RESUMEN
We intended to examine the molecular mechanism of action of isorhamnetin (IHN) to regulate the pathway of insulin signaling. Molecular analysis, immunofluorescence, and histopathological examination were used to assess the anti-hyperglycemic and insulin resistance lowering effects of IHN in streptozotocin /high fat diet-induced type 2 diabetes using Wistar rats. At the microscopic level, treatment with IHN resulted in the restoration of myofibrils uniform arrangement and adipose tissue normal architecture. At the molecular level, treatment with IHN at three different doses showed a significant decrease in m-TOR, IGF1-R & LncRNA-RP11-773H22.4. expression and it up-regulated the expression of AKT2 mRNA, miR-1, and miR-3163 in both skeletal muscle and adipose tissue. At the protein level, IHN treated group showed a discrete spread with a moderate faint expression of m-TOR in skeletal muscles as well as adipose tissues. We concluded that IHN could be used in the in ameliorating insulin resistance associated with type 2 diabetes mellitus.
Asunto(s)
Tejido Adiposo/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Resistencia a la Insulina , Insulina/sangre , Miofibrillas/efectos de los fármacos , Quercetina/análogos & derivados , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Animales , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/enzimología , Diabetes Mellitus Tipo 2/patología , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Miofibrillas/metabolismo , Miofibrillas/patología , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quercetina/farmacología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Ratas Wistar , Receptor IGF Tipo 1/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
AIM: Depression associating patients with chronic liver diseases is a major treatment goal. This study aimed to evaluate the potential hepatoprotective and antidepressant effects of celecoxib in a model of experimental autoimmune hepatitis (EAH) and depressive-like behavior in C57BL/6 mice. MAIN METHODS: EAH was induced by immunization with S-100 liver antigen emulsified in complete Freund's adjuvant (CFA). Mice were randomly allocated to 5 groups; control phosphate buffered saline group; control CFA group; EAH group, and 2 groups of EAH plus celecoxib (7.5 or 15mg/kg/d respectively). Mice were assessed behaviorally by novelty-suppressed test, tail suspension test, locomotor assessment and forced swimming tests. Serum liver enzymes and hepatic hydroxyproline content were biochemically analyzed. Histopathological analysis for liver and brain sections and immunohistochemical studies for hepatic and hippocampal tumor necrosis factor (TNF-α), nuclear factor Kappa-B (NF-κB) and caspase-3 were performed. KEY FINDINGS: EAH group exhibited significant depressive-like changes, increase in liver enzymes and hepatic hydroxyproline content. Signs of autoimmune hepatitis and structural changes in hippocampus were confirmed by histopathological studies. Immunohistochemical examination revealed overexpression of hepatic and hippocampal TNF-α, NF-κB and caspase-3 positive cells. Celecoxib (7.5mg/kg/d) significantly ameliorated hepatic biochemical changes, hepatic and hippocampal histopathological and immunohistochemical changes induced in EAH group. Celecoxib (15mg/kg/d) significantly ameliorated the behavioral changes, histopathological and immunohistochemical changes in hippocampus, with non-significant change in hepatic biochemical profile, histopathological and immunohistochemical changes induced in EAH group. SIGNIFICANCE: The celecoxib (7.5mg/kg/d) through its anti-inflammatory effect may represent a new therapeutic approach to treat autoimmune hepatitis associated with depressive symptoms.
Asunto(s)
Celecoxib/farmacología , Depresión/complicaciones , Depresión/tratamiento farmacológico , Hepatitis Animal/complicaciones , Hígado/efectos de los fármacos , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Conducta Animal/efectos de los fármacos , Encéfalo/patología , Caspasa 3/metabolismo , Celecoxib/uso terapéutico , Depresión/psicología , Relación Dosis-Respuesta a Droga , Hepatitis Animal/inmunología , Hepatitis Animal/metabolismo , Hepatitis Animal/patología , Hipocampo/metabolismo , Hidroxiprolina/metabolismo , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Proteínas S100/efectos adversos , Proteínas S100/inmunologíaRESUMEN
BACKGROUND AND OBJECTIVES: Bone marrow derived mesenchymal stem cells (BM-MSCs) have been proposed as effective treatment of many diseases owing to their unique ability to differentiate into other cell types in vivo. Schistosoma mansoni (S. mansoni) infection is characterized by hepatic granuloma formation around schistosome eggs at acute stage of infection, followed by hepatic fibrosis at chronic and advanced stages. Whether BM-MSCs have an ameliorative effect on hepatic tissue injury caused by S. mansoni infection or not, was inspected in the current study. MATERIALS AND RESULTS: Female Swiss Albino mice were divided into a control group and an experimental group. Half of control animals served as donors for bone marrow stem cells, and the other half was used to collect liver samples. Experimental group was injected with circariae of S. mansoni, and then subdivided into three subgroups; Subgroup B1, sacrificed after eight weeks of infection without treatment, subgroup B2, received BM-MSCs at the eighth week and sacrificed four weeks later, and subgroup B3, was untreated till the twelfth week of infection. Histological examination of liver samples showed the formation of granulomas and liver fibrosis which were extensive in subgroup B3. However, treated subgroup illustrated improvement of liver histology, signs of hepatocytes regeneration, and possible contribution of oval cell in the process of hepatic and biliary regeneration. CONCLUSION: BM-MSCs decreased liver fibrosis and contributed to an increase in oval cells, generation of new hepatocytes and/or to the improvement of resident hepatocytes in S. mansoni infected mice.