Luciferase-Based Reporter System for Investigating GPx4-Mediated Ferroptosis and Its Therapeutic Implications in Diabetes.

Ferroptosis, a distinct form of regulated cell death, is characterized by iron-dependent lipid peroxide accumulation in cell membranes from dysregulated cellular iron homeostasis and compromised antioxidant defense mechanisms. Glutathione peroxidase 4 (GPx4) is crucial in the regulation of ferroptosis by controlling lipid peroxide accumulation. Recent research established the association of ferroptosis with several diseases, prompting investigation toward ferroptosis-targeted therapeutic approaches.

Sodium-Glucose Cotransporter-2 Inhibitor Suppresses Endoplasmic Reticulum Stress and Oxidative Stress in Diabetic Nephropathy Through Nrf2 Signaling: A Clinical and Experimental Study.

Diabetic nephropathy (DN), a severe complication of type 2 diabetes mellitus (T2DM), is marked by heightened endoplasmic reticulum stress (ERS) and oxidative stress (OS) due to protein misfolding and free radical generation. We investigated the sodium-glucose co-transporter-2 inhibitor (SGLT2i), canagliflozin (Cana), in alleviating ERS and OS in DN patients and THP-1 cells under hyperglycemic condition. A total of 120 subjects were divided into four groups, with 30 subjects in each group: healthy controls, T2DM individuals, DN patients receiving standard treatment, and those treated with Cana.

Pterostilbene accelerates wound healing response in diabetic mice through Nrf2 regulation.

Pterostilbene (PTS), known for its diverse beneficial effects via Nuclear factor erythroid-2 related factor (Nrf2) activation, holds potential for Diabetic Foot Ulcer (DFU) treatment. However, PTS-mediated Nrf2 regulation in diabetic wounds has yet to be elucidated. We used IC21 macrophage-conditioned media to simulate complex events that can influence the fibroblast phenotype using L929 cells during the wound healing process under a hyperglycemic microenvironment.

Pterostilbene attenuates hemin-induced dysregulation of macrophage M2 polarization via Nrf2 activation in experimental hyperglycemia.

Macrophages exhibit a high degree of plasticity that is physiologically relevant in wound healing, and disruption in normal macrophage response leads to delayed wound closure resulting in chronic wounds. Here, we attempt to discern macrophage responses to hemin via regulation of the nuclear factor-erythroid factor 2-related factor 2 (Nrf2) that could help us better understand the pathophysiology of diabetic foot ulcers (DFU). We demonstrate the alleviation of hemin-mediated Nrf2 suppression and M2 macrophage polarization by pterostilbene (PTS), a proven Nrf2 activator.

Nrf2 driven macrophage responses in diverse pathophysiological contexts: Disparate pieces from a shared molecular puzzle.

The wide anatomical distribution of macrophages and their vast array of functions match various polarization states and their involvement in homeostasis and disease. The confluence of different cellular signaling networks, including direct involvement in inflammation, at the doorstep of the transcription factor Nuclear Factor- erythroid (NF-E2) p45-related factor 2 (Nrf2) activation raises the importance of deciphering the molecular circuitry at the background of multiple-discrete and antagonistic yet flexible and contextual pathways. While we primarily focus on wound healing and repair mechanisms that are affected in diabetic foot ulcers (DFUs), we strive to explore the striking similarities and differences in molecular events including inflammation, angiogenesis, and fibrosis during tissue injury and wound persistence that accumulates pro-inflammatory senescent macrophages, as a means to identify possible targets or cellular mediators to lessen DFU disease burden.

Dysregulation of Nrf2 redox pathway in macrophages under diabetic microenvironment.

In the present study, we characterized the aberration in Nrf2 signaling in macrophages under a hyperglycemic microenvironment that reflects diabetic wounds in vitro and studied the effect of an Nrf2 activator pterostilbene (PTS) in these experimental conditions. Macrophages were exposed to pro-inflammatory cytokines TNFα and IFNγ with (HG+) or without high glucose (NG+) followed by the treatment with or without PTS. Western blotting was undertaken to assess the Nrf2 translocation from cytosol to nucleus followed by its downstream and upstream mediators, heme oxygenase-1 and Akt, respectively, the latter via phosphorylation.

Metabolic reprogramming and immune regulation in viral diseases.

The recent outbreak and transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide and the ensuing coronavirus disease 2019 (COVID-19) pandemic has left us scrambling for ways to contain the disease and develop vaccines that are safe and effective. Equally important, understanding the impact of the virus on the host system in convalescent patients, healthy otherwise or with co-morbidities, is expected to aid in developing effective strategies in the management of patients afflicted with the disease. Viruses possess the uncanny ability to redirect host metabolism to serve their needs and also limit host immune response to ensure their survival.

Crosstalk between endoplasmic reticulum stress and oxidative stress in the progression of diabetic nephropathy.

Increasing evidence in substantiating the roles of endoplasmic reticulum stress, oxidative stress, and inflammatory responses and their interplay is evident in various diseases. However, an in-depth mechanistic understanding of the crosstalk between the intracellular stress signaling pathways and inflammatory responses and their participation in disease progression has not yet been explored. Progress has been made in our understanding of the cross talk and integrated stress signaling network between endoplasmic reticulum stress and oxidative stress towards the pathogenesis of diabetic nephropathy.

Macrophage mediation in normal and diabetic wound healing responses.

Purpose: The failure in timely healing of wounds is a central feature in chronic wounds that leads to physiological, psychological and economic burdens. Macrophages have been demonstrated to have various functions in wounds including host defense, the promotion and resolution of inflammation, the removal of apoptotic cells and tissue restoration following injury. Accumulated evidence suggests that macrophage dysfunction is a component of the pathogenesis of non-healing wounds.