Syed Kazim Hasan

Rutin ameliorates cyclophosphamide induced oxidative stress and inflammation in Wistar rats: role of NFκB/MAPK pathway.

Cyclophosphamide is a potent anticancer agent. However its clinical use is restricted because of its marked organ toxicity associated with increased oxidative stress and inflammation. The present study was designed to demonstrate the protective effects of rutin, a naturally occurring bioflavonoid against the hepatotoxicity induced by CP. Rats were subjected to oral pretreatment of rutin (50 and 100 mg/kg b wt) against hepatotoxicity induced by i.p. injection of CP (150 mg/kg b wt) and were sacrificed after 24 h. Hepatoprotective effects of rutin were associated with upregulation of antioxidant enzyme activities and down regulation of serum toxicity markers. Rutin was able to down regulate the levels of inflammatory markers like TNF-α, IL-6 and expressions of p38-MAPK, NFκB, i-NOS and COX-2. Histopathological changes further confirmed the biochemical and immunohistochemical results showing that CP caused significant structural damage to liver which were reversed by pretreatment of rutin. Therefore, our study revealed that rutin may be a promising modulator in attenuating CP induced oxidative stress, inflammation and hepatotoxicity via targeting NFκB and MAPK pathway.

Geraniol attenuates 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidative stress and inflammation in mouse skin: Possible role of p38 MAP Kinase and NF-κB

Abnormal production of reactive oxygen species (ROS) and proinflammatory cytokines often act as trigger for development of most of the chronic human diseases including cancer via up-regulation of transcription factors and activation of MAP kinases. We investigated the protective effects of geraniol (GOH) against 12-O-tetradecanoyl phorbol-13-acetate (TPA) induced oxidative and inflammatory responses, expression of p38MAPK, NF-κB and COX-2 in mouse skin. Animals were divided into four groups I-IV (n=6). Group II and III received topical application of TPA at the dose of 10 nmol/0.2 ml of acetone/animal/day, for two days. Group III was pre-treated with GOH (250 μg) topically 30 min prior to each TPA administration. While group I and IV were given acetone (0.2 ml) and GOH respectively. Our results show that GOH significantly inhibited TPA induced lipid peroxidation (LPO), inflammatory responses, proinflammatory cytokine release, up regulates reduced glutathione (GSH) content and the activity of different antioxidant enzymes. Interestingly, GOH also inhibited TPA induced altered activity of p38MAPK. Further, TPA induced altered expression of NF-κB (p65) and COX-2 was also attenuated by GOH. Thus, our results suggest that GOH attenuates early tumor promotional changes, and it may serve as one of the various ways to prevent carcinogenesis.

Alleviation of doxorubicin-induced nephrotoxicity and hepatotoxicity by chrysin in Wistar rats

Abstract Objective: Doxorubicin (DXR) is an anticancer drug used in the treatment of many human malignancies. However, its clinical use is limited because of several side effects like cardiotoxicity, nephrotoxicity and hepatotoxicity. In the present study, we investigated the protective efficacy of chrysin against DXR-induced oxidative stress, nephro- and hepatotoxicity in male Wistar rats using biochemical and histopathological approaches. Methodology: Wistar rats were subjected to concomitant pre- and post-phylactic oral treatment of chrysin (40 and 80 mg/kg b.wt.) against nephro- and hepatotoxicity induced by single i.p. injection of DXR (40 mg/kg b.wt). Nephrotoxicity and hepatotoxicity were assessed by measuring the level of serum creatinine, BUN, AST, ALT and LDH. The level of antioxidant armory of kidney and liver tissue was also measured. Key findings: Treatment with chrysin significantly decreased the levels of serum toxicity markers and additionally elevated antioxidant defense enzyme levels. Histopathological changes further confirmed the biochemical results showing that DXR caused significant structural damage to kidney and liver tissue architecture which were reversed with chrysin. Conclusion: The results suggest that chrysin attenuated nephro and hepatic damage induced by DXR.

Beneficial effects of Chrysin against Methotrexate-induced hepatotoxicity via attenuation of oxidative stress and apoptosis

Methotrexate (MTX), a folic acid antagonist, an effective chemotherapeutic agent is used in the treatment of a wide range of tumors and autoimmune diseases. Moreover, hepatotoxicity limits its clinical use. Several studies have already confirmed that the oxidative stress plays a major role in the pathogenesis of MTX-induced damage in the various organs especially in liver. The aim of this study was to determine the protective effect of Chrysin against MTX-induced hepatic oxidative stress and apoptosis in rats. In the present study, efficacy of Chrysin was investigated against hepatotoxicity caused by MTX in terms of biochemical investigations of antioxidant enzymes, apoptosis, and histopathological alteration in rat liver. In the MTX-treated group there was a significant increase in alanine transaminase, aspartate aminotransferase, lactate dehydrogenase activity and malondialdehyde content as well as decreased glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase activities and reduced glutathione content were also observed compared to the control group as a marker of oxidative stress. Histopathological alterations and apoptosis through the immunopositive staining of p53, cleaved caspases-3 and Bcl-2-associated X protein in rat liver were observed. Pretreatment of Chrysin at both doses prevents the hepatotoxicity by ameliorating oxidative stress, histopathological alterations, and apoptosis and thus our results suggest that Chrysin has a protective effect against hepatotoxicity induced by MTX and it may, therefore, improve the therapeutic index of MTX if co-administration is done.

Mitigation of 5-Fluorouracil induced renal toxicity by chrysin via targeting oxidative stress and apoptosis in wistar rats.

5-Fluorouracil (5-FU) is a potent antineoplastic agent commonly used for the treatment of various malignancies. It has diverse adverse effects such as cardiotoxicity, nephrotoxicity and hepatotoxicity which restrict its wide and extensive clinical usage. It causes marked organ toxicity coupled with increased oxidative stress and apoptosis. Chrysin (CH), a natural flavonoid found in many plant extracts, propolis, blue passion flower. It has antioxidative and anti-cancerous properties. The present study was designed to investigate the protective effects of CH against 5-FU induced renal toxicity in wistar rats using biochemical, histopathological and immunohistochemical approaches. Rats were subjected to prophylactic oral treatment of CH (50 and 100mg/kg b.wt.) for 21 days against renal toxicity induced by single intraperitoneal administration of 5-FU (150 mg/kg b.wt.). The possible mechanism of 5-FU induced renal toxicity is the induction of oxidative stress; activation of apoptotic pathway by upregulation of p53, bax, caspase-3 and down regulating Bcl-2. However prophylactic treatment of CH decreased serum toxicity markers, increased anti-oxidant armory as well as regulated apoptosis in kidney. Histopathological changes further confirmed the biochemical and immunohistochemical results. Therefore, results of the present finding suggest that CH may be a useful modulator in mitigating 5-FU induced renal toxicity.

Diosmin abrogates chemically induced hepatocarcinogenesis via alleviation of oxidative stress, hyperproliferative and inflammatory markers in murine model

Hepatocellular carcinoma (HCC) is a global health problem and is fourth leading cause of cancer related deaths. Now-a-days new strategies have been accounted for the chemoprevention of liver cancer due to ineffective traditional treatments against HCC. In the present study, we have shown that diosmin attenuates 2-AAF induced hepatic toxicity and early tumor promotion markers (ODC, PCNA and Ki67), its chemopreventive efficacy against DEN initiated and 2-AAF promoted hyper-proliferation and hepatocarcinogenesis in Wistar rats. Hepatocarcinogenesis has been characterized by the presence of apparent hepatic nodules, hepatic proliferation, elevation in the levels of proliferation markers (PCNA and Ki67), and inflammatory markers (COX-2 and iNOS) in DEN and 2-AAF administered rats. Protective efficacy of diosmin has been investigated in terms of its potential in reducing the percentage of visible hepatic nodules and the restoration of early tumor markers (PCNA, Ki67 and ODC), oxidative stress biomarkers, serum cytotoxicity markers (AST, ALT and LDH), cell necrosis markers (NF-kappa B and TNF-α) and inflammatory markers (COX-2 and iNos). Our study demonstrates that the inhibition of cell proliferation and down regulation of inflammatory markers may be, at least in part, the underlying mechanisms related to the liver tumor inhibition by diosmin. The present study allows us to conclude that diosmin being a dietary supplement, could be used as chemopreventive agent to prevent hepatocarcinogenesis.

18-β Glycyrrhetinic acid alleviates 2-acetylaminofluorene-induced hepatotoxicity in Wistar rats Role in hyperproliferation, inflammation and oxidative stress

2-Acetylaminofluorene (2-AAF) is a known hepatic carcinogen which leads to tumour formation in rodents. 18-β Glycyrrhetinic acid (18β-GA) derived from liquorice plant has various pharmacological properties such as anti-ulcer, anti-inflammatory, antiviral, hepatoprotective and antioxidant. This study is designed to elucidate the chemopreventive properties of 18β-GA against 2-AAF-induced liver toxicity in Wistar rats and evaluated its effect on inflammatory and tumour promotion marker and activities of different oxidative stress enzymes. Administration of 2-AAF at the dose of (50 mg/kg body weight (b.w.) intraperitoneally (i.p.)) for five consecutive days induces hepatic toxicity, inflammation, oxidative stress and hyperproliferation. Pretreatment with 18β-GA at two different doses (45 and 75 mg kg−1 b.w.) significantly ameliorates 2-AAF-induced increased lipid peroxidation, alanine transaminase and aspartate transaminase, xanthine oxidase activities and activities of phase-II detoxifying enzymes along with the levels of glutathione content. Administration of 18β-GA also significantly restored the expressions of proliferating cell nuclear antigen, cyclooxygenase 2, inducible nitric oxide synthase and nuclear factor κB. Furthermore, histological observations also support the preventive effects of 18β-GA. Our findings suggest that pretreatment with 18β-GA showed potential hepatoprotective effects via attenuation of oxidative stress, inflammation and hyperproliferation.

Chemopreventive effect of 18β-glycyrrhetinic acid via modulation of inflammatory markers and induction of apoptosis in human hepatoma cell line (HepG2)

Hepatocellular carcinoma is one of the most common lethal diseases worldwide and there is no effective treatment till date. Natural products derived from the plants play an important role in chemoprevention and act as therapeutic antitumor agents. Licorice is a plant that has been used in food and medicine for the treatment of various diseases. 18β-Glycyrrhetinic acid (18β-GA), a pentacyclic triterpenoid obtained from the roots of licorice plant, is reported to possess various pharmacological properties such as antitumor and antiinflammatory activities. The present study was designed to elucidate the chemopreventive effect of 18β-GA through antiinflammation, antiproliferation, and induction of apoptosis in human hepatoma cell line HepG2. 18β-GA significantly inhibits the proliferation of HepG2 cell without affecting the normal liver cell line (Chang’s). In the present study, 18β-GA increased the formation of reactive oxygen species, nitric oxide production, and loss of mitochondrial membrane potential, suggesting the involvement of 18β-GA in apoptosis which was also confirmed by assessing the markers involved in apoptosis like caspase-3, caspase-9, Bax:Bcl-2 ratio, and cleaved PARP. 18β-GA also downregulated the expression of inflammatory proteins such as NF-κB, iNOS, and COX-2. Keeping these data into consideration, our results suggest that 18β-GA may be used as a chemopreventive agent in liver cancer.

Geraniol attenuates 2-acetylaminofluorene induced oxidative stress, inflammation and apoptosis in the liver of wistar rats

Abstract 2-Acetylaminofluorene (2-AAF), is a well-known liver toxicant, generally used to induce tumors in laboratory animals. Geraniol (GE), a monoterpene found in essential oils of herbs and fruits, has been known to possess preventive efficacy against chemically induced toxicities. The present study was designed to analyze the protective effect of GE against 2-AAF induced oxidative stress, inflammation, hyperproliferation and apoptotic tissue damage in the liver of female Wistar rats. 2-AAF (0.02% w/w in diet) was administered and subjected to partial hepatectomy, as a mitogenic stimulus for the induction of hyperproliferation of liver tissue. GE was pre-treated orally at two different doses (100 and 200 mg/kg b.wt.) dissolved in corn oil. GE pre-treatment significantly ameliorated 2-AAF induced oxidative damage by diminishing tissue lipid peroxidation accompanied by the increase in enzymatic activities of catalase, glutathione peroxidase, glutathione reductase, superoxide dismutase and reduced glutathione content. The level of serum toxicity markers (AST, ALT, LDH) was found to be decreased. Pre-treatment with GE downregulated the expression of caspase-3,9, COX-2, NFkB, PCNA, iNOS, VEGF and significantly decreased disintegration of DNA. Histological findings further revealed that GE significantly restores the architecture of liver tissue. In the light of the above observations it may be concluded that GE may be used as preventive agent against 2-AAF induced oxidative stress, inflammation, hyperproliferation and apoptotic damage.

Silibinin Inhibits Tumor Promotional Triggers and Tumorigenesis Against Chemically Induced Two-Stage Skin Carcinogenesis in Swiss Albino Mice: Possible Role of Oxidative Stress and Inflammation

Silibinin is a major bioactive flavonolignan present in milk thistle (Silybum marianum) that possesses antioxidant, antiinflammatory, and anticarcinogenic activity. However, the precise underlying mechanism remains to be elucidated. The present study was designed to investigate underlying molecular mechanism for antitumorigenic potential of silibinin against chemically induced skin tumorigenesis in Swiss albino mice. In light of the important role of nuclear factor-kappaB (NF-κB), cyclooxygenase-2 (COX-2), iNOS, proinflammatory cytokines, vascular endothelial growth factor, and oxidative stress in carcinogenesis, chemopreventive efficacy of silibinin against 7, 12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate-induced 2-stage skin carcinogenesis was studied in terms of cytoprotective enzymes activity, lipid peroxidation, inflammatory responses, and the expression of various molecular marker in skin tissue. We found that topical application of silibinin at the dose of 9 mg/mouse effectively suppressed oxidative stress and deregulated activation of inflammatory mediators and tumorigenesis. Thus, findings of the present study suggest that the chemopreventive effect of silibinin is associated with upregulation of endogenous cytoprotective machinery and down regulation of inflammatory mediators (nitric oxide, tumor necrosis factor-α, interleukin-6, interleukin -1β, COX-2, iNOS, and NF-κB).