Search

Copper (Cu) is essential for brain development and function, yet its overload induces neuronal damage and contributes to neurodegeneration and other neurological disorders. Multiple studies demonstrated that Cu neurotoxicity is associated with mitochondrial dysfunction, routinely assessed by reduction of mitochondrial membrane potential. Nonetheless, the role of alterations of mitochondrial dynamics in brain mitochondrial dysfunction induced by Cu exposure is still debatable. Therefore, the objective of the present narrative review was to discuss the role of mitochondrial dysfunction in Cu-induced neurotoxicity with special emphasis on its influence on brain mitochondrial fusion and fission, as well as mitochondrial clearance by mitophagy. Existing data demonstrate that, in addition to mitochondrial electron transport chain inhibition, membrane damage, and mitochondrial reactive oxygen species (ROS) overproduction, Cu overexposure inhibits mitochondrial fusion by down-regulation of Opa1, Mfn1, and Mfn2 expression, while promoting mitochondrial fission through up-regulation of Drp1. It has been also demonstrated that Cu exposure induces PINK1/Parkin-dependent mitophagy in brain cells, that is considered a compensatory response to Cu-induced mitochondrial dysfunction. However, long-term high-dose Cu exposure impairs mitophagy, resulting in accumulation of dysfunctional mitochondria. Cu-induced inhibition of mitochondrial biogenesis due to down-regulation of PGC-1α further aggravates mitochondrial dysfunction in brain. Studies from non-brain cells corroborate these findings, also offering additional evidence that dysregulation of mitochondrial dynamics and mitophagy may be involved in Cu-induced damage in brain. Finally, Cu exposure induces cuproptosis in brain cells due mitochondrial proteotoxic stress, that may also contribute to neuronal damage and pathogenesis of certain brain diseases. Based on these findings, it is assumed that development of mitoprotective agents, specifically targeting mechanisms of mitochondrial quality control, would be useful for prevention of neurotoxic effects of Cu overload.

Background and Aim: The existing data demonstrate that gut microbiota is involved in regulating mineral metabolism in cattle, although the data are quite contradictory. The study aimed to evaluate Saccharomyces cerevisiae-based probiotic’s effects on gut microbiota, systemic metabolism, and dairy cows’ essential trace element and mineral body burden. Materials and Methods: Fifteen cows received a daily supplement of a 50 g S. cerevisiae-based probiotic, fortified with methionine, choline, eugenol, cinnamaldehyde, and Capsicum oleoresin, for a month. 16S metagenomic sequencing was used to evaluate the taxonomic features of fecal microbiota. Serum trace elements and minerals levels were determined through inductively coupled plasma mass spectrometry. Results: Supplementation with S. cerevisiae-based probiotic complex significantly increased alpha and beta diversity, as well as the abundance of Mediterranea and Clostridium IV within the Bacillota phylum, whereas that of Bacteroidota and specifically unclassified Bacteroidales and unclassified Oscillospiraceae decreased. Following probiotic supplementation with the S. cerevisiae-based complex, gut microbiota modulation led to a significant boost in circulating levels of calcium, copper, selenium, and zinc. Creatinine levels decreased while total cholesterol levels increased within normal limits in the serum analysis. Conclusion: The observed improvement in trace elements and minerals in dairy cows might be due to changes in intestinal microflora caused by supplementation. Therefore, probiotic supplementation in cattle may be considered a potential tool for improvement of mineral nutrition in cattle. However, the influence of probiotic treatment and modulation of mineral metabolism on milk productivity and overall performance in cattle is yet to be estimated.

Background: Kashin-Beck disease (KBD) is an endemic osteoarthropathy characterized by excessive chondrocytes apoptosis. T-2 toxin exposure has been proved to be its etiology. Connective tissue growth factor (CTGF) exerts a profound influence on cartilage growth and metabolism. We investigated the potential role of CTGF in KBD development and examined CTGF alterations under T-2 toxin stimulation. Methods: The levels of CTGF and chondrocyte apoptosis-related markers in cartilage and primary chondrocytes from KBD and control groups were measured using qRT-PCR, Western blotting, immunohistochemistry, and immunofluorescence. We analyzed expression changes of these genes in response to T-2 toxin. Apoptosis rates of chondrocytes induced by T-2 toxin were measured by flow cytometry and TUNEL assay. The active pharmaceutical ingredient targeting CTGF was screened through Comparative Toxicogenomics Database, and molecular docking was performed using AutoDock Tools. Results: The CTGF levels in KBD cartilage and chondrocytes were significantly elevated and positively associated with the levels of apoptosis-related genes. T-2 toxin exposure increased CTGF and apoptosis-related gene levels in chondrocytes, with apoptosis rates rising alongside T-2 toxin concentration. Curcumin was identified as targeting CTGF and exhibited effective binding. It could down-regulate CTGF, apoptosis-related genes, such as Cleaved caspase 3 and BAX, and also significantly reduce apoptosis rate in chondrocytes treated with T-2 toxin. Conclusion: CTGF plays a crucial role in the development of KBD. Curcumin has shown potential in inhibiting CTGF levels and reducing chondrocyte apoptosis, highlighting its promise as a therapeutic agent for preventing cartilage damage in KBD. Our findings provided valuable insights into the pathogenesis of KBD and could promote the development of novel therapeutic strategies for this debilitating disease.

Manganese (Mn) overexposure has been associated with the development of neurological damage reminiscent of Parkinson's disease, while the underlying mechanisms have yet to be fully characterized. This study aimed to investigate the mechanisms leading to injury in dopaminergic neurons induced by Mn and identify novel treatment approaches. In the in vivo and in vitro models, ICR mice and dopaminergic neuron-like PC12 cells were exposed to Mn, respectively. We treated them with anti-ferroptotic agents ferrostatin-1 (Fer-1), deferoxamine (DFO), HIF-1α activator dimethyloxalylglycine (DMOG) and inhibitor LW6. We also used p53-siRNA to verify the mechanism underlying Mn-induced neurotoxicity. Fe and Mn concentrations increased in ICR mice brains overexposed to Mn. Additionally, Mn-exposed mice exhibited movement impairment and encephalic pathological changes, with decreased HIF-1α, SLC7A11, and GPX4 proteins and increased p53 protein levels. Fer-1 exhibited protective effects against Mn-induced both behavioral and biochemical changes. Consistently, in vitro, Mn exposure caused ferroptosis-related changes and decreased HIF-1α levels, all ameliorated by Fer-1. Upregulation of HIF-1α by DMOG alleviated the Mn-associated ferroptosis, while LW6 exacerbated Mn-induced neurotoxicity through downregulating HIF-1α. p53 knock-down also rescued Mn-induced ferroptosis without altering HIF-1α protein expression. Mn overexposure resulted in ferroptosis in dopaminergic neurons, mediated through the HIF-1α/p53/SLC7A11 pathway.

The COVID-19 pandemic has altered respiratory infection patterns in pediatric populations. The emergence of the SARS-CoV-2 Omicron variant and relaxation of public health measures have increased the likelihood of coinfections. Previous studies show conflicting results regarding the impact of viral and bacterial coinfections with SARS-CoV-2 on severity of pediatric disease. This study investigated the prevalence and clinical impact of coinfections among children hospitalized with COVID-19 during the Omicron wave. A retrospective analysis was conducted on 574 hospitalized patients aged under 18 years in Russia, from January 2022 to March 2023. Samples from patients were tested for SARS-CoV-2 and other respiratory pathogens using qRT-PCR, bacterial culture tests and mass spectrometry, and ELISA. Approximately one-third of COVID-19 cases had coinfections, with viral and bacterial coinfections occurring at similar rates. Adenovirus and Staphylococcus aureus were the most common viral and bacterial coinfections, respectively. Viral coinfections were associated with higher fevers and increased bronchitis, while bacterial coinfections correlated with longer duration of illness and higher pneumonia rates. Non-SARS-CoV-2 respiratory viruses were linked to more severe lower respiratory tract complications than SARS-CoV-2 monoinfection. These findings suggest that during the Omicron wave, seasonal respiratory viruses may have posed a greater threat to children’s health than SARS-CoV-2.

The objective of the present narrative review was to synthesize existing clinical and epidemiological findings linking manganese (Mn) exposure biomarkers to autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), and to discuss key pathophysiological mechanisms of neurodevelopmental disorders that may be affected by this metal. Existing epidemiological data demonstrated both direct and inverse association between Mn body burden and ASD, or lack of any relationship. In contrast, the majority of studies revealed significantly higher Mn levels in subjects with ADHD, as well as direct relationship between Mn body burden with hyperactivity and inattention scores in children, although several studies reported contradictory results. Existing laboratory studies demonstrated that impaired attention and hyperactivity in animals following Mn exposure was associated with dopaminergic dysfunction and neuroinflammation. Despite lack of direct evidence on Mn-induced neurobiological alterations in patients with ASD and ADHD, a plethora of studies demonstrated that neurotoxic effects of Mn overexposure may interfere with key mechanisms of pathogenesis inherent to these neurodevelopmental disorders. Specifically, Mn overload was shown to impair not only dopaminergic neurotransmission, but also affect metabolism of glutamine/glutamate, GABA, serotonin, noradrenaline, thus affecting neuronal signaling. In turn, neurotoxic effects of Mn may be associated with its ability to induce oxidative stress, apoptosis, and neuroinflammation, and/or impair neurogenesis. Nonetheless, additional detailed studies are required to evaluate the association between environmental Mn exposure and/or Mn body burden and neurodevelopmental disorders at a wide range of concentrations to estimate the potential dose-dependent effects, as well as environmental and genetic factors affecting this association.

Titanium dioxide nanoparticles (TiO2NPs) are widely produced and used nanoparticles. Yet, TiO2NP exposure may possess toxic effects to different cells and tissues, including the brain. Recent studies significantly expanded the understanding of the molecular mechanisms underlying TiO2NP neurotoxicity implicating a number of both direct and indirect mechanisms. In view of the significant recent progress in research on TiO2NP neurotoxicity, the objective of the present study is to provide a narrative review on the molecular mechanisms involved in its neurotoxicity, with a special focus on the studies published in the last decade. The existing data demosntrate that although TiO2NP may cross blood-brain barrier and accumulate in brain, its neurotoxic effects may be mediated by systemic toxicity. In addition to neuronal damage and impaired neurogenesis, TiO2NP exposure also results in reduced neurite outgrowth and impaired neurotransmitter metabolism, especially dopamine and glutamate. TiO2NP exposure was also shown to promote α-synuclein and β-amyloid aggregation, thus increasing its toxicity. Recent findings also suggest that epigenetic effects and alterations in gut microbiota biodiversity contribute to TiO2NP neurotoxicity. Correspondingly, in vivo studies demosntrated that TiO2NPs induce a wide spectrum of adverse neurobehavioral effects, while epidemiological data are lacking. In addition, TiO2NPs were shown to promote neurotoxic effects of other toxic compounds. Here we show the contribution of a wide spectrum of molecular mechanisms to TiO2NP-induced neurotoxicity; yet, the role of TiO2NP exposure in adverse neurological outcomes in humans has yet to be fully appreciated.

Metabolic syndrome (MetS) is an important public health issue that affects millions of people around the world and is growing to pandemic-like proportions. This syndrome is defined by the World Health Organization (WHO) as a pathologic condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Moreover, the etiology of MetS is multifactorial, involving many environmental factors, including toxicant exposures. Several studies have associated MetS with heavy metals exposure, which is the focus of this review. Environmental and/or occupational exposure to heavy metals are a major risk, contributing to the development of chronic diseases. Of particular note, toxic metals such as mercury, lead, and cadmium may contribute to the development of MetS by altering oxidative stress, IL-6 signaling, apoptosis, altered lipoprotein metabolism, fluid shear stress and atherosclerosis, and other mechanisms. In this review, we discuss the known and potential roles of heavy metals in MetS etiology as well as potential targeted pathways that are associated with MetS. Furthermore, we describe how new approaches involving proteomic and transcriptome analysis, as well as bioinformatic tools, may help bring about an understanding of the involvement of heavy metals and metalloids in MetS.

Mitochondria play a crucial role in cellular respiration, ATP production, and the regulation of various cellular processes. Mitochondrial dysfunctions have been directly linked to pathophysiological conditions, making them a significant target of interest in toxicological research. In recent years, there has been a growing need to understand the intricate effects of xenobiotics on human health, necessitating the use of effective scientific research tools. Caenorhabditis elegans (C. elegans), a nonpathogenic nematode, has emerged as a powerful tool for investigating toxic mechanisms and mitochondrial dysfunction. With remarkable genetic homology to mammals, C. elegans has been used in studies to elucidate the impact of contaminants and drugs on mitochondrial function. This review focuses on the effects of several toxic metals and metalloids, drugs of abuse and pesticides on mitochondria, highlighting the utility of C. elegans as a model organism to investigate mitochondrial dysfunction induced by xenobiotics. Mitochondrial structure, function, and dynamics are discussed, emphasizing their essential role in cellular viability and the regulation of processes such as autophagy, apoptosis, and calcium homeostasis. Additionally, specific toxins and toxicants, such as arsenic, cadmium, and manganese are examined in the context of their impact on mitochondrial function and the utility of C. elegans in elucidating the underlying mechanisms. Furthermore, we demonstrate the utilization of C. elegans as an experimental model providing a promising platform for investigating the intricate relationships between xenobiotics and mitochondrial dysfunction. This knowledge could contribute to the development of strategies to mitigate the adverse effects of contaminants and drugs of abuse, ultimately enhancing our understanding of these complex processes and promoting human health.

The objective of the present study was to review recent epidemiological and clinical data on the association between selected minerals and trace elements and osteoporosis, as well as to discuss the molecular mechanisms underlying these associations. We have performed a search in the PubMed-Medline and Google Scholar databases using the MeSH terms “osteoporosis”, “osteogenesis”, “osteoblast”, “osteoclast”, and “osteocyte” in association with the names of particular trace elements and minerals through 21 March 2023. The data demonstrate that physiological and nutritional levels of trace elements and minerals promote osteogenic differentiation through the up-regulation of BMP-2 and Wnt/β-catenin signaling, as well as other pathways. miRNA and epigenetic effects were also involved in the regulation of the osteogenic effects of trace minerals. The antiresorptive effect of trace elements and minerals was associated with the inhibition of osteoclastogenesis. At the same time, the effect of trace elements and minerals on bone health appeared to be dose-dependent with low doses promoting an osteogenic effect, whereas high doses exerted opposite effects which promoted bone resorption and impaired bone formation. Concomitant with the results of the laboratory studies, several clinical trials and epidemiological studies demonstrated that supplementation with Zn, Mg, F, and Sr may improve bone quality, thus inducing antiosteoporotic effects.

Abstract Background Non-steroidal anti-inflammatory drugs such as aspirin are used for the treatment of cardiovascular disease. Chronic use of low-dose aspirin is associated with the occurrence of gastric ulcer. The aim of this study was to investigate the healing potential of Lycium barbarum polysaccharides (LBP) from Chinese Goji berry and C-phycocyanin (CPC) from Spirulina platensis on gastric ulcer in rats. Methods Male Sprague–Dawley rats were divided into five groups: normal, aspirin (700 mg/kg bw), LBP (aspirin + 100 mg/kg bw/d LBP), CPC (aspirin + 50 mg/kg bw/d CPC), and MIX (aspirin + 50 mg/kg bw/d LBP + 25 mg/kg bw/d CPC) groups. Gastric ulcer was developed by daily oral feeding of aspirin for 8 weeks. Treatments were given orally a week before ulcer induction for 9 weeks. Results The MIX group elevated gastric cyclooxygenase-1, prostaglandin E2, and total nitrite and nitrate levels by 139%, 86%, and 66%, respectively, compared with the aspirin group (p

MeHg is an environmental neurotoxin that can adversely affect the development of the nervous system. The molecular integrity of chromatin in the nucleus is an important target of MeHg. Low levels of MeHg trigger epigenetic mechanisms that may be involved in long-lasting and transgenerational neurotoxicity after exposure. Emerging evidence has shown that these mechanisms include histone modification, siRNA, and DNA methylation. The MeHg-induced inhibition of neurodifferentiation and neurogenesis are mechanistically associated with epigenetic alterations in critical genes, such as neurotrophin brain-derived neurotrophic factor (BDNF). Further, MeHg exposure has been shown to alter the activity and/or expression of the upstream regulators of chromatin structure, including histone deacetylases (HDACs) and DNA methyltransferase (DNMTs), which may trigger permanent alterations in histone modifications and DNA methylation. MeHg-exposure also alters several species of miRNA that are associated with neurodevelopment. Genetic studies in the C. elegans model of MeHg-induced toxicity proposes a potential interplay between exogenous RNAi and antioxidant defense. In this review, we discuss the molecular basis for MeHg exposure-induced alterations in chromatin structure and the roles of histone modifications, siRNA, and DNA methylation in MeHg-induced neurotoxic effects.

N,N’ bis-(2-mercaptoethyl) isophthalamide (NBMI) is a lipophilic thiol-containing agent that has high affinity for toxic metal ions, such as Hg2+, Pb2+, and Cd2+. Studies have shown that NBMI is a potent chelator of heavy metals, yet its potential toxicity in animals has yet to be determined. Using the model organism Caenorhabditis elegans (C. elegans), we show no significant change in worms’ death rate or lifespan following NBMI treatment (10−1000 μM). However, NBMI treatment was associated with a significant developmental delay. To determine if the daf-2/age-1/daf-16 pathway is involved in NBMI toxicity, mRNA levels of these genes were assessed in worms treated with NBMI. Here, we found that while NBMI failed to significantly alter the expression of daf-16 or daf-2; age-1 was significantly downregulated by NBMI. Furthermore, NBMI significantly increased DAF-16 nuclear localization. Consistent with a role for this pathway in NBMI toxicity, the developmental arrest by NBMI was more prominent in the DAF-16 transgenic strain than in the wild type N2 strain. Moreover, in the mutant strains harboring null alleles of daf-16, NBMI had no effect on development. In addition, NBMI repressed the expression of detoxifying genes (skn-1, gst-4 and gcs-1). In summary, NBMI has a low developmental toxicity in the C. elegans model, and the nuclear translocation of DAF-16 is involved in the developmental effect of NBMI.

Abstract Background The increasing prevalence of obesity has become a pandemic problem, and dietary patterns are one of the important factors causing obesity. Although the correlation between dietary patterns and obesity has been well explored, the gender difference on the association between dietary patterns and obesity remains unclear. The objective of this study examined whether gender difference existed in the relationship of dietary patterns with metabolic parameters and specific indices of adiposity among young and middle-aged adults with dyslipidemia and abnormal fasting plasma glucose (FPG) in Taiwan. Methods A total of 14,087 subjects aged between 20 and 50 years with dyslipidemia and abnormal FPG were recruited in Taiwan between 2001 and 2010 for a cross-sectional study. Dyslipidemia was defined primarily according to the National Cholesterol Education Program Adult Treatment Panel III guidelines with minor modification. Abnormal FPG level was defined by the American Diabetes Association. Principal component analysis was conducted to identify dietary patterns. Multivariate logistic regression analysis was performed to evaluate the association of dietary patterns and metabolic parameters with different indices of adiposity including general obesity, central obesity, and high body fat, stratified by gender. Results Two dietary patterns derived from principal component analysis were the prudent dietary pattern and the western dietary pattern. Both men and women in the highest quartile of the western dietary pattern had a significantly increased odds ratio of general obesity, central obesity, and high body fat. However, only male subjects in the higher quartiles of the prudent dietary pattern had a significantly decreased odds ratio of all indices of obesity. Both men and women with higher high-density lipoprotein cholesterol and total cholesterol levels had a significantly reduced odds ratio of general and central obesity, while those with higher triglycerides and FPG levels had a significantly increased odds ratio of general and central obesity. Higher low-density lipoprotein cholesterol level was significantly associated with an elevated odds ratio of high body fat, while higher total cholesterol level was significantly correlated with a reduced odds ratio of high body fat only in women. Conclusions Gender difference exists in the association of dietary patterns and metabolic parameters with obesity and body fat in young and middle-aged adults with dyslipidemia and abnormal FPG in Taiwan.

Lead (Pb) is an environmental neurotoxicant, and has been implicated in several neurological disorders of dopaminergic dysfunction; however, the molecular mechanism of its toxicity has yet to be fully understood. This study investigated the effect of Pb exposure on dopaminergic neurodegeneration and function, as well as expression level of several dopaminergic signaling genes in wild type (N2) and protein kinase C (pkc) mutant Caenorhabditis elegans. Both N2 and pkc mutant worms were exposed to Pb2+ for 1 h. Thereafter, dopaminergic (DAergic) neurodegeneration, behavior and gene expression levels were assessed. The results revealed that Pb2+ treatment affects dopaminergic cell morphology and structure in worms expressing green fluorescent protein (GFP) under a DAergic cell specific promoter. Also, there was a significant impairment in dopaminergic neuronal function as tested by basal slowing response (BSR) in wild-type, N2 worms, but no effect was observed in pkc mutant worms. Furthermore, Pb2+ exposure increased dat-1 gene expression level when compared with N2 worms, but no alteration was observed in the pkc mutant strains. LC–MS analysis revealed a significant decrease in dopamine content in worms treated with Pb2+ when compared with controls. In summary, our results revealed that Pb2+ exposure induced dopaminergic dysfunction in C. elegans by altering dat-1 gene levels, but pkc mutants showed significant resistance to Pb2+ toxicity. We conclude that PKC activation is directly involved in the neurotoxicity of Pb. Keywords: Pb, Neurotoxicant, PKC, Dopaminergic neuron, dat-1

Persistent organic pollutants (POPs) are considered as potential obesogens that may affect adipose tissue development and functioning, thus promoting obesity. However, various POPs may have different mechanisms of action. The objective of the present review is to discuss the key mechanisms linking exposure to POPs to adipose tissue dysfunction and obesity. Laboratory data clearly demonstrate that the mechanisms associated with the interference of exposure to POPs with obesity include: (a) dysregulation of adipogenesis regulators (PPARγ and C/EBPα); (b) affinity and binding to nuclear receptors; (c) epigenetic effects; and/or (d) proinflammatory activity. Although in vivo data are generally corroborative of the in vitro results, studies in living organisms have shown that the impact of POPs on adipogenesis is affected by biological factors such as sex, age, and period of exposure. Epidemiological data demonstrate a significant association between exposure to POPs and obesity and obesity-associated metabolic disturbances (e.g., type 2 diabetes mellitus and metabolic syndrome), although the existing data are considered insufficient. In conclusion, both laboratory and epidemiological data underline the significant role of POPs as environmental obesogens. However, further studies are required to better characterize both the mechanisms and the dose/concentration-response effects of exposure to POPs in the development of obesity and other metabolic diseases.

BXD recombinant inbred (RI) lines represent a genetic reference population derived from a cross between C57BL/6J mice (B6) and DBA/2J mice (D2), which through meiotic recombination events possesses recombinant chromosomes containing B6 or D2 haplotype segments. The quantitative trait loci (QTLs) are the locations of segregating genetic polymorphisms and are fundamental to understanding genetic diversity in human disease susceptibility and severity. QTL mapping represents the typical approach for identifying naturally occurring polymorphisms that influence complex phenotypes. In this process, genotypic values at markers of known genomic locations are associated with phenotypic values measured in a segregating population. Indeed, BXD RI strains provide a powerful tool to study neurotoxicity induced by different substances. In this review, we describe the use of BXD RI lines to understand the underlying mechanisms of neurotoxicity in response to ethanol and cocaine, as well as metals and pesticide exposures.

Manganese (Mn) is an essential metal, which at high exposures causes neurotoxic effects and neurodegeneration. The neurotoxic effects of Mn are mediated by neuroinflammation, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, and other mechanisms. Recent findings have demonstrated the potential impact of Mn overexposure on gut microbiota dysbiosis, which is known to contribute to neurodegeneration via secretion of neuroactive and proinflammatory metabolites. Therefore, in this review, we discuss the existing data on the impact of Mn exposure on gut microbiota biodiversity, bacterial metabolite production, and gut wall permeability regulating systemic levels. Recent data have demonstrated that Mn exposure may affect gut microbiota biodiversity by altering the abundance of Shiegella, Ruminococcus, Dorea, Fusicatenibacter, Roseburia, Parabacteroides, Bacteroidetes, Firmicutes, Ruminococcaceae, Streptococcaceae, and other bacterial phyla. A Mn-induced increase in Bacteroidetes abundance and a reduced Firmicutes/Bacteroidetes ratio may increase lipopolysaccharide levels. Moreover, in addition to increased systemic lipopolysaccharide (LPS) levels, Mn is capable of potentiating LPS neurotoxicity. Due to the high metabolic activity of intestinal microflora, Mn-induced perturbations in gut microbiota result in a significant alteration in the gut metabolome that has the potential to at least partially mediate the biological effects of Mn overexposure. At the same time, a recent study demonstrated that healthy microbiome transplantation alleviates Mn-induced neurotoxicity, which is indicative of the significant role of gut microflora in the cascade of Mn-mediated neurotoxicity. High doses of Mn may cause enterocyte toxicity and affect gut wall integrity through disruption of tight junctions. The resulting increase in gut wall permeability further promotes increased translocation of LPS and neuroactive bacterial metabolites to the systemic blood flow, ultimately gaining access to the brain and leading to neuroinflammation and neurotransmitter imbalance. Therefore, the existing data lead us to hypothesize that gut microbiota should be considered as a potential target of Mn toxicity, although more detailed studies are required to characterize the interplay between Mn exposure and the gut, as well as its role in the pathogenesis of neurodegeneration and other diseases.

The objective of this study was to evaluate serum, hair, and urinary trace element and mineral content in normal-weight and obese women in relation to metabolic risk factors. A total of 80 women aged 30–70 y.o. were enrolled in the obese group (n = 40) and normal-weight group (n = 40). Serum, hair, and urinary trace element and mineral levels were assessed using inductively coupled plasma spectrometry. Body fat percentage was evaluated using bioimpedance. Obese subjects were characterized by significantly higher body fat percentage, blood pressure, serum triglyceride concentration, and insulin resistance. Serum Ca, Fe, Mg, Se, V, Zn levels, hair Fe, Mg, V content, and urinary Se and V concentrations were found to be lower in obese subjects as compared to lean controls. In turn, serum Cu and urinary Fe levels in obese women were characterized by a significant increase. In multiple regression models serum Cu, Se, and Zn levels were significantly associated with BMI even after adjustment for blood biochemistry, body composition, and blood pressure. Serum trace element and mineral levels also significantly contributed to group discrimination. These findings allow to propose that obesity-associated disturbances in trace element and mineral status may at least partially contribute to metabolic risk in obese subjects.

The objective of the present study was to evaluate of serum metal levels in COVID-19 patients with different disease severity, and to investigate the independent association between serum metal profile and markers of lung damage. The cohort of COVID-19 patients consisted of groups of subjects with mild, moderate, and severe illness, 50 examinees each. Forty-four healthy subjects of the respective age were involved in the current study as the control group. Serum metal levels were evaluated using inductively-coupled plasma mass-spectrometry. Examination of COVID-19 patients demonstrated that heart rate, respiratory rate, body temperature, C-reactive protein levels, as well as lung damage increased significantly with COVID-19 severity, whereas SpO2 decreased gradually. Increasing COVID-19 severity was also associated with a significant gradual decrease in serum Ca, Fe, Se, Zn levels as compared to controls, whereas serum Cu and especially Cu/Zn ratio were elevated. No significant group differences in serum Mg and Mn levels were observed. Serum Ca, Fe, Se, Zn correlated positively with SpO2, being inversely associated with fever, lung damage, and C-reactive protein concentrations. Opposite correlations were observed for Cu and Cu/Zn ratio. In regression models, serum Se levels were inversely associated with lung damage independently of other markers of disease severity, anthropometric, biochemical, and hemostatic parameters. Cu/Zn ratio was also considered as a significant predictor of lower SpO2 in adjusted regression models. Taken together, these findings demonstrated that metal metabolism significantly interferes with COVID-19 pathogenesis, although the causal relations as well as precise mechanisms are yet to be characterized.

Selenium (Se) homeostasis is tightly related to carbohydrate and lipid metabolism, but its possible roles in obesity development and in adipocyte metabolism are unclear. The objective of the present study is to review the current data on Se status in obesity and to discuss the interference between Se and selenoprotein metabolism in adipocyte physiology and obesity pathogenesis. The overview and meta-analysis of the studies on blood Se and selenoprotein P (SELENOP) levels, as well as glutathione peroxidase (GPX) activity in obese subjects, have yielded heterogenous and even conflicting results. Laboratory studies demonstrate that Se may modulate preadipocyte proliferation and adipogenic differentiation, and also interfere with insulin signaling, and regulate lipolysis. Knockout models have demonstrated that the selenoprotein machinery, including endoplasmic reticulum-resident selenoproteins together with GPXs and thioredoxin reductases (TXNRDs), are tightly related to adipocyte development and functioning. In conclusion, Se and selenoproteins appear to play an essential role in adipose tissue physiology, although human data are inconsistent. Taken together, these findings do not support the utility of Se supplementation to prevent or alleviate obesity in humans. Further human and laboratory studies are required to elucidate associations between Se metabolism and obesity.

The literature suggests a bidirectional relationship between testosterone (T) and iron, but mechanisms underlying this relationship remain unclear. We investigated effects of iron on advanced glycation end products (AGEs) in obesity-related androgen deficiency. In total, 111 men were recruited, and iron biomarkers and N(ɛ)-(carboxymethyl)lysine (CML) were measured. In an animal study, rats were fed a 50% high-fat diet (HFD) with (0.25, 1, and 2 g ferric iron/kg diet) or without ferric citrate for 12 weeks. Obese rats supplemented with >1 g iron/kg diet had decreased testicular total T compared to HFD alone. Immunohistochemical staining showed that >1 g of ferric iron increased iron and AGE retention in testicular interstitial tissues, which is associated with increased expression of the receptor for AGEs (RAGE), tumor necrosis factor-α, and nitric oxide. Compared with normal weight, overweight/obese men had lower T levels and higher rates of hypogonadism (19% vs. 11.3%) and iron overload (29.8% vs.15.9%). A correlation analysis showed serum total T was positively correlated with transferrin saturation (r = 0.242, p = 0.007) and cathepsin D (r = 0.330, p = 0.001), but negatively correlated with red blood cell aggregation (r = −0.419, pr = −0.209, p < 0.05). In conclusion, AGEs may partially explain the underlying relationship between dysregulated iron and T deficiency.

Methylmercury (MeHg) is a hazardous environmental pollutant, which elicits significant toxicity in humans. The accumulation of MeHg through the daily consumption of large predatory fish poses potential health risks, and the central nervous system (CNS) is the primary target of toxicity. Despite well-described neurobehavioral effects (i.e., motor impairment), the mechanisms of MeHg-induced toxicity are not completely understood. However, several lines of evidence point out the oxidative stress as an important molecular mechanism in MeHg-induced intoxication. Indeed, MeHg is a soft electrophile that preferentially interacts with nucleophilic groups (mainly thiols and selenols) from proteins and low-molecular-weight molecules. Such interaction contributes to the occurrence of oxidative stress, which can produce damage by several interacting mechanisms, impairing the function of various molecules (i.e., proteins, lipids, and nucleic acids), potentially resulting in modulation of different cellular signal transduction pathways. This review summarizes the general aspects regarding the interaction between MeHg with regulators of the antioxidant response system that are rich in thiol and selenol groups such as glutathione (GSH), and the selenoenzymes thioredoxin reductase (TrxR) and glutathione peroxidase (Gpx). A particular attention is directed towards the role of the PI3K/Akt signaling pathway and the nuclear transcription factor NF-E2-related factor 2 (Nrf2) in MeHg-induced redox imbalance.