RESUMEN
BACKGROUND: Interferon and nucleos(t)ide analogues are current therapeutic treatments for chronic Hepatitis B virus (HBV) infection with the limitations of a functional cure. Chrysin (5, 7-dihydroxyflavone) is a natural flavonoid, known for its antiviral and hepatoprotective activities. However, its anti-HBV activity is unexplored. METHODS: In the present study, the anti-hepatitis B activity of chrysin was investigated using the in vitro experimental cell culture model, HepG2 cells. In silico studies were performed where chrysin and lamivudine (used here as a positive control) were docked with high mobility group box 1 protein (HMGB1). For the in vitro studies, wild type HBV genome construct (pHBV 1.3X) was transiently transfected in HepG2. In culture supernatant samples, HBV surface antigen (HBsAg) and Hepatitis B e antigen (HBeAg) were measured by enzyme-linked immunosorbent assay (ELISA). Secreted HBV DNA and intracellular covalently closed circular DNA (cccDNA) were measured by SYBR green real-time PCR. The 3D crystal structure of HMGB1 (1AAB) protein was developed and docked with the chrysin and lamivudine. In silico drug-likeness, Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties of finest ligands were performed by using SwissADME and admetSAR web servers. RESULTS: Data showed that chrysin significantly decreases HBeAg, HBsAg secretion, supernatant HBV DNA and cccDNA, in a dose dependent manner. The docking studies demonstrated HMGB1 as an important target for chrysin as compared to lamivudine. Chrysin revealed high binding affinity and formed a firm kissing complex with HMGB1 (∆G = - 5.7 kcal/mol), as compared to lamivudine (∆G = - 4.3 kcal/mol), which might be responsible for its antiviral activity. CONCLUSIONS: The outcome of our study establishes chrysin as a new antiviral against HBV infection. However, using chrysin to treat chronic HBV disease needs further endorsement and optimization by in vivo studies in animal models.
RESUMEN
Introduction: Chikungunya is caused by an alpha virus transmitted to humans by an infected mosquito. Infection is generally considered to be self-limiting and non-critical. Chikungunya infection may be diagnosed by severe joint pain with fever, but it is difficult to diagnose because the symptoms of chikungunya are common to many pathogens, including dengue fever. Diagnosis mainly depends on viral culture, reverse transcriptase polymerase chain reaction (RT-PCR), and IgM ELISA. Early and accurate diagnosis of the virus can be achieved by the application of PCR methods, but the high cost and the need for a thermal cycler restrict the use of such methods. On the other hand, antibody-based IgM ELISA is considered to be inexpensive, but antibodies against chikungunya virus (CHIKV) only develop after 4 days of infection, so it has limited application in the earlier diagnosis of viral infection and the management of patients. Because of these challenges, a simple antigen-based sensitive, specific, and rapid detection method is required for the early and accurate clinical diagnosis of chikungunya. Methods: The amino acid sequence of CHIKV ectodomain E1 and E2 proteins was analyzed using bioinformatics tools to determine the antigenic residues, particularly the B-cell epitopes and their characteristics. Recombinant E2-E1 CHIKV antigen was used for the development of polyclonal antibodies in hamsters and IgG was purified. Serological tests of 96 CHIKV patients were conducted by antigen-capture ELISA using primary antibodies raised against rCHIKV E2-E1 in hamsters and human anti-CHIKV antibodies. Results: We observed high specificity and sensitivity, of 100% and 95.8%, respectively, and these values demonstrate the efficiency of the test as a clinical diagnostic tool. There was no cross-reactivity with samples taken from dengue patients. Discussion: Our simple and sensitive sandwich ELISA for the early-phase detection of CHIKV infection may be used to improve the diagnosis of chikungunya.
RESUMEN
OBJECTIVES: Saussurea lappa, CB Clarke (S.lappa) is a perennial herb of the Compositae family. The root of S.lappa has been used for the treatment of various diseases such as hepatitis, jaundice, intestinal worms, bronchial asthma, and a variety of skin diseases. The aim of the study was to ensure quality control of S.lappa and its preparation HAESL (hydroalcoholic extract of S.lappa) along with assessment of HAESL antimicrobial and antioxidant activities in vitro. METHODS: HAESL was prepared with 50% ethanol, (v/v). Physiochemical analysis of the root of S.lappa, and phytochemical screening, thin-layer chromatography (TLC), high-performance thin-layer chromatography (HPTLC), and in vitro antimicrobial and antioxidant activity of HAESL were performed using the standard protocol. RESULTS: Physiochemical and phytochemical assessments of S.lappa and HAESL showed the greater quality of the drug. HAESL showed the presence of many phytochemical constituents corresponding to colorful spots, peaks, area under the curve, and corresponding Rf values as evident in the TLC and HPTLC analysis. HAESL showed a concentration-dependent effect on radical scavenging activity against DPHH (2,2-diphenyl-1-picrylhydrazyl) and hydroxyl radical with IC50 value of 19.10 µg/mL and 82.23 µg/mL, respectively. HAESL exhibited antimicrobial activity against the growth of micro-organisms such as Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella typhi, Aspergillus flavus, and Candida albicans. HASEL showed no antimicrobial activity against Aspergillus niger. CONCLUSIONS: The procured and an identified sample of Saussurea lappa was good in quality and the prepared HAESL contained many phytochemical compounds. HAESL substantiated significant antioxidant and antimicrobial activity in vitro.
RESUMEN
The protective efficacy of methanolic bark extract of Acacia catechu Willd. (MEBA) against 1,2-dimethylhydrazine (DMH)-induced colon toxicity was investigated. Acacia catechu is considered one of the most potent medicines for various diseases in Ayurveda, a traditional system of Indian medicine. It is a widely used herb that contains a variety of bioactive components such as phenolic acids, alkaloids, and flavonoids among others. In the present study, MEBA was used as a pretreatment orally at two doses (250 and 500 mg/kg body weight [b.w.] once daily for 7 days), and DMH was administered (at a dose of 40 mg/kg b.w.) subcutaneously on day 7 in Wistar rats. The protective potential of MEBA was assessed in terms of the activity of antioxidant enzymes, lipid peroxidation, and expression of inflammatory markers (iNOS, COX-2, NF-κB, IL-6). Pretreatment with MEBA significantly abrogated oxidative damage by diminishing tissue lipid peroxidation, increasing enzymatic activities of various antioxidant enzymes (catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, reduced glutathione), and diminishing the induced expression of inflammatory markers in the colon tissue of Wistar rats. Furthermore, histopathological findings revealed that pretreatment with (MEBA) reduced intense filtration of inflammatory cells and significantly restored the architecture of colonic tissue. The results of this study indicate that MEBA significantly suppresses DMH-induced toxicity by ameliorating oxidative stress and inflammation and by restoring the architecture of colon tissue.
Asunto(s)
1,2-Dimetilhidrazina/toxicidad , Acacia , Carcinógenos/toxicidad , Colon/efectos de los fármacos , Corteza de la Planta , Extractos Vegetales/farmacología , Sustancias Protectoras/farmacología , Animales , Biomarcadores/metabolismo , Colon/metabolismo , Colon/patología , Esquema de Medicación , Femenino , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Inflamación/prevención & control , Metanol , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Fitoterapia/métodos , Plantas Medicinales , Distribución Aleatoria , Ratas , Ratas WistarRESUMEN
BACKGROUND: Cisplatin (CP) is a potent chemotherapeutic agent commonly used for the treatment of various malignancies. It has varied undesirable effects such as nephrotoxicity, intestinal toxicity which limit its wide and extensive clinical usage. 18ß-Glycyrrhetinic acid (GA) is a pentacyclic triterpenoid derivative, obtained from the herb liquorice having pharmacological properties such as anti-inflammatory, hepatoprotective and antioxidant. The present study was designed to investigate in vivo efficacy of GA against CP induced small intestinal toxicity. METHODS: Rats were subjected to prophylactic oral treatment of GA (50 and 100mg/kg body weight) for 21days against intestinal toxicity induced by single intra peritoneal injection of CP (10mg/kg body weight) on day 18th and sacrificed on 21st day. RESULTS: The plausible mechanism of CP induced small intestinal toxicity is via deficit in anti-oxidant armory, induction of oxidative stress; TNF-α, NFkB, activation of apoptotic pathway proteins by up regulation of caspases. However prophylactic treatment of GA diminished oxidative stress markers, TNF-α, NFkB expression and enhanced anti-oxidant status, down regulated apoptosis, recovered histopatholgical alterations in small intestine. CONCLUSION: Therefore, results of the present finding provide strong evidence that GA may be a useful modulator in alleviating CP induced intestinal toxicity.
Asunto(s)
Caspasas/metabolismo , Cisplatino/toxicidad , Ácido Glicirretínico/análogos & derivados , Enfermedades Intestinales/inducido químicamente , FN-kappa B/metabolismo , Animales , Biomarcadores , Regulación de la Expresión Génica/efectos de los fármacos , Glutatión/metabolismo , Ácido Glicirretínico/farmacología , Masculino , Estrés Oxidativo , Distribución Aleatoria , Ratas , Ratas WistarRESUMEN
Methotrexate (MTX) is a drug which is used to treat different types of cancers but hepatotoxicity limits its clinical use. Chlorogenic acid (CGA) is one of the most abundant naturally occurring polyphenols in the human diet. Here, we assessed the effect of CGA against MTX-induced hepatotoxicity and investigated the underlying possible mechanisms in Wistar Rats. Rats were pre-treated with CGA (50 or 100 mg kg/b.w) and administered a single dose of MTX (20 mg/kg, b.w.). MTX caused hepatotoxicity as evidenced by significant increase in serum toxicity markers, histopathological changes. decreased activities of anti-oxidant armory (SOD, CAT, GPx, GR) and GSH content. MTX significantly causes upregulation of iNOS, Cox-2, Bax and downregulation of Bcl-2 expressions, it causes higher caspase 3, 9 activities. However CGA pretreatment alleviates the hepatotoxicity by decreasing the oxidative stress. CGA inhibited Cox-2, iNOS, Bax, Bcl-2 and Caspases 3, 9 mediated inflammation and apoptosis, and improve the histology induced by MTX. Thus, these findings demonstrated the hepatoprotective nature of CGA by attenuating the pro-inflammatory and apoptotic mediators and improving antioxidant competence in hepatic tissue. These results imply that CGA has perfective effect against MTX-induced liver injury. Hence CGA supplementation might be helpful in abrogation of MTX toxicity.
Asunto(s)
Apoptosis/efectos de los fármacos , Ácido Clorogénico/farmacología , Hígado/efectos de los fármacos , Metotrexato/toxicidad , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Animales , Antioxidantes/metabolismo , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Glutatión/metabolismo , Inflamación/prevención & control , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Masculino , Óxido Nítrico Sintasa de Tipo II/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Wistar , Proteína X Asociada a bcl-2/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
Benzo(a)pyrene [B(a)P], a polycyclic aromatic hydrocarbon (PAH) is a strong mutagen and potent carcinogen. The aim of the present study was to investigate the efficacy of catechin hydrate against B(a)P induced genotoxicity, oxidative stress, inflammation, apoptosis and to explore its underlying molecular mechanisms in the lungs of Swiss albino mice. Administration of B(a)P (125 mg/kg b. wt., p. o.) increased the activities of toxicity markers such as LPO, LDH and B(a)P metabolizing enzymes [NADPH-cytochrome P450 reductase (CYPOR) and microsomal epoxide hydrolase (mEH)] with subsequent decrease in the activities of tissue anti-oxidant armory (SOD, CAT, GPx, GR, GST, QR and GSH). It also caused DNA damage and activation of apoptotic and inflammatory pathway by upregulation of TNF-α, IL-6, NF-kB, COX-2, p53, bax, caspase-3 and down regulating Bcl-2. However, pre-treatment with catechin at a dose of 20 and 40 mg/kg significantly decreased LDH, LPO, B(a)P metabolizing enzymes and increased anti-oxidant armory as well as regulated apoptosis and inflammation in lungs. Histological results also supported the protective effects of catechin. The findings of the present studies suggested that catechin as an effective natural product attenuates B(a)P induced lung toxicity.
Asunto(s)
Apoptosis/efectos de los fármacos , Benzo(a)pireno/toxicidad , Catequina/farmacología , Daño del ADN/efectos de los fármacos , Inflamación/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/metabolismo , Daño del ADN/genética , Técnicas para Inmunoenzimas , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/patología , Masculino , Ratones , FN-kappa B/metabolismoRESUMEN
BACKGROUND: Benzo(a)pyrene [B(a)P] is an environmental contaminant and potential carcinogenic agent that causes lung injuries which leads to lung cancer. Rutin, a well-known flavonoid present in various natural sources, possesses biological activities such as anti-oxidative and anti-inflammatory properties. The aim of this study was to evaluate the protective effects of rutin against B(a)P-induced genotoxicity, oxidative stress, apoptosis and inflammation in Swiss albino mice. METHODS: Pretreatment of rutin was given by oral gavage at doses of 40 and 80 mg/kg body weight (b.wt.) for 7 days before the administration of a single oral dose of B(a)P (125 mg/kg b.wt.). The ameliorative effect of rutin on oxidative stress, apoptotic and inflammatory markers in lung tissues and genotoxicity was studied using an alkaline unwinding assay and DNA fragmentation. RESULTS: B(a)P enhanced lipid peroxidation, xanthine oxidase, H2O2 generation and lactate dehydrogenase (LDH) activity; depleted activities of anti-oxidant enzymes and glutathione content; induced DNA strand breaks and fragmentation; disrupted normal histopathological architecture and also showed abnormal expression of NF-κB, COX-2, IL-6, TNF-α and Bcl-2. Rutin pretreatment caused a significant reduction in lipid peroxidation and LDH activity; increased glutathione content; restored antioxidant enzyme activity; reduced DNA strand breaks and fragmentation; modulated the expression of inflammatory, and apoptotic markers and restored the histopathological structure. CONCLUSIONS: The findings of the present study supported the protective effect of rutin against B(a)P-induced lung toxicity and genotoxicity.
Asunto(s)
Antioxidantes/farmacología , Estrés Oxidativo/fisiología , Neumonía/prevención & control , Rutina/farmacología , Animales , Apoptosis/efectos de los fármacos , Benzo(a)pireno/toxicidad , Carcinógenos/toxicidad , Ciclooxigenasa 2/metabolismo , ADN/efectos de los fármacos , Peróxido de Hidrógeno/metabolismo , Interleucina-6/metabolismo , L-Lactato Deshidrogenasa/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , Ratones , FN-kappa B/metabolismo , FN-kappa B/fisiología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/fisiología , Superóxido Dismutasa/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
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
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.
Asunto(s)
Antineoplásicos Alquilantes/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Ciclofosfamida/toxicidad , Hígado/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/uso terapéutico , Rutina/uso terapéutico , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/complicaciones , Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Interleucina-6/inmunología , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Masculino , FN-kappa B/inmunología , Ratas Wistar , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
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
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
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.
Asunto(s)
Antimetabolitos Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Flavonoides/farmacología , Fluorouracilo/toxicidad , Riñón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Nitrógeno de la Urea Sanguínea , Glutatión/metabolismo , Riñón/enzimología , Riñón/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Masculino , Malondialdehído/metabolismo , Ratas , Ratas WistarRESUMEN
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 -1ß, COX-2, iNOS, and NF-κB).
Asunto(s)
Antioxidantes/farmacología , Carcinogénesis/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Inflamación/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Silimarina/farmacología , Animales , Antiinflamatorios/farmacología , Carcinogénesis/metabolismo , Catalasa/genética , Catalasa/metabolismo , Transformación Celular Neoplásica/metabolismo , Quimioprevención , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Regulación hacia Abajo , Femenino , Glucosafosfato Deshidrogenasa/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Ratones , FN-kappa B/genética , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Silibina , Piel/efectos de los fármacos , Piel/patología , Acetato de Tetradecanoilforbol/toxicidad , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
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.
Asunto(s)
Apoptosis/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Flavonoides/farmacología , Flavonoides/uso terapéutico , Metotrexato/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/metabolismo , Biomarcadores/sangre , Caspasa 3/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Glutatión/metabolismo , Inmunohistoquímica , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Masculino , Malondialdehído/metabolismo , Ratas , Ratas Wistar , Proteína p53 Supresora de Tumor/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
OBJECTIVES: In the present study we have evaluated the chemopreventive efficacy of Bauhinia purpurea against Diethylnitrosamine (DEN) initiated and 2 Acetylaminofluorine (2-AAF) promoted hepatocarcinogenesis in Wistar rats. MATERIALS AND METHODS: Efficacy of Bauhinia purpurea against 2-AAF-induced hepatotoxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities (reduced hepatic GSH, glutathione peroxidase, glutathione reductase, catalase, and quinone reductase), histopathological changes and expressions of early tumor markers viz., ornithine decarboxylase activity (ODC) and proliferating cell nuclear antigen (PCNA) and also expressions of p53, Bax, Bcl-2, and caspase-3 were evaluated. RESULTS: Oral pretreatment with B. purpurea significantly decreased the levels of serum toxicity markers, elevated antioxidant defense enzyme activities, suppressed the expression of ODC and PCNA and P53 along with the induction of apoptosis in the pretreatment groups. Tumor incidences are reduced by pretreatment of B. purpurea. Histopathological findings revealed that B. purpurea-pretreated groups showed marked recovery. CONCLUSION: The results support the protective effect of B. purpurea against chemically induced liver cancer and acts possibily by virtue of its antioxidant, antiproliferative, and apoptotic activities.
RESUMEN
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.