Yan Zhang,Hong Huang,Chuanlin Luo,Xinfeng Zhang,Yanjing Chen,Fenfang Yue,Bingqing Xie,Tingtao Chen,Changwei Zou
Cadmium (Cd) is recognized as being linked to several liver diseases. Currently, due to the limited spectrum of drugs available for the treatment of Cd intoxication, developing and designing antidotes with superior detoxification capacity and revealing their underlying mechanisms remains a major challenge. Therefore, we developed the first next-generation probioticE. coli 1917-pSK18a-MT that delivers metallothionein (MT) to overcome Cd-induced liver injury in C57BL/6 mice by utilizing bacterial surface display technology. The results demonstrate thatE. coli 1917-pSK18a-MT could efficiently express MT without altering the growth and probiotic properties of the strain. Moreover, we found thatE. coli 1917-pSK18a-MT ameliorated Cd contamination-induced hepatic steatosis, inflammatory cell infiltration, and liver fibrosis by decreasing the expression of aminotransferases along with inflammatory factors. Activation of the Nrf2-Keap1 signaling pathway also further illustrated the hepatoprotective effects of the engineered bacteria. Finally, we showed thatE. coli 1917-pSK18a-MT improved the colonic barrier function impaired by Cd induction and ameliorated intestinal flora dysbiosis in Cd-poisoned mice by increasing the relative abundance of the Verrucomicrobiota. These data revealed that the combination ofE. coli 1917and MT both alleviated Cd-induced liver injury to a greater extent and restored the integrity of colonic epithelial tissues and bacterial dysbiosis.
Ethnopharmacological relevance Cadmium (Cd) can first damage the kidney, leading to renal tubular dysfunction and irreversible renal damage. Ganoderma lucidum is a traditional Chinese herb that can enhances kidney qi and is extensively used in the management of renal diseases. As a new type of high-quality Ganoderma lucidum , Ganoderma leucocontextum (GL) has been shown to have antioxidant, anti-apoptotic, and anti-inflammatory properties, demonstrating significant potential for application in the treatment of cadmium-toxic nephropathy Aim of the study This study intends to investigate the impact and mechanism of GL extract on cadmium-toxic nephropathy Materials and methods A mouse Cd-toxic nephropathy model was established by intragastric administration of cadmium chloride for 4 weeks. Serum was collected for renal function index detection, and renal tissue was collected for Cd content, histopathology, oxidative stress index, apoptosis, and autophagy index detection to evaluate the damage of renal function and the intervention effect of the extract. The chemical ingredients of the extracts were detected by ultra-high liquid chromatography coupled with mass spectrometry detection (UPLC-MS/MS), and the total antioxidant capacity was determined. The targets and pathways of interest were derived from the integration of transcriptomic and network pharmacology results. Western blot (WB) and quantitative real-time PCR (qPCR) were used for subsequent validation. Results GL extract effectively improved kidney damage caused by Cd-toxic nephropathy, especially the GL ethanol extract (GLE). Compared with the model group, the intervention group exhibited a significant reduction in serum creatinine (Scr) and blood urea nitrogen (BUN) levels, an enhancement in histopathological integrity, a notable decrease in malondialdehyde levels, a significant increase in glutathione levels and superoxide dismutase activity, as well as a marked elevation in the ratios of Bcl-2/Bax and LC3BⅡ/LC3BⅠ. Expression of Cleaved Caspase-3 and P62 protein was markedly reduced. Comprehensive network pharmacology and transcriptomic analysis showed that the AMPK signaling pathway is a crucial pathway, and PPARα is an important target and downstream regulator of the AMPK pathway. WB and qPCR analyses showed that the activation of AMPK, SIRT1, PGC-1α, and PPARα in the kidney tissue of mice in the model group was markedly diminished, whereas it was dramatically elevated following GLE intervention Conclusions GL extract can effectively ameliorate kidney damage caused by Cd accumulation, most likely through the AMPK/SIRT1/PGC-1α/PPARα signaling pathway.
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