Salidroside Protects against Cadmium-Induced Hepatotoxicity in Rats via GJIC and MAPK Pathways

Abstract

It is known that cadmium (Cd) induces cytotoxicity in hepatocytes; however, the underlying mechanism is unclear. Here, we studied the molecular mechanisms of Cd-induced hepatotoxicity in rat liver cells (BRL 3A) and in vivo. We observed that Cd treatment was associated with a time- and concentration-dependent decrease in the cell index (CI) of BRL 3A cells and cellular organelle ultrastructure injury in the rat liver. Meanwhile, Cd treatment resulted in the inhibition of gap junction intercellular communication (GJIC) and activation of mitogen-activated protein kinase (MAPK) pathways. Gap junction blocker 18-β-glycyrrhetinic acid (GA), administered in combination with Cd, exacerbated cytotoxic injury in BRL 3A cells; however, GA had a protective effect on healthy cells co-cultured with Cd-exposed cells in a co-culture system. Cd-induced cytotoxic injury could be attenuated by co-treatment with an extracellular signal-regulated kinase (ERK) inhibitor (U0126) and a p38 inhibitor (SB202190) but was not affected by co-treatment with a c-Jun N-terminal kinase (JNK) inhibitor (SP600125). These results indicate that ERK and p38 play critical roles in Cd-induced hepatotoxicity and mediate the function of gap junctions. Moreover, MAPKs induce changes in GJIC by controlling connexin gene expression, while GJIC has little effect on the Cd-induced activation of MAPK pathways. Collectively, our study has identified a possible mechanistic pathway of Cd-induced hepatotoxicity in vitro and in vivo, and identified the participation of GJIC and MAPK-mediated pathways in Cd-induced hepatotoxicity. Furthermore, we have shown that salidroside may be a functional chemopreventative agent that ameliorates the negative effects of Cd via GJIC and MAPK pathways.

Modelling cadmium‐induced cardiotoxicity using human pluripotent stem cell‐derived cardiomyocytes

“…We first sought to determine whether cadmium can induce morphological changes and cell death in H9‐CMs. Previous studies have investigated cadmium‐induced cytotoxicity in different cell types within a range of 0‐300 μmol/L . Therefore, cells were exposed to escalating concentrations of cadmium chloride (CdCl 2 ) from 0.1 to 100 μmol/L for 24 hours, and significantly morphological changes appeared in cells treated with 30 and 100 μmol/L CdCl 2 (Videos ).…”

“…To relate changes in gene expression to functional consequences, we next investigated MAPK signalling pathway, which was associated with cadmium‐induced apoptosis of several cell types in previous studies and was dramatically up‐regulated in CdCl 2 ‐treated H9‐CMs …”

Salidroside pretreatment attenuates apoptosis and autophagy during hepatic ischemia–reperfusion injury by inhibiting the mitogen-activated protein kinase pathway in mice

“…What is more, Sal protects myocardia from IRI in rats by inhibiting apoptosis and inflammation 24. In addition, Sal inhibits MAPK signal transduction to protect organs from damaging factors, such as cardiac exhaustive injury, cadmium-induced hepatotoxicity, and cigarette smoke-induced lung diseases 18,25. Therefore, it is reasonable to infer that Sal could protect hepatic IRI through the downregulation of MAPKs to inhibit inflammation, apoptosis, and autophagy.…”

Mixing ratio optimization for functional complex extracts of Rhodiola crenulata, Panax quinquefolius, and Astragalus membranaceus using mixture design and verification of immune functional efficacy in animal models

“…In Europe and Asia, R. crenulata is a traditional drug with efficacy in stimulating the nervous system, reducing depression, enhancing work capacity, promoting fatigue recovery, and preventing altitude sickness (Ishaque, Shamseer, Bukutu, & Vohra, 2012;Kelly, 2001;Lee, 1998). Unofficially, R. crenulata has been used as a fever reducer, sedative, and astringent and has been reported to show antioxidant, anti-inflammatory, antidiabetic, and liver toxicity protection activities (Choe et al, 2012;Kwon, Jang, & Shetty, 2006;Wu, Lian, Jiang, & Nan, 2009;Zou et al, 2015). Recently, researchers have reported that R. crenulata has additional beneficial effects, including antioxidant activity (Kanupriya et al, 2005) and protection against neuron damage (Mook-Jung et al, 2002).…”