Preventive effect of berberine against DMBA-induced breast cancer in female Sprague Dawley rats.

Breast cancer is the prime cause for cancer mortality in women worldwide. The importance of diverse natural and dietary agents to reduce the risk of developing breast cancer is well established. Berberine, a natural isoquinoline alkaloid found in many medicinal plants is widely used in traditional Indian and Chinese medicine. Because of its capability to seize the cell cycle and induce apoptosis of numerous malignant cells, berberine has received considerable attention as a potential anticancer agent. In the present study, breast cancer was induced in Sprague Dawley (SD) rats by intragastric administration of 7, 12-dimethylbenz[a]anthracene (DMBA) at a dose of 80mg/kg of body weight. Treatment of berberine (50mg/kg BW) to breast tumor bearing rats was found to be effective against DMBA induced mammary carcinoma. The increased levels of lipid peroxide (malonaldehyde), pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α), enzymatic antioxidants (SOD and CAT), non-enzymatic antioxidants (GSH and vitamin C) and transcription factor NF-κB were decreased significantly by administration of berberine. Furthermore, RT-PCR and western blot analysis showed the down-regulation of NF-κB and PCNA in breast tumors. Histopathological studies validated that berberine is effective against DMBA induced ductal carcinoma & invasive carcinoma. Altogether, these findings demonstrate the preventive role of berberine against DMBA induced mammary carcinoma in SD rats.

The renoprotective activity of hesperetin in cisplatin induced nephrotoxicity in rats: Molecular and biochemical evidence.

Nephrotoxicity remain a major life-threatening complication in cancer patients on cisplatin chemotherapy. In this study, we investigated the protective effect and possible cellular mechanism of the hesperetin, a naturally-occurring bioflavonoid against cisplatin-induced renal injury in rats. Hesperetin was administered at a dose of 50mg/kg and 100mg/kg orally for 10days and cisplatin (7.5mg/kg, ip) was administered on the 5th day of experiment. Cisplatin induced nephrotoxicity was evidenced by alteration in the level of markers such as blood urea nitrogen, creatinine, serum albumin and severe histopathological changes in kidney. Cisplatin administration also resulted in significant increase in the tissue oxidative stress and inflammatory cytokines. The level of antioxidants enzymes were decreased significantly in the cisplatin administered rats. Hesperetin treatment (50mg/kg and 100mg/kg) normalized the renal function by attenuation of the cisplatin-induced oxidative stress, lipid peroxidation, and inflammatory cytokines and histopathological alterations. On the basis of these experimental findings our present study postulate that co-administration of hesperetin with cisplatin chemotherapy may be promising preventive approach to limit the major mortal side effect of cisplatin.

Molecular and biochemical evidence on the protective effects of quercetin in isoproterenol-induced acute myocardial injury in rats.

Cardioprotection represents one of the most important and realistic aspects of preventive therapy today. Quercetin, a naturally occurring dietary flavone, has been studied extensively for its antioxidant properties. The objective of present study is to find out the cardioprotective activity and to explore the underlying mechanisms of quercetin pretreatment (50 mg/kg body weight, orally) for 14 days against isoproterenol (ISO; 100 mg/kg body weight, subcutaneously) induced myocardial infarction in Wistar rats. Cardiac diagnostic markers, oxidative stress, inflammatory cytokines, histopathology along with gene expression analysis of calpain 1 and 2 were carried out in experimental rats. Quercetin pretreatment showed protective effects on heart by significantly attenuating the ISO-induced oxidative stress, inflammation, protecting heart architecture, and by downregulation of the expression of calpain. Overall, these findings revealed the cardio-protective potential of quercetin and its mechanism of action against ISO-induced MI in rats.

Antioxidant and antitumor efficacy of Luteolin, a dietary flavone on benzo(a)pyrene-induced experimental lung carcinogenesis.

The present study is designed to assess the antioxidant and antitumor potential of luteolin against benzo(a)pyrene [B(a)P]-induced lung carcinogenesis in Swiss albino mice. Here, we reported that oral administration of B(a)P (50mg/kg body weight) to mice resulted in raised lipid peroxides (LPO), lung specific tumor markers such as carcinoembryonic antigen (CEA) and neuron specific enolase (NSE) with concomitant decrease in the levels of both enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx) and glutathione-s-transferase (GST), and non-enzymatic antioxidants such as reduced glutathione (GSH), vitamin E and vitamin C. Luteolin treatment (15mg/kg body weight, p.o) significantly counteracted all these alterations and maintained cellular normalcy. Moreover, assessment of protein expression levels by western blot analysis revealed that luteolin treatment effectively negates B(a)P-induced upregulated expression of proliferating cell nuclear antigen (PCNA), cytochrome P450 1A1 (CYP1A1) and nuclear factor-kappa B (NF-κB). Furthermore, histopathology of lung tissue and immunohistochemistry of CYP1A1 were carried out to substantiate the anti- lung cancer effect of luteolin. Overall, these findings confirm the chemopreventive potential of luteolin against B(a)P induced lung carcinogenesis.

Baicalein protects isoproterenol induced myocardial ischemic injury in male Wistar rats by mitigating oxidative stress and inflammation.

OBJECTIVE: The aim of the present study was to investigate the cardioprotective effects of baicalein, main bioactive constituent from roots of Scutellaria baicalensis and Scutellaria lateriflora, on isoproterenol (ISO) induced acute myocardial infarction model in rats and to explore the underlying mechanisms. METHOD: Rats were treated with baicalein (50 mg/kg and 100 mg/kg) orally for 14 days and on 13th and 14th day, myocardial injury was induced by ISO injection (100 mg/kg, subcutaneous) at an interval of 24 h. RESULT: Our study showed that ISO administration resulted in significant elevations in the levels of cardiac injury biomarkers such as cardiac troponin I, creatine kinase-MB, AST and ALT. Concentrations of reactive nitrogen species and reactive oxygen species in the heart tissue increased significantly while antioxidant enzymes level declined. The levels of tissue pro-inflammatory cytokines tumor necrosis factor-α and interleukin-6 were significantly increased after ISO administration. Pretreatment with baicalein significantly reversed these alterations induced by ISO administration. Exploration of the underlying mechanisms of protective effect of baicalein pretreatment revealed that it repressed the expression of nuclear factor kappa B and restored the ISO induced elevation of pro-inflammatory cytokines, oxidative and nitrosative stress. We found that baicalein pretreatment enhanced the level of antioxidant defense enzymes like SOD, catalase and GSH. Furthermore, the present study also demonstrated cardioprotective effects of baicalein by the histopathological findings. CONCLUSION: Taken together, our findings demonstrated that baicalein pretreatment might have a potential benefit in prevention and terminating ischemic heart diseases like myocardial infarction.

Morin Hydrate Mitigates Cisplatin-Induced Renal and Hepatic Injury by Impeding Oxidative/Nitrosative Stress and Inflammation in Mice.

Cisplatin is a widely used chemotherapeutic drug; however, it induces damage on kidney and liver at clinically effective higher doses. Morin hydrate possesses antioxidant, anti-inflammatory, and anticancer properties. Therefore, we aimed to investigate the effects of morin hydrate (50 and 100 mg/kg, orally) against the renohepatic toxicity induced by a high dose of cisplatin (20 mg/kg, intraperitoneally). Renal and hepatic function, oxidative/nitrosative stress, and inflammatory markers along with histopathology were evaluated. Morin hydrate ameliorated cisplatin-induced renohepatic toxicity significantly at 100 mg/kg as evidenced from the significant reversal of cisplatin-induced body weight loss, mortality, functional and structural alterations of kidney, and liver. The protective role offered by morin hydrate against cisplatin-induced renohepatic toxicity is by virtue of its free radical scavenging property, thereby abating the depletion of cellular antioxidant defense components and through modulation of inflammatory cytokines. We speculate morin hydrate as a protective candidate against renohepatic toxicity of cisplatin.

Animal models of myocardial infarction: Mainstay in clinical translation.

Preclinical models with high prognostic power are a prerequisite for translational research. The closer the similarity of a model to myocardial infarction (MI), the higher is the prognostic value for clinical trials. An ideal MI model should present cardinal signs and pathology that resemble the human disease. The increasing understanding of MI stratification and etiology, however, complicates the choice of animal model for preclinical studies. An ultimate animal model, relevant to address all MI related pathophysiology is yet to be developed. However, many of the existing MI models comprising small and large animals are useful in answering specific questions. An appropriate MI model should be selected after considering both the context of the research question and the model properties. This review addresses the strengths, and limitations of current MI models for translational research.

Chemopreventive effect of chrysin, a dietary flavone against benzo(a)pyrene induced lung carcinogenesis in Swiss albino mice.

BACKGROUND: Chemoprevention is considered as one of the most promising and realistic approaches in the prevention of lung cancer. Chrysin, a naturally occurring dietary flavone widely found in Passiflora family of plants and honey, has been studied extensively for its chemopreventive properties. The objective of present study is to divulge the chemopreventive role of chrysin against benzo(a)pyrene [B(a)P] induced lung carcinogenesis in Swiss albino mice. METHODS: B(a)P was administered orally (50mg/kg body weight) twice a week for four weeks to induce lung cancer in mice. The body weight, lung weight, tumor incidence, lipid peroxidation, carcinoembryonic antigen, enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase) and non-enzymatic antioxidants (reduced glutathione, vitamin E and vitamin C) were estimated. Further, histopathological analysis of lung tissue and western blotting analysis of PCNA, COX-2 and NF-κB were also carried out. RESULTS: Administration of B(a)P resulted in increased lipid peroxides and carcinoembryonic antigen with concomitant decrease in the levels of both enzymatic antioxidants and non-enzymatic antioxidants. Chrysin treatment (250mg/kg body weight) significantly attenuated all these changes thereby showing potent anti lung cancer effect. Further, the anticancer effect of chrysin was confirmed by histopathology of lungs, and immunoblotting analysis of PCNA, COX-2 and NF-κB, where chrysin supplementation downregulated the expression of these proteins and maintained cellular homeostasis. CONCLUSION: Overall, these findings confirm the chemopreventive potential of chrysin against B(a)P induced lung cancer in Swiss albino mice.

Naringenin ameliorates inflammation and cell proliferation in benzo(a)pyrene induced pulmonary carcinogenesis by modulating CYP1A1, NFκB and PCNA expression.

Lung cancer is the major cause of cancer-related mortality and is a growing economic burden worldwide. Chemoprevention has emerged as a very effective preventive measure against carcinogenesis and several bioactive compounds in diet have shown their cancer curative potential on lung cancer. Naringenin (NRG), a predominant flavanone found in citrus fruits has been reported to possess anti-oxidative, anti-inflammatory and anti-proliferative activity in a wide variety of cancer. The aim of the present study is to divulge the chemopreventive nature of NRG against benzo(a)pyrene (B[a]P) induced lung carcinogenesis in Swiss albino mice. Administration of B[a]P (50mg/kg, p.o.) to mice resulted in increased lipid peroxidation (LPO), proinflammatory cytokines (TNF-α, IL-6 and IL-1ß) with subsequent decrease in activities of tissue enzymic antioxidants (SOD, CAT, GPx, GR, GST) and non-enzymic antioxidants (GSH and Vit-C). Treatment with NRG (50mg/kg body weight) significantly counteracted all these alterations thereby showing potent anti-cancer effect in lung cancer. Moreover, assessment of protein expression by immunoblotting and mRNA expression by RT-PCR revealed that NRG treatment effectively negates B[a]P-induced upregulated expression of CYP1A1, PCNA and NF-κB. Further, the antiproliferative effect of NRG was confirmed by histopathological analysis and PCNA immunostaining in B[a]P induced mice which showed increased PCNA expression that was restored upon NRG administration. Overall, these findings substantiate the chemopreventive potential of NRG against chemically induced lung cancer in mice.

Antiproliferative and antioxidant potential of hesperetin against benzo(a)pyrene-induced lung carcinogenesis in Swiss albino mice.

Lung cancer is the foremost cause of cancer mortality and is a growing economic burden worldwide. Chemoprevention, employing the use of natural, dietary or synthetic agents has become an appealing strategy to combat the increasing cases of cancers worldwide. The present study was designed to investigate the mechanism-based chemopreventive nature of hesperetin (HSP) against B[a]P induced lung carcinogenesis in Swiss albino mice. We analyzed the chemopreventive potential of HSP by estimating the status of lipid peroxidation (LPO), enzymic (SOD, CAT, GPx, GR, and GST), nonenzymic antioxidants (GSH, Vit C and Vit E), proinflammatory cytokine (TNF-α), western blotting (CYP1A1, PCNA, Nrf2 and NF-κB expression) and histopathology of lung tissues of control and experimental mice. Administration of B[a]P (50 mg/kg, p.o.) resulted in an increase in lung weight, LPO with concomitant decrease in body weight, enzymic (SOD, CAT, GPx, GR, and GST) and non-enzymic (GSH, Vit C and Vit E) antioxidants. Histological examination of lungs revealed severe alveolar and bronchiolar damages in B[a]P-induced mice. Further, elevated levels of TNF-α along with activated expression of NF-κB, PCNA and CYP1A1, and downregulation of Nrf2 was observed in B[a]P intoxicated animals. Pre- and post-treatment with HSP effectively suppressed B[a]P induced lung carcinoma and the associated preneoplastic lesions by alleviating LPO, modulating antioxidants and decreasing the expression of NF-κB, PCNA and CYP1A1. These findings demonstrate that HSP possesses a potential chemopreventive activity against B[a]P induced lung cancer and this is attributed to its free radical scavenging, antioxidant, anti-inflammatory and antiproliferative properties.

Benzo(a)pyrene induced lung cancer: Role of dietary phytochemicals in chemoprevention.

Lung cancer is the major cause of overall cancer deaths, and chemoprevention is a promising strategy to control this disease. Benzo(a)pyrene [B(a)P], a polycyclic aromatic hydrocarbon, is one among the principal constituents of tobacco smoke that plays a key role in lung carcinogenesis. The B(a)P induced lung cancer in mice offers a relevant model to study the effect of natural products and has been widely used by many researchers and found considerable success in ameliorating the pathophysiological changes of lung cancer. Currently available synthetic drugs that constitute the pharmacological armamentarium are themselves effective in managing the condition but not without setbacks. These hunches have accelerated the requisite for natural products, which may be used as dietary supplement to prevent the progress of lung cancer. Besides, these agents also supplement the conventional treatment and offer better management of the condition with less side effects. In the context of soaring interest toward dietary phytochemicals as newer pharmacological interventions for lung cancer, in the present review, we are attempting to give a silhouette of mechanisms of B(a)P induced lung carcinogenesis and the role of dietary phytochemicals in chemoprevention.

Resveratrol ameliorates depressive-like behavior in repeated corticosterone-induced depression in mice.

A mouse model of depression has been recently developed by exogenous corticosterone (CORT) administration, which has shown to mimic HPA-axis induced depression-like state in animals. The present study aimed to examine the antidepressant-like effect and the possible mechanisms of resveratrol, a naturally occurring polyphenol of phytoalexin family, on depressive-like behavior induced by repeated corticosterone injections in mice. Mice were injected subcutaneously (s.c.) with 40mg/kg corticosterone (CORT) chronically for 21days. Resveratrol and fluoxetine were administered 30min prior to the CORT injection. After 21-days treatment with respective drugs, behavioral and biochemical parameters were estimated. Since brain derived neurotrophic factor (BDNF) has been implicated in antidepressant activity of many drugs, we also evaluated the effect of resveratrol on BDNF in the hippocampus. Three weeks of CORT injections in mice resulted in depressive-like behavior, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test and tail suspension test. Further, there was a significant increase in serum corticosterone level and a significant decrease in hippocampus BDNF level in CORT-treated mice. Treatment of mice with resveratrol significantly ameliorated all the behavioral and biochemical changes induced by corticosterone. These results suggest that resveratrol produces an antidepressant-like effect in CORT-induced depression in mice, which is possibly mediated by rectifying the stress-based hypothalamic-pituitary-adrenal (HPA) axis dysfunction paradigm and upregulation of hippocampal BDNF levels.

Chrysin and its emerging role in cancer drug resistance.

This letter illustrates the significant chemosensitizing effects of chrysin to resistance cancer cells and refers to the article on "Combination of chrysin and cisplatin promotes the apoptosis of Hep G2 cells by up-regulating p53" by Li et al., published in your journal recently. Recent studies have demonstrated that chrysin is able to sensitize or kill cancer cells which are resistant to chemotherapeutic drugs such as cisplatin, doxorubicin and adriamycin. Owing to its potential anti-cancer effects and devoid of toxicity to non-transformed cells, further research is required to completely explore its chemosensitizing effects in other cancers and also assess and evaluate its safety, before going for possible human application.

BAY 11-7082 ameliorates diabetic nephropathy by attenuating hyperglycemia-mediated oxidative stress and renal inflammation via NF-κB pathway.

Diabetic nephropathy is a serious microvascular complication for patients associated with diabetes mellitus. Recent studies have suggested that NF-κB is the main transcription factor for the inflammatory response mediated progression of diabetic nephropathy. Hence, the present study is hypothesized to explore the renoprotective nature of BAY 11-7082 an IκB phosphorylation inhibitor on Streptozotocin (STZ) induced diabetic nephropathy in Sprague-Dawley (SD) rats. Male SD rats were divided into five groups, group I sham control, group II drug control, group III diabetic control (STZ 50mg/kg), group IV and V are test drug groups to which a single dose of STZ 50mg/kg was injected initially and later received BAY 11-7082 1mg/kg and 3mg/kg, respectively from 5th to 8th week. Eight weeks after STZ injection, diabetic rats exhibited significant renal dysfunction, as evidenced by reduced creatinine clearance, increased blood glucose, urea nitrogen and creatinine, which were reversed to near normal by BAY 11-7082. BAY 11-7082 treated rats showed significant improvement in the decreased enzymatic antioxidant SOD, non-enzymatic antioxidant GSH levels, and elevated lipid peroxidation and nitric oxide levels as observed in the diabetic rats. BAY 11-7082 treatment was found to significantly recover kidney histological architecture in the diabetic rats. Altered levels of inflammatory cytokines like TNF-α, IL-1ß, IL-6 and nuclear transcriptional factor subunit NF-κB p65 were reverted to the normal level upon treatment with BAY 11-7082. Our results suggest that by limiting the activation of NF-κB, thereby reducing the expression of inflammatory cytokines and by inhibiting the oxidative damage BAY 11-7082 protect the rats against diabetic nephropathy.

Evaluation of antitumor activity and antioxidant status of Alternanthera brasiliana against Ehrlich ascites carcinoma in Swiss albino mice.

OBJECTIVE: The main objective of the present study was to explore the antitumor activity of the ethyl acetate extract of the Alternanthera brasiliana (EAAB) and its antioxidant status against Ehrlich ascites carcinoma (EAC) in Swiss albino mice. MATERIALS AND METHODS: Based on the preliminary in vitro cytotoxicity studies, EAAB was selected for anti-tumor and antioxidant effects. Anticancer activity of EAAB was evaluated against EAC in Swiss albino mice at the doses of 200 and 400 mg/kg. EAAB was administered for 14 consecutive days after induction of cancer. After 24 h of the last dose and 18 h of fasting, half of the mice were sacrificed and rest were kept alive for assessing any increase in life span. The antitumor effect of EAAB was assessed by evaluating tumor volume, viable and nonviable tumor cell count, tumor weight, hematological and biochemical parameters of EAC bearing host. Furthermore, the antioxidant and histopathological parameters were evaluated. RESULTS: EAAB treatment has shown significant decrease in tumor volume, viable cell count, tumor weight and elevated the life span of EAC tumor bearing mice in a dose dependent manner. In hematological profile count of RBC, hemoglobin, and WBC were found reverted to normal. EAAB also significantly decreased the levels of lipid peroxidation and significantly increased the levels of GSH, SOD and Catalase. CONCLUSION: From the above results it may be concluded that EAAB has potent dose dependent antitumor activity and is comparable to that of 5-flourouracil.

Chemopreventive and therapeutic potential of chrysin in cancer: mechanistic perspectives.

Chrysin, a naturally occurring flavone, abundantly found in numerous plant extracts including propolis and in honey is one of the most widely used herbal medicine in Asian countries. Nowadays, chrysin has become the foremost candidate exhibiting health benefits, owing to its multiple bioactivities such as antioxidant, anti-inflammatory, anti-allergic, anti-diabetic, anti-estrogenic, antibacterial and antitumor activities. Anticancer activity is most promising among the multiple pharmacological effects displayed by chrysin. In vitro and in vivo models have shown that chrysin inhibits cancer growth through induction of apoptosis, alteration of cell cycle and inhibition of angiogenesis, invasion and metastasis without causing any toxicity and undesirable side effects to normal cells. Chrysin displays these effects through selective modulation of multiple cell signaling pathways which are linked to inflammation, survival, growth, angiogenesis, invasion and metastasis of cancer cells. This broad spectrum of antitumor activity in conjunction with low toxicity underscores the translational value of chrysin in cancer therapy. The present review highlights the chemopreventive and therapeutic effects, molecular targets and antineoplastic mechanisms that contribute to the observed anticancer activity of chrysin.

Natural killer cells: the journey from puzzles in biology to treatment of cancer.

Natural Killer (NK) cells are innate immune effectors that are primarily involved in immunosurveillance to spontaneously eliminate malignantly transformed and virally infected cells without prior sensitization. NK cells trigger targeted attack through release of cytotoxic granules, and secrete various cytokines and chemokines to promote subsequent adaptive immune responses. NK cells selectively attack target cells with diminished major histocompatibility complex (MHC) class I expression. This "Missing-self" recognition by NK cells at first puzzled researchers in the early 1990s, and the mystery was solved with the discovery of germ line encoded killer immunoglobulin receptors that recognize MHC-I molecules. This review summarizes the biology of NK cells detailing the phenotypes, receptors and functions; interactions of NK cells with dendritic cells (DCs), macrophages and T cells. Further we discuss the various strategies to modulate NK cell activity and the practice of NK cells in cancer immunotherapy employing NK cell lines, autologous, allogeneic and genetically engineered cell populations.

Targeting poly(ADP-ribose)polymerase1 in neurological diseases: A promising trove for new pharmacological interventions to enter clinical translation.

The highly conserved abundant nuclear protein poly(ADP-ribose)polymerase1 (PARP1) functions at the center of cellular stress response and is mainly implied in DNA damage repair mechanism. Apart from its involvement in DNA damage repair, it does sway multiple vital cellular processes such as cell death pathways, cell aging, insulator function, chromatin modification, transcription and mitotic apparatus function. Since brain is the principal organ vulnerable to oxidative stress and inflammatory responses, upon stress encounters robust DNA damage can occur and intense PARP1 activation may result that will lead to various CNS diseases. In the context of soaring interest towards PARP1 as a therapeutic target for newer pharmacological interventions, here in the present review, we are attempting to give a silhouette of the role of PARP1 in the neurological diseases and the potential of its inhibitors to enter clinical translation, along with its structural and functional aspects.

Chemopreventive and therapeutic effects of nimbolide in cancer: the underlying mechanisms.

Cancer chemoprevention is a strategy taken to block, reverse or retard the multistep process of carcinogenesis, including the blockage of its vital morphogenetic milestones viz. normal-preneoplasia-neoplasia-metastasis. Naturally occurring phytochemicals are becoming increasingly popular over synthetic drugs for several reasons, including safety, efficacy and easy availability. Nimbolide, a triterpene derived from the leaves and flowers of neem, is widely used in traditional medical practices for treating various human ailments. The neem limonoid exhibits multiple pharmacological effects among which its anticancer activity is the most promising. The preclinical and mechanistic studies carried over the decades have shown that nimbolide inhibits tumorigenesis and metastasis without any toxicity and unwanted side effects. Nimbolide exhibits anticancer activity through selective modulation of multiple cell signaling pathways linked to inflammation, survival, growth, invasion, angiogenesis and metastasis. The present review highlights the current knowledge on molecular targets that contribute to the observed anticancer activity of nimbolide related to (i) inhibition of carcinogenic activation and induction of antioxidant and carcinogen detoxification enzymes, (ii) induction of growth arrest and apoptosis; and (iii) suppression of proinflammatory signaling pathways related to cancer progression.