Ganapathy Sindhu

Nephroprotective effect of vanillic acid against cisplatin induced nephrotoxicity in wistar rats: A biochemical and molecular study

Cisplatin is one of the extensively used anticancer drugs against various cancers. Dosage dependent nephrotoxicity is the major problem in cisplatin chemotherapy. Cisplatin induced nephrotoxicity results in the depletion of renal antioxidant defence system. Our present study is aimed to investigate the nephroprotective effect of vanilic acid to against cisplatin induced nephrotoxicity in male wistar rats. Elevated levels of serum creatinine, blood urea nitrogen, serum uric acid and reduced antioxidant status were observed as indicatives of nephrotoxicity in cisplatin (7mg/kg bw) alone administered rats. Animals which are pre-treated with vanillic acid (50mg/kg and 100mg/kg) restored the elevated levels of renal function markers and reduced antioxidant status to near normalcy when compared to cisplatin alone treated animals. Cisplatin induced lipid peroxidation was markedly reduced by oral administration of vanillic acid at a high dose. The findings in the present study suggest that vanillic acid is a potential antioxidant that reduce cisplatin nephrotoxicity and can be as a combinatorial regimen in cancer chemotherapy.

Berberine prevents 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis: a biochemical approach.

Chemoprevention, a novel and useful approach in experimental oncology, deals with the prevention, suppression, or inhibition of carcinogenesis using natural or synthetic entities. This study evaluated the chemopreventive potential of berberine on 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. Oral squamous cell carcinoma was developed in the buccal pouch of golden Syrian hamsters by painting with 0.5% DMBA in liquid paraffin three times a week for 14 weeks. Tumor incidence, tumor volume, tumor burden, phase I and phase II carcinogen detoxification agents, lipid peroxidation, antioxidant status, and histopathological changes were assessed in hamsters treated with DMBA alone and in DMBA+berberine-treated animals. Hundred percent tumor incidences with an imbalance in carcinogen-metabolizing enzymes and cellular redox status were observed in hamsters treated with DMBA alone. Oral administration of berberine at a dose of 75 mg/kg body weight (bw) to DMBA-treated hamsters completely prevented tumor incidence and restored the status of the above-mentioned biochemical markers. Berberine, a traditional drug from Southeast Asia, shows promising chemopreventive efficacy in hamster buccal pouch carcinogenesis.

Anti-clastogenic effect of berberine against DMBA-induced clastogenesis.

Our aim was to evaluate the protective effect of berberine on 7,12-dimethylbenz[a]anthracene (DMBA)-induced chromosomal aberrations and micro-nucleated polychromatic erythrocytes (MnPCEs) frequency in bone marrow cells of golden Syrian hamsters. The anti-clastogenic effect of berberine (50 mg/kg b.w. p.o.) was also assessed by measuring the status of phase II detoxification enzymes and oxidative stress, as biochemical endpoints, during DMBA (30 mg/kg b.w. i.p.) induced clastogenesis. Marked chromosomal aberrations, increased MnPCEs frequency and enhanced status of lipid peroxidation, antioxidants and phase I and II detoxification enzymes were noticed in hamsters treated with DMBA alone. Oral pre-treatment with berberine for 5 days to DMBA-treated hamsters significantly reduced the frequency of MnPCEs and chromosomal abnormalities as well as reversed the status of lipid peroxidation, antioxidants and phase I and II detoxification enzymes. The present study thus suggests that berberine has potent anti-clastogenic potential against DMBA-induced clastogenesis, which is probably due to its anti-lipid peroxidative potential and effect on modulation of phase I and II detoxification cascade.

Umbelliferone arrest cell cycle at G0/G1 phase and induces apoptosis in human oral carcinoma (KB) cells possibly via oxidative DNA damage

Umbelliferone (UMB) has widespread pharmacological activity, comprising anti-inflammatory, anti-oxidant, anti-genotoxic and anti-immunomodulatory but the anticancer activity remains unknown in human oral carcinoma (HOC) KB cells. MTT assay determinations was revealed that treatment of KB cells with UMB, prevent and reduce the cell proliferation with the IC50 - 200μM as well as induces loss of cell viability, morphology change and internucleosomal DNA fragmentation in a concentration dependent manner. Acridine orange and ethidium bromide dual staining assay established that UMB induced apoptosis in KB cells in a dose dependent manner. Alkaline comet assay determination revealed UMB has the potential to increase oxidative DNA damage in KB cells through DNA tail formation significantly (p<0.05). Furthermore, UMB brought a dose-dependent elevation of reactive oxygen species (ROS), which is evidenced by the DCF fluorescence, altered the mitochondrial membrane potential in KB cells. Similarly, we observed increased DNA damage stimulated apoptotic morphological changes in UMB treated cells. Taken together, the present study suggests that UMB exhibits anticancer effect on KB cell line with the increased generation of intracellular ROS, triggered oxidative stress mediated depolarization of mitochondria, which contributes cell death via DNA damage as well as cell cycle arrest at G0/G1 phase. The results have also provided us insight in the pharmacological backgrounds for the potential use of UMB, to target divergent pathways of cell survival and cell death. To conclude UMB could develop as a novel candidate for cancer chemoprevention and therapy, which is our future focus and to develop a connectivity map between in vivo and in vitro activity.

Dose responsive efficacy of umbelliferone on lipid peroxidation, anti-oxidant, and xenobiotic metabolism in DMBA-induced oral carcinogenesis

This study evaluated the chemopreventive potential of umbelliferone (UMB) on 7,12- dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch carcinogenesis. The mechanistic pathway for chemopreventive potential of UMB was evaluated by measuring the status of tumour incidence, tumour volume, and tumour burden as well as by analyzing the status of phase I, phase II detoxification agents, lipid peroxidation, antioxidants, histopathological changes and also expression patterns of cell proliferation (PCNA, Cyclin D1) and apoptotic (p53) markers using immunohistochemistry in DMBA induced hamster buccal pouch carcinogenesis. Oral squamous cell carcinoma was created by painting of 0.5% DMBA in liquid paraffin three times a week for 14 weeks, in the golden Syrian hamsters buccal pouches. We observed 100% tumor formation with high tumor volume, tumor burden and over expression of mutant p53, PCNA, and cyclin D1 in the DMBA alone painted hamsters as compared to control hamsters. Oral administration of UMB at a dose of 30mg/kg body weight to DMBA-treated hamsters completely prevented tumor incidences and restored the status of the biochemical markers in the plasma, liver and buccal mucosa, and also prevented the deregulation in the expression of molecular markers in group 4. Therefore, the present study suggests that UMB has potent chemopreventive, anti-lipid peroxidative and antioxidant potential as well as modulating effect on phase I and phase II detoxification system with reduced cell proliferation and induced apoptosis in experimental oral carcinogenesis.

Nephroprotective effect of β-sitosterol on N-diethylnitrosamine initiated and ferric nitrilotriacetate promoted acute nephrotoxicity in Wistar rats.

Abstract Background: The most abundant plant sterol β-sitosterol is widely used for treating heart diseases and chronic inflammatory conditions. The objective of the current study was to evaluate the nephroprotective effect of β-sitosterol against nephrotoxicants which were studied using renal function markers, antioxidant and lipid peroxidation status, and inflammatory markers. Methods: Male albino Wistar rats were randomly grouped into four: group 1 was vehicle control rats (0.1% carboxymethyl cellulose [CMC]); group 2 was rats treated with N-diethylnitrosamine (DEN) (200 mg/kg body weight [bw] i.p. on the 15th day) and ferric nitrilotriacetate (Fe-NTA) (9 mg/kg bw i.p. on 30th and 32nd days); group 3 was rats that received β-sitosterol (20 mg/kg bw in 0.1% CMC, p.o. for 32 days) 2 weeks prior to the exposure to the nephrotoxicant; and group 4 was rats that received β-sitosterol alone. The experiment was terminated after the 24 h of last dosage of Fe-NTA, and all the animals were sacrificed. The blood, liver and kidney from each group were analyzed for biochemical, molecular and histological changes. Results: All the parameters showed significant changes in DEN and Fe-NTA treated animals, whereas β-sitosterol pretreated animals’ altered biochemical parameters were restored to near normal. Histopathological and immunoexpression studies on tissues also corroborate the biochemical endpoints. Conclusions: Administration of β-sitosterol to nephrotoxicity induced rats showed significant positive changes in biochemical parameters, histopathological and immunohistochemical observations, and up-regulation of Nrf2 gene expression. From this, it was clear that β-sitosterol showed renal protective function.

Data on efficacy of umbelliferone on glycoconjugates and immunological marker in 7,12-dimethylbenz(a)anthracene induced oral carcinogenesis

Umbelliferone, a phenolic coumarin and dietary agent is believed to play a key role in pharmacological activities including anti-cancer and anti-oxidants effect in various in vitro and in vivo models. In present data on the pre-treatment of umbelliferone (30 mg/kg b.w.) for 16 weeks to 7,12-dimethylbenz(a)anthracene induced hamsters provides protection on cellular integrity by observing the status of cell surface glycoconjugates in the circulation and buccal mucosa and cytokeratin immunoexpression in the buccal mucosa of experimental animals. Data presented in this article brief that umbelliferone exhibits potent to clear cell surface abnormalities in buccal tissues and circulation during carcinogenesis and restored the expression of cytokeratin effect against 7,12-dimethylbenz(a)anthracene induced hamster buccal pouch carcinogenesis, which is attributes to its inhibitory role on glycoprotein synthesis or on the activity of the glycosyltransferase. In an article associates with this data set given the relevance to the research article entitled “Dose responsive efficacy of umbelliferone on lipid peroxidation, anti-oxidant, and xenobiotic metabolism in 7,12-dimethylbenz(a)anthracene-induced oral carcinogenesis” namely Vijayalakshmi and Sindhu, 2017 assessed 100% tumour formation in 7,12-dimethylbenz(a)anthracene treated hamsters and oral administration of umbelliferone at a dose of 30 mg/kg b.w to 7,12-dimethylbenz(a)anthracene treated hamsters prevents tumour incidence, restores the status of the biochemical markers in circulation and buccal mucosa and also dysregulation in the expression of molecular markers. Given the relevance to this article entitled “Berberine protects cellular integrity during 7,12-dimethylbenz[a]anthracene-induced oral carcinogenesis in golden Syrian hamsters” namely Sindhu and Manoharan 2010, which were based on spectrophotometry and florescence microscope analysis.

Protective effect of 18β-glycyrrhetinic acid on cell surface glycoconjugates abnormalities in 7,12-dimethylbenz(a)anthracene-induced hamster buccal pouch carcinogenesis

Aim: The aim of this study was to evaluate the protective effect of 18β-glycyrrhetinic acid against cell surface glycoconjugates (protein-bound hexose, hexosamine, sialic acid, and fucose) abnormalities in 7,12-dimethylbenz(a)anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. Materials and Methods: Topical application of DMBA three times a week for 14 weeks on the buccal pouches of hamsters resulted in well-developed squamous cell carcinoma. Glycoconjugates status in plasma and tumor tissues were estimated using specific and sensitive colorimetric methods. Results: Increases in plasma and tumor tissue glycoconjugates were noticed in hamsters treated with DMBA. Oral administration of glycyrrhetinic acid at a dose of 45 mg/kg body weight restored the status of glycoconjugates in hamsters treated with DMBA. Conclusion: The results of this study suggest that glycyrrhetinic acid might provide protection against cell surface abnormalities during DMBA-induced buccal pouch carcinogenesis in hamsters.