Association of plasma vitamin A level with type 2 diabetes mellitus:a community aging population-based cross-sectional study

Recent studies indicated that vitamin A(VA)might be involved in the pathology of type 2 diabetes mellitus(T2DM).This cross-sectional study was conducted to explore the association between circulating VA level and T2DM.A total of 1818 subjects aged 50 years old and above were recruited from the community.Binomial logistic regression and restricted cubic spline(RCS)were applied to analyze the association of plasma VA level with the risk of T2DM.Serum VA and lipid-adjusted VA levels of T2DM patients were significantly higher than that of non-T2DM subjects(P<0.05).The ratios of plasma VA/total cholesterol(TC),VA/high-density lipoprotein cholesterol(HDL-c)and VA/low-density lipoprotein cholesterol(LDL-c)were positively associated with the risk of T2DM in the aging population(P<0.05).Compared with the Q1 level,subjects with Q2 to Q3 levels of plasma VA/triglyceride(TG)have decreased risk of T2DM(odds ratio(OR)Q2=0.68,P_(Q2)=0.021;ORQ3=0.59,P_(Q3)<0.01).Our results indicated that the imbalance of circulating lipids and VA might affect the relationship between VA and T2DM.The middle and aging subjects with higher ratios of plasma VA/TC,VA/HDL-c,and VA/LDL-c displayed increased risk for T2DM,but the moderate ratio of VA/TG might protect against risk of T2DM.

Enhanced hepatic metabolic perturbation of polystyrene nanoplastics by UV irradiation-induced hydroxyl radical generation

The environmental behavior of and risks associated with nanoplastics(NPs)have attracted considerable attention.However,compared to pristine NPs,environmental factors such as ultraviolet(UV)irradiation that lead to changes in the toxicity of NPs have rarely been studied.We evaluated the changes in morphology and physicochemical properties of polystyrene(PS)NPs before and after UV irradiation,and compared their hepatotoxicity in mice.The results showed that UV irradiation caused particle size reduction and increased the carbonyl index(CI)and negative charge on the particle surface.UV-aged PS NPs(aPS NPs)could induce the generation of hydroxyl radicals(·OH),but also further promoted the generation of·OH in the Fenton reaction system.Hepatic pathological damage was more severe in mice exposed to aPS NPs,accompanied by a large number of vacuoles and hepatocyte balloon-like changes and more marked perturbations in blood glucose and serum lipoprotein,alanine aminotransferase and aspartate aminotransferase levels.In addition,exposure to PS NPs and aPS NPs,especially aPS NPs,triggered oxidative stress and significantly damaged the antioxidant capacity of mice liver.Compared with PS NPs,exposure to aPS NPs increased the number of altered metabolites in hepatic and corresponding metabolic pathways,especially glutathione metabolism.Our research suggests that UV irradiation can disrupt the redox balance in organisms by promoting the production of·OH,enhancing PS NPs-induced liver damage and metabolic disorders.This study will help us understand the health risks of NPs and to avoid underestimation of the risks of NPs in nature.

Fasn involved in the nephrotoxicity induced by polystyrene nanoplastics and the intervention of melatonin through intestinal microbiota-mediated lipid metabolism disorder

Nanoplastics(NPs)can accumulate in the kidney and cause kidney injury,but the multi-organ interaction mechanism and preventive measures of kidney injury are still unclear.In this study,in vivo(60μg/day,42 days)and in vitro(0.4μg/μL,24 h)exposure models of polystyrene nanoplastics(PS-NPs,80 nm)in mice and human kidney cortex proximal tubule epithelial cells(HK-2 cells)were established,respectively.Our study revealed that PS-NPs caused obvious pathological changes and impaired renal function in mice,which were related to lipid metabolism disorders mediated by intestinal flora.Desulfovibrionales-fatty acid synthase(Fasn)-docosahexaenoic acid(DHA)pathway may be one of the mechanisms of kidney injury in mice.Importantly,we also found that melatonin attenuates PS-NPs-induced nephrotoxicity by modulating lipid metabolism disorders(represented by DHA)and affects Fasn expression.In conclusion,our study revealed the important role of intestinal flora-mediated lipid metabolism in PS-NPs-induced nephrotoxicity and preliminarily provided potential key gene targets and effective preventive measures for PS-NPs-induced nephrotoxicity.

Decabromodiphenyl ether induces the chromosome association disorders of spermatocytes and deformation failures of spermatids in mice

The environmental presence of decabromodiphenyl ether(BDE-209),which is toxic to the male reproductive system,is widespread.The current study investigated its mechanism of toxicity in mice.The results showed,that BDE-209 induced DNA damage,decreased the expression of the promoter of meiosis spermatogenesis-and oogenesis-specific basic helix-loop-helix 1(Sohlh1),meiosis related-factors Lethal(3)malignant brain tumor like 2(L3MBTL2),PIWI-like protein 2(MILI),Cyclin-dependent kinase 2(CDK2),Cyclin A,synaptonemal complex protein 1(SYCP1)and synaptonemal complex protein 3(SYCP3),and caused spermatogenic cell apoptosis,resulting in a decrease in sperm quantity and quality.Furthermore,BDE-209 downregulated the levels of anaphase-promoting complex/cyclosome(APC/C),increased the expression of PIWI-like protein 1(MIWI)in the cytoplasm of elongating spermatids,and decreased the nuclear levels of RING finger protein 8(RNF8),ubiquitinated(ub)-H2A/ub-H2B,and Protamine 1(PRM1)/Protamine 2(PRM2),while increasing H2A/H2B nuclear levels in spermatids.The reproductive toxicity was persistent for 50 days following the withdrawal of BDE-209 exposure.The results suggested that BDE-209 inhibits the initiation of meiosis by decreasing the expression of Sohlh1.Furthermore,the reduced expression of L3MBTL2 inhibited the formation of chromosomal synaptonemal complexes by depressing the expression of meiosis regulators affecting the meiotic progression and also inhibited histone ubiquitination preventing the replacement of histones by protamines,by preventing RNF8 from entering nuclei,which affected the evolution of spermatids into mature sperm.

Associations of heavy metal mixtures with blood pressure among U.S.adults in NHANES 2017-2018 by four statistical models

To the Editor:Hypertension is one of the leading risk factors for cardiovascular disease and affects approximately 30%of the adult population.^([1,2])Environmental heavy metal pollution is an important public health concern.Toxic metals may increase the risk of hypertension or other cardiovascular diseases,even beyond the influence of conventional behavioral risk factors.^([3])Meanwhile certain essential trace elements,such as selenium,zinc,and iron,are involved in various enzyme reactions directly related to blood pressure regulation and are beneficial to the human body within a specific range.^([4])The analysis of health outcomes specific to metal mixtures is challenging by nonlinear relationships and interactions between toxic metals and essential trace elements.^([5])The development of innovative statistical methods for analyzing mixtures has greatly facilitated the exploration of the health effects of multiple pollutant exposures,such as Bayesian kernel machine regression(BKMR)and quantile g-computation(QG-C).

An Overview of Adverse Outcome Pathway Links between PM_(2.5)Exposure and Cardiac Developmental Toxicity

Fine particulate matter(PM_(2.5))is a significant risk factor for birth defects.As the first and most important organ to develop during embryogenesis,the heart’s potential susceptibility to PM_(2.5)has attracted growing concern.Despite several studies supporting the cardiac developmental toxicity of PM_(2.5),the diverse study types,models,and end points have prevented the integration of mechanisms.In this Review,we present an adverse outcome pathway framework to elucidate the association between PM_(2.5)-induced molecular initiating events and adverse cardiac developmental outcomes.Activation of the aryl hydrocarbon receptor(AhR)and excessive generation of reactive oxygen species(ROS)were considered as molecular initiating events.The excessive production of ROS induced oxidative stress,endoplasmic reticulum stress,DNA damage,and inflammation,resulting in apoptosis.The activation of the AhR inhibited the Wnt/β-catenin pathway and then suppressed cardiomyocyte differentiation.Impaired cardiomyocyte differentiation and persistent apoptosis resulted in abnormalities in the cardiac structure and function.All of the aforementioned events have been identified as key events(KEs).The culmination of these KEs ultimately led to the adverse outcome,an increased morbidity of congenital heart defects(CHDs).This work contributes to understanding the causes of CHDs and promotes the safety evaluation of PM_(2.5).

Psychosocial Stress Modifies the Acute Cardiac Health Effects of Traffic-Related Air Pollution

Previous studies have shown that exposure to black carbon(BC,a tracer of traffic-related air pollution)and psychosocial stress are both associated with adverse cardiac effects,but whether psychosocial stress could modify the cardiac effects of BC is unclear.To investigate the potential modifying effect of psychosocial stress on the associations between acute exposure to BC and typical cardiac health variables,real-time personal 24 h measurements were conducted in a repeated-measure study among adults with elevated blood pressure(high-risk group)and a panel study among normal adults(low-risk group)in China.Measured cardiac health variables included ST-segment depression events,heart rate,and heart rate variability(HRV)variables.Perceived Stress Scale,State Anxiety Inventory and Self-rating Depression Scale were used to assess the recent psychosocial stress status of the participants,and a composite stress index was established based on these scales.Generalized linear mixed-effects model was used to analyze the associations between BC exposure and cardiac health variables and potential effect modification by psychosocial stress.A total of 9724 h measurements among 97 participants in the repeated-measure study and 20224 h measurements among 87 participants in the panel study were included in the final analysis.Acute BC exposure was significantly associated with increased ST-segment depression events and heart rate and decreases in HRV in both studies.The marginal effects of acute BC exposure on most cardiac health variables generally tended to be amplified under higher vs low levels of psychosocial stress in both studies,with the composite stress index apparently modifying the associations of BC exposure with most ST-segment depression events and HRV variables.These findings suggest that psychosocial stress may increase the participants’cardiac susceptibility to BC exposure,which could be helpful for the identification of susceptible individuals in the context of traffic-related air pollution.

Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca_(ER)^(2+)perturbation in hepatocellular carcinoma

The well-known insulin-like growth factor 1(IGF1)/IGF-1 receptor(IGF-1R)signaling pathway is overexpressed in many tumors,and is thus an attractive target for cancer treatment.However,results have often been disappointing due to crosstalk with other signals.Here,we report that IGF-1R signaling stimulates the growth of hepatocellular carcinoma(HCC)cells through the translocation of IGF-1R into the ER to enhance sarco-endoplasmic reticulum calcium ATPase 2(SERCA2)activity.In response to ligand binding,IGF-1Rβis translocated into the ER byβ-arrestin2(β-arr2).Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1Rβ.SERCA2 activity is heavily dependent on the increase in ER IGF-1Rβlevels.ER IGF-1Rβphosphorylates SERCA2 on Tyr^(990)to enhance its activity.Mutation of SERCA2-Tyr^(990)disrupted the interaction of ER IGF-1Rβwith SERCA2,and therefore ER IGF-1Rβfailed to promote SERCA2 activity.The enhancement of SERCA2 activity triggered Ca_(ER)^(2+)perturbation,leading to an increase in autophagy.Thapsigargin blocked the interaction between SERCA2and ER IGF-1Rβand therefore SERCA2 activity,resulting in inhibition of HCC growth.In conclusion,the translocation of IGF-1R into the ER triggers Ca_(ER)^(2+)perturbation by enhancing SERCA2 activity through phosphorylating Tyr^(990)in HCC.

Activation of insulin-like growth factor-1 receptor (IGF-1R) promotes growth of colorectal cancer through triggering the MEX3A-mediated degradation of RIG-Ⅰ

Insulin-like growth factor-1 receptor(IGF-1R) has been made an attractive anticancer target due to its overexpression in cancers.However,targeting it has often produced the disappointing results as the role played by cross talk with numerous downstream signalings.Here,we report a disobliging IGF-1R signaling which promotes growth of cancer through triggering the E3 ubiquitin ligase MEX3A-mediated degradation of RIG-I.The active β-arrestin-2 scaffolds this disobliging signaling to talk with MEX3A.In response to ligands,IGF-1Rβ activated the basal βarr2 into its active state by phosphorylating the interdomain domain on Tyr64 and Tyr250,opening the middle loop(Leu130-Cys141) to the RING domain of MEX3A through the conformational changes of βarr2.The models of βarr2/IGF-1Rβ and βarr2/MEX3A could interpret the mechanism of the activated-IGF-1R in triggering degradation of RIG-I.The assay of the mutants βarr2Y64Aand βarr2Y250Afurther confirmed the role of these two Tyr residues of the interlobe in mediating the talk between IGF-1Rβ and the RING domain of MEX3A.The truncated-βarr2 and the peptide ATQAIRIF,which mimicked the RING domain of MEX3A could prevent the formation of βarr2/IGF-1Rβ and βarr2/MEX3A complexes,thus blocking the IGF-1R-triggered RIG-I degradation.Degradation of RIG-I resulted in the suppression of the IFN-I-associated immune cells in the TME due to the blockade of the RIG-I-MAVS-IFN-I pathway.Poly(I:C) could reverse anti-PD-L1 insensitivity by recovery of RIG-I.In summary,we revealed a disobliging IGF-1R signaling by which IGF-1Rβ promoted cancer growth through triggering the MEX3A-mediated degradation of RIG-I.

Chronic Real-Ambient PM_(2.5)Exposure Exacerbates Cardiovascular Risk via Amplifying Liver Injury in Mice Fed with a High-Fat and High-Cholesterol Diet

Epidemiology has associated fine particulate matter(PM_(2.5))exposure with an increased cardiovascular risk.However,the underlying mechanism,particularly from the liver perspective,remains unclear.Here,the influence of chronic PM_(2.5)exposure on cardiovascular risk in mice fed a high-fat and high-cholesterol diet(HFCD)was studied by using a real-world PM_(2.5)exposure system.Results showed that PM_(2.5)exposure elevated the serum levels of nonhigh-density lipoprotein cholesterol(non-HDL-C)and oxidized low-density lipoprotein(oxLDL)in HFCD-fed mice,demonstrating increased cardiovascular risk.To investigate the molecular mechanism,lipidomics and metabolomics analyses were conducted and revealed that PM_(2.5)exposure enhanced lipid accumulation and disturbed purine metabolism and glutathione metabolism in the liver of HFCD-fed mice,contributing to the elevated non-HDL-C levels and intensified oxidative stress.Moreover,PM_(2.5)exposure increased total cholesterol levels by upregulating Hmgcr expression and downregulating Cyp7a1 expression in the livers of HFCD-fed mice.The HDL-C level was reduced by inhibiting the hepatic Abca1 and Abcg1 expression and decreasing the levels of ApoA-I and LCAT.Additionally,the PM_(2.5)-induced pro-oxidative environment impeded the oxLDL clearance and further triggered inflammation,in turn exacerbating oxidative stress and oxLDL production.This study demonstrated a synergy of PM_(2.5)and HFCD on cardiovascular risk and illuminated the molecular mechanism in PM_(2.5)-susceptible populations.

Surveillance of emerging infectious diseases for biosecurity

Emerging infectious diseases, such as COVID-19, continue to pose significant threats to human beings and their surroundings. In addition, biological warfare, bioterrorism, biological accidents, and harmful consequences arising from dual-use biotechnology also pose a challenge for global biosecurity. Improving the early surveillance capabilities is necessary for building a common biosecurity shield for the global community of health for all. Furthermore, surveillance could provide early warning and situational awareness of biosecurity risks. However, current surveillance systems face enormous challenges, including technical shortages, fragmented management, and limited international cooperation. Detecting emerging biological risks caused by unknown or novel pathogens is of particular concern. Surveillance systems must be enhanced to effectively mitigate biosecurity risks. Thus, a global strategy of meaningful cooperation based on efficient integration of surveillance at all levels, including interdisciplinary integration of techniques and interdepartmental integration for effective management, is urgently needed. In this paper, we review the biosecurity risks by analyzing potential factors at all levels globally. In addition to describing biosecurity risks and their impact on global security, we also focus on analyzing the challenges to traditional surveillance and propose suggestions on how to integrate current technologies and resources to conduct effective global surveillance.

Melatonin and probiotics ameliorate nanoplastics-induced hematopoietic injury by modulating the gut microbiotametabolism

Plastic pollution has become a non-negligible global pollution problem.Nanoplastics(NP)can reach the bone marrow with blood circulation and develop hematotoxicity,but potential mechanisms and prevention strategies are lacking.Here,we report the biological distribution of NP particles in the bone marrow of mice and hematopoietic toxicity after exposure to 60μg of 80 nm NP for 42 days.NP exposure inhibited the capability of bone marrow hematopoietic stem cells to renew and differentiate.Notably,probiotics and melatonin supplementation significantly ameliorated NP-induced hematopoietic damage,and the former was superior to the latter.And interestingly,melatonin and probiotic interventions may involve different microbes and metabolites.After melatonin intervention,creatine showed a stronger correlation with NP-induced gut microbiota disorders.In contrast,probiotic intervention reversed the levels of more gut microbes and plasma metabolites.Of these,threonine,malonylcarnitine,and 3-hydroxybutyric acid might be potential performers in the regulation of hematopoietic toxicity by gut microbes,as they had a more significant relationship with the identified microbes.In conclusion,supplementation with melatonin or probiotics may be two candidates to prevent hematopoietic toxicity attributable to NP exposure.Also,the multi-omics results may lay the foundation for future investigations into in-depth mechanisms.

DNA methylation changes induced by BDE-209 are related to DNA damage response and germ cell development in GC-2spd

Decabrominated diphenyl ether(BDE-209)is generally utilized in multiple polymer materials as common brominated flame retardant.BDE-209 has been listed as persistent organic pollutants(POPs),which was considered to be reproductive toxin in the environment.But it still remains unclear about the effects of BDE-209 on DNA methylation and the inducedmale reproductive toxicity.Due to the extensive epigenetic regulation in germ line development,we hypothesize that BDE-209 exposure impacts the statue of DNA methylation in spermatocytes in vitro.Therefore,the mouse GC-2spd(GC-2)cells were used for the genome wide DNA methylation analysis after treated with 32μg/mL BDE-209 for 24 hr.The results showed that BDE-209 caused genomic methylation changes with 32,083 differentially methylated CpGs in GC-2 cells,including 16,164(50.38%)hypermethylated and 15,919(49.62%)hypomethylated sites.With integrated analysis ofDNAmethylation data and functional enrichment,we found that BDE-209 might affect the functional transcription in cell growth and sperm development by differential gene methylation.qRT-PCR validation demonstrated the involvement of p53-dependent DNA damage response in the GC-2 cells after BDE-209 exposure.In general,our findings indicated that BDE-209-induced genome wide methylation changes could be interrelated with reproductive dysfunction.This study might provide new insights into the mechanisms of male reproductive toxicity under the environmental exposure to BDE-209.

The Malaysian health care system:Ecology,plans,and reforms

Malaysia is on its way to achieving developed nation status in the next 4 years.Currently,Malaysia is on track for three Millennium Development Goals(MDG1,MDG4,and MDG7).The maternal mortality rate,infant mortality rate,and mortality rate of children younger than 5 years improved from 25.6%(2012)to 6.6%(2013),and 7.7%(2012)per 100,000 live births,respectively whereas immunization coverage for infants increased to an average of 90%.As of 2013 the ratio of physicians to patients improved to 1:633 while the ratio of health facilities to the population was 1:10,272.The current government administration has proposed a reform in the form of the 10th Malaysian Plan coining the term“One Care for One Malaysia”as the newly improved and reorganized health care plan,where efficiency,effectiveness,and equity are the main focus.This review illustrates Malaysia’s transition from pre-independence to the current state,and its health and socioeconomic achievement as a country.It aims to contribute knowledge through identifying the plans and reforms by the Malaysian government while highlighting the challenges faced as a nation.