In view of the emerging COVID‑19 pandemic caused by SARS‑CoV‑2 virus, the search for potential protective and therapeutic antiviral strategies is of particular and urgent interest. Zinc is known to ...modulate antiviral and antibacterial immunity and regulate inflammatory response. Despite the lack of clinical data, certain indications suggest that modulation of zinc status may be beneficial in COVID‑19. In vitro experiments demonstrate that Zn2+ possesses antiviral activity through inhibition of SARS‑CoV RNA polymerase. This effect may underlie therapeutic efficiency of chloroquine known to act as zinc ionophore. Indirect evidence also indicates that Zn2+ may decrease the activity of angiotensin‑converting enzyme 2 (ACE2), known to be the receptor for SARS‑CoV‑2. Improved antiviral immunity by zinc may also occur through up‑regulation of interferon α production and increasing its antiviral activity. Zinc possesses anti‑inflammatory activity by inhibiting NF‑κB signaling and modulation of regulatory T‑cell functions that may limit the cytokine storm in COVID‑19. Improved Zn status may also reduce the risk of bacterial co‑infection by improving mucociliary clearance and barrier function of the respiratory epithelium, as well as direct antibacterial effects against S. pneumoniae. Zinc status is also tightly associated with risk factors for severe COVID‑19 including ageing, immune deficiency, obesity, diabetes, and atherosclerosis, since these are known risk groups for zinc deficiency. Therefore, Zn may possess protective effect as preventive and adjuvant therapy of COVID‑19 through reducing inflammation, improvement of mucociliary clearance, prevention of ventilator‑induced lung injury, modulation of antiviral and antibacterial immunity. However, further clinical and experimental studies are required.
The role of glutathione in autism spectrum disorder (ASD) is emerging as a major topic, due to its role in the maintenance of the intracellular redox balance. Several studies have implicated ...glutathione redox imbalance as a leading factor in ASD, and both ASD and many other neurodevelopmental disorders involve low levels of reduced glutathione (GSH), high levels of oxidized glutathione (GSSG), and abnormalities in the expressions of glutathione-related enzymes in the blood or brain. Glutathione metabolism, through its impact on redox environment or redox-independent mechanisms, interferes with multiple mechanisms involved in ASD pathogenesis. Glutathione-mediated regulation of glutamate receptors e.g., N-methyl-d-aspartate (NMDA) receptor, as well as the role of glutamate as a substrate for glutathione synthesis, may be involved in the regulation of glutamate excitotoxicity. However, the interaction between glutathione and glutamate in the pathogenesis of brain diseases may vary from synergism to antagonism. Modulation of glutathione is also associated with regulation of redox-sensitive transcription factors nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) and downstream signaling (proinflammatory cytokines and inducible enzymes), thus providing a significant impact on neuroinflammation. Mitochondrial dysfunction, as well as neuronal apoptosis, may also provide a significant link between glutathione metabolism and ASD. Furthermore, it has been recently highlighted that glutathione can affect and modulate DNA methylation and epigenetics. Review analysis including research studies meeting the required criteria for analysis showed statistically significant differences between the plasma GSH and GSSG levels as well as GSH:GSSG ratio in autistic patients compared with healthy individuals (P = 0.0145, P = 0.0150 and P = 0.0202, respectively). Therefore, the existing data provide a strong background on the role of the glutathione system in ASD pathogenesis. Future research is necessary to investigate the role of glutathione redox signaling in ASD, which could potentially also lead to promising therapeutics.
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•Glutathione (GSH) redox imbalance is a key factor in autism spectrum disorder (ASD).•GSH metabolism interferes with multiple mechanisms involved in ASD pathogenesis.•In ASD, plasma GSH and GSSG levels and their ratio is different from neurotypical controls.
•Interaction of Hg with biomolecules is mediated through its affinity to Cys thiol.•Cys and GSH Hg-conjugates play a significant role in Hg transport in vivo.•Hg-SH affinity interferes with Akt/CREB, ...Keap1/Nrf2, NF-κB-mediated apoptotic pathways.•Hg binding to Mn-SOD (Cys196) and TrxR (Cys497) may underlie its prooxidant effects.•Hg binding limits GSH and Trx (Cys32, 35, 62, 65, 73) availability for redox reactions.
The present study addresses existing data on the affinity and conjugation of sulfhydryl (thiol; -SH) groups of low- and high-molecular-weight biological ligands with mercury (Hg). The consequences of these interactions with special emphasis on pathways of Hg toxicity are highlighted. Cysteine (Cys) is considered the primary target of Hg, and link its sensitivity with thiol groups and cellular damage. In vivo, Hg complexes play a key role in Hg metabolism. Due to the increased affinity of Hg to SH groups in Cys residues, glutathione (GSH) is reactive. The geometry of Hg(II) glutathionates is less understood than that with Cys. Both Cys and GSH Hg-conjugates are important in Hg transport. The binding of Hg to Cys mediates multiple toxic effects of Hg, especially inhibitory effects on enzymes and other proteins that contain free Cys residues. In blood plasma, albumin is the main Hg-binding (Hg2+, CH3Hg+, C2H5Hg+, C6H5Hg+) protein. At the Cys34 residue, Hg2+ binds to albumin, whereas other metals likely are bound at the N-terminal site and multi-metal binding sites. In addition to albumin, Hg binds to multiple Cys-containing enzymes (including manganese-superoxide dismutase (Mn-SOD), arginase I, sorbitol dehydrogenase, and δ-aminolevulinate dehydratase, etc.) involved in multiple processes. The affinity of Hg for thiol groups may also underlie the pathways of Hg toxicity. In particular, Hg-SH may contribute to apoptosis modulation by interfering with Akt/CREB, Keap1/Nrf2, NF-κB, and mitochondrial pathways. Mercury-induced oxidative stress may ensue from Cys-Hg binding and inhibition of Mn-SOD (Cys196), thioredoxin reductase (TrxR) (Cys497) activity, as well as limiting GSH (GS-HgCH3) and Trx (Cys32, 35, 62, 65, 73) availability. Moreover, Hg-thiol interaction also is crucial in the neurotoxicity of Hg by modulating the cytoskeleton and neuronal receptors, to name a few. However, existing data on the role of Hg-SH binding in the Hg toxicity remains poorly defined. Therefore, more research is needed to understand better the role of Hg-thiol binding in the molecular pathways of Hg toxicology and the critical role of thiols to counteract negative effects of Hg overload.
The role of cadmium in obesity and diabetes Tinkov, Alexey A.; Filippini, Tommaso; Ajsuvakova, Olga P. ...
The Science of the total environment,
12/2017, Letnik:
601-602
Journal Article
Recenzirano
Multiple studies have shown an association between environmental exposure to hazardous chemicals including toxic metals and obesity, diabetes, and metabolic syndrome. At the same time, the existing ...data on the impact of cadmium exposure on obesity and diabetes are contradictory. Therefore, the aim of the present work was to review the impact of cadmium exposure and status on the risk and potential etiologic mechanisms of obesity and diabetes. In addition, since an effect of cadmium exposure on incidence of diabetes mellitus and insulin resistance was suggested by several epidemiologic studies, we carried out a meta-analysis of all studies assessing risk of prevalence and incidence of diabetes. By comparing the highest versus the lowest cadmium exposure category, we found a high risk of diabetes incidence (odds ratio=1.38, 95% confidence interval 1.12–1.71), which was higher for studies using urine as exposure assessment. On the converse, results of epidemiologic studies linking cadmium exposure and overweight or obesity are far less consistent and even conflicting, also depending on differences in exposure levels and the specific marker of exposure (blood, urine, hair, nails). In turn, laboratory studies demonstrated that cadmium adversely affects adipose tissue physiopathology through several mechanisms, thus contributing to increased insulin resistance and enhancing diabetes. However, intimate biological mechanisms linking Cd exposure with obesity and diabetes are still to be adequately investigated.
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•Human data on the association between Cd exposure and obesity are contradictory.•Laboratory studies demonstrate that Cd exposure causes adipose tissue dysfunction.•Cd-induced adipose tissue dysfunction promotes insulin resistance without obesity.•Human and laboratory studies indicate the role of Cd in diabetes.
Cadmium has been proposed to be the one of the factors of atherosclerosis development, although the existing data are still controversial. The primary objective of the present study is the review and ...the meta-analysis of studies demonstrating the association between Cd exposure and atherosclerosis as well as review of the potential mechanisms of such association. We performed a systematic search in the PubMed-Medline database using the MeSH terms cadmium, cardiovascular disease, atherosclerosis, coronary artery disease, myocardial infarction, stroke, mortality and humans up through December 20, 2017. Elevated urinary Cd levels were associated with increased mortality for cardiovascular disease (HR = 1.34, 95% CI: 1.07–1.67) as well as elevated blood Cd levels (HR = 1.78, 95% CI: 1.24–2.56). Analysis restricted to never smokers showed similar, though more imprecise, results. Consistently, we also observed an association between Cd exposure markers (blood and urine) and coronary heart disease, stroke, and peripheral artery disease. Moreover, Cd exposure was associated with atherogenic changes in lipid profile. High Cd exposure was associated with higher TC levels (OR = 1.48, 95% CI: 1.10–2.01), higher LDL-C levels (OR = 1.31, 95% CI 0.99–1.73) and lower HDL-C levels (OR = 1.96, 95% CI: 1.09–3.55). The mechanisms of atherogenic effect of cadmium may involve oxidative stress, inflammation, endothelial dysfunction, enhanced lipid synthesis, up-regulation of adhesion molecules, prostanoid dysbalance, as well as altered glycosaminoglycan synthesis.
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 objective of this study was to investigate of selenium (Se), zinc (Zn), chromium (Cr), and vanadium (V) levels in blood serum, hair, and urine of adult obese patients. A total of 199 lean and 196 ...obese subjects were enrolled in the study. Serum, hair, and urinary metal and metalloid analysis were performed by inductively coupled plasma mass spectrometry at NexION 300D (PerkinElmer Inc., USA). The results established that obese subjects were characterized by 47% and 30% lower serum Cr and V levels compared with controls, respectively, whereas serum Se levels exceeded control values by 9%. In contrast, hair Cr, Se, and V content in obese subjects exceeded the control values by 51%, 21%, and 50%, respectively. In turn, hair Zn levels were found to be significantly lower by 11% compared with the lean control values. In urine, the levels of V and Zn were found to be 30% and 18% higher in obese patients. Prevalence of hypertension in obese subjects was associated with a trend for impaired Se and Zn levels. In a regression model adjusted for age, gender, hypertension, atherosclerosis, and glucose intolerance, serum Cr, V, and hair Zn were inversely associated with body mass index (BMI), whereas hair Se was considered as the positive predictor. Our data allow proposing that the observed alterations may at least partially contribute to metabolic disturbances in obesity. In turn, monitoring of Se exposure in a well-nourished adult population is required to reduce its potential contribution to obesity.
Developing brain is very sensitive to the influence of environmental factors during gestation and the neonatal period. The aim of the study is to assess cobalt and iron accumulation in the brain as ...well as changes in the expression of iron-regulatory proteins transferrin receptor 1, hepcidin, and ferroportin in suckling mice. Perinatal exposure to cobalt chloride increased significantly cobalt content in brain tissue homogenates of 18-day-old (d18) and 25-day-old (d25) mice inducing alterations in brain iron homeostasis. Higher degree of transferrin receptor 1 expression was demonstrated in cobalt chloride-exposed mice with no substantial changes between d18 and d25 mice. A weak ferroportin expression was found in 18-day-old control and cobalt-treated mouse brain. Cobalt exposure of d25 mice resulted in increased ferroportin expression in brain compared to the untreated age-matched control group. Hepcidin level in cobalt-exposed groups was decreased in d18 mice and slightly increased in d25 mice. The obtained data contribute for the better understanding of metal toxicity impact on iron homeostasis in the developing brain with further possible implications in neurodegeneration.
•Late prenatal and early postnatal exposure to cobalt chloride increases significantly brain Co content in suckling mice.•CoCl2 provokes changes in the expression of iron-regulatory proteins transferrin receptor 1, hepcidin and ferroportin.•Cobalt toxicity affects iron homeostasis in the developing brain with further possible implications in neurodegeneration.
A significant interrelation between heavy metal exposure and metabolic syndrome (MetS) development has been demonstrated earlier. Despite the presence of a number of works aimed at the investigation ...of the role of Hg in MetS development, the existing data remain contradictory. Therefore, the primary objective of the current work is to review the existing data regarding the influence of mercury on universal mechanisms involved in the pathogenesis of the development of MetS and its components. The brief chemical characterization of mercury is provided. The role of mercury in induction of oxidative stress has been discussed. In particular, Hg-induced oxidative stress may occur due to both prooxidant action of the metal and decrease in antioxidant enzymes. Despite the absence of direct indications, it can be proposed that mercury may induce endoplasmic reticulum stress. As it is seen from both in vivo and in vitro studies, mercury is capable of inducing inflammation. The reviewed data demonstrate that mercury affects universal pathogenetic mechanisms of MetS development. Moreover, multiple investigations have indicated the role of mercury in pathogenesis of MetS components: dyslipidemia, hypertension, insulin resistance, and obesity to a lesser extent. The present state of data regarding the interrelation between mercury and MetS denotes the following perspectives: (1) Further clinic-epidemiologic and experimental studies are required to estimate the association between mercury exposure and the development of MetS components, especially obesity; (2) Additional investigations of the possible effect of organism’s mercury content modulation on MetS pathogenesis should be undertaken.
Lipid peroxidation results in generation of a variety of lipid hydroperoxides and other highly reactive species that covalently modify proteins, nucleic acids, and other lipids, thus resulting in ...lipotoxicity. Although biological relevance of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) is well studied, the existing data on the role of isolevuglandins (isoLGs) in pathology are insufficient. Therefore, the objective of the present study was to review the existing data on biological effects of isoLG and isoLG adducts and their role in multiple diseases. Sixty four highly reactive levuglandin-like γ-ketoaldehyde (γ-KA, or isoketals, IsoK, or isolevuglandins, IsoLG) regio- and stereo-isomers are formed as products of arachidonic acid oxidation. IsoLGs react covalently with lysyl residues of proteins to form a stable adduct and intramolecular aminal, bispyrrole, and trispyrrole cross-links. Phosphatidylethanolamine was also shown to be the target for isoLG binding as compared to proteins and DNA. Free IsoLGs are not detectable in vivo, although isolevuglandin adduction to amino acid residues of particular proteins may be evaluated with liquid chromatography-tandem mass spectrometry. Adducts formed were shown to play a significant role in the development and maintenance of oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and inflammation. These, and more specific molecular pathways, link isoLG and isoLG-adduct formation to develop a variety of pathologies, including cardiovascular diseases (atherosclerosis, hypertension, heart failure), obesity and diabetes, cancer, neurodegeneration, eye diseases (retinal degeneration and glaucoma), as well as ageing. Hypothetically, isoLGs and isoLG adduct formation may be considered as the potential target for treatment of oxidative stress-related diseases.
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•Isolevuglandins or isoketals are formed as products of arachidonic acid oxidation.•IsoLGs react covalently with lysyl residues of proteins to form stable adducts.•IsoLGs are involved in inflammation and endoplasmic reticulum stress.•IsoLG and isoLG-adduct formation is linked to variety of pathologies.•IsoLGs may be a potential target for treatment of oxidative stress-related diseases.
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