RESUMEN
This study aimed to evaluate the potential neuroprotective effects of ketogenic diet (KD) against the neuronal disruptions induced by SE in lithium-pilocarpine rat model of status epilepticus (SE). Four groups of female rats include; groups I and III received standard diet and groups II and IV received KD for 3 weeks. Groups I and II were left untreated, while groups III and IV were injected with LiCl (127 mg/kg, i.p.) followed by pilocarpine HCl (10 mg/kg, i.p.) 18-24 h later, repeatedly, till induction of SE. 72 h post-SE, KD effectively ameliorated the balance between excitatory (glutamate) and inhibitory (GABA) neurotransmitters and the oxidative stress indices, increased adenine nucleotides and decreased immunoreactivity of iNOS, TNFα, glial fibrillary acidic protein, and synaptophysin. Thiswas in association with improvement in inflammatory response and neuronal tissue characteristics in hippocampus of SE rats. Histological changes showed preservation of neuronal integrity. These findings highlight the protective effects of KD in the acute phase post-SE via ameliorating biochemical and histological changes involved. PRACTICAL APPLICATIONS: Epilepsy is the fourth most common neurological disorder that requires lifelong treatment. It stigmatizes patients and their families. The use of the ketogenic diet (KD) as a therapy for epilepsy developed from observations that fasting could reduce seizures. From 1920s, the KD was a common epilepsy treatment until it was gradually superseded by anticonvulsant drugs so that by the 1980s it was rarely used. However, there has been a resurgence of interest and usage of the KD for epilepsy since the turn of the century. Despite its long history, the mechanisms by which KD exhibits its anti-seizure action are not fully understood. Our study aims to identify the mechanism of KD which may help further studies to achieve the same benefits with a drug or supplement to overcome its unpalatability and gastrointestinal side effects.
Asunto(s)
Dieta Cetogénica , Epilepsia , Estado Epiléptico , Animales , Epilepsia/inducido químicamente , Femenino , Hipocampo , Pilocarpina/efectos adversos , Ratas , Estado Epiléptico/inducido químicamente , Estado Epiléptico/tratamiento farmacológicoRESUMEN
Parkinson's disease (PD) is the second common age-related neurodegenerative disease. It is characterized by control loss of voluntary movements control, resting tremor, postural instability, bradykinesia, and rigidity. The aim of the present work is to evaluate curcumin, niacin, dopaminergic and non-dopaminergic drugs in mice model of Parkinson's disease through behavioral, biochemical, genetic and histopathological observations. Mice treated with rotenone rerecorded significant increase in adenosine A2A receptor (A2AR) gene expression, α synuclein, acetylcholinesterase (AchE), malondialdehyde (MDA), angiotensin-II (Ang-II), c-reactive protein (CRP), interleukin-6 (IL-6), caspase-3 (Cas-3) and DNA fragmentation levels as compared with the control group. While, significant decrease in dopamine (DA), norepinephrine (NE), serotonin (5-HT), superoxide dismutase (SOD), reduced glutathione (GSH), ATP, succinate and lactate dehydrogenases (SDH &LDH) levels were detected. Treatment with curcumin, niacin, adenosine A2AR antagonist; ZM241385 and their combination enhanced the animals' behavior and restored all the selected parameters with variable degrees of improvement. The brain histopathological features of hippocampal and substantia nigra regions confirmed our results. In conclusion, the combination of curcumin, niacin and ZM241385 recorded the most potent treatment effect in Parkinsonism mice followed by ZM241385, as a single treatment. ZM241385 succeeded to antagonize adenosine A2A receptor by diminishing its gene expression and ameliorating all biochemical parameters under investigation. The newly investigated agent; ZM241385 has almost the same pattern of improvement as the classical drug; Sinemet®. This could shed the light to the need of detailed studies on ZM241385 for its possible role as a promising treatment against PD. Additionally, food supplements such as curcumin and niacin were effective in Parkinson's disease eradication.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Curcumina/farmacología , Niacina/farmacología , Enfermedad de Parkinson Secundaria , Receptor de Adenosina A2A/metabolismo , Rotenona/administración & dosificación , Animales , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Masculino , Ratones , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/metabolismo , Enfermedad de Parkinson Secundaria/patología , Rotenona/farmacología , Sustancia Negra/metabolismo , Sustancia Negra/patologíaRESUMEN
MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs that regulate gene expression at the post-transcriptional level. Because of their size, specificity, and relative stability in plasma, miRNAs can be used as diagnostic and prognostic biomarkers to monitor liver injury, such as that caused by hepatitis C virus (HCV) and liver cancer. In this study, we investigated miRNA expression patterns from the serum of Egyptian patients with HCV and liver cancer compared with matched healthy controls. Using microarray-based expression profiling followed by real-time quantitative polymerase chain reaction validation, we compared the levels of circulating miRNA-122 and miRNA-222 in serum from patients with hepatitis C virus (n = 40) and liver cancer (n = 60) to matched healthy controls (n = 30). MiRNA SNORD68 was the housekeeping endogenous control. We found that the serum levels of miR-122 and miR-222 were significantly elevated in HCV patients, but not in liver cancer patients, compared with controls. Receiver operating characteristic analysis revealed that miR-122 and miR-222 have a high diagnostic potential in discriminating patients with HCV from controls. Serum miR-222 was significantly higher in HCV patients compared to liver cancer patients. Our results indicate that serum miR-122 and miR-222 are elevated in Egyptian patients with chronic HCV, and these miRNAs have a strong potential to serve as novel biomarkers for liver injury but not specifically for liver cancer.
Asunto(s)
Biomarcadores/análisis , Carcinoma Hepatocelular/diagnóstico , Hepatitis C Crónica/diagnóstico , Neoplasias Hepáticas/diagnóstico , MicroARNs/genética , Adulto , Anciano , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/virología , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/sangre , Hepatitis C Crónica/genética , Hepatitis C Crónica/virología , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Curva ROC , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto JovenRESUMEN
Imatinib mesylate (IM), a tyrosine kinase inhibitor, is used as targeted cancer therapy. However, mono-targeting by IM does not always achieve full tumor eradication and thus it is recommended to combine IM with other anticancer agents. Clotrimazole (CLT) is an antifungal azole derivative with promising anticancer effects due to inhibiting the activity of glycolytic enzymes. The present study aimed to evaluate the effect of combining CLT with IM on breast cancer cell line in an attempt to establish effective new combination. T47D human breast cancer cell line was treated with different concentrations of IM and/or CLT for 48 h. IM-CLT interaction was determined by isobologram equation and combination index. Cell viability was confirmed by measuring LDH activity. As indicators of glycolysis inhibition, the expression of hexokinase-2 (HK-2) and 6-phosphofructo-1-kinase (PFK-1) plus the activity of intracellular lactate dehydrogenase (LDH) and pyruvate kinase (PK) were determined. In addition, glucose consumption and adenosine triphosphate (ATP) production were measured. Moreover, nitric oxide (NO), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-α (HIF-α) were also determined as they are modulators for glycolysis. This study demonstrated that IM or CLT synergistically inhibited cell growth in T47D as shown by combination and dose reduction indices. The combination of 15 µM IM and 20 µM CLT significantly decreased glucose consumption, activity of both PK and intracellular LDH, while increased leaked LDH, VEGF and NO in the medium compared to each drug alone. Furthermore the combination decreased gene expression of HK-2, PFK-1 and ATP content compared to the control. In conclusion, the synergistic effect of CLT on IM cytotoxicity in T47D cell line maybe mediated through inhibition of glycolysis and increasing both NO and VEGF. Further studies are required to confirm the efficiency and safety of this combination.
Asunto(s)
Antifúngicos/farmacología , Antineoplásicos/farmacología , Benzamidas/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Clotrimazol/farmacología , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Adenosina Trifosfato/metabolismo , Mama/efectos de los fármacos , Mama/metabolismo , Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Hexoquinasa/metabolismo , Humanos , Mesilato de Imatinib , Fosfofructoquinasa-1/metabolismo , Piruvato Quinasa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. The present study was undertaken to investigate the pretreatment effects of standardized Ginkgo biloba extract (EGb761(®)) and low-dose whole-body γ-irradiation on the neurological dysfunction in the reserpine model of PD. Male Wistar rats were pretreated orally with EGb761 or fractionated low-dose whole-body γ-irradiation or their combination, then subjected to intraperitoneal injection of reserpine (5 mg/kg body weight) 24 h after the final dose of EGb761 or radiation. Reserpine injection resulted in the depletion of striatal dopamine (DA) level, increased catalepsy score, increased oxidative stress indicated via depletion of glutathione (GSH), increased malondialdehyde (MDA) and iron levels, decreased DA metabolites metabolizing enzymes; indicated by inhibition by glutathione-S-transferase, and nicotinamide adenine dinucleotide phosphate (NADPH)-quinone oxidoreductase (NQO) activities, mitochondrial dysfunction; indicated by declined complex I activity, and adenosine triphosphate (ATP) level and increased apoptosis; indicated by decreased mitochondrial B cell lymphoma-2 (Bcl-2) protein level and by transmission electron microscope. EGb761 and low-dose γ-radiation ameliorated the reserpine-induced state of oxidative stress, mitochondrial dysfunction, and apoptosis in brain. It can be concluded that EGb761, a widely used herbal medicine and low dose of γ-irradiation have protective effects for combating Parkinsonism possibly via replenishment of GSH levels.
Asunto(s)
Cuerpo Estriado/efectos de la radiación , Suplementos Dietéticos , Neuronas/efectos de la radiación , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/prevención & control , Extractos Vegetales/uso terapéutico , Irradiación Corporal Total , Animales , Antiparkinsonianos/uso terapéutico , Apoptosis/efectos de la radiación , Conducta Animal/efectos de la radiación , Química Encefálica/efectos de la radiación , Catalepsia/etiología , Catalepsia/prevención & control , Terapia Combinada , Cuerpo Estriado/metabolismo , Cuerpo Estriado/ultraestructura , Modelos Animales de Enfermedad , Rayos gamma/uso terapéutico , Ginkgo biloba , Masculino , Neuronas/metabolismo , Neuronas/ultraestructura , Estrés Oxidativo/efectos de la radiación , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Proyectos Piloto , Distribución Aleatoria , Ratas Wistar , ReserpinaRESUMEN
Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) proteins including collagen that occurs in most types of chronic liver diseases. Studies concerning the capacity of mesenchymal stem cells (MSCs) and simvasatain (SIMV) to repair fibrotic tissues through reducing inflammation, collagen deposition, are still controversial. This study aimed to investigate the therapeutic efficacy of bone marrow (BM)-derived MSCs and SIMV on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Rats were divided into: normal, CCl4, CCl4/MSCs, CCl4/SIMV, CCl4/MSCs/SIMV, and SIMV groups. BM-derived MSCs were detected by RT-PCR of CD29 and were then infused into the tail vein of female rats that received CCl4 injection to induce liver fibrosis. Sex-determining region Y (SRY) gene on Y-chromosome gene was assessed by PCR to confirm homing of the male stem cells in liver tissue of the female recipients. Serum liver function tests, liver procollagens I and III, tissue inhibitors of metalloproteinase-1 (TIMP-1), endoglin, matrix metalloproteinase-1 (MMP-1) gene expressions, transforming growth factor-beta (TGF-ß1) immunostaining, and histopathologicl examination were performed. MSCs and SIMV decreased liver procollagens I and III, TIMP-1 and endoglin gene expressions, TGF-ß1 immunostaining, and serum liver function tests compared with the CCl4 group. MMP-1 expression was increased in the CCl4/MSCs group. Histopathological examination as well as fibrosis score supports the biochemical and molecular findings. It can be concluded that MSCs and SIMV were effective in the treatment of hepatic CCl4-induced fibrosis-rat model. Treatment with MSCs was superior to SIMV. This antifibrotic effect can be attributed to their effect on the MMPs/TIMPs balance which is central in fibrogenesis.
Asunto(s)
Células de la Médula Ósea/citología , Cirrosis Hepática/terapia , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Simvastatina/uso terapéutico , Animales , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Modelos Animales de Enfermedad , Endoglina , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hipolipemiantes/farmacología , Hipolipemiantes/uso terapéutico , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología , Masculino , Ratas , Ratas Wistar , Índice de Severidad de la Enfermedad , Proteína de la Región Y Determinante del Sexo/genética , Proteína de la Región Y Determinante del Sexo/metabolismo , Simvastatina/farmacología , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismoRESUMEN
Colorectal cancer is one of the leading causes of tumour-related deaths. In the present study, the chemopreventive effect of green tea on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis was studied in male Wistar rats. The DMH group received subcutaneous injections of DMH (30 mg kg(-1) body weight) once a week for 30 weeks, the normal group received the vehicle of DMH, and the DMH + green tea group received DMH simultaneously with 1% green tea as their sole source of drinking fluid throughout the experimental period. In the DMH group treated with green tea, significant reductions in gene overexpressions of colonic nuclear factor κB (NF-κB), tumour necrosis factor α, inducible nitric oxide synthase and cyclooxygenase 2, and NF-κB immunostaining indicates the anti-inflammatory effect of green tea in attenuating colon cancer. Moreover, the anti-angiogenic and anti-invasiveness effects of green tea were revealed as reductions of both vascular endothelial growth factor and matrix metalloproteinase-7 mRNA expression levels. These effects were confirmed by the significant reduction of serum tumour necrosis factor α, C-reactive protein levels, inhibition of tumour incidence, and nearly normal survival rate and colonic architecture. It can be concluded that green tea exerts a potent chemopreventive effect on colon carcinogenesis possibly due to the inhibition of NF-κB.
Asunto(s)
Neoplasias del Colon/prevención & control , Extractos Vegetales/uso terapéutico , Té/química , 1,2-Dimetilhidrazina/toxicidad , Animales , Proteína C-Reactiva/análisis , Quimioprevención , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/patología , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Masculino , Metaloproteinasa 7 de la Matriz/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Extractos Vegetales/química , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
This study investigated the potential role of folate in the dimethylhydrazine (DMH) colon cancer model in male Wistar rats. For induction of colon cancer, group 1 rats were injected subcutaneously with 30 mg DMH/kg body weight weekly for 30 wk. Group 2 received DMH vehicle. Group 3 rats received DMH as in Group 1 but their diet was supplemented with 8 mg folate/kg diet. Group 4 was fed diet supplemented with 8 mg folate/kg diet. Upregulation of DNA damage repair genes Apurinic/apyrimidinic endonuclease 1, X-ray repair complementing defective repair in Chinese hamster cells 5, 8-oxoguanine-DNA glycosylase, and proliferating cell nuclear antigen, associated with a reduction of folic acid level was observed in colons of DMH group. Reductions of these gene upregulations and a significant increase of colonic folic acid level occurred in the DMH group supplemented with folic acid and this group also had significant inhibition of tumor incidence, normal survival rate and histologically nearly normal colonic architecture. It can be concluded that folate supplementation exerts a potent protective effect on rat colon carcinogenesis via significant modulation of DNA repair, providing a mechanism by which it plays a role in the etiology of human cancer.
Asunto(s)
Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/prevención & control , Dieta , Dimetilhidrazinas , Ácido Fólico/administración & dosificación , Animales , Colon/química , Colon/patología , Neoplasias del Colon/patología , Daño del ADN , Reparación del ADN/efectos de los fármacos , Enzimas Reparadoras del ADN/genética , Suplementos Dietéticos , Ácido Fólico/análisis , Masculino , ARN Mensajero/análisis , Ratas , Ratas Wistar , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND AND AIM: Recently, it has been suggested that single nucleotide polymorphisms (SNPs) in some cytokine genes may influence the production of the associated cytokines that affect the host immune response to pegylated interferon-α (Peg-IFN-α) with ribavirin (RBV) in hepatitis C virus (HCV) patients. The aim of the present study was to investigate the possible role of the SNPs of IL-10 and Il-28B and their serum levels in predicting the response to treatment of HCV-4. METHODS: Egyptian patients were treated with Peg-IFN-α/RBV. A total of 100 HCV genotype 4-infected patients and 80 healthy control subjects were included in the present study. SNPs in the IL-10 (-592 A/C and -819 T/C) and IL-28B (rs8099917 T/G and rs12979860 C/T) genes and their serum levels were assessed. The IL-10-592-CC, IL-28-rs8099917-TT and IL-28-rs12979860-CC genotypes were significantly higher in responders than in non-responders. RESULTS: Interestingly, the serum levels of IL-10 were significantly increased; in contrast, the serum levels of Il-28B were significantly decreased in HCV patients compared with normal patients. Polymorphisms in IL-28B are more sensitive (P < 0.001) than those in IL-10-592 (P = 0.03). However, the serum level of IL-10 is higher than that of IL-28, and this difference can serve as a prognostic marker using a receiver operator characteristic (ROC) analysis. CONCLUSIONS: It can be concluded that SNPs in IL-28B and the serum levels of Il-10 and IL-28 may be promising predictors for HCV therapy.
Asunto(s)
Antivirales/uso terapéutico , Genotipo , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/genética , Interferón-alfa/uso terapéutico , Interleucina-10/genética , Interleucinas/genética , Polietilenglicoles/uso terapéutico , Polimorfismo de Nucleótido Simple , Ribavirina/uso terapéutico , Adulto , Quimioterapia Combinada , Egipto , Femenino , Predicción , Humanos , Interferones , Interleucina-10/sangre , Interleucinas/sangre , Masculino , Persona de Mediana Edad , Curva ROC , Proteínas Recombinantes/uso terapéutico , Resultado del TratamientoRESUMEN
Osteopontin (OPN) is an extracellular matrix glycophosphoprotein produced by several types of cells including the immune system. The present study examined the possibility that single-nucleotide polymorphisms (SNP) in the promoter region of the OPN at nt -443 is a marker predicting the therapeutic efficacy of pegylated interferon (peg-IFN-α2b)-ribavirin combination therapy in Egyptian patients with chronic hepatitis C. Blood was collected from 95 patients with chronic hepatitis C who had received peg-IFN-α2b-ribavirin combination therapy and 100 age and sex matched controls. SNP in OPN at nucleotide (nt) -443 and its serum protein level were analyzed. Sustained virological response (SVR) was higher in patients with T/T at nt -443 than in those with C/C or C/T. A univariate logistic regression analysis showed that fibrosis grade, serum OPN protein level and T/T homozygotes of SNP at -443 were significant predictors for response. Receiver operating characteristics (ROC) analysis revealed the diagnostic and prognostic efficacy of serum OPN. It can be concluded that SNP in the promoter region of OPN at nt -443 and serum OPN protein level are predictors of response to the efficacy of peg-IFN-α2b-ribavirin therapy in Egyptian patients with chronic hepatitis C.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Osteopontina/genética , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , Adulto , Egipto , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Masculino , Persona de Mediana Edad , Osteopontina/química , Polietilenglicoles/uso terapéutico , Valor Predictivo de las Pruebas , Proteínas Recombinantes/uso terapéutico , Ribavirina/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
The pathogenesis of acute kidney injury (AKI) occurring due to sepsis is incompletely understood. Endothelial activation, defined as up-regulation of adhesion molecules by proinflammatory cytokines, may be central to the development of sepsis-induced AKI. Our aim was to determine levels of circulating adhesion molecules endothelial (E)-selectin, intercellular adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM), inflammatory mediators; tumor necrosis factor-α (TNF-α) and transforming growth factor-ß (TGF-ß), vasoactive mediators; endothelin-1 (ET-1) and nitric oxide (NO), soluble receptor for advanced glycated end products (sRAGE) and serum fetuin-A in septic AKI patients before and after antibiotic therapy. Nineteen AKI patients with sepsis and fifteen healthy controls were enrolled in this prospective study. Results revealed that 12 weeks of therapy caused amelioration of endothelial and inflammatory injuries as well as renal function markers. Moreover, the positive correlations between levels of RAGE and E-selectin (r=0.88), ET-1 (r=0.90), and TNF-α (r=0.94) and negative with NO (r=-0.75-0.95) suggest that possible interaction of RAGE and inflammation may contribute to endothelial dysfunction in septic AKI patients.
Asunto(s)
Endotelio Vascular/fisiopatología , Productos Finales de Glicación Avanzada , Mediadores de Inflamación , Enfermedades Renales/etiología , Enfermedades Renales/patología , Sepsis/complicaciones , Antibacterianos/uso terapéutico , Estudios de Casos y Controles , Endotelio Vascular/efectos de los fármacos , Femenino , Humanos , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Enfermedades Renales/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sepsis/tratamiento farmacológico , Sepsis/patologíaRESUMEN
BACKGROUND/AIMS: It is well known that diabetes mellitus is associated with the impairment of testicular function. In the present study, we aimed to study the effects of sulphurous mineral water or sodium hydrosulphide (NaHS) on apoptotic testicular damage in rats with streptozotocin (STZ)-induced diabetes. METHODS: Sulphurous mineral water (as drinking water) or NaHS (14 µmol/kg body weight/day, I.P.) was administered for 7 wks to rats with STZ-induced diabetes. RESULTS: Hyperglycaemia, an overproduction of glycated haemoglobin (HbA1C) and a decline in serum insulin, C-peptide and insulin-like growth factor-I (IGF-I) were observed in diabetic rats. A decline in the serum testosterone level and an impairment of spermatogenesis, as indicated by a histopathological examination of diabetic rats, demonstrated significant testicular damage. Sulphurous mineral water and NaHS treatment may have improved the level of testicular GSH by blocking the overexpression of some apoptosis-related regulatory proteins such as Bax/Bcl-2, cytochrome c, caspase-9 and -3, and p53. This anti-apoptotic potential was associated with an increase in serum testosterone level and the amelioration of hyperglycaemia-related biochemical parameters. The histopathological examination was in harmony with the biochemical and molecular findings. CONCLUSION: Our study provides the first indication that sulphurous mineral water and NaHS may have a novel anti-apoptotic potential that could be a useful treatment in preventing diabetes-induced testicular dysfunction.
Asunto(s)
Apoptosis/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Aguas Minerales/uso terapéutico , Sulfuros/uso terapéutico , Azufre/farmacología , Testículo/efectos de los fármacos , Animales , Antibióticos Antineoplásicos/toxicidad , Péptido C/metabolismo , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Citocromos c/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/patología , Hemoglobina Glucada/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Wistar , Espermatogénesis/efectos de los fármacos , Estreptozocina/toxicidad , Azufre/química , Testosterona/sangre , Proteína p53 Supresora de Tumor/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
This study examined the downstream signaling whereby hyperglycemia may lead to myocardial fibrosis and apoptosis in the left ventricle of diabetic rats. The effects of sulfurous mineral water or sodium hydrosulfide (NaHS) as possible modulators were also examined. Sulfurous mineral water (as drinking water) and NaHS (14µmol/kg/day, IP) were administered for 7 week to rats with streptozotocin (STZ)-induced diabetes. Hyperglycemia, overproduction of glycated hemoglobin (HbA1C) and serum decline in insulin, C-peptide and insulin like growth factor-I (IGF-I) were observed in diabetic rats. Up-regulation of gene expressions of nuclear factor (NF-κB), profibrogenic growth factor such as transforming growth factor-ß1 (TGF-ß1), matrix metalloproteniase-2 (MMP-2), procollagen-1 and Fas ligand (Fas-L) were observed in the left ventricle of diabetic rats. A linear positive correlation between TGF-ß1 and MMP-2 was also detected in diabetic group. An increase in hydroxyproline level and a disturbance in oxidative balance were detected in heart of diabetic rats. Sulfurous mineral water and NaHS treatment possibly, by improving cardiac GSH level, counteracted the enhanced expression of NF-κB, the profibrogenic and apoptotic parameters. Histopathological examination was in accordance with the biochemical and molecular findings of this study. We suggest a novel therapeutic approach of sulfurous mineral water and exogenous supplementation of H(2)S in diabetic cardiomyopathy.
Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/terapia , Cardiomiopatías Diabéticas/prevención & control , Aguas Minerales/administración & dosificación , Sulfuros/administración & dosificación , Azufre/administración & dosificación , Administración Oral , Animales , Secuencia de Bases , Glucemia/metabolismo , Cartilla de ADN/genética , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/terapia , Proteína Ligando Fas/genética , Expresión Génica , Disulfuro de Glutatión/metabolismo , Hemoglobina Glucada/metabolismo , Ventrículos Cardíacos/metabolismo , Masculino , Metaloproteinasa 2 de la Matriz/genética , Miocardio/patología , FN-kappa B/genética , Ratas , Ratas Wistar , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
The present study aimed to evaluate the role of DL-alpha-lipoic acid (LA) and squalene (SQ) on oxidative cardiac, testicular and urotoxic damage induced by cyclophosphamide (CP). Male Wistar rats were divided into four groups; three groups received a single intraperitoneal injection of CP (200mg/kg BW) to induce toxicity, and two of these groups received either LA (35 mg/kg BW) or SQ (0.4 ml/rat) orally 7 days before and 7 days after CP injection. A vehicle-treated control group was also included. Oxidative damage was observed by decreased serum total antioxidant capacity (TAC) level and abnormal alterations in glutathione peroxidase (GPx) and glutathione reductase (GR) activities, levels of glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO) and calcium (Ca(+2)) in the heart, testes and urinary bladder of CP-administered rats. Cardiac marker enzyme activities; creatine phosphokinase (CPK), lactate dehydrogenase (LDH), and aspartate transaminase (AST) showed severe declines whereas testicular markers; sorbitol dehydrogenase (SDH), gamma-glutamyl transferase (gamma-GT), acid and alkaline phosphatases (ACP and ALP), serum testosterone (T) level and haemoglobin (Hb) absorbance were abnormal. Histopathological observations were also altered. These CP-induced pathological alterations were attenuated by treatment with LA or SQ. These findings highlight the efficacy of LA and SQ as cytoprotectants in CP-induced toxicity.
Asunto(s)
Antineoplásicos Alquilantes/antagonistas & inhibidores , Antineoplásicos Alquilantes/toxicidad , Antioxidantes/farmacología , Ciclofosfamida/antagonistas & inhibidores , Ciclofosfamida/toxicidad , Miocardio/patología , Estrés Oxidativo/efectos de los fármacos , Escualeno/farmacología , Testículo/patología , Ácido Tióctico/farmacología , Vejiga Urinaria/patología , Animales , Antioxidantes/metabolismo , Biomarcadores , Peso Corporal/efectos de los fármacos , Calcio/metabolismo , Supervivencia Celular/efectos de los fármacos , Masculino , Óxido Nítrico/metabolismo , Ratas , Ratas Wistar , SobrevidaRESUMEN
Cadmium (Cd) is one of the environmental pollutants that affect various tissues and organs including testis. Harmful effect of cadmium on testis is known to be germ cell degeneration and impairment of testicular steroidogenesis. In the present study, the effect of diallyl sulfide (DAS), a sulfur-containing volatile compound present in garlic, and zinc (Zn) was investigated on cadmium-induced testicular toxicity in rats. Male adult Wistar rats treated with cadmium (2.5 mg/kg body wt, five times a week for 4 weeks) showed decreased body weight, paired testicular weight, relative testicular weight, serum testosterone, luteinizing hormone, follicle-stimulating hormone, and testicular total antioxidant capacity (TAC) and protein levels. Testicular steroidogenic enzymes, such as 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD), and marker enzymes, such as sorbitol dehydrogenase (SDH), lactate dehydrogenase (LDH), acid phosphatase (ACP), alkaline phosphatase (ALP), and glucose-6-phosphate dehydrogenase (G6PD), showed a significant decrease in activities whereas that of gamma-glutamyl transferase was significantly increased after cadmium exposure. The results have revealed that concurrent treatment with DAS or zinc restored key steroidogenic enzymes, SDH, LDH, and G6PD and increased testicular weight significantly. DAS restored the TAC level and increased testosterone level and relative testicular weight significantly. Zinc restored testicular protein level and body weight. It can be concluded that cadmium causes testicular toxicity and inhibits androgen production in adult male rats probably by affecting pituitary gonadotrophins and that concurrent administration of DAS or zinc provides protection against cadmium-induced testicular toxicity.