Search Results (538)

Obesity and pediatric fatty liver disease are increasingly prevalent, yet the underlying mechanisms linking these conditions to heightened inflammatory and immune responses remain poorly understood. Using a murine model reflecting early-life obesity and hepatic steatosis, we tested the hypothesis that obesity-driven hepatic inflammation intensifies systemic immune responses and exacerbates vascular dysfunction following innate immune activation. Newly weaned C57BL/6 mice were fed either a high-saturated-fat, high-cholesterol diet (HFD) or a control diet (CD) for four weeks, modeling adolescence in humans. HFD-fed mice exhibited hepatic and splenic enlargement, elevated plasma cholesterol levels, increased activity levels of liver enzymes (alanine and aspartate aminotransferases), and higher plasma serum amyloid A (SAA) concentrations. Following a sublethal dose of lipopolysaccharide (LPS), the expression of hepatic inflammatory genes (VCAM-1 and iNOS) was significantly elevated in HFD-fed mice, indicating an exaggerated local immune response. Mice fed an HFD also showed significant impairment in endothelium-dependent vasorelaxation compared to CD mice and saline-treated controls, while endothelium-independent responses remained intact. These vascular changes occurred in the context of hepatic inflammation, suggesting that early-life diet-induced steatosis sensitizes the vasculature to inflammatory insult. These findings suggest that obesity-driven hepatic inflammation primes exaggerated systemic immune responses to innate immune stimuli, potentially contributing to the vascular dysfunction and variable clinical morbidity observed in pediatric inflammatory conditions. Full article

Cardiovascular diseases (CVDs) are the leading causes of death worldwide, and most of them are connected with atherosclerosis (AS). Hypertension (HT), hyperlipidemia (HPL), and hyperglycaemia (HG) are the main risk factors responsible for CVD and have become a significant public health issue. AS might be a prime causative factor in CVD, and it originates from endothelial cell dysfunction. On the other hand, the factors mentioned above might cause endothelial cell damage as a consequence of endothelial dysfunction (ED) or might be regarded as a consequence of ED. Thus, endothelial cells are critical for maintaining vascular health and homeostasis, and their function is a key contributor to the initiation and progression of AS. The autoregulation of microcirculation, which is functionally present in the brain and kidneys, and from the physiological and pathophysiological point of view, is of high importance to preserve the proper function of the endothelium of blood vessels. The key factor responsible for cardiovascular system regulation and proper action is nitric oxide (NO). Disturbances in NO synthesis and/or bioavailability, caused by oxidative stress and/or inflammation, accompany or even precede diseases such as HT, angiogenesis-associated disorders, HPL, and HG, which are on the pathway of AS development. In the present review, we attempted to synthesize recent advances in understanding the pathophysiology of multifactorial-related AS. Full article

In endothelial cells, high-dose irradiation induces numerous dysfunctions including alteration in junctional proteins such as VE-Cadherin, apoptosis and enhanced adhesiveness linked to overexpression of adhesion molecules like Intercellular Adhesion Molecule 1 (ICAM-1). Such endothelial dysfunctions can lead to altered tissue perfusion, development of tissue inflammation through increased endothelial permeability, and ultimately organ damage. As intracellular cyclic AMP (cAMP) levels are known to control intercellular junctions or apoptosis in the endothelium, we investigated here the effect of the Phosphodiesterase 4 inhibitor Roflumilast, a drug increasing cAMP levels, on irradiation-induced endothelial dysfunctions in human pulmonary microvascular endothelial cells (HPMECs). Using continuous impedance measurements in confluent endothelial cell monolayers, Roflumilast was found to rapidly reinforce the endothelial barrier and to prevent irradiation-induced barrier disruption. In accordance, irradiation-induced alteration in membrane VE-Cadherin-composed adherens junctions was prevented by Roflumilast treatment after irradiation, which was correlated with its protective effect of the actin cytoskeleton. Post-irradiation treatment with Roflumilast also protected HPMECs from irradiation-induced late apoptosis, but was without effect on irradiation-induced ICAM-1 overexpression. Overall, our results indicate that the beneficial effects of Roflumilast after irradiation are linked to the strengthening/protection of the endothelial barrier and reduced apoptosis, suggesting that this medicine may be useful for the treatment of endothelial damages after exposure to a high dose of radiation. Full article

Background/Objective: Hypertension and other modifiable risk factors for cardiovascular disease are characterized by a dysfunctional vascular endothelium and decreased nitric oxide (NO) bioavailability. The oral supplementation of inorganic nitrate (NO₃⁻) has been shown to increase the salivary and plasma nitrite (NO₂⁻), a precursor to NO, though there may be significant variation in the pharmacokinetics of this process between different supplements. The purpose of this open-label, phase 1, single-arm study was to investigate the pharmacokinetic profile of the plasma and salivary NO₃⁻ and NO₂⁻ concentrations following the administration of a single serving of a plant-based bioequivalent inorganic nitrate oral supplement (“Berkeley Life Nitric Oxide Foundation Capsules”, Chicago, IL, USA). Methods: Nine males and three females (age: 33 ± 15 years; BP: 129 ± 6 mmHg; BMI: 27.58 ± 4.27 kg/m²) participated in the protocol. Following the baseline collection of saliva and plasma samples, the participants consumed 314 mg (two capsules) of the supplement. Saliva and plasma samples were collected at 2 h, 4 h, 8 h, and 24 h post consumption. Results: The peak salivary NO₃⁻ (13,326.12 ± 4926.60 µM), salivary NO₂⁻ (1375.27 ± 679.28 µM), plasma NO₃⁻ (498.37 ± 168.89 µM), and plasma NO₂⁻ (231.66 ± 97.26 nM) were observed at 2 h post-supplementation (p < 0.01 vs. the baseline). The concentrations of the salivary and plasma NO₂⁻ remained elevated at 8 h after administration (220% and 50% above the baseline, respectively), and the concentrations of the salivary and plasma NO₃⁻ remained elevated at 24 h after administration (22% and 50% above the baseline, respectively). Conclusions: These data suggest that a single serving of “Berkeley Life Nitric Oxide Foundation Capsules” taken once to twice per day is a viable strategy to provide sustained salivary and plasma NO₃⁻ and NO₂⁻ availability over 24 h and therefore may provide a viable approach for long-term blood pressure maintenance. Full article

Background/Objectives: Recent studies show that the gut microbiome plays a pivotal role in the (patho)physiology of metabolic dysfunction-associated steatotic liver disease (MASLD), likely via metabolites they produce that are transported via the portal vein towards the liver where they first encounter liver sinusoidal endothelial cells (LSECs). LSECs may modulate the effects the gut microbes have on the liver, e.g., on the progression of MASLD. Methods: This review aims to describe the current knowledge on the role of LSECs in mediating the effect of gut microbial products in MASLD. Results: Various studies show that LSECS have a contributing role in MASLD pathogenesis, suggesting that proper LSEC functionality is required to protect the liver from gut-driven attacks. Conclusions: Dedicated studies on the role and effects of gut-derived molecules on LSEC functionality are lacking, likely because such studies depend on labor-intensive techniques such as scanning electron microscopy (SEM). Full article

Peripheral artery disease (PAD) is a chronic progressive accumulation of atherosclerotic lesions with varying degrees of arterial obstruction determining ischemic symptoms of the involved extremities. PAD is associated with decreased bioavailable nitric oxide due to endothelial cell dysfunction and the development and progression of vascular arterial stiffening (VAS). Atherosclerosis also plays an essential role in the development and progression of vascular arterial stiffening (VAS), which is associated with endothelial cell activation and dysfunction that results in a proinflammatory endothelium with a decreased ability to produce bioavailable nitric oxide (NO). NO is one of three gasotransmitters, along with carbon monoxide and hydrogen sulfide, that promotes vasodilation. NO plays a crucial role in the regulation of PAD, and a deficiency in its bioavailability is strongly linked to the development of atherosclerosis, VAS, and PAD. A decreased arterial patency may also occur due to a reduction in the elasticity or diameter of the vessel wall due to the progressive nature of VAS and atherosclerosis in PAD. Progressive atherosclerosis and VAS promote narrowing over time, which leads to impairment of vasorelaxation and extremity blood flow. This narrative review examines how atherosclerosis, aging and hypertension, metabolic syndrome and type 2 diabetes, tobacco smoking, and endothelial cell activation and dysfunction with decreased NO and VAS with its increased damaging pulsatile pulse pressure result in microvessel remodeling. Further, the role of ischemia and ischemia–reperfusion injury is discussed and how it contributes to ischemic skeletal muscle remodeling, ischemic neuropathy, and pain perception in PAD. Full article

Psoriasis is a chronic inflammatory disease mediated by the innate and adaptive immune systems, and its pathogenesis involves multiple aspects, including abnormal interleukin (IL)-23–Th17 axis, dysfunction of Tregs and other immune cells, and a complex relationship between keratinocytes and the vascular endothelium. Dysfunction of mesenchymal stem cells in psoriatic skin may also be the main reason for the dysregulated inflammatory response. Mesenchymal stem cells, a type of adult stem cells with multidifferentiation potential, are involved in the regulation of multiple links and targets in the pathogenesis of psoriasis. Thus, a detailed exploration of these mechanisms may lead to the development of new therapeutic strategies for the treatment of psoriasis. In this paper, the role of mesenchymal stem cells in skin homeostasis, the pathogenesis of psoriasis, and the multimodal function of using mesenchymal stem cells in the treatment of psoriasis are reviewed. Full article

Menopause is the natural period of aging in women induced by ovary deterioration, resulting in estrogen deficiency. We evaluated the antioxidative and anti-inflammatory properties of Cnidium officinale, Pueraria lobata Ohwi, and Leonurus japonicus (CPL) extracts on vascular endothelial dysfunction. After treatment, CPL extracts decreased serum lipid profiles, serum vasoactive substances, tail temperatures, and cardiovascular risk indices. In ovariectomized rats, vasodilation significantly increased, with an increase in endothelial nitric oxide synthase (eNOS) in the CPL200 and CPL500 groups compared with the OVX group (p < 0.05). The extracts also significantly reduced vascular cell adhesion protein 1 (VCAM-1) in the CPL50, CPL100, and CPL200 groups compared with the OVX group (p < 0.05, p < 0.01, and p < 0.001, respectively). Intercellular adhesion molecule 1 (ICAM-1) was also reduced in the CPL100 and CPL200 groups compared with the OVX group (p < 0.001 and p < 0.0001, respectively); this was achieved through the downregulation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and inducible nitric oxide (iNOS), which resulted in the synthesis of nuclear factor erythroid 2-related factor 2 (NRF2) and eNOS in HUVECs. Our results show that CPL extracts could provide cardioprotective effects against vascular endothelium dysfunction by decreasing inflammation and upregulating vasodilation, ascertained by evaluating the antioxidant systems of ovariectomized rats. Further studies are needed to explore the long-term cardioprotective effects. Full article

Extracellular vesicles (EVs) have a key role in intercellular communication. We hypothesized that EVs are biomarkers of nephropathy or kidney allograft rejection. We screened patients with chronic kidney disease (CKD) and kidney transplant (KT) recipients. We measured the urine and plasma levels of total EVs overall and EV subpopulations (positive for podocalyxin, aquaporin-1, CD133, CD144, CD19, CD3, CD16, CD56, or CD41). We included 92 patients with CKD, 70 KT recipients, and 33 healthy volunteers. In CKD, the total urine EV concentration was correlated positively with the estimated glomerular filtration rate (eGFR), but none of the subpopulations was identified as a potential biomarker of nephropathy. Among the KT recipients, 30 had good allograft function and 40 had allograft disease (13 with antibody-mediated rejections (ABMR), 12 with T-cell-mediated rejection (TCMR), and 15 with allograft dysfunction). Patients with ABMR had low plasma levels of EVs derived from B-cells, T-cells, and endothelium (p = 0.003, 0.009, and 0.005, respectively). Patients with TCMR had a low urine level of EVs derived from endothelium (p = 0.05). EVs derived from B-cells, T-cells, and endothelium might be biomarkers of kidney allograft rejection. However, we did not identify biomarkers of nephropathy in CKD. Full article

The numerous side effects and adverse health implications associated with chemotherapies have long plagued the field of cancer care. Whilst in some cases a curative measure, this highly toxic intervention consistently scores poorly on quantitative measures of tolerability and safety. Of these side effects, cardiac and microvascular defects pose the greatest health risk and are the leading cause of death amongst cancer survivors who do not succumb to relapse. In fact, in many low-grade cancers, the risk of recurrence is far outweighed by the cardiovascular risk of morbidity. As such, there is a pressing need to improve outcomes within these populations. Polyphenols are a group of naturally occurring metabolites that have shown potential vasoprotective effects. Studies suggest they possess antioxidant and anti-inflammatory activities, in addition to directly modulating vascular signalling pathways and gene expression. Leveraging these properties may help counteract the vascular toxicity induced by chemotherapy. In this review, we outline the main mechanisms by which the endothelium is damaged by chemotherapeutic agents and discuss the ability of polyphenols to counteract such side effects. We suggest future considerations that may help overcome some of the published limitations of these compounds that have stalled their clinical success. Finally, we briefly explore their pharmacological properties and how novel approaches could enhance their efficacy while minimising treatment-related side effects. Full article

Empagliflozin (EMPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, prevents endothelial dysfunction, but its effects on vascular tone in hypertension remain unclear. This study investigated whether EMPA modulates vasomotor tone via sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) pathways in spontaneously hypertensive rats (SHR) and controls (Wistar Kyoto rats, WKY). Functional (wire myography, organ bath) and biochemical (Western blot) studies were conducted on the third-order of the superior mesenteric arteries (sMAs) and/or aortas. EMPA induced concentration-dependent relaxation of preconstricted sMAs in both groups. In SHR, EMPA enhanced acetylcholine (Ach)-induced relaxation in sMAs and aortas and reduced constriction induced by phenylephrine (Phe) and U46619 in sMAs. The SIRT1 inhibitor (EX527) abolished EMPA’s effects on Ach-mediated relaxation and U46619-induced vasoconstriction, while AMPK inhibition reduced Ach-mediated relaxation and Phe-induced vasoconstriction. SHR showed increased SGLT2 and SIRT1 expression and decreased pAMPK/AMPK levels in sMAs. In conclusion, EMPA might exert vasoprotective effects in hypertension by enhancing endothelium-dependent relaxation and reducing constriction via AMPK/SIRT1 pathways. These properties could improve vascular health in patients with hypertension and related conditions. Further studies are needed to explore new indications for SGLT2 inhibitors. Full article

Fuchs endothelial corneal dystrophy (FECD) is a progressive disorder characterized by endothelial cell loss and excessive extracellular matrix (ECM) accumulation leading to corneal dysfunction. Emricasan, a pan-caspase inhibitor, was investigated for its therapeutic potential in suppressing these pathological changes. Patient-derived FECD cells and stress-induced cell models were treated with emricasan to assess its effects on apoptosis and ECM production. Caspase-specific knockdown experiments were performed to identify key mediators. Col8a2^Q455K/Q455K mice, model mice of early-onset FECD, received twice-daily administration of 0.1% emricasan eye drops from 8 to 28 weeks of age. Endothelial cell density, hexagonality, cell size variation, and guttae area were evaluated by contact specular microscopy, while transcriptomic changes were analyzed via RNA sequencing. Emricasan effectively reduced apoptosis and ECM production in vitro by selectively inhibiting caspase-7 without affecting canonical TGF-β signaling. In vivo, emricasan-treated mice exhibited significantly higher endothelial cell density, improved hexagonality, and reduced variation in cell size compared with controls. Transcriptome analysis revealed distinct gene expression changes in the corneal endothelium following emricasan treatment. These findings suggest that emricasan exerts dual protective effects by inhibiting caspase-7-mediated ECM accumulation and broadly suppressing apoptosis, highlighting its potential as a pharmacological therapy for FECD. Full article

Extracorporeal membrane oxygenation (ECMO) can be a life-saving intervention, but it is associated with high complication rates. ECMO induces systemic inflammation and endothelial hyperpermeability, thereby causing tissue edema, microcirculatory perfusion disturbances, and organ failure. This study investigated whether the inhibition of vascular endothelial protein tyrosine phosphatase (VE-PTP), a regulator of endothelial permeability, reduces extracorporeal circulation (ECC)-induced microvascular dysfunction. Rats were subjected to ECC after treatment with Razuprotafib (n = 11) or a placebo (n = 11), or they underwent a sham procedure (n = 8). Razuprotafib had no effect on the ECC-induced impairment of capillary perfusion, as assessed with intravital microscopy, nor did it influence the increased wet-to-dry weight ratio in kidneys, a marker of edema associated with ECC. Interestingly, Razuprotafib suppressed the ECC-induced increase in TNFα, whereas angiopoietin-2 even further increased, following the discontinuation of ECC. Circulating interleukin-6, ICAM-1, angiopoietin-1, and soluble Tie2 and tissue VE-PTP, Tie1, and Tie2 mRNA expression were not affected by Razuprotafib. Furthermore, Razuprotafib improved the PaO₂/FiO₂ ratio and reduced histopathological pulmonary interstitial inflammation following ECC compared to the placebo. To conclude, treatment with Razuprotafib did not improve ECC-induced microcirculatory perfusion disturbances nor renal edema. Full article

Platelet dysfunction plays a critical role in the pathogenesis of various disorders affecting the hemostatic-coagulant system. This review aims to explore the mechanisms by which platelet dysfunctions contribute to the disruption of hemostasis, leading to an increased risk of both thrombosis and bleeding. Platelets, traditionally known for their role in clot formation, can exhibit altered functionality under pathological conditions such as cardiovascular diseases, metabolic disorders, and autoimmune diseases, impacting their interaction with coagulation factors and vascular endothelium. The review discusses the molecular and cellular mechanisms underlying platelet dysfunction, including aberrations in platelet activation, aggregation, and secretion. It also highlights the interplay between platelets and other components of the coagulation cascade, such as fibrinogen and clotting factors, in maintaining vascular integrity. Moreover, the review examines clinical implications, including how platelet dysfunction can be a contributing factor in conditions like deep vein thrombosis, stroke, and disseminated intravascular coagulation (DIC). Finally, current therapeutic approaches targeting platelet dysfunctions, including antiplatelet agents and emerging therapies, are reviewed to provide insights into potential strategies for managing fluid-coagulation system imbalances. This review underscores the importance of a comprehensive understanding of platelet dysfunction to improve diagnosis and treatment of hemostatic disorders. Full article

Delayed reperfusion of the ischemic heart (I/R) is known to impair the recovery of cardiac function and produce a wide variety of myocardial defects, including ultrastructural damage, metabolic alterations, subcellular Ca²⁺-handling abnormalities, activation of proteases, and changes in cardiac gene expression. Although I/R injury has been reported to induce the formation of reactive oxygen species (ROS), inflammation, and intracellular Ca²⁺ overload, the generation of oxidative stress is considered to play a critical role in the development of cardiac dysfunction. Increases in the production of superoxide, hydroxyl radicals, and oxidants, such as hydrogen peroxide and hypochlorous acid, occur in hearts subjected to I/R injury. In fact, mitochondria are a major source of the excessive production of ROS in I/R hearts due to impairment in the electron transport system as well as activation of xanthine oxidase and NADPH oxidase. Nitric oxide synthase, mainly present in the endothelium, is also activated due to I/R injury, leading to the production of nitric oxide, which, upon combination with superoxide radicals, generates nitrosative stress. Alterations in cardiac function, sarcolemma, sarcoplasmic reticulum Ca²⁺-handling activities, mitochondrial oxidative phosphorylation, and protease activation due to I/R injury are simulated upon exposing the heart to the oxyradical-generating system (xanthine plus xanthine oxidase) or H₂O₂. On the other hand, the activation of endogenous antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, and the concentration of a transcription factor (Nrf2), which modulates the expression of various endogenous antioxidants, is depressed due to I/R injury in hearts. Furthermore, pretreatment of hearts with antioxidants such as catalase plus superoxide dismutase, N-acetylcysteine, and mercaptopropionylglycerine has been observed to attenuate I/R-induced subcellular Ca²⁺ handling and changes in Ca²⁺-regulatory activities; additionally, it has been found to depress protease activation and improve the recovery of cardiac function. These observations indicate that oxidative stress is intimately involved in the pathological effects of I/R injury and different antioxidants attenuate I/R-induced subcellular alterations and improve the recovery of cardiac function. Thus, we are faced with the task of developing safe and effective antioxidants as well as agents for upregulating the expression of endogenous antioxidants for the therapy of I/R injury. Full article