Background and Objective Chronic kidney disease (CKD) is an important public health concern. With the decline of renal function, CKD patients gradually progress to end-stage kidney disease and need to undergo dialysis or kidney transplantation to maintain life, bringing a heavy economic burden to the family and society. Therefore, it is necessary to effectively prevent and delay the progression of CKD. Essential trace elements play an indispensable role in CKD, and the objective of this study is to systematically review their benefits in the disease and summarize the risks of their excess. Methods The keywords “trace elements”, “chronic kidney disease”, “dialysis”, “inflammation”, and “fibrosis” and their combinations were used to search for relevant literature published in the PubMed database and Web of Science. We then summarized the role of trace element abnormalities in CKD patients in anemia, oxidative stress, inflammation, and chronic fibrosis, and the risk of their excess. Key Content and Findings Imbalance of essential trace elements is a common complication of CKD and a risk factor for CKD progression, cardiovascular events, and death. This article reviews the effects of essential trace elements (iron, zinc, selenium, copper, iodine, and manganese) on CKD. We analyze literature and discuss the advantages and disadvantages of various essential trace elements. Conclusions Research shows CKD patients have an imbalance of essential trace elements, and treatment based on these is an important direction for future exploration. A knowledge of the homeostasis of trace elements is important to improving the prognosis of CKD patients and delaying the progression of the disease.

https://atm.amegroups.com/article/viewFile/107335/pdf

Benefits and risks of essential trace elements in chronic kidney disease: a narrative review

Manganese (Mn) is an essential trace element, but insufficient or excessive bodily amounts can induce neurotoxicity. Mn can directly increase neuronal insulin and activate insulin-like growth factor (IGF) receptors. As an important cofactor, Mn regulates signaling pathways involved in various enzymes. The IGF signaling pathway plays a protective role in the neurotoxicity of Mn, reducing apoptosis in neurons and motor deficits by regulating its downstream protein kinase B (Akt), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR). In recent years, some new mechanisms related to neuroinflammation have been shown to also play an important role in Mn-induced neurotoxicity. For example, DNA-sensing receptor cyclic GMP–AMP synthase (cCAS) and its downstream signal efficient interferon gene stimulator (STING), NOD-like receptor family pyrin domain containing 3(NLRP3)-pro-caspase1, cleaves to the active form capase1 (CASP1), nuclear factor κB (NF-κB), sirtuin (SIRT), and Janus kinase (JAK) and signal transducers and activators of the transcription (STAT) signaling pathway. Moreover, autophagy, as an important downstream protein degradation pathway, determines the fate of neurons and is regulated by these upstream signals. Interestingly, the role of autophagy in Mn-induced neurotoxicity is bidirectional. This review summarizes the molecular signaling pathways of Mn-induced neurotoxicity, providing insight for further understanding of the mechanisms of Mn.

Signaling Pathways Involved in Manganese-Induced Neurotoxicity

Global manganese pollution to air and water is a significant threat to human health. The associations between manganese and liver stiffness and steatosis have not been reported in epidemiological studies. This study aimed to explore the clinical relevance of blood manganese with liver stiffness and steatosis in adults from the 2017–2018 National Health and Nutrition Examination Survey (N = 4,192). Subjects with excessive alcohol consumption and hepatitis B or C infection were excluded. Liver stiffness and steatosis were detected by transient elastography. Logistic regression and restricted cubic splines were adopted to explore the non-linear dose–response relationships. In multivariate analysis, while higher blood manganese concentrations were not associated with liver stiffness in the total sample and in males, an increased odds of significant liver fibrosis was found with higher blood manganese concentrations (tertile 3 vs. tertile 1) in females [odds ratios (95% confidence intervals): 2.34 (1.32–4.14), P trend < 0.01] and in other races [1.47 (1.05–2.05), P trend = 0.03]. Higher blood manganese concentrations were associated with liver steatosis in the total sample [1.33 (1.04–1.70), P trend = 0.03], in females [1.58 (1.02–2.44), P trend = 0.04], in other races [1.91 (1.50–2.43), P trend < 0.01], and in obese subjects [2.29 (1.13–4.65), P trend = 0.02]. Dose–response analysis showed that the departures from non-linear relationships between blood manganese concentrations and significant liver fibrosis (Pnon-linearity = 0.30) and steatosis (Pnon-linearity = 0.47) were not significant, suggesting that the observed associations were linear. In conclusion, higher blood manganese concentrations were positively associated with liver stiffness and steatosis, and the associations were mainly observed in females, in races other than Non-Hispanic White, and in obese subjects.

Clinical relevance of environmental manganese exposure with liver stiffness and steatosis detected by transient elastography in adults.

Prolonged exposure to manganese (Mn) contributes to hippocampal Mn accumulation, which leads to neurodegenerative diseases called manganese poisoning. However, the underlying molecular mechanisms remain unclear and there are no ideal biomarkers. Oxidative stress is the essential mechanisms of Mn-related neurotoxicity. Furthermore, histone acetylation has been identified as being engaged in the onset and development of neurodegenerative diseases. Therefore, the work aims to understand the molecular mechanisms of oxidative damage in the hippocampus due to Mn exposure from the aspect of histone acetylation modification and to assess whether H3K18 acetylation (H3K18ac) modification level in peripheral blood reflect Mn-induced oxidative damage in the hippocampus. Here, we randomly divided 60 male rats into four groups and injected them intraperitoneally with sterile pure water and MnCl2 ⋅4H2 O (5, 10, and 15 mg/kg) for 16 weeks, 5 days a week, once a day. The data confirmed that Mn exposure down-regulated superoxide dismutase activity and glutathione level as well as up-regulated malondialdehyde level in the hippocampus and plasma, and that there was a positive correlation between these indicators in the hippocampus and plasma. Besides, we noted that Mn treatment upregulated H3K18ac modification levels in the hippocampus and peripheral blood and that H3K18ac modification levels correlated with oxidative stress. Further studies demonstrated that Mn treatment decreased the amounts of H3K18ac enrichment in the manganese superoxide dismutase (SOD2) and glutathione transferase omega 1 (GSTO1) gene promoter regions, contributing to oxidative damage in the hippocampus. In short, our results demonstrate that Mn induces oxidative damage in the hippocampus by inhibiting the expression of SOD2 and GSTO1 genes via modulation of H3K18ac. In assessing Mn-induced hippocampal neurotoxicity, oxidative damage in plasma may reflect hippocampal oxidative damage in Mn-exposed groups.

Manganese induces oxidative damage in the hippocampus by regulating the expression of oxidative stress-related genes via modulation of H3K18 acetylation.

ABSTRACT Excessive manganese (Mn) exposure can result in significant liver toxicity in humans and animals. Histone demethylation, a crucial epigenetic modification, is believed to play a pivotal role in liver disease progression. However, the involvement of histone demethylation‐associated genes in Mn‐induced hepatotoxicity remains poorly understood. This study aimed to identify these genes related to Mn exposure. We analyzed gene expression data, which included liver samples treated with manganese chloride (MnCl 2) and control samples. Our analysis revealed 351 differentially expressed genes (DEGs) on Day 3 and 494 DEGs on Day 5 in livers treated with 700 mg/kg MnCl 2 . Notably, we identified 24 overlapping histone demethylation‐associated DEGs across both time points. Biological process analysis indicated that these DEGs are linked to organ regeneration, cell proliferation, responses to xenobiotic substances and toxins, bile transport, fatty acid metabolism, and posttranscriptional regulation. Pathway analysis identified associations with IL‐17 signaling, cAMP pathways, chemical carcinogenesis, and parathyroid hormone synthesis and action. Furthermore, we highlighted several histone demethylation‐associated hub genes, including CDKN1A , PPARA , CYP7A1 , CAV1 , GDF15 , and GRP , implicated in Mn‐induced hepatotoxicity. 

Epigenetic Regulation of Manganese‐Induced Hepatotoxicity Uncovering Histone Demethylation‐Associated Gene Networks

This study investigated hepatic oxidative damage in rats following long-term manganese (Mn) exposure and clarified the underlying mechanisms. Forty-eight rats (SPF, male) were randomly assigned to receive low (10 mg/kg, n = 16) or high doses of Mn (50 mg/kg, n = 16) or sterilized distilled water (control group, n = 16). Rats were euthanized after 12 months, and liver Mn levels and histopathological changes were determined. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and liver malondialdehyde (MDA), glutathione peroxidase (GSH-PX), nuclear factor E2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H quinine oxidoreductase-1 (NQO1) levels were also determined. The Mn concentration and relative liver weights were significantly higher in the high-dose Mn group than in the control and low-dose Mn exposure groups. Low-dose Mn exposure resulted in mild expansion of hepatic sinuses and intact nuclei, whereas high-dose exposure led to pathological alterations in hepatocytes. High-dose Mn treatment significantly increased AST, ALT, and MDA activities and decreased GSH-PX activity. Additionally, liver Nrf2, HO-1, and NQO1 protein expression were markedly reduced by Mn exposure. Under the study conditions, long-term low-dose Mn exposure resulted in slight pathological changes in liver structure, but high-dose Mn exposure affected both liver structure and function, which might be related to the inhibition of Nrf2 expression, suppression of the transcription of its underlying antioxidant genes, and down regulation of the corresponding proteins. Consequently, the antioxidant capacity in the rat liver was weakened.

Hepatic oxidative damage and Nrf2 pathway protein changes in rats following long-term manganese exposure.

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Hepatic oxidative damage and Nrf2 pathway protein changes in rats following long-term manganese exposure.