Effects of Hypericin on Cultured Primary Normal Human Dermal Fibroblasts Under Increased Oxidative Stress.

INTRODUCTION: Wound healing is a dynamic process that begins with inflammation, proliferation, and cell migration of a variety of fibroblast cells. As a result, identifying possible compounds that may improve fibroblast cell wound healing capacity is crucial. Hypericin is a natural quinine that has been reported to possess a wide range of pharmacological profiles, including antioxidant and anti-inflammatory, activities. Herein we examined for the first time the effect of hypericin on normal human dermal fibroblasts (NHDFs) under oxidative stress. METHODS: NHDF were exposed to different concentrations of hypericin (0-20 µg/mL) for 24 h. For the oxidative stress evaluation, H2O2 was used as a stressor factor. Cell viability and proliferation levels were evaluated. Immunohistochemistry and flow cytometry were performed to assess cell apoptosis levels and with confocal microscopy we identified the mitochondrial superoxide production under oxidative stress and after the treatment with hypericin. Scratch assay was performed under oxidative stress to evaluate the efficacy of hypericin in wound closure. To gain an insight into the molecular mechanisms of hypericin bioactivity, we analyzed the relative expression levels of genes involved in oxidative response and in wound healing process. RESULTS: We found that the exposure of NHDF to hypericin under oxidative stress resulted in an increase in cell viability and ATP levels. We found a decrease in apoptosis and mitochondrial superoxide levels after treatment with hypericin. Moreover, treatment with hypericin reduced wound area and promoted wound closure. The levels of selected genes showed that hypericin upregulated the levels of antioxidants genes. Moreover, treatment with hypericin in wound under oxidative stress downregulated the levels of proinflammatory cytokines, and metalloproteinases; and upregulated transcription factors and extracellular matrix genes. CONCLUSION: These findings indicated that hypericin possesses significant in vitro antioxidant activity on NHDF and provide new insights into its potential beneficial role in the management of diabetic ulcers.

COVID-19 Outcomes and Diabetes Mellitus: A Comprehensive Multicenter Prospective Cohort Study.

The link between type 2 diabetes (T2D) and the severe outcomes of COVID-19 has raised concerns about the optimal management of patients with T2D. This study aimed to investigate the clinical characteristics and outcomes of T2D patients hospitalized with COVID-19 and explore the potential associations between chronic T2D treatments and adverse outcomes. This was a multicenter prospective cohort study of T2D patients hospitalized with COVID-19 in Greece during the third wave of the pandemic (February-June 2021). Among the 354 T2D patients included in this study, 63 (18.6%) died during hospitalization, and 16.4% required ICU admission. The use of DPP4 inhibitors for the chronic management of T2D was associated with an increased risk of in-hospital death (adjusted odds ratio (adj. OR) 2.639, 95% confidence interval (CI) 1.148-6.068, p = 0.022), ICU admission (adj. OR = 2.524, 95% CI: 1.217-5.232, p = 0.013), and progression to ARDS (adj. OR = 2.507, 95% CI: 1.278-4.916, p = 0.007). Furthermore, the use of DPP4 inhibitors was significantly associated with an increased risk of thromboembolic events (adjusted OR of 2.249, 95% CI: 1.073-4.713, p = 0.032) during hospitalization. These findings highlight the importance of considering the potential impact of chronic T2D treatment regiments on COVID-19 and the need for further studies to elucidate the underlying mechanisms.

Effects of Advanced Glycation End Products via Oxidative Stress on Beta Cells: Insights from in vitro and in vivo Studies and Update on Emerging Therapies.

BACKGROUND: Protein, lipid, and nucleic acid glycation reactions begin and continue as a result of persistent hyperglycemia in patients with diabetes mellitus. Advanced glycated end products (AGEs) are a complex group of chemical moieties that are formed as a result of the glycation process and play an important role in the pathogenesis of diabetes mellitus. When AGEs interact with their cellular receptor (RAGE), numerous signaling pathways, including nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB), c-Jun N-terminal kinase (JNK), and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), are activated, increasing oxidative stress. OBJECTIVE: The aim of this review was to summarize in vitro and in vivo studies underlining the involvement of AGEs on beta cell dysfunction and death via oxidative stress. METHODS: A literature search of publications published between 1912 and December 2022 was conducted using MEDLINE, EMBASE, and the Cochrane Library, with restrictions on articles written in English. RESULTS: Recent insights have revealed that oxidative stress has a crucial role in the development of beta cell dysfunction and insulin resistance, the major hallmarks of type 2 diabetes mellitus. Studies also revealed that AGEs decrease insulin synthesis and secretion in the pancreatic beta cells and induce cell apoptosis. CONCLUSION: Experimental data have shown that both AGEs and oxidative stress contribute to beta cell dysfunction and development as well as to the progression of diabetic complications. Many anti- AGE therapies are being developed; however, it remains to be seen whether these therapies can help maintain beta cell function and prevent diabetes complications.

Diabetes mellitus-associated vascular impairment: novel circulating biomarkers and therapeutic approaches.

It is widely accepted that diabetes mellitus (DM) impairs endothelial nitric oxide synthase activity as well as enhances the production of reactive oxygen species, thus resulting in diminished nitric oxide bioavailability and the consequent pro-atherogenetic alterations. Important biomarkers of the vasculature are related to endothelial dysfunction, to inflammatory and coagulation processes, and to oxidative stress in DM. Several therapeutic strategies might exert favorable effects on the vasculature of diabetic patients, such as insulin analogues, antihypertensive agents, statins, and hypoglycemic agents, whereas in spite of the prominent role of oxidative stress in diabetes, antioxidant therapy remains controversial. The use of specific biomarkers related to vascular function could be a useful therapeutic approach in such patients.

Left atrial function, cytokines and soluble apoptotic markers in mitral stenosis: effects of valvular replacement.

BACKGROUND: Patients with mitral stenosis (MS) and heart failure (HF) are characterized by changes in the left atrial (LA) function and activation of the apoptotic process. The purpose of the present study was the evaluation of the effect of mitral valve replacement on the LA function, on inflammatory process and apoptotic markers in patients with MS and HF. METHODS: We studied 30 patients with MS and HF (15 in NYHA III-IV and 15 in NYHA IV) in sinus rhythm (mean age 56.2 +/- 4.6 years), and 20 age and gender matched healthy volunteers. Blood samples were obtained before and 6 months after surgical mitral valve replacement, and plasma levels of soluble Fas/APO-1 receptor (sFas), tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6) were measured. Echocardiographically, LA volumes were measured at mitral valve opening (Vmax), at the onset of left atrial systole (P wave of the electrocardiogram, Vp) and at the mitral valve closure (Vmin). LA contractile function was assessed by the LA active emptying fraction (ACTEF). RESULTS: After mitral valve replacement, TNF-a, IL-6 and sFas levels, as well as the Vmax LA volume, were significantly reduced (p < 0.05). ACTEF showed a significant postoperative decrease (0.29 +/- 0.09 vs. 0.23 +/- 0.06, p < 0.01) and it was significantly correlated with sFas (r = -0.88, p = 0.001), TNF-a (r = -0.81, p = 0.001) and IL-6 (r = -0.74, p = 0.001) levels. CONCLUSION: The present findings indicate that mitral valve replacement in patients with mitral valve stenosis, reduces the size of the left atrium, improves left atrial contractile function and depresses inflammatory and apoptotic process.