We examined whether endoplasmic reticulum (ER) stress-induced autophagy provides cytoprotection from renal tubular epithelial cell injury due to oxidants and chemical hypoxia in vitro, as well as from ischemia-reperfusion (IR) injury in vivo. We demonstrate that the ER stress inducer tunicamycin triggers an unfolded protein response, upregulates ER chaperone Grp78, and activates the autophagy pathway in renal tubular epithelial cells in culture. Inhibition of ER stress-induced autophagy accelerated caspase–3 activation and cell death suggesting a pro-survival role of ER stress-induced autophagy. Compared to wild-type cells, autophagy-deficient MEFs subjected to ER stress had enhanced caspase–3 activation and cell death, a finding that further supports the cytoprotective role of ER stress-induced autophagy. Induction of autophagy by ER stress markedly afforded cytoprotection from oxidants H2O2 and tert-Butyl hydroperoxide and from chemical hypoxia induced by antimycin A. In contrast, inhibition of ER stress-induced autophagy or autophagy-deficient cells markedly enhanced cell death in response to oxidant injury and chemical hypoxia. In mouse kidney, similarly to renal epithelial cells in culture, tunicamycin triggered ER stress, markedly upregulated Grp78, and activated autophagy without impairing the autophagic flux. In addition, ER stress-induced autophagy markedly ameliorated renal IR injury as evident from significant improvement in renal function and histology. Inhibition of autophagy by chloroquine markedly increased renal IR injury. These studies highlight beneficial impact of ER stress-induced autophagy in renal ischemia-reperfusion injury both in vitro and in vivo.

Cdc42 is a member of the Rho subfamily of Ras-related proteins, which were among the first oncogenic proteins to be identified as playing a significant role in a variety of cellular events [Barbacaid, 1987, Ann. Rev. Biochem]. Equally important, Protein-Protein Interactions [PPIs] involving Cdc42 continue to highlight the role of Ras-related proteins' relevance to cancer. As these proteins have been considered incapable of being "druggable", due to a perceived lack of binding surface [s] that are amenable to small molecule targeting, there remains limited development of therapies to tackle diseased states caused by Cdc42-stimulated hyperactivity. Thusly, it has become important to characterize molecular details, including dynamics, of PPIs involving Cdc42 that may lend themselves as potential targets for therapeutic approaches. Recently, two small molecules, ZCL278 and AZA197, have shown promise in directly targeting Cdc42 to influence PPIs that are capable of causing Cdc42-stimulated abnormal signaling. In this editorial, we highlight recent studies that show case how these two small molecules may influence Cdc42-protein interactions.

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It has almost been 40 years since the Ras proteins were discovered as the first human oncogenes. They remain among the most important genes for regulating mammalian cell growth and are involved in more than a quarter of human cancers. Out of 167 members of the Ras superfamily, K-Ras mutations are the most abundant in human cancers. Particularly, the K-Ras G12C mutations are known to be involved in pancreatic, colon and lung cancers as well as leukemias. Though progress has been made, approaches that target Ras proteins for therapeutic purposes still remain challenging. In fact, no drugs treating Ras-related cancers are currently on the market. However, there is now renewed interest in the Ras area and newer approaches have highlighted the targeting of several types of tumors and treating cancer patients. In this review, we will summarize recent K-Ras drug candidates and approaches in the pre-clinical, clinical and post clinical pipelines that show promise for targeting and reducing Ras-related tumors. Macromolecules such as mRNA vaccines, siRNA, and T-cell receptors that target Ras will also be discussed. The newer molecules and the recent approaches to be discussed suggest that the “undruggable” era of Ras proteins could be coming to an end.

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in 52.8%. ARI on admission was found in 81.1%. 35.8% of patients underwent dialysis on admission and 41,5% pregressed to terminal stage of chronic kidney disease.The mean proteinuria was 3.11g / 24h +/-2.79 with extremes of 2.19 and 2.97g / 24h. nophrotic syndrom was present in 22,6% of patiens. Renal biopsy was performed in 23 cases It showed myeloma cast nephropathy in 14 patients, AL amyloidosis in 9 patients, a case of membranoproliferative glomerulonephritis (MPGN) and a case of membranous nephropathy (MN).The majority of patients received a chemotheray (80,8%), only 7 patients had a graft of hematopoietic stem cells .26,4% of cases showed a favorable renal evolution and 73,6% had a bad evolution of renal function. The mean of overal survival was 17,97. The major cause of death was infectious complications and progression of the disease. Conclusions: Renal impairement in MM is a commen complication that worsen the prognosis of the disease.Treating early and efficacy with new chemotheray drugs can stop or delay the progression and improve survival outcomes.

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