Search Results (1,170)

Traffic-related air pollution (TRAP) is known to contribute to oxidative stress in the central nervous system (CNS) and has been linked to increased risk of Alzheimer’s disease (AD). Alterations in the renin–angiotensin system (RAS), specifically increased angiotensin II (Ang II) signaling via the angiotensin II type 1 (AT₁) receptor, are implicated in increased oxidative stress in the CNS via activation of NADPH oxidase (NOX). As exposure to TRAP may further elevate AD risk, we investigated whether exposure to inhaled mixed gasoline and diesel vehicle emissions (MVE) promotes RAS-dependent expression of factors that contribute to AD pathophysiology in an apolipoprotein E-deficient (ApoE^−/−) mouse model. Male ApoE^−/− mice (6–8 weeks old) on a high-fat diet were treated with either an ACE inhibitor (captopril, 4 mg/kg/day) or water and exposed to filtered air (FA) or MVE (200 µg PM/m³) for 30 days. MVE exposure elevated plasma Ang II, inflammation, and oxidative stress in the hippocampus, associated with increased levels of Aph-1 homolog B (APH1B), a gamma-secretase subunit, and beta-secretase 1 (BACE1), involved in Aβ production. Each of these endpoints was normalized with ACEi treatment. These findings indicate that TRAP exposure in ApoE^−/− mice drives a RAS- and NOX-dependent oxidative and inflammatory response and shifts Aβ processing towards an amyloidogenic profile before overt Aβ deposition, suggesting a potential therapeutic approach for air pollution-induced AD risk. Full article

The circulating renin–angiotensin–aldosterone system (RAAS) plays a key role in regulating blood volume and electrolyte levels. While important for the maintenance of intravascular volume systemically, the local activation of tissue RAAS and the generation of angiotensin II contribute to inflammation and fibrosis. In the kidney, angiotensin II plays a key role in the development and progression of glomerular injury. Angiotensin-converting enzyme 2 (ACE2), an enzyme that degrades angiotensin II, is expressed in the glomerulus, focusing attention not only on the complexity of the RAAS but also identifying a potential new determinant of glomerular injury. Accordingly, we performed a narrative review using the search terms ACE2 and glomerulus in PubMed and Google Scholar to summarize the current understanding of the role of ACE2 in glomerular injury. We also discuss the role of ACE2 as a cellular receptor for SARS-CoV-2 and the potential impact of this function on glomerular injury in the setting of COVID-19. Full article

Audiovestibular disorders arising from the inner ear (e.g., hearing loss, tinnitus, vertigo) are widely prevalent in the United States. Yet, medical treatments targeting the underlying pathology of these disorders remain scarce. The practice of repurposing FDA-approved drugs for new therapeutic indications has become increasingly common, offering a lower risk route to treatment development with fewer barriers to implementation, as safety profiles are already established. The renin–angiotensin system (RAS) is well known for its role in blood pressure and fluid balance, and its overactivation induces acute and chronic inflammation and oxidative stress. This review discusses existing evidence and proposed otoprotective mechanisms of RAS inhibition, specifically using angiotensin II type 1 receptor blockers (ARBs), which support the repurposing of these medications as novel treatments to affect the inner ear pathologies that underlay hearing loss, tinnitus, and vertigo. Full article

Osteoporosis and chronic conditions such as type 2 diabetes mellitus, cardiovascular disease, heart failure, and chronic kidney disease share several common biological mechanisms, including chronic inflammation, oxidative stress, hormonal dysregulation, and metabolic alterations. In this context, multimorbidity presents an increasing clinical challenge, particularly in older populations, where osteoporosis remains frequently underdiagnosed and undertreated. This review aims to explore the complex interplay between skeletal fragility and cardiometabolic diseases, emphasizing the role of nutritional deficiencies (such as iron and vitamin C), shared molecular pathways (advanced glycation end-products, Renin–Angiotensin–Aldosterone System, RANK Ligand, RANK), and the systemic impact of chronic inflammation and tissue hypoperfusion. The review also addresses the effects of various drug classes—antidiabetics, antihypertensives, anticoagulants, and anti-osteoporotic agents—on bone metabolism and cardiovascular risk. Special focus is given to the implementation of integrated and personalized care models, particularly multidisciplinary team-based approaches, which have demonstrated significant reductions in mortality and refracture rates, despite their still limited adoption in clinical practice. In conclusion, this review highlights the shared mechanisms between osteoporosis and cardiometabolic conditions in the context of multimorbidity, underscoring persistent clinical challenges related to diagnosis, drug interactions, and care fragmentation that warrant further research into integrated care models. Full article

Objective: Current data on the association between attention-deficit/hyperactivity disorder (ADHD) and essential hypertension (EH) in pediatric populations are very limited, as most research has focused on adults. This study investigated the long-term prevalence of EH in Israeli youth aged 5–18 years with ADHD, examining also trends in antihypertensive medication use. Methods: A retrospective cohort study was conducted using data from Leumit Health Services. The ADHD cohort (N = 18,558) was compared in a 1:2 ratio to controls (N = 37,116), who were strictly matched for age, gender, birth year and quarter, socioeconomic status (SES), sectors, region, and cumulative years of LHS membership up to the index date. Diagnoses of ADHD and EH were identified using ICD-9/10 codes, depending on the year of diagnosis. Logistic regression analyses were used to assess the associations between ADHD, EH and the use of antihypertensive medications over a 20-year follow-up. Results: ADHD-diagnosed children had a higher prevalence of EH, with odds ratios (ORs) of 3.17 (95% CI: 1.46–7.16, p = 0.0017) at 5 years, 2.94 (95% CI: 1.45–6.09, p = 0.0013) at 10 years, and 1.92 (95% CI: 1.26–2.93, p = 0.0015) at 20 years. ADHD patients showed a greater use of antihypertensive medications, including calcium channel blockers (OR 1.85, 95% CI: 1.02–3.35, p = 0.035), renin angiotensin system blockers (OR 2.20, 95% CI: 1.15–4.25, p = 0.013), and diuretics (OR 1.77, 95% CI: 1.21–2.60, p = 0.0028). Conclusions: These findings highlight an association between ADHD diagnosis and EH, suggesting regular cardiovascular monitoring of children with ADHD. Further studies are needed to uncover the role of stimulant medications and shared biological and behavioral factors involved in the pathogenesis. Full article

Biventricular Takotsubo cardiomyopathy (TCM) is a rare variant characterized by involvement of both the left and right ventricles. This variant is associated with greater hemodynamic instability and longer hospital stays compared to the isolated left ventricular-only variant. We report the case of a 67-year-old female patient who underwent elective resection of a left adrenal adenoma. While her preoperative and intraoperative courses were uneventful, she developed cardiogenic shock postoperatively, necessitating prolonged intensive care unit (ICU) management and vasopressor support. Further evaluation revealed elevated high-sensitivity troponin levels and reduced ejection fraction on echocardiography (30–35%). Hypokinesis was noted in the apical and mid-ventricular segments of both ventricles. A coronary angiogram performed two months prior to admission showed no significant coronary artery disease. Based on these findings, a diagnosis of biventricular TCM was established. The patient was managed supportively and discharged in stable condition with ongoing therapy, including beta-blockers, renin–angiotensin–aldosterone system inhibitors (RAASis), and statins. Follow-up echocardiography showed resolution of regional wall motion abnormalities. Although rare, biventricular TCM is associated with increased severity and a higher risk of complications. Early recognition and timely management are essential to improve outcomes in affected patients. Full article

Sodium–glucose cotransporter 2 inhibitors (SGLT2is) have revolutionized the management of type 2 diabetes mellitus, heart failure, and chronic kidney disease (CKD), providing cardiorenal and metabolic benefits that extend beyond glycemic control. While their clinical efficacy is well established, the underlying molecular mechanisms remain only partially understood. This review focuses on current knowledge of SGLT2 expression and regulation in health and metabolic diseases, as well as transcriptional and epigenetic consequences of pharmacological SGLT2 inhibition. Human and experimental studies demonstrate that SGLT2 expression is confined to proximal tubular cells and regulated by insulin, the renin–angiotensin–aldosterone system, the sympathetic nervous system, oxidative stress, and transcriptional and epigenetic pathways. SGLT2 expression follows a biphasic pattern in metabolic disorder-associated CKD: upregulation in early phases and reduction in advanced stages. Evidence from animal models and single-cell transcriptomic studies indicates that SGLT2is normalize metabolic and inflammatory gene networks. To our knowledge, a recent single-cell RNA sequencing study provides the only currently available human dataset linking SGLT2i therapy with tubular metabolic rewiring and suppression of the energy-sensitive mechanistic target of rapamycin complex 1. Collectively, these findings support a model in which SGLT2 inhibition mitigates metabolic stress by restoring energy homeostasis across multiple nephron segments. Full article

More than 30% of diabetic patients develop dermatopathies linked to inflammation and increased vascular permeability. Considering the role of the renin–angiotensin–aldosterone system (RAAS) in diabetic complications, this study examined whether aldosterone (ALDO) and the mineralocorticoid receptor (MR) contribute to diabetes-related skin microangiopathy. Vascular permeability was measured in normoglycemic rats and insulin-dependent (streptozotocin-induced) diabetic rats. The expression of MR, 11β-hydroxysteroid dehydrogenase type 2 (HSD11β2), vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), and the tight junction protein ZO-1 was determined by PCR and immunohistochemistry. Diabetic rats received the MR antagonist eplerenone (EPL, 100 mg/kg) for 10 days. Additionally, the effects of ALDO and EPL on endothelial permeability were evaluated in human dermal microvascular endothelial cells (HMEC-1) using a Transwell system. Diabetic rats showed skin atrophy, collagen damage, elevated ALDO levels, reduced MR and HSD11β2 expression, and increased vascular permeability, along with upregulation of VEGF and vWF. EPL markedly reduced these abnormalities. In vitro, ALDO increased endothelial permeability under hyperglycemia, and EPL counteracted this effect. These findings indicate that activation of the ALDO/MR pathway promotes skin vascular permeability in diabetes through VEGF- and vWF-dependent mechanisms. MR blockade limits these changes, suggesting therapeutic potential in preventing diabetes-associated skin complications. Full article

Background/Objectives: Human serum albumin (HSA) is a major endogenous inhibitor of angiotensin-converting enzyme (ACE) and helps fine-tune the activity of the renin–angiotensin–aldosterone system (RAAS), thereby potentially influencing the development of cardiovascular (CV) diseases. As the principal transport protein for free fatty acids (FFAs), HSA may have its ACE-inhibitory capacity modified by its FFA cargo and, through this mechanism, may also affect CV disease risk. We therefore tested the hypothesis that the composition of HSA-bound FFAs determines the magnitude of endogenous ACE inhibition. Methods: We quantified endogenous ACE inhibition and examined the effect of FFA concentration on this inhibition in clinical patients (n = 161 and n = 101, respectively). We measured the effects of HSA treated with saturated, monounsaturated, and polyunsaturated FFAs, as well as FFA-free HSA, on recombinant ACE and on tissue ACE. Results: Endogenous ACE inhibition was stronger in patients with higher serum HSA concentrations (Spearman’s rho = 0.422, 95% CI 0.281–0.544, p < 0.001), whereas total FFA concentration was not associated with endogenous ACE inhibition (Spearman’s rho = 0.088, p = 0.38, n = 101). However, removal of free fatty acids substantially worsened the ACE-inhibitory effect of HSA on recombinant ACE (charcoal-treated HSA: IC₅₀ = 23.24 [19.40–29.78] g/L vs. control HSA: 7.84 [6.58–9.75] g/L, p < 0.001) and on tissue ACE isolated from lung, heart, and lymph node. FFA chain length, degree and position of unsaturation, and cis/trans configuration all differentially modulated endogenous ACE inhibition. Among saturated fatty acids, stearic acid (IC₅₀ = 7.98 [7.04–9.23] g/L), and among omega-3 and omega-6 fatty acids, α-linolenic (IC₅₀ = 5.60 [4.28–6.15] g/L) and γ-linolenic acids (IC₅₀ = 5.09 [4.28–6.15] g/L) produced the greatest enhancement of the ACE-inhibitory capacity of HSA. Conclusions: The present results indicate that HSA concentration relates to endogenous ACE inhibition in serum, and in vitro experiments demonstrate that HSA-bound FFAs can modulate HSA-mediated ACE inhibition, a mechanism that may be relevant to cardiovascular physiology and disease. Full article

Overactivation of the renin–angiotensin–aldosterone system (RAAS) promotes haemodynamic overload, inflammation, and fibrosis in the heart and kidneys. Recently, sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as a cornerstone therapy in cardiorenal protection. Emerging data indicate that adding SGLT2 inhibitors to angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, or angiotensin receptor–neprilysin inhibitors confers additional cardiorenal protection, yet their mechanistic basis and optimal clinical use in cardiovascular (CV) disease remain unclear. This review will integrate pre-clinical and clinical evidence on dual RAAS/SGLT2 modulation in CV disease, providing mechanistic insight into dual therapy. The review will finally outline priorities for future translational and outcome studies. Clinically, adding SGLT2 inhibitors to RAAS-based therapy reduces heart failure hospitalizations and slows kidney disease progression without new safety liabilities in type 2 diabetes, heart failure, and chronic kidney disease. Mechanistically, SGLT2 inhibition restores tubuloglomerular feedback and constricts the afferent arteriole; RAAS blockade dilates the efferent arteriole, and together, they lower intraglomerular pressure. Both classes also reduce oxidative stress, inflammatory signalling, and pro-fibrotic pathways, with SGLT2 inhibitors in several settings shifting RAAS balance toward the protective ACE2/angiotensin-(1–7)/Mas receptor axis. Key gaps include the scarcity of adequately powered trials designed to test combination therapy versus either component alone, limited evidence on timing and sequencing, incomplete characterization in high-risk groups, and mechanistic insight limited by study design in animal and cell models. Collectively, current data support layering SGLT2 inhibitors onto RAAS-based therapy, while definitive evidence from dedicated clinical trials is awaited. Full article

Background: Sarcopenia, which has traditionally been considered to be an exclusively geriatric syndrome, has an increased frequency within the general population and fosters interest in its complex neuromuscular, cardiovascular, and metabolic basis. The current systematic review, adopting the recognized Preferred Reporting Items for Systematic Reviews (PRISMA) methodology, seeks to highlight current evidence on the underlying mechanisms as well as approaches to sarcopenia diagnosis and management. Methods: A comprehensive search of major international databases identified studies published between January 2023 and December 2024, from which 42 articles were retained according to prespecified criteria. To further enrich the present work, eleven additional studies of high relevance were included. Results: The selected literature describes sarcopenia’s multifactorial pathophysiology, including mitochondrial dysfunction, neuromuscular junction (NMJ) degeneration, chronic inflammation, anabolic resistance, endocrine and metabolic dysregulation, altered motor-unit remodeling, and molecular alterations. Diagnostic methods focus on functional assessments, especially muscle strength and physical performance. In addition, imaging techniques and new circulating biomarkers enhance precision in specific situations. Over the years, rehabilitation has proven to be one of the most effective therapeutic approaches. Complementary strategies, ranging from nutritional optimization to pharmacologic modulation of the renin–angiotensin system, show promise in specific patient subsets. Discussion and Conclusions: As supported by the works collected within the current study, future approaches will need to consider sarcopenia as a multifactorial disease that goes beyond aging. Full article

Background/Objectives: Testicular dysfunction is a side effect of radiotherapy due to off-target damage. Germ cells are highly vulnerable. Although Sertoli and Leydig cells are more resistant, they are still affected, impairing spermatogenesis and steroidogenesis. With rising youth cancer rates, strategies to preserve fertility are crucial. Losartan (LOS) has potential to mitigate this damage. This work aimed to determine acute and late effects of radiotherapy in testicular metabolism and if LOS mitigates those effects. Methods: Male Wistar rats (n = 47, 12 weeks old) received 2.5 Gy of ionizing radiation to the scrotum (1.05 Gy/min). LOS-treated rats received 34 mg/kg twice daily before, during and after irradiation. Animals were euthanized at 2 and 60 days post-exposure, to represent acute and late effects, respectively. Reproductive organs were weighed, serum hormones assessed (ELISA), testicular mRNA expression quantified (qPCR) and oxidative stress markers, such as lipid peroxidation, protein carbonylation, and protein nitration measured (slot-blot). Metabolomic profiles were obtained via ¹H-NMR. Results: Acute irradiation reduced seminal vesicle weight, increased FSH, and decreased sperm concentration. Late effects included reduced testicular and epididymal weight, impaired sperm quality, increased protein carbonylation, and altered metabolic profiles. LOS mitigated acute weight loss but not sperm decline. Long-term, LOS improved sperm quality, reduced oxidative stress, and promoted adaptive metabolic responses. Conclusions: Irradiation-based cancer therapy causes structural and functional testicular damage and changes the testicular metabolome of rats, while LOS has the potential to be used as a radioprotector to mitigate the adverse acute and late effects of radiation on male fertility. Full article

Background/Objectives: The renin–angiotensin–aldosterone system (RAAS) is pivotal for neonatal circulation and renal adaptation; however, postnatal changes in serum renin and aldosterone immediately after birth remain unclear. This study aimed to establish postnatal changes in these hormones at birth and over the first week of life. Methods: We retrospectively analyzed 374 neonates admitted to Kobe University Hospital between October 2020 and September 2023, with serum renin and aldosterone measured on days 0 and 5 of life. Exclusion criteria were multiple congenital anomalies, severe asphyxia, major peripartum hemorrhage, and in utero exposure to angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Hormone levels were compared between term and preterm infants, and correlations with gestational age were assessed. Results: Serum renin concentrations were higher on day 0 than on day 5 (median 99.9 pg/mL [2.6–773.3] vs. 19.9 pg/mL [0.6–2304], p < 0.0001), and aldosterone concentrations similarly decreased (714 pg/mL [6.9–6334] vs. 551 pg/mL [0–11,930], p < 0.0001). At birth, renin and aldosterone levels did not differ significantly between groups. By day 5, both renin (32.8 pg/mL [0.6–2304] vs. 14.5 pg/mL [0.6–208]) and aldosterone (689 pg/mL [4–11,930] vs. 471 pg/mL [13–4697]) concentrations were significantly higher in preterm than in term neonates (p < 0.0001). Conclusions: This study describes early postnatal changes in renin and aldosterone, with higher concentrations at birth than on day 5 and persistently elevated levels in preterm infants. These findings indicate increased RAAS activity in preterm neonates and suggest a greater vulnerability to fluid, electrolyte, and blood pressure instability during early life. Full article

Vitamin D, traditionally regarded as a nutrient, is increasingly recognized as a pharmacologically active secosteroid with pleiotropic effects extending beyond calcium homeostasis and bone integrity. Together with vitamin K2, it participates in the fine-tuning of mineral metabolism and vascular health, potentially modulating cardiometabolic risk through intertwined endocrine and paracrine pathways. Despite widespread fortification and supplementation, vitamin D deficiency remains a major global health concern, driven by limited sun exposure, obesity, and metabolic dysfunction. Observational and mechanistic studies consistently link low serum 25(OH)D concentrations with hypertension, insulin resistance, heart failure, and increased cardiovascular mortality. At the molecular level, vitamin D exerts pharmacological actions—modulating the renin–angiotensin–aldosterone system, exerting anti-inflammatory and antifibrotic effects, and influencing endothelial and cardiomyocyte signaling. While experimental and epidemiological evidence suggests potential cardiovascular benefits, large randomized controlled trials (RCTs) provide conflicting results, particularly regarding hypertension and heart failure. However, these often-neutral results do not preclude a targeted action. On the contrary, clinical efficacy is strongly dependent on baseline deficiency status and the presence of metabolic cofactors. In this context, high-dose supplementation of Vitamin D, in combination with Vitamin K2 to prevent vascular calcification, elevates the supplement to a genuine pharmacological agent, with a distinct therapeutic potential for modulating cardiometabolic risk in selected patient subgroups. Emerging evidence supports the concept that vitamin D, when appropriately dosed and combined with K2, may act more as a low-potency pharmacological modulator than a simple nutritional supplement. This review synthesizes current mechanistic, observational, and interventional evidence, aiming to clarify whether vitamin D should be reclassified—from a micronutrient to a pharmacologically relevant agent—in cardiometabolic prevention and therapy, proposing a paradigm shift toward personalized and targeted dosing strategies, characteristic of precision pharmacology. Full article

The renin–angiotensin–aldosterone system (RAAS) is essential for controlling blood pressure and maintaining fluid balance, driving significant structural changes throughout the cardiovascular system, including the heart and blood vessels. As a result, the RAAS is a key therapeutic target for various chronic cardiovascular diseases, ranging from arterial hypertension (AH) to heart failure (HF). In this review, one of our objectives is to describe the new evidence over the last 4 years regarding the RAAS. Moreover, we pay attention to the structure and function of the angiotensin II type 1 receptor (AT1R) and its role in hypertension, as well as define its active site. Later, we discuss the most potent, selective inhibitors of AT1 receptors, based on in vitro and in vivo experiments, from 2020 to 2024. Large peptide molecules, small non-peptide-like molecules, and sartan derivatives are analyzed. The low IC₅₀ values of the entities that do not resemble sartans showcase the vast chemical space that can be explored for the creation of more potent antihypertensive medications. We have also employed computational chemistry tools in order to identify key molecular interactions between the compounds of the literature studied in order to elucidate the underlying reasons why these different molecules exhibit variations in their binding energies and overall potency. Full article