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Alcoholic steatohepatitis (ASH) is a progression hepatitis with severe fatty liver and its mortality rate for 30-days in patients are over 30%. Additionally, ASH is well known for one-fifth all alcoholic related liver diseases in the world. Excessive chronic alcohol consumption is one of the most common causes of the progression of ASH and is associated with poor prognosis and liver failure. Alcohol abuse dysregulates the lipid homeostasis and causes oxidative stress and inflammation in the liver. Consequently, metabolic pathways stimulating hepatic accumulation of excessive lipid droplets are induced. Recently, many studies have indicated a link between ASH and epigenetic changes, showing differential expression of alcohol-induced epigenetic genes in the liver. However, the specific mechanisms underlying the pathogenesis of ASH remain elusive. Thus, we here summarize the current knowledge about the roles of epigenetics in lipogenesis, inflammation, and apoptosis in the context of ASH pathophysiology. Especially, we highlight the latest findings on the roles of Sirtuins, a conserved family of class-III histone deacetylases, in ASH. Additionally, we discuss the involvement of DNA methylation, histone modifications, and miRNAs in ASH as well as the ongoing efforts for the clinical translation of the findings in ASH-related epigenetic changes. [ABSTRACT FROM AUTHOR]

Background: Bisphenol A (BPA) is a well‐recognized endocrine disruptor and is globally used in the manufacture of many plastic items. Multiple studies suggest links between prenatal BPA exposure and alterations in neurodevelopment and behaviors in children, even at lower levels. This study was conducted to reveal the role of astrocyte morphology and Gamma aminobutyric acid (GABA) signaling in BPA induced cognitive defects in the offspring of Wistar albino rats when exposed during the prenatal and postnatal periods. Methods: Dams of Wistar albino rats were exposed to a dose of 5 mg/kg body weight of BPA throughout the pregnancy and lactation period until the third postnatal day (PND). After delivery of pups, cognitive tests were carried out on the 21st, 24th, and 28th PNDs. Blood samples were collected for measurement of serum GABA levels. On the same day as the blood collections, pups were sacrificed and their right frontal cortices were dissected out. Immunohistochemical analysis for glial fibrillar acidic protein + astrocytes was conducted. Results: Pre and postnatal BPA exposure led to anxiety like behavior in pups. This exposure also resulted in reduced serum GABA concentrations. Immunohistochemical analysis revealed reduced astrocyte numbers as well as decreased numbers of dendritic spines in the BPA exposed pups. Conclusion: BPA exposure during critical periods of development leads to cognitive impairments that correlate with the defects in the GABA signaling pathways and deteriorated morphology of the astrocytes in the offspring of the Wistar rats. [ABSTRACT FROM AUTHOR]

Background: During early development, environmental compounds can induce adult onset diseases and disrupt the circulating vitamin D (VitD) levels. Aim: This study aimed to examine the protective role of VitD against the adverse effects of BPA on male and female mice. Methods: A total of 60 male and female Swiss Albino mice (3 weeks old) were randomly divided into 5 groups; each consisted of 12 mice (6 males and 6 females) and was treated as follows: Group I received no treatment (sham control); Group II, sterile corn oil only (vehicle control); Group III, BPA (400 μg/kg); Group IV, VitD (2,195 IU/kg); and Group V, BPA + VitD. At 10.5 weeks, the animals were sacrificed to conduct histological examinations. Results: BPA-exposed mice were found to have neurobehavioral abnormalities, heart, kidney, and lung diseases with increased apoptotic indices in both sexes. On the other hand, the treatment of BPA mice with VitD altered this scenario with modulated motor activity, enhanced body and organ weights, and preserved the heart, kidney, and lung architecture, alongside a decreased percent apoptotic index. Conclusion: Our findings illustrate that VitD protects mice against BPA-induced heart, kidney, and lung abnormalities. [ABSTRACT FROM AUTHOR]

The single gene that correlates with many genetic diseases and disorders, as well as ageing and age-related diseases, is the subject of this research. SIRT1 is a gene that plays a role in the ageing process and age-related disorders including early ageing, vision, Alzheimer's disease, dementia, cancer, skin problems, and so on. The extraordinary and significant capacity of the quality is to upgrade the telomerase action. Telomerase is the protein that shields the finish of the chromosomes from the harm. Telomerase goes about as defensive container layer that forestalls the chromosomes. The shortening of telomerase prompts the way toward maturing. Many exploration shows that the polyphenolic compound particularly resveratrol from grapes shows dynamic outcome in the incitement of sirtuins quality and studies shows that the cycle lead expansion of life expectancy. The examination on the specific quality shws that it includes in different exercises like cell cycle, apoptosis, disease, Neurodegenerative problems and so forth, The point of the investigation centering towards the significant exploration work on the sirtuins quality and its capacities in different measurements. [ABSTRACT FROM AUTHOR]

Humans are changing and challenging nature in many ways. Conservation Biology seeks to limit human impacts on nature and preserve biological diversity. Traditionally, Developmental Biology and Conservation Biology have had nonoverlapping objectives, operating in distinct spheres of biological science. However, this chasm can and should be filled to help combat the emerging challenges of the 21st century. The means by which to accomplish this goal were already established within the conceptual framework of evo‐ and eco‐devo and can be further expanded to address the ways that anthropogenic disturbance affect embryonic development. Herein, I describe ways that these approaches can be used to advance the study of reptilian embryos. More specifically, I explore the ways that a developmental perspective can advance ongoing studies of embryonic physiology in the context of global warming and chemical pollution, both of which are known stressors of reptilian embryos. I emphasize ways that these developmental perspectives can inform conservation biologists trying to develop management practices that will address the complexity of challenges facing reptilian embryos. Research Highlights: Reptiles and their embryos are under threat of emerging anthropogenic change such as pollution and thermal stress. Herein, I outline areas of future research where greater information about reptilian development in the context of real‐world challenges may inform conservation efforts. [ABSTRACT FROM AUTHOR]

Trypanosoma cruzi is a digenetic parasite that requires triatomines and mammalian host to complete its life cycle. T. cruzi replication in mammalian host induces immune-mediated cytotoxic proinflammatory reactions and cellular injuries, which are the common source of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during the acute parasitemic phase. Mitochondrial dysfunction of electron transport chain has been proposed as a major source of superoxide release in the chronic phase of infection, which renders myocardium exposed to sustained oxidative stress and contributes to Chagas disease pathology. Sirtuin 1 (SIRT1) is a class III histone deacetylase that acts as a sensor of redox changes and shapes the mitochondrial metabolism and inflammatory response in the host. In this review, we discuss the molecular mechanisms by which SIRT1 can potentially improve mitochondrial function and control oxidative and inflammatory stress in Chagas disease. [ABSTRACT FROM AUTHOR]

Estrogen receptor alpha (ERα) belongs to the nuclear hormone receptor family of ligand-inducible transcription factors and regulates gene networks in biological processes such as cell growth and proliferation. Disruption of these networks by chemical compounds with estrogenic activity can result in adverse outcomes such as unscheduled cell proliferation, ultimately culminating in tumor formation. To distinguish disruptive activation from normal physiological responses, it is essential to quantify relationships between different key events leading to a particular adverse outcome. For this purpose, we established fluorescent protein MCF7 reporter cell lines for ERα-induced proliferation by bacterial artificial chromosome-based tagging of 3 ERα target genes: GREB1 , PGR , and TFF1. These target genes are inducible by the non-genotoxic carcinogen and ERα agonist 17β-estradiol in an ERα-dependent manner and are essential for ERα-dependent cell-cycle progression and proliferation. The 3 GFP reporter cell lines were characterized in detail and showed different activation dynamics upon exposure to 17β-estradiol. In addition, they demonstrated specific activation in response to other established reference estrogenic compounds of different potencies, with similar sensitivities as validated OECD test methods. This study shows that these fluorescent reporter cell lines can be used to monitor the spatial and temporal dynamics of ERα pathway activation at the single-cell level for more mechanistic insight, thereby allowing a detailed assessment of the potential carcinogenic activity of estrogenic compounds in humans. [ABSTRACT FROM AUTHOR]

To explore the potential function of miR-9-5p in wear-particle-induced osteoclastogenesis, we examined the expression of SIRT1 and miR-9-5p in particle-induced osteolysis (PIO) mice calvariae and polyethylene (PE)-induced RAW 264.7 cells and found that SIRT1 expression was downregulated while miR-9-5p expression was upregulated in both models. We then verified that miR-9-5p targets SIRT1. miR-9-5p was found to promote PE-induced osteoclast formation from RAW 264.7 cells by tartrate-resistant acid phosphatase staining and detection of osteoclast markers, and miR-9-5p activation of the SIRT1/NF-kB signaling pathway was found in cells by detecting the expression of SIRT1/NF-kB pathway-related proteins and rescue assays. In conclusion, we found that miR-9-5p activated the SIRT1/NF-κB pathway to promote wear-particle-induced osteoclastogenesis. miR-9-5p may be a useful therapeutic target for PIO remission and treatment. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a group of heterogenous diseases considered as an important public health problem in several countries. This neglected disease is caused by over 20 parasite species of the protozoa belonging to the Leishmania genus and is spread by the bite of a female phlebotomine sandfly. Depending on the parasite specie and the immune status of the patient, leishmaniasis can present a wide spectrum of clinical manifestations. As an obligate intracellular parasite, Leishmania colonize phagocytic cells, mainly the macrophages that orchestrate the host immune response and determine the fate of the infection. Once inside macrophages, Leishmania triggers different signaling pathways that regulate the immune and metabolic response of the host cells. Various transcription factors regulate such immune-metabolic responses and the associated leishmanicidal and inflammatory reaction against the invading parasite. In this review, we will highlight the most important transcription factors involved in these responses, their interactions and their impact on the establishment and the progression of the immune response along with their effect on the physiopathology of the disease. [ABSTRACT FROM AUTHOR]

Dynamin‐related protein‐1 (Drp1) is a key regulator in mitochondrial fission. Excessive Drp1‐mediated mitochondrial fission in skeletal muscle under the obese condition is associated with impaired insulin action. However, it remains unknown whether pharmacological inhibition of Drp1, using the Drp1‐specific inhibitor Mitochondrial Division Inhibitor 1 (Mdivi‐1), is effective in alleviating skeletal muscle insulin resistance and improving whole‐body metabolic health under the obese and insulin‐resistant condition. We subjected C57BL/6J mice to a high‐fat diet (HFD) or low‐fat diet (LFD) for 5‐weeks. HFD‐fed mice received Mdivi‐1 or saline injections for the last week of the diet intervention. Additionally, myotubes derived from obese insulin‐resistant humans were treated with Mdivi‐1 or saline for 12 h. We measured glucose area under the curve (AUC) from a glucose tolerance test (GTT), skeletal muscle insulin action, mitochondrial dynamics, respiration, and H2O2 content. We found that Mdivi‐1 attenuated impairments in skeletal muscle insulin signaling and blood glucose AUC from a GTT induced by HFD feeding (p < 0.05). H2O2 content was elevated in skeletal muscle from the HFD group (vs. LFD, p < 0.05), but was reduced with Mdivi‐1 treatment, which may partially explain the improvement in skeletal muscle insulin action. Similarly, Mdivi‐1 enhanced the mitochondrial network structure, reduced reactive oxygen species, and improved insulin action in myotubes from obese humans (vs. saline, p < 0.05). In conclusion, inhibiting Drp1 with short‐term Mdivi‐1 administration attenuates the impairment in skeletal muscle insulin signaling and improves whole‐body glucose tolerance in the setting of obesity‐induced insulin resistance. Targeting Drp1 may be a viable approach to treat obesity‐induced insulin resistance. [ABSTRACT FROM AUTHOR]

Protein phosphorylation constitutes a major post-translational modification that critically regulates the half-life, intra-cellular distribution, and activity of proteins. Among the large number of kinases that compose the human kinome tree, those targeting RNA-binding proteins, in particular serine/arginine-rich (SR) proteins, play a major role in the regulation of gene expression by controlling constitutive and alternative splicing. In humans, these kinases belong to the CMGC [Cyclin-dependent kinases (CDKs), Mitogen-activated protein kinases (MAPKs), Glycogen synthase kinases (GSKs), and Cdc2-like kinases (CLKs)] group and several studies indicate that they also control viral replication via direct or indirect mechanisms. The aim of this review is to describe known and emerging activities of CMGC kinases that share the common property to phosphorylate SR proteins, as well as their interplay with different families of viruses, in order to advance toward a comprehensive knowledge of their pro- or anti-viral phenotype and better assess possible translational opportunities. [ABSTRACT FROM AUTHOR]

Retinoic acid (RA) binding proteins, CRABP1 and CRABP2, are molecular chaperones that mediate intracellular activity of RA, the key promoter of cell differentiation with tumor suppressor activity. One of the main functions of CRABP2 is delivery and transfer of RA to the nuclear receptors RAR/RXR, which leads to activation of the transcription of a wide range of retinoid-responsive genes. The functions of CRABP1 are less studied but are apparently associated with sequestration of RA in cytoplasm and limitation of its transcriptional activity, suggesting involvement of this protein in the development of RA resistance. The mechanisms regulating activity of CRABP1 are also poorly understood. Comparison of the CRABP1 level in tumor cell lines of various origins, performed for the first time here, showed absence of the CRABP1 protein in the cell lines of tumors considered to be RA-resistant, and pronounced production of this protein in the RA-sensitive cells. However, analysis carried out with a panel of breast cancer cell lines with different levels of RA-sensitivity showed that there was no correlation between the production of CRABP1 protein and the sensitivity of the cells to RA. At the same time, we found strong correlation between the expression of CRABP1 and CRABP2 proteins in all studied cell types, regardless of their origin and RA-sensitivity/resistance. Moreover, suppression of the CRABP1 level in both RA-sensitive and RA-resistant cells was shown in the cells with cells with knockdown of CRABP2 gene. The revealed CRABP2-dependent regulation of CRABP1 production is a new mechanism of the intracellular retinoic signaling system. [ABSTRACT FROM AUTHOR]

Objectives: Common complications associated with dental implant surgery are well recognized and are usually explained to patients during the process of informed consent. For the general dental practitioner, the periodontist, and the oral and maxillofacial surgeon, it is relevant to also be familiar with less frequent complications. This review gathers unusual complications of this surgical procedure and presents unique complications from single case reports. Method and Materials: Studies were located using systematic searches in Medline and the Cochrane Library electronic databases. Key words included the terms "implant", "dental", "oral", "complication", "unusual", and "rare". References from the relevant articles were also double-checked. The review was limited to English and German language articles, published within the last 15 years. Results: 17 different unusual complications were identified. The majority of studies report five different complications: permanent nerve injury, damage to teeth adjacent to the implant, excessive bleeding resulting in hematoma of the floor of the mouth, mandibular fracture, and displacement of implants into the maxillary sinus. Benign paroxysmal positional vertigo and a plunging ranula were reported sporadically. Another 10 complications were only described once in our literature search. Conclusion: Unusual complications are challenging. It is important for the dental practitioner to be aware of all the possible complications and to recognize them early so that adequate therapy can immediately be ensured. [ABSTRACT FROM AUTHOR]

Four cationic surfactants with various length and number of long alkyl chains such as dodecyltrimethylammonium, tetradecyltrimethyl-ammonium, hexadecyltrimethylammonium and didodecyldimethyl-ammonium were intercalated at different concentrations into two natural clays from Burkina Faso via solid-state reaction. Each organoclay was used to explore bisphenol A (BPA) removal from water. Various factors including adsorbent dose, agitation time, concentration, surfactant loading levels, pH and temperature were evaluated. Further, pseudo-first and pseudo-second kinetics, Langmuir and Freundlich isotherms and thermodynamics of adsorption onto organoclays were investigated. The adsorption mechanism was perfectly described by pseudo-second-order kinetic model and Langmuir isotherm. Spontaneous and exothermic processes were associated with BPA removal. This study showed that both physisorption and chemisorption are involved in BPA adsorption. Adsorption capacities ranging from 88 to 127 mg/g were observed at ambient temperature and acidic environment. The ranking of organoclays sorption capacities depends on the surfactant loading level. The pH effect on the adsorption showed a remarkable decrease in the quantity of BPA removed when pH ≥ 10. The BPA amount adsorbed onto the organoclays was not varying significantly for pH < 10. Organoclays prepared via solid-state surfactant intercalation are as effective adsorbents for BPA removal from water as those prepared in aqueous solution through cation exchange. [ABSTRACT FROM AUTHOR]

The prenatal period is a critical window for the development of autism spectrum disorder (ASD). The relationship between prenatal nutrients and gestational gene expression in mothers of children later diagnosed with ASD or non‐typical development (Non‐TD) is poorly understood. Maternal blood collected prospectively during pregnancy provides insights into the effects of nutrition, particularly one‐carbon metabolites, on gene pathways and neurodevelopment. Genome‐wide transcriptomes were measured with microarrays in 300 maternal blood samples in Markers of Autism Risk in Babies‐Learning Early Signs. Sixteen different one‐carbon metabolites, including folic acid, betaine, 5′‐methyltretrahydrofolate (5‐MeTHF), and dimethylglycine (DMG) were measured. Differential expression analysis and weighted gene correlation network analysis (WGCNA) were used to compare gene expression between children later diagnosed as typical development (TD), Non‐TD and ASD, and to one‐carbon metabolites. Using differential gene expression analysis, six transcripts (TGR‐AS1, SQSTM1, HLA‐C, and RFESD) were associated with child outcomes (ASD, Non‐TD, and TD) with genome‐wide significance. Genes nominally differentially expressed between ASD and TD significantly overlapped with seven high confidence ASD genes. WGCNA identified co‐expressed gene modules significantly correlated with 5‐MeTHF, folic acid, DMG, and betaine. A module enriched in DNA methylation functions showed a suggestive protective association with folic acid/5‐MeTHF concentrations and ASD risk. Maternal plasma betaine and DMG concentrations were associated with a block of co‐expressed genes enriched for adaptive immune, histone modification, and RNA processing functions. These results suggest that the prenatal maternal blood transcriptome is a sensitive indicator of gestational one‐carbon metabolite status and changes relevant to children's later neurodevelopmental outcomes. Lay Summary Pregnancy is a time when maternal nutrition could interact with genetic risk for autism spectrum disorder. Blood samples collected during pregnancy from mothers who had a prior child with autism were examined for gene expression and nutrient metabolites, then compared to the diagnosis of the child at age three. Expression differences in gene pathways related to the immune system and gene regulation were observed for pregnancies of children with autism and non‐typical neurodevelopment and were associated with maternal nutrients. [ABSTRACT FROM AUTHOR]

Cholesteatoma is characterized by both the overgrowth of hyperkeratinized squamous epithelium and bone erosion. However, the exact mechanism underlying the hyperproliferative ability of cholesteatoma remains unknown. In this study, we investigated PPAR β/δ expression in human surgical specimens of cholesteatoma and analyzed its functional role as a regulator of epithelial keratinocyte hyperproliferation. We found that the expression of PPAR β/δ was significantly upregulated in cholesteatoma and ligand-activated PPAR β/δ markedly promoted the proliferation of cholesteatoma keratinocytes. Furthermore, we showed that PPAR β/δ activation increased PDK1 expression and decreased PTEN generation, which led to increased phosphorylation of AKT and GSK3β and increased the expression level of Cyclin D1. Overall, our data suggested that the proliferating effect of PPAR β/δ on the cholesteatoma keratinocytes was mediated by the positive regulation of the PDK1/PTEN/AKT/GSK3β/Cyclin D1 pathway. These findings warranted further investigation of PPAR β/δ as a therapeutic target for recurrent or residual cholesteatoma. [ABSTRACT FROM AUTHOR]

The post-war introduction of new chemicals to consumer products created a range of complex environmental health issues. Despite recent evidence demonstrating the issues associated with using particular chemicals in the home, responses from industry and regulators have failed to account for the complex ways that chemicals interact with each other, humans and microorganisms to cause harm. This paper draws together the scientific and social science literature to make two key contributions: first, it demonstrates why investigating everyday practices will be crucial to improve knowledge of how human/environment interactions in the home are contributing to certain health conditions; second, it draws on examples of Endocrine Disrupting Chemicals to show how these health conditions cannot be addressed by replacing individual products, or chemicals, as many toxic ingredients have become central to the functionality of interdependent networks of products, and the routines they enable. By failing to engage with these issues, future research and planning to establish healthy homes will not be able to account for these crucial sources of harm. We conclude that further research addressing indoor environmental health should expand the boundaries of inquiry across disciplines and knowledge perspectives to analyse how social practices structure micro-scale interactions between humans, microbes and chemicals, in the home. [ABSTRACT FROM AUTHOR]

There is compelling evidence that developmental exposure to toxic metals increases risk for obesity and obesity-related morbidity including cardiovascular disease and type 2 diabetes. To explore the hypothesis that developmental Cd exposure increases risk of obesity later in life, male, and female CD-1 mice were maternally exposed to 500 ppb CdCl2 in drinking water during a human gestational equivalent period (gestational day 0-postnatal day 10 [GD0-PND10]). Hallmark indicators of metabolic disruption, hepatic steatosis, and metabolic syndrome were evaluated prior to birth through adulthood. Maternal blood Cd levels were similar to those observed in human pregnancy cohorts, and Cd was undetected in adult offspring. There were no observed impacts of exposure on dams or pregnancy-related outcomes. Results of glucose and insulin tolerance testing revealed that Cd exposure impaired offspring glucose homeostasis on PND42. Exposure-related increases in circulating triglycerides and hepatic steatosis were apparent only in females. By PND120, Cd-exposed females were 30% heavier with 700% more perigonadal fat than unexposed control females. There was no evidence of dyslipidemia, steatosis, increased weight gain, nor increased adiposity in Cd-exposed male offspring. Hepatic transcriptome analysis on PND1, PND21, and PND42 revealed evidence for female-specific increases in oxidative stress and mitochondrial dysfunction with significant early disruption of retinoic acid signaling and altered insulin receptor signaling consistent with hepatic insulin sensitivity in adult females. The observed steatosis and metabolic syndrome-like phenotypes resulting from exposure to 500 ppb CdCl2 during the pre- and perinatal period of development equivalent to human gestation indicate that Cd acts developmentally as a sex-specific delayed obesogen. [ABSTRACT FROM AUTHOR]

Endogenous steroid hormones and Endocrine Disrupting Chemicals (EDC) interact with gut microbiota through different pathways. We suggest the use of the term "endobolome" when referring to the group of gut microbiota genes and pathways involved in the metabolism of steroid hormones and EDC. States of dysbiosis and reduced diversity of the gut microbiota may impact and modify the endobolome resulting at long-term in the development of certain pathophysiological conditions. The endobolome might play a central role in the gut microbiota as seen by the amount of potentially endobolome-mediated diseases and thereby it can be considered an useful diagnostic tool and therapeutic target for future functional research strategies that envisage the use of next generation of probiotics. In addition, we propose that EDC and other xenobiotics that alter the gut microbial composition and its metabolic capacities should be categorized into a subgroup termed "microbiota disrupting chemicals" (MDC). This will help to distinguish the role of contaminants from other microbiota natural modifiers such as those contained or released from diet, environment, physical activity and stress. These MDC might have the ability to promote specific changes in the microbiota that can ultimately result in common intestinal and chronic or long-term systemic diseases in the host. The risk of developing certain disorders associated with gut microbiota changes should be established by determining both the effects of the MDC on gut microbiota and the impact of microbiota changes on chemicals metabolism and host susceptibility. In any case, further animal controlled experiments, clinical trials and large epidemiological studies are required in order to establish the concatenated impact of the MDC-microbiota-host health axis. [ABSTRACT FROM AUTHOR]

The global prevalence of metabolic disorders, such as obesity, diabetes and fatty liver disease, is dramatically increasing. Both genetic and environmental factors are well-known contributors to the development of these diseases and therefore, the study of epigenetics can provide additional mechanistic insight. Dietary interventions, including caloric restriction, intermittent fasting or time-restricted feeding, have shown promising improvements in patients' overall metabolic profiles (i.e., reduced body weight, improved glucose homeostasis), and an increasing number of studies have associated these beneficial effects with epigenetic alterations. In this article, we review epigenetic changes involved in both metabolic diseases and dietary interventions in primary metabolic tissues (i.e., adipose, liver, and pancreas) in hopes of elucidating potential biomarkers and therapeutic targets for disease prevention and treatment. [ABSTRACT FROM AUTHOR]

Despite the fact that the estrogenic effects of bisphenols were first described 80 years ago, recent data about its potential negative impact on birth outcome parameters raises a strong rationale to investigate further. The adverse health effects of plastics recommend to measure the impacts of endocrine‐disrupting compounds (EDCs) such as bisphenols (BPA, BPS, BPF), bis(2‐ethylhexyl) phthalate, and dibutyl phthalate (DBP) in human health. Exposure to these compounds in utero may program the diseases of the testis, prostate, kidney and abnormalities in the immune system, and cause tumors, uterine hemorrhage during pregnancy and polycystic ovary. These compounds also control the processes of epigenetic transgenerational inheritance of adult‐onset diseases by modulating DNA methylation and epimutations in reproductive cells. The early developmental stage is the most susceptible window for developmental and genomic programming. The critical stages of the events for a normal human birth lie between the many transitions occurring between spermatogenesis, egg fertilization and the fully formed fetus. As the cells begin to grow and differentiate, there are critical balances of hormones, and protein synthesis. Data are emerging on how these plastic‐derived compounds affect embryogenesis, placentation and feto‐placental development since pregnant women and unborn fetuses are often exposed to these factors during preconception and throughout gestation. Impaired early development that ultimately influences fetal outcomes is at the center of many developmental disorders and contributes an independent risk factor for adult chronic diseases. This review will summarize the current status on the impact of exposure to plastic derived EDCs on the growth, gene expression, epigenetic and angiogenic activities of the early fetal development process and their possible effects on birth outcomes. [ABSTRACT FROM AUTHOR]

Phthalates and bisphenols are high production volume chemicals that are used in the manufacturing of consumer and medical products. Given the ubiquity of bisphenol and phthalate chemicals in the environment, biomonitoring studies routinely detect these chemicals in 75–90% of the general population. Accumulating evidence suggests that such chemical exposures may influence human health outcomes, including cardiovascular health. These associations are particularly worrisome for sensitive populations, including fetal, infant and pediatric groups—with underdeveloped metabolic capabilities and developing organ systems. In the presented article, we aimed to review the literature on environmental and clinical exposures to bisphenols and phthalates, highlight experimental work that suggests that these chemicals may exert a negative influence on cardiovascular health, and emphasize areas of concern that relate to vulnerable pediatric groups. Gaps in our current knowledge are also discussed, so that future endeavors may resolve the relationship between chemical exposures and the impact on pediatric cardiovascular physiology. [ABSTRACT FROM AUTHOR]

Nuclear factor erythroid-2 related factor 2 (NRF2) encoded by the NFE2L2 gene is a transcription factor critical for protecting cells from chemically-induced oxidative stress. We developed computational procedures to identify chemical modulators of NRF2 in a large database of human microarray data. A gene expression biomarker was built from statistically-filtered gene lists derived from microarray experiments in primary human hepatocytes and cancer cell lines exposed to NRF2-activating chemicals (oltipraz, sulforaphane, CDDO-Im) or in which the NRF2 suppressor Keap1 was knocked down by siRNA. Directionally consistent biomarker genes were further filtered for those dependent on NRF2 using a microarray dataset from cells after NFE2L2 siRNA knockdown. The resulting 143-gene biomarker was evaluated as a predictive tool using the correlation-based Running Fisher algorithm. Using 59 gene expression comparisons from chemically-treated cells with known NRF2 activating potential, the biomarker gave a balanced accuracy of 93%. The biomarker was comprised of many well-known NRF2 target genes (AKR1B10, AKR1C1, NQO1, TXNRD1, SRXN1, GCLC, GCLM), 69% of which were found to be bound directly by NRF2 using ChIP-Seq. NRF2 activity was assessed across ~9840 microarray comparisons from ~1460 studies examining the effects of ~2260 chemicals in human cell lines. A total of 260 and 43 chemicals were found to activate or suppress NRF2, respectively, most of which have not been previously reported to modulate NRF2 activity. Using a NRF2-responsive reporter gene in HepG2 cells, we confirmed the activity of a set of chemicals predicted using the biomarker. The biomarker will be useful for future gene expression screening studies of environmentally-relevant chemicals. [ABSTRACT FROM AUTHOR]

Polychlorinated biphenyls (PCBs) are ubiquitously detected and have been linked to metabolic diseases. Gut microbiome is recognized as a critical regulator of disease susceptibility; however, little is known how PCBs and gut microbiome interact to modulate hepatic xenobiotic and intermediary metabolism. We hypothesized the gut microbiome regulates PCB-mediated changes in the metabolic fingerprints and hepatic transcriptome. Ninety-day-old female conventional and germ-free mice were orally exposed to the Fox River Mixture (synthetic PCB mixture, 6 or 30 mg/kg) or corn oil (vehicle control, 10 ml/kg), once daily for 3 consecutive days. RNA-seq was conducted in liver, and endogenous metabolites were measured in liver and serum by LC-MS. Prototypical target genes of aryl hydrocarbon receptor, pregnane X receptor, and constitutive androstane receptor were more readily upregulated by PCBs in conventional conditions, indicating PCBs, to the hepatic transcriptome, act partly through the gut microbiome. In a gut microbiome-dependent manner, xenobiotic, and steroid metabolism pathways were upregulated, whereas response to misfolded proteins-related pathways was downregulated by PCBs. At the high PCB dose, NADP, and arginine appear to interact with drug-metabolizing enzymes (ie, Cyp1 – 3 family), which are highly correlated with Ruminiclostridium and Roseburia , providing a novel explanation of gut-liver interaction from PCB-exposure. Utilizing the Library of Integrated Network-based Cellular Signatures L1000 database, therapeutics targeting anti-inflammatory and endoplasmic reticulum stress pathways are predicted to be remedies that can mitigate PCB toxicity. Our findings demonstrate that habitation of the gut microbiota drives PCB-mediated hepatic responses. Our study adds knowledge of physiological response differences from PCB exposure and considerations for further investigations for gut microbiome-dependent therapeutics. [ABSTRACT FROM AUTHOR]

The prevalence of diabetes and its related complications are increasing significantly globally. Collected evidence suggested that several genetic and environmental factors contribute to diabetes mellitus. Associated complications such as retinopathy, neuropathy, nephropathy and other cardiovascular complications are a direct result of diabetes. Epigenetic factors include deoxyribonucleic acid (DNA) methylation and histone post-translational modifications. These factors are directly related with pathological factors such as oxidative stress, generation of inflammatory mediators and hyperglycemia. These result in altered gene expression and targets cells in the pathology of diabetes mellitus without specific changes in a DNA sequence. Environmental factors and malnutrition are equally responsible for epigenetic states. Accumulated evidence suggested that environmental stimuli alter the gene expression that result in epigenetic changes in chromatin. Recent studies proposed that epigenetics may include the occurrence of 'metabolic memory' found in animal studies. Further study into epigenetic mechanism might give us new vision into the pathogenesis of diabetes mellitus and related complication thus leading to the discovery of new therapeutic targets. In this review, we discuss the possible epigenetic changes and mechanism that happen in diabetes mellitus type 1 and type 2 separately. We highlight the important epigenetic and non-epigenetic therapeutic targets involved in the management of diabetes and associated complications. [ABSTRACT FROM AUTHOR]

The epigenome of an individual can be altered by endogenous hormones, environment, age, diet, and exposure to endocrine disrupting chemicals (EDCs), and the effects of these modifications can be seen across generations. Epigenetic modifications to the genome can alter the phenotype of the individual without altering the DNA sequence itself. Epigenetic modifications include DNA methylation, histone modification, and aberrant microRNA (miRNA) expression; they begin during germ cell development and embryogenesis and continue until death. Hormone modulation occurs during the ageing process due to epigenetic modifications. Maternal overnutrition or undernutrition can affect the epigenome of the fetus, and the effects can be seen throughout life. Furthermore, maternal care during the childhood of the offspring can lead to different phenotypes seen in adulthood. Diseases controlled by the endocrine system, such as obesity and diabetes, as well as infertility in females can be associated with epigenetic changes. Not only can these phenotypes be seen in F1, but also some chemical effects can be passed through the germline and have effects transgenerationally, and the phenotypes are seen in F3. The following literature review expands upon these topics and discusses the state of the science related to epigenetic effects of age, diet, and EDCs on the endocrine system. [ABSTRACT FROM AUTHOR]

In recent years, the use of Bisphenol A (BPA) has been regulated in many countries because of its potential adverse effects on human health. As a result of the restriction, structural analogues such as bisphenol F (BPF) have already been used for industrial applications as alternatives to BPA. Although much information on the endocrine activity of BPA is available, a proper human hazard assessment of analogues that are believed to have a less harmful toxicity profile is lacking. The aim of our in vitro study was to assess the potential effect of BPF on H295R cell viability, membrane integrity and lysosomal function. Adrenocortical carcinoma cells were cultivated during 24 h in the presence of BPF (0.1, 0.5, 1, 10, 25, 50, 75, 100, 300, 500 µM). Metabolic activity decreased with increasing dose of BPF - from 10 μM (84.33 ± 4.31%). A significant increase in metabolic activity after 24 hours of exposure was observed after cultivation with 0.1 µM BPF (111.50 ± 3.89%) and a slight was observed after cultivation with 1 µM BPF (101,70 ± 1.61%). Exposure doses of BPF caused a slight increase in esterase activity at the lowest concentrations and a significant decrease at higher concentrations. We observed a slight increase in lysosomal function after cultivation with 0.1 and 1 µM, higher exposure doses (25 - 500 µM) caused decrease in lysosomal function. The obtained results confirmed that BPF at higher concentrations caused cytotoxicity. A substitution of BPA by BPF should be thus considered with caution. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is an aggressive primary hepatic malignancy with a significant morbidity and mortality rate. Although chemotherapy along with surgical incision is believed to be an effective therapeutic approach, to date recurrence is being lifted a major concern. Thus, identifying another best therapeutic approach is becoming the main aim of physicians and scholars. In support of this, recently, several studies reported a significant observation of Sirtuin1 (SIRT1) overexpression in the malignant tumor cells, including HCC. As a result, they believed that overexpression of SIRT1 may have an effect on the progression of HCC by targeting growth and/or apoptotic controlling transcriptional factors/signaling pathways. Similarly, other reports confirmed that SIRT1 inhibition had a direct or indirect role in the control of tumor cell growth and metastasis. Therefore, inhibiting the expression and activity of SIRT1 might have a therapeutic effect to handle HCC. However, there are a limited number of reviews regarding the issue, and here, we summarized hepatocellular expression of SIRT1 and its role on HCC progression. [ABSTRACT FROM AUTHOR]

Exposure to vanadium has been associated with deleterious effects on the central nervous system in animals and humans. Although vanadium‐derived pro‐oxidant species were reported to be involved in vanadium‐mediated neurotoxicity, the ability of this metal to induce oxidative stress markers in glial cells remains to be elucidated. In this study, we investigated the cytotoxicity and the generation of reactive oxygen species (ROS) and nitric oxide (NO) by mouse primary astrocytes after treatment with vanadyl sulfate (VOSO4) at concentrations of 20, 50, 100, 200, and 500 μM. The resazurin assay revealed that treatment with VOSO4 for 24 and 48 h at concentrations of 50 and 100 μM, respectively, or higher substantially induced astrocytic cytotoxicity. Intracellular ROS increased after 6‐h exposure to the lowest concentration tested (20 μM VOSO4) and tended to intensify after 24‐ and 48‐h treatments reaching significant values for 20 and 500 μM VOSO4. In turn, NO production in the examined cells was elevated after exposure to all concentrations at the 6‐, 24‐, and 48‐h incubation periods. Our study demonstrated the ability of VOSO4 to induce H2O2 generation in cell‐free DMEM/F12 medium. The H2O2 levels were in the micromolar range (up to 5 μM) and were detected mostly during the first few minutes after VOSO4 addition, suggesting that the generated H2O2 could not induce toxic effects on the cells. Taken together, these results show VOSO4 induced cytotoxicity in primary astrocyte cells, which may have resulted from vanadyl‐stimulated intracellular ROS and NO generation in these cells. The regression analysis for the levels of H2O2 produced by VOSO4 in the culture medium showed that 86% and 85% of the variation in the concentration of H2O2 (measured after the 0‐ and 5‐min incubation with VOSO4, respectively) was determined by vanadium. [ABSTRACT FROM AUTHOR]

Humans are spending less time in biodiverse environments, and according to the Old Friends and Biodiversity hypotheses, this has led to fewer interactions with diverse immunoregulatory micro‐organisms or 'old friends'.Non‐communicable diseases such as asthma and inflammatory bowel disease are on the rise, and the development and progression of these 'modern' diseases may be attributed in part, to the breakdown of this evolutionary relationship between humans and environmental microbiota.There is a growing interest in the environment–microbiome–health axis as a mechanism to explain some of the health benefits linked to spending time in nature.This may provide a platform for proposing a new, holistic and transdisciplinary approach to public and environmental health.The field of landscape research—which combines social and natural sciences—responds to emerging socioecological issues and can make a significant contribution towards this approach.This paper explores innovative, landscape research‐based approaches to understanding the complex relationships between the environment, the microbiome and human health.Transdisciplinarity will play an important role moving forward. This forms a major discussion point in this paper, along with future research directions, key research questions and novel concepts supported by recent technological advancements.The development of a new field of study—Microbioscape Research as a crossover between microbiome science and landscape research—is also discussed. A free plain language summary can be found within the Supporting Information of this article. A free plain language summary can be found within the Supporting Information of this article. [ABSTRACT FROM AUTHOR]

We report the synthesis and antimicrobial properties of a partially reduced dihydronathphthoquinone analogue of 2-methoxy, 5-acetoxy calamenene, extracted from Subergorgia reticulata. The growth of a pathogenic Vibrio harveyi strain was effectively controlled by the calamenene derivative 1 (Cala1) and its synthetic analog 2 (Cala2). Complete mortality of V. harveyi was observed with 2.5 and 0.5 µg mL−1 concentrations of Cala1 and Cala2, respectively. The metabolic assays demonstrated that Cala1 is a bacteriostatic agent while Cala2 showed bactericidal properties. It was confirmed that translocation of Cala2 into the cytoplasm does not induce any change to the integrity of the bacterial cell wall. The Cala2 induced damage to the genetic material of 70% of cells while genetic material of 91% of cells treated with Cala1 remained intact. The Cala2 is, therefore, proposed as a potential bactericidal compound against the aquaculture pathogen V. harveyi. The fact that the Cala2 exhibited minimal cytotoxicity to Artemia nauplii indicates its potential use as an antimicrobial agent for aquaculture operations. [ABSTRACT FROM AUTHOR]

Agrochemicals are a major cause of concern for the aquatic environment because of their toxicity, persistence, and tendency to accumulate in the organisms. The impact of these chemicals on aquatic organisms is due to their movement from various diffuse or point sources, which poses a great threat to aquatic fauna especially fishes, which constitute one of the major sources of protein‐rich food for mankind. The present study is a first of its kind, where the toxic potential of two sublethal concentration (LC1/10th and LC1/25th) of four different classes of agrochemicals have been tested (Insecticide‐ Imidacloprid‐0.074 ppm, 0.02 ppm, Fungicide‐Curzate‐ 4.9 ppm, 1.96 ppm, Herbicide‐ Pyrazosulphuron ethyl‐50 ppm, 20 ppm and Fertilizer‐Micronutrient mixture 500 ppm, 200 ppm) on candidate markers of hypothalamus pituitary‐thyroid axis (TSH, T3, T4, TSHβr) in Oreochromis mossambicus (tilapia) by validating hormonal level and mRNA expression. The results reveal that exposure to agrochemicals resulted in a broad range of alterations with maximum damage being caused by insecticide followed by herbicide and fungicide in that order on the thyroid axis. The results of the present study highlight the need for more detailed studies on the effects of agrochemicals that accumulate in organisms and propose that there should be a check on the rampant use of agrochemicals. [ABSTRACT FROM AUTHOR]

Background: Currently, active ingredients of herbal extracts that can suppress lipid accumulation in the liver have been considered a potential treatment option for non-alcoholic fatty liver disease. Methods: Steatosis rat model was created by high fat and high sucrose diet feeding and treated with oxymatrine (OMT). Serum biochemical parameters, liver histology and lipid profiles were examined. Hepatic differentially expressed proteins (DEPs) which were significantly changed by OMT treatment were identified by iTRAQ analysis. The expressions of representative DEPs, Sirt1 and AMPKα were evaluated by western blotting. Results: OMT significantly reduced the body weight and liver weight of steatosis animals, decreased the serum levels of triglyceride and total cholesterol as well as the hepatic triglyceride and free fatty acid levels, and effectively alleviated fatty degeneration in the liver. A list of OMT-related DEPs have been screened and evaluated by bioinformatics analysis. OMT significantly decreased the expressions of L-FABP, Plin2, FASN and SCD1 and increased Sirt1 expression and AMPKα phosphorylation in the liver of rats with steatosis. Conclusion: The present study has confirmed the significant efficacy of OMT for improving steatosis and revealed hepatic proteomic changes and Sirt1/AMPK signaling activation by OMT treatment in rats with steatosis. [ABSTRACT FROM AUTHOR]

Obesity is a worldwide epidemic disease that induces important structural and functional changes to the heart and predisposes a patient to devastating cardiac complications. Sirtuin1 (SIRT1) has been found to have roles in regulating cardiac function, but whether it can help in cardioprotection is not clear. The aim of the present study was to determine whether melatonin, by modulating SIRT1 and in turn mitochondria signaling, may alleviate obesity-induced cardiac injuries. We investigated 10 lean control mice and 10 leptin-deficient obese mice (ob/ob) orally supplemented with melatonin for 8 weeks, as well as equal numbers of age-matched lean and ob/ob mice that did not receive melatonin. Hearts were evaluated using multiple parameters, including biometric values, morphology, SIRT1 activity and expression of markers of mitochondria biogenesis, oxidative stress, and inflammation. We observed that ob/ob mice experienced significant heart hypertrophy, infiltration by inflammatory cells, reduced SIRT1 activity, altered mitochondrial signaling and oxidative balance, and overexpression of inflammatory markers. Notably, melatonin supplementation in ob/ob mice reverted these obesogenic heart alterations. Melatonin prevented heart remodeling caused by obesity through SIRT1 activation, which, together with mitochondrial pathways, reduced oxidative stress and inflammation. [ABSTRACT FROM AUTHOR]

Endocrine disruptors (EDs) are defined as environmental pollutants capable of interfering with the functioning of the hormonal system. They are environmentally distributed as synthetic fertilizers, electronic waste, and several food additives that are part of the food chain. They can be considered as obesogenic compounds since they have the capacity to influence cellular events related to adipose tissue, altering lipid metabolism and adipogenesis processes. This review will present the latest scientific evidence of different EDs such as persistent organic pollutants (POPs), heavy metals, "nonpersistent" phenolic compounds, triclosan, polybrominated diphenyl ethers (PBDEs), and smoke-derived compounds (benzo -alpha-pyrene) and their influence on the differentiation processes towards adipocytes in both in vitro and in vivo models. [ABSTRACT FROM AUTHOR]

1. Lipid parameters and expression of ACACA, APOA1, CPT1A, FASN, FOXO1, LIPG, PPARα and SIRT1 genes involved in lipid metabolism were investigated in two groups of high (HW) and low (LW) weight broilers from the same strain. 2. Blood cholesterol and liver triglyceride levels were significantly increased in HW chickens compared to LW broilers, while other parameters, i.e. blood triglyceride, blood HDL/LDL, liver cholesterol and total liver fat showed no significant changes in either group. 3. The relative expression of ACACA, APOA1 and CPT1A genes was significantly lower in the liver tissues of HW broilers than in the LW group. The mRNA levels of these three genes showed a significant negative correlation with abdominal fat deposition and live weight of broilers. However, relative expression of FASN, FOXO1, LIPG, PPARα and SIRT1 hepatic genes did not differ among broilers. 4. It was concluded that, of eight hepatic genes implicated in lipid metabolism, only the expression of three (ACACA, APOA1 and CPT1A) were significant for fat and leanness within the same strain of chicken. Since reducing body fat is a major goal in the broiler industry, these data can provide fresh insight into the molecular processes underlying the regulation of fat deposition in broilers. [ABSTRACT FROM AUTHOR]

Activated hepatic stellate cells promote hepatocellular carcinoma (HCC) progression. Hepatic stellate cells play a key role in retinoid metabolism, and activation of stellate cells increases retinoic acid (RA) in the liver. However, the role of RA in HCC proliferation remains unclear. We aimed to analyse the mechanism of RA in HCC proliferation. Thirty‐eight patients who had undergone hepatic resection for HCCs were recruited. Paired non‐tumour tissues, adjacent and distal to HCCs, were collected, and the RA levels in the tissues were analysed. The mechanisms of RA and HCC proliferation were assessed in liver cancer cell lines by protein and gene expression analyses. Early recurrence of HCC was significantly higher in patients with a higher RA concentration than in those with a lower RA concentration in tissues adjacent to HCCs (61.1% vs. 20%, p = .010). RA promoted HCC cell proliferation and activated the expression of Amphiregulin, a growth factor in hepatocarcinogenesis. The promoter of Amphiregulin contained the binding sites of the RA receptor, RXRα. Wnt signalling also activated the expression of Amphiregulin, and the RA and Wnt pathways acted synergistically to increase the expression of Amphiregulin. Furthermore, RXRα interacted with β‐catenin and then translocated to the nucleus to activate Amphiregulin. An increased RA concentration in the tissues adjacent to the tumour was associated with an early recurrence of HCC. RA activated the expression of Amphiregulin, and then promoted HCC proliferation, which might partly contribute to early recurrence of HCC after hepatic resection. [ABSTRACT FROM AUTHOR]

Sirtuin1 (SIRT1) is a crucial regulator of metabolism and it is implicated in the metabolic pathophysiology of several disorders inclusive of Type 2 diabetes and fatty liver disease (NAFLD). The aim of this study was to investigate the role of miR‐141 in hepatic steatosis via regulation of SIRT1/AMP‐activated protein kinase (AMPK) pathway in hepatocytes. Liver hepatocellular cells (HepG2) were treated with high concentration of glucose to be subsequently used for the assessment of miR‐141 and SIRT1 levels in a model of hepatic steatosis. On the other hand, cells were transfected with miR‐141 to investigate its effect on hepatocyte steatosis and viability as well as SIRT1 expression and activity along with AMPK phosphorylation. Targeting of SIRT1 by miR‐141 was evaluated by bioinformatics tools and confirmed by luciferase reporter assay. Following the intracellular accumulation of lipids in HepG2 cells, the level of miR‐141 was increased while SIRT1 mRNA and protein levels, as well as AMPK phosphorylation, was decreased. Transfection with miR‐141 mimic significantly downregulated SIRT1 expression and activity while miR‐141 inhibitor had the opposite effects. Additionally, modulation of miR‐141 levels significantly influenced AMPK phosphorylation status. The results of luciferase reporter assay verified SIRT1 to be directly targeted by miR‐141. miR‐141 could effectively suppress SIRT1 and lead to decreased AMPK phosphorylation in HepG2 cells. Thus, miR‐141/SIRT1/AMPK signaling pathway may be considered a potential target for the therapeutic management of NAFLD. [ABSTRACT FROM AUTHOR]

Much of the early work on Nuclear Hormone Receptors (NHRs) focused on their essential roles as mediators of sex steroid hormone signaling in reproductive development and function, and thyroid hormone-dependent formation of the central nervous system. However, as NHRs display tissue-specific distributions and activities, it is not surprising that they are involved and vital in numerous aspects of human development and essential for homeostasis of all organ systems. Much attention has recently been focused on the role of NHRs in energy balance, metabolism, and lipid homeostasis. Dysregulation of NHR function has been implicated in numerous pathologies including cancers, metabolic obesity and syndrome, Type II diabetes mellitus, cardiovascular disease, hyperlipidemia, male and female infertility and other reproductive disorders. This review will discuss the dysregulation of NHR function by environmental endocrine disrupting chemicals (EDCs), and the associated pathological consequences of exposure in numerous tissues and organ systems, as revealed by experimental, clinical, and epidemiological studies. [ABSTRACT FROM AUTHOR]

Early weaning (EW) is a risk factor for metabolic syndrome. Male rats that were precociously weaned present neonatal malnutrition and, in adulthood, developed overweight, accumulation of body fat, dyslipidemia, changes in glycemic homeostasis, hyperleptinemia, and increase of vitamin D. As metabolic profile of early-weaned females is not known, we investigated the endocrine-metabolic parameters in adolescence and adult female rats of 2 different EW models. Wistar lactating rats and pups from both sexes were separated into 3 groups: non-pharmacological EW (NPEW), dams were involved with a bandage interrupting suckling in the last 3 days of lactation; pharmacological EW (PEW), dams were bromocriptine-treated (0.5 mg/twice a day via intraperitoneal injection) for 3 days before weaning; and control, dams whose pups ate milk throughout lactation. At 21 days-old, NPEW and PEW females had lower body weight. At 180 days-old, NPEW and PEW females showed higher feed efficiency, weight gain, body fat percentage, and greater accumulation of gonadal and retroperitoneal fat depots associated with adipocyte hypertrophy. NPEW females also showed hyperphagia. Only NPEW females presented hyperleptinemia. Plasma thyroid hormones and vitamin D were unchanged among EW females. Regarding sex hormones, at 45 days-old, no change was found in EW females, while at 180 days-old, PEW females had hypoestrogenemia. EW increases the risk for obesity in female rats in adulthood, as already demonstrated for males, although through distinct mechanisms involving some hormones. [ABSTRACT FROM AUTHOR]

Polychlorinated biphenyls (PCBs) are highly persistent and ubiquitously distributed environmental pollutants. Based on their chemical structure, PCBs are classified into non- ortho -substituted and ortho -substituted congeners. Non- ortho -substituted PCBs are structurally similar to dioxin and their toxic effects and mode of action are well-established. In contrast, very little is known about the effects of ortho -substituted PCBs, particularly, during early development. The objective of this study is to investigate the effects of exposure to an environmentally prominent ortho -substituted PCB (2,2',4,4',5,5'-hexachlorobiphenyl; PCB153) on zebrafish embryos. We exposed zebrafish embryos to 3 different concentrations of PCB153 starting from 4 to 120 hours post-fertilization (hpf). We quantified gross morphological changes, behavioral phenotypes, gene expression changes, and circadian behavior in the larvae. There were no developmental defects during the exposure period, but starting at 7 dpf, we observed spinal deformity in the 10 μM PCB153 treated group. A total of 633, 2227, and 3378 differentially expressed genes were observed in 0.1 μM (0.036 μg/ml), 1 μM (0.36 μg/ml), and 10 μM (3.6 μg/ml) PCB153-treated embryos, respectively. Of these, 301 genes were common to all treatment groups. KEGG pathway analysis revealed enrichment of genes related to circadian rhythm, FoxO signaling, and insulin resistance pathways. Behavioral analysis revealed that PCB153 exposure significantly alters circadian behavior. Disruption of circadian rhythms has been associated with the development of metabolic and neurological diseases. Thus, understanding the mechanisms of action of environmental chemicals in disrupting metabolism and other physiological processes is essential. [ABSTRACT FROM AUTHOR]

All-trans retinoic acid (ATRA), an active form of vitamin A, exerts immunomodulatory functions. In this study, we examined the immune potentiating effect of ATRA on bacterial flagellin-induced NF-κB activation and proinflammatory cytokine production in human monocytic cell line THP-1. ATRA treatment significantly enhanced the flagellin-induced NF-κB/AP-1 activity in THP-1 via the RAR/RXR pathway. Similarly, ATRA enhanced the expression and production of TNF-α and IL-1β in THP-1 cells upon flagellin challenge. The cell surface expression of toll-like receptor 5 (TLR5), which is the receptor for bacterial flagellin, was significantly reduced by ATRA in a concentration- and time-dependent manner. To determine the mechanisms underlying the ATRA-enhanced immune response against bacterial flagellin despite the reduced cell surface expression of TLR5 in ATRA-treated THP-1, we examined the cell surface expression of CD14, which has been proposed to be a TLR co-receptor that enhances the response to microbial components. The cell surface expression of CD14 was significantly enhanced by ATRA treatment, especially in the presence of flagellin. Anti-CD14 antibody treatment prior to ATRA and flagellin treatments completely abolished ATRA-enhanced TNF-α and IL-1β production. Our results suggest that ATRA enhances flagellin-stimulated proinflammatory responses in human monocyte THP-1 cells by upregulating CD14 in a RAR/RXR-dependent manner. [ABSTRACT FROM AUTHOR]

Engineered nanomaterials (ENM) are being used in a wide range of consumer products and pharmaceuticals; hence, there is an increasing risk for human exposure and potential adverse outcomes. The immune system, vital in host defense and protection against environmental agents, is typically initiated and executed by innate effector immune cells including macrophages and neutrophils. Previous literature has reported the immune system as a major target of ENM toxicity; however, there is inconsistency regarding the immunotoxicity of ENM. This could be attributed to differences in ENM physicochemical properties, cellular models examined, biocorona formation, etc. Thus, the current study examined the toxicity and immunomodulatory effects of silver nanoparticles (AgNP), one of the most utilized ENM in consumer and medical products, in two key innate immune cell models, e.g. RAW 264.7 cells (macrophages) and differentiated MPRO 2.1 cells (promyelocytes/neutrophils). The results showed that despite a generation of reactive oxygen species, exposure to 20 nm citrate-coated AgNP was not associated with major oxidative damage, inflammatory responses, nor cytotoxicity. Nevertheless, and most importantly, pre-exposure to the AgNP for 24 h enhanced RAW 264.7 cell phagocytic ability as well as the release of inflammatory cytokine interleukin-6 in response to lipopolysaccharide (LPS). In MPRO 2.1 cells, AgNP pre-exposure also resulted in enhanced phagocytic ability; however, these cells manifest reduced cell degranulation (elastase release) and oxidative burst in response to phorbol myristate acetate (PMA). Taken together, these findings indicated to us that exposure to AgNP, despite not being directly (cyto)toxic to these cells, had the potential to alter immune cell responses. The findings underscore the import of assessing immune cell function post-exposure to ENM beyond the standard endpoints such as oxidative stress and cytotoxicity. In addition, these findings further illustrate the importance of understanding the underlying molecular mechanisms of ENM-cellular interactions, particularly in the immune system. [ABSTRACT FROM AUTHOR]