Search Results (639)

The role of hepatic stellate cells (HSCs) in the development of liver fibrosis and portal hypertension has already been largely clarified. Activation of HSCs might lead to self-increased proliferation and enhanced contractile activity, causing their transdifferentiation into myofibroblasts (activated HSCs), which drive the release of proinflammatory mediators, collagen, proteoglycans, and other extracellular matrix components, responsible for liver fibrosis and portal hypertension development. A possible mechanism for the pathophysiological role of HSCs in liver fibrosis might be autophagy, which breaks down the lipid droplets in quiescent HSCs, releasing fatty acids and providing the energy required for their activation into myofibroblasts. An ever-growing body of scientific evidence indicates that renin–angiotensin system (RAS) blockade can inhibit the evolution of fibrosis in patients with chronic liver diseases, and especially metabolic dysfunction-associated steatotic liver disease (MASLD), although the use of both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has not yet been officially identified as a potential fibrosis treatment. More recently, researchers have shown that overexpression of ACE2, induced by ACE inhibitor (ACEI) activity and leading to the degradation of angiotensin (ANG) II into ANG 1-7, inhibition of autophagy and consequent HSC activation, might prevent liver fibrosis development. This review aims to summarize recent pre-clinical studies and to identify a common thread underlying the latest scientific evidence in this field. Full article

Background: Hypertension and its complications are a major global health problem, and natural compounds with vasorelaxant effects are being investigated as potential antihypertensive agents. Objective: This study aimed to determine whether rosmarinic acid (RA) induces vasorelaxation in the rat thoracic aorta and to elucidate the underlying mechanisms. Methods: Isolated thoracic aortic rings, with or without endothelium, were precontracted with phenylephrine and subsequently exposed to cumulative concentrations of RA. The roles of endothelium-derived factors, potassium channels, and calcium signaling were evaluated using selective pharmacological inhibitors and activators. In addition, the involvement of the AMPK pathway, adenylate cyclase/cAMP pathway, PKC signaling, β-adrenergic receptors, muscarinic receptors, and angiotensin II in RA-induced vasorelaxation was investigated. Results: RA induced a concentration-dependent vasorelaxation in endothelium-intact thoracic aortic rings (p < 0.001; pD₂ = 7.67 ± 0.04). The vasorelaxant effect of RA was attenuated in endothelium-denuded vessels (pD2: 5.26 ± 0.18). The relaxation response was significantly attenuated by inhibitors of the PI3K/Akt/eNOS/NO/cGMP pathway and by blockers of BK_Ca, IK_Ca, and Kv potassium channels (p < 0.001). Furthermore, RA markedly inhibited both extracellular Ca²⁺ influx and intracellular Ca²⁺ release from the sarcoplasmic reticulum (p < 0.001). RA incubation also significantly reduced the contractions induced by angiotensin II (Ang II) and by the PKC activator PMA (p < 0.001). Other tested pathways had no significant influence on the vasorelaxant effect of RA (p > 0.05). Conclusions: These findings demonstrate that rosmarinic acid induces both endothelium-dependent and endothelium-independent vasorelaxation in the rat thoracic aorta through activation of the PI3K/Akt/eNOS/NO/cGMP pathway, opening of BK_Ca, IK_Ca, and Kv potassium channels, and suppression of Ca²⁺ mobilization. Additionally, inhibition of PKC- and angiotensin II-mediated vascular contraction contributes to RA-induced vasorelaxation. RA may therefore have therapeutic potential in the management of hypertension. Full article

Background: Abdominal aortic aneurysm (AAA) is a life-threatening condition with no proven pharmacological treatment to halt its progression. While animal models offer insights into pathophysiology and drug response, clinical translation remains limited. Methods: We conducted a systematic review of repurposed drugs, classified by Anatomical Therapeutic Chemical (ATC) codes, tested in animal models for their effects on AAA progression. Following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and a PROSPERO-registered protocol (CRD42024323430), we screened 14,127 articles and included 144 studies across 13 of the 14 ATC categories. Results: Most drug classes, particularly cardiovascular, metabolic, and immunomodulatory agents—including statins, angiotensin II receptor blockers (ARBs), metformin, and rapamycin—showed a reduced aneurysm diameter. However, high heterogeneity in models, treatment timing, and methodological shortcomings, including a lack of blinding and power calculations, limit translational value. The predominance of positive findings suggests potential publication bias. Conclusions: Nevertheless, drugs effective post-aneurysm initiation may offer the greatest clinical promise. Our findings underscore the need for standardized, high-quality, preclinical research to support future human trials. Full article

Diabetes mellitus (DM) continues to be a global world health problem. Despite medical advances, both DM and chronic kidney disease (CKD) remain global health issues with high mortality and limited options to prevent end-stage renal failure. Current therapies encompass five classes of drugs: (1) angiotensin-converting-enzyme inhibitors (ACEI) or angiotensin II receptor blockers (AIIRB); (2) sodium-glucose-transporter 2 (SGLT2) inhibitors; (3) glucagon-like peptide-1 receptor agonists (GLP-1 RA); and (4) an antagonist of type 1 endothelin receptor (ET1R) with proven efficacy to reduce albuminuria and proteinuria. (5) The mineralocorticoid receptor antagonist (MRA) finerenone has been tested in RCTs as a kidney protective agent. In our review, we summarize many of the principal trials that have generated evidence in this regard. Many novel agents—many of them proven not only for DM management but also for the treatment of obesity with or without DM or heart failure (HF)—are now in development and may be added to the five classical pillars: other non-steroidal MRA (balcinrenone); aldosterone synthase inhibitors (baxdrostat and vicadrostat); other GLP-1 RA (tirzepatide, survodutide, retatrutide, and cagrilintide); ET1 R antagonists, (zibotentan); and soluble guanylate cyclase activators (avenciguat). These new agents aim to slow disease progression further and reduce cardiovascular risk. Future strategies rely on integrated, patient-centered approaches and personalized therapy to curb renal disease and its related complications. Full article

Background: Finerenone has emerged as a promising nonsteroidal mineralocorticoid receptor antagonist for patients with chronic kidney disease (CKD), yet its safety and efficacy in kidney transplant recipients remain unstudied. Methods: A total of 1750 kidney transplant recipients were screened, and 39 were prescribed finerenone alongside angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Fifteen patients who met inclusion criteria and used finerenone consistently for at least six months were compared with 15 matched controls. Proteinuria, renal function, serum potassium, and other laboratory and clinical parameters were assessed at baseline and at 1, 3, and 6 months. Results: Finerenone was discontinued in two patients (5.1%) due to flushing and headache. Severe hyperkalemia occurred in four patients (10.2%). In the finerenone group, proteinuria significantly decreased at all time points (p < 0.05), with a 40% reduction at six months. No significant changes in estimated glomerular filtration rate or serum creatinine were observed. Conclusions: Finerenone is a promising adjunct therapy in kidney transplant patients for reducing proteinuria without impairing renal function for those patients who can tolerate it. However, in the early phase of treatment initiation, patients should be closely monitored for adverse effects including hyperkalemia. Full article

Hypertension is a leading risk factor for cardiovascular disease and is associated with maladaptive cardiac remodeling, including hypertrophy and fibrosis. The roles of the receptor for advanced glycation end-products (RAGE) and the small GTPase Rap1a in angiotensin II (AngII)-induced remodeling remain unclear. This study examined how RAGE and Rap1a influence cardiac responses to AngII using wild-type (WT), RAGE knockout (RAGE KO), and Rap1a knockout (RapKO) mice. Cardiac structure and function were evaluated following AngII infusion. RapKO mice were protected from AngII-induced hypertrophy, whereas RAGE KO mice exhibited altered remodeling patterns. AngII consistently increased left ventricular wall thickness across all genotypes, indicating that structural remodeling is primarily treatment-driven. Measures of cardiac output and stroke volume also changed significantly with AngII, suggesting hemodynamic load as a key driver of functional adaptation. In contrast, diastolic functional parameters were genotype-dependent and remained stable with AngII exposure, demonstrating an intrinsic influence of RAGE and Rap1a on myocardial relaxation. These findings highlight distinct roles for RAGE and Rap1a in modulating hypertensive cardiac remodeling and may parallel human hypertensive heart disease, where increased RAGE and Rap1a expression associate with fibrosis and impaired relaxation. Targeting the crosstalk between the RAGE-AT1R axis and the cAMP-EPAC-Rap1a pathway may offer therapeutic potential to reduce adverse cardiac remodeling in hypertension. Full article

The deep fascia, traditionally regarded as a passive structural tissue, is now recognized as a metabolically and biologically active structure where biochemical signals and biomechanical forces interact to influence proprioception, pain, force transmission, and adaptation to mechanical load. In this study, the convergence point between Angiotensin II (Ang II) signaling via its receptor, Angiotensin type 1 receptor (AT1R), and the mechanosensor Yes-associated protein (YAP) was investigated in human fascial fibroblasts. The presence of angiotensin II (Ang II) receptors was confirmed in fibroblasts from the deep fascia, with the AT1 receptor being the most prevalent subtype. Short-term exposure to Ang II (15–30 min) caused YAP dephosphorylation and its translocation to the nucleus, indicating YAP activation. Notably, prolonged Ang II treatment (7 days) significantly increased the expression of fibrosis-related genes, including collagen types I and III (COL1A1, COL3A1), and hyaluronan binding protein 2 (HABP2). This gene expression was decreased by pretreatment with the AT1R antagonist irbesartan or the YAP inhibitor verteporfin. Additionally, Ang II promoted fibroblast proliferation/migration, key features of fibrotic progression, through AT1R-dependent pathways. These findings show that Ang II acts as both a biochemical and biomechanical signal in the deep fascia, activating YAP signaling and promoting fibrotic remodeling. Our results uncover a new Ang II–YAP pathway in fascial fibroblasts, offering potential targets for therapy in fibrosis and related conditions involving the deep fascia. Full article

The current known data on the involvement of the peptidergic systems in breast cancer progression is overwhelmingly vast. Peptidergic systems are useful tools for imaging, diagnosis, prognosis and treatment of breast cancer. These systems play a crucial role in both basic and clinical breast cancer research by enabling the exploration of novel molecular mechanisms, signaling pathways, and the development of effective drug design strategies. Breast cancer cells overexpress peptide receptors; at the same time they are known to interact with peptides that (a) exert an oncogenic action (adrenomedullin 2, endothelin, gastrin-releasing peptide, neurokinin A, neuromedin, neuropeptide Y, neurotensin, substance P, vasoactive intestinal peptide), (b) exert an anticancer action (angiotensin (1–7), ghrelin, peptide YY) or (c) exert dual oncogenic and anticancer effects (adrenomedullin, angiotensin II, bradykinin, corticotropin-releasing factor, β-endorphin, glucagon-like peptide 1, gonadotropin-releasing hormone, kisspeptin, methionine-enkephalin, oxytocin). This indicates that peptides, as well as peptide receptor agonists and antagonists, may serve as antitumor agents due to their diverse actions against breast cancer development, including the inhibition of cell proliferation, migration and invasion, induction of apoptosis, and anti-angiogenesis. Multiple strategies have been developed to combat breast cancer, including peptide receptor silencing; antibodies conjugated to specific signaling proteins; antibodies targeting specific peptide receptors or oncogenic peptides; and the use of peptides or peptide receptor agonists/antagonists loaded with antitumor cargo. Future lines of research are suggested in breast cancer using promising anti-breast-cancer peptide receptor antagonists (HOE-140, exendin (9–39), bosentan, macitentan, PD168,368, CGP71,683A, SR48,692, aprepitant) or agonists (FR190,997, semaglutide, exendin 4, goserelin) mentioned in this review. Peptidergic systems have tremendous anti-breast-cancer clinical potential which must be exploited and developed. Taken together, the available data highlight the enormous promise of translational research into breast cancer and peptidergic systems for the development of effective treatments. A full understanding of the roles played by the peptidergic systems in breast cancer will serve to improve diagnosis and treatment. Full article

Endometrial cancers increase expression of the renin–angiotensin system (RAS). This study aimed to determine if inhibiting the RAS would reduce the viability and proliferation of endometrial cancer cells. The expression of RAS genes was measured in three endometrial epithelial adenocarcinoma cell lines (Ishikawa, HEC-1-A, AN3CA). Ishikawa cells had the highest expression of REN, ACE, and AGTR1 mRNA. AGT mRNA and protein levels were most abundant in HEC-1-A cells. We then determined the effects of drugs that inhibit the action of renin (VTP-27999 and aliskiren) or angiotensin-converting enzyme (perindoprilat) or block the angiotensin II type 1 receptor (losartan and telmisartan). Overall, VTP-27999, aliskiren, perindoprilat, and losartan had minimal effects on cell viability in all three cell lines, and combinations of these drugs did not have any effect. Telmisartan (a dual angiotensin receptor blocker and PPAR-γ agonist) significantly reduced the viability of all three cell lines and reduced the proliferation of both Ishikawa and AN3CA cells. Telmisartan was more effective than troglitazone (PPAR-γ agonist) in Ishikawa and HEC-1-A cells. RAS inhibitors were most effective in Ishikawa cells, which had the highest levels of RAS expression. Therefore, levels of RAS expression in endometrial cancers might indicate the potential efficacy of RAS drugs. Full article

Hypertension, a leading factor for cardiovascular diseases (CVD), is a particularly heavy burden in women during middle age, when cardioprotective hormones begin to decline. The abnormal handling of calcium (Ca²⁺) in vascular smooth muscle cells (VSMCs) leads to increased vasoconstriction, remodeling, and altered arterial compliance during hypertension. The Spontaneously Hypertensive Rats (SHR) is a model of essential hypertension, and middle-aged females with hypertension represent a stage of disease where vascular dysfunction is prominent but understudied. Losartan, a widely prescribed angiotensin II (AngII) receptor (AT1R) blocker, exerts antihypertensive effects by affecting Ang II/Ca²⁺ signaling. However, whether it corrects the Ca²⁺ mishandling in the aorta of middle-aged female SHR has not been established. In this study, the thoracic aorta from 36-week-old female SHRs treated with losartan was assessed for Ca²⁺ mishandling using myography and biochemical assays. Meanwhile, biomechanical properties and stiffness were evaluated using Pulse Wave Velocity (PWV), Atomic Force Microscopy (AFM), and assessments of collagen and elastin contents. Compared with normotensive controls, SHR demonstrated disrupted Ca²⁺ handling, increased stiffness, and Extracellular Matrix (ECM) remodeling in middle-aged females. Treatment with losartan abrogated Ca²⁺ mishandling influx and efflux in the VSMC, decreased stiffness, and restored the aortic structural changes. These findings demonstrate that losartan abolishes Ca²⁺ mishandling and highlight a mechanistic role of AT1R blockade in restoring vascular function in the aorta of middle-aged females during hypertension. Full article

Matrix metalloproteinase-9 (MMP-9) is a zinc-dependent endopeptidase that plays a central role in extracellular matrix (ECM) remodeling, angiogenesis, immune cell trafficking, and cytokine activation. Dysregulated MMP-9 activity has been implicated in the pathogenesis of diverse conditions, including atherosclerosis, aneurysm formation, chronic obstructive pulmonary disease (COPD), asthma, neurodegeneration, and malignancy. Although broad-spectrum synthetic MMP inhibitors were initially developed as therapeutic agents, clinical trials failed due to lack of selectivity, poor tolerability, and impairment with physiological tissue repair. This outcome has shifted attention toward indirect pharmacological modulation of MMP-9 using drugs that are already approved for other indications. In this paper, we review the evidence supporting MMP-9 modulation by established therapeutics and adjunctive strategies. Cardiometabolic agents such as statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), metformin, and pioglitazone reduce MMP-9 expression and enzymatic activity, contributing to vascular protection, improved insulin sensitivity, and attenuation of aneurysm progression. Anti-inflammatory and respiratory drugs, including glucocorticoids, phosphodiesterase-4 (PDE4) inhibitors, macrolide antibiotics, montelukast, and nonsteroidal anti-inflammatory drugs (NSAIDs), suppress MMP-9-driven airway inflammation and pathological tissue remodeling in asthma, COPD, and acute lung injury. Tetracycline derivatives, particularly sub-antimicrobial dose doxycycline, directly inhibit MMP-9 activity and are clinically validated in the treatment of periodontal disease and vascular remodeling. Hormone-related therapies such as rapamycin, estradiol, and tamoxifen exert tissue- and disease-specific effects on MMP-9 within endocrine and oncologic pathways. In parallel, nutritional interventions—most notably omega-3 polyunsaturated fatty acids and antioxidant vitamins—provide adjunctive strategies for mitigating MMP-9 activity in chronic inflammatory states. Taken together, these findings position MMP-9 as a modifiable and clinically relevant therapeutic target. The systematic integration of approved pharmacologic agents with lifestyle and nutritional interventions into disease-specific treatment paradigms may facilitate safer, context-specific modulation of MMP-9 activity and unveil novel opportunities for therapeutic repurposing. Full article

We evaluated the effects of fenofibrate (FF) in a SU5416/hypoxia model of pulmonary arterial hypertension (PAH) with a specific focus on its influence on the renin–angiotensin system (RAS). We assessed right ventricular systolic pressure (RVSP), mean pulmonary artery pressure (mPAP), medial pulmonary artery wall thickening, right ventricular (RV) hypertrophy, systolic pulmonary artery pressure (SPAP), pulmonary artery effective elastance (PAEa), RV diastolic pressure (RVDP), RV developed pressure (RVDevP), right ventricular–pulmonary arterial coupling index (RVPAC), RV dp/dt max and dp/dt min. Levels of angiotensin II, angiotensin (1–7), angiotensin-converting enzyme 2 (ACE2), Bmpr2, Smad5 and nitrite (NO₂⁻) and nitrate (NO₃⁻) in the lung and RV were evaluated. The expression of AT1R, MAS receptors, and ACE2 in lung tissue was assessed. FF prevented the increase in RVSP, mPAP, RV hypertrophy, reduced pulmonary arterioles remodeling, and attenuated the rise in SPAP, mPAP, and PAEa. In the RV, it reduced RVDevP and prevented the decrease in dp/dt min, without affecting RVDP. RVPAC showed partial improvement. In lung tissue, FF decreased angiotensin II levels, the Ang II/Ang-(1–7) ratio, and reduced angiotensin II receptor type 1 (AT1R) expression, while preserving the receptor for the angiotensin-(1–7) (MAS) and ACE2. FF tended to restore Bmpr2/Smad5 expression. NO₂⁻ levels were preserved and tended to preserve (NO₃⁻) levels. In the RV, Ang-(1–7) increased, ACE2 was preserved, and NO₂⁻ and NO₃ levels were maintained. FF exerts protective effects in Su/Hx-induced PAH. Full article

Melicoccus bijugatus (Guinep) is traditionally consumed in the Caribbean and Latin America for its health benefits, yet its cardiovascular effects remain underexplored. This study investigated the therapeutic potential of Guinep by combining experimental and computational approaches. The biological evaluation of the Guinep extract was conducted by assessing the effects of modulating Angiotensin-Converting Enzyme (ACE), Angiotensin II Type 1 Receptor (AT1R), and Voltage-Gated Calcium Channels (VGCC) on vascular reactivity. Metabolites previously identified by high-resolution UHPLC-Q-Orbitrap mass spectrometry were further examined using in silico tools, including ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) prediction (pkCSM), biological activity prediction (PASS server), and molecular docking (AutoDock Vina) against cardiovascular targets (ACE: PDB 1O86, AT1R: PDB 4ZUD, VGCC: PDB 8WE8). Docking results revealed that phytochemicals such as isorhamnetin-3-O-glucoside and 3-O-caffeoylquinic acid displayed strong binding affinities with ACE (−9.3 and −8.5 kcal/mol), AT1R (−8.2 and −7.6 kcal/mol), and VGCC (−8.6 and −7.6 kcal/mol), in several cases matching or surpassing standard antihypertensive drugs. Key hydrogen bond interactions closely resembled those of reference ligands, suggesting pharmacophoric similarity. ADMET modeling confirmed favorable pharmacokinetic profiles and low predicted toxicity, supporting their drug-like potential. These findings are consistent with in vivo evidence of Guinep’s hypotensive, antioxidant, and vasodilatory properties. Vascular relaxation of Guinep extract was predominantly mediated by blockade of VGCC (53%) and AT1R (48%), while ACE inhibition accounted for 24%. Collectively, the results demonstrate that Guinep contains bioactive phytochemicals with multitarget cardiovascular activity, particularly as ACE, AT1R, and VGCC modulators. This study validates the traditional use of Guinep. Full article

The SARS-CoV-2 spike protein, through its receptor binding domain (S1-RBD), binds to the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell membrane, leading to viral infection. Several mutations in S1-RBD in SARS-CoV-2 variants are known to enhance infection through an increased affinity for ACE2. While many reports are available describing the SARS-CoV-2 infection mechanism, there is a dearth of studies towards understanding the initial interaction of the S1-RBD with ACE2 on living host cells and the role of endocytosis and cytoskeleton in the process. Here, we reconstituted the interaction between S1-RBD- and ACE2-expressing host cells in a hybrid live cell-supported lipid bilayer (SLB) platform enabling live monitoring of the interaction between S1-RBD on SLBs and the ACE2 receptor on living cells and showed that cells depleted Omicron S1-RBD from SLB corrals, likely through endocytosis. Specifically, interaction of living host cells with S1-RBD-functionalized SLB substrates resulted in the enrichment of S1-RBD and ACE2 at the cell–SLB interface. Interaction of host cells with wild type (WT), Omicron, and Omicron Revertant S1-RBD functionalized on micron-scale SLB corrals, which mimic viral membranes but are flat, also resulted in their enrichment. However, cells interacting with Omicron S1-RBD revealed a depletion of the protein from many corrals, which was generally not observed with the WT S1-RBD and was reduced with the Omicron Revertant, which contains the Q493R mutation reversion, S1-RBD. Further, S1-RBD depletion coincided with the localization of the early endosomal marker EEA1. Importantly, treatment of cells with the clathrin inhibitor, pitstop 2, but not the myosin II inhibitor, blebbistatin, significantly reduced Omicron S1-RBD depletion. Collectively, these observations suggest that the SARS-CoV-2 Omicron variant has evolved, through mutations in its S1-RBD, to take advantage of the cellular endocytic pathway for enhanced infection, which is not observed with the parental SARS-CoV-2 and appears to be lost in the Omicron Revertant variant. Additionally, these results underscore the significance of the hybrid live cell–SLB platform in studying SARS-CoV-2 S1-RBD-ACE2 interaction and the potential impact of mutations in the S1-RBD on adapting to a specific cellular entry mechanism. Full article

Renin–angiotensin system (RAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), have been associated with improved outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to assess the differential impact of ACEIs versus ARBs on survival and cardiovascular outcomes in individuals with MASLD. Using data from the UK Biobank, we identified 52,143 participants with exclusive use of either an ACEI or ARB. Individuals with viral, autoimmune, cholestatic, or alcohol-related liver disease were excluded. MASLD was defined as fatty liver index ≥ 60 with ≥1 cardiometabolic risk factor. Inverse probability of treatment weighting (IPTW) was used to adjust for confounders. Outcomes included all-cause mortality, cardiovascular events, hepatic decompensation, and hepatocellular carcinoma (HCC), analyzed using Cox proportional hazards models. Among MASLD participants, ARB use was associated with significantly lower all-cause mortality compared to ACEI use (HR, 0.94; 95% CI, 0.90–1.00; p = 0.031) after IPTW adjustment. Cardiovascular risk was also lower with ARBs (HR, 0.92; 95% CI, 0.89–0.96; p < 0.001), particularly in subgroups with BMI ≥ 25 kg/m², no diabetes, and advanced fibrosis. No differences in hepatic decompensation or HCC incidence were observed. Benefits of ARBs were not significant in participants without steatotic liver disease. ARB use was associated with improved survival and reduced cardiovascular events in individuals with MASLD, whereas ACEIs expressed no comparable benefit. These findings suggest that ARBs might be a more effective RAS inhibitor subclass in MASLD and support their preferential use in patients with steatotic liver disease requiring antihypertensive therapy. Full article