Is the new angel better than the old devil? Challenges and opportunities in CD47- SIRPα-based cancer therapy.

The efficacy of immunotherapies is limited due to the impenetrable nature of the tumor microenvironment (TME). The TME of many tumors is immune-privileged, thus allowing them to evade host immunosurveillance. One mechanism through which this occurs is via the overexpression of CD47, a 'don't eat me' protein that can interact with SIRPα on myeloid cells to suppress their phagocytic action. In recent times, many studies are focusing on CD47-SIRPα-dependent immunotherapies to incite a 'seek and eat' interaction between phagocytes and tumors. Thus, in this review, we highlight the basic molecular properties and mechanisms of CD47-SIRPα cascade. In addition, we discuss the major challenges and potential remedies associated with CD47-SIRPα-based immunotherapies.

Direct Keap1-kelch inhibitors as potential drug candidates for oxidative stress-orchestrated diseases: A review on In silico perspective.

The recent outcry in the search for direct keap1 inhibitors requires a quicker and more effective drug discovery process which is an inherent property of the Computer Aided Drug Discovery (CADD) to bring drug candidates into the clinic for patient's use. This Keap1 (negative regulator of ARE master activator) is emerging as a therapeutic strategy to combat oxidative stress-orchestrated diseases. The advances in computer algorithm and compound databases require that we highlight the functionalities that this technology possesses that can be exploited to target Keap1-Nrf2 PPI. Therefore, in this review, we uncover the in silico approaches that had been exploited towards the identification of keap1 inhibition in the light of appropriate fitting with relevant amino acid residues, we found 3 and 16 other compounds that perfectly fit keap1 kelch pocket/domain. Our goal is to harness the parameters that could orchestrate keap1 surface druggability by utilizing hotspot regions for virtual fragment screening and identification of hotspot residues.

Neurotrophic, anti-neuroinflammatory, and redox balance mechanisms of chalcones.

The passage of time that evoke aging; the tilted redox balance that contribute oxidative entropy; the polarization of microglia cells that produce inflammatory phenotype; all represent the intricacies of CNS-dependent disease progression. Neurological diseases that result from CNS injury raise social concerns and the available therapeutic strategies are frustrated by low efficacy, high toxicity, and multiple side effects. However, emergent studies have shown the neuroprotective role of natural compounds - including chalcones - with high efficacy in the protection of CNS structures. These compounds reportedly demonstrate neurotrophic mechanism through the upregulation of neurotrophic factors, anti-apoptotic Bcl-2, and downregulation of Bax protein; anti-neuroinflammatory mechanism via the inhibition of neuroinflammatory pathways, attenuated secretion of pro-inflammatory cytokines, prevention of blood brain barrier (BBB) disruption, and protection against nerve senescence; antioxidant mechanism through the upregulation of Nrf2 activities, inhibition of Keap1, synthesis of antioxidant enzymes, and maintenance of high antioxidant/oxidant ratio. All these mechanisms represent chalcones' neuroprotective mechanisms. In this review, we highlight different pathways involved in CNS-related diseases and elucidate various mechanisms by which chalcones can perturb these shunts as a potential therapeutic modality.

AMPK allostery: A therapeutic target for the management/treatment of diabetic nephropathy.

Diabetic nephropathy (DN) is a chronic complication of diabetes mellitus (DM) with approximately 30-40% of patients with DM developing nephropathy, and it is the leading cause of end-stage renal diseases and diabetic morbidity. The pathogenesis of DN is primarily associated with irregularities in the metabolism of glucose and lipid leading to hyperglycemia-induced oxidative stress, which has been a major target together with blood pressure regulation in the control of DN progression. However, the regulation of 5' adenosine monophosphate-activated protein kinase (AMPK), a highly conserved protein kinase for maintaining energy balance and cellular growth and repair has been implicated in the development of DM and its complications. Therefore, targeting AMPK pathway has been explored as a therapeutic strategy for the treatment of diabetes and its complication, although most of the mechanisms have not been fully elucidated. In this review, we discuss the structure of AMPK relevant to understanding its allosteric regulation and its role in the pathogenesis and progression of DN. We also identify therapeutic agents that modulate AMPK and its downstream targets with their specific mechanisms of action in the treatment of DN.