Vitamin D₃ and calcium cosupplementation alleviates cadmium hepatotoxicity in the rat: Enhanced antioxidative and anti‐inflammatory actions by remodeling cellular calcium pathways

Abstract

Although vitamin D (VD) and calcium (Ca) attenuate cadmium (Cd) metabolism, their combined antioxidant and anti‐inflammatory actions against Cd toxicity have not been previously explored. Hence, this study measured the protective effects of VD ± Ca supplements against Cd hepatotoxicity. Forty adult male rats were distributed to: negative controls (NCs), positive controls (PCs), VD, Ca, and VD3 and Ca (VDC) groups. All groups, except NC, received CdCl2 in drinking water (44 mg/L) for 4 weeks individually or concurrently with intramuscular VD3 (600 IU/kg; three times per week) and/or oral Ca (100 mg/kg; five times per week). The PC group showed abnormal hepatic biochemical parameters and increase in cellular cytochrome C, caspase‐9, and caspase‐3 alongside the apoptotic/necrotic cell numbers by terminal deoxynucleotidyl transferase dUTP nick end labeling technique. The PC hepatic tissue also had substantially elevated pro‐oxidants (malondialdehyde [MDA]/H2O2/protein carbonyls) and inflammatory cytokines (interleukin 1β [IL‐1β]/IL‐6/IL17A/tumor necrosis factor‐α), whereas the anti‐inflammatory (IL‐10/IL‐22) and antioxidants (glutathione [GSH]/GPx/catalase enzyme [CAT]) markers declined. Hypovitaminosis D, low hepatic tissue Ca, aberrant hepatic expression of VD‐metabolizing enzymes (Cyp2R1/Cyp27a1/cyp24a1), receptor and binding protein alongside Ca‐membrane (CaV1.1/CaV3.1), and store‐operated (RyR1/ITPR1) channels, and Ca‐binding proteins (CAM/CAMKIIA/S100A1/S100B) were observed in the PC group. Both monotherapies decreased serum, but not tissue Cd levels, restored the targeted hepatic VD/Ca molecules' expression. However, these effects were more prominent in the VD group than the Ca group. The VDC group, contrariwise, disclosed the greatest alleviations on serum and tissue Cd, inflammatory and oxidative markers, the VD/Ca molecules and tissue integrity. In conclusion, this report is the first to reveal boosted protection for cosupplementing VD and Ca against Cd hepatotoxicity that could be due to enhanced antioxidative, anti‐inflammatory, and modulation of the Ca pathways.

Protective antioxidative and anti-inflammatory actions of β-caryophyllene against sulfasalazine-induced nephrotoxicity in rat

“…Euthanasia was then performed on day-15 by cervical dislocation under anesthesia as previously reported. 18 Blood samples were obtained, and serum was kept at −20°C following centrifugation. Both kidneys were removed from each rat, and a specimen was used for histopathological experiments.…”

Exploration of the optimal strategy for dietary calcium intervention against the toxicity of liver and kidney induced by cadmium in mice: An in vivo diet intervention study

“…It has been reported that the content of Ca in body can significantly influence Cd absorption in the gastrointestinal tract, for Cd use the same intestinal transporters as Ca in both animals and humans [ 17 , 21 ]. With a high chemical similarity to Cd, Ca can regulate physiological or metabolic changes in organisms induced by Cd [ 33 ]. In our study, all indicators in Ca-group were not significantly different from those in control-group, which excluded the threat of Ca supplementation on the health of mice, whereas there was significant toxicity of liver and kidneys in mice exposed to Cd as compared with the mice in control-group.…”

Role of Autophagy in Cadmium-Induced Hepatotoxicity and Liver Diseases

“…Cd is an indirect genotoxic carcinogen, and it has been shown that chronic Cd exposure strongly correlates with an increased risk of several cancers including prostate, genitourinary, breast, lung, pancreas, and hepatocellular carcinoma (HCC) [25][26][27][28][29][30] mechanism of Cd carcinogenesis has shown that chronic Cd exposure can induce oxidative stress [31][32][33], inhibit DNA repair [34,35], promote abnormal methylation of DNA [36][37][38], interfere with gene expression [29,38], affect cell cycle regulation [39,40], inhibit cell apoptosis [41], induce inflammatory signaling [42], and promote genomic instability and mutation in key genes to promote tumorigenesis [43]. Indeed, high concentrations of Cd from acute exposure or low concentrations of chronic exposure are both linked to severe hepatotoxicity/liver injury that promotes liver diseases and HCC development (Figure 2).…”