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One of the best antipsychotics for treating schizophrenia and bipolar disorders is olanzapine (OLA). However, its use is restricted owing to unfavorable adverse effects as liver damage, dyslipidemia, and weight gain. The primary objective of the present investigation was to examine the signaling mechanisms that underlie the metabolic disruption generated by OLA. Besides, the potential protective effect of sulforaphane (SFN) and β-sitosterol (βSS) against obesity and metabolic toxicity induced by OLA were inspected as well. A total of five groups of male Wistar rats were established, including the control, OLA, SFN+OLA, βSS+OLA, and the combination + OLA groups. Hepatic histopathology, biochemical analyses, ultimate body weights, liver function, oxidative stress, and pro-inflammatory cytokines were evaluated. In addition to the relative expression of FOXO, the signaling pathways for PI3K/AKT, JAK/STAT3, and MAPK were assessed as well. All biochemical and hepatic histopathological abnormalities caused by OLA were alleviated by SFN and/or βSS. A substantial decrease in systolic blood pressure (SBP), proinflammatory cytokines, serum lipid profile parameters, hepatic MDA, TBIL, AST, and ALT were reduced through SFN or/and βSS. To sum up, the detrimental effects of OLA are mediated by alterations in the Akt/FOXO3a/ATG12, Ras/SOS2/Raf-1/MEK/ERK1/2, and Smad3,4/TGF-β signaling pathways. The administration of SFN and/or βSS has the potential to mitigate the metabolic deficit, biochemical imbalances, hepatic histological abnormalities, and the overall unfavorable consequences induced by OLA by modulating the abovementioned signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Compound Zaoren Granules (CZG), an optimized herbal formulation based on the traditional Chinese medicine prescription Suanzaoren decoction, are designed specifically for insomnia treatment. However, the mechanisms underlying its efficacy in treating insomnia are not yet fully understood., Aim of the Study: The research investigated the mechanisms of CZG's improvement in insomnia by regulating cAMP/CREB signaling pathway and metabolic profiles., Methods: The main components of CZG were characterized by liquid chromatography-mass spectrometry (LC-MS). Subsequently, these validated components were applied to network pharmacological analysis to predict signaling pathways associated with insomnia. We evaluated the effect of CZG on BV-2 cells in vitro. We also evaluated the behavioral indexes of CUMS combined with PCPA induced insomnia in rats. HE staining and Nissl staining were used to observe the pathological damage of hippocampus. ELISA was used to detect the levels of various neurotransmitters, orexins, HPA axis, and inflammatory factors in insomnia rats. Then we detected the expression of cAMP/CREB signaling pathway through ELISA, WB, and IHC. Finally, the metabolomics was further analyzed by using UHPLC-QTOF-MS/MS to investigate the changes in the hippocampus of insomnia rats and the possible metabolic pathways were also speculated., Results: The results of CZG in vitro experiments showed that CZG has protective and anti-inflammatory effects on LPS induced BV-2 cells. A total of 161 chemical components were identified in CZG. After conducting network pharmacology analysis through these confirmed components, we select the cAMP/CREB signaling pathway for further investigate. The behavioral research results on insomnia rats showed that CZG significantly prolonged sleep time, mitigated brain tissue pathological damage, and exhibited liver protective properties. CZG treats insomnia by regulating the content of various neurotransmitters, reducing levels of orexin, HPA axis, and inflammatory factors. It can also treat insomnia by upregulating the expression of the cAMP/CREB signaling pathway. Hippocampus metabolomics analysis identified 69 differential metabolites associated with insomnia. The metabolic pathways related to these differential metabolites have also been predicted., Conclusion: These results indicate that CZG can significantly prolong sleep time. CZG is used to treat insomnia by regulating various neurotransmitters, HPA axis, inflammatory factors, cAMP/CREB signaling pathways, and metabolic disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: The course of HIV infection has changed radically with the introduction of antiretroviral therapy (ART), which has significantly reduced mortality and improved quality of life. However, antiretroviral drugs can cause adverse effects, including cardiometabolic complications and diseases, which are among the most common. Compared to the adult population, there are fewer studies in the pediatric population on treatment-related complications. The purpose of this review is to provide an update on the literature regarding cardiometabolic complications and diseases in children and adolescents with HIV., Areas Covered: A comprehensive literature review was conducted using PubMed and related bibliographies to provide an overview of the current knowledge of metabolic complications (dyslipidemia, insulin resistance, lipodystrophy, weight gain and liver complications) and diseases (prediabetes/diabetes and cardiovascular diseases) associated with ART in children and adolescents with HIV., Expert Opinion: Metabolic complications are conditions that need to be closely monitored in children and adolescents with HIV, as they increase the risk of early development of non-communicable diseases, such as cardiovascular disease. Key areas for improvement include ensuring access to treatment, reducing side effects and improving diagnostic capabilities. Overcoming existing challenges will require collaborative efforts across disciplines, advances in technology, and targeted interventions to address socioeconomic disparities.

Butylparaben, a common preservative, is widely used in food, pharmaceuticals and personal care products. Epidemiological studies have revealed the close relationship between butylparaben and diabetes; however the mechanisms of action remain unclear. In this study, we administered butylparaben orally to mice and observed that exposure to butylparaben induced glucose intolerance and hyperlipidemia. RNA sequencing results demonstrated that the enrichment of differentially expressed genes was associated with lipid metabolism, bile acid metabolism, and inflammatory response. Western blot results further validated that butylparaben promoted hepatic lipogenesis, inflammation, gluconeogenesis, and insulin resistance through the inhibition of the farnesoid X receptor (FXR) pathway. The FXR agonists alleviated the butylparaben-induced metabolic disorders. Moreover, 16 S rRNA sequencing showed that butylparaben reduced the abundance of Bacteroidetes, S24-7, Lactobacillus, and Streptococcus, and elevated the Firmicutes/Bacteroidetes ratio. The gut microbiota dysbiosis caused by butylparaben led to decreased bile acids (BAs) production and increased inflammatory response, which further induced hepatic glycolipid metabolic disorders. Our results also demonstrated that probiotics attenuated butylparaben-induced disturbances of the gut microbiota and hepatic metabolism. Taken collectively, the findings reveal that butylparaben induced gut microbiota dysbiosis and decreased BAs production, which further inhibited FXR signaling, ultimately contributing to glycolipid metabolic disorders in the liver., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nitrite is the most common nitrogen-containing compound in nature. It is widely used in food processing like in pickled foods so it has caused widespread public concern about the safety of nitrites due to the formation of nitrosamine, a carcinogen, during the food process. Recent research has shown nitrite has therapeutic potential for cardiovascular disease due to its similar function to NO, yet the safety of oral nitrite and the physiological and biochemical responses induced after oral administration still require further validation. In addition, the relationship between nitrite and glycolipid metabolism still needs to be elucidated. As aquatic animals, fish are more susceptible to nitrite compared to mammals. Herein, we utilized tilapia (Oreochromis niloticus) as an animal model to explore the relationship between nitrite and glycolipid metabolism in organisms. In the present study, we found that nitrite elicited a hypoxic metabolic response in tilapia and deepened this metabolic response under the co-stress of the pathogenic bacterium S.ag (Streptococcus agalactiae). In addition, nitrite-induced elevation of MetHb (Methemoglobin) and its by-product heme was involved in the metabolic response to nitrite-induced hypoxia through the HO/CO pathway, which has not yet been mentioned in previous studies. Moreover, heme affected hepatic metabolic responses through the ROS-ER stress-VLDL pathway. These findings, for the first time, reveal that nitrite exposure leads to glycolipid metabolic disorder via the heme-HO pathway in teleost. It not only provides new insights into the results of nitrite on the body but also is beneficial for developing healthy strategies for fish farming., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Per- and polyfluoroalkyl substances (PFAS) pose potential risks to human health. In real-world settings, humans are exposed to various PFAS through numerous pathways., Objectives: This study evaluated the associations between co-exposure to PFAS and obesity and its comorbidities, along with the mediating roles of inflammation and oxidative stress., Methods: We analyzed 11,090 participants from National Health and Nutrition Examination Survey (NHANES), 2003-2018. Linear regression, logistic regression, and generalized additive models were used to assess the individual effects of PFAS exposure on obesity and its comorbidities. The environmental risk score (ERS) was calculated using the adaptive elastic-net model to assess the co-exposure effects. Linear and logistic regression models explored the associations between ERS and obesity and its comorbidities. Mediation analyses explored the roles of inflammatory (neutrophils, lymphocytes, and alkaline phosphatase) and oxidative stress (gamma-glutamyl transferase, total bilirubin, and uric acid) markers in the associations between ERS and obesity and its comorbidities., Results: For each unit increase in ERS, the odds of obesity and type 2 diabetes mellitus (T2DM) increased 3.60-fold (95 % CI: 2.03, 6.38) and 1.91-fold (95 % CI: 1.28, 2.86), respectively. For each unit increase in ERS, BMI increased by 2.36 (95 % CI: 1.24, 3.48) kg/m 2 , waist circumference increased by 6.47 (95 % CI: 3.56, 9.37) cm, and waist-to-height ratio increased by 0.04 (95 % CI: 0.02, 0.06). Lymphocytes, alkaline phosphatase, and total bilirubin were significantly associated with both ERS and obesity, with mediation proportions of 4.17 %, 3.62 %, and 7.37 %, respectively. Lymphocytes, alkaline phosphatase, total bilirubin, and uric acid were significantly associated with both ERS and T2DM, with the mediation proportions of 8.90 %, 8.74 %, 29.73 %, and 38.19 %, respectively., Conclusions: Co-exposure to PFAS was associated with obesity and T2DM, and these associations may be mediated by inflammation and oxidative stress. Further mechanistic and prospective studies are required to verify these associations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Accumulating animal studies have demonstrated associations between ambient air pollution (AP) and metabolic dysfunction-associated fatty liver disease (MAFLD), but relevant epidemiological evidence is limited. We evaluated the association of long-term exposure to AP with the risk of incident MAFLD in Northwest China. The average AP concentration between baseline and follow-up was used to assess individual exposure levels. Cox proportional hazard models and restricted cubic spline functions (RCS) were used to estimate the association of PM 2.5 and its constituents with the risk of MAFLD and the dose-response relationship. Quantile g-computation was used to assess the joint effects of mixed exposure to air pollutants on MAFLD and the weights of the various pollutants. We observed 1516 cases of new-onset MAFLD, with an incidence of 10.89%. Increased exposure to pollutants was significantly associated with increased odds of MAFLD, with hazard ratios (HRs) of 2.93 (95% CI: 1.22, 7.00), 2.86 (1.44, 5.66), 7.55 (3.39, 16.84), 4.83 (1.89, 12.38), 3.35 (1.35, 8.34), 1.89 (1.02, 1.62) for each interquartile range increase in PM 2.5 , SO 4 2- , NO 3 - , NH 4 + , OM, and BC, respectively. Stratified analyses suggested that females, frequent exercisers and never-drinkers were more susceptible to MAFLD associated with ambient PM 2.5 and its constituents. Mixed exposure to SO 4 2- , NO 3 - , NH 4 + , OM and BC was associated with an increased risk of MAFLD, and the weight of BC had the strongest effect on MAFLD. Exposure to ambient PM 2.5 and its constituents increased the risk of MAFLD., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Cadmium (Cd) is a common environmental pollutant associated with an increased incidence of renal metabolic diseases. Luteolin (Lut), a natural flavonoid, is widely used for its multifaceted therapeutic properties in inflammatory diseases. However, whether Lut protects against Cd-induced nephrotoxicity is still equivocal. The present study investigated the effects of Lut supplementation on renal oxidative stress, inflammation and metabolism and their related mechanisms. Therefore, 40 chickens were treated with Cd and/or Lut with automatic water and free food intake for 1 mo and then the kidney tissues were collected to explore this issue. In this study, Cd exposure induced renal glycolipid metabolism disorders and resultant kidney damage by periodic acid Schiff (PAS) staining, Oil Red O staining, total cholesterol (TC), triglyceride (TG), and glucose (Glu) levels in kidney, which were significantly ameliorated by Lut. Moreover, Lut also normalized the expression levels of factors related to Cd-disturbed glycolipid metabolism, improving metabolic homeostasis, and contributing to alleviating kidney damage. Furthermore, Lut demonstrated therapeutic potential against Cd-induced renal oxidative stress and inflammation by enhancing antioxidant capacity and inhibiting cytokine production in the kidney tissues. Mechanistically, Lut activated the AMPK/SIRT1/FOXO1 signaling pathway, attenuating oxidative stress and inflammatory responses, ameliorating the metabolic disturbance. In conclusion, these observations demonstrate that Lut treatment activates AMPK/SIRT1/FOXO1 signaling pathway, decreases oxidative stress and inflammation response, which may contribute to prevent Cd-induced metabolism disorder and consequent kidney damage., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Inhibitors of mTOR (mTORi) are frequently used as anticancer treatment. They were responsible for metabolic side-effects in phase 3 studies, which provided only an incomplete picture of these metabolic complications. The aim of our study was therefore to evaluate, in a real-life setting, outcomes for patients with dyslipidemia or diabetes under mTORi, and the incidence and management of metabolic abnormalities occurring under mTORi in the absence of known metabolic history., Methods: This single-center retrospective study included all 177 patients receiving everolimus in the Cancer Center of Dijon, France, between May 2015 and November 2018., Results: Diabetes was diagnosed in 15 patients (9%), with an estimated mean time to onset of 160±173 days. Antidiabetic treatment was introduced in 41% of these patients. After mTORi discontinuation, diabetes persisted in 60% of patients in whom it had been diagnosed. Dyslipidemia was diagnosed in 22 patients (14%): 55% with hypercholesterolemia and 45% with hypertriglyceridemia. 18% were placed on lipid-lowering therapy. While all patients were screened for hyperglycemia and monitored for known diabetes, only 42% of patients without dyslipidemia were screened for lipids, and only 8% of patients with known dyslipidemia were monitored for lipids., Conclusion: Our study is one of the few to look at metabolic complications secondary to mTORi in a real-life situation. The incidence of diabetes was high, but the use of antidiabetic treatment was variable. Normalization of glucose homeostasis after mTORi discontinuation is possible, particularly in patients who have not been placed on antidiabetic therapy. Screening for dyslipidemia was clearly inadequate in our study, making the data on this point more difficult to interpret. It appears that adherence to guidelines needs to be improved to optimize the management of patients treated with mTORi., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Objective: We sought to determine the association of hormonal contraception (HC) and cardiometabolic outcomes among women with human immunodeficiency virus (HIV). Methods: We included women with HIV aged 18-45 years in clinical care in the Southeastern United States between 1998 and 2018. Oral and injectable HC use was captured from medication records. Our outcomes included incident cardiovascular/thrombotic disease (CVD) (atherosclerosis, hypertension, cerebrovascular disease, thrombosis, and heart failure) and incident metabolic disorders (diabetes, dyslipidemia, obesity, and non-alcoholic steatohepatitis). We excluded women with prevalent conditions. We used multivariable marginal structural models to examine time-varying current and cumulative HC use and cardiometabolic outcomes in separate analyses, adjusting for age, race, smoking, time-varying comorbidities, CD4 cell count, HIV RNA, and antiretroviral use. Women with HC exposure were compared with women without HC exposure. Results: Among the 710 women included, 201 women (28%) used HC. CVD analyses included 603 women without prevalent CVD and 93 incident events; metabolic analyses included 365 women without prevalent metabolic disease and 150 incident events. Current and cumulative oral HC use was associated with increased odds of CVD, though this was not statistically significant (adjusted odds ratio [aOR] = 2.08, [95% confidence interval (CI): 0.80-5.43] and aOR = 1.24 [95% CI: 0.96-1.60] per year of use, respectively). Oral HC was not associated with risk of incident metabolic disorders. Depot medroxyprogesterone acetate (DMPA) was not associated with risk of incident CVD. Current and cumulative DMPA use was significantly associated with decreased odds of incident metabolic disorders (aOR = 0.48 [95% CI: 0.23, 1.00] and aOR = 0.65 [95% CI: 0.42-1.00] per year of use, respectively). Conclusion: Our results suggest that cardiovascular risk should be considered when selecting contraception for women with HIV.

Dietary emulsifiers are linked to various diseases. The recent discovery of the role of gut microbiota-host interactions on health and disease warrants the safety reassessment of dietary emulsifiers through the lens of gut microbiota. Lecithin, sucrose fatty acid esters, carboxymethylcellulose (CMC), and mono- and diglycerides (MDG) emulsifiers are common dietary emulsifiers with high exposure levels in the population. This study demonstrates that sucrose fatty acid esters and carboxymethylcellulose induce hyperglycemia and hyperinsulinemia in a mouse model. Lecithin, sucrose fatty acid esters, and CMC disrupt glucose homeostasis in the in vitro insulin-resistance model. MDG impairs circulating lipid and glucose metabolism. All emulsifiers change the intestinal microbiota diversity and induce gut microbiota dysbiosis. Lecithin, sucrose fatty acid esters, and CMC do not impact mucus-bacterial interactions, whereas MDG tends to cause bacterial encroachment into the inner mucus layer and enhance inflammation potential by raising circulating lipopolysaccharide. Our findings demonstrate the safety concerns associated with using dietary emulsifiers, suggesting that they could lead to metabolic syndromes., (© 2024. The Author(s).)

Birds are sensitive to heavy metal pollution, and lead (Pb) contamination can negatively affect their liver and gut. Therefore, we used budgerigars to examine liver and gut toxicosis caused by Pb exposure in bird, and the possible toxic mechanisms. The findings showed Pb exposure increased liver weight and decreased body weight. Moreover, histopathological and immunofluorescence assay results demonstrated obvious liver damage and cell apoptosis increased in Pb- treated budgerigars. Quantitative polymerase chain reaction (qPCR) results also showed Pb caused an increase in apoptosis by inhibiting the PPAR-γ/PI3K/Akt pathway. The gut microbe analyses indicated Firmicutes, Proteobacteria, and Bacteroidetes were dominant microbial phyla, and Network analysis results shown Arthrobacter, Bradyrhizobium and Alloprevotella as the hubs of Modules I, II, and III, respectively. Phenylpropanoids and polyketides, Organoheterocyclic compounds, Organic oxygen compounds, and Organic nitrogen compounds were dominant metabolite superclasses. Tauroursodeoxycholic acid, taurochenodeoxycholic acid (sodium salt), and 2-[2-(5-bromo-2-pyridyl)diaz-1-enyl]-5-(diethylamino)phenol were significantly enriched in the Pb-treated group. It showed that 41 Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologues and 183 pathways differed between the Pb-treated and control budgerigars using microbial and metabolomic data. Moreover, orthogonal partial least-squares discrimination analysis (OPLS-DA) based on microbial and metabolite indicated distinct clusters in the Pb-treated and control groups. Additionally, the correlation analysis results indicated that a positive correlation for the Pb-treated and control groups between gut microbiota and metabolomic data, respectively. Furthermore, the microenvironment of the gut and liver were found to affect each other, and this study demonstrated heavy metal especially Pb may pose serious health risks to birds through the "gut-liver axis" too., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This review discusses long-term complications from immunosuppressants after liver transplantation and the management of these complications. Common complications of calcineurin inhibitors include nephrotoxicity and metabolic diseases. Nephrotoxicity can be managed by targeting a lower drug level and/or adding an immunosuppressant of a different class. Metabolic disorders can be managed by treating the underlying condition and targeting a lower drug level. Gastrointestinal adverse effects and myelosuppression are common complications of antimetabolites that are initially managed with dose reduction or discontinuation if adverse events persist. Mammalian targets of rapamycin inhibitors are associated with myelosuppression, proteinuria, impaired wound healing, and stomatitis, which may require dose reduction or discontinuation. Induction agents and agents used for steroid-refractory rejection or antibody-mediated rejection are reviewed. Other rare complications of immunosuppressants are discussed as well., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Metabolic dysfunction-associated steatotic liver disease (MASLD), described as the most prominent cause of chronic liver disease worldwide, has emerged as a significant public health issue, posing a considerable challenge for most countries. Endocrine-disrupting chemicals (EDCs), commonly found in daily use items and foods, are able to interfere with nuclear receptors (NRs) and disturb hormonal signaling and mitochondrial function, leading, among other metabolic disorders, to MASLD. EDCs have also been proposed to cause transgenerationally inherited alterations leading to increased disease susceptibility. In this review, we are focusing on the most prominent linking pathways between EDCs and MASLD, their role in the induction of epigenetic transgenerational inheritance of the disease as well as up-to-date practices aimed at reducing their impact.

Introduction: Late-life major depression (MD) is a frequent and high-cost psychiatric disorder. Our purpose was to detect clinical and biological factors possibly associated with this condition to better prevent and treat it., Methods: We recruited 343 patients, consecutively admitted for a Major Depressive Episode to the inpatient clinic of Policlinico of Milan and ASST Monza, Italy. A large set of clinical and biochemical variables was collected from clinical charts. Univariate analyses were performed both dividing the sample into two groups (age < or ≥65) and considering age as a continuous quantitative variable. Regression analyses were then performed considering as independent variables only those statistically significant at univariate analyses., Results: Patients aged ≥ 65 resulted in having longer duration of illness, shorter duration of last antidepressant therapy, higher number of antidepressants assumed in the past, higher frequency of treatment-resistant depression, higher frequency of overweight/obesity and diabetes. As for biochemical parameters, patients ≥ 65 showed lower total plasmatic proteins and albumin, higher uric acid and creatinine., Conclusions: These preliminary results suggest less effectiveness of antidepressants, more susceptibility to metabolic disorders and poor nutritional status in patients with late-life depression; such aspects may consequently be taken into consideration for a proper therapeutic approach. KEY POINTSDepression in late life seems to be associated with poorer response to antidepressants;Clinicians should prefer compounds with minimal pharmacokinetic interactions and less risk of side effects including metabolic ones;The poor nutritional status and the higher risk of metabolic disorders in older patients points out the importance of proper diet and healthy lifestyle in this group of subjects;Further studies are needed to confirm the results of this research.

Excess glucocorticoid (GC) signaling in adipose tissue is a key driver of insulin resistance and hepatic steatosis, but underlying mechanisms have not been fully elucidated. Signal transducer and activator of transcription 5 (STAT5) signaling in adipocytes has also been implicated in the progression of similar metabolic disturbances. Although STAT5 has been shown to interact with the glucocorticoid receptor (GR) in many cell types including adipocytes, the relevance of the STAT5/GR complex has not been investigated in adipocytes. Adult male and female adipocyte-specific STAT5 knockout (STAT5 AKO ) and floxed mice were given corticosterone (CORT) or vehicle in their drinking water for 1 wk and examined for differences in their metabolic responses to GC excess. CORT-induced lipolysis, insulin resistance, and changes in body composition were comparable between genotypes and in both sexes. Adipocyte STAT5 is not necessary for GC-mediated progression of metabolic disease. NEW & NOTEWORTHY Both STAT5 and glucocorticoid receptor contribute to metabolic processes and type 2 diabetes, in large part, due to their functions in adipocytes. These two transcription factors can form a complex and function together. Our novel studies determined the role of adipocyte STAT5 in glucocorticoid-induced diabetes. We observed that STAT5 in adipocytes is not needed for glucocorticoid-induced diabetes.

T-2 toxin, an omnipresent environmental contaminant, poses a serious risk to the health of humans and animals due to its pronounced cardiotoxicity. This study aimed to elucidate the molecular mechanism of cardiac tissue damage by T-2 toxin. Twenty-four male Sprague-Dawley rats were orally administered T-2 toxin through gavage for 12 weeks at the dose of 0, 10, and 100 nanograms per gram body weight per day (ng/(g·day)), respectively. Morphological, pathological, and ultrastructural alterations in cardiac tissue were meticulously examined. Non-targeted metabolomics analysis was employed to analyze alterations in cardiac metabolites. The expression of the Sirt3/FoxO3α/MnSOD signaling pathway and the level of oxidative stress markers were detected. The results showed that exposure to T-2 toxin elicited myocardial tissue disorders, interstitial hemorrhage, capillary dilation, and fibrotic damage. Mitochondria were markedly impaired, including swelling, fusion, matrix degradation, and membrane damage. Metabonomics analysis unveiled that T-2 toxin could cause alterations in cardiac metabolic profiles as well as in the Sirt3/FoxO3α/MnSOD signaling pathway. T-2 toxin could inhibit the expressions of the signaling pathway and elevate the level of oxidative stress. In conclusion, the T-2 toxin probably induces cardiac fibrotic impairment by affecting amino acid and choline metabolism as well as up-regulating oxidative stress mediated by the Sirt3/FoxO3α/MnSOD signaling pathway. This study is expected to provide targets for preventing and treating T-2 toxin-induced cardiac fibrotic injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this study., (Copyright © 2024. Published by Elsevier B.V.)

The use of pesticides in the past century has lot helped humankind in improving crops' field and general hygiene level. Nevertheless, there has been countless evidences on the toxic effects of pesticides on the living systems. The link of exposure to pesticides with different human chronic diseases in the context of carcinogenicity, neurotoxicity, developmental toxicity, etc., have been evaluated in various types of studies. There are also some evidences on the link of exposure to pesticides with higher incidence of metabolic diseases associated with insulin resistance like diabetes, obesity, metabolic syndrome, hypertension, polycystic ovary syndrome and chronic kidney diseases. Physiologically, weakening intracellular insulin signaling is considered as a compensatory mechanism for cells to cope with cellular stresses like xenobiotic effects, oxidative stress and inflammatory responses, but it can pathologically lead to a defective cycle with lowered sensitivity of the cells to insulin which happens in metabolic disorders. In this work, the data related to metabolic toxicity of pesticides categorized in the mentioned metabolic diseases with a focus on the effects of pesticides on insulin signaling pathway and the mechanisms of development of insulin resistance will be systematically reviewed and presented., Competing Interests: Declaration of Competing Interest The authors report there are no competing interests to declare., (Copyright © 2023. Published by Elsevier Inc.)

Background: Studies which analyse the joint effect of acoustic or chemical air pollution variables and different meteorological variables on neuroendocrine disease are practically nonexistent. This study therefore sought to analyse the impact of air pollutants and environmental meteorological variables on daily unscheduled admissions due to endocrine and metabolic diseases in the Madrid Region from January 01, 2013 to December 31, 2018., Material and Methods: We conducted a longitudinal, retrospective, ecological study of daily time series analysed by Poisson regression, with emergency neuroendocrine-disease admissions in the Madrid Region as the dependent variable. The independent variables were: mean daily concentrations of PM 10 , PM 2.5 , NO 2 and O 3 ; acoustic pollution; maximum and minimum daily temperatures; hours of sunlight; relative humidity; wind speed; and air pressure above sea level. Estimators of the statistically significant variables were used to calculate the relative risks (RRs)., Results: A statistically significant association was found between the increase in temperatures in heat waves, RR: 1.123 95% CI (1.001-1.018), and the number of emergency admissions, making it the main risk factor. An association between a decrease in sunlight and an increase in hospital admissions, RR: 1.005 95% CI (1.002 1.008), was likewise observed. Similarly, ozone, in the form of mean daily concentrations in excess of 44 μg/m 3 , had an impact on admissions due to neuroendocrine disease, RR: 1.010 95% CI (1.007-1.035). The breakdown by sex showed that in the case of women, NO 2 was also a risk factor, RR: 1.021 95% CI (1.007-1.035)., Conclusion: The results obtained in this study serve to identify risk factors for this disease, such as extreme temperatures in heat waves, O 3 or NO 2 . The robust association found between the decrease in sunlight and increase in hospital admissions due to neuroendocrine disease serves to spotlight an environmental factor which has received scant attention in public health until now., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Androgen deprivation therapy (ADT), a backbone treatment for advanced prostate cancer (PC), is known to have a variety of metabolic side effects. We conducted an updated meta-analysis to quantify the metabolic risks of ADT., Materials and Methods: We searched PubMed, Web of Science, and Scopus in May of 2022 for studies investigating the risk of metabolic syndrome (MetS), diabetes, and hypertension from ADT in PC patients using keywords. Only full-length studies with a control group of PC patients not on ADT were included. All results compatible with each outcome domain in each included study were sought. For included studies, relative risk (RR) was pooled using a random effects model and a trim-fill approach was used to adjust for publication bias., Results: 1,846 records were screened, of which 19 were found suitable for data extraction. Five studies, including 891 patients, were evaluated for MetS as an outcome, with the random effects model showing a pooled RR of 1.60 ([95% Confidence Interval (CI), 1.06-2.42]; P=0.03) for patients on ADT while twelve studies, including 336,330 patients, examined diabetes as an outcome, and the random effects model showed a RR of 1.43 ([95% CI, 1.28-1.59]; P< 0.01). After adjustment for publication bias, ADT was associated with a 25% increased risk for diabetes but was not associated with MetS. 4 studies, including 7,051 patients, examined hypertension as an outcome, and the random effects model showed a RR of 1.30 ([95% CI, 1.08-1.55]; P=0.18) in ADT patients., Conclusion: In patients with PC, ADT was not associated with MetS and the association with diabetes was not as strong as previously reported. Our novel meta-analysis of hypertension showed that ADT increased the risk of hypertension by 30%. These results should be understood in the context of collaborating care between a patient's oncologist and primary care provider to optimize care., Competing Interests: Disclosure Neeraj Agarwal: consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Exelixis, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Gilead Sciences. Research Funding: Bayer (Inst), Bristol Myers Squibb (Inst), Takeda (Inst), Pfizer (Inst), Exelixis (Inst), Amgen (Inst), AstraZeneca (Inst), Calithera Biosciences (Inst), Celldex (Inst), Eisai (Inst), Genentech (Inst), Immunomedics (Inst), Janssen (Inst), Merck (Inst), Lilly (Inst), Nektar (Inst), ORIC Pharmaceuticals (Inst), CRISPR therapeutics (Inst), Arvinas (Inst)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Psychotropic drugs may be associated with metabolic disorders, often but not only triggered by weight gain. Disorders include dysglycemia and diabetes, atherogenic dyslipidemia and metabolic syndrome. Overall, metabolic risk is lower with antidepressants than with antipsychotics. Among antidepressants, metabolic disorders may occur with both selective serotonin reuptake inhibitors and tricyclics, but with some between-molecule differences in each pharmacological family. Among antipsychotics, the risk is higher with second-generation (atypical) than first-generation agents. Higher risk was reported with clozapine and olanzapine, and lower risk with risperidone and aripiprazole. Weight gain is associated with increased insulin resistance, but impaired insulin secretion was also reported with clozapine and olanzapine. Metabolic disorders may be attenuated by the medication withdrawal and replacement by another safer drug. Besides deleterious effects of medications, the psychiatric population is also exposed to bad lifestyle habits (unhealthy diet and sedentary life), which also increase the risk of metabolic disorders. Management should first reinforce lifestyle measures. If this proves insufficient, specific drugs may be considered to tackle the metabolic disorder on a strategy similar to that applied in the general population., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Exposure to ubiquitous plastic-associated endocrine disrupting chemicals (EDCs) is associated with the increased risk of many chronic diseases. For example, phthalate exposure is associated with cardiometabolic mortality in humans, with societal costs ∼ $39 billion/year or more. We recently demonstrated that several widely used plastic-associated EDCs increase cardiometabolic disease in appropriate mouse models. In addition to affecting adult health, parental exposure to EDCs has also been shown to cause metabolic disorders, including obesity and diabetes, in the offspring. While most studies have focused on the impact of maternal EDC exposure on the offspring's health, little is known about the effects of paternal EDC exposure. In the current study, we investigated the adverse impact of paternal exposure to a ubiquitous but understudied phthalate, dicyclohexyl phthalate (DCHP) on the metabolic health of F1 and F2 offspring in mice. Paternal DCHP exposure led to exacerbated insulin resistance and impaired insulin signaling in F1 offspring without affecting diet-induced obesity. We previously showed that sperm small non-coding RNAs including tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs) contribute to the intergenerational transmission of paternally acquired metabolic disorders. Using a novel PANDORA-seq, we revealed that DCHP exposure can lead to sperm tsRNA/rsRNA landscape changes that were undetected by traditional RNA-seq, which may contribute to DCHP-elicited adverse effects. Lastly, we found that paternal DCHP can also cause sex-specific transgenerational adverse effects in F2 offspring and elicited glucose intolerance in female F2 descendants. Our results suggest that exposure to endocrine disrupting phthalates may have intergenerational and transgenerational adverse effects on the metabolic health of their offspring. These findings increase our understanding of the etiology of chronic human diseases originating from chemical-elicited intergenerational and transgenerational effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Bisphenol A (BPA) is an endocrine-disrupting chemical widely present in many consumer goods that poses a significant threat to our health upon exposure. Humans are exposed to BPA, which directly or indirectly causes endocrine dysfunctions that lead to metabolic disorders like obesity, fatty liver diseases, insulin resistance, polycystic ovarian syndrome, and other endocrine- related imbalances. The duration, quantity, and period of exposure to BPA, especially during the critical stage of development, determine its impact on reproductive and non-reproductive health. Because of its endocrine-disrupting effects, the European Chemical Agency has added BPA to the candidate list of chemicals of very serious concern. Due to its estrogenic properties and structural similarities with thyroid hormones, BPA disrupts the endocrine system at different levels. It interacts with estrogen receptors at the molecular level and acts as an antagonist or agonist via an estrogen receptor-dependent signaling pathway. In particular, BPA binds to G-protein coupled receptors and estrogen receptors, activating signaling pathways that influence cellular apoptosis, proliferation, differentiation, and inflammation. BPA acts as an obesogen that promotes adipogenesis and correlates with increased lipid accumulation and elevated expression of adipogenic markers. As a metabolic and endocrine disruptor, BPA impairs cellular homeostasis by increasing oxidative mediators and decreasing antioxidant enzymes, resulting in mitochondrial dysfunction. Due to its endocrine-disrupting properties, BPA exposure induces endocrine dysfunctions, causing metabolic syndrome. This review article gives recent development and novel insights into the cellular and molecular mechanisms of BPA-induced endocrine dysfunctions and their associated metabolic disorders., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Ambient air pollution is one of the most serious public health problems over the last decade. It causes about 4.2 million deaths worldwide each year, and fine particulate matter (PM2 .5 ) is one of the major components of air pollution. Many chronic non-communicable diseases may originate from the early-life environment that alters the development of offspring. Pregnancy and lactation are plastic "window periods" for offspring metabolism, during which PM 2.5 exposure is associated with long-term metabolic dysfunction in offspring. In this review, we summarized the scientific evidence from both epidemiological and toxicological studies, which suggest that perinatal exposure to PM 2.5 causes obesity and metabolic diseases in progeny, including hypertension, cardiometabolic dysfunction, diabetes, and non-alcoholic fatty liver disease (NAFLD). Therefore, prevention strategies are needed to inform government policies and clinical counseling to reduce maternal exposure and its associated health hazards, and ultimately improve the quality of the newborn population., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Background: Explanted livers from patients with inherited metabolic liver diseases possess the potential to be a cell source of good-quality hepatocytes for hepatocyte transplantation (HT). This study evaluated the therapeutic effects of domino HT using hepatocytes isolated from explanted human livers for acute liver failure (ALF)., Methods: Isolated hepatocytes were evaluated for viability and function and then transplanted into D-galactosamine/lipopolysaccharide-induced ALF mice via splenic injection. The survival rate was analyzed by the Kaplan-Meier method and log-rank test. Liver function was evaluated by serum biochemical parameters, and inflammatory cytokine levels were measured by ELISA. The pathological changes in the liver tissues were assessed by hematoxylin-eosin staining. Hepatocyte apoptosis was investigated by TUNEL, and hepatocyte apoptosis-related proteins were detected by western blot. The localization of human hepatocytes in the injured mouse livers was detected by immunohistochemical analyses., Results: Hepatocytes were successfully isolated from explanted livers of 10 pediatric patients with various liver-based metabolic disorders, with an average viability of 85.3% ± 13.0% and average yield of 9.2 × 10 6  ± 3.4 × 10 6 cells/g. Isolated hepatocytes had an excellent ability to secret albumin, produce urea, uptake indocyanine green, storage glycogen, and express alpha 1 antitrypsin, albumin, cytokeratin 18, and CYP3A4. Domino HT significantly reduced mortality, decreased serum levels of alanine aminotransferase and aspartate aminotransferase, and improved the pathological damage. Moreover, transplanted hepatocytes inhibited interleukin-6 and tumor necrosis factor-α levels. Domino HT also ameliorates hepatocyte apoptosis, as evidenced by decreased TUNEL positive cells. Positive staining for human albumin suggested the localization of human hepatocytes in ALF mice livers., Conclusion: Explanted livers from patients with inheritable metabolic disorders can serve as a viable cell source for cell-based therapies. Domino HT using hepatocytes with certain metabolic defects has the potential to be a novel therapeutic strategy for ALF., (© 2022. The Author(s).)

Metabolic syndrome (MS) is a multifactorial disease entity and is not fully understood. Growing evidence suggests that early exposure to bisphenol A (BPA) is a significant risk factor for the development of metabolic diseases. BPA is a monomer used in the manufacturing of polycarbonate plastics, thermal receipt paper, and epoxy resins. Owing to its widespread use, BPA has been detected in human fluids and tissues, including blood, placental breast milk, and follicular fluid. In the present review, we aimed to review the impact of prenatal exposure to different doses of BPA on metabolic parameters as determined by in vivo and epidemiological studies. The PubMed, Scopus, and Web of Science electronic databases were searched to identify articles published during a period of 15 years from 2006 to 2021, and 29 studies met the criteria. Most studies demonstrated that prenatal exposure to low BPA concentrations correlated with alterations in metabolic parameters in childhood and an increased risk of metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM), in adulthood. Therefore, prenatal exposure to low doses of BPA may be associated with an increased risk of obesity and T2DM in a sex-specific manner.

Purpose of Review: There is substantive and accumulating evidence that endemic exposure to plastic-associated chemicals (PACs) contribute to the pathophysiology of metabolic conditions, like obesity, diabetes, and heart disease. The consequences of this endemic exposure in inducing a pro-inflammatory state in adipose tissues as a critical link between exposure and disease is reviewed., Recent Findings: In general, PACs are classified as nonpersistent in vivo because of their rapid metabolism to easily excreted forms. The parental chemicals, however, are typically lipophilic, with the potential to bioaccumulate. Recent data from selected association studies suggest exposure to PACs drive predisease states like obesity and inflammation of the adipose tissues. A range of experimental studies are discussed with a focus on biological mechanisms that are susceptible to the influence of PACs and which may promote metabolic disease, the detection of PACs within susceptible tissues and biological effects that are detectable at doses that correspond to real-life exposures to these chemicals., Summary: If we hypothesize the toxic pressure from chronic exposure to PACs will progress disease processes, then individuals with comprehensively characterized indicators of premetabolic disease could undergo trials of quantifiable interventions to reduce exposure to PACs to test if the trajectory of disease-associated analytes, is altered., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Diabetes mellitus is a common endocrine metabolic disorder, and previous studies have shown that diabetics are more sensitive to the toxic environmental contaminants. Acrylamide (ACR) is both an industrially multipurpose compound and a common endogenous food contaminant to which people are frequently exposed and at high risk. However, the toxicity of ACR on diabetes hasn't attracted much attention. In this study, both healthy mice and diabetic mice received ACR administration orally to investigate the ACR-induced metabolic toxicity, mechanism and susceptibility to ACR toxicity in adult diabetic male mice. The results showed that ACR significantly increased FBG level and decreased bodyweight, serum lipid and liver lipid biomarkers (TC, TG, LDL-C, HDL-C) levels as well as expression of lipid and glucose metabolism-related genes in diabetic mice, indicating that ACR can exacerbate metabolic disorders of glucose and lipid in diabetic male mice. Moreover, ACR exposure significantly increased levels of MDA and COX-2), decreased GSH level and antioxidant enzyme activity (SOD, GSH-PX and CAT) by downregulating expression of Nrf2 and Keap1 in diabetic mice. Factorial analysis showed ACR had a more significant disturbance in diabetic mice compared with healthy mice. Our results indicated that ACR exposure can cause oxidative stress and inflammatory damage, which can exacerbate abnormal glucose and lipid metabolism. This work helps to elucidate the effects and underlying mechanisms of ACR-induced metabolic toxicity in adults with diabetes., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Busulfan is a commonly used alkylating agent in the conditioning regimens of hematopoietic cell transplantation (HCT). Population pharmacokinetic (popPK) models enable description of busulfan PK and optimization of exposure, which leads to improvement of event-free survival after HCT. Prior busulfan popPK analysis has been limited by small numbers in patients with inherited metabolic disorders (IMD). The primary objective was to characterize population PK of busulfan in a large cohort of children and young adults undergoing HCT for IMD. PopPK analysis of busulfan drug concentrations was performed using data from 78 patients with IMD who received intravenous busulfan (every 24 hours, 4 doses) as part of pretransplantation combination chemotherapy. The final model for busulfan drug clearance was used to estimate individual doses aimed to achieve a target cumulative area under the curve (cAUC) of 80 to 100 mg · h/L. We then compared the probability of cAUC within the range of 80 to 100 mg · h/L by the developed dosing regimen versus conventional regimen. A 1-compartment, linear elimination model best described the PK of busulfan. Significant covariates demonstrated to affect busulfan clearance included total body weight and the time (in days) from busulfan infusion start. The probability of target cAUC attainment by the developed dosing versus the conventional dosing were 47% versus 43% for body weight <12 kg, and 48% versus 36% for body weight ≥12 kg. We described population PK of intravenous busulfan in a large IMD cohort. The proposed dosing regimen based on the developed model can improve the target cAUC attainment of busulfan for IMD., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Olanzapine is one of the most commonly used antipsychotic drugs; however, its metabolic disorders are the main obstacle in the clinic. Olanzapine is a potent antagonist of the M3 acetylcholine muscarinic receptor (M3R), while the downregulated hepatic M3R-AMPKα signalling pathway is involved in metabolic disorders., Aim: This study investigated the effects of chronic co-treatment with cevimeline (an agonist of M3Rs) in attenuating olanzapine-induced metabolic disorders and the underlying mechanisms., Methods: Forty-eight adult female Sprague-Dawley rats were treated orally with olanzapine (2 mg/kg, 3 times/day (t.i.d.)) and/or cevimeline (9 mg/kg, t.i.d.), or control (vehicle) for 9 weeks., Results: Cevimeline co-treatment significantly attenuated olanzapine-induced body weight gain and glucolipid metabolic disorders. Importantly, cevimeline co-treatment attenuated olanzapine-induced upregulation of M3Rs, while the co-treatment improved olanzapine-induced downregulation of AMPKα in the liver. Cevimeline co-treatment attenuated olanzapine-induced dyslipidaemia by modulating the hepatic M3R-AMPKα downstream pathways. Cevimeline co-treatment also improved lower activated AKT-GSK3β signalling to reverse impairment of glucose metabolism and insulin resistance caused by chronic olanzapine treatment., Conclusion: These results not only support the important role of M3R antagonism and its related AMPKα and downstream pathways in antipsychotic-induced metabolic disorders but also indicate that these pathways might be promising targets for pharmacological intervention to control these side effects caused by antipsychotic therapy.

Central and peripheral serotonin (5-hydroxytryptamine, 5-HT) regulate feeding signals for energy metabolism. Disruption of central 5-HT signaling via 5-HT2C receptors (5-HT2CRs) induces leptin-independent hyperphagia in mice, leading to late-onset obesity, insulin resistance, and impaired glucose tolerance. 5-HT2CR mutant mice are more responsive than wild-type mice to a high-fat diet, exhibiting earlier-onset obesity and type 2 diabetes. High-fat and high-carbohydrate diets increase plasma 5-HT and fibroblast growth factor-21 (FGF21) levels. Plasma 5-HT and FGF21 levels are increased in rodents and humans with obesity, type 2 diabetes, and non-alcohol fatty liver diseases (NAFLD). The increases in plasma FGF21 and hepatic FGF21 expression precede hyperinsulinemia, insulin resistance, hyperglycemia, and weight gain in mice fed a high-fat diet. Nutritional, pharmacologic, or genetic inhibition of peripheral 5-HT synthesis via tryptophan hydroxylase 1 (Tph1) decreases hepatic FGF21 expression and plasma FGF21 levels in mice. Thus, perturbing central 5-HT signaling via 5-HT2CRs alters feeding behavior. Increased energy intake via a high-fat diet and/or high-carbohydrate diet can upregulate gut-derived 5-HT synthesis via Tph1. Peripheral 5-HT upregulates hepatic FGF21 expression and plasma FGF21 levels, leading to metabolic diseases such as obesity, insulin resistance, type 2 diabetes, and NAFLD. The 5-HT network in the brain-gut-liver axis regulates feeding signals and may be involved in the development and/or prevention of metabolic diseases.

Animals must partition limited resources between their own growth and subsequent reproduction. Endocrine disruptors (ED) may cause maternal metabolic disorders that decrease successful reproduction and might be responsible for multi- and transgenerational effects in amphibians. We found that the frog Silurana (Xenopus) tropicalis, exposed to environmentally relevant concentrations of benzo[a]pyrene and triclosan throughout its life cycle, produced F1 females with delayed sexual maturity and decreased size and weight. These F1 females displayed a marked metabolic syndrome associated with decreased fasting plasma cholesterol and triglyceride concentrations and decreased gonadal development. F1 females from F0 exposed animals also had decreased reproductive investment highlighted by a decrease of oocyte lipid reserves associated with significant F2-tadpole mortality. F2 females from F0 exposed animals also displayed a marked metabolic syndrome but were able to correctly direct liver lipid metabolism to the constitution of fat bodies and oocyte yolk stores. In addition, the F2 females produced progeny that had normal mortality levels at 5 days post hatching compared to the controls suggesting a good reproductive investment. Our data confirmed that these ED, at concentrations often found in natural ponds, can induce multi- and transgenerational metabolic disorders in the progeny of amphibians that are not directly exposed. We present a hypothesis to explain the transmission of the metabolic syndrome across generations through modification of egg reserves. However, when high mortality occurred at the tadpole stage, surviving females were able to cope with metabolic costs and produce viable progeny through sufficient investment in the contents of oocyte reserves., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Curcumin has been reported to have a therapeutic effect on Alzheimer's disease (AD), but the specific mechanism remains to be elucidated. In the present research, we aimed to investigate the effect and molecular mechanism of curcumin on AD. Mouse primary hippocampal neuron cells were treated with various concentrations of beta-amyloid 42 (Aβ 42 ) and the results found that Aβ 42 inhibited cell viability in a dose-dependent manner. Compared with 50 ng/mL Aβ 42 , 500 ng/mL Aβ 42 could further promote cell apoptosis, reduce the ratio of Nicotinamide adenine dinucleotide (NAD(+))/Nicotinamide adenine diphosphate hydride (NADH) and Adenosine 5'-triphosphate (ATP) level, and inhibit Sirtuins 3 (SIRT3) deacetylation activity and protein expression of Thyroid hormone receptor beta (Thrb) and SIRT3. Hence, 500 ng/mL Aβ 42 was used to establish a cell model of AD. Curcumin significantly reversed the inhibitory effects of Aβ 42 on cell viability, SIRT3 deacetylation activity, the ratio of NAD + /NADH, ATP level and the protein expression of Thrb and SIRT3, and the promotive effect on apoptosis. ChIPBase was used to predict the binding region of Thrb and SIRT3. Dual luciferase reporter gene and Chromatin immune precipitation (ChIP) assays were employed to verify the relationship between Thrb and promoter of SIRT3 mRNA. Overexpression of Thrb recovered Aβ 42 induced metabolic dysfunction, while Thrb silence aggravated Aβ 42 induced metabolic dysfunction. Moreover, Thrb silence or 3-TYP (a selective inhibitor of SIRT3) treatment abolished the amelioration of curcumin on Aβ 42 induced metabolic dysfunction. Additionally, curcumin attenuated memory deficits in Amyloid precursor protein transgenic (APP TG ) mice. Collectively, curcumin alleviated Aβ 42 -induced neuronal metabolic dysfunction through increasing Thrb expression and SIRT3 activity and improved cognition in APP TG mice., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Given that fructose consumption has increased by more than 10-fold in recent decades, it is possible that excess maternal fructose consumption causes harmful effects in the next generation. This study attempted to elucidate the mechanism of the harmful effects of excessive maternal fructose intake from the perspective of offspring liver function. Female rats during gestation and lactation were fed water containing fructose, and their offspring were fed normal water. We attempted to elucidate the mechanism of fructose-induced transgenerational toxicity by conducting a longitudinal study focusing on hepatic programming prior to disease onset. Impaired Insulin resistance and decreased high-density lipoprotein-cholesterol levels were observed at 160 days of age. However, metabolic disorders were not observed in 60-day-old offspring. Microarray analysis of 60-day-old offspring livers showed the reduction of hepatic insulin-like growth factor-1 (Igf1) mRNA expression. This reduction continued until the rats were aged 160 days and attenuated Igf1 signaling. Hepatic microRNA-29 (miR-29a) and miR-130a, which target Igf1 mRNA, were also found to be upregulated. Interestingly, these miRNAs were upregulated in the absence of metabolic disorder. In this study, we found that maternal fructose intake resulted in dysregulated expression of Igf1 and its target miRNAs in the offspring liver, and that these offspring were more likely to develop metabolic disorders. Abnormal hepatic programming induced by an imbalanced maternal nutritional environment is maintained throughout life, implying that it may contribute to metabolic disorders., (© 2021 Federation of American Societies for Experimental Biology.)

Abstract: Paracetamol (PAR) is the most common over-the-counter drug recommended by physicians for treatment of pain and fever during gestation. This drug is not teratogenic, being considered safe for fetus; however, PAR crosses the blood-placental barrier. Considering that, the present study aimed to evaluate the vascular and metabolic safety of PAR exposure during intrauterine and neonatal development in adult male and female-exposed offspring. Wistar female rats were gavaged, with PAR (350 mg/kg/d), from gestational day 6-21 or from gestational day 6 until postnatal day 21. Control dams received water by gavage at the same periods. The male and female offspring were evaluated at adulthood (80 days of life). The thoracic aorta reactivity to acetylcholine, sodium nitroprusside, and phenylephrine was evaluated in male and female adult offspring. It was observed that aortic relaxation was similar between the PAR and control offspring. In addition, the contraction to phenylephrine was similar between the groups. Further, the insulin sensitivity, adipose tissue deposition and blood pressure were not different between PAR and control adult offspring. These results suggest that the protocol of PAR exposure used in the present study did not program vascular and metabolic alterations that would contribute to the development of cardiometabolic diseases in adult life, being safe for the exposed offspring., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The use of cannabidiol (CBD), the non-psychotropic compound derived from Cannabis sativa, for therapeutic purposes is growing exponentially by targeting the management of multiple medical disorders, including metabolic-related diseases. Nevertheless, substantial questions have emerged in concerning the potential metabolic disturbances in adulthood as consequence of the long-term uses of CBD during early years of life. Therefore, we studied whether chronic CBD injections (5, 10 or 30 mg/kg; i.p.) given to juvenile rats (from post-natal day [PND] 30) for 14 days might influence in adulthood the activity of metabolic markers, such as glucose, total cholesterol, triglycerides as well as activity of antioxidants (DPPH) from plasma, white adipose tissue (WAT), brown adipose tissue (BAT), liver, and hypothalamus. Our results showed that adult rats treated during juvenile ages with CBD (5, 10 or 30 mg/kg) for two weeks increased the contents of glucose whereas with no changes on total cholesterol in adulthood were observed. Additionally, a significant decrease in the levels of triglycerides were found in plasma, WAT, BAT, and liver in adult rats treated with chronic injections of CBD during the adolescence. However, unexpectedly, the contents of triglycerides in hypothalamus were found enhanced. Finally, the DPPH assay showed a significant enhancement in triglycerides analyzed from WAT and liver whereas opposite findings were observed in BAT and no significant changes were found in hypothalamus in adult rats that received during the adolescence chronic injections of CBD. In conclusion, repeated CBD administration to juvenile rats induced significant alterations in multiple metabolic markers analyzed in the adulthood. Our findings highlight the relevance of chronic CBD treatment in disturbed metabolic activity and remark the need for studying the underlying mechanisms involved., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Since 2016, more and more studies have been conducted to explore the combination of obesity and perfluoroalkyl substances (PFASs) exposure, and the results indicate that PFASs may be connected with the occurrence of obesity-associated glucolipid metabolic disease (GLMD)., Objectives: This article summarizes the epidemiological studies on PFASs and obesity-related GLMD, as well as relevant experimental evidence., Results: (i) Both obesity and PFASs exposure can cause disorder of glucose and lipid metabolism (GLM). (ii) Obesity is a pivotal factor in the high incidence of GLMD induce by PFASs. (iii) PFASs are aggravating the occurrence of obesity-associated GLMD [e.g., diabetes, cardiovascular disease (CVD), and liver disease]., Conclusion: The paper fills the gaps among environmental chemistry/epidemiology/toxicology area research. More importantly, PFASs should be taken into account to explain the high-prevalence of obesity-related GLMD., Future Direction: Three research programs are proposed to explore the synergistic mechanism of PFASs and obesity. In addition, three suggestions are recommended to solve the harm of PFASs pollutants to human beings., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Bisphenol A (BPA) is an artificial chemical widely used in the production of polycarbonate plastics and epoxy resins. Accumulating evidence indicates that BPA exposure is associated with metabolic disorders. The beneficial effects of green tea and epigallocatechin gallate (EGCG), major catechin present in green tea, on alleviating BPA-induced metabolic disorders have been shown in various studies., Purpose: Protective effects of green tea extract and EGCG on BPA-induced metabolic disorders and possible underlying mechanisms were investigated., Methods: Rats were randomly divided into control, green tea extract (50 and 100 mg/kg, IP), EGCG (20 and 40 mg/kg, IP), BPA (10 mg/kg, gavage), BPA plus green tea extract (25, 50, and 100 mg/kg, IP), BPA plus EGCG (10, 20, and 40 mg/kg, IP), and BPA plus vitamin E (200 IU/kg, IP). After two months, body weight, blood pressure, biochemical blood tests, hepatic malondialdehyde (MDA), and glutathione (GSH) were assessed. By enzyme-linked immunosorbent assay, serum levels of insulin, leptin, adiponectin, TNFα, and IL-6, and by western blotting, hepatic insulin signaling (IRS-1, PI3K, Akt) were measured., Results: BPA increased body weight, blood pressure, and MDA, decreased GSH, elevated serum levels of low-density lipoprotein cholesterol, total cholesterol, triglyceride, glucose, insulin, leptin, TNFα, IL-6, and liver enzymes including alanine aminotransferase and alkaline phosphatase, and lowered high-density lipoprotein cholesterol and adiponectin levels. In western blot, decreased phosphorylation of IRS-1, PI3K, and Akt was obtained. Administration of green tea extract, EGCG, or vitamin E with BPA reduced the detrimental effects of BPA., Conclusion: These findings indicate that green tea extract and EGCG can be effective in preventing or reducing metabolic disorders induced by BPA linked to their antioxidant and anti-inflammatory activity, regulating the metabolism of lipids, and improving insulin signaling pathways., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Methamphetamine (METH) abuse has become a global public health problem. However, the potential mechanisms involving METH-induced metabolic disorders have thus far remained poorly understood. Metabolomics can provide a clue for the cause of apparent changes and consequently be used to investigate the METH-induced dysregulation of metabolite expression and the mechanism of metabolic disorder mechanism. This laboratory investigation included 80 METH abusers and 80 healthy people. The serum metabolites were detected and analysed by gas chromatography/time-of-flight mass spectrometry. Raw data were processed with the software MS DIAL, which includes deconvolution, peak alignment and compound identification. The data matrix was processed by univariate and multivariate analyses for significant metabolite screening with the criteria of variable importance in projection values > 1, fold change > 1.5 and the t test (p value < 0.05). Significant differences in 16 metabolites (deoxycholic acid, cholic acid, hydroxylamine, etc.) in serum were found between the METH abuse group and the control group. Energy metabolic pathways and several amino acid metabolic pathways (alanine, aspartic acid and glutamate metabolism and tryptophan metabolism) were primarily involved. Further analysis indicated that the area under the receiver operating characteristic curve (AUC) was 0.998 for these 16 metabolites. Among the metabolites, three carbohydrates (d-ribose, cellobiose and maltotriose) had an AUC of 0.975, which were determined as potential markers of abuse. We observed metabolic disturbances in METH abusers, particularly perturbation in energy metabolism and amino acid metabolism, which can provide new insights into the search for biomarkers and the mechanisms underlying the adverse effects of METH on human health., (© 2021 Society for the Study of Addiction.)

Most strategies to treat obesity-related disorders have involved prevention of diet-induced weight gain in lean mice. Treatment of obese individuals will require therapies that reverse the detrimental effects of excess body weight. Cyclin-dependent kinases have been shown to contribute to obesity and its adverse complications. Here, we show that roscovitine; a an orally available cyclin-dependent kinase inhibitor; given to male mice during the last six weeks of a 19-week high fat diet, reduced weight gain and prevented accompanying insulin resistance, hepatic steatosis, visceral adipose tissue (eWAT) inflammation/fibrosis as well as restored insulin secretion and enhanced whole body energy expenditure. Proteomics and phosphoproteomics analysis of eWAT demonstrated that roscovitine suppressed expression of peptides and phosphopeptides linked to inflammation and extracellular matrix proteins. It also identified 17 putative protein kinases perturbed by roscovitine, including CMGC kinases, AGC kinases and CAMK kinases. Pathway enrichment analysis showed that lipid metabolism, TCA cycle, fatty acid beta oxidation and creatine biosynthesis are enriched following roscovitine treatment. For brown adipose tissue (BAT), analysis of upstream kinases controlling the phosphoproteome revealed two major kinase groups, AGC and CMGC kinases. Among the top enriched pathways were insulin signaling, regulation of lipolysis in adipocytes, thyroid hormone signaling, thermogenesis and cAMP-PKG signaling. We conclude that roscovitine is effective at preventing prolonged diet-induced metabolic disruption and restoring mitochondrial activity in BAT and eWAT., (© 2021. The Author(s).)

Aims: To assess the effects of a ketogenic diet on metabolism and renal fibrosis in spontaneously hypertensive rats., Materials and Methods: Male spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats were randomly divided into a ketogenic diet group and a normal diet group. Blood glucose and metabolites were measured after 4 weeks. Renal autophagy-related protein expression was detected by Western blot, and renal fibrosis was detected by Masson staining., Results: Compared with the normal diet, the ketogenic diet led to significantly decreased glucose tolerance and metabolism; overactivated the renin-angiotensin-aldosterone system; and reduced renal autophagy-related protein expression in SHRs; Masson staining and other experiments showed that the ketogenic diet had no significant effect on hypertensive renal fibrosis., Conclusion: A Ketogenic diet could lead to disorders of glucose and lipid metabolism, increase hypertension by activating the RAAS, reduce renal autophagy levels and aggravate renal parenchymal damage. Therefore, a ketogenic diet, as a kind of natural therapy, should be vigilantly monitored to prevent further damage in patients with hypertension., Competing Interests: Declaration of competing interest Ping Jia and Huang Bi are the co-first author, Lingyun Gao is the corresponding authors. The authors declare that they have no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Up to 20% of pregnant women ages 18-24 consume cannabis during pregnancy. Moreover, clinical studies indicate that cannabis consumption during pregnancy leads to fetal growth restriction (FGR), which is associated with an increased risk of obesity, type II diabetes (T2D), and cardiovascular disease in the offspring. This is of great concern considering that the concentration of Δ 9 - tetrahydrocannabinol (Δ9-THC), a major psychoactive component of cannabis, has doubled over the last decade and can readily cross the placenta and enter fetal circulation, with the potential to negatively impact fetal development via the endocannabinoid (eCB) system. Cannabis exposure in utero could also lead to FGR via placental insufficiency. In this review, we aim to examine current pre-clinical and clinical findings on the direct effects of exposure to cannabis and its constituents on fetal development as well as indirect effects, namely placental insufficiency, on postnatal metabolic diseases.

Background: There have been a few systematic reviews and conventional meta-analyses reporting effect of drugs on metabolic disturbance induced by atypical antipsychotics (AAPs). However, few of them provided sufficient and comprehensive comparisons between pharmacological interventions., Aims: We aimed to qualitatively compare drugs' effect on AAPs-induced metabolic abnormalities by using network meta-analysis (NMA)., Methods: We searched PubMed, EMBASE, Web of Science, Cochrane Controlled Register of Trials (CENTRAL), and PsycINFO on March 26, 2019. Of 5889 records identified, 61 randomized clinical trials including 3467 participants were included. We estimated weighted mean difference (WMD) and odds ratio (OR) using NMA. We assessed the risk of bias of individual studies with the Review Manager 5.3. Primary outcomes included change of body weight and body mass index (BMI). Secondary outcomes included change of other cardiometabolic risk factors, acceptability, and tolerability., Results: For body weight, topiramate (WMD -5.4, 95% CI -7.12 to -3.68), zonisamide (-3.44, 95% CI -6.57 to -0.36), metformin (-3.01, 95% CI -4.22 to -1.83), glucagon-like peptide-1 receptor agonists (GLP-1RAs) (-3.23, 95% CI -5.47 to -0.96), and nizatidine (-2.14, 95% CI -4.01 to -0.27) were significantly superior to placebo. Results regarding to BMI were similar to that of body weight. With respect to tolerability, only topiramate (OR 24, 95% CI 3.15 to 648) was inferior to placebo., Conclusions: Considering both efficacy and tolerability, evidence from this NMA indicates zonisamide, metformin, GLP-1RAs, and nizatidine in adults should be the first-line treatment for alleviating AAPs-induced weight gain or elevated BMI.

Purpose: The overexposure to synthetic glucocorticoids (GC) during pregnancy can predispose to metabolic diseases during adulthood. Vitamin D is not only crucial for fetal development, but also exerts direct effects on the GC sensitivity and down-regulates GC receptors. Given the vitamin D effects on glucocorticoid-related parameters, we aimed to investigate a possible protective role of maternal vitamin D administration on the glucose homeostasis of rats exposed to dexamethasone in utero., Methods: Pregnant rats received dexamethasone (0.1 mg/kg, Dex) daily between the 14th and 19th days of pregnancy. A subgroup of dexamethasone-treated dams received oral administration of vitamin D (500UI, DexVD) during the whole gestation. The corresponding control groups of dams were included (CTL and VD groups, respectively). Male and female offspring were evaluated at 3, 6 and 12 months of age., Results: Prenatal exposure to dexamethasone caused metabolic disruption in an age and sex-dependent manner being the older male offspring more susceptible to insulin resistance, fatty liver and beta-cell mass expansion than females. Furthermore, we demonstrated that prenatal GC led to glucose intolerance in male and female offspring in an age-dependent manner. Maternal vitamin D administration did not influence glucose intolerance but attenuated the insulin resistance, liver lipid accumulation and prevented the beta-cell mass expansion caused by prenatal dexamethasone in the male offspring., Conclusion: Maternal vitamin D administration mitigates metabolic disturbances that occur later in life in male rats exposed to GC in utero. Moreover, our data suggest vitamin D as an important nutritional supplement for pregnant overexposed to GC during gestation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The Estudo de Descontinuação de Imatinibe após Pioglitazona (EDI-PIO) is a single-center, longitudinal, prospective, phase 2, non-randomized, open, clinical trial (NCT02852486, August 2, 2016 retrospectively registered) for the discontinuation of imatinib after concomitant use of pioglitazone, being the first of its kind in a Brazilian population with chronic myeloid leukemia. Due to remaining of leukemic quiescent cells that are not affected by tyrosine kinase inhibitors, it has been suggested the use of pioglitazone, a PPARγ agonist, together with imatinib as a strategy for the maintenance of deep molecular response. The clinical benefit to this association is still controversial, and the metabolic alteration along this process remains unclear. Therefore, we applied a metabolomic protocol using high-resolution mass spectrometry to profile plasmatic metabolic response of a prospective cohort of ten individuals under discontinuation of imatinib and pioglitazone protocol. By comparing patients under pioglitazone and imatinib treatment with imatinib monotherapy and discontinuation phase, we were able to annotate 41 and 36 metabolites, respectively. The metabolic alterations observed during imatinib-pioglitazone combined therapy are associated with an extensive lipid remodeling, with activation of β-oxidation pathway, in addition to the presence of markers that suggest mitochondrial dysfunction., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system as significant cofactors for several enzymes, including the antioxidant enzyme superoxide dismutase (SOD) and other enzymes that take part in the creation and breakdown of neurotransmitters in the brain. An imbalance in the levels of these metals weakens the structural, regulatory, and catalytic roles of different enzymes, proteins, receptors, and transporters and is known to provoke the development of various neurological conditions through different mechanisms, such as via induction of oxidative stress, increased α-synuclein aggregation and fibril formation, and stimulation of microglial cells, thus resulting in inflammation and reduced production of metalloproteins. In the present review, the authors focus on neurological disorders with psychiatric signs associated with copper, iron, and manganese excess and the diagnosis and potential treatment of such disorders. In our review, we described diseases related to these metals, such as aceruloplasminaemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN) and other very rare classical NBIA forms, manganism, attention-deficit/hyperactivity disorder (ADHD), ephedrone encephalopathy, HMNDYT1-SLC30A10 deficiency (HMNDYT1), HMNDYT2-SLC39A14 deficiency, CDG2N-SLC39A8 deficiency, hepatic encephalopathy, prion disease and "prion-like disease", amyotrophic lateral sclerosis, Huntington's disease, Friedreich's ataxia, and depression.

Rationale and Objective: Clozapine (CLZ) is the most effective drug for treatment-resistant schizophrenia but is associated with many side effects, including glycometabolism disorders. Immunological mechanisms may be involved in the development of clozapine side effects. Research relating the immunomodulatory effects of clozapine and its early markers to clinically relevant adverse events is needed to reduce the harmful side effects of clozapine. This study aimed to investigate the role of proinflammatory cytokines in clozapine-associated glycometabolism disorders., Methods: We measured the effect of a range of doses of clozapine on glycometabolism-related parameters and proinflammatory cytokines levels in mice peripheral blood. We also examined the differences between these indicators in the peripheral blood of clozapine-treated schizophrenia patients and healthy controls. Furthermore, we detected proinflammatory cytokines expression in mice pancreatic tissue., Results: Following clozapine administration, glucagon significantly decreased in mouse serum, and proinflammatory cytokine IL-β levels markedly increased. Clozapine reliably increased proinflammatory cytokines (IL-1β, IL-6, and TNF-α) expression in murine pancreatic tissue. Compared with healthy controls, clozapine-treated patients' BMI, blood glucose, and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) increased significantly. In clozapine-treated patients, a higher clozapine daily dosage was associated with higher levels of the proinflammatory cytokines IL-1β and IL-6, and a significant positive correlation was observed between blood glucose levels and the proinflammatory cytokines IL-6 and TNF-α., Conclusion: Findings from animal experiments and clinical trials have shown clear evidence that clozapine has a regulatory effect on immune-related proinflammatory cytokines and influences glycometabolism indicators.

The finding that high-dose dexamethasone improves survival in those requiring critical care due to COVID-19 will mean much greater usage of glucocorticoids in the subsequent waves of coronavirus infection. Furthermore, the consistent finding of adverse outcomes from COVID-19 in individuals with obesity, hypertension and diabetes has focussed attention on the metabolic dysfunction that may arise with critical illness. The SARS coronavirus itself may promote relative insulin deficiency, ketogenesis and hyperglycaemia in susceptible individuals. In conjunction with prolonged critical care, these components will promote a catabolic state. Insulin infusion is the mainstay of therapy for treatment of hyperglycaemia in acute illness but what is the effect of insulin on the admixture of glucocorticoids and COVID-19? This article reviews the evidence for the effect of insulin on clinical outcomes and intermediary metabolism in critical illness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Whyte, Vas and Umpleby.)