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en Bone Marrow-Derived Mesenchymal Stem Cells and Pioglitazone or Exendin-4 Synergistically Improve Insulin Resistance via Multiple Modulatory Mechanisms in High-Fat Diet/Streptozotocin-Induced Diabetes in Rats بیوشیمی Biochemistry مقالات اصلی Original Article <div style="text-align: justify;">Background: Diabetes mellitus (DM) is a metabolic disease, characterized by hyperglycemia resulting from defects in insulin secretion and/or insulin action. The current study was designed to assess the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) alone and in combination with pioglitazone (Pz) or exendin-4 (Ex) in high-fat diet/streptozotocin (HFD/STZ)-induced diabetes in rats. Methods: The rats were subjected to the HFD for three weeks before being injected with a single low dosage of STZ (35 mg/kg bw). The animals were assigned to different treatment groups after type II diabetes mellitus (T2DM) induction was confirmed. Results: Severe insulin resistance was verified in untreated HFD/STZ T2DM rats, along with the exaggeration of oxidative stress, inflammation, apoptosis, and autophagy suppression in the adipose tissues. Monotherapy of HFD/T2DM rats with BM-MSCs and Pz or Ex alleviated diabetic complications by increasing insulin sensitivity, decreasing apoptosis and inflammation as evidenced by a decrease in serum tumor necrosis factor-alpha, caspase-3, and nuclear factor-kappa B (NF-kB) genes expression and Janus kinase (JNK) protein expression, and enhancing autophagy as revealed by upregulation in beclin and LC3, as well as peroxisome proliferator-activated receptor-g coactivator-1 alpha (PGC-1α) genes expression in the adipose tissues. An augmented ameliorative efficacy was recorded in combined treatments. The biochemical and molecular results were confirmed by histological investigation of pancreatic tissues. Conclusions: Combining Pz or Ex with BM-MSCs is a synergistic therapeutic option that reduces insulin resistance and subsequent complications in T2DM via multiple molecular mechanisms.</div> Exendin-4, High-fat diet, Mesenchymal stem cells, Pioglitazone, Streptozotocin, Type II diabetes mellitus. 42 58 http://rbmb.net/browse.php?a_code=A-10-1191-1&slc_lang=en&sid=1 Mohamed Mohamed Mesbah 100319475328460017807 100319475328460017807 No Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt. Laila Ahmed Rashed 100319475328460017808 100319475328460017808 No Department of Medical Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt. Noha Ahmed El-Boghdady 100319475328460017809 100319475328460017809 No Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Mahmoud Mohamed Said mahmoudmsaid@sci.asu.edu.eg 100319475328460017810 100319475328460017810 Yes Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt.