spectrum disorder in children: a systematic review and meta-analysis.

Several studies have explored the link of antenatal multivitamin supplementation with autism spectrum disorder (ASD) in offspring, but the findings are inconsistent. The purpose of the current study was to perform a systematic review and meta-analysis of published studies to evaluate the actual association between maternal multivitamin supplementation during the prenatal period and the risk of ASD in children. PubMed, EMBASE, PsycINFO, Web of Science, and Cochrane Library were searched up to August 26, 2018. The random-effects model was used to calculate the pooled results. The adjusted risk ratios (RRs) were used as the common measure of association among studies. Sensitivity and subgroup analyses were also conducted. A total of 5 articles (9 independent trials; 231 163 children encompassing 4459 cases) were included. The results of overall analysis showed that the likelihood of ASD in offspring whose mothers used multivitamin supplements during the prenatal period was significantly reduced compared with that in offspring of mothers without such supplementation (RR, 0.62; 95% CI, 0.45-0.86; P = .003). Additionally, the primary outcome of the meta-analysis was quite robust after being verified by sensitivity analyses and no publication bias was found. Furthermore, the findings of overall analysis were generally consistent with those of subgroup analyses. In conclusion, this meta-analysis supports a protective association between maternal multivitamin supplementation during the prenatal period and the subsequent risk of ASD in children. Further investigation is needed and should address the constituent(s) contributing to the protective effect of multivitamin on ASD risk and the underlying molecular mechanisms.