Shen Ren

Supplementation of American ginseng berry extract mitigated cisplatin-evoked nephrotoxicity by suppressing ROS-mediated activation of MAPK and NF-κB signaling pathways

Nephrotoxicity induced by cisplatin in 30% of all cisplatin treated patients seriously limits its clinical implication as a widely used anticancer agent, and may even cause patients to alter or give up cisplatin therapy. The purpose of this study is to test a protective effect of American ginseng berry extract (AGBE) on cisplatin-induced nephrotoxicity in mice. In this study, the histopathological changes and elevated levels of serum creatinine (CRE) and urea nitrogen (BUN) caused by cisplatin were significantly diminished by AGBE treatment. Oxidative stress caused by cisplatin, evidenced by increases in kidney tissues malondialdehyde (MDA) content, cytochrome P450 E1 (CYP2E1), renal 4-hydroxynonenal (4-HNE) levels and decreases of glutathione (GSH) and superoxide dismutase (SOD) contents, was significantly ameliorated by AGBE pretreatment. The expression levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were inhibited by AGBE treatment, suggesting a suppression of inflammatory response. Additionally, AGBE clearly inhibited cisplatin-induced activations of nuclear factor-kappa B (NF-κB) and mitogen activated protein kinase (MAPK) signal pathways. Supplementation of cisplatin-intoxicated mice with AGBE also significantly reduced apoptotic protein levels of Bax, cleaved caspase-3, cytochrome c and increased anti-apoptotic protein Bcl-2. These findings highlight nephroprotective effect of AGBE against cisplatin-evoked nephrotoxicity through ROS-mediated MAPK and NF-κB signaling pathways.

Improvement of Cisplatin-induced renal dysfunction by Schisandra chinensis stems via anti-inflammation and anti-apoptosis effects

ETHNOPHARMACOLOGICAL RELEVANCEnSchisandra chinensis (Turcz.) Baill is a frequently used traditional Chinese medicine, and modern pharmacological research has proven that S. chinensis has antioxidant, anti-hepatotoxity, anti-inflammatory, and anti-nephrotoxic effects. Cisplatin is widely used as antineoplastic drug at present, but the clinical application is limited owing to its nephrotoxicity.nnnAIM OF THE STUDYnTo demonstrate the renoprotective activity of the extract of the stems of S. chinensis (SCE) in mice established by cisplatin-triggering acute kidney injury (AKI). The possible molecular mechanism of nephroprotection exhibited by SCE was evaluated for the first time.nnnMATERIALS AND METHODSnMice in SCE groups were pre-treated with SCE for 10 consecutive days, and on 7th day 1u202fh after final administration, following intraperitoneal injection of cisplatin with 20u202fmg/kg was treated to cisplatin group and SCE groups. On the 10th day, renal function, histopathological change, and oxidative stress markers were investigated.nnnRESULTSnRenal oxidative stress level characterized by elevated heme oxygenase 1 (HO-1), cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) expression was obviously reduced by SCE pre-treatment. In addition, SCE was found to suppress inflammatory response through the reduction of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) p65 activation. SCE treatment also inhibited activation of apoptotic pathways through down-regulating Bax, cleaved caspase-3, 8, 9 and up-regulating Bcl-2 expression levels.nnnCONCLUSIONnThese findings illustrated that SCE possessed powerful protective effect on AKI caused by cisplatin via amelioration of oxidative stress, inflammation and apoptosis.

NF-κB and AMPK/PI3K/Akt signaling pathways are involved in the protective effects of Platycodon grandiflorum saponins against acetaminophen-induced acute hepatotoxicity in mice: Platycodon grandiflorum saponins alleviate APAP-induced hepatotoxicity

Acute liver injury (ALI) induced by acetaminophen (APAP) overdose is the most common cause of drug‐induced liver injury. Saponins from Platycodon grandiflorum (PGSs) ameliorate alcohol‐induced hepatotoxicity and enhance human lung carcinoma cell death via AMPK signaling pathway. However, whether PGS could protect from APAP‐induced ALI through AMPK activation and its downstream signals is still poorly elucidated. This work investigated the protective effect and the underlying mechanisms of PGS against APAP‐induced liver toxicity in mouse. PGS was administered at 15 or 30 mg/kg i.g./day for 1 week before a single injection of APAP (250 mg/kg, i.p.) 1 hr after last treatment of PGS. Serum alanine/aspartate aminotransferases, liver tumor necrosis factor‐α and interleukin‐1β levels, liver malondialdehyde formation, liver glutathione depletion, cytochrome P450 E1, and 4‐hydroxynonenal levels were measured to demonstrate the protective efficacy of PGS against APAP‐induced ALI. Liver histological observation provided further evidence on PGSs protective effects. PGS treatment altered the phosphorylation of AMPK and PI3K/Akt, as well as the downstream signals including Bcl‐2 family, caspase, and NF‐κB in a dose‐dependent manner. In conclusion, we demonstrate that PGS exhibits a significant liver protection against APAP‐induced ALI, mainly through NF‐κB and AMPK/PI3K/Akt signaling pathways.

20(R)-ginsenoside Rg3, a rare saponin from red ginseng, ameliorates acetaminophen-induced hepatotoxicity by suppressing PI3K/AKT pathway-mediated inflammation and apoptosis

ABSTRACT Although ginsenoside Rg3 was isolated as a major component of Korea red ginseng and confirmed to exert potential hepatoprotective effect on acetaminophen (APAP)‐induced liver injury via induction of glutathione S‐transferase (GST) in vitro, thein vivo hepatoprotective effect of Rg3 and the underlying molecular mechanism of action remain unclear. The current study was aimed to explore whether 20(R)‐Ginsenoside Rg3 (20(R)‐Rg3) could alleviate acetaminophen‐induced liver injury in mice and to determine the involvement of PI3K/AKT signaling pathway. Our findings demonstrated that a single injection of APAP (250mg/kg) increased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor‐&agr; (TNF‐&agr;), and interleukin‐1&bgr; (IL‐1&bgr;); such increases were attenuated by pretreatment of mice with 20(R)‐Rg3 for seven days. The depletion of glutathione (GSH), generation of malondialdehyde (MDA) and the over expression of cytochrome P450 E1 (CYP2E1) and 4‐hydroxynonenal (4‐HNE) caused by APAP exposure were also inhibited by 20(R)‐Rg3 pretreatment. Moreover, 20(R)‐Rg3 pretreatment significantly alleviated APAP‐induced apoptosis, necrosis, and inflammatory infiltration in liver tissues. Importantly, 20(R)‐Rg3 effectively attenuated APAP‐induced liver injury in part via activating PI3K/AKT signaling pathway. In summary, 20(R)‐Rg3 exerted liver protection against APAP‐caused hepatotoxicity evidenced by inhibition of oxidative stress and inflammatory response, alleviation of hepatocellular necrosis and apoptosis via activation of PI3K/AKT signaling pathway, showing potential as a novel therapeutic agent to prevent liver damage. Highlights20(R)‐Rg3 exerts protective effect against APAP‐induced hepatotoxicity in mice.The adjustment of oxidative stress is involved in the protective effects of 20(R)‐Rg3 on APAP‐induced ALI.The liver protection effect of 20(R)‐Rg3 is due to suppressing PI3K/AKT pathway‐mediated inflammation and apoptosis in mice.

The protective effects of maltol on cisplatin-induced nephrotoxicity through the AMPK-mediated PI3K/Akt and p53 signaling pathways

Cisplatin, a potent anticancer drug, is usually causing nephrotoxicity; limiting its therapeutic application and efficiency. Maltol may be used to prevent such toxic effect. The aim of this study was to investigate the underlying protective mechanisms of maltol on nephrotoxicity by cisplatin using a cisplatin-treated mouse model and a cellular toxicity model of HEK293 cells. The blood urea nitrogen (BUN), creatinine (CRE) and neutrophil gelatinase-associated lipocalin (NGAL) levels in mice were increased by cisplatin but decreased to normal ranges by maltol pretreatment (50 and 100u2009mg/kg) for ten days. Besides, maltol pretreatment decreased oxidative stress, lipid peroxidation and apoptosis in cisplatin-treated mice. The inhibitory action of maltol on inflammatory responses was achieved by reducing the expressions in NF-κB, IL-1β, iNOS, and TNF-α in the mice in vivo. Additionally, maltol restored the reduction of PI3K/Akt and mTOR levels by cisplatin through increasing AMPK expression in cisplatin-treated HEK293 cells. Maltol also suppressed the expression of Bax and caspase 3 by inhibiting the p53 activity in HEK293 cells. Overall, maltol may serve as a valuable potential drug to prevent cisplatin-induced nephrotoxicity, and the underlying molecular mechanisms of maltol action may involve intracellular AMPK/PI3K/Akt and p53 signaling pathways.

Improved protective effects of American ginseng berry against acetaminophen-induced liver toxicity through TNF-α-mediated caspase-3/-8/-9 signaling pathways

BACKGROUNDnSimilar to the leaves of P. Quinquefolius, American ginseng berry (AGB) is another important part of P. Quinquefolius with alternative therapeutic potential. The liver protection capabilities of the former have been demonstrated previously, however, the later has not yet been evaluated.nnnPURPOSEnBased on our previous observation, the present work was designed to evaluate the hepatic protective effects for novel mechanisms of AGB in acetaminophen (APAP)-induced liver injury in vivo.nnnSTUDY DESIGN/METHODSnAll mice were divided into four groups as follows: normal group, APAP group and APAPu202f+u202fAGB (150u202fmg/kg and 300u202fmg/kg) groups. AGB were orally administered for one week before exposure to APAP (250u202fmg/kg). Severe liver injury was observed and hepatotoxicity was evaluated after 24u202fh through evaluating the biochemical markers, protein expressions levels and liver histopathology.nnnRESULTSnOur study results clearly demonstrated that AGB pretreatment ameliorated APAP-induced hepatic injury as evidenced by decreasing plasma alanine aminotransferase (ALT), aspartate transaminase (AST), tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) compared to the APAP group. Western blotting analysis showed that pretreatment with AGB decreased the expressions levels of TNF-α and nuclear transcription factor-κB (NF-κB p65) in liver tissues. Meanwhile, the protein expression levels of caspases, cytochrome c, and Bax were elevated by AGB treatment for seven days, while the protein expression level of Bcl-2 was inhibited comparison with that in APAP group. Furthermore, supplement of AGB resulted in increase of superoxide dismutase (SOD) and glutathione (GSH), while decrease of malondialdehyde (MDA) content and the expression levels of 4-hydroxynonenal (4-HNE) and cytochrome P450 E1 (CYP2E1). The results of histopathological staining demonstrated that AGB pretreatment inhibited APAP-induced hepatocyte infiltration, congestion, and necrosis.nnnCONCLUSIONnThe present study demonstrated that AGB pretreatment protected liver cells against APAP-induced hepatotoxicity through inhibition of oxidative stress, inflammation responses via TNF-α-mediated caspase-3/-8/-9 signaling pathways.

The Liver Protection Effects of Maltol, a Flavoring Agent, on Carbon Tetrachloride-Induced Acute Liver Injury in Mice via Inhibiting Apoptosis and Inflammatory Response

The purpose of this research was to evaluate whether maltol could protect from hepatic injury induced by carbon tetrachloride (CCl4) in vivo by inhibition of apoptosis and inflammatory responses. In this work, maltol was administered at a level of 100 mg/kg for 15 days prior to exposure to a single injection of CCl4 (0.25%, i.p.). The results clearly indicated that the intrapulmonary injection of CCl4 resulted in a sharp increase in serum aspartate transaminase (AST) and alanine transaminase (ALT) activities, tumor necrosis factor-α (TNF-α), irreducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NF-κB) and interleukin-1β (IL-1β) levels. Histopathological examination demonstrated severe hepatocyte necrosis and the destruction of architecture in liver lesions. Immunohistochemical staining and western blot analysis suggested an accumulation of iNOS, NF-κB, IL-1β and TNF-α expression. Maltol, when administered to mice for 15 days, can significantly improve these deleterious changes. In addition, TUNEL and Hoechst 33258 staining showed that a liver cell nucleus of a model group diffused uniform fluorescence following CCl4 injection. Maltol pretreatment groups did not show significant cell nuclear condensation and fragmentation, indicating that maltol inhibited CCl4-induced cell apoptosis. By evaluating the liver catalase (CAT), glutathione (GSH), superoxide dismutase (SOD) activity, and further using a single agent to evaluate the oxidative stress in CCl4-induced hepatotoxicity by immunofluorescence staining, maltol dramatically attenuated the reduction levels of hepatic CAT, GSH and SOD, and the over-expression levels of CYP2E1 and HO-1. In the mouse model of CCl4-induced liver injury, we have demonstrated that the inflammatory responses were inhibited, the serum levels of ALT and AST were reduced, cell apoptosis was suppressed, and liver injury caused by CCl4 was alleviated by maltol, demonstrating that maltol may be an efficient hepatoprotective agent.

Dietary α-Mangostin Provides Protective Effects against Acetaminophen-Induced Hepatotoxicity in Mice via Akt/mTOR-Mediated Inhibition of Autophagy and Apoptosis

Acetaminophen overdose-induced hepatotoxicity is the most common cause of acute liver failure in many countries. Previously, alpha-mangostin (α-MG) has been confirmed to exert protective effects on a variety of liver injuries, but the protective effect on acetaminophen-induced acute liver injury (ALI) remains largely unknown. This work investigated the regulatory effect and underlying cellular mechanisms of α-MG action to attenuate acetaminophen-induced hepatotoxicity in mice. The increased serum aminotransferase levels and glutathione (GSH) content and reduced malondialdehyde (MDA) demonstrated the protective effect of α-MG against acetaminophen-induced hepatotoxicity. In addition, α-MG pretreatment inhibited increases in tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β) caused by exposure of mice to acetaminophen. In liver tissues, α-MG inhibited the protein expression of autophagy-related microtubule-associated protein light chain 3 (LC3) and BCL2/adenovirus E1B protein-interacting protein 3 (BNIP3). Western blotting analysis of liver tissues also proved evidence that α-MG partially inhibited the activation of apoptotic signaling pathways via increasing the expression of Bcl-2 and decreasing Bax and cleaved caspase 3 proteins. In addition, α-MG could in part downregulate the increase in p62 level and upregulate the decrease in p-mTOR, p-AKT and LC3 II /LC3 I ratio in autophagy signaling pathways in the mouse liver. Taken together, our findings proved novel perspectives that detoxification effect of α-MG on acetaminophen-induced ALI might be due to the alterations in Akt/mTOR pathway in the liver.