Search Results (3,782)

Background and Objectives: Inhaled corticosteroids exert broad immunomodulatory effects in patients with chronic airway diseases. However, their direct impact on pulmonary endothelial immune responses and coronavirus-associated receptor expression remains unclear. This study investigated the effects of budesonide on immune responses and the expression of coronavirus entry receptors in human lung microvascular endothelial cells (HMVEC-L). Materials and Methods: HMVEC-L cells were exposed to budesonide (1 ng/mL), a non-cytotoxic concentration selected based on cell viability assays. The mRNA expression of angiotensin-converting enzyme 2 (ACE2), dipeptidyl peptidase-4 (DPP4), aminopeptidase N (AP-N), intercellular adhesion molecule 1 (ICAM-1), interferon beta (IFN-β), RANTES/CCL5, and interleukin-8 (IL-8/CXCL8) was analyzed using quantitative RT-PCR. The surface expression of ACE2, DPP4, AP-N, and ICAM-1 was assessed using flow cytometry. Secreted IL-8 concentration was measured using ELISA. Results: Budesonide significantly reduced AP-N and DPP4 mRNA expression, accompanied by a decrease in the surface expression of both receptors. ACE2 mRNA expression was transiently reduced, whereas ACE2 surface expression was modestly increased by approximately 5% at 72 h. Budesonide also reduced early ICAM-1 mRNA expression but increased its surface expression at the later time point. Budesonide significantly reduced RANTES/CCL5 and IL-8/CXCL8 mRNA expression, with a corresponding decrease in secreted IL-8 concentration, whereas IFN-β mRNA expression showed a non-significant statistical decrease. Conclusion: Budesonide directly modulates pulmonary endothelial immune responses and coronavirus-associated receptor expression. These findings indicate that budesonide modulates the expression of coronavirus-associated receptors and basal antiviral and inflammatory mediators in HMVEC-L cells. Because viral binding, entry, replication, and infection were not assessed, these results should be interpreted as evidence of receptor and immune-mediator modulation rather than as demonstrating altered coronavirus susceptibility. Full article

Cancer therapy-related cardiac dysfunction (CTRCD) is a significant complication of anthracycline-based regimens and anti-HER2 agents. Global longitudinal strain (GLS) detects subclinical dysfunction before ejection fraction decline and is recommended by the 2022 ESC guidelines for surveillance. Sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor, has shown cardioprotective potential in recent trials. Following PRISMA 2020 guidelines, we searched PubMed, EMBASE, and Cochrane CENTRAL through February 2026. Three RCTs met eligibility criteria (n= 350; PROSPERO: CRD420261383124): Hsu 2025 (n = 100, 12 months), PRADA II 2025 (n = 138, 18 months), and SARAH 2025 (n = 112, 6 months). Random-effects meta-analysis used REML with Hartung–Knapp–Sidik–Jonkman adjustment. The pooled mean difference in final GLS significantly favored sacubitril/valsartan (MD −0.95%; 95% CI −1.40 to −0.50; p = 0.012; I² = 0%). Final LVEF showed a consistent trend (MD +1.53%; 95% CI −0.47 to 3.52; p = 0.082; I² = 0%). Hypotension was numerically more frequent with sacubitril/valsartan (OR 5.10; 95% CI 0.52–49.50; p = 0.091). Sacubitril/valsartan initiated during anthracycline therapy was associated with significant GLS preservation. However, GLS is a surrogate imaging marker and hard clinical events were rare or absent, so the modest effect magnitude and limited number of trials warrant cautious interpretation; the clinical benefit remains uncertain and requires confirmation in adequately powered trials with hard clinical endpoints. Full article

Hypertension is a prevalent disorder that results in millions of deaths worldwide. In this regard, timely diagnosis and effective treatment are paramount for maintaining optimal blood pressure levels in the early stages of the disease. The objective of the present study was to synthesize and assess the effect of peptides derived from chia seeds that had undergone fermentation with Lacticaseibacillus paracasei strain 2501 (hereinafter referred to as LPDP, i.e., L. paracasei-derived products from this fermentation) on the angiotensin-converting enzyme (ACE) and the spontaneously hypertensive rat model (SHR). LPDP exhibited competitive inhibition, as evidenced by the identification of seven peptides in the <1 kDa fraction by HPLC-QToF-MS. The LPDP exhibited an IC₅₀ of 11.1 μg/mL on ACE. The oral administration of 50 mg/kg body weight (BW) to SHR over a 14-day period resulted in a significant reduction in systolic pressure from 152 to 87 mmHg, accompanied by a substantial decrease in diastolic pressure from 117 to 74 mmHg. It is noteworthy that doses of 500 mg/kg BW led to a significant reduction in systolic pressure, from 154 to 68 mmHg and diastolic pressure, from 117 to 42 mmHg under identical experimental conditions. The hematological profiling of the assayed animals revealed that LPDP has no adverse effects at the cellular or biochemical level. These findings indicate the anti-hypertensive properties of LPDP and its possible application in the treatment of blood pressure. Full article

Background: Heart transplantation (HT) remains the definitive therapy for end-stage heart failure, yet rejection and cardiac allograft vasculopathy (CAV) continue to limit long-term outcomes. Beyond donor-specific HLA antibodies, non-HLA antibodies, particularly anti-angiotensin II type 1 receptor antibodies (AT1R-Abs), have been implicated in allograft injury, but published findings are heterogeneous. Aim: The aim of this study is to systematically evaluate the evidence linking AT1R gene expression and anti-AT1R antibodies with key post-heart transplant outcomes. Methods: We conducted a systematic review in accordance with PRISMA guidelines. Scopus, PubMed, Web of Science, and the Cochrane Library were searched (December 2025) for cohort and case–control studies evaluating AT1R gene expression and/or AT1R-Ab status in HT recipients and their association with post-transplant outcomes. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the NIH Quality Assessment Tool. Results: Twelve studies encompassing 951 recipients met the inclusion criteria. Five studies evaluated AT1R mRNA expression, reporting variable patterns: several observed reduced AT1R/AT2R transcription after transplantation without clear clinical correlation, whereas others associated higher donor or recipient AT1R expression with transplant coronary artery disease and recurrent rejection. AT1R-Ab prevalence varied widely and appeared to increase after mechanical circulatory support, with substantial seroconversion reported during LVAD support in initially antibody-negative patients. Associations between AT1R-Ab and acute cellular rejection and antibody-mediated rejection were inconsistent across studies, and survival findings were inconclusive; however, some reports linked elevated AT1R-Abs to poorer long-term freedom from adverse events. Evidence regarding CAV was mixed, with signals of increased vasculopathy risk in some cohorts but not others. Conclusions: Current evidence suggests a potential role for AT1R expression and AT1R-Abs in cardiac allograft dysfunction, including rejection phenotypes and vasculopathy. Larger prospective studies with harmonized testing strategies are needed to define clinically meaningful AT1R-Ab cutoffs and clarify their utility in risk stratification and targeted therapeutic trials. Full article

The carotid body (CB) is an interoceptive organ that transmits afferent information to the brain via the carotid sinus nerve (CSN) to maintain homeostasis, i.e., the regulation of internal equilibrium despite external changes. It functions as a complex polymodal receptor capable of sensing multiple stimuli, including blood flow, osmolarity, pO₂, pH, pCO₂, CO₂/H⁺, and temperature. In addition, the CB responds to a wide range of circulating molecules such as angiotensin II, endothelin-1, aldosterone, insulin, histamine, and leptin, and expresses receptors for interleukins (ILs) and tumor necrosis factor-α (TNF-α) (1). CB dysfunction has been associated with conditions such as obstructive sleep apnea (OSA), in which intermittent hypoxemia induces an inflammatory response mediated, among other mechanisms, by reactive oxygen species (ROS). This process contributes to alterations in respiratory drive and enhanced sympathetic nervous system activity. Following streptococcal toxic shock syndrome due to Streptococcus Pyogenes, severe abdominal septic shock, and multiple infectious complications, our patient developed an altered respiratory pattern and a hypercatabolic state that precluded weaning from mechanical ventilation (MV) despite respiratory physiotherapy. Given treatment failure, we hypothesized underlying carotid body (CB) hyperexcitability, likely pre-existing due to obstructive sleep apnea (OSA) and exacerbated by cytokine storm and severe systemic inflammation related to Strept. Pyogenes toxins and subsequent abdominal sepsis from colonic perforation. This may have contributed to sustained sympathetic overactivation and immune dysregulation. Clinically, the patient exhibited increased respiratory drive (30–35 breaths/min), excessive inspiratory effort, and marked patient–ventilator asynchrony in the absence of hypoxemia. Non-targeted physiotherapy may have acted as a second inflammatory hit, perpetuating the inflammatory cycle. Full article

Background: Migrated foreign bodies in the prevertebral region represent a rare but potentially serious condition. This case underscores the importance of thorough visual and digital intraoperative exploration for successful foreign body retrieval and highlights the potential diagnostic and surgical challenges associated with migrated foreign bodies in the cervical region. Case report: A 77-year-old female patient presented with dysphagia following the intake of an Angiotensin-Converting Enzyme (ACE) inhibitor. Due to hemodynamic instability and laboratory findings that indicated multiple organ failure, a computed tomography (CT) scan was performed, which revealed a left-sided prevertebral abscess with gas collections. Because of persistently elevated and fluctuating inflammatory markers, multiple CT scans were performed, which showed an obliquely oriented, wire-like tubular structure approximately 30 mm in length, 5 mm in width and 1 mm in diameter in the prevertebral region of the previous abscess cavity. Eventually, after three surgical interventions—one transoral and two transcervical approaches—the foreign body could be identified and removed. Afterwards, the patient’s inflammatory markers decreased and her dysphagia resolved. Conclusions: This case demonstrates that early diagnosis and timely removal of foreign bodies in the cervical space are essential to prevent complications such as retropharyngeal abscess formation or mediastinitis. A combination of careful clinical examination, endoscopic evaluation, and cross-sectional imaging—particularly CT scan—is crucial for accurate localization. Finally, this report highlights the importance of maintaining a high index of suspicion for migrated foreign bodies in patients presenting with persistent symptoms or unexplained cervical infections following suspected foreign body ingestion. Full article

Background: Cardiometabolic syndrome is a cardiovascular disease characterized by metabolic dysregulation, with obesity triggering overactivation of the cardiac Renin–Angiotensin System (RAS). This leads to pathological cardiac changes and dysfunction. Empagliflozin (EMPA) modulates local RAS components in the kidney and liver, but its role in regulating cardiac RAS needs further study. Methods: Twenty-four male Wistar rats were separated into the following two groups: (1) control and (2) metabolic syndrome (MS) fed a high-fat diet, and after 8 weeks, half of each group was treated with EMPA (10 mg/kg) for 8 subsequent weeks. Finally, the animals underwent echocardiography, and under sodium thiopental anesthesia, blood samples were taken for FBS and lipid profile measurement. Finally, the left ventricle was isolated and used to measure the levels of proteins in the RAS pathway, including AngII (Angiotensin2), AT1R (Angiotensin2type1receptor), AT2R (Angiotensin2type2 receptor), and downstream pathway proteins pERK1/2 (Phosphorylated Extracellular Signal-Regulated Kinase1/2), NHE1 (Na+/H+ Exchanger1), NCX (Na+/Ca²+Exchanger), and NLRP3 (NOD-like-receptor-protein3) by Western blot, as well as ROS (reactive oxygen species) levels by ELISA. Results: EMPA treatment in MS significantly decreased FBS, TG, and LDL, increased HDL, and improved cardiac function. It was also associated with increased AT2R expression and attenuation of AngII, AT1R, pERK1/2–NHE1–NCX signaling, oxidative stress, and inflammatory markers (ROS and NLRP3) in rats with MS. Conclusion: Our findings suggest that EMPA treatment is associated with improvement in selected local cardiac RAS components and modulation of the pERK1/2–NHE1–NCX signaling pathway, along with reduced oxidative stress, decreased inflammation, and improved cardiac function in MS. Full article

Tilapia (Oreochromis niloticus) scales represent an underutilized by-product with considerable potential as a source of bioactive peptides that can be released through enzymatic hydrolysis. This study evaluated the production of protein hydrolysates from demineralized tilapia scales using Alkaline Protease or Esperase 8.0 L^® (Alkaline Protease and Esperase 8.0 L® were kindly provided by Novozymes, Bagsværd, Denmark), and examined the impact of simulated gastrointestinal digestion (SGID) on their bioactivities. The highest degree of hydrolysis (DH) was obtained with Alkaline Protease (12.4%), generating peptide fractions predominantly below 1000 Da, with a major population around 888 Da. Both hydrolysates exhibited antioxidant activity, with the Alkaline Protease hydrolysate showing higher ferric reducing antioxidant power (FRAP) and Fe(II)-chelating activity. The hydrolysates also displayed significant angiotensin-converting enzyme (ACE) inhibitory activity (IC₅₀: 13–14 µg/mL), dipeptidyl peptidase IV (DPP-IV) inhibitory activity (IC₅₀: 0.66–0.69 mg/mL), and prolyl endopeptidase (PEP) inhibitory activity (IC₅₀: 0.63–0.72 mg/mL). The digests were non-cytotoxic at the concentrations tested (<10 mg/mL) in STC-1 enteroendocrine cells. Following SGID, increased ACE-inhibitory activity was observed, with IC₅₀ values as low as 4.6 µg/mL, whereas DPP-IV and PEP-inhibitory activities decreased. The intestinal digest of the Esperase hydrolysate also exhibited significant cellular antioxidant activity in the ROS assay. Overall, these results indicate that tilapia scale hydrolysates are a promising source of peptides associated with in vitro enzyme inhibitory and antioxidant activities. However, the specific bioactive peptides responsible for these effects were not identified. Therefore, further studies involving peptide characterization, bioavailability assessment, and in vivo validation are required to establish their physiological relevance and potential applications as functional ingredients. Full article

Hypertension threatens the health of aging captive giant pandas, yet its molecular signatures remain poorly characterized. Here, multi-omics sequencing was applied to explore the molecular regulatory process of hypertension and the pharmacodynamic effect of levamlodipine on this endangered species. Six aged giant pandas were divided into hypertensive and normotensive groups (three hypertensive and three normotensive pandas) based on clinical phenotypes and blood pressure measurements. A multi-omics approach was employed, including blood RNA-seq, Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq), single-cell RNA-seq (scRNA-seq) of peripheral blood mononuclear cells, and time-series RNA-seq following levamlodipine administration. Our transcriptomic analysis revealed a statistically significant decline in ACE2 transcript abundance (Padj < 0.05), which suggests a possible shift in renin–angiotensin system signaling linked to hypertensive status in giant pandas. Single-cell analysis of 88,693 cells revealed that hypertension-associated genes were predominantly enriched in monocytes and T cells, implicating immune cell activation. Time-dependent transcriptional changes after levamlodipine administration. Temporal gene dynamics showed early activation of metabolic pathways followed by delayed inhibition of ion channels and calcium signaling. This study provides a transcriptional molecular perspective into the pathogenesis of hypertension in giant pandas, which is conducive to developing more effective antihypertensive treatment strategies, thereby protecting the health of this endangered species. Full article

Background: Long COVID is a heterogeneous post-viral condition in which persistent neurological, autonomic, cognitive, and psychometric symptoms often occur without clear isolated biomarker abnormalities. This mismatch suggests that disease persistence may be driven not only by changes in individual markers, but by longitudinal reorganization of biological and clinical interactions. Materials and Methods: This observational longitudinal study evaluated patients with persistent symptoms after confirmed SARS-CoV-2 infection at 3 and 6 months. Clinical assessment included neurological examination, Hospital Anxiety and Depression Scale, Beck Depression Inventory, and COMPASS-31. Biomarkers representing hypoxia signaling, oxidative/redox stress, endothelial and renin–angiotensin system activity, glycation-related processes, and complement regulation were analyzed. Correlation analysis, association-level biomarker–clinical network modeling, and complementary Graphical LASSO-based sparse network estimation were used to compare network density, community organization, centrality, and edge rewiring between time points. Results: Conventional paired analysis identified HIF-1$\alpha$ as the only continuous variable with a statistically significant longitudinal change (Wilcoxon statistic = 610.0, $p=0.000350$), whereas association-level network analysis revealed a broader systems-level signal. The association-level biomarker–clinical network preserved a similar global size at 3 and 6 months, with 16 nodes, 27 versus 26 edges, and densities of 0.225 versus 0.217. However, this apparent stability concealed substantial rewiring: 19 edges were shared, 8 were lost, and 7 emerged. Complementary Graphical LASSO analysis with 1000 bootstrap resamples supported this pattern by identifying a conservative sparse conditional-dependency core, including seven shared conditional-dependency edges across time points and selective weakening of four early conditional dependencies. The C3–C4 relationship reversed from negative to positive correlation ($r=-0.618$ to $r=0.618$), indicating marked remodeling of complement-associated regulation. A psychometric–autonomic module involving Beck, HADS I, HADS II, and COMPASS-31 remained stable across both assessments. Conclusions: Long COVID progression was characterized by dynamic remodeling of immune, endothelial/RAS, oxidative-redox, hypoxia-related, autonomic, and psychometric interactions. Longitudinal network analysis identified a systems-level interaction structure that was not captured by isolated biomarker comparisons alone and that was further supported by complementary sparse conditional-dependency analysis. Full article

Background and Objectives: Guideline-directed medical therapy (GDMT) remains a challenge due to its low rates worldwide. Adherence to GDMT in patients with heart failure (HF) and reduced ejection fraction (rEF) in the Baltics (Estonia, Latvia, and Lithuania) has been unknown. This is the first study to describe the characteristics of patients with HFrEF and their treatment patterns in the Baltics. Materials and Methods: The EVOLUTION-HF study was a longitudinal, real-world evidence study that enrolled patients with HFrEF following newly initiated sodium–glucose cotransporter-2 inhibitor (SGLT2i) dapagliflozin therapy. In total, 12 study sites (four from each country) were included. Patients were followed up for 12 months. A pooled data set including adherence to GDMT, dapagliflozin’s usage, and patients’ profiles was evaluated. Results: Between April and December 2022, 178 patients with a median left ventricular ejection fraction of 32% were enrolled. At baseline, 155 (87%) patients received renin–angiotensin–aldosterone system inhibitors (RAASi), 168 (94%) received beta-blockers (BB), and 106 (60%) received mineralocorticoid receptor antagonists (MRA); however, only 47.8% of the study population were found to be treated with GDMT (including RAASi, BB, MRA, and dapagliflozin) at the beginning of the study. At the end of the follow-up, the percentage of GDMT users decreased to 42.3%. The number of dapagliflozin discontinuations per 100 patient-years was found to be 13.2 (95% CI 8.2–18.2). Conclusions: The findings indicate a low rate of dapagliflozin discontinuation (13%) and an overall suboptimal proportion of patients receiving GDMT for HFrEF (almost half of the patients). The low rate of GDMT use in the Baltics prompts great attention. Additional research and incremental joint efforts are needed to ensure an increase in GDMT use across diverse HF patient populations. Full article

In this study, Apocynum venetum was employed as the raw material to optimize protein extraction and enzymatic hydrolysis processes for the preparation of highly active angiotensin-converting enzyme (ACE)-inhibitory peptides, achieving an ACE inhibition rate of 92.34%. Multispectral analyses and microstructural characterization demonstrated that enzymatic hydrolysis induced the unfolding of protein secondary structures, resulting in a looser and more porous morphology enriched with characteristic amino acids. A total of 2567 peptide sequences were identified by LC–MS/MS, among which 18 potential bioactive peptides were screened. Molecular docking analysis revealed that these peptides interact with the active site of ACE primarily through hydrogen bonding and hydrophobic interactions, with WLRDFL exhibiting the strongest binding affinity. This study systematically elucidates the structural characteristics and antihypertensive molecular mechanisms of ACE-inhibitory peptides derived from Apocynum venetum, providing both theoretical insights and experimental support for the development of natural antihypertensive functional foods and the high-value utilization of this plant. Full article

Amphibian malformation syndromes significantly impact both conservation efforts and aquaculture, yet their underlying systemic pathophysiological mechanisms remain poorly characterized. This study comprehensively examines the multi-level pathological processes associated with the “short-leg” malformation syndrome in the black-spotted frog (Pelophylax nigromaculatus) using an integrated methodology, encompassing morphological, histopathological, gut microbiome, and hepatic transcriptomic analyses. Affected frogs demonstrated shortened limbs, impaired motor function, and a distinctive metabolic phenotype, including increased body weight despite a shorter body length, accumulation of visceral fat, and shortened intestines. Gut microbiota analysis identified significant compositional shifts, characterized by a decreased Firmicutes-to-Bacteroidota ratio, expansion of pro-inflammatory Proteobacteria, and reduction in beneficial Actinobacteriota, suggesting microbial niche restructuring that likely promotes metabolic and inflammatory disorders. Hepatic transcriptome profiling revealed 2617 differentially expressed genes, demonstrating a clear molecular dichotomy with concurrent up-regulation of immune-related pathways (e.g., neutrophil extracellular trap formation, complement cascades, and inflammatory signaling) and broad suppression of metabolic pathways (e.g., lipid oxidation, nutrient absorption, and PPAR and renin–angiotensin systems). This integrated analysis illustrates that the malformation syndrome represents a systemic pathophysiological state involving dysfunction of the gut–liver axis, characterized by the coexistence of gut microbiota alterations, hepatic metabolic suppression, and immune activation. These findings provide a framework for understanding amphibian malformations and suggest potential strategies to improve health outcomes in aquaculture. Full article

Membranous nephropathy (MN) is a leading cause of nephrotic syndrome (NS). The remission rate of MN remains limited, and effective strategies for refractory MN are not established. We present the case of a 49-year-old Japanese woman with severe NS caused by MN. Kidney biopsy revealed glomerular basement membrane thickening with granular deposition of immunoglobulin G (IgG) and complement component 3. IgG subclass analysis showed predominant IgG1 deposition, with weak IgG2 and IgG3 deposition. Phospholipase A2 receptor (PLA2R) deposition was equivocal in the first kidney biopsy and negative in the second. Serum anti-PLA2R antibody was not detected. Electron microscopy revealed subepithelial, subendothelial, and mesangial electron-dense deposits. Detailed screening revealed no significant abnormalities other than appendiceal findings, suggesting secondary MN associated with appendiceal infection. Although combined therapy with prednisolone, cyclosporine, rituximab, and low-density lipoprotein apheresis was administered during the first 6 months, remission of MN was not achieved. During dialysis, initiated because of kidney failure, long-term multidisciplinary management, including control of appendiceal infection and inflammation and initiation of angiotensin II receptor blocker therapy, ultimately led to remission of MN and discontinuation of dialysis. Overall, even refractory MN requiring dialysis may have a reversible clinical course with careful conservative management and long-term follow-up. Full article

Kefir is a probiotic beverage produced by symbiotic bacteria and yeasts. Polysaccharide-rich extracts from yellow and black soybeans (S and B) were obtained and subsequently fermented to produce S-F and B-F. The fermented extracts were further subjected to oxidative degradation using ascorbic acid and hydrogen peroxide to generate S-FD and B-FD. Physicochemical analyses revealed distinct differences in composition, phenolic profiles, and molecular weight among S-F, S-FD, B-F, and B-FD. Fourier transform infrared (FTIR) spectra indicated that oxidative degradation altered specific functional group intensities without disrupting the fundamental polysaccharide framework. Fermentation enhanced angiotensin-converting enzyme (ACE) inhibitory activity, and subsequent oxidative degradation further improved this effect. Both fermented and degraded extracts exhibited antioxidant activities, including 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging capacity, ferrous-ion chelating ability, and reducing power, with degraded samples showing greater activity. The effects of the extracts on SH-SY5Y human neuroblastoma cells were evaluated in vitro. No cytotoxicity was observed at concentrations up to 400 μg/mL. Treatment at 200 μg/mL increased cell viability and reduced apoptosis in rotenone (ROT)-treated cells. Multivariate analysis further indicated that oxidative degradation enhanced antioxidant and ACE inhibitory activities but may reduce the protective effects observed in SH-SY5Y cells. Overall, soybean-derived kefir polysaccharide-rich extracts show potential as functional ingredients for applications related to blood pressure regulation and antioxidant activity, while their protective effects in neuronal cell models warrant further investigation. Full article