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C-Myc overexpression is a common finding in pancreatic cancer and predicts the aggressive behavior of cancer cells. It binds to the promoter of different genes, thereby regulating their transcription. C-Myc is downstream of KRAS and interacts with several oncogenic and proliferative pathways in pancreatic cancer. C-Myc enhances aerobic glycolysis in cancer cells and regulates glutamate biosynthesis from glutamine. It provides enough energy for cancer cells’ metabolism and sufficient substrate for the synthesis of organic molecules. C-Myc overexpression is associated with chemoresistance, intra-tumor angiogenesis, epithelial-mesenchymal transition (EMT), and metastasis in pancreatic cancer. Despite its title, c-Myc is not “undruggable” and recent studies unveiled that it can be targeted, directly or indirectly. Small molecules that accelerate c-Myc ubiquitination and degradation have been effective in preclinical studies. Small molecules that hinder c-Myc-MAX heterodimerization or c-Myc/MAX/DNA complex formation can functionally inhibit c-Myc. In addition, c-Myc can be targeted through transcriptional, post-transcriptional, and translational modifications.

Background. Recent meta-analyses have shown that sodium-glucose cotransporter 2 (SGLT-2) inhibitors alleviate chronic kidney disease and acute kidney injury in diabetic patients. In this study, we aimed to investigate the effect of empagliflozin on renal ischemia/reperfusion (I/R) in nondiabetic rats and find the possible mechanisms. Experimental Approach. Eighteen male Wistar rats were randomly divided into three groups, including healthy control, ischemic control, and empagliflozin-treated group. Thirty minutes of bilateral renal ischemia was induced by clamping the renal hilum. Forty-eight hours after reopening the clamps, rats’ blood samples and tissue specimens were collected. Empagliflozin 10 mg/kg was administered by gavage, 2 hours before ischemia and 24 hours after the first dose. Results. I/R injury led to a significant rise in serum creatinine and blood urea nitrogen which was significantly decreased after treatment with empagliflozin. Empagliflozin also alleviated tubulointerstitial and glomerular damage and significantly decreased tissue histology scores. Empagliflozin decreased the increased levels of malondialdehyde, interleukin 1β, and tumor necrosis factor α. SGLT2 inhibition increased the decreased expression of nuclear factor erythroid 2-related factor 2 and PPARG coactivator 1 alpha that conduct antioxidant defense and mitochondrial biogenesis, respectively. Furthermore, empagliflozin markedly increased LC3-II/LC3-I and bcl2/bax ratios, showing its beneficial effect on activation of autophagy and inhibition of apoptosis. Despite its effects on diabetic nephropathy, empagliflozin did not activate the Sestrin2/AMP-activated protein kinase pathway in this study. Conclusion. Empagliflozin improved renal I/R injury in nondiabetic rats in this study by promoting autophagy and mitochondrial biogenesis and attenuation of oxidative stress, inflammation, and apoptosis.

Sildenafil, approved two decades ago, is the inhibitor of phosphodiesterase 5 (PDE5). First of all, it was designated for angina pectoris, but soon it showed a wonderful efficacy in erectile dysfunction (ED) and then pulmonary arterial hypertension (PAH). Due to the distribution of phosphodiesterase (PDE) in almost all organs, maybe it effects other diseases. Hence, a great number of investigations began to understand the role of PDEi in different organs. Preliminary research on sildenafil in cell culture and animal models has yielded promising results. Soon, a greater number of animal researches and clinical trials joined them. The results disclosed sildenafil can have beneficial effects in each organ such as heart, liver, kidney, brain, and intestines. Furthermore, it has significantly improved the prognosis of organ ischemia in various animal models. Clinical trials in several diseases, such as recurrent spontaneous miscarriage, fatty liver disease, bronchopulmonary dysplasia (BPD), heart failure, and premature ejaculation (PE) brought promising results. Although some clinical trials are available on the effects of sildenafil on various diseases, further studies on humans are needed to consolidate the ultimate effects of sildenafil. The aim of this review was to describe the effects of sildenafil on each organ and explain its mechanisms of action. Further, other PDE inhibitors such as tadalafil and vardenafil have been briefly discussed in parts of this review.