Exploring the Therapeutic Potential of Bromelain: Applications, Benefits, and Mechanisms.

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.

Dysfunctional mitochondria elicit bioenergetic decline in the aged heart.

Aging represents a complex biological progression affecting the entire body, marked by a gradual decline in tissue function, rendering organs more susceptible to stress and diseases. The human heart holds significant importance in this context, as its aging process poses life-threatening risks. It entails macroscopic morphological shifts and biochemical changes that collectively contribute to diminished cardiac function. Among the numerous pivotal factors in aging, mitochondria play a critical role, intersecting with various molecular pathways and housing several aging-related agents. In this comprehensive review, we provide an updated overview of the functional role of mitochondria in cardiac aging.

Prediabetes Increases the Risk of Frailty in Prefrail Older Adults With Hypertension: Beneficial Effects of Metformin.

BACKGROUND: Prediabetes has garnered increasing attention due to its association with cardiovascular conditions, especially hypertension, which heightens the risk of prefrailty and frailty among older individuals. METHODS: We screened elders with prefrail hypertension from March 2021 to January 2023. We assessed the correlation linking cognitive dysfunction (Montreal Cognitive Assessment score), insulin resistance (triglyceride-to-glucose index), and physical impairment (5-meter gait speed). Then, we measured the risk of developing frailty after a 1-year follow-up period, adjusting the outcome using multivariable Cox regression analysis. We also investigated the impact of administering 500 mg of metformin once daily to a subset of frail subjects for an additional 6 months. RESULTS: We assessed the relationship between the triglyceride-to-glucose index and the Montreal Cognitive Assessment score, observing a significant correlation (r, 0.880; P<0.0001). Similarly, we analyzed the association between the triglyceride-to-glucose index and 5-meter gait speed, uncovering a significant link between insulin resistance and physical impairment (r, 0.809; P<0.0001). Prediabetes was found to significantly (P<0.0001) elevate the risk of frailty development compared with individuals without prediabetes by the end of the 1-year follow-up, a finding confirmed via multivariable analysis with Cox regression. Furthermore, among the subgroup of subjects who developed frailty, those who received metformin exhibited a significant decrease in frailty levels (P<0.0001). CONCLUSIONS: Insulin resistance and prediabetes play substantial roles in the development of cognitive and physical impairments, highlighting their importance in managing hypertension, even before the onset of frank diabetes. Metformin, a well-established drug for the treatment of diabetes, has shown favorable effects in mitigating frailty.

Frail hypertensive older adults with prediabetes and chronic kidney disease: insights on organ damage and cognitive performance - preliminary results from the CARYATID study.

BACKGROUND: Hypertension and chronic kidney disease (CKD) pose significant public health challenges, sharing intertwined pathophysiological mechanisms. Prediabetes is recognized as a precursor to diabetes and is often accompanied by cardiovascular comorbidities such as hypertension, elevating the risk of pre-frailty and frailty. Albuminuria is a hallmark of organ damage in hypertension amplifying the risk of pre-frailty, frailty, and cognitive decline in older adults. We explored the association between albuminuria and cognitive impairment in frail older adults with prediabetes and CKD, assessing cognitive levels based on estimated glomerular filtration rate (eGFR). METHODS: We conducted a study involving consecutive frail older patients with hypertension recruited from March 2021 to March 2023 at the ASL (local health unit of the Italian Ministry of Health) of Avellino, Italy, followed up after three months. Inclusion criteria comprised age over 65 years, prior diagnosis of hypertension without secondary causes, prediabetes, frailty status, Montreal Cognitive Assessment (MoCA) score < 26, and CKD with eGFR > 15 ml/min. RESULTS: 237 patients completed the study. We examined the association between albuminuria and MoCA Score, revealing a significant inverse correlation (r: 0.8846; p < 0.0001). Subsequently, we compared MoCA Score based on eGFR, observing a significant difference (p < 0.0001). These findings were further supported by a multivariable regression analysis, with albuminuria as the dependent variable. CONCLUSIONS: Our study represents the pioneering effort to establish a significant correlation between albuminuria and eGFR with cognitive function in frail hypertensive older adults afflicted with prediabetes and CKD.

The interplay between sodium/glucose cotransporter type 2 and mitochondrial ionic environment.

Mitochondrial volume is maintained through the permeability of the inner mitochondrial membrane by a specific aquaporin and the osmotic balance between the mitochondrial matrix and cellular cytoplasm. Various electrolytes, such as calcium and hydrogen ions, potassium, and sodium, as well as other osmotic substances, affect the swelling of mitochondria. Intracellular glucose levels may also affect mitochondrial swelling, although the relationship between mitochondrial ion homeostasis and intracellular glucose is poorly understood. This article reviews what is currently known about how the Sodium-Glucose transporter (SGLT) may impact mitochondrial sodium (Na+) homeostasis. SGLTs regulate intracellular glucose and sodium levels and, therefore, interfere with mitochondrial ion homeostasis because mitochondrial Na+ is closely linked to cytoplasmic calcium and sodium dynamics. Recently, a large amount of data has been available on the effects of SGLT2 inhibitors on mitochondria in different cell types, including renal proximal tubule cells, endothelial cells, mesangial cells, podocytes, neuronal cells, and cardiac cells. The current evidence suggests that SGLT inhibitors (SGLTi) may affect mitochondrial dynamics regarding intracellular Sodium and hydrogen ions. Although the regulation of mitochondrial ion channels by SGLTs is still in its infancy, the evidence accumulated thus far of the effect of SGLTi on mitochondrial functions certainly will foster further research in this direction.

Endothelial Extracellular Vesicles Enriched in microRNA-34a Predict New-Onset Diabetes in Coronavirus Disease 2019 (COVID-19) Patients: Novel Insights for Long COVID Metabolic Sequelae.

Emerging evidence indicates that the relationship between coronavirus disease 2019 (COVID-19) and diabetes is 2-fold: 1) it is known that the presence of diabetes and other metabolic alterations poses a considerably high risk to develop a severe COVID-19; 2) patients who survived a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have an increased risk of developing new-onset diabetes. However, the mechanisms underlying this association are mostly unknown, and there are no reliable biomarkers to predict the development of new-onset diabetes. In the present study, we demonstrate that a specific microRNA (miR-34a) contained in circulating extracellular vesicles released by endothelial cells reliably predicts the risk of developing new-onset diabetes in COVID-19. This association was independent of age, sex, body mass index (BMI), hypertension, dyslipidemia, smoking status, and D-dimer. SIGNIFICANCE STATEMENT: We demonstrate for the first time that a specific microRNA (miR-34a) contained in circulating extracellular vesicles released by endothelial cells is able to reliably predict the risk of developing diabetes after having contracted coronavirus disease 2019 (COVID-19). This association was independent of age, sex, body mass index (BMI), hypertension, dyslipidemia, smoking status, and D-dimer. Our findings are also relevant when considering the emerging importance of post-acute sequelae of COVID-19, with systemic manifestations observed even months after viral negativization (long COVID).

Leukocytes and Endothelial Cells Participate in the Pathogenesis of Alzheimer's Disease: Identifying New Biomarkers Mirroring Metabolic Alterations.

Alzheimer's disease (AD) is a neurodegenerative disorder marked by amyloid-ß accumulation, tau dysfunction, and neuroinflammation, involving endothelial cells and leukocytes. The breakdown of the blood-brain barrier allows immune cell infiltration, intensifying inflammation. A decreased ratio of Connexin-37 (Cx37, also known as GJA4: Gap Junction Protein Alpha 4) and Prolyl Hydroxylase Domain-Containing Protein 3 (PHD3, also known as EGLN3: Egl-9 Family Hypoxia Inducible Factor 3), Cx37/PHD3, consistently observed in different AD-related models, may represent a novel potential biomarker of AD, albeit the exact mechanisms underlying this phenomenon, most likely based on gap junction-mediated cellular interaction that modulate the cellular metabolite status, remain to be fully elucidated.

Ketone Bodies Rescue Mitochondrial Dysfunction Via Epigenetic Remodeling.

Ischemic cardiac disease is a major cause of mortality worldwide. However, the exact molecular processes underlying this disorder are not fully known. This study includes a comprehensive and coordinated set of in vivo and in vitro experiments using human cardiac specimens from patients with postischemic heart failure (HF) and healthy control subjects, a murine model of HF, and cellular systems. These approaches identified for the first time a specific pattern of maladaptive chromatin remodeling, namely a double methylation of histone 3 at lysine 27 and a single methylation at lysine 36 (H3_K27me2K36me1) consistently induced by ischemic injury in all these settings: human HF; murine HF; and in vitro models. Mechanistically, this work demonstrates that this histone modification mediates the ischemia-induced transcriptional repression of PPARG coactivator 1α (PGC1α), master regulator of mitochondrial function and biogenesis. Intriguingly, both the augmented H3_K27me2K36me1 and the mitochondrial dysfunction ensued by PGC1α down-regulation were significantly attenuated by the treatment with ß-hydroxybutyrate, the most abundant ketone body in humans, revealing a novel pathway coupling metabolism to gene expression. Taken together, these findings establish maladaptive chromatin remodeling as a key mechanism in postischemic heart injury, functionally modulated by ketone bodies.

Functional Role of Taurine in Aging and Cardiovascular Health: An Updated Overview.

Taurine, a naturally occurring sulfur-containing amino acid, has attracted significant attention in recent years due to its potential health benefits. Found in various foods and often used in energy drinks and supplements, taurine has been studied extensively to understand its impact on human physiology. Determining its exact functional roles represents a complex and multifaceted topic. We provide an overview of the scientific literature and present an analysis of the effects of taurine on various aspects of human health, focusing on aging and cardiovascular pathophysiology, but also including athletic performance, metabolic regulation, and neurological function. Additionally, our report summarizes the current recommendations for taurine intake and addresses potential safety concerns. Evidence from both human and animal studies indicates that taurine may have beneficial cardiovascular effects, including blood pressure regulation, improved cardiac fitness, and enhanced vascular health. Its mechanisms of action and antioxidant properties make it also an intriguing candidate for potential anti-aging strategies.

SGLT2 inhibitors: an evidence-based update on cardiovascular implications.

INTRODUCTION: Sodium Glucose co-Transporter 2 (SGLT2) inhibitors (also known as 'gliflozins') represent a cornerstone to treat diabetes mellitus. Moreover, recent randomized clinical trials have demonstrated important cardioprotective effects of gliflozins, independent of the presence of diabetes. Herein, we summarize the recent therapeutic progress in the cardiovascular field obtained with SGLT2 inhibitors. AREA COVERED: We critically examine the rationale and results of recent clinical studies examining the effects of SGLT2 inhibitors on cardiovascular outcomes, along with a brief overview of the main ongoing trials that have been designed in order to answer the many pending questions in the field of gliflozins and cardiovascular disease. EXPERT OPINION: The favorable results of several clinical trials have broadened the therapeutic scenario for SGLT2 inhibitors, opening, at the same time, new challenges. Additionally, recent preclinical findings have evidenced off-target effects of SGLT2 inhibitors.

Functional and Clinical Importance of SGLT2-inhibitors in Frailty: From the Kidney to the Heart.

SGLT2 (sodium-glucose cotransporter 2) enables glucose and sodium reabsorption in the kidney. SGLT2-inhibitors (also known as gliflozins, which include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) act by increasing glycosuria, thereby reducing glycemia. These drugs are critical to reach and keep glycemic control, a crucial feature, especially in patients with comorbidities, like frail individuals. Several studies evaluated the effects of SGLT2-inhibitors in different settings beyond diabetes, revealing that they are actually pleiotropic drugs. We recently evidenced the favorable effects of SGLT2-inhibition on physical and cognitive impairment in frail older adults with diabetes and hypertension. In the present overview, we summarize the latest clinical and preclinical studies exploring the main effects of SGLT2-inhibitors on kidney and heart, emphasizing their potential beneficial actions in frailty.