Repositioning the Role of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) on the TRAIL to the Development of Diabetes Mellitus: An Update of Experimental and Clinical Evidence

Abstract

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF protein superfamily, represents a multifaceted cytokine with unique biological features including both proapoptotic and pro-survival effects in different cell types depending on receptor interactions and local stimuli. Beyond its extensively studied anti-tumor and immunomodulatory properties, a growing body of experimental and clinical evidence over the past two decades suggests a protective role of TRAIL in the development of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus. This evidence can be briefly summarized by the following observations: (i) acceleration and exacerbation of T1DM and T2DM by TRAIL blockade or genetic deficiency in animal models, (ii) prevention and amelioration of T1DM and T2DM with recombinant TRAIL treatment or systemic TRAIL gene delivery in animal models, (iii) significantly reduced circulating soluble TRAIL levels in patients with T1DM and T2DM both at disease onset and in more advanced stages of diabetes-related complications such as cardiovascular disease and diabetic nephropathy, (iv) increase of serum TRAIL levels in diabetic patients after initiation of antidiabetic treatment and metabolic improvement. To explore the underlying mechanisms and provide mechanistic links between TRAIL and diabetes, a number of animal and in vitro studies have reported direct effects of TRAIL on several tissues involved in diabetes pathophysiology such as pancreatic islets, skeletal muscle, adipose tissue, liver, kidney, and immune and vascular cells. Residual controversy remains regarding the effects of TRAIL on adipose tissue homeostasis. Although the existing evidence is encouraging and paves the way for investigating TRAIL-related interventions in diabetic patients with cardiometabolic abnormalities, caution is warranted in the extrapolation of animal and in vitro data to the clinical setting, and further research in humans is imperative in order to uncover all aspects of the TRAIL-diabetes relationship and delineate its therapeutic implications in metabolic disease.

Thymoquinone Alterations of the Apoptotic Gene Expressions and Cell Cycle Arrest in Genetically Distinct Triple-Negative Breast Cancer Cells

“…However, our hypothesis urges further investigation and could be a valuable therapeutic target for TNBC patients. TRAF2 mediates apoptosis in breast, cervical, and lung cancer cells by stabilizing the caspase-2 dimer complex and enhancing its activity to fully commit the cell to death, according to prior research [ 109 , 110 ]. In this study, TQ’s overexpression of these two negative regulator proteins may play a role in the apoptotic effects of TQ and could be a useful therapeutic target for TNBC patients.…”

Do Intestinal Unicellular Parasites Have a Role in the Inflammatory and Redox Status among the Severely Obese?

“…The most remarkable feature of these cells is the phenotypic switch of the macrophage towards a pro-inflammatory (M1) profile, which unbalances the physiological M1/M2 ratio [ 6 , 7 , 8 ]. This enhances the insulin resistance phenomenon and promotes metabolically unhealthy obesity [ 9 , 10 , 11 ]. Some studies suggest that gut dysbiosis can start the macrophage phenotypic polarization by augmenting the release of lipopolysaccharides that are derived from Gram-negative bacteria of the dysbiotic intestinal ecosystem [ 12 , 13 ], coupled to the increased intestinal barrier permeability that is associated with obesity [ 14 , 15 , 16 ].…”

Partial Synthetic PPARƳ Derivative Ameliorates Aorta Injury in Experimental Diabetic Rats Mediated by Activation of miR-126-5p Pi3k/AKT/PDK 1/mTOR Expression

“…It has been reported in individuals with T2D exposed to high-fat meals that protein, lipid, and carbohydrate load was connected to increased ROS generation and impaired endothelium-dependent vasodilation [ 54 ], lowering the endothelial function [ 55 , 56 ]. The activation of vascular endothelial cells results in the release of pro-inflammatory adhesion molecules such as Intracellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Protein 1 (VCAM-1), and E-selectin expression [ 57 ], as well as an increase in pro-inflammatory cytokines such as tumor necrosis factor-, interleukins, and platelet-derived growth factor [ 58 ]. The simultaneous activation of dual alpha and gamma PPARs agonists may provide superior glucose and lipid regulation compared to single subtype-selective drugs [ 59 , 60 ].…”