ABSTRACT
AIMS: Chronic inflammation is associated with the production of high levels of proinflammatory cytokines via the JAK-STAT and NF-κB signalling pathways which are known to be inhibited by tofacitinib and aspirin respectively. High levels of these cytokines increase the synthesis of suppressors of cytokines (SOCS), which at high levels inhibit insulin signalling leading to insulin resistance. The effects of tofacitinib and aspirin on the degree of insulin resistance in type 2 diabetic rats were determined. MATERIALS AND METHODS: Rats were induced with type 2 diabetes (T2D) by administration of 10% fructose solution (ad libitum) followed by streptozotocin injection (40â¯mg/kg BW) and treated with different doses of tofacitinib (10 and 20â¯mg/kg BW), aspirin (100 and 200â¯mg/kg BW) and combination of the two drugs at both doses for 9 weeks. KEY FINDINGS: Results showed that separate treatment with 10â¯mg/kg BW tofacitinib and 100â¯mg/kg BW aspirin significantly (Pâ¯<â¯0.05) decreased tumour necrosis factor-α (TNF-α), interleukin 6 (IL-6) and serum amyloid A when compared to diabetic untreated rats. However, the combined therapy (10â¯mg/kg BW tofacitinib and 100â¯mg/kg BW aspirin) significantly decreased the levels of TNF-α, IL-6, serum amyloid A, HOMA-IR, blood glucose level and SOC-3 gene expression but significantly (Pâ¯<â¯0.05) improved glucose homoestasis, insulin secretion, HOMA-ß and GLUT-4 gene expression when compared to diabetic untreated rat. CONCLUSION: It was concluded that simultaneous inhibition of the JAK-STAT and NF-κB signalling pathways with tofacitinib and aspirin respectively, could mitigate insulin resistance and hyperglycemia in T2D.
Subject(s)
Aspirin/pharmacology , Diabetes Mellitus, Type 2/drug therapy , Piperidines/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Animals , Aspirin/metabolism , Blood Glucose/drug effects , Cytokines , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/metabolism , Disease Models, Animal , Female , Hyperglycemia/drug therapy , Hypoglycemic Agents/pharmacology , Insulin/metabolism , Insulin Resistance/physiology , Interleukin-6/metabolism , Janus Kinases/metabolism , Male , NF-kappa B/metabolism , Piperidines/metabolism , Pyrimidines/metabolism , Pyrroles/metabolism , Rats , Rats, Wistar , STAT Transcription Factors/metabolism , Serum Amyloid A Protein/metabolism , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Neurodegenerative diseases (NDDs) are pathological conditions characterised by progressive damage of neuronal cells leading to eventual loss of structure and function of the cells. Due to implication of multi-systemic complexities of signalling pathways in NDDs, the causes and preventive mechanisms are not clearly delineated. The study was designed to investigate the potential signalling pathways involved in neuroprotective activities of purely isolated glucomoringin isothiocyanate (GMG-ITC) against H2O2-induced cytotoxicity in neuroblastoma (SH-SY5Y) cells. GMG-ITC was isolated from Moringa oleifera seeds, and confirmed with NMR and LC-MS based methods. Gene expression analysis of phase II detoxifying markers revealed significant increase in the expression of all the genes involved, due to GMG-ITC pre-treatment. GMG-ITC also caused significant decreased in the expression of NF-kB, BACE1, APP and increased the expressions of IkB and MAPT tau genes in the differentiated cells as confirmed by multiplex genetic system analysis. The effect was reflected on the expressed proteins in the differentiated cells, where GMG-ITC caused increased in expression level of Nrf2, SOD-1, NQO1, p52 and c-Rel of nuclear factor erythroid factor 2 (Nrf2) and nuclear factor kappa-B (NF-kB) pathways respectively. The findings revealed the potential of GMG-ITC to abrogate oxidative stress-induced neurodegeneration through Nrf2 and NF-kB signalling pathways.
Subject(s)
Hydrogen Peroxide/toxicity , Isothiocyanates/pharmacology , Neuroprotective Agents/pharmacology , Rhamnose/analogs & derivatives , Blotting, Western , Cell Line, Tumor , Electrophoresis, Polyacrylamide Gel , Gene Expression Regulation/drug effects , Humans , Hydrogen Peroxide/antagonists & inhibitors , Metabolic Networks and Pathways/drug effects , Neuroblastoma , Reverse Transcriptase Polymerase Chain Reaction , Rhamnose/pharmacology , Transcriptome/drug effectsABSTRACT
The antioxidant and neuroprotective activity of Glucomoringin isothiocyanate (GMG-ITC) have been reported in in vivo and in vitro models of neurodegenerative diseases. However, its neuroprotective role via mitochondrial-dependent pathway in a noxious environment remains unknown. The main objective of the present study was to unveil the mitochondrial apoptotic genes' profile and prospectively link with neuroprotective activity of GMG-ITC through its ROS scavenging. The results showed that pre-treatment of differentiated SH-SY5Y cells with 1.25⯵g/mL purified isolated GMG-ITC, significantly reduced reactive oxygen species (ROS) production level, compared to H2O2 control group, as evidenced by flow cytometry-based evaluation of ROS generation. Presence of GMG-ITC prior to development of oxidative stress condition, downregulated the expression of cyt-c, p53, Apaf-1, Bax, CASP3, CASP8 and CASP9 genes with concurrent upregulation of Bcl-2 gene in mitochondrial apoptotic signalling pathway. Protein Multiplex revealed significant decreased in cyt-c, p53, Apaf-1, Bax, CASP8 and CASP9 due to GMG-ITC pre-treatment in oxidative stress condition. The present findings speculated that pre-treatment with GMG-ITC may alleviate oxidative stress condition in neuronal cells by reducing ROS production level and protect the cells against apoptosis via neurodegenerative disease potential pathways.
