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OBJECTIVE@#To examine the role of carvacrol in modulating PI3K/AKT signaling involved in human breast cancer pathogenesis using in vitro experimental model MCF-7 cells.@*METHODS@#MTT and lactate dehydrogenase assays were performed with cells treated with different doses of carvacrol (0-250 p mol/L) at different time points (24 and 48 h). The nuclear morphology was assessed in MCF-7 cells with propidium iodide (PI) and acridine orange/ethidium bromide (AO/EB) staining and analyzed by fluorescence microscopy. Events like cell cycle arrest, apoptosis was observed by flow cytometric analysis and expressions of p-Rb, cyclin D1, cyclin-dependent kinase 4 (CDK4), CDK6, Bax, Bcl-2, PI3K/p-AKT was analyzed by immunoblot.@*RESULTS@#Carvacrol significantly reduced cell viability with the half maximal inhibitory concentration value of 200 µmol/L at 24 and 48 h (P<0.05). importantly, there was a significant increase in the accumulation of the G@*CONCLUSION@#Carvacrol significantly inhibited the breast cancer MCF-7 cell proliferation and induced apoptosis via suppressing PI3/AKT signaling pathway.
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Functional perturbation of mitochondria is associated with fulminant hepatic failure (FHF). d-Galactosamine/lipopolysaccharide (d-GalN/LPS)-induced FHF is a renowned model to evaluate the efficacy of hepatoprotective agents. Lycopene is an antioxidant and phytonutrient from the carotenoid family. The health benefits of lycopene are prominent against cancer and cardiovascular, lung, liver, and skin problems. Recent studies have demonstrated the hepatoprotective, antidyslipidemic, and antioxidant roles of lycopene. The current study was designed to appraise the ability of lycopene to prevent mitochondrial dysfunction during the d-GalN/LPS-induced FHF. The administration of d-GalN/LPS (300 mg and 30 µg/kg body weight, respectively) to the experimental rats induced several disturbances in mitochondrial function. The lipid peroxide and hydrogen peroxide levels were increased (p < 0.05). The activities of mitochondrial antioxidants, tricarboxylic acid (TCA) cycle, and electron transport chain enzymes and the cellular adenosine triphosphate (ATP) content were decreased (p < 0.05). Lycopene (10 mg/kg body weight for 6 days) pretreatment attenuated lipid peroxidation and prohibited the excessive synthesis of hydrogen peroxide. The d-GalN/LPS-induced impairment in ATP production and increased enzyme activities were effectively prevented by the lycopene administration. The lycopene-mediated mitochondrial protection was mainly ascribed to the strong antioxidant potential of this phytonutrient. Molecular modeling results obtained show evidence that lycopene inhibits several lipoxygenases and provides rationale for the observed prevention of lipid peroxidation in the mitochondrial membrane. The carotenoid lycopene combatted oxidative stress, scavenged free radicals, prevented ROS generation, and inhibited the toxic effects of d-GalN/LPS during FHF.
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Antioxidantes/farmacologia , Carotenoides/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Inibidores de Lipoxigenase/farmacologia , Lipoxigenases/metabolismo , Falência Hepática Aguda/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Trifosfato de Adenosina/agonistas , Trifosfato de Adenosina/antagonistas & inibidores , Trifosfato de Adenosina/biossíntese , Animais , Antioxidantes/química , Sítios de Ligação , Carotenoides/química , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ciclo do Ácido Cítrico/efeitos dos fármacos , Complexo de Proteínas da Cadeia de Transporte de Elétrons/agonistas , Complexo de Proteínas da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Galactosamina/toxicidade , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Inibidores de Lipoxigenase/química , Lipoxigenases/química , Fígado , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Licopeno , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Simulação de Acoplamento Molecular , Estresse Oxidativo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Ratos , Ratos WistarRESUMO
Geraniol, an acyclic monoterpene found in lemon grass and aromatic herb oil, has been shown to exert antitumor and antioxidant activities against various cancer types. The objective of this study was to investigate the potential chemoprotective role of geraniol against 4-nitroquinoline-1-oxide (4NQO)-induced oral carcinogenesis in male Wistar rats and furthermore to study anti-inflammatory mechanisms of action through possible NF-κB signaling. 4NQO was administered to rats at the dose of 50 ppm through drinking water to induce tongue cancer in 20 weeks. 4NQO provoked inflammation by upregulating the expressions of the p65 subunit nuclear factor kappa-ß (NF-κB) in the nucleus, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). Additionally, staining for immature and mature mast cells in cancer niche by toluidine blue staining and alcian blue-safranin staining showed more accumulation. Co-treatment of geraniol 200 mg/kg b.w. showed a significant decrease in the level of p65 NF-κB in the nucleus, and this might be due to the inhibition of NF-κB activation/translocation into nucleus, which was further confirmed by decreased immature and mature mast cell density and the expression of inflammatory downstream mediators such as TNF-α, IL-1ß, COX-2, and iNOS. Collectively, our results suggested that geraniol as a potential anti-inflammatory agent having the capability to obstruct 4NQO initiated NF-κB activation and modulated the expression of inflammatory mediators.
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Anticarcinógenos/uso terapêutico , Carcinógenos/toxicidade , Regulação para Baixo/efeitos dos fármacos , NF-kappa B/metabolismo , Quinolonas/toxicidade , Terpenos/farmacologia , Neoplasias da Língua/prevenção & controle , 4-Nitroquinolina-1-Óxido/toxicidade , Monoterpenos Acíclicos , Animais , Contagem de Células Sanguíneas , Western Blotting , Inflamação/complicações , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Ratos , Ratos Wistar , Neoplasias da Língua/induzido quimicamente , Neoplasias da Língua/complicações , Neoplasias da Língua/metabolismoRESUMO
Liver cancer is the fifth most common cancer and is still one of the leading causes of death world wide, due to food additives, alcohol, fungal toxins, air, toxic industrial chemicals, and water pollutants. Chemopreventive drugs play a potential role in liver cancer treatment. Obviously in the production of anticancer drugs, the factors like poor solubility, bioavailability, biocompatibility, limited chemical stability, large amount of dose etc., plays a major role. Against this backdrop, the idea of designing the chemopreventive nature of bio flavanoid hesperetin (HP) drug conjugated with pegylated gold nanoparticles to increasing the solubility, improve bioavailability and enhance the targeting capabilities of the drug during diethylnitrosamine (DEN) induced liver cancer in male wistar albino rats. The dose fixation studies and the toxicity of pure HP and HP conjugated gold nanoparticles (Au-mPEG(5000)-S-HP) were analysed. After concluded the dose fixation and toxicity studies the experimental design were segregated in six groups for the anticancer analysis of DEN induced HCC for 16 weeks. After the experimental period the body weight, relative liver weight, number of nodules and size of nodules, the levels of tumor markers like CEA, AFP and the level of lipid peroxidation, lipid hydroperoxides and the activities of antioxidant enzymes were assessed. The administration of DEN to rats resulted in increased relative liver weight and serum marker enzymes aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase, and gamma glutamyl transpeptidase. The levels of lipid peroxides elevated (in both serum and tissue) with subsequent decrease in the final body weight and tissue antioxidants like superoxide dismutase, catalase, reduced glutathione, glutathione peroxidise, and glutathione reductase. HP supplementation (20 mg/kg b.wt) significantly attenuated these alterations, thereby showing potent anticancer effect in liver cancer and the HP loaded gold nanoparticels (Au-mPEG(5000)-S-HP) treated animals shows the better treatment than the pure HP due to the solubility of drug, bioavailability and the target drug delivery of the biodegradable polymer. Histological observations were also carried out, which added supports to the chemopreventive action of the pure HP and HP loaded gold nanoparticles (Au-mPEG(5000)-S-HP) against DEN induction during liver cancer progression. These findings suggest that HP loaded gold nanoparticels (Au-mPEG(5000)-S-HP) shows better efficacy than the pure HP against lipid peroxidation, hepatic cell damage and protects the antioxidant system in DEN induced hepatocellular carcinogenesis.
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OBJECTIVES: Capsaicin (CAP) is the chief pungent principle found in the hot red peppers and the chili peppers that have long been used as spices, food additives and drugs. This study investigated the anticancer potential of CAP through its ability to modify extracellular matrix components and proteases during mice lung carcinogenesis. METHODS: Swiss albino mice were treated with benzo(a) pyrene (50 mg/kg body weight dissolved in olive oil) orally twice a week for four successive weeks to induce lung cancer at the end of 14(th) week. CAP was administrated (10 mg/kg body weight dissolved in olive oil) intraperitoneally. Extracellular matrix components were assayed; Masson's trichome staining of lung tissues was performed. Western blot analyses of matrix metalloproteases 2 and 9 were also carried out. RESULTS: In comparison with the control animals, animals in which benzo(a)pyrene had induced lung cancer showed significant increases in extracellular matrix components such as collagen (hydroxy proline), elastin, uronic acid and hexosamine and in glycosaminoglycans such as hyaluronate, chondroitin sulfate, keratan sulfate and dermatan sulfate. The above alterations in extracellular matrix components were effectively counteracted in benzo(a)pyrene along with CAP supplemented animals when compared to benzo(a) pyrene alone supplemented animals. The results of Masson's trichome staining for collagen and of, immunoblotting analyses of matrix metalloproteases 2 and 9 further supported the biochemical findings. CONCLUSION: The apparent potential of CAP in modulating extracellular matrix components and proteases suggests that CAP plays a chemomodulatory and anti- cancer role working against experimentally induced lung carcinogenesis.
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Superparamagnetic iron oxide nanoparticles are being used in medical imaging, drug delivery, cancer therapy, and so on. However, there is a direct need to identify any nanotoxicity associated with these nanoparticles. However uncommon, drug-induced liver injury (DILI) is a major health concern that challenges pharmaceutical industry and drug regulatory agencies alike. In this study we have synthesized and evaluated the dose interval dependent hepatotoxicity of polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticles (PUSPIOs). To assess the hepatotoxicity of intravenously injected PUSPIOs, alterations in basic clinical parameters, hematological parameters, hemolysis assay, serum levels of liver marker enzymes, serum and liver lipid peroxidation (LPO) levels, enzymatic antioxidant levels, and finally histology of liver, kidney, spleen, lung, brain, and heart tissues were studied in control and experimental Wistar rat groups over a 30-day period. The results of our study showed a significant increase in the aspartate transaminase (AST) enzyme activity at a dose of 10mg/kg b.w. PUSPIOs twice a week. Besides, alanine transaminase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) enzyme activity showed a slender increase when compared with control experimental groups. A significant increase in the serum and liver LPO levels at a dose of 10mg/kg b.w. PUSPIOs twice a week was also observed. Histological analyses of liver, kidney, spleen, lung, brain and heart tissue samples showed no obvious uncharacteristic changes. In conclusion, PUSPIOs were found to posses excellent biocompatibility and Wistar rats showed much better drug tolerance to the dose of 10mg/kg b.w. per week than the dose of 10mg/kg b.w. twice a week for the period of 30 days.
Assuntos
Óxido Ferroso-Férrico/toxicidade , Nanopartículas/toxicidade , Administração Intravenosa , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Aspartato Aminotransferases/sangue , Encéfalo/anatomia & histologia , Encéfalo/efeitos dos fármacos , Catalase/metabolismo , Óxido Ferroso-Férrico/química , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Coração/anatomia & histologia , Coração/efeitos dos fármacos , Rim/anatomia & histologia , Rim/efeitos dos fármacos , Fígado/anatomia & histologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/anatomia & histologia , Pulmão/efeitos dos fármacos , Fenômenos Magnéticos , Masculino , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Nanopartículas/ultraestrutura , Polietilenoglicóis/química , Ratos Wistar , Espectroscopia de Infravermelho com Transformada de Fourier , Baço/anatomia & histologia , Baço/efeitos dos fármacos , Superóxido Dismutase/metabolismo , gama-Glutamiltransferase/sangueRESUMO
The lungs mainly serve as a primary site for xenobiotic metabolism and constitute an important defense mechanism against inhalation of carcinogens. Our current study aimed to evaluate the chemotherapeutic efficacy of baicalein (BE) in Swiss albino mice exposed to tobacco-specific carcinogen benzo(a)pyrene [B(a)P] for its ability to mitigate pulmonary carcinogenesis. Here, we report that altered activities/levels of lysosomal enzymes (cathepsin-D, cathepsin-B, acid phosphatase, ß-D-galactosidase, ß-D-glucuronidase, and ß-D-N-acetyl glucosaminidase), phase I biotransformation enzymes (cytochrome P450, cytochrome b5, NADPH-cytochrome P450 reductase, and NADH-cytochrome b5 reductase), and phase II enzymes (glutathione S-transferase, UDP-glucuronyl transferase, and DT-diaphorase) were observed in the B(a)P-induced mice. Treatment with BE significantly restored back the activities/levels of lysosomal enzymes, phase I and phase II biotransformation enzymes. Moreover, assessment of lysosomal abnormalities by transmission electron microscopic examination revealed that BE treatment effectively counteract B(a)P-induced oxidative damages. Protein expression levels studied by immunohistochemistry, immunofluorescence, and immunoblot analysis of CYP1A1 revealed that BE treatment effectively negate B(a)P-induced upregulated expression of CYP1A1. Further analysis of scanning electron microscopic studies in lung was carried out to substantiate the anticarcinogenic effect of BE. The overall data suggest that BE treatment significantly inhibits lysosomal and microsomal dysfunction, thus revealing its potent anticarcinogenic effect.
Assuntos
Anticarcinógenos/uso terapêutico , Benzo(a)pireno/toxicidade , Flavanonas/uso terapêutico , Neoplasias Pulmonares/enzimologia , Pulmão/efeitos dos fármacos , Lisossomos/enzimologia , Xenobióticos/farmacocinética , Animais , Anticarcinógenos/administração & dosagem , Benzo(a)pireno/farmacocinética , Western Blotting , Citocromo P-450 CYP1A1/biossíntese , Flavanonas/administração & dosagem , Imuno-Histoquímica , Pulmão/enzimologia , Pulmão/ultraestrutura , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/prevenção & controle , Lisossomos/efeitos dos fármacos , Lisossomos/ultraestrutura , Masculino , Desintoxicação Metabólica Fase I , Desintoxicação Metabólica Fase II , Camundongos , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de TransmissãoRESUMO
Abstract Context: Ulva lactuca Linnaeus (Chlorophyceae), a commonly distributed seaweed, is rich in polysaccharide but has not been studied extensively. Objective: The present study investigated the effects of crude fraction of Ulva lactuca polysaccharide (ULP) on d-galactosamine (d-Gal)-induced DNA damage, hepatic oxidative stress, and necrosis in rats. Materials and methods: The rats were treated with ULP (100 mg/kg, orally) for 4 weeks before a single intraperitoneal injection of d-Gal (500 mg/kg). In addition to liver cell necrosis and DNA damage, antioxidant parameters, such as lipid peroxide (LPO), superoxide dismutase, and catalase, and histopathology of liver tissue were evaluated. Results: ULP pre-treatment significantly attenuated a d-Gal-induced decrease in DNA and RNA levels (3.67 ± 0.38) and (5.42 ± 0.46), respectively. Comet tail length and acridine staining confirmed the number of cells undergoing necrosis were relatively lower in ULP treated rats (30 µm and 8-10% of counted cells) compared to rats treated with d-Gal (60 µm and 16% of counted cells). Biochemical (LPO, SOD and CAT) and histological evaluation (p < 0.01) confirmed the anti-hepatotoxic and antioxidant property of crude polysaccharide against d-Gal-induced elevation of LPO and infiltration of inflammatory cells into liver tissue. Discussion and conclusion: Although our previous studies have reported on the protective role of ULP against liver toxicity, our present findings show that ULP improved the hepatic antioxidant defense system against d-Gal-induced DNA damage and necrosis in rats.
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Dysregulated cell proliferation and tumorigenesis is frequently encountered in several cancers including hepatocellular carcinogenesis (HCC). Thus, agents that inhibit cell proliferation and restrain hepatic tumorigenesis through cell cycle regulation have a beneficial effect in the treatment of hepatocellular carcinogenesis. The present study was aimed to investigate the efficacy of thymoquinone (TQ), an active compound derived from the medicinal plant Nigella sativa, on N-nitrosodiethylamine (NDEA) [0.01% in drinking water for 16 weeks]-induced hepatocarcinogenesis in experimental rats. After experimental period, the hepatic nodules, liver injury markers and tumor markers levels were substantially increased in NDEA induced liver tumors in rats. However, TQ (20mg/kg body weight) treatment greatly reduced liver injury markers and decreased tumor markers and prevented hepatic nodule formation and reduced tumor multiplicity in NDEA induced hepatic cancer bearing rats and this was evident from argyrophilic nucleolar organizer region (AgNORs) staining. Moreover, the uncontrolled cell proliferation was assessed by specific cell proliferative markers [proliferating cell nuclear antigen (PCNA) and Ki67] by immunofluorescence, immunoblot and analysis of mRNA expression. Simultaneously, we assessed the activity of TQ on G1/S phase cell cycle regulation with specific cell cycle proteins (p21(WAF1/CIP1), CDK4, Cyclin D1 and Cyclin E) by immunoprecipitation in experimental rats. Treatment with TQ significantly reduced the detrimental alterations by abrogating cell proliferation, which strongly induced G1/S arrest in cell cycle transition. In conclusion, our results suggest that TQ has a potent anti proliferative activity by regulating the G1/S phase cell cycle transition and exhibit a beneficial role in the treatment of HCC.
Assuntos
Benzoquinonas/farmacologia , Dietilnitrosamina/toxicidade , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Immunoblotting , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Masculino , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , RNA Mensageiro/química , RNA Mensageiro/genética , Distribuição Aleatória , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Organismos Livres de Patógenos EspecíficosRESUMO
Xenobiotic metabolizing enzymes are chief determinants in both the susceptibility to mutagenic effect of chemical carcinogens and in the response of tumors to chemotherapy. The present study was aimed to analyze the effect of geraniol administration on the activity of phase I and phase II carcinogen metabolizing enzymes through the nuclear factor erythroid 2-related factor-2 (Nrf2) activation against 4-niroquinoline-1-oxide (4NQO) induced oral carcinogenesis. The well-known chemical carcinogen 4NQO (50 ppm) was used to induce oral carcinogenesis through drinking water for 4, 12, and 20 weeks. The degree of cancer progression at each stage was confirmed by histological examination. At the end of the experimental period, 100% tumor formation was observed in the oral cavity of 4NQO induced animals with significant (P<0.05) alteration in the status of tumor markers, tongue and liver phase I and phase II drug metabolizing enzymes indicating progression of disease. Oral administration of geraniol at the dose of 200 mg/kg b.wt., thrice a week to 4NQO induced animals was able to inhibit tumor formation and thereby delayed the progression of oral carcinogenesis by modulating tongue and liver phase I and phase II drug metabolizing enzymes, as substantiated further by the histological and transmission electron microscopic studies. Our results demonstrate that geraniol exerts its chemopreventive potential by altering activities of phases I and II drug metabolizing enzymes to achieve minimum bioactivation of carcinogen and maximum detoxification.
Assuntos
Anticarcinógenos/farmacologia , Fígado/efeitos dos fármacos , Terpenos/farmacologia , Neoplasias da Língua/metabolismo , 4-Nitroquinolina-1-Óxido , Monoterpenos Acíclicos , Animais , Carcinógenos , Sistema Enzimático do Citocromo P-450/metabolismo , Citocromos b5/metabolismo , Fígado/metabolismo , Masculino , Microssomos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Wistar , Neoplasias da Língua/induzido quimicamente , Neoplasias da Língua/prevenção & controle , Neoplasias da Língua/ultraestruturaRESUMO
Our current study aimed to evaluate the chemotherapeutic efficacy of baicalein (BE) in Swiss albino mice, which is exposed to benzo(a)pyrene [B(a)P] for its ability to alleviate mitochondrial dysfunction and systolic failure. Here, we report that oral administration of B(a)P (50 mg/kg body weight)-induced pulmonary genotoxicities in mice was assessed in terms of elevation in reactive oxygen species (ROS) generation and DNA damage in lung mitochondria. MDA-DNA adducts were formed in immunohistochemical analysis, which confirmed nuclear DNA damage. mRNA expression levels studied by RT-PCR analysis of voltage-dependent anion channel (VDAC) and adenine nucleotide translocase (ANT) were found to be significantly decreased and showed a marked increase in membrane permeability transition pore (MPTP) opening. Accompanied by up-regulated Bcl-xL and down-regulated Bid, Bim and Cyt-c proteins studied by immunoblot were observed in B(a)P-induced lung cancer-bearing animals. Administration of BE (12 mg/kg body weight) significantly reversed all the above deleterious changes. Moreover, assessment of mitochondrial enzyme system revealed that BE treatment effectively counteracts B(a)P-induced down-regulated levels/activities of isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, NADH dehydrogenase, cytochrome-C-oxidase and ATP levels. Restoration of mitochondria from oxidative damage was further confirmed by transmission electron microscopic examination. Further analysis of lipid peroxidation, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase, reduced glutathione, vitamin E and vitamin C in lung mitochondria was carried out to substantiate the antioxidant effect of BE. The overall data conclude that chemotherapeutic efficacy of BE might have strong mitochondria protective and restoration capacity in sub-cellular level against lung carcinogenesis in Swiss albino mice.
Assuntos
Flavanonas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Administração Oral , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Benzo(a)pireno/toxicidade , Dano ao DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Flavanonas/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Microscopia Eletrônica de Transmissão , Mitocôndrias/patologia , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima/efeitos dos fármacosRESUMO
Current study aims to evaluate the efficacy of baicalein (BE), a naturally occurring bioactive flavanoid (5,6,7-trihydroxy-flavone), at a dose of 12 mg/kg body wt in Swiss albino mice exposed to tobacco-specific carcinogen benzo(a)pyrene [B(a)P] (50 mg/kg body wt) for its ability to mitigate pulmonary adenoma formation and growth. Under coarse observation, B(a)P-administered mice, after 16 weeks, developed macroscopically detectable tumors, whereas oral treatment with BE to the lung cancer-induced mice significantly reduced tumor incidence in 16-week pre- and posttreated groups. A detailed histopathological examination of lung was conducted to determine the degree of cancer progression. Incidence of anaplasia, hyperplasia, dysplasia, severe dysplasia, and adenocarcinoma were evident in carcinogen-administrated group in 6, 10, 12, 14, and 16th weeks, respectively, whereas these anomalies were effectively reduced after pre- and posttreatment with BE. In the pretreatment group, BE significantly arrested tumor multiplicity by approximately 65% and tumor load by approximately 88%, while in the posttreatment, the compound significantly reduced the tumor multiplicity by approximately 48% and tumor load by approximately 61%. Further analysis of serum tumor markers like carcinoembryonic antigen, CK 19 fragments (CYFRA 21-1), and tissue marker enzymes like aryl hydrocarbon hydroxylase, adenosine deaminase, γ-glutamyl transpeptidase, 5'-nucleotidase, and lactate dehydrogenase in serum and lung homogenate was carried out to substantiate the anticarcinogenic effect of BE. The overall data from our experiments suggested that BE significantly inhibited pulmonary adenoma formation and growth, thus revealing its potent antitumorigenic effect.
Assuntos
Adenocarcinoma/prevenção & controle , Anticarcinógenos/farmacologia , Flavanonas/farmacologia , Neoplasias Pulmonares/prevenção & controle , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Administração Oral , Animais , Anticarcinógenos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacologia , Benzo(a)pireno/toxicidade , Biomarcadores Tumorais/sangue , Progressão da Doença , Flavanonas/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Fatores de TempoRESUMO
Antioxidants are one of the key players in tumorigenesis, several natural and synthetic antioxidants were shown to have anticancer effects. The aim of the present study is to divulge the chemopreventive nature of carvacrol during diethylnitrosamine (DEN)-induced liver cancer in male wistar albino rats. Administration of DEN to rats resulted in increased relative liver weight and serum marker enzymes aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and gamma glutamyl transpeptidase (γGT). The levels of lipid peroxides elevated (in both serum and tissue) with subsequent decrease in the final body weight and tissue antioxidants like superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), glutathione peroxidase (GPx), and glutathione reductase (GR). Carvacrol supplementation (15 mg/kg body weight) significantly attenuated these alterations, thereby showing potent anticancer effect in liver cancer. Histological observations and transmission electron microscopy studies were also carried out, which added supports to the chemopreventive action of the carvacrol against DEN-induction during liver cancer progression. These findings suggest that carvacrol prevents lipid peroxidation, hepatic cell damage, and protects the antioxidant system in DEN-induced hepatocellular carcinogenesis.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/prevenção & controle , Neoplasias Hepáticas Experimentais/prevenção & controle , Monoterpenos/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antioxidantes/metabolismo , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Cimenos , Dietilnitrosamina , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas Experimentais/sangue , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/patologia , Masculino , Malondialdeído/sangue , Monoterpenos/farmacologia , Tamanho do Órgão , Estresse Oxidativo , Ratos , Ratos Wistar , Carga Tumoral/efeitos dos fármacosRESUMO
Nowadays, in developing countries like India, incidence of lung cancer is increasing rapidly, and as a consequence it has become the most common cause of malignancy-associated death. This study is aimed to evaluate the therapeutic efficacy of beta-ionone (ION), a precursor for carotenoids against benzo(a)pyrene [B(a)P]-induced lung carcinogenesis. B(a)P (50 mg/kg body weight, orally twice a week for 4 successive weeks)-induced lung cancer in mice was assessed both in tissue and serum in terms of increase LPO and tissue marker enzymes, such as aryl hydrocarbon hydroxylase, γ-glutamyl transpeptidase, 5'-nucleotidase, and lactate dehydrogenase, and serum tumor markers such as carcinoembryonic antigen and neuron-specific enolase with concordant decrease in activities of tissue enzymic and non-enzymic antioxidants were observed on the treatment of ION (60 mg/kg body weight, orally twice a week for 16 weeks) significantly attenuated LPO and restored all cancer marker enzymes and antioxidants levels to near normal, which indicates the anticancer effect of ION. This was further confirmed by histological staining of argyrophilic nucleolar organizer region and histopathological analysis of lung tissue, immunohistochemical and immunoblot analysis of proliferating cell nuclear antigen. Overall findings suggested that the ION effectively ameliorated the lung carcinogenesis, which is attributed to the antiproliferative and antioxidant potential through free radical scavenging property.
Assuntos
Anticarcinógenos/farmacologia , Benzo(a)pireno , Proliferação de Células/efeitos dos fármacos , Sequestradores de Radicais Livres/farmacologia , Neoplasias Pulmonares/prevenção & controle , Pulmão/efeitos dos fármacos , Norisoprenoides/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Antígenos Nucleares/metabolismo , Biomarcadores Tumorais/metabolismo , Peso Corporal/efeitos dos fármacos , Enzimas/metabolismo , Imuno-Histoquímica , Peroxidação de Lipídeos/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Fatores de TempoRESUMO
OBJECTIVE: To investigate the effect of lycopene on lipoprotein metabolism during D-galactosamine/lipopolysaccharide (D-Gal/LPS) induced hepatitis in experimental rats. METHODS: The efficacy of lycopene was validated during D-Gal/LPS induced hepatitis by analyzing the activity of lipid metabolizing enzymes such as lipoprotein lipase (LPL), lecithin-cholesterol acyl transferase (LCAT) and hepatic triglyceride lipase (HTGL). Lipo protein analyses were done by the estimation of very low density lipoprotein cholesterol (VLDL), low density lipoprotein cholesterol (LDL) and high density lipoprotein cholesterol (HDL). RESULTS: The toxic insult of D-galactosamine/lipopolysaccharide (D-Gal/LPS) in experimental group of animals reduces the normal values of lipid metabolizing enzymes due to liver injury. The significant drop in the levels of HDL and concomitant increase in the values of VLDL and LDL were observed. The pretreatment of lycopene restore these altered values to near normal level in experimental group of animals. CONCLUSIONS: In the light of results, it can be concluded that administration lycopene stabilizes the lipoprotein levels by regulating the lipid metabolizing enzymes through its antioxidant defense and helps to maintain the normal lipid metabolism during toxic injury in liver.
Assuntos
Antioxidantes/farmacologia , Carotenoides/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Hepatite/tratamento farmacológico , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Galactosamina/farmacologia , Hepatite/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoproteínas , Fígado/patologia , Licopeno , Masculino , Ratos , Ratos WistarRESUMO
Objective: To investigate the effect of lycopene on lipoprotein metabolism during D-galactosamine/lipopolysaccharide (D-Gal/LPS) induced hepatitis in experimental rats. Methods: The efficacy of lycopene was validated during D-Gal/LPS induced hepatitis by analyzing the activity of lipid metabolizing enzymes such as lipoprotein lipase (LPL), lecithin-cholesterol acyl transferase (LCAT) and hepatic triglyceride lipase (HTGL). Lipo protein analyses were done by the estimation of very low density lipoprotein cholesterol (VLDL), low density lipoprotein cholesterol (LDL) and high density lipoprotein cholesterol (HDL). Results: The toxic insult of D-galactosamine/lipopolysaccharide (D-Gal/LPS) in experimental group of animals reduces the normal values of lipid metabolizing enzymes due to liver injury. The significant drop in the levels of HDL and concomitant increase in the values of VLDL and LDL were observed. The pretreatment of lycopene restore these altered values to near normal level in experimental group of animals. Conclusions: In the light of results, it can be concluded that administration lycopene stabilizes the lipoprotein levels by regulating the lipid metabolizing enzymes through its antioxidant defense and helps to maintain the normal lipid metabolism during toxic injury in liver.
RESUMO
The present study is designed to assess the mitochondrial status during benzo(a)pyrene (B(a)P)-induced lung carcinogenesis in Swiss albino mice and to reveal the modulatory effect of hesperidin over it. B(a)P (50 mg/kg body weight)-induced mitochondrial abnormalities was evident from alterations in mitochondrial lipid peroxides, antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, reduced glutathione, vitamin E, and vitamin C), major tricarboxylic acid (TCA) cycle enzyme activities (isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, alpha-ketoglutarate dehydrogenase), electron transport chain (ETC) complexes activities and ATP levels. Ultrastructural changes in lung mitochondria were also in accord with the above aberrations. Hesperidin (25 mg/kg body weight) supplementation effectively counteracted all the above changes and restored cellular normalcy, indicating its protective role during B(a)P-induced lung cancer.
Assuntos
Anticarcinógenos/farmacologia , Hesperidina/farmacologia , Neoplasias Pulmonares/prevenção & controle , Mitocôndrias/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Antioxidantes/metabolismo , Benzo(a)pireno/toxicidade , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Mitocôndrias/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Experimentais/prevenção & controleRESUMO
Hesperidin is a naturally occurring flavonoid that has been reported to possess anticancer effects. The purpose of this study is to evaluate the effect of hesperidin in modulating the expressions of cyclooxygenase-2 (COX-2), mast cells (MCs) and matrix metalloproteinases (MMPs) during benzo(a)pyrene (B(a)P) induced lung carcinogenesis in mice. B(a)P (50 mg/kg body weight) induced animals showed increased mast cell density (MCD) as revealed by toluidine blue staining and severe expression of COX-2 along with upregulated expression of MMP-2 and MMP-9 as revealed by Western blotting and immunohistochemistry. Supplementation of hesperidin (25 mg/kg body weight) to lung cancer bearing mice attenuated MCD and downregulated the expressions of COX-2, MMP-2 and MMP-9. These observations show that hesperidin exerts its anti-carcinogenic activity against lung cancer by altering the expressions of COX-2, MMP-2 and MMP-9.
Assuntos
Anticarcinógenos/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Hesperidina/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/prevenção & controle , Metaloproteinases da Matriz Secretadas/metabolismo , Animais , Anticarcinógenos/efeitos adversos , Antineoplásicos Fitogênicos/efeitos adversos , Benzo(a)pireno/toxicidade , Western Blotting , Carcinógenos/toxicidade , Contagem de Células , Suplementos Nutricionais , Regulação para Baixo/efeitos dos fármacos , Hesperidina/efeitos adversos , Imuno-Histoquímica , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/patologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , CamundongosRESUMO
A voluminous number of evidence suggests that an increased consumption of fruits and vegetables is a relatively easy and practical strategy to reduce significantly the incidence of cancer. The present study is an effort to identify the chemopreventive role of alkaloid capsaicin against benzo(a)pyrene-induced lung cancer in Swiss albino mice. Benzo(a)pyrene-induced lung cancer-bearing animals showed abnormal changes in body weight, lung weight, tumour incidence and alterations in the activities of marker enzymes adenosine deaminase, aryl hydrocarbon hydroxylase, gamma-glutamyl transpeptidase, 5'-nucleotidase and lactate dehydrogenase. On capsaicin pre-co-treatment, all the above alterations were returned to near normal. Immunohistochemical analysis of proliferating cell nuclear antigen together with lung histological examination further supported our biochemical findings that demonstrated the chemoprotective role of capsaicin against benzo(a)pyrene-induced experimental lung cancer.
Assuntos
Anticarcinógenos/uso terapêutico , Benzo(a)pireno/toxicidade , Capsaicina/uso terapêutico , Neoplasias Pulmonares/prevenção & controle , Pulmão/efeitos dos fármacos , Animais , Anticarcinógenos/administração & dosagem , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Capsaicina/administração & dosagem , Imuno-Histoquímica , Pulmão/enzimologia , Pulmão/patologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismoRESUMO
Chemoprevention is regarded as one of the most promising and realistic approaches in the prevention of cancer. Several bioactive compounds present in fruits and vegetables have revealed their cancer curative potential on lung cancer. Hesperidin is one such naturally occurring flavonoid widely found in citrus fruits. The aim of the present study is to divulge the chemopreventive nature of hesperidin during benzo(a)pyrene (B(a)P) induced lung cancer in Swiss albino mice. Administration of B(a)P (50 mg/kg body weight) to mice resulted in increased lipid peroxides (LPO), lung specific tumor marker carcinoembryonic antigen (CEA) and serum marker enzymes aryl hydrocarbon hydroxylase (AHH), gamma glutamyl transpeptidase (GGT), 5'nucleotidase (5'ND) and lactate dehydrogenase (LDH) with concomitant decrease in the levels of tissue antioxidants like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), vitamin E and vitamin C. Hesperidin supplementation (25 mg/kg body weight) significantly attenuated these alterations thereby showing potent anticancer effect in lung cancer. Further the antiproliferative effect of hesperidin was confirmed by histopathological analysis and proliferating cell nuclear antigen (PCNA) immunostaining. Overall, these findings substantiate the chemopreventive potential of hesperidin against chemically induced lung cancer in mice.