ABSTRACT
Type 2 diabetes mellitus (T2DM) is an immensely debilitating chronic disease that progressively undermines the well-being of various bodily organs and, indeed, most patients succumb to the disease due to post-T2DM complications. Although there is evidence supporting the activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway by insulin, which is essential in regulating glucose metabolism and insulin resistance, the significance of this pathway in T2DM has only been explored in a few studies. The current review aims to unravel the mechanisms by which different classes of PI3Ks control the metabolism of glucose; and also to discuss the original data obtained from international research laboratories on this topic. We also summarized the role of the PI3K/Akt signaling axis in target tissues spanning from the skeletal muscle to the adipose tissue and liver. Furthermore, inquiries regarding the impact of disrupting this axis on insulin function and the development of insulin resistance have been addressed. We also provide a general overview of the association of impaired PI3K/Akt signaling pathways in the pathogenesis of the most prevalent diabetes-related complications. The last section provides a special focus on the therapeutic potential of this axis by outlining the latest advances in active compounds that alleviate diabetes via modulation of the PI3K/Akt pathway. Finally, we comment on the future research aspects in which the field of T2DM therapies using PI3K modulators might be developed.
ABSTRACT
Over the past two decades, molecular targeted therapy has revolutionized the landscape of cancer treatment due to lower side effects as well as higher anticancer effects. Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor which plays a crucial role in cell proliferation and death and the efficacy of PPARγ ligands either as monotherapy or in combination with traditional chemotherapy drugs has been proved by recent studies. In this study, we aimed to investigate the effects of pioglitazone, a well-known PPARγ stimulator, in ALL-derived NALM6 cells by using trypan blue assay, MTT assay, and flow cytometry analysis. Moreover, to investigate the molecular mechanism action of pioglitazone in these cells, we assessed the possible alterations in the expression of some target genes which regulate cell proliferation, apoptosis, and autophagy system. Our result demonstrated that pioglitazone induced a remarkable antileukemic effect on NALM6 cells through a PTEN-mediated manner. Based on the fact that PI3K hyperactivation is one of the main properties of ALL cells, the effects of PI3K inhibition using CAL-101 on pioglitazone-induced cytotoxicity were evaluated by combinatorial experiments. Moreover, the result of cell cycle assay and qRT-PCR demonstrated that pioglitazone-CAL-101 induced antileukemic effect mainly through induction of p21 and p27-mediated G1 arrest. Additionally, our result showed that inhibition of proteasome and autophagy system, two main cellular processes, increased the antileukemic effects of the agents. Taken together, we suggest a novel therapeutic application for PPARγ stimulators as a single agent or in combination with PI3K inhibitors that should be clinically evaluated in ALL patients.
ABSTRACT
In the dark path of tumorigenesis, the more carefully the cancer biology is studied, the more brilliant answers could be given to the countless questions about its orchestrating derivers. The identification of the correlation between Toll-like receptors (TLRs) and different processes involved in carcinogenesis was one of the single points of blinding light highlighting the interconnection between the immune system and cancer. TLRs are a wide family of single-pass membrane-spanning receptors that have developed through the evolution to recognize the structurally conserved molecules derived from microorganisms or damaged cells. But this is not everything about these receptors as they could orchestrate several downstream signalling pathways leading to the formation or suppression of cancer cells. The present review is tempted to provide a concise schematic about the biology and the characters of TLRs and also summarize the major findings of the regulatory role of TLRs and their associated signalling in the pathogenesis of human cancers.
