Antiapoptotic and anti-inflammatory effects of Pparγ agonist, pioglitazone, reversed Dox-induced cardiotoxicity through mediating of miR-130a downregulation in C57BL/6 mice.

Doxorubicin (Dox) is an antitumor agent widely used in cancer therapy, with notable side effects of cardiac toxicity. Peroxisome proliferator-activated receptor γ (PPARγ), is a transcriptional factor with antiapoptotic and anti-inflammatory properties. Recently we indicated that cardiac toxicity of Dox was due to upregulation of miR-130a and further suppressive effect on cardiac Pparγ in vitro. In this study, we extended our proposed hypothesis in vivo. To achieve this, pioglitazone (Pio) and GW9662 were used as the specific agonist and antagonist of Pparγ to treat Dox-injected mice. Heart function, apoptosis, and inflammation in heart tissue were studied. Pretreatment of Dox-injected mice with Pio resulted in elevated expression of Pparγ and suppression of miR-130a. However, GW9662 pretreatment was unable to increase miR-130a expression. Pio pretreatment led to partially cardiac toxicity limitation of Dox whereas GW9662 caused heart damage. Finally, our observation determined that activation of Pparγ was not adequate to reverse the Dox-induced toxicity completely.

Alteration in messenger RNA neurotrophin 4 and tyrosine kinase receptors B expression levels following spinal cord injury.

BACKGROUND: Neurotrophins as polypeptide growth factors have important roles during nervous system development and are involved in neuronal differentiation and survival and spinal cord reorganization. Neurotrophins have been recognized as factors which are involved in the development of damaged axons and increase the axon growth ability and neuroplasticity. Spinal cord injury (SCI) is associated with numerous physiological damages, leading to neuron death, axon extended destruction healthy and intact neurons demyelination, inflammation, cell death and severe motor/sensory defects. The aim of this study was to investigate the alteration in messenger RNA neurotrophin 4 and tyrosine kinase receptors B expression levels following SCI. METHODS: In this research, to know expression level alterations of neurotrophin 4 mRNA and its receptor Trk- B at 6 hours and 1, 3, 7 and 10 days after SCI, we developed competitive RT-qPCR. mRNA was extracted from T9 injury site (epicenter, rostral and caudal to the epicenter) and reversed to cDNA. RESULTS: The results showed that the expression of these genes changed after SCI. The NT4 mRNA expression level in the rostral to the epicenter decreased after enhancement in the 1st 6 hours. At the epicenter and in the caudal to the epicenter, it decreased. mRNA expression level of Trk-B decreased after an increase in the initial hours in all the areas. CONCLUSIONS: The present results showed that NT4 and Trk-B are expressed temporary and spatially following SCI and the adjustment of these neurotrophins rate in SCI may provide therapeutic benefits.

Downregulation of miR-130a, antagonized doxorubicin-induced cardiotoxicity via increasing the PPARγ expression in mESCs-derived cardiac cells.

Doxorubicin (Dox) is a widely used powerful chemotherapeutic component for cancer treatment. However, its clinical application has been hampered due to doxorubicin-induced cardiomyopathy upon the cessation of chemotherapy. Previous studies revealed that PPARγ plays a crucial protective role in cardiomyocytes. Modulation of miRNA expression is an applicable approach for prohibition of toxicity induction. Therefore, the aim of present study is uprising of PPARγ transcript levels via manipulation of miRNAs to limit Dox-induced cardiotoxicity in mESCs-derived cardiac cells, as in vitro model cell to provide a simple direct approach for further clinical therapies. Based on bioinformatics data mining, eventually miR-130a was selected to target PPARγ. This miRNA is highly expressed in heart. The expression of miR-130a increases sharply upon Dox treatment while specific antagomiR-130a reverses Dox-induced reduced expression of PPARγ, cellular apoptosis, and inflammation. Our data strongly suggest that antagomiR-130a limits Dox-induced cellular toxicity via PPARγ upregulation and may have clinical relevance to limit in vivo Dox toxicity.