RESUMEN
Lung cancer, one of the most common cancer is a cause of concern associated with cancer-related mortality. Benzo[a]pyrene [B(a)P], a potent carcinogen as well as an environmental contaminant is reported to be found in cigarette smoke among various sources. The present study focuses on the chemopreventive potential of Diosmin against B[a]P-induced lung carcinogenesis and its possible mechanism in male Swiss Albino mice (SAM). SAM were treated orally with Diosmin (200 mg/kg b.w.) for 16 weeks and/or B[a]P (50 mg/kg b.w) for a period of 4 weeks. B[a]P treated cancerous mice showed increased peroxidation of membrane lipid as well as a decrease in the level/activity of antioxidant proteins. Cancerous mice also showed an increased level of carcinoembryonic antigen (CEA) and neuron-specific enolase (NSE). Diosmin treatment, however, leads to decreased peroxidation of lipids, increased antioxidant proteins as well decrease in the level of CEA and NSE. B[a]P-induced cancerous animals also exhibited increased expression of cyclic AMP response element-binding protein (CREB), COX2 as well as prostaglandin-E2 (PGE2) while Diosmin-treated mice were found to have an ameliorative effect. Histopathological results further confirm the protective effect of Diosmin in averting B[a]P-induced pathological alterations of lung tissue. Overall, our results suggest Diosmin exerts its chemopreventive potential possibly via targeting the CREB/cyclooxygenase-2 (COX-2)/PGE2 pathway thereby repressing inflammation.
Asunto(s)
Diosmina , Neoplasias Pulmonares , Masculino , Ratones , Animales , Benzo(a)pireno/toxicidad , Diosmina/efectos adversos , Diosmina/metabolismo , Antígeno Carcinoembrionario/metabolismo , Antioxidantes/farmacología , Dinoprostona/metabolismo , Pulmón/metabolismo , Carcinogénesis , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/metabolismo , Ciclooxigenasa 2/metabolismoRESUMEN
1,2-Dimethylhydrazine (DMH), a colon-specific environmental toxicant is one among the carcinogen responsible for the cause of colon cancer. The present study was designed to evaluate the protective effect of Hesperetin (HST) against colon toxicity induced by DMH in Wistar rats. HST, a flavonoid widely found in citrus fruits possesses several biological activities including anti-microbial, anti-oxidant properties among others. A single dose of DMH (40 mg/kg body weight) was administered subcutaneously on 1st day for induction of colon toxicity followed by oral treatment with HST at a dose of 20 mg/kg bodyweight for 14 consecutive days. DMH administration leads to excessive ROS generation, resulting in an imbalance in redox homeostasis and causing membrane lipid peroxidation, which is also partly due to the decrease in the level of tissue antioxidant machinery. Our result showed HST significantly ameliorates DMH-induced lipid peroxidation and also substantially increases the activity/level of various anti-oxidant proteins (GR, GPx, GST, GSH, and SOD). HST was also found to reduce the expression of inflammatory proteins (TNF-α, IL-6, i-NOS, COX-2, NF-kB-p65), goblet cell disintegration as well as mucin depletion (sulfo and sialomucin) in the colon that was found to be elevated upon administration of DMH. Our histological results further provide confirmation of the protective role of HST against DMH-induced pathological alterations. The results of the present study demonstrate supplementation of HST is beneficial in ameliorating DMH-induced toxicity by suppressing oxidative stress, inflammation, goblet cell disintegration as well mucin depletion in the colon of Wistar rats.
Asunto(s)
Neoplasias del Colon , Hesperidina , Estrés Oxidativo , 1,2-Dimetilhidrazina/toxicidad , Animales , Antioxidantes/metabolismo , Catalasa/metabolismo , Colon/metabolismo , Neoplasias del Colon/patología , Glutatión/metabolismo , Hesperidina/farmacología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Mucinas/metabolismo , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismoRESUMEN
1,2 Dimethyl hydrazine (DMH), a cogent environmental toxicant, targets the colon. Previous reports suggest that DMH-mediated dysregulation of the Wnt/ß-catenin pathway plays a vital role in the initial events of colon carcinogenesis. Our study was designed to investigate the effect of quercetin on DMH-mediated colon cancer by targeting adenomatous polyposis coli (APC) and ß-catenin in Wistar rats. Animals were pretreated orally with quercetin at doses of either 25 or 50 mg/kg bodyweight (bw) and DMH at a dose of 20 mg/kg bw subcutaneously up to the 15th week and sacrificed after the 30th week. DMH administration leads to reactive oxygen species generation, resulting in an imbalance in redox homeostasis and causing membrane lipid peroxidation, which is also partly due to the decrease in the level of tissue antioxidant machinery. Increased inflammatory and proliferative proteins were observed in DMH-induced colon cancerous rats. DMH treatment also led to dysregulation in the apoptotic pathway with decreased Bax:Bcl-2 ratio. Quercetin pretreatment ameliorates DMH-induced proliferation, activities of detoxifying enzymes, and putative early markers (mucin depletion and goblet cell disintegration) in colonic tissue. It also significantly regulates APC and ß-catenin expression and inhibits tumor incidence and multiplicity. Histological results further confirm the beneficial role of quercetin in averting DMH-induced pathological alterations.
Asunto(s)
Neoplasias del Colon/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Quercetina/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , beta Catenina/metabolismo , Animales , Neoplasias del Colon/patología , Femenino , Humanos , Quercetina/farmacología , Ratas , Ratas WistarRESUMEN
1,2-Dimethylhydrazine (DMH), an environmental toxicant specifically targets the colon. The present study was aimed to evaluate the efficacy of gallic acid (GA) against colon toxicity induced by DMH in Wistar rats. GA, a phenolic acid has numerous beneficial properties, which include antiviral, antifungal and antioxidant properties which help cells to overcome oxidative stress and balance the redox homeostasis. GA was administered orally at two doses (25 and 50 mg/kg body weight) once daily for 14 days and a single dose (40 mg/kg body weight) of DMH was administered subcutaneously on 14th day. Animals were sacrificed on the 15th day and we could find that GA at both the doses significantly ameliorates DMH-induced increased toxicity markers and also substantially increases the glutathione content level and activities of detoxifying enzymes. It also ameliorates the expression of proliferation, inflammation, apoptosis, goblet cell disintegration, and mucin depletion in the colon that was elevated upon administration of DMH. Histological alterations provide further confirmation of the protective role of GA against DMH-induced colon toxicity. The results of this study clearly indicate supplementation of GA is beneficial in ameliorating DMH-induced oxidative stress, inflammation, proliferation, apoptosis, mucin depletion, and goblet cell disintegration in colon of Wistar rats.
Asunto(s)
1,2-Dimetilhidrazina/toxicidad , Antiinflamatorios/toxicidad , Proliferación Celular/efectos de los fármacos , Ácido Gálico/farmacología , Células Caliciformes/efectos de los fármacos , Mucinas/metabolismo , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Glutatión/metabolismo , Células Caliciformes/metabolismo , Células Caliciformes/patología , Inflamación , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Diosmin, a naturally occurring flavonoid commonly present in citrus fruit, is known to exhibit anti-inflammatory, antimutagenic, antioxidant, and free radical scavenging as well as blood lipid lowering activities among others. Diosmin has also been used for the treatment of various diseases including diabetes mellitus and Alzheimer's disease. Our study explores the role of Diosmin in pulmonary toxicity (lung injury) induced by environmental contaminant benzo(a)pyrene [B(a)P]. Swiss Albino Mice (SAM) were administered with either Diosmin 100 or 200 mg/kg body weight daily for 14 days and then challenged with a single dose of B(a)P. On the 15th day, animals were sacrificed; lung tissues and blood were collected for molecular analysis. B(a)P administration in mice induced the thickening of lung epithelium, damaged alveolar architecture, and promoted inflammatory cell infiltration in the lung tissues. Also, B[a]P significantly increased the expression of NF-kB, COX-2, IL-6, Bax, cleaved caspase 3, and cleaved PARP proteins and decreased antioxidant enzyme levels. Diosmin-100 and Diosmin-200 significantly attenuated the damage to lung epithelium, alveolar architecture, and reduced inflammatory cell infiltration in the lung tissues of mice. Diosmin significantly (P < .05) attenuated the levels of oxidative stress markers: lactate dehydrogenase and xanthine oxidase. A decrease in expression of NF-kB, COX-2, IL-6, Bax, cleaved caspase 3, and cleaved PARP proteins in mice was challenged with B[a]P. Diosmin thus could be a promising therapeutic adjuvant against B[a]P-induced oxidative stress and lung damage.
Asunto(s)
Antiinflamatorios/farmacología , Antioxidantes/metabolismo , Benzo(a)pireno/toxicidad , Diosmina/farmacología , Contaminantes Ambientales/toxicidad , Lesión Pulmonar/prevención & control , Animales , Caspasa 3/metabolismo , Ciclooxigenasa 2/metabolismo , Pulmón/efectos de los fármacos , Lesión Pulmonar/metabolismo , Masculino , Ratones , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacosRESUMEN
Hesperidin (HD), a citrus bioflavonoid possesses a variety of biological activities including antioxidant, anti-inflammatory, anti-apoptotic and anti-carcinogenic properties. In the present study, we investigated the effect of HD treatment on N,N'-dimethylhydrazine (DMH) induced oxidative stress, inflammation, apoptosis and goblet cell disintegration in the colon of Wistar rats. Administration of HD was done at two doses (100 and 200 mg/kg body weight) orally to rats daily for 14 days followed by a single subcutaneous injection of DMH (40 mg/kg body weight) on the 14th day and next day animals were sacrificed. The protective potential of HD against colon toxicity was measured through membrane oxidation, antioxidant status, inflammatory and apoptotic markers expression, and histological changes. Results demonstrated that HD inhibited DMH mediated oxidative damage by diminishing the level of peroxidation of lipids and increasing the activity of superoxide dismutase, catalase, reduced glutathione, glutathione peroxidase, glutathione-s-transferase, and glutathione reductase. Moreover, HD attenuated inflammatory (NF-кB, IL-6, and COX-2) and apoptotic (p38-MAPK, p53, and caspase-3) markers expression. HD also attenuated the DMH induced goblet cell disintegration and restored histoarchitecture of the colon. The results of the present study demonstrate that HD efficiently protects against DMH induced colon toxicity by modulating oxidative stress, inflammation, and apoptosis.
RESUMEN
The present study was designed to evaluate the protective effects of hesperidin, a flavonoid on DEN initiated and Fe-NTA promoted renal carcinogenesis in Wistar rats. Renal cancer was initiated by a single i.p. injection of DEN (200 mg/kg b.wt.) and promoted with Fe-NTA (9 mg Fe/kg b.wt. i.p.) twice a week for 16 weeks. Rats were simultaneously administered with hesperidin (100 and 200 mg/kg b.wt.) for 16 consecutive weeks. The chemopreventive effect of hesperidin was assessed in terms of antioxidant activities, renal function, PGE2 level, and the expressions of COX-2 and VEGF. Hesperidin decreased the DEN and Fe-NTA induced lipid peroxidation, improved the renal function (by decreasing the levels of BUN, creatinine, and KIM-1) and restored the renal antioxidant armory (GSH, GPx, GR, SOD, and catalase). Hesperidin was also found to decrease the level of PGE2 and downregulate the expressions of COX-2 and VEGF. Histological findings further revealed the protective effects of hesperidin against DEN and Fe-NTA induced kidney damage. The result of our present findings suggest that hesperidin may be a promising modulator in preventing renal cancer possibly by virtue of its ability to alleviate oxidative stress and inhibit COX-2/PGE2 pathway.
Asunto(s)
Anticarcinógenos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Hesperidina/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Animales , Anticarcinógenos/farmacología , Antioxidantes/metabolismo , Carcinogénesis/inducido químicamente , Carcinogénesis/efectos de los fármacos , Carcinoma de Células Renales/inducido químicamente , Carcinoma de Células Renales/metabolismo , Proliferación Celular/efectos de los fármacos , Dietilnitrosamina , Compuestos Férricos , Hesperidina/farmacología , Riñón/metabolismo , Neoplasias Renales/inducido químicamente , Neoplasias Renales/metabolismo , Peroxidación de Lípido , Masculino , Ácido Nitrilotriacético/análogos & derivados , Estrés Oxidativo , Extractos Vegetales/farmacología , Ratas WistarRESUMEN
OBJECTIVES: Colon cancer is the major health disease related with high mortality. Glycyrrhizic acid (GA) is an active constituent of licorice with anti-inflammatory and anticarcinogenesis effects. We investigated the chemopreventive potential of GA against 1,2-dimethylhydrazine (DMH)-induced colon tumorigenesis in Wistar rats. METHODS: Glycyrrhizic acid was administered orally at the dose of 15 mg/kg b.wt. and DMH was administered at the dose of 20 mg/kg b.wt. once a week for first 15 weeks. All the rats were euthanized after 30 weeks. GA supplementation significantly inhibited the tumor incidence and multiplicity. RESULTS: Glycyrrhizic acid treatment reduced the expression of Ki-67, proliferating cell nuclear antigen (PCNA), nuclear factor-kappa B (NF-kB), cyclooxygenase-2 (COX-2), induced nitric oxide synthase (iNOS), and vascular endothelial growth factor (VEGF) while enhanced the expression of p53, connexin-43, b-cell lymphoma-2 (Bcl-2), survivin, and cleaved caspase-3. Glycyrrhizic acid also significantly ameliorated DMH-induced decreased activities of caspase-9 and caspase-3. Furthermore, GA treatment reduced mast cells infiltration, attenuated the shifting of sialomucin to sulphomucin as well the levels of pro-inflammatory cytokines. CONCLUSION: The findings of the study suggest that GA has chemopreventive potential against DMH-induced colon tumorigenesis plausibly through the attenuation of hyperproliferative responses, pro-inflammatory cytokines level, inflammatory and angiogenic markers, and apoptotic responses.
Asunto(s)
Apoptosis/efectos de los fármacos , Carcinogénesis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/prevención & control , Ácido Glicirrínico/farmacología , Inflamación/prevención & control , Neovascularización Fisiológica/efectos de los fármacos , 1,2-Dimetilhidrazina , Animales , Anticarcinógenos/farmacología , Biomarcadores/análisis , Biomarcadores/metabolismo , Carcinogénesis/inducido químicamente , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/patología , Masculino , Ratas , Ratas WistarRESUMEN
Benzo(a)pyrene [B(a)P] is a well-known carcinogen present in the environment. In this study, we evaluated the protective potential of methanolic bark extract of Acacia catechu Willd. (MEBA) against the lung toxicity induced by B(a)P in Swiss albino mice. To determine the protective efficacy of MEBA, it was orally administered to the mice at two doses (200 and 400 mg/kg body weight) once daily for 7 days. Mice were also exposed (orally) to B(a)P at a dose of 125 mg/kg body weight on 7th day. Administration of B(a)P increased the activities of toxicity markers such as LDH, LPO, and XO with a subsequent decrease in the activities of tissue anti-oxidant armory (CAT, SOD, GST, GPx, GR, QR, and GSH). It also caused activation of the apoptotic and inflammatory pathway by upregulation of TNF-α, NF-kB, COX-2, p53, bax, caspase-3, and downregulating Bcl-2. Pretreatment with MEBA at two different doses (200 and 400 mg/kg body weight) significantly ameliorates B(a)P-induced increased toxicity markers and activities of detoxifying enzymes along with the levels of glutathione content. It also significantly attenuated expression of apoptotic and inflammatory markers in the lungs. Histological results further confirmed the protective role of MEBA against B(a)P-induced lung toxicity. The results indicate that MEBA may be beneficial in ameliorating the B(a)P-induced oxidative stress, inflammation, and apoptosis in the lungs of mice. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1566-1577, 2017.
Asunto(s)
Acacia/química , Apoptosis/efectos de los fármacos , Benzo(a)pireno/toxicidad , Pulmón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Neumonía/prevención & control , Animales , Antioxidantes/metabolismo , Carcinógenos/toxicidad , Caspasa 3/metabolismo , Citoprotección/efectos de los fármacos , Glutatión/metabolismo , Pulmón/fisiología , Masculino , Metanol/química , Ratones , FN-kappa B/metabolismo , Corteza de la Planta/química , Extractos Vegetales/química , Neumonía/inducido químicamente , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Chrysin (CH) is natural, biologically active compound, belongs to flavoniod family and possesses diverse pharmacological activities as anti-inflammatory, anti-oxidant and anti-cancer. It is found in many plants, honey and propolis. In the present study, we investigated the chemopreventive efficacy of CH against N-nitrosodiethylamine (DEN) initiated and Fe-NTA induced precancerous lesions and its role in regulating oxidative injury, hyperproliferation, tumor incidences, histopathological alterations, inflammation, and apoptosis in the kidneys of Wistar rats. Renal cancer was initiated by single intraperitoneal (i.p.) injection of DEN (200 mg/kg bw) and promoted by twice weekly injection of ferric nitrilotriacetate (Fe-NTA) 9 mg Fe/kg bw for 16 weeks. CH attenuated Fe-NTA enhanced renal lipid peroxidation, serum toxicity markers and restored renal anti oxidant armory significantly. CH supplementation suppressed the development of precancerous lesions via down regulation of cell proliferation marker like PCNA; inflammatory mediators like TNF-α, IL-6, NFkB, COX-2, iNOS; tumor incidences. CH up regulated intrinsic apoptotic pathway proteins like bax, caspase-9 and caspase-3 along with down regulation of Bcl-2 triggering apoptosis. Histopathological and ultra structural alterations further confirmed biochemical and immunohistochemical results. These results provide powerful evidence for the chemopreventive efficacy of CH against chemically induced renal carcinogenesis possibly by modulation of multiple molecular pathways.
Asunto(s)
Flavonoides/química , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/prevención & control , Lesiones Precancerosas/fisiopatología , Animales , Anticarcinógenos/química , Antioxidantes/química , Apoptosis , Carcinogénesis , Proliferación Celular , Compuestos Férricos , Inflamación , Riñón/patología , Neoplasias Renales/fisiopatología , Peroxidación de Lípido , Masculino , Ácido Nitrilotriacético/análogos & derivados , Estrés Oxidativo , Lesiones Precancerosas/inducido químicamente , Ratas , Ratas Wistar , Regulación hacia ArribaRESUMEN
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. 18ß-Glycyrrhetinic acid (18ß-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 18ß-GA through antiinflammation, antiproliferation, and induction of apoptosis in human hepatoma cell line HepG2. 18ß-GA significantly inhibits the proliferation of HepG2 cell without affecting the normal liver cell line (Chang's). In the present study, 18ß-GA increased the formation of reactive oxygen species, nitric oxide production, and loss of mitochondrial membrane potential, suggesting the involvement of 18ß-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. 18ß-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 18ß-GA may be used as a chemopreventive agent in liver cancer.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/biosíntesis , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/biosíntesis , Carcinoma Hepatocelular/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ácido Glicirretínico/análogos & derivados , Mediadores de Inflamación/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/biosíntesis , Carcinoma Hepatocelular/patología , Ácido Glicirretínico/farmacología , Células Hep G2 , Humanos , Neoplasias Hepáticas/patologíaRESUMEN
BACKGROUND: Pancreatic cancer, one of the most dreadful gastrointestinal tract malignancies, with the current chemotherapeutic drugs has posed a major impediment owing to poor prognosis and chemo-resistance thereby suggesting critical need for additional drugs as therapeutics in combating the situation. Fluoroquinolones have shown promising and significant anti-tumor effects on several carcinoma cell lines. METHODS: Previously, we reported growth inhibitory effects of fourth generation fluoroquinolone Gatifloxacin, while in the current study we have investigated the anti-proliferative and apoptosis-inducing mechanism of older generation fluoroquinolones Moxifloxacin and Ciprofloxacin on the pancreatic cancer cell-lines MIA PaCa-2 and Panc-1. Cytotoxicity was measured by MTT assay. Apoptosis induction was evaluated using annexin assay, cell cycle assay and activation of caspase-3, 8, 9 were measured by western blotting and enzyme activity assay. RESULTS: Herein, we found that both the fluoroquinolones suppressed the proliferation of pancreatic cancer cells by causing S-phase arrest and apoptosis. Blockade in S-phase of cell cycle was associated with decrease in the levels of p27, p21, CDK2, cyclin-A and cyclin-E. Herein we also observed triggering of extrinsic as well as intrinsic mitochondrial apoptotic pathway as suggested by the activation of caspase-8, 9, 3, and Bid respectively. All this was accompanied by downregulation of antiapoptotic protein Bcl-xL and upregulation of proapoptotic protein Bak. Our results strongly suggest the role of extracellular-signal-regulated kinases (ERK1/2), but not p53, p38 and c-JUN N-terminal kinase (JNK) in fluoroquinolone induced growth inhibitory effects in both the cell lines. Additionally, we also found both the fluoroquinolones to augment the apoptotic effects of broad spectrum anticancer drug Cisplatin via ERK. CONCLUSION: The fact that these fluoroquinolones synergize the effect of cisplatin opens new insight into therapeutic index in treatment of pancreatic cancer.
Asunto(s)
Ciprofloxacina/farmacología , Cisplatino/farmacología , Fluoroquinolonas/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Fase S/efectos de los fármacos , Apoptosis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Moxifloxacino , Neoplasias Pancreáticas/metabolismoRESUMEN
Trichloroethylene (TCE), a nephrotoxicant is known to cause severe damage to the kidney. In this study, the nephroprotective potential of hesperidin was evaluated against TCE-induced nephrotoxicity in wistar rats. Oral administration of TCE (1000 mg/kg b.wt) for 15 days enhanced renal lipid peroxidation and reduced antioxidant enzymes armoury viz., reduced renal glutathione, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, catalase and superoxide dismutase. It also enhanced the levels of blood urea nitrogen, creatinine and kidney injury molecule (KIM-1). Caspase-3 and bax expression were found to be elevated, while that of bcl-2 reduced suggesting that TCE induces apoptosis. However, pretreatment with hesperidin at a dose of 100 and 200 mg/kg b.wt for 15 days significantly decreased lipid peroxidation, increased the levels of antioxidant enzymes and reduced blood urea, creatinine and KIM-1 levels. Hesperidin also modulated the apoptotic pathways by altering the expressions of caspase-3, bax and bcl-2 to normal. Our results suggest that hesperidin can be used as a nephroprotective agent against TCE-induced nephrotoxicity.
Asunto(s)
Antioxidantes/farmacología , Apoptosis , Hesperidina/farmacología , Riñón/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/uso terapéutico , Proteínas Reguladoras de la Apoptosis/metabolismo , Catalasa/metabolismo , Evaluación Preclínica de Medicamentos , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Glutatión Transferasa/metabolismo , Hesperidina/uso terapéutico , Riñón/efectos de los fármacos , Riñón/patología , Masculino , Malondialdehído/metabolismo , Ratas Wistar , Insuficiencia Renal/inducido químicamente , Insuficiencia Renal/metabolismo , Superóxido Dismutasa/metabolismo , TricloroetilenoRESUMEN
Skin cancer is the most common malignancy in the world and also one of the major causes of death worldwide. The toxic environmental pollutant 7,12-dimethylbenz[a]anthracene (DMBA) is a skin-specific carcinogen. Tannic acid (TA) is reported to be effective against various types of chemical-induced toxicities and carcinogenesis as well. In the present study, we have evaluated the therapeutic potential of tannic acid in DMBA + croton oil-induced skin cancer in Swiss albino mice. Protective effect of TA against skin cancer was evaluated in terms of antioxidant enzymes activities, lipid peroxidation, histopathological changes and expression of inflammation and early tumour markers. DMBA + croton oil causes depletion of antioxidant enzymes (p < 0.001) and elevation of early inflammatory and tumour promotional events. TA prevents the DMBA + croton oil-induced toxicity through a protective mechanism that involves the reduction of oxidative stress as well as COX-2, i-NOS, PCNA protein expression and level of proinflammatory cytokine such as IL-6 release at a very significant level (p < 0.001). It could be concluded from our results that TA attenuates DMBA + croton oil-induced tumour promotional potential possibly by inhibiting oxidative and inflammatory responses and acts as antioxidant, anti-inflammatory and antiproliferative agent.
Asunto(s)
Anticarcinógenos/farmacología , Neoplasias Cutáneas/tratamiento farmacológico , Taninos/farmacología , 9,10-Dimetil-1,2-benzantraceno , Animales , Anticarcinógenos/uso terapéutico , Croton/química , Ciclooxigenasa 2/metabolismo , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Glutatión/metabolismo , Peróxido de Hidrógeno/metabolismo , Interleucina-6/metabolismo , Peroxidación de Lípido , Ratones , Óxido Nítrico Sintasa de Tipo II/metabolismo , Aceites de Plantas , Antígeno Nuclear de Célula en Proliferación/metabolismo , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patología , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/patología , Taninos/uso terapéutico , Xantina Oxidasa/metabolismoRESUMEN
In the present study, chemopreventive efficacy of hesperidin was evaluated against ferric nitrilotriacetate (Fe-NTA) induced renal oxidative stress and carcinogenesis in wistar rats. Nephrotoxicity was induced by single intraperitoneal injection of Fe-NTA (9 mg Fe/kg b.wt). Renal cancer was initiated by the administration of N-nitrosodiethylamine (DEN 200mg/kg b.wt ip) and promoted by Fe-NTA (9 mg Fe/kg b.wt ip) twice weekly for 16 weeks. Efficacy of hesperidin against Fe-NTA-induced nephrotoxicity was assessed in terms of biochemical estimation of antioxidant enzyme activities viz. reduced renal GSH, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, catalase, superoxide dismutase and renal toxicity markers (BUN, Creatinine, KIM-1). Administration of Fe-NTA significantly depleted antioxidant renal armory, enhanced renal lipid peroxidation as well as the levels of BUN, creatinine and KIM-1. However, simultaneous pretreatment of hesperidin restored their levels in a dose dependent manner. Expression of apoptotic markers caspase-3, caspase-9, bax, bcl-2 and proliferative marker PCNA along with inflammatory markers (NFκB, iNOS, TNF-α) were also analysed to assess the chemopreventive potential of hesperidin in two-stage renal carcinogenesis model. Hesperidin was found to induce caspase-3, caspase-9, bax expression and downregulate bcl-2, NFκB, iNOS, TNF-α, PCNA expression. Histopathological findings further revealed hesperidin's chemopreventive efficacy by restoring the renal morphology. Our results provide a powerful evidence suggesting hesperidin to be a potent chemopreventive agent against renal carcinogenesis possibly by virtue of its antioxidant properties and by modulation of multiple molecular pathways.
Asunto(s)
Carcinogénesis/efectos de los fármacos , Carcinoma de Células Renales/prevención & control , Hesperidina/farmacología , Neoplasias Renales/prevención & control , Estrés Oxidativo/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Carcinógenos/toxicidad , Carcinoma de Células Renales/inducido químicamente , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Compuestos Férricos/toxicidad , Inmunohistoquímica , Neoplasias Renales/inducido químicamente , Masculino , Ácido Nitrilotriacético/análogos & derivados , Ácido Nitrilotriacético/toxicidad , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacosRESUMEN
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.
Asunto(s)
2-Acetilaminofluoreno/farmacología , Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Hepatitis/tratamiento farmacológico , Hígado/metabolismo , Terpenos/farmacología , Monoterpenos Acíclicos , Animales , Proliferación Celular/efectos de los fármacos , Daño del ADN , Dieta , Femenino , Hepatectomía , Hepatitis/patología , Hígado/efectos de los fármacos , Hígado/patología , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
OBJECTIVE: The present study was designed to investigate underlying molecular mechanism for antitumorigenic potential of Terminalia chebula (TC) against chemically-induced skin tumorigenesis in Swiss albino mice. It is used as herbal medicine because it exhibits antioxidant, anti-inflammatory, and anticarcinogenic activity. However, the précised underlying mechanism remains to be elucidated. MATERIALS AND METHODS: In light of the important role of nuclear factor-kappaB (NF-κB), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (i-NOS), ornithine decarboxylase (ODC), proinflammatory cytokines, oxidative stress in carcinogenesis, chemopreventive efficacy of TC against 7,12-dimethylbenz[a] anthracene (DMBA), and croton oil-induced 2-stage skin carcinogenesis was studied in terms of cytoprotective antioxidant enzymes activity, lipid peroxidation (LPO), inflammatory responses, and expression of various molecular markers in skin tissues. RESULTS: We found that topical application of TC at dose of 30 mg/kg b. wt. mouse effectively suppressed oxidative stress and deregulated activation of inflammatory mediators and tumorigenesis. Histological findings further supported the protective effects of TC against DMBA/croton oil-induced cutaneous damage. CONCLUSION: The findings of the present study suggest that the chemopreventive effect of TC is associated with upregulation of endogenous cytoprotective machinery and downregulation of inflammatory mediators (interleukin (IL)-6, COX-2, i-NOS, ODC, and NF-κB).
RESUMEN
In the present study, we showed the correlation of EZH2, SUV39H1 or G9a expression and histone modifications with the urethane induced mouse lung tumorigenesis in the presence or absence of antitumor agent, inositol hexaphosphate (IP6). Tumorigenesis and the molecular events involved therein were studied at 1, 4, 12 or 36 weeks after the exposure. There were no tumors at 1 or 4 weeks but tumors started appearing at 12 weeks and grew further till 36 weeks after urethane exposure. Among the molecular events, upregulation of EZH2 and SUV39H1 expressions appeared to be time dependent, but G9a expression was altered significantly only at later stages of 12 or 36 weeks. Alteration in miR-138 expression supports the upregulation of its target, EZH2. H3K9me2, H3K27me3 or H4K20me3 was found to be altered at 12 or 36 weeks. However, ChIP analysis of p16 and MLH1 promoters showed their binding with H3K9me2 and H3K27me3 which was maximum at 36 weeks. Thus, histone modification and their interactions with gene promoter resulted in the reduced expression of p16 and MLH1. IP6 prevented the incidence and the size of urethane induced lung tumors. IP6 also prevented the urethane induced alterations in EZH2, SUV39H1, G9a expressions and histone modifications. Our results suggest that the alterations in the histone modification pathways involving EZH2 and SUV39H1 expressions are among the early events in urethane induced mouse lung tumorigenesis and could be exploited for cancer control.
Asunto(s)
N-Metiltransferasa de Histona-Lisina/fisiología , Neoplasias Pulmonares/inducido químicamente , Metiltransferasas/fisiología , Complejo Represivo Polycomb 2/fisiología , Proteínas Represoras/fisiología , Uretano/toxicidad , Animales , Proteína Potenciadora del Homólogo Zeste 2 , Femenino , Histonas/metabolismo , Histona Demetilasas con Dominio de Jumonji/metabolismo , Neoplasias Pulmonares/metabolismo , Metilación , Ratones , Ratones Endogámicos BALB C , MicroARNs/análisis , Complejo Represivo Polycomb 2/genética , Regiones Promotoras GenéticasRESUMEN
We examined the clastogenic and cell-transforming potential of ultrafine particulate matter fraction PM0.056 of urban ambient aerosol using mammalian cells. PM1.0, PM0.56 and PM0.056 fractions were sampled from roadside atmosphere of an urban area using the cascade impactor MOUDI-NR-110. The potential to induce cytotoxicity, DNA damage and micronuclei formation was examined at the test concentrations of 3, 6, 12.5, 25, 50 and 100 µg/ml using the 3-4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, the plasmid relaxation assay and the C3H10T1/2 (10T1/2) cells. The cell-transforming potential was investigated in vitro using 10T1/2 cell transformation assay and the soft agar assay. PM1, PM0.56 and PM0.056 fractions were found to be toxic in dose-dependent manner. These induced cytotoxicity at five test concentrations, the ultrafine particle fraction PM0.056 showed greater cytotoxic potential. PM0.056 induced micronucleus formation in 10T1/2 cells. The effect was statistically significant. The DNA-damaging potential was measured in a plasmid relaxation assay. Both fine and ultrafine particle fraction PM0.56 and PM0.056 displayed greater effect as compared to larger PM1 fraction. DNA damage was found to be dependent on particulate matter intrinsic pro-oxidant chemicals. The ability of the ultrafine particle fraction PM0.056 to induce morphological cell transformation was demonstrated by significant and dose-dependent increases in type III focus formation by morphologically transformed cells in culture flasks and their clonal expansion in soft agar. It is concluded that the traffic-linked ultrafine particle fraction PM0.056 in the atmosphere by the roadside of an urban area is clastogenic and able to induce morphological transformation of mammalian cells.
Asunto(s)
Monitoreo del Ambiente/métodos , Material Particulado/química , Contaminantes Atmosféricos/química , Contaminantes Atmosféricos/toxicidad , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Ratones , Pruebas de Micronúcleos , Tamaño de la Partícula , Material Particulado/toxicidadRESUMEN
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.