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Background: Organ toxicity limits the therapeutic efficacy of methotrexate (MTX), an anti-metabolite therapeutic that is frequently used as an anti-cancer and immunosuppressive medicine. Hepatocellular toxicity is among the most severe side effects of long-term MTX use. The present study unveils new confirmations as regards the remedial effects of morin on MTX-induced hepatocellular injury through regulation of oxidative stress, apoptosis and MAPK signaling., Methods and Results: Rats were subjected to oral treatment of morin (50 and 100 mg/kg body weight) for 10 days. Hepatotoxicity was induced by single intraperitoneal injection of MTX (20 mg/kg body weight) on the 5th day. MTX related hepatic injury was associated with increased MDA while decreased GSH levels, the activities of endogen antioxidants (glutathione peroxidase, superoxide dismutase and catalase) and mRNA levels of HO-1 and Nrf2 in the hepatic tissue. MTX treatment also resulted in apoptosis in the liver tissue via increasing mRNA transcript levels of Bax, caspase-3, Apaf-1 and downregulation of Bcl-2. Conversely, treatment with morin at different doses (50 and 100 mg/kg) considerably mitigated MTX-induced oxidative stress and apoptosis in the liver tissue. Morin also mitigated MTX-induced increases of ALT, ALP and AST levels, downregulated mRNA expressions of matrix metalloproteinases (MMP-2 and MMP-9), MAPK14 and MAPK15, JNK, Akt2 and FOXO1 genes., Conclusion: According to the findings of this study, morin may be a potential way to shield the liver tissue from the oxidative damage and apoptosis., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Diclofenac (DF) is a non-steroidal anti-inflammatory drug (NSAID) generally prescribed for the treatment of pain. In spite of the widespread use of DF, hepatotoxicity has been reported after its administration. The current study discloses new evidence as regards of the curative effects of chrysin (CHR) on DF-induced hepatotoxicity by regulating oxidative stress, apoptosis, autophagy, and endoplasmic reticulum (ER) stress., Methods: The animals were separated into five different groups. Group-I was in control. Group-II received CHR-only (50 mg/kg bw, p.o.) on all 5 days. Group-III received DF-only (50 mg/kg bw, i.p.) on 4th and 5th day. Group-IV received DF (50 mg/kg bw) + CHR (25 mg/kg, bw) and group-V received DF (50 mg/kg, bw) + CHR (50 mg/kg, bw) for 5 days., Results: DF injection was associated with increased MDA while reduced GSH level, activities of superoxide dismutase, glutathione peroxidase, and catalase and mRNA levels of HO-1 and Nrf2 in the liver. DF injection caused apoptosis and autophagy in the liver by up-regulating caspase-3, Bax, LC3A, and LC3B levels and down-regulating Bcl-2. DF also caused ER stress by increasing mRNA transcript levels of ATF-6, IRE1, PERK, and GRP78. Additionally, it was observed that DF administration up-regulated MMP2 and MMP9. However, treatment with CHR at a dose of 25 and 50 mg/kg considerably ameliorated oxidative stress, apoptosis, autophagy, and ER stress in liver tissue., Conclusion: Overall, the data of this study indicate that liver damage associated with DF toxicity could be ameliorated by CHR administration., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Clinical use of cyclophosphamide (CP) causes apoptosis-induced cell death in the immune system, liver, heart and kidneys. To prevent the cells against side effects of CP and its metabolites, increasing antioxidant defence mechanism of the body with supplemental antioxidants is important. Therefore, there is a requirement for effective agents which could prevent the healthy cells from the harmful effects of drug-induced toxicities. Several antioxidants have been used in protecting or alleviating CP-induced cell death. However, no such study is reported in CP-induced SH-SY5Y cell toxicity. The aim of this study was to evaluate likelihood ameliorative effects of caffeic acid, chrysin, quercetin and ferulic acid against CP-induced toxicity in SH-SY5Y neuron cells. In this study protective effects of quercetin, chrysin, caffeic acid and ferulic acid against CP-induced cell toxicity in SH-SY5Y cells was evaluated by cell proliferation assay, lipid peroxidation (LPO) analysis to decipher antioxidant capacity, tunel assay and qRT-PCR experiments to examine anti-apoptotic activities of the antioxidants. The results showed that CP-induced cell toxicity in SH-SY5Y cells and treatments with the antioxidants suppressed the cell death. Our results suggests that these anti-oxidants protected SH-SY5Y cells via a decrease in LPO levels, downregulating the expression of Cas-3, Cyt c and Bax and upregulating expression of anti-apoptotic gene Bcl-2. The use of antioxidant as nutritional supplements, and in particular of caffeic acid, chrysin, quercetin and ferulic acid, reduce apoptotic effects of CP in SH-SY5Y cells that could add insight into therapeutic approaches to CP-induced cell injuries.

A relationship exists between hyperhomocysteinemia and cardiovascular diseases, although the underlying mechanisms are still incompletely defined. One possibility involves a homocysteine (Hcy)-induced increased oxidative stress. Melatonin (Mel) and vitamin E (vitE) are important anti-oxidants. The main purpose of this study was (1) to compare the effect of treatments with Mel, vitE or both, on Hcy-induced apoptosis in human umbilical vein endothelial cells (HUVECs), and (2) to investigate the underlying mechanisms. Cell proliferation assay was carried out by Water Soluble Tetrazolium-1 (WST-1) assay kit. Apoptotic index was calculated by TUNEL Assay. Anti-oxidant parameters were studied by measurement of reactive oxygen species (ROS) and lipid peroxidation (LPO) levels. mRNA and protein expression levels of apoptotic and anti-apoptotic genes and proteins were studied by quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting experiments respectively. The results showed that treatments with Mel, vitE or Mel + vitE suppressed Hcy-induced cell death, with a higher efficiency for the Mel and Mel + vitE treatments. Our results suggests that the mechanisms by which these anti-oxidants protected endothelial cells include the decrease in ROS and LPO levels, an increase in cell migration, the downregulation of pro-apoptotic proteins Cas 3, Cas 9, Cyt C and Bax and the upregulation of anti-apoptotic protein Bcl 2. Collectively, these results revealed the protective role of vitE and Mel against Hcy-induced cell apoptosis, which may add insight into therapeutic approaches to Hcy-induced damages.