Search Results (80)

Background/Objectives: During oral and gut microbiota dysbiosis, lipopolysaccharides (LPSs) of major bacteria, such as Porphyromonas gingivalis and Escherichia coli, translocate into the bloodstream and lead to endotoxemia. Cerebral endothelial cells are targets of LPSs that may aggravate inflammation and cerebrovascular disorders. This study aimed to evaluate the protective role of the characterized polyphenol-rich extract of the Dodonaea viscosa medicinal plant and a predominant component, epicatechin, on murine bEnd.3 cerebral endothelial cells exposed to P. gingivalis or E. coli LPSs. Methods: The effects of LPSs and polyphenols were assessed on cell viability (MTT, trypan blue exclusion assays) and inflammatory, redox, vasoactive and permeability markers (RT-qPCR, Western blot, ELISA, FITC-Dextran test). Results: The data show that LPSs activated the TLR2-4/NFĸB signaling pathway and promoted IL-1β, IL-6, TNF-α, MCP-1, COX-2, iNOS, ICAM-1, VCAM-1 and E-selectin production without affecting cell viability. LPSs induced oxidative stress by elevating intracellular ROS levels and altering the expression of genes encoding NOX2-4, SOD, catalase, GPx, HO-1 and Nrf2. LPSs imbalanced NO vasodilator and ET-1 vasoconstrictor levels and reduced the production of occludin and ZO-1 tight junction proteins. Meanwhile, LPSs raised the permeability to FITC-Dextran, suggesting cell integrity loss. The extent of endothelial dysfunction caused by LPSs depended on their bacterial origin. Importantly, plant polyphenols and epicatechin exerted anti-inflammatory and antioxidant effects, and attenuated LPSs’ deleterious action on vasoactive and permeability markers. Conclusions: This study shows that polyphenols limit cerebral endothelial cell dysfunction under inflammatory conditions mediated by LPSs, highlighting their therapeutic potential in protecting brain homeostasis during oral and gut microbiota dysbiosis. Full article

The Middle Meningeal Artery (MMA) occupies a pivotal role in the pathophysiology of migraine, functioning as a vascular and neuroimmune interface that precipitates the characteristic pulsatile pain. The inhibition of this pathophysiological cascade has been investigated as a therapeutic strategy. However, fewer than a dozen centers globally have disseminated procedural or mechanistic data. Given the nascency of this field and the imperative for standardization, the present review synthesizes mechanistic and clinical evidence underpinning intra-arterial pharmacological modulation of the MMA for migraine management. Methods: A focused narrative review was undertaken, drawing upon select but influential studies from pioneering research groups investigating intra-arterial interventions targeting the MMA. The extant literature was thematically categorized and organized according to the loci of cascade interruption and their corresponding clinical outcomes. Results: Since 2009, intra-arterial therapies for severe headache syndromes have evolved, initially utilizing nimodipine for vasospasm-related headaches, progressing to verapamil for reversible cerebral vasoconstriction, and more recently, lidocaine for refractory or status migrainosus, occasionally in conjunction with MMA embolization. Contemporary research uses language that conceptualizes migraine as an immunologically mediated neurovascular disorder, as opposed to a purely vascular or neuronal entity. Recent investigations have identified interleukins such as Interleukin-1β, Tumor Necrosis Factor-α, and Interleukin-6 as critical amplifiers of trigeminovascular activation. Purinergic signaling through the P2X3 receptor and the P2Y13 receptor, in conjunction with pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide pathways, has been implicated in the modulation of MMA excitability and neuropeptide release. The development of novel calcitonin gene-related peptide receptor antagonists, such as zavegepant, further substantiates the artery’s significance as a pharmacological target. Conclusions: These findings support a shift toward immune-modulating intra-arterial therapeutic strategies, with migraine interventions targeting cytokine and neuroimmune signaling within the MMA, rather than relying exclusively on vasodilatory mechanisms. Full article

Background: Atrial fibrillation (AF) is common among intensive care unit (ICU) patients and is associated with increased mortality, prolonged length of stay (LOS), and greater resource utilization. Widely used AF risk scores were developed for stable outpatient populations and have limited applicability in critically ill patients. This study aimed to (1) characterize ICU patients with AF, (2) develop and temporally externally validate machine learning models to predict ICU mortality and ICU LOS, and (3) identify early clinical factors associated with these outcomes using interpretable methods. Methods: Adult ICU patients with AF from MIMIC-IV (n = 20,058) were used for model development with grouped cross-validation, and MIMIC-III (n = 11,475) served as a temporal external validation cohort. Predictors included demographics, admission characteristics, vital signs, laboratory values, vasoactive support, and AF-related medications available within the first 24 h of ICU admission. Eight classification algorithms were evaluated for ICU mortality, and six regression algorithms were evaluated for ICU LOS. Discrimination was primarily assessed using the area under the receiver operating characteristic curve (AUC) and average precision (AP), with additional threshold-dependent metrics reported to characterize operating-point behavior under low event prevalence. Probability-threshold optimization using out-of-fold predictions was applied to the primary mortality model. LOS performance was evaluated using mean absolute error (MAE), root mean squared error (RMSE), and the coefficient of determination (R²). Model interpretability was assessed using SHapley Additive exPlanations (SHAP). Results: The median age was 75 years, and ICU mortality was 8.9%. For mortality prediction, the XGBoost model demonstrated preserved discrimination on temporal external validation (MIMIC-III) (AUC = 0.743; AP = 0.226). At the default probability threshold (0.50), recall and F1 scores were low due to low event prevalence; applying a prespecified F1-optimized threshold derived from the development cohort improved sensitivity while maintaining overall discrimination. For ICU LOS, models explained little variance on temporal validation; LightGBM performed best, but the explained variance was low (MAE = 88.9 h; RMSE = 163.9 h; R² = 0.038), indicating that the first 24-h structured data provide an insufficient signal to accurately predict ICU LOS, likely due to downstream clinical and operational factors. SHAP analysis identified clinically plausible predictors of mortality and prolonged ICU stay, including reduced urine output, renal dysfunction, metabolic derangement, hypoxemia, early vasopressor use, advanced age, and admission pathways. Full article

Sexual size dimorphism (SSD) refers to the phenomenon where males and females of the same species exhibit differences in overall or partial body size, and it is widespread among mammals, birds, reptiles, and fish. Notably, this dimorphism is significantly influenced by the sexually dimorphic secretion of growth hormone (gh), a key pituitary-derived growth regulator. Commonly, the secretion of gh is positively regulated by glucagon family members such as growth hormone-releasing hormone (ghrh) and adenylate cyclase-activating polypeptide 1 (adcyap1). To explore the stimulators for pituitary hormones (especially gh) in the teleost, we performed genome-wide identification and functional characterization of the glucagon family on Chinese tongue sole (Cynoglossus semilaevis) that exhibits typical female-biased sexual size dimorphism. Four members of adcyap1/vasoactive intestinal polypeptide(vip)/ghrh family and ten members of their receptor family were identified. Expression pattern analysis revealed high expression of adenylate cyclase-activating polypeptide 1b (adcyap1b) and its receptors in the brain. Moreover, two alternative splice variants for the adcyap1b gene were discovered, resulting from the skipping of exon 4. Following the acquisition of the two eukaryotic recombinant protein splice variants (ADCYAP1b_tv1 and ADCYAP_tv2) from HEK 293T cells, incubation experiments were conducted using C. semilaevis pituitary cell line. The results demonstrated that both variants promoted the expression of gh, pro-opiomelanocortin (pomc), and corticoliberin (crh), but ADCYAP1b_tv1 had a significantly stronger effect and uniquely stimulated prolactin (prl) and somatolactin (sl). This study demonstrates a functional divergence between the two ADCYAP1b splice variants in teleosts, with ADCYAP1b_tv1 acting as a more potent and versatile pituitary hormone stimulator. Further research on their receptor-binding affinity and downstream signaling pathways would be valuable for exploring the mechanism underlying sexual size dimorphism. Full article

Glucagon-like peptide-1 receptor (GLP1R) agonists, such as semaglutide, are used for treating type 2 diabetes mellitus and promoting weight loss. This study investigates genetic and molecular mechanisms underlying GLP1R activation using a novel in silico approach to identify effects on metabolism, glucose and insulin production, gastrointestinal motility, behavior, and satiety. This approach used three separate searchable web-based programs and databases (STRING, Pathway Commons, and BioGRID) to identify and analyze functional gene and protein interactions with mechanisms to query GLP1R and related metabolic and appetite regulatory networks with disease associations. We examined integrated gene–gene and protein–protein interactions, pathways, molecular functions, associated diseases, and biological processes for GLP1R, that reportedly involved in diabetes and obesity. GLP1R signaling cascades were described with the activation of the adenylate cyclase-modulating G protein-coupled receptor and increased intracellular cyclic AMP, collectively impacting glucagon production, insulin, glycogenolysis, vasoactive intestinal peptide, and other peptides and hormones required for satiety. Additional factors found were obesity-related peptides (i.e., POMC), hormone signaling, renin secretion, electrolytes and diuresis, circadian rhythm, and insulin secretion. These associations and interactions shift from hypoglycemia to broader endocrine dysfunction. A relationship was noted for GNAS having a role in growth, electrolytes, and skeletal disturbances with specific hormone sensitivity patterns. Understanding established and new interactions with genetics and gene-protein variants that impact type 2 diabetes and obesity would provide further insight into therapeutic GLP1R agonists response and consequences. Potential long-term systemic effects should be monitored, studied, and recorded with treatment protocols adjusted accordingly. 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

Preeclampsia (PE) and intrauterine growth restriction (IUGR) are major pregnancy complications that are linked to placental dysfunction and environmental stimulation such as the use of electronic cigarettes (eCig). This study investigates the molecular impacts of timed eCig exposure in a C57BL/6 mouse model of PE and IUGR using bulk RNA-sequencing of placental tissues. Pregnant mice were exposed to eCig vapor via nose-only system starting at embryonic day 12.5 (eCig-6d, before spiral artery (SA) invasion) or 14.5 (eCig-4d, after SA invasion) until E18.5 (necropsy), with healthy controls exposed to room air (n = 6/group). The eCig-4d group developed PE, whereas the eCig-6d group developed both PE and IUGR. RNA-seq analysis revealed 429 differentially expressed genes (DEGs) in eCig-4d (IUGR-like) group and 64 DEGs in eCig-6d (PE + IUGR-like) group compared to controls. Pathway and gene network analyses indicated that eCig-4d exposure activated NF-κB–driven inflammation, suppressed ECM organization and collagen biosynthesis, and downregulated vasoactive genes/mitochondrial-associated genes (NOS1/2), accompanied by impaired complement initiation and reduced both macrophage and monocyte signals. Similarly, eCig-6d exposure led to downregulation of complement-associated genes and granule-related components, possibly implicating weakened neutrophil responsiveness and compromised inflammatory resolution at the maternal–fetal interface. Our findings align with prior studies on physiological dysfunctions in PE and IUGR, while also providing novel insights into the temporally specific cellular responses induced by eCig exposure. Full article

Purpose: This study sets out to analyze the correlation of ET-1, a vasoactive peptide, along with various cytokines and vascular factors, with clinical parameters and OCT/OCT-A measurements in glaucoma participants. Methods: Eyes of participants with cataract (n = 30) or glaucoma (n = 87) were examined with optical coherence tomography (OCT) and OCT angiography (OCT-A). Aqueous humor (AqH) from the examined eye and plasma were sampled during cataract or glaucoma surgery and analyzed by means of ELISA and Luminex assay to determine their levels of ET-1 and 35 proteins deemed relevant for regulation of the AqH outflow pathway, ocular perfusion (OP), and glucose metabolism. Results: Glaucomatous eyes are characterized by reductions in RNFL thickness and OP, reflected by reduced vessel density. Furthermore, significantly elevated peripheral ET-1 levels were detected in participants with glaucoma. In addition, significantly elevated AqH levels of MMP-2, MMP-3, ET-1, sEMMPRIN, ZAG, sLOX-1, follistatin, cortisol, endostatin, sTIE-2, and PDGF-BB were detected in the glaucomatous eyes, with correlation to reduced VD for APN, C3a, MMP-3, resistin, sTIE-2, and ZAG. Multivariable analysis showed a correlation of AqH APN levels with the reduced VD in glaucomatous eyes. Conclusions: The peripheral ET-1 level and the intraocular levels of APN, C3a, MMP-3, resistin, sTIE-2, and ZAG are associated with impaired OP in glaucoma. Furthermore, elevated intraocular levels of MMP-3, ZAG, and APN were identified as biomarkers for impaired perfusion in glaucoma. Full article

Backgrounds/Objective: The impact of metabolic disturbances induced by an unbalanced diet on cognitive decline in mid-life is now widely observed, although the mechanisms are not well identified. Here we report that glutamatergic vasoactive pathways are a key feature of high-fat-diet (HFD)-induced neurogliovascular uncoupling in mice. Methods: C57Bl6/J mice are fed either with normal diet (ND) or high-fat diet (HFD) during 6 or 12 months and characterized for metabolic status. Cerebral vascular tree from pial to intraparenchymal arteries, is investigated with Halpern’s arteriography and with differential interference contrast infrared imaging of brain slices. Results: A 70% alteration in the myogenic tone of the basilar artery is observed as early as 6 months (M6) after the HFD. Infrared imaging revealed a 77% reduction in the glutamate-induced vasodilation of intraparenchymal arterioles appearing after 12 months (M12) of the HFD. The respective contributions of enzymes involved in glutamatergic pathways were altered as a function of HFD and time. The decrease in astrocytic COX I observed at M6 was followed by a loss of neuronal COX II and a compensatory action of NOS at M12. Conclusions: This HFD-induced neurogliovascular uncoupling pathway offers therapeutic targets to consider for improving cerebral vasoactive functions while preventing peripheral metabolic disturbances. Full article

Hyperbaric oxygenation (HBO₂) can modify gene and protein expression, signaling pathways, and vascular function, leading to altered vasomotor responses. Adenosine receptors (ARs) may mediate these effects by modulating vasoactivity. This study investigated flow-induced dilation (FID) and hypoxia-induced dilation (HID) in the presence or absence of A1R/A2aR agonists (CCPA and CGS-21680, respectively) and antagonists (DPCPX and SCH-58261, respectively) in isolated middle cerebral arteries (MCAs) from Sprague Dawley rats of both sexes and the direct dose-dependent effects of A1R and A2aR agonists on the vascular reactivity of MCAs. Rats were exposed to either acute HBO₂ (Ac-HBO₂) or intermittent HBO₂ over four days (In-HBO₂). Ac-HBO₂ impaired vascular responses to A1R and A2aR agonists and significantly decreased FID and HID. In both Ac-HBO₂ and In-HBO₂, A1R modulation did not significantly affect FID or HID. A2aR stimulation reduced FID in the In-HBO₂ group, while A2aR antagonism had no significant effect on HID. However, the A2aR agonist’s presence enhanced HID in In-HBO₂-exposed rats. Protein expression of A1R and A2aR decreased after Ac-HBO₂, while gene expression increased following In-HBO₂. These findings suggest that ARs play a role in HBO₂-induced vasoreactivity, which possibly changes in MCA, potentially via the modulation of ARs gene and protein expression. Full article

Retinoic acid (RA), a vitamin A derivative, has been shown to prevent the development of neurological disorders by ensuring the integrity of the physiological structure of the neurovascular unit and regulating the physiological cell’s function. After an ischemia event, RA reduces the effects of blood–brain barrier disruption by blocking the apoptotic signaling pathway. However, the effect of RA on smooth muscle cells (SMCs), which are crucial to maintaining blood perfusion, has never been investigated. This study aimed to evaluate the effect of RA on the vasoactive response of middle cerebral artery SMCs in normal and ischemic contexts (O₂ and glucose deprivation, OGD). For this purpose, SMCs cultures were incubated with RA, and the vasoactive response was evaluated in both conditions (OGD and non-OGD). To simulate OGD, co-cultures of neurons and astrocytes were made and incubated with RA to analyze the effect of the secretome released by these cells on SMCs contractility. In non-OGD conditions, RA induced rapid relaxation of SMCs and, in the long term (24 h), promoted cell contraction. In OGD conditions, SMCs contractility patterns were different when pre-incubated with RA. In these conditions, NA loses its contractility effect, and SNP seems to revert its relaxant effect. However, SMCs pre-incubated with 5 uM RA show the vasorelaxant pattern typical of SNP, despite the OGD condition. These effects demonstrate an effect of RA on the vasoactive profile of SMCs, with therapeutic potential in OGD conditions. Full article

Bisphenol A (BPA) is the most used widely synthetic compound for the manufacture of polycarbonate plastics and epoxy resins produced worldwide. Given its androgenic and estrogenic activities, BPA is an endocrine disruptor that is linked to neurological and vascular outcomes, including strokes. Therefore, this study aims to investigate the mechanisms by which a 24 h exposure to BPA (0.002–20 μM) modifies the contractile function of rat middle cerebral artery (MCA) smooth muscle cells (SMCs). Thus, MCA explants were isolated from Wistar rats, and the SMC-MCA vasoactive response was assessed using planar cell surface area, while the gene expression of proteins and ion channel subunits involved in the MCA vasoactive response was evaluated by real-time quantitative PCR. The exposure to BPA (0.02 and 2 μM) decreased the noradrenaline (NA) vasocontractile response and sodium nitroprusside (SNP) vasorelaxant response. Moreover, exposure to BPA (0.02 and 2 μM) increased the gene expression of the soluble guanyl cyclase protein and the large conductance Ca²⁺-activated K⁺ channels (1.1 α-subunit). These results suggest an impairment of the SMC-MCA vasoactive response induced by intermediate BPA concentrations, an effect not attained for the lowest or highest exposure concentrations (non-monotonic inverted U-shaped response). In summary, these findings suggest that BPA exposure modifies MCA vascular homeostasis by interfering with the nitric oxide (NO) pathway and may, thus, be involved in ischemic stroke development. Full article

Diabetic nephropathy (DN) is a progressive microvascular disorder of diabetes that contributes as a primary reason for end-stage renal disease worldwide. The pathological hallmarks of DN include diffuse mesangial expansion, thicker basement membrane of glomeruli, and arteriole hyalinosis. Hypertension and chronic hyperglycemia are the primary risk factors contributing to the occurrence of DN. The complex pathophysiology of DN involves the interplay amongst metabolic and hemodynamic pathways, growth factors and cytokines production, oxidative stress, and ultimately impaired kidney function. Hyperglycemia-induced vascular dysfunction is the main pathological mechanism that initiates DN. However, several other pathogenic mechanisms, such as oxidative stress, inflammatory cell infiltration, and fibrosis, contribute to disease progression. Different vasoactive hormone processes, including endothelin and renin–angiotensin, are activated as a part of the pathophysiology of DN, which also involves increased intraglomerular and systemic pressure. The pathophysiology of DN will continue to be better understood because of recent developments in genomics and molecular biology, but attempts to develop a comprehensive theory that explains all existing cellular and biochemical pathways have been thwarted by the disease’s multifactorial nature. This review extensively discusses the current understanding regarding the metabolic and hemodynamic pathological mechanisms, along with other signaling pathways and molecules responsible for the pathogenesis of DN. This work will encourage a greater in-depth understanding and investigation of the present status of the biochemical mechanistic processes underlying the pathogenesis of DN, which may assist in the determination of different biomarkers and help in the design and development of novel drug candidates in the near future. Full article

Background/Objectives: Sepsis has been shown to depress arterial baroreceptor function, and this effect is counterbalanced by the cholinergic anti-inflammatory pathway. Considering the importance of central adenosine receptors in baroreceptor function, this study tested whether central adenosine A3 receptors (A3ARs) modulate the cholinergic-baroreflex interaction in sepsis and whether this interaction is modulated by mitogen-activated protein kinases (MAPKs) and related proinflammatory cytokines. Methods: Sepsis was induced by cecal ligation and puncture (CLP) and rats were instrumented with femoral and intracisternal (i.c.) catheters. Baroreflex sensitivity (BRS) was measured 24 h later in conscious animals using the vasoactive method, which correlates changes in blood pressure caused by i.v. phenylephrine (PE) and sodium nitroprusside (SNP) to concomitant reciprocal changes in heart rate. Results: The reduction in reflex bradycardic (BRS-PE), but not tachycardic (BRS-SNP), responses elicited by CLP was reversed by i.v. nicotine in a dose-related manner. The BRS-PE effect of nicotine was blunted following intracisternal administration of IB-MECA (A3AR agonist, 4 µg/rat). The depressant action of IB-MECA on the BRS facilitatory action of nicotine was abrogated following central inhibition of MAPK-JNK (SP 600125), PI3K (wortmannin), and TNFα (infliximab), but not MAPK-ERK (PD 98059). Additionally, the nicotine suppression of sepsis-induced upregulation of NFκB and NOX2 expression in the nucleus tractus solitarius (NTS) was negated by A3AR activation. The molecular effect of IB-MECA on NFκB expression disappeared in the presence of SP 600125, wortmannin, or infliximab. Conclusions: The central PI3K/MAPK-JNK/TNFα pathway contributes to the restraining action of A3ARs on cholinergic amelioration of sepsis-induced central neuroinflammatory responses and impairment of the baroreceptor-mediated negative chronotropism. Full article

The complement system includes soluble and cell surface proteins and is an important arm of the innate immune system. Once activated, the complement system rapidly generates proteins with inflammatory and vasoactive activities. Although complement is crucial to host defense and homeostasis, its inappropriate or uncontrolled activation can also drive tissue injury. Glomerulopathy encompasses a spectrum of diseases with diverse etiologies, clinical presentations, and outcomes. Among the intricate web of factors contributing to glomerulopathies pathogenesis, the role of complement activation has emerged as a focal point of research interest and therapeutic intervention. The pioneer drug was eculizumab, which made it possible to drastically change the prognosis of atypical hemolytic uremic syndrome, an otherwise fatal disease. This comprehensive review aims to elucidate the multifaceted interplay between complement pathways and glomerulopathies, shedding light on potential pathways for targeted therapies and improved patient care. Full article