Protective effect of Euphorbia thymifolia and Euphorbia hirta against carbon tetrachloride-induced hepatotoxicity in Wistar rats.

OBJECTIVES: The present study aims to investigate the protective effect of Euphorbia thymifolia and Euphorbia hirta extracts on in vitro antioxidant activity and in vivo analysis on hepatic marker enzyme levels and histopathological changes in the liver of carbon tetrachloride (CCl4) induced hepatotoxicity rats. MATERIALS AND METHODS: This study includes 42 adult male Albino Wistar rats randomly divided into seven treatment groups, including control (basal diet, G1), CCl4-induced single dose (1.5 ml/kg, i.p.) as the negative control (G2), G1 supplemented with 300 mg/kg of ethanol extract of E. thymifolia (G3) and E. hirta (G4), G2 supplemented with 300 mg/kg of ethanol extract of E. thymifolia (G5), E. hirta (G6), and silymarin (25 mg/kg b.w.) used as a standard drug (G7) for 21-days experimental period. RESULTS: The ethanolic extracts of E. thymifolia and E. hirta exhibited potential in vitro antioxidant activity in a dose-dependent manner (25 µg/ml, 50 µg/ml, 100 µg/ml, 200 µg/ml and 250 µg/ml). Oxidative stress caused by CCl4-induced the liver damage, including changes in liver marker enzymes (aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase), enzymatic (superoxide dismutase and catalase), non-enzymatic antioxidants (lipid peroxides and glutathione) and hepatocellular alterations such as hydropic degeneration, irregular hepatocytes, and distention of the vein. Administration of E. thymifolia and E. hirta significantly (p < 0.05) restored the enzyme activity along with the histology of the liver. CONCLUSION: The results from the current study demonstrate that E. thymifolia and E. hirta have the property of restoring hepatic redox capacity and antioxidant activities against CCl4-induced acute liver damage.

GRP78 and next generation cancer hallmarks: An underexplored molecular target in cancer chemoprevention research.

Glucose regulated protein 78 (GRP 78), a master regulator of endoplasmic reticulum stress has been reported to be up regulated in various cancers and remains a crucial link between tumor glycolysis and tumor microenvironment. Overexpressed GRP78 has also shown to induce immune suppressive molecules and thereby tumor immune evasion. On the other hand emerging reports indicates that the next generation hallmarks viz., metabolic reprogramming and immune evasion, the two distinct processes are suggested to be fundamentally linked which is yet to be explored. Our concern is, if GRP78 is considered as a connecting link between these two different processes then targeting this triangle would be a promising approach in anticancer drug discovery. Lack of sufficient literature on this aspect represents GRP78 as an under explored target in anti-cancer research. The objective of this review is to provide a concise and integrated information on GRP78 and its association with tumor glycolysis and immune evasion which will revive and draw attention of the researchers to consider GRP78 as a potential drug target for cancer intervention and it also highlights few potential natural products investigated so far as GRP78 inhibitors.

Morin supplementation modulates PERK branch of UPR and mitigates 1,2-dimethylhydrazine-induced angiogenesis and oxidative stress in the colon of experimental rats.

Angiogenesis, disturbance in redox homeostasis, and deregulated redox signaling are considered as common hallmarks of cancer progression and chemo resistance. In this context, PERK (protein kinase PKR-like ER kinase) branch of the unfolded protein response (UPR), an adaptive mechanism triggered by endoplasmic reticulum (ER) stress to cope with protein misfolding and perturbed proteostasis, has shown to regulate angiogenesis and oxidative stress. This study aimed to investigate the impact of morin, a poly phenolic compound from the family of Moraceae on PERK-Nrf2-VEGF axis in experimental rats challenged with the colon specific procarcinogen 1,2-dimethylhydrazine (DMH). Male albino Wistar rats were randomized into four groups (n = 6) viz., control, morin control, DMH control, and DMH administered rats treated with morin. Immunohistochemical analysis of colonic cross-section revealed that DMH alone administered rats showed significantly increased expression of Nrf2 predominantly in the cytoplasm. Angiogenic growth factors viz., VEGF, PDGF, and bFGF are also shown to be increased in the DMH alone administered tumor bearing rats as compared to control. Significant downregulation was also observed in the downstream targets of Nrf2 such as hemeoxygenase 1 (HO1), glutathione peroxidase 2 (GPX2), thioredoxin (TRXN), glutathione S transferase (GST), and uridine glucuronyl transferase (UGT) as evidenced by the qPCR analysis. Immunoblot analysis revealed that onset of oxidative stress and angiogenesis in the colon of DMH alone administered rats were due to downregulation of pPERK along with its downstream targets such as peIF2α and CHOP. Supplementation of morin reversed the DMH-induced alterations and suppresses oxidative stress and angiogenesis via PERK phosphorylation.