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.

OBJECTIVE: To assess whether the sodium–glucose cotransporter 2 (SGLT2) inhibitor empagliflozin improves cognitive impairment in frail older adults with diabetes and heart failure with preserved ejection fraction (HFpEF). RESEARCH DESIGN AND METHODS: We designed a prospective study to assess cognitive and physical function in consecutive frail older adults with diabetes and HFpEF, comparing the effects of empagliflozin, metformin, and insulin. RESULTS: A total of 162 frail older adults with HFpEF and diabetes successfully completed the study. Montreal Cognitive Assessment scores at baseline and after 1 month were 19.80 ± 3.77 vs. 22.25 ± 3.27 (P < 0.001) in the empagliflozin group, 19.95 ± 3.81 vs. 20.71 ± 3.56 (P = 0.26) in the metformin group, and 19.00 ± 3.71 vs. 19.1 ± 3.56 (P = 0.81) in the insulin group. A multivariable regression analysis confirmed the beneficial effects of empagliflozin. Additionally, we observed a marked amelioration of physical impairment, assessed by the 5-m gait speed test, in the empagliflozin and metformin groups but not in the insulin group. CONCLUSIONS: This study is the first to show significant beneficial effects of the SGLT2 inhibitor empagliflozin on cognitive and physical impairment in frail older adults with diabetes and HFpEF.

Chronic Kidney Disease (CKD) is a debilitating disease associated with several secondary complications that increase comorbidity and mortality. In patients with CKD, there is a significant qualitative and quantitative alteration in the gut microbiota, which, consequently, also leads to reduced production of beneficial bacterial metabolites, such as short-chain fatty acids. Evidence supports the beneficial effects of short-chain fatty acids in modulating inflammation and oxidative stress, which are implicated in CKD pathogenesis and progression. Therefore, this review will provide an overview of the current knowledge, based on pre-clinical and clinical evidence, on the effect of SCFAs on CKD-associated inflammation and oxidative stress.

Mitochondria serve an essential metabolic and energetic role in cellular activity, and their dysfunction has been implicated in a wide range of disorders, including cardiovascular conditions, neurodegenerative disorders, and metabolic syndromes. Mitochondria-targeted therapies, such as Elamipretide (SS-31, MTP-131, Bendavia), have consequently emerged as a topic of scientific and clinical interest. Elamipretide has a unique structure allowing for uptake in a variety of cell types and highly selective mitochondrial targeting. This mitochondria-targeting tetrapeptide selectively binds cardiolipin (CL), a lipid found in the inner mitochondrial membrane, thus stabilizing mitochondrial cristae structure, reducing oxidative stress, and enhancing adenosine triphosphate (ATP) production. Preclinical studies have demonstrated the protective and restorative efficacy of Elamipretide in models of heart failure, neurodegeneration, ischemia–reperfusion injury, metabolic syndromes, and muscle atrophy and weakness. Clinical trials such as PROGRESS-HF, TAZPOWER, MMPOWER-3, and ReCLAIM elaborate on preclinical findings and highlight the significant therapeutic potential of Elamipretide. Further research may expand its application to other diseases involving mitochondrial dysfunction as well as investigate long-term efficacy and safety of the drug. The following review synthesizes current knowledge of the structure, mechanisms of action, and the promising therapeutic role of Elamipretide in stabilizing mitochondrial fitness, improving mitochondrial bioenergetics, and minimizing oxidative stress.

Endothelial dysfunction represents a key mechanism underlying heart failure with preserved ejection fraction (HFpEF), diabetes mellitus (DM), and frailty. However, reliable biomarkers to monitor endothelial dysfunction in these patients are lacking. In this study, we evaluated the expression of a panel of circulating microRNAs (miRs) involved in the regulation of endothelial function in a population of frail older adults with HFpEF and DM treated for 3 months with empagliflozin, metformin, or insulin. We identified a distinctive pattern of miRs that were significantly regulated in HFpEF patients compared to healthy controls and to HFpEF patients treated with the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin. Three miRs were significantly downregulated (miR-126, miR-342-3p, and miR-638) and two were significantly upregulated (miR-21 and miR-92) in HFpEF patients compared to healthy controls. Strikingly, two of these miRs (miR-21 and miR-92) were significantly reduced in HFpEF patients after the 3-month treatment with empagliflozin, whereas no significant differences in the profile of endothelial miRs were detected in patients treated with metformin or insulin. Taken together, our findings demonstrate for the first time that specific circulating miRs involved in the regulation of endothelial function are significantly regulated in frail HFpEF patients with DM and in response to SGLT2 inhibition. SIGNIFICANCE STATEMENT We have identified a novel microRNA signature functionally involved in the regulation of endothelial function that is significantly regulated in frail patients with HFpEF and diabetes. Moreover, the treatment with the SGLT2 inhibitor empagliflozin caused a modification of some of these microRNAs in a direction that was opposite to what observed in HFpEF patients, indicating a rescue of endothelial function. Our findings are relevant for clinical practice inasmuch as we were able to establish novel biomarkers of disease and response to therapy.

Bromelain is a mixture of proteolytic enzymes primarily extracted from the fruit and stem of the pineapple plant (Ananas comosus). It has a long history of traditional medicinal use in various cultures, particularly in Central and South America, where pineapple is native. This systematic review will delve into the history, structure, chemical properties, and medical indications of bromelain. Bromelain was first isolated and described in the late 19th century by researchers in Europe, who identified its proteolytic properties. Since then, bromelain has gained recognition in both traditional and modern medicine for its potential therapeutic effects.