Renoprotective effect of empagliflozin in cafeteria diet-induced insulin resistance in rats: Modulation of HMGB-1/TLR-4/NF-κB axis

Al-Wakeel, Dina E; El‐Kashef, Dalia H.; Nader, Manar A.

doi:10.1016/j.lfs.2022.120633

Cited by 8 publications

(4 citation statements)

References 46 publications

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“…Remarkably, our data also indicate a direct effect of empagliflozin on endothelial cells, which goes beyond its actions merely attributable to a reduction of blood glucose 80–82 or to the offsetting of insulin resistance. 83–86 Specifically, we show that SGLT2 inhibition significantly attenuates mitochondrial Ca 2+ overload and the subsequent increase in ROS production in human endothelial cells.…”

Section: Discussionmentioning

confidence: 76%

SGLT2 Inhibition via Empagliflozin Improves Endothelial Function and Reduces Mitochondrial Oxidative Stress: Insights From Frail Hypertensive and Diabetic Patients

et al. 2022

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Background: Frailty is a multidimensional condition often diagnosed in older adults with hypertension and diabetes, and both these conditions are associated with endothelial dysfunction and oxidative stress. We investigated the functional role of the SGLT2 (sodium glucose cotransporter 2) inhibitor empagliflozin in frail diabetic and hypertensive older adults. Methods: We studied the effects of empagliflozin in consecutive hypertensive and diabetic older patients with frailty presenting at the ASL (local health unit of the Italian Ministry of Health) of Avellino, Italy, from March 2021 to January 2022. Moreover, we performed in vitro experiments in human endothelial cells to measure cell viability, permeability, mitochondrial Ca 2+ , and oxidative stress. Results: We evaluated 407 patients; 325 frail elders with diabetes successfully completed the study. We propensity-score matched 75 patients treated with empagliflozin and 75 with no empagliflozin. We observed a correlation between glycemia and Montreal Cognitive Assessment (MoCA) score and between glycemia and 5-meter gait speed (5mGS). At 3-month follow-up, we detected a significant improvement in the MoCA score and in the 5mGS in patients receiving empagliflozin compared with non-treated subjects. Mechanistically, we demonstrate that empagliflozin significantly reduces mitochondrial Ca 2+ overload and reactive oxygen species production triggered by high glucose in human endothelial cells, attenuates cellular permeability, and improves cell viability in response to oxidative stress. Conclusions: Taken together, our data indicate that empagliflozin reduces frailty in diabetic and hypertensive patients, most likely by decreasing the mitochondrial generation of reactive oxygen species in endothelial cells.

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Section: Discussionmentioning

confidence: 76%

SGLT2 Inhibition via Empagliflozin Improves Endothelial Function and Reduces Mitochondrial Oxidative Stress: Insights From Frail Hypertensive and Diabetic Patients

et al. 2022

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“…The diabetic microenvironment predisposes the vasculature to the ageing process [118] and perturbs endothelial cell, VSMC, and EPC function through activations of growth hormone/insulin-like growth factor-I and SIRT1/dimethylarginine dimthylaminohydrolase/asymmetric dimethylarginine pathways, which then systemically induce the process of vascular ageing [62,119]. Senescent cells can directly cause insulin resistance and aggravate the burden of diabetes through SASP containing MCP-1, insulin-like growth factor binding protein 3 (IGFBP-3), high mobility group box 1 (HMGB-1), IL-6, and PAI-1 [120][121][122]. The vicious cycle between age-related diabetes and vascular complications suggests that an effective therapeutic approach with senolytics and senomorphics may help preserve vascular homeostasis and extend a healthy lifespan.…”

Section: Diabetesmentioning

confidence: 99%

Vascular Ageing: Mechanisms, Risk Factors, and Treatment Strategies

Bayraktutan

2023

IJMS

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Ageing constitutes the biggest risk factor for poor health and adversely affects the integrity and function of all the cells, tissues, and organs in the human body. Vascular ageing, characterised by vascular stiffness, endothelial dysfunction, increased oxidative stress, chronic low-grade inflammation, and early-stage atherosclerosis, may trigger or exacerbate the development of age-related vascular diseases, which each year contribute to more than 3.8 million deaths in Europe alone and necessitate a better understanding of the mechanisms involved. To this end, a large number of recent preclinical and clinical studies have focused on the exponential accumulation of senescent cells in the vascular system and paid particular attention to the specific roles of senescence-associated secretory phenotype, proteostasis dysfunction, age-mediated modulation of certain microRNA (miRNAs), and the contribution of other major vascular risk factors, notably diabetes, hypertension, or smoking, to vascular ageing in the elderly. The data generated paved the way for the development of various senotherapeutic interventions, ranging from the application of synthetic or natural senolytics and senomorphics to attempt to modify lifestyle, control diet, and restrict calorie intake. However, specific guidelines, considering the severity and characteristics of vascular ageing, need to be established before widespread use of these agents. This review briefly discusses the molecular and cellular mechanisms of vascular ageing and summarises the efficacy of widely studied senotherapeutics in the context of vascular ageing.

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“…The HMGB1 signaling pathway plays a promoting role in the overwhelming factors of oxidative stress, inflammation, and angiogenesis. 14,31,32 Because glycyrrhizin is a strong inhibitor of HMGB1, 14,33 and EMP also exhibits activity that markedly reduces the levels of HMGB1, 34 the regulation of the HMGB1 signaling pathway might play a vital role in strong treatment efficacies. In the present study, the results of the mRNA and protein levels confirmed that regulating the HMGB1 signaling pathway highly involved in this treatment.…”

Section: Papermentioning

confidence: 99%

A simple but novel glycymicelle ophthalmic solution based on two approved drugs empagliflozin and glycyrrhizin: in vitro/in vivo experimental evaluation for the treatment of corneal alkali burns

Zong-jian

Zhang

Wei³

et al. 2023

Biomater. Sci.

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Renoprotective effect of empagliflozin in cafeteria diet-induced insulin resistance in rats: Modulation of HMGB-1/TLR-4/NF-κB axis

Cited by 8 publications

References 46 publications

SGLT2 Inhibition via Empagliflozin Improves Endothelial Function and Reduces Mitochondrial Oxidative Stress: Insights From Frail Hypertensive and Diabetic Patients

SGLT2 Inhibition via Empagliflozin Improves Endothelial Function and Reduces Mitochondrial Oxidative Stress: Insights From Frail Hypertensive and Diabetic Patients

Vascular Ageing: Mechanisms, Risk Factors, and Treatment Strategies

A simple but novel glycymicelle ophthalmic solution based on two approved drugs empagliflozin and glycyrrhizin: in vitro/in vivo experimental evaluation for the treatment of corneal alkali burns

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