RESUMEN
About 50% of infertility is caused by men. This study aimed to investigate the efficiency of photobiomodulation on spermatogenesis in a busulfan-induced infertile mouse as a testicular degeneration treatment. Thirty-two adult NMRI male mice were divided into 4 groups: control, busulfan, PBMT 0.03 J/cm2, and laser 0.2 J/cm2. In the study, azoospermia was induced by busulfan as a testicular degeneration, and then, they were treated using photobiomodulation therapy at 0.03 J/cm2 and 0.2 J/cm2 energy densities. Sperm parameters, stereological analysis, serum testosterone levels, together with SDH activity, MDA production oxidized as a marker for lipid peroxidation, glutathione (GSSG) and glutathione (GSH), mitochondrial membrane permeability (MMP), reactive oxygen species (ROS) production, and ATP production as well as TUNEL assay were assessed. Photobiomodulation therapy with 0.03 J/cm2 energy densities group revealed a significant increase the testosterone hormone level and spermatogenic cells with the reduction of apoptotic cells and marked increase in GSH, ATP, and SDH levels and decrease the levels of MDA and ROS production in the busulfan-induced mice when compared with the control and sham groups. In conclusion, the photobiomodulation therapy (0.03 J/cm2 energy density) may provide benefits on the spermatogenesis following busulfan injection and might be an alternative treatment to the patients with oligospermia and azoospermia in a dose-dependent manner.
Asunto(s)
Alquilantes/toxicidad , Busulfano/toxicidad , Infertilidad Masculina/inducido químicamente , Infertilidad Masculina/radioterapia , Terapia por Luz de Baja Intensidad/métodos , Espermatogénesis/fisiología , Animales , Infertilidad Masculina/patología , Masculino , Ratones , Espermatogénesis/efectos de los fármacosRESUMEN
Ginger (Zingiber officinale) is a spice and also an herbal medicine used worldwide for managing GI tract disturbances. However, its role in gastric cancer is sparingly known. This study ensures the standardization of gastric cancer by the induction of N-nitroso N-methyl Urea (MNU) and to determine the role of the aqueous extract of ginger (AGE) in MNU-induced gastric cancer in albino Wistar rats. Accordingly, the anticancer potential of AGE and its possible mode of action were assessed on rats exposed to MNU, by various biochemical and molecular assays. As evidenced by the extent of lipid peroxidation, gastrin levels and histopathological sections in MNU-induced cancerous lesions at 8 wk which was stabilized at 16 wk confirming the induction of gastric carcinoma by the chemical carcinogen. Further, results revealed that AGE alleviated the oxidative stress as evidenced by the stomach antioxidant enzymes (SOD, catalase, GPx, and GR), markers of oxidative stress (TRx, GRx) and Gastrin, a specific marker for gastric cancer and a decreased level of pro-inflammatory markers (NF-kB, TNF-α, IL-6, PGE2) which was further confirmed by histopathological analysis. AGE is responsible to mitigate oxidative stress and inflammation related to gastric cancer and could be used as a potential dietary intervention in gastric cancer therapy.
Asunto(s)
Alquilantes/toxicidad , Metilnitrosourea/toxicidad , Neoplasias Experimentales/tratamiento farmacológico , Fitoterapia/métodos , Extractos Vegetales/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Zingiber officinale/química , Animales , Modelos Animales de Enfermedad , Glutatión Peroxidasa/metabolismo , Humanos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/patología , Estrés Oxidativo/efectos de los fármacos , Cuidados Paliativos , Ratas , Ratas Wistar , Neoplasias Gástricas/inducido químicamente , Neoplasias Gástricas/patologíaRESUMEN
Unearthing and employment of healthy substitutes is now in demand to tackle a number of diseases due to the excessive repercussions of synthetic drugs. In this frame of reference pomegranate juice (PGJ) is a boon comprising of anthocyanins and hydrolysable tannins, known for its anti-oxidant and anti-inflammatory properties. Despite various documented roles of PGJ, there are no studies on antifibrotic potential in NDEA-induced mammalian liver fibrotic model. Hepatic fibrosis in rats was induced by the intra-peritoneal injection of NDEA (10 mlkg-1b.wt. of 1% NDEA) in two weeks. Biochemical, histopathological and ultra-structural studies were carried out on control, fibrotic and treated rats. The liver function indices and LPO were increased significantly by intoxication of NDEA. The antioxidant status was disturbed with the decrease in SOD, GST and catalase in the liver and membrane-ATPases as well. Histopathological observations by H&E, M&T, picro-sirius and ultra-structural scrutiny by SEM and TEM indicated liver damage and increase in COX2 and α-SMA by NDEA which was successfully rectified by the supplementation of PGJ. PGJ abrogates liver fibrosis instigated by NDEA in Wistar rats by declining oxidative stress via regulation of Nrf2 and NFκB. These findings point towards pomegranate as a potential and efficacious therapeutic agent against liver fibrosis.
Asunto(s)
Antiinflamatorios/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Dietilnitrosamina/toxicidad , Cirrosis Hepática/prevención & control , Lythraceae/química , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Alquilantes/administración & dosificación , Alquilantes/toxicidad , Animales , Antiinflamatorios/aislamiento & purificación , Antioxidantes/administración & dosificación , Antioxidantes/aislamiento & purificación , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Dietilnitrosamina/administración & dosificación , Histocitoquímica , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología , Estrés Oxidativo , Extractos Vegetales/administración & dosificación , Extractos Vegetales/aislamiento & purificación , Ratas Wistar , Resultado del TratamientoRESUMEN
BACKGROUND: Sulfur mustard is an alkylating agent which cause to short and long term incapacitations on various organs including lung. There is no definite treatment for lung disorders induced by SM exposure. In the present study, the preventive effect of Zataria multiflora (Z. multiflora) on hematological parameters, oxidant/antioxidant markers and pulmonary function tests (PFT) in veterans, 27-30 years after exposed to SM were studied. MATERIALS AND METHODS: Forty seven veterans allocated to three groups included: placebo group (P) and two groups treated with 5 and 10â¯mg/kg/day of Z. multiflora (Zat 5 and Zat 10). Drugs were prescribed in a double-blind manner for two months. Total and different WBC, hematological indices, oxidant/antioxidant markers and PFT values included; force vital capacity (FVC) and peak expiratory flow (PEF) were assessed at the beginning (step 0), one and two month (step I and II, respectively) after starting treatment. RESULTS: Total and different white blood cell in Zat 5 and 10â¯mg/kg treated groups in Step I and II were significantly decreased compared to Step 0 (pâ¯<â¯0.05 to pâ¯<â¯0.001). The levels of thiol, superoxide dismutase (SOD) and catalase (CAT) in Zat 5 and 10â¯mg/kg treated groups in step I and II were significantly increased (pâ¯<â¯0.05 to pâ¯<â¯0.001) but the level of malondialdehyde (MDA) significantly decreased in two treatment groups compared to Step 0 (pâ¯<â¯0.05 and pâ¯<â¯0.001 respectively). FVC and PEF values were significant increase in Zat 5 and 10â¯mg/kg treated groups in step I and II compared to step 0 (pâ¯<â¯0.05 to pâ¯<â¯0.001). Furthermore, FVC and PEF values in Zat 5â¯mg/kg were also increased in step II compared to step I (pâ¯<â¯0.01 for both). The percentage improvement of total and differential WBC, oxidant/antioxidant markers, FVC and PEF values during two moth treatment period significantly improved in the treated groups compared to the placebo group. CONCLUSION: Z. multiflora reduces inflammatory cells and oxidant biomarkers, while increase antioxidant biomarkers and improved PFT tests in SM exposed patients in a two moth treatment period.
Asunto(s)
Alquilantes/toxicidad , Sustancias para la Guerra Química/toxicidad , Lamiaceae , Enfermedades Pulmonares/tratamiento farmacológico , Gas Mostaza/toxicidad , Extractos Vegetales/uso terapéutico , Anciano , Catalasa/sangre , Método Doble Ciego , Exposición a Riesgos Ambientales/efectos adversos , Humanos , Recuento de Leucocitos , Pulmón/efectos de los fármacos , Enfermedades Pulmonares/sangre , Enfermedades Pulmonares/inducido químicamente , Enfermedades Pulmonares/fisiopatología , Masculino , Malondialdehído/sangre , Persona de Mediana Edad , Extractos Vegetales/farmacología , Pruebas de Función Respiratoria , Compuestos de Sulfhidrilo/sangre , Superóxido Dismutasa/sangre , VeteranosRESUMEN
Antrodia cinnamomea (A. cinnamomea), a popular medicinal mushroom in Taiwan, is widely used to prevent or treat liver diseases. Systematic studies on the anti-inflammatory effect of A. cinnamomea and its molecular mechanisms have not yet been fully investigated. HPLC fingerprint analysis identified seven ergostane-type triterpenoids from A. cinnamomea water extract (ACW), including high amounts of Antcin K (AC), Antcin C, Antcin H, Dehydrosulphurenic acid, Antcin B, Antcin A and Dehydroeburicoic acid. Here, we explored the effects and mechanisms of ACW and the highest content AC on N-nitrosodiethylamine (DEN) induced liver inflammation, fibrosis and carcinogenesis in rats. In the in vitro study, we measured how ACW and AC dose-dependently scavenged O[Formula: see text], H2O2 and HOCl by a chemiluminescence analyzer. In the in vivo experiment, oral intake ACW and AC significantly inhibited DEN-enhanced hepatocellular inflammation, fibrosis and carcinoma by pathologic observation, the elevated bile and liver reactive oxygen species (ROS) amounts, plasma [Formula: see text]-glutamyl transpeptidase, and oxidative stress including 3-nitrotyrosine, 4-hydroxynonenal and Kuppfer cell infiltration (ED-1 stains) in the inflammatory livers. DEN enhanced nuclear factor-[Formula: see text]B (NF-[Formula: see text]B) translocation, whereas ACW and AC suppressed DEN-enhanced NF-[Formula: see text]B translocation through the inhibition of its upstream signaling of p85/phosphoinositide-3-kinase, mitogen activated protein kinase and CYP2E1 expression. In conclusion, DEN can induce hepatocellular inflammation, fibrosis and carcinoma by increasing NF-[Formula: see text]B translocation to the nucleus, and oxidative injury. ACW and its active component, Antcin K, counteract DEN-induced hepatic injury and inflammation by the protective and therapeutic mechanisms of a direct scavenging ROS activity and an upregulation of anti-oxidant defense mechanisms.
Asunto(s)
Antrodia , Carcinogénesis/efectos de los fármacos , Carcinoma Hepatocelular/prevención & control , Colestenos/farmacología , Hepatitis/prevención & control , Cirrosis Hepática/prevención & control , Neoplasias Hepáticas Experimentales/prevención & control , Hígado/efectos de los fármacos , Alquilantes/toxicidad , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Carcinoma Hepatocelular/inducido químicamente , Dietilnitrosamina/toxicidad , Cuerpos Fructíferos de los Hongos , Hepatitis/etiología , Peróxido de Hidrógeno/metabolismo , Ácido Hipocloroso/metabolismo , Técnicas In Vitro , Hígado/metabolismo , Cirrosis Hepática/inducido químicamente , Neoplasias Hepáticas Experimentales/inducido químicamente , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Superóxidos/metabolismo , gamma-Glutamiltransferasa/efectos de los fármacos , gamma-Glutamiltransferasa/metabolismoRESUMEN
Although there is a concomitance of zinc deficiency and high incidence/mortality for hepatocellular carcinoma in certain human populations, there are no experimental studies investigating the modifying effects of zinc on hepatocarcinogenesis. Thus, we evaluated whether dietary zinc deficiency or supplementation alter the development of hepatocellular preneoplastic lesions (PNL). Therefore, neonatal male Balb/C mice were submitted to a diethylnitrosamine/2-acetylaminefluorene-induced hepatocarcinogenesis model. Moreover, mice were fed adequate (35 mg/kg diet), deficient (3 mg/kg) or supplemented (180 mg/kg) zinc diets. Mice were euthanized at 12 (early time-point) or 24 weeks (late time-point) after introducing the diets. At the early time-point, zinc deficiency decreased Nrf2 protein expression and GSH levels while increased p65 and p53 protein expression and the number of PNL/area. At the late time-point, zinc deficiency also decreased GSH levels while increased liver genotoxicity, cell proliferation into PNL and PNL size. In contrast, zinc supplementation increased antioxidant defense at both time-points but not altered PNL development. Our findings are the first to suggest that zinc deficiency predisposes mice to the PNL development in chemically-induced hepatocarcinogenesis. The decrease of Nrf2/GSH pathway and increase of liver genotoxicity, as well as the increase of p65/cell proliferation, are potential mechanisms to this zinc deficiency-mediated effect.
Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/etiología , Dieta/efectos adversos , Neoplasias Hepáticas Experimentales/etiología , Zinc/deficiencia , Alquilantes/toxicidad , Animales , Animales Recién Nacidos , Antioxidantes/metabolismo , Carcinoma Hepatocelular/patología , Proliferación Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Suplementos Dietéticos , Dietilnitrosamina/toxicidad , Femenino , Humanos , Neoplasias Hepáticas Experimentales/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Tamaño de los Órganos/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Mutational signatures associated with specific forms of DNA damage have been identified in several forms of human cancer. Such signatures provide information regarding mechanisms of tumor induction which, in turn, can reduce exposure to carcinogens by shaping public health policy. Using a molecular epidemiologic approach that takes advantage of recent advances in genome sequencing while applying sensitive and specific analytical methods to characterize DNA damage, it has become increasingly possible to establish causative linkages between certain environmental mutagens and disease risk. In this perspective, we use aristolochic acid, a human carcinogen and nephrotoxin found in Aristolochia herbs, to illustrate the power and effectiveness of this multidisciplinary approach. The genome-wide mutational signature for this toxin, detected initially in cancers of the upper urinary tract, has subsequently been associated with cancers of the liver and kidney. These findings have significant implications for global public health, especially in China, where millions of individuals have used Aristolochia herbal remedies as part of traditional Chinese medicine and, thus, are at risk of developing aristolochic acid nephropathy and/or upper urinary tract carcinomas. The studies reported here set the stage for research into prevention and early detection, both of which will be required to manage a potentially devastating global disease.
Asunto(s)
Alquilantes/toxicidad , Ácidos Aristolóquicos/toxicidad , Carcinógenos/toxicidad , Carcinoma/genética , Mutación , Neoplasias Urológicas/genética , Aristolochia/química , Aristolochia/toxicidad , Carcinoma/inducido químicamente , Carcinoma/diagnóstico , Carcinoma/epidemiología , Aductos de ADN/agonistas , Aductos de ADN/biosíntesis , Daño del ADN , Reparación del ADN , Predisposición Genética a la Enfermedad , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/metabolismo , Vejiga Urinaria/patología , Neoplasias Urológicas/inducido químicamente , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/epidemiologíaRESUMEN
BACKGROUND: Fetal alcohol exposure (FAE) increases the susceptibility to carcinogen-induced mammary cancer progression in rodent models. FAE also decreases ß-endorphin (ß-EP) level and causes hyperstress response, which leads to inhibition of immune function against cancer. Previous studies have shown that injection of nanosphere-attached dibutyryl cyclic adenosine monophosphate (dbcAMP) into the third ventricle increases the number of ß-EP neurons in the hypothalamus. In this study, we assessed the therapeutic potential of stress regulation using methods to increase hypothalamic levels of ß-EP, a neuropeptide that inhibits stress axis activity, in treatment of carcinogen-induced mammary cancer in fetal alcohol exposed rats. METHODS: Fetal alcohol exposed and control Sprague Dawley rats were given a dose of N-Nitroso-N-methylurea (MNU) at postnatal day 50 to induce mammary cancer growth. Upon detection of mammary tumors, the animals were either transplanted with ß-EP neurons or injected with dbcAMP-delivering nanospheres into the hypothalamus to increase ß-EP peptide production. Spleen cytokines were detected using reverse transcription polymerase chain reaction assays. Metastasis study was done by injecting mammary cancer cells MADB106 into jugular vein of ß-EP-activated or control fetal alcohol exposed animals. RESULTS: Both transplantation of ß-EP neurons and injection of dbcAMP-delivering nanospheres inhibited MNU-induced mammary cancer growth in control rats, and reversed the effect of FAE on the susceptibility to mammary cancer. Similar to the previously reported immune-enhancing and stress-suppressive effects of ß-EP transplantation, injection of dbcAMP-delivering nanospheres increased the levels of interferon-γ and granzyme B and decreased the levels of epinephrine and norepinephrine in fetal alcohol exposed rats. Mammary cancer cell metastasis study also showed that FAE increased incidence of lung tumor retention, while ß-EP transplantation inhibited lung tumor growth in both normal and fetal alcohol exposed rats. CONCLUSIONS: Our results suggest that increase of ß-EP production in the hypothalamus may serve as a potential therapeutic strategy for treating the cancer growth in patients with chronic stress and compromised immune function, such as the patients with FAE.
Asunto(s)
Hipotálamo/metabolismo , Neoplasias Mamarias Experimentales/patología , Neuronas/metabolismo , Efectos Tardíos de la Exposición Prenatal , betaendorfina/metabolismo , Alquilantes/toxicidad , Animales , Bucladesina/farmacología , Depresores del Sistema Nervioso Central/farmacología , Citocinas/efectos de los fármacos , Citocinas/genética , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Epinefrina/metabolismo , Etanol/farmacología , Femenino , Granzimas/efectos de los fármacos , Granzimas/metabolismo , Hipotálamo/citología , Hipotálamo/efectos de los fármacos , Interferón gamma/efectos de los fármacos , Interferón gamma/metabolismo , Neoplasias Mamarias Experimentales/inducido químicamente , Metilnitrosourea/toxicidad , Neuronas/citología , Neuronas/trasplante , Norepinefrina/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Virgin coconut oil (VCO) is an unrefined kernal oil, prepared from Cocos nucifera L., having substantial nutritional and medicinal value. Experimental studies have suggested its antioxidant, anti-inflammatory, immunostimulatory and hypolipidemic effects. The present study assesses its effect on formalin-induced chronic inflammation and cyclophosphamide (CTX)-induced systemic toxicity in murine models. Oral administration of VCO effectively reduced formalin-induced paw oedema in mice with more or less similar efficacy as that of diclofenac. The CTX-induced hike in blood urea, creatinine, thiobarbituric acid reactive substances (TBARS) and liver marker enzymes in mice was marginally decreased by VCO (8 g/kg body weight) ingestion orally. The liver and kidney catalase, superoxide dismutase and glutathione peroxidase activities, together with cellular glutathione and TBARS levels, were found to be improved in these animals. Overall the study reveals the protective efficacy of VCO against secondary toxicity induced by CTX possibly through its antioxidant and anti-inflammatory properties.
Asunto(s)
Alquilantes/toxicidad , Ciclofosfamida/antagonistas & inhibidores , Ciclofosfamida/toxicidad , Aceites de Plantas/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/farmacología , Nitrógeno de la Urea Sanguínea , Aceite de Coco , Creatinina/metabolismo , Suplementos Dietéticos , Edema/patología , Edema/prevención & control , Formaldehído , Inflamación/inducido químicamente , Inflamación/prevención & control , Hígado/enzimología , Masculino , Ratones , Ratones Endogámicos BALB C , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
Fourier transform infrared spectroscopy was employed in the present study to obtain information about the molecular composition of hepatic tumor versus hepatic tissue. A hepatic cancer model was developed by administering N-nitrosodiethylamine (NDEA) to male Balb/c mice. The results revealed that NDEA-induced hepatic cancer tumor tissue had altered molecular composition compared with normal liver tissue. Compared with the normal tissue, the saturation level of membrane phospholipids was observed to be decreased in tumors along with an abnormal distribution of protein secondary structures. A significant decrease in glycogen and a significant increase in total nucleic acid content were also observed in tumor cells. The administration of aqueous Azadirachta indica leaf extract (AAILE) prior to NDEA treatment resulted in the normalization of saturation levels in phospholipids and total nucleic acid content and in the distribution of protein secondary structures in tumors. A significant increase in the amount of stored glycogen was observed in AAILE cotreated tumors compared with NDEA-induced tumors, which might indicate that AAILE cotreatment impeded the ability of tumor cells to consume glucose at a faster rate. The normalization of molecular composition upon AAILE cotreatment in hepatic tumors might indicate that AAILE hampered the process of evolution of tumors, which could be responsible for its observed chemopreventive action.
Asunto(s)
Alquilantes/toxicidad , Azadirachta/química , Carcinogénesis , Dietilnitrosamina/toxicidad , Neoplasias Hepáticas/inducido químicamente , Espectroscopía Infrarroja por Transformada de Fourier , Animales , Masculino , Ratones , Ratones Endogámicos BALB C , Extractos Vegetales/farmacología , Hojas de la Planta/química , Distribución AleatoriaRESUMEN
Caudatin is a potential antitumor agent isolated from the traditional Chinese medicine "baishouwu", which was the root tuber of Cynanchum auriculatum Royle ex Wight. In our previous studies, caudatin showed selectivity on human hepatoma cell line SMMC7721 among several different tumor cell lines, and further in vivo tests validated the inhibitory action of caudatin against hepatic cancer using an H22 solid tumor model in mice, but to our knowledge, the biopharmaceutical properties of caudatin are largely unknown. In this study, a simple, rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the determination of caudatin in rat plasma and tissues, which kept the run time to detect one sample within 4 min, was developed and validated. Pharmacokinetics and tissue distribution studies of caudatin in conventional rats and hepatocellular carcinoma (HCC) model rats were then conducted for the first time. Statistically significant differences were observed between conventional rats and diethylnitrosamine (DEN)-induced HCC rats with respect to pharmacokinetic parameters, including maximum concentration (Cmax), time to reach Cmax (Tmax), half-life (t1/2), area under the concentration-time curve (AUC0-t, AUC0-∞), mean residence time (MRT0-t and MRT0-∞), and oral clearance (CL/F). Increased exposures of caudatin were found in the plasma and livers of HCC model rats, which would be helpful for a better understanding of pharmacological effect of caudatin in treating HCC disease.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacocinética , Glicósidos/farmacocinética , Neoplasias Hepáticas/metabolismo , Esteroides/farmacocinética , Alquilantes/toxicidad , Animales , Carcinoma Hepatocelular/inducido químicamente , Cromatografía Liquida , Dietilnitrosamina/toxicidad , Humanos , Neoplasias Hepáticas/inducido químicamente , Masculino , Ratones , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem , Distribución TisularRESUMEN
The possible molecular mechanisms of Nano-selenium (nano-se) in attenuating hepatocellular carcinoma (HCC) was investigated in this study. To achieve this target, the apoptotic/necrotic rate in hepatic cells was investigated morphologically by double staining with acridine orange/ethidium bromide to address the type of cell death induced by nano-Se in HCC-bearing rats. To predict the oxidative stress and DNA damage, the generation of 8-hydroxy-2-deoxyguanosine (8-OHdG) and 2-deoxyguanosine (2-dG) was examined. Moreover, the expression of some HCC-related genes was investigated such as aldo-keto reductase 1B10 (Akr1b10), ING3 and Foxp1 genes. As well as the histopathological study of liver tissue sections was performed. The results obtained from this study revealed that (HCC+Nano Se) group shows the highest number of damaged cancerous cells. Furthermore, the necrotic/apoptotic rate was significantly higher in (nano-Se+HCC), (HCC+Doxo) and (HCC+Doxo+nano-se) compared to that in the untreated HCC group. Treatment of HCC group with nano-se decreased the ratio of 8-OHdG/2-dG generation significantly with respect to the untreated HCC group. The opposite was observed regarding the gene expression of AKr1b10 and ING3. The treatment of HCC group with nano-se elicited significant increase in the expression of Akr1b10 and ING3 genes compared with untreated HCC group. On the other hand, the expression of Foxp1 gene was significantly decreased in HCC group treated with nano-se in comparison with the untreated HCC group. The histopathological study provided a supportive evidence for the molecular genetics study. Our data shed light on the molecular mechanisms of nano-se in attenuating HCC in the experimental model.
Asunto(s)
Anticarcinógenos/uso terapéutico , Carcinógenos/antagonistas & inhibidores , Carcinoma Hepatocelular/prevención & control , Neoplasias Hepáticas/prevención & control , Hígado/efectos de los fármacos , Nanopartículas/uso terapéutico , Selenio/uso terapéutico , Aldehído Reductasa/química , Aldehído Reductasa/genética , Aldehído Reductasa/metabolismo , Alquilantes/química , Alquilantes/toxicidad , Animales , Apoptosis/efectos de los fármacos , Biomarcadores/metabolismo , Carcinógenos/toxicidad , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Daño del ADN/efectos de los fármacos , Dietilnitrosamina/antagonistas & inhibidores , Dietilnitrosamina/toxicidad , Factores de Transcripción Forkhead/antagonistas & inhibidores , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Necrosis , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Organismos Libres de Patógenos Específicos , Proteínas Supresoras de Tumor/química , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
BACKGROUND: Retinitis pigmentosa (RP) is a group of inherited neurodegenerative human diseases characterized by the loss of photoreceptor cells by apoptosis and eventual blindness. A single intraperitoneal (ip) injection of N-methyl-N-nitrosourea (MNU) causes photoreceptor cell apoptosis within 7 days in rats. Green tea extract (THEA-FLAN 90S; GTE) is a common herbal supplement with pluripotent properties including antioxidant activity. The purpose of the present study was to evaluate the efficacy of GTE against photoreceptor apoptosis in 7-week-old female Sprague-Dawley rats that received a single ip injection of 40 mg/kg MNU. METHODS: The oral administration of 250 mg/kg/day GTE was initiated 3 days prior to MNU injection and continued once daily throughout the experiment. Rats were sacrificed at 12, 24, and 72 h and 7 days after MNU injection, and the eyes were examined morphologically and morphometrically. The photoreceptor cell ratio, retinal damage ratio, and retinal preservation ratio were used to determine the structural and functional alterations. The number of apoptotic photoreceptor cells per mm(2) was determined in situ by TdT-mediated dUTP-digoxigenin nick end labeling (TUNEL). Our results indicated that oral administration of GTE significantly suppressed the loss of photoreceptor cells morphometrically 7 days after MNU injection. The number of TUNEL-positive cells per mm(2) in MNU-exposed rat central retina with or without GTE administration was 981 vs. 2056 at 24 h after MNU injection. CONCLUSIONS: GTE structurally and functionally suppressed MNU-induced photoreceptor cell apoptosis. These findings indicate that GTE may help to ameliorate the onset and progression of human RP.
Asunto(s)
Alquilantes/toxicidad , Apoptosis/efectos de los fármacos , Metilnitrosourea/toxicidad , Células Fotorreceptoras de Vertebrados/efectos de los fármacos , Fitoterapia , Degeneración Retiniana/tratamiento farmacológico , Té , Administración Oral , Animales , Catequina/análogos & derivados , Catequina/sangre , Cromatografía Liquida , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 6/metabolismo , Femenino , Etiquetado Corte-Fin in Situ , Inyecciones Intraperitoneales , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/patología , Extractos Vegetales , Ratas , Ratas Sprague-Dawley , Degeneración Retiniana/inducido químicamente , Degeneración Retiniana/metabolismo , Degeneración Retiniana/patología , Rodopsina/metabolismo , Espectrometría de Masas en TándemRESUMEN
Baccharis dracunculifolia (Asteraceae), the main botanical source of green propolis, also known as 'alecrim-do-campo' and 'vassourinha', is a shrub of the Brazilian 'cerrado' and is native to the South and Southeast of Brazil. The effects of B. dracunculifolia ethyl acetate extract (Bd-EAE) were evaluated on the 1,2-dimethylhydrazine (DMH)-induced DNA damage and aberrant crypt foci (ACF) in the colon of male Wistar rats by the comet and ACF assays, respectively. The animals were treated by gavage with doses of 6, 12, and 24 mg/kg body weight/day. Animals were also administered a single subcutaneous injection of 40 mg/kg DMH and were killed after 4 h for evaluation of DNA damage. Also, two doses of 40 mg/kg of DMH were administered weekly for 2 weeks, and animals were killed 2 weeks after the last injection for evaluation of ACF development in the colon. The results showed a significant reduction in the frequency of DNA damage and ACF in the group treated with the Bd-EAE plus DMH in comparison with those treated with DMH alone, suggesting that Bd-EAE reduced DNA damage and suppressed the formation of ACF and also exerted a protective affect against colon carcinogenesis.
Asunto(s)
1,2-Dimetilhidrazina/toxicidad , Alquilantes/toxicidad , Baccharis , Colon/efectos de los fármacos , Neoplasias del Colon/inducido químicamente , Daño del ADN/efectos de los fármacos , Extractos Vegetales/farmacología , Lesiones Precancerosas/inducido químicamente , Animales , Colon/patología , Neoplasias del Colon/patología , Ensayo Cometa , Masculino , Neoplasias Experimentales , Lesiones Precancerosas/patología , Ratas , Ratas WistarRESUMEN
PURPOSE: To study the effect of Cleistocalyx nervosum extract (CE) on diethylnitrosamine (DEN) and phenobarbital (PB) induced oxidative stress in early stages of rat hepatocarcinogenesis. MATERIALS AND METHODS: Male Wistar rats were divided into 4 groups, with Group 1 as a negative control and Group 2 was a positive control receiving DEN injections once a week and PB in drinking water for 6 weeks. Two weeks before DEN initiation and PB treatment, Groups 3 and 4, were fed with 500 and 1000 mg/kg of CEs, respectively, for 8 weeks. RESULTS: A number of GST-P-positive foci, preneoplastic lesions, in the liver were markedly increased in carcinogen administered rats, but was comparatively decreased in rats treated with 1000 mg/kg of CE. The CE reduced malondialdehyde in serum and in the livers of rats treated with DEN and PB. Moreover, CE significantly increased the activities of glutathione peroxidase and catalase in rat liver. CONCLUSIONS: CE appeared to exert its chemopreventive effects by modulating antioxidant status during DEN and PB induced early stages of hepatocarcinogenesis in rats.
Asunto(s)
Dietilnitrosamina/toxicidad , Neoplasias Hepáticas Experimentales/prevención & control , Estrés Oxidativo/efectos de los fármacos , Fenobarbital/toxicidad , Extractos Vegetales/farmacología , Lesiones Precancerosas/prevención & control , Syzygium/química , Alquilantes/toxicidad , Animales , Anticonvulsivantes/toxicidad , Antioxidantes/metabolismo , Técnicas para Inmunoenzimas , Peroxidación de Lípido/efectos de los fármacos , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/patología , Masculino , Lesiones Precancerosas/inducido químicamente , Lesiones Precancerosas/patología , Ratas , Ratas WistarRESUMEN
PURPOSE: To investigate the effect of cyanidin-3-O-glucoside (C3G) on a rat retinal degeneration (RD) model. MATERIALS AND METHODS: Experimental RD was induced in rats by the intraperitoneal injection of N-methyl-N-nitrosourea (MNU) at 50 mg/kg. C3G extracted from mulberry (Morus alba L.) fruit (50 mg/kg) was orally administered, daily for 1, 2 and 4 weeks after MNU injection. The effects of C3G administration on MNU-induced RD retinas were histologically and functionally assessed by hematoxylin and eosin staining and electroretinography (ERG), respectively. The degree of retinal injury in C3G-administered RD rats was evaluated by immunohistochemistry with an antibody against glial fibrillary acidic protein (GFAP). The preferential protective effect of C3G on scotopic vision was examined by western blot analysis. RESULTS: Marked loss of photoreceptors in the outer nuclear layer (ONL) was observed in RD rats at 2 and 4 weeks after MNU injection, while the ONL in the MNU-induced RD rats given C3G was relatively well preserved. Immunohistochemistry with anti-GFAP showed that retinal injury was also reduced in the retinas of the rats given C3G. Functional assessment by using ERG recordings showed that scotopic ERG responses were significantly increased in RD rats given C3G for 4 weeks (p < 0.01) compared with that of untreated RD rats. In the RD rats given short-term C3G (for 1 and 2 weeks), the increase in ERG responses was not significant. In addition, western blot analysis showed that rhodopsin level in the C3G-administered RD retinas significantly increased compared to that in the non-administered RD retinas (p < 0.05), whereas red/green opsin level did not show any significant difference. CONCLUSIONS: Long-term administration of C3G extracted from mulberry fruit could structurally reduce photoreceptor damage and functionally improve scotopic visual functions in the RD rat model induced by MNU.
Asunto(s)
Antocianinas/farmacología , Glucósidos/farmacología , Metilnitrosourea/toxicidad , Morus/química , Extractos Vegetales/farmacología , Degeneración Retiniana/inducido químicamente , Degeneración Retiniana/tratamiento farmacológico , Alquilantes/toxicidad , Animales , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Electrorretinografía , Masculino , Visión Nocturna/efectos de los fármacos , Células Fotorreceptoras de Vertebrados/efectos de los fármacos , Células Fotorreceptoras de Vertebrados/patología , Ratas , Ratas Sprague-Dawley , Degeneración Retiniana/patologíaRESUMEN
BACKGROUND: Diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) have been used as initiator and promoter respectively to establish an animal model for investigating molecular events appear to be involved in development of liver cancer. Use of herbal medicine in therapeutics to avoid the recurrence of hepatocarcinoma has already generated considerable interest among oncologists. In this context studies involving S-allyl-cysteine (SAC) and berberine have come up with promising results. Here we have determined the individual effect of SAC and berberine on the biomolecules associated with DEN+CCl4 induced hepatocarcinoma. Effective therapeutic value of combined treatment has also been estimated. METHODS: ROS accumulation was analyzed by FACS following DCFDA incubation. Bcl2-Bax and HDAC1-pMdm2 interaction were demonstrated by co-immunoprecipitation. Immunosorbent assay was performed to analyze PP2A and caspase3 activities. MMP was determined cytofluorimetrically by investigating JC-1 fluorescence. AnnexinV binding was demonstrated by labeling the cells with AnV-FITC followed by flow cytometry. RESULTS: CytochromeP4502E1 mediated bioactivation of DEN+CCl4 induced Akt dependent pMdm2-HDAC1 interaction that led to p53 deacetylation, probable cause of its degradation. In parallel, oxidative stress dependent Nrf2-HO1 activation increased Bcl2 expression which in turn stimulated cell proliferation. SAC in combination with berberine inhibited Akt mediated cell proliferation. Activation of PP2A as well as inhibition of JNK resulted in induction of apoptosis after 30 days of treatment. Extension of combined treatment reverted tissue physiology towards control. Co-treated group displayed normal tissue structure. CONCLUSION AND GENERAL SIGNIFICANCE: SAC and berberine mediated HDAC1/Akt inhibition implicates the efficacy of combined treatment in the amelioration of DEN+CCl4 induced hepatocarcinoma.
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Antineoplásicos/farmacología , Berberina/farmacología , Tetracloruro de Carbono/toxicidad , Carcinoma Hepatocelular/prevención & control , Cisteína/análogos & derivados , Dietilnitrosamina/toxicidad , Neoplasias Hepáticas/prevención & control , Alquilantes/toxicidad , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/metabolismo , Caspasa 3/metabolismo , Células Cultivadas , Cisteína/farmacología , Citocromo P-450 CYP2E1/metabolismo , Citocromos c/metabolismo , Citometría de Flujo , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Histona Desacetilasa 1/metabolismo , Técnicas para Inmunoenzimas , Inmunoprecipitación , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/metabolismo , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Proteínas de Transporte de Membrana Mitocondrial , Poro de Transición de la Permeabilidad Mitocondrial , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Chronic pain is the most prominent and disabling symptom of osteoarthritis (OA). Clinical data suggest that subchondral bone lesions contribute to the occurrence of joint pain. The present study investigated the effect of the inhibition of subchondral bone lesions on joint pain. METHODS: Osteoarthritic pain was induced by an injection of monosodium iodoacetate (MIA) into the rat knee joint. Zoledronic acid (ZOL), a third generation of bisphosphonate, was used to inhibit subchondral bone lesions. Joint histomorphology was evaluated using X-ray micro computed tomography scanning and hematoxylin-eosin staining. The activity of osteoclast in subchondral bone was evaluated using tartrate-resistant acid phosphatase staining. Joint pain was evaluated using weight-bearing asymmetry, the expression of calcitonin gene-related peptide (CGRP) in the dorsal root ganglion (DRG), and spinal glial activation status using glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) immunofluorescence. Afferent neurons in the DRGs that innervated the joints were identified using retrograde fluorogold labeling. RESULTS: MIA injections induced significant histomorphological alterations and joint pain. The inhibition of subchondral bone lesions by ZOL significantly reduced the MIA-induced weight-bearing deficit and overexpression of CGRP in DRG neurons, GFAP and Iba-1 in the spinal dorsal horn at 3 and 6 weeks after MIA injection; however, joint swelling and synovial reaction were unaffected. CONCLUSIONS: The inhibition of subchondral bone lesions alleviated joint pain. Subchondral bone lesions should be a key target in the management of osteoarthritic joint pain.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Enfermedades de la Médula Ósea/tratamiento farmacológico , Dolor Crónico/tratamiento farmacológico , Difosfonatos/farmacología , Ganglios Espinales/metabolismo , Imidazoles/farmacología , Neuronas/metabolismo , Osteoartritis/tratamiento farmacológico , Soporte de Peso , Alquilantes/toxicidad , Animales , Artritis Experimental/inducido químicamente , Conducta Animal/efectos de los fármacos , Conservadores de la Densidad Ósea/farmacología , Enfermedades de la Médula Ósea/inducido químicamente , Péptido Relacionado con Gen de Calcitonina/metabolismo , Proteínas de Unión al Calcio , Dolor Crónico/inducido químicamente , Proteínas de Unión al ADN/metabolismo , Técnica del Anticuerpo Fluorescente , Ganglios Espinales/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Yodoacetatos/toxicidad , Articulación de la Rodilla/efectos de los fármacos , Articulación de la Rodilla/metabolismo , Articulación de la Rodilla/patología , Masculino , Proteínas de Microfilamentos , Neuronas/efectos de los fármacos , Osteoartritis/inducido químicamente , Ratas , Ratas Sprague-Dawley , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Microtomografía por Rayos X , Ácido ZoledrónicoRESUMEN
Obesity is associated with increased risk in hepatocellular carcinoma (HCC) development and mortality. An important disease control strategy is the prevention of obesity-related hepatic inflammation and tumorigenesis by dietary means. Here, we report that apo-10'-lycopenoic acid (APO10LA), a cleavage metabolite of lycopene at its 9',10'-double bond by carotene-9',10'-oxygenase, functions as an effective chemopreventative agent against hepatic tumorigenesis and inflammation. APO10LA treatment on human liver THLE-2 and HuH7 cells dose dependently inhibited cell growth and upregulated sirtuin 1 (SIRT1), a NAD(+)-dependent protein deacetylase that may suppress hepatic carcinogenesis. This observed SIRT1 induction was associated with decreased cyclin D1 protein, increased cyclin-dependent kinase inhibitor p21 protein expression, and induced apoptosis. APO10LA supplementation (10 mg/kg diet) for 24 weeks significantly reduced diethylnitrosamine-initiated, high fat diet (HFD)-promoted hepatic tumorigenesis (50% reduction in tumor multiplicity; 65% in volume) and lung tumor incidence (85% reduction) in C57Bl/6J mice. The chemopreventative effects of APO10LA were associated with increased hepatic SIRT1 protein and deacetylation of SIRT1 targets, as well as with decreased caspase-1 activation and SIRT1 protein cleavage. APO10LA supplementation in diet improved glucose intolerance and reduced hepatic inflammation [decreased inflammatory foci, TNFα, interleukin (IL)-6, NF-κB p65 protein expression, and STAT3 activation] in HFD-fed mice. Furthermore, APO10LA suppressed Akt activation, cyclin D1 gene, and protein expression and promoted PARP protein cleavage in transformed cells within liver tumors. Taken together, these data indicate that APO10LA can effectively inhibit HFD-promoted hepatic tumorigenesis by stimulating SIRT1 signaling while reducing hepatic inflammation.
Asunto(s)
Carcinoma Hepatocelular/prevención & control , Carotenoides/uso terapéutico , Transformación Celular Neoplásica/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Dietilnitrosamina/toxicidad , Ácidos Grasos Insaturados/uso terapéutico , Inflamación/prevención & control , Neoplasias Hepáticas/prevención & control , Alquilantes/toxicidad , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/patología , Carotenoides/metabolismo , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/patología , Ciclina D1/genética , Ciclina D1/metabolismo , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Inflamación/inducido químicamente , Inflamación/patología , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/patología , Licopeno , Ratones , Ratones Endogámicos C57BL , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This study was undertaken to understand how Lentinula edodes modulates in vivo mutagenesis induced by alkylating agents in bone marrow and peripheral blood as described in our previous article. Male Swiss mice were pretreated for 15 consecutive days with aqueous extracts prepared from L. edodes, after which, the number of circulating blood cells, normal erythroid bone marrow cell cycling, and phagocytosis of micronucleated reticulocyte (MNRET) and activation of spleen macrophages were assessed. The results indicate that the antimutagenicity seen in bone marrow and peripheral blood is exerted by distinct compounds with different actions. The antimutagenic effect in bone marrow is exerted by compounds subject to degradation at deep-freeze storage temperature of -20°C. On the other hand, compounds responsible for antimutagenicity in peripheral blood are not subject to degradation at -20°C. The results also indicate that the antimutagenic action in peripheral blood leading to the reduction of circulating MNRET occurs in the spleen primarily through a phagocytic activity due to higher macrophage numbers and probably not due to the enhanced activation state of individual cells.