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BACKGROUND: Although VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) have been associated with incident heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF), the associations of VCAM-1 and ICAM-1 with sensitive measures of cardiac structure/function are unclear. The objective of this study is to evaluate associations between VCAM-1, ICAM-1, and measures of cardiac structure and function as potential pathways through which cellular adhesion molecules promote HFpEF and AF risk. METHODS AND RESULTS: In MESA (Multi-Ethnic Study of Atherosclerosis), we evaluated the associations of circulating VCAM-1 and ICAM-1 at examination 2 (2002-2004) with measures of cardiac structure/function on cardiac magnetic resonance imaging at examination 5 (2010-2011) after multivariable adjustment. Mediation analysis of left atrial (LA) strain on the association between VCAM-1 or ICAM-1 and AF or HFpEF was also performed. Overall, 2304 individuals (63±10 years; 47% men) with VCAM-1 or ICAM-1, cardiac magnetic resonance imaging, and covariate data were included in analysis. Higher VCAM-1 and ICAM-1 were associated with lower LA peak longitudinal strain and worse global circumferential left ventricular strain but were not associated with left ventricular myocardial scar or interstitial fibrosis. Lower LA peak longitudinal strain mediated 8% (95% CI, 2-30) of the relationship between VCAM-1 and HFpEF and 9% (95% CI, 2-21) of the relationship between VCAM-1 and AF. CONCLUSIONS: Higher VCAM-1 and ICAM-1 were associated with lower LA function and left ventricular systolic function but were not associated with myocardial scar or interstitial fibrosis. VCAM-1 and ICAM-1 may promote HFpEF and AF risk through impaired LA reservoir function.

Vascular cell adhesion molecule-1 (VCAM-1) and E-selectin are involved in different inflammatory diseases and may be potential cardiovascular risk biomarkers in psoriasis. They play an important role in regulating the recruitment and adhesion to endothelial cells during inflammation, affecting various conditions like vasculitis, atherosclerosis, and cardiovascular diseases. Positive outcomes have been observed when using Tumor Necrosis Factor Alpha (TNF-α) inhibitors and biological therapies that target selectins to control the functioning of endothelial cells and reduce inflammation in psoriasis and related conditions. Moreover, the effects of systemic treatments and ultraviolet B (UVB) phototherapy on VCAM-1 and E-selectin levels in psoriasis patients highlights the potential to impact the severity of psoriasis and activation of endothelial cells. In addition, various factors such as age, sex, metabolic syndrome, hyperglycemia, migraines, and tobacco smoking have been found to affect levels of VCAM-1 and E-selectin. This sheds light on understanding the complex relationship between endothelial activation and the development of diseases. Studies show the potential of using the levels of VCAM-1 and E-selectin as indicators of systemic treatment effectiveness and the progression of the disease. In summary, this review highlights the importance of VCAM-1 and E-selectin as potential biomarkers for assessing inflammation, disease severity and cardiovascular risk in individuals with psoriasis. The shared mechanisms of psoriasis and atherosclerosis, along with the effect of treatments on endothelial activation markers, provide significant insights for further research and approaches to manage inflammatory diseases in the future. [ABSTRACT FROM AUTHOR]

The document discusses the critical role of signaling pathways in liver diseases, such as hepatitis, cirrhosis, fatty liver disease, and hepatocellular carcinoma, which contribute to significant morbidity and mortality globally. It highlights the intricate pathogenesis of liver diseases influenced by genetic predisposition, environmental exposures, metabolic disturbances, and immune system dysregulation. The document emphasizes recent advancements in understanding signaling cascades like MAPK, NF-κB, TGF-β, and apoptotic pathways, offering insights into potential therapeutic interventions. The research presented involves 110 authors from eight countries, providing a comprehensive overview of signaling mechanisms in liver pathology, aiming to enhance understanding and develop effective management strategies for liver diseases. [Extracted from the article]

Type H vessels have been proven to couple angiogenesis and osteogenesis. The decline of type H vessels contributes to bone loss in the aging process. Aging is accompanied by the accumulation of advanced oxidation protein products (AOPPs). However, whether AOPP accumulation is involved in age-related decline of type H vessels is unclear. Here, we show that the increase of AOPP levels in plasma and bone was correlated with the decline of type H vessels and loss of bone mass in old mice. Exposure of microvascular endothelial cells to AOPPs significantly inhibited cell proliferation, migration, and tube formation; increased NADPH oxidase activity and excessive reactive oxygen species generation; upregulated the expression of vascular cell adhesion molecule-1 and intercellular cell adhesion molecule-1; and eventually impaired angiogenesis, which was alleviated by redox modulator N-acetylcysteine and NADPH oxidase inhibitor apocynin. Furthermore, reduced AOPP accumulation by NAC treatment was able to alleviate significantly the decline of type H vessels, bone mass loss, and deterioration of bone microstructure in old mice. Collectively, these findings suggest that AOPPs accumulation contributes to the decline of type H vessels in the aging process, and illuminate a novel potential mechanism underlying age-related bone loss. [ABSTRACT FROM AUTHOR]

Background: The objective of the current study was to investigate the potential effects of syringin against dextran sulphate colitis (DSS)‐induced ulcerative colitis (UC) in mice. Material and methods: In vitro study was performed on the RAW 264.7 cells and cytokines and inflammatory level were estimated. The oxidative stress, inflammatory cytokines, apoptosis and inflammatory parameters were estimated. The mRNA expression and faecal samples were estimated in the colon tissue. Results: Syringin treatment enhanced the body weight, colon length and reduced the disease activity index (DAI), spleen index. Syringin treatment remarkably suppressed the level of nitric oxide (NO), myeloperoxidase (MPO), intercellular adhesion molecule‐1 (ICAM‐1) and vascular cell adhesion molecule 1 (VCAM‐1) along with alteration of antioxidant parameters. Syringin treatment also altered level of cytokines in the serum and colon tissue; inflammatory parameters viz., platelet‐activating factor (PAF), cyclooxygenase‐2 (COX‐2), prostaglandin (PGE2), inducible nitric oxide synthetase (iNOS), nuclear factor κ‐B (NF‐κB); matrix metalloproteinases (MMP) level. Syringin significantly (p < 0.001) enhanced the level of nuclear factor erythroid 2‐related factor (Nrf2) and heme oxygenase‐1 (HO‐1). Syringin remarkably altered the relative abundance of gut microbiota like Firmicutes, Bacteroidetes, F/B ratio, Verrucomicrobia and Actinobacteria. Conclusion: Syringin exhibited the protective effect against DSS‐induced UC in mice via alteration of NF‐κB signalling pathway. [ABSTRACT FROM AUTHOR]

Endocannabinoids have been shown to play a complex role in the pathophysiology of a number of cardiovascular disorders. In the present study, the effects of the two major endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were investigated in human coronary artery smooth muscle cells (HCASMC) and human coronary artery endothelial cells (HCAEC) with regard to potential atheroprotective and anti-inflammatory effects. In HCASMC, AEA showed an inhibitory effect on platelet-derived growth factor-induced migration, but not proliferation, independent of major cannabinoid-activatable receptors (CB1, CB2, TRPV1), while 2-AG left both responses unaffected. In HCAEC, AEA at concentrations of 6 and 10 µM significantly inhibited the interleukin (IL)-1β- and lipopolysaccharide (LPS)-stimulated expression of vascular cell adhesion molecule-1 (VCAM-1) and LPS-induced intercellular adhesion molecule-1 (ICAM-1), again independently of the abovementioned receptors. Corresponding effects were observed to a lesser extent in the presence of 2-AG, in most cases not significantly. The detection of activated phosphoproteins as well as experiments with inhibitors of corresponding signaling pathways suggest that AEA interferes with IL-1β-induced VCAM-1 expression via inhibition of protein kinase B/Akt and Src kinase activation and attenuates LPS-induced VCAM-1 and ICAM-1 expression via inhibition of signal transducer and activator of transcription 3 (STAT3) phosphorylation. As expected, AEA also led to a significant inhibition of monocyte adhesion to IL-1β- and LPS-stimulated HCAEC, with siRNA experiments confirming the functional role of VCAM-1 and ICAM-1 in this assay. 2-AG showed a comparatively weaker but, in the case of LPS stimulation, still significant inhibition of adhesion. In summary, the results emphasize the potential of AEA as a protective regulator of atherosclerotic and inflammation-related changes in HCASMC and HCAEC and encourage further corresponding preclinical studies with this endocannabinoid. [ABSTRACT FROM AUTHOR]

The document contains abstracts from the 49th Annual Meeting of the Japanese Society for Microcirculation, covering various topics related to microcirculation research. Topics include intravital imaging of immune cellular dynamics in bones, correlation of VCAM-1 expression with ulcerative colitis, xenophagy and neovascularization in gastric lymphoid follicles, and the effects of water intake on mesenteric lymph flow. Other topics include the activation of the innate immune system in intestinal ischemia-reperfusion injury, the correlation of choroidal pulsatility with cardiovascular risk, and the effects of succinic acid on gut immunity in mice. The document also discusses the spatiotemporal structure of capillary diameter fluctuations in the brain and the effects of lower extremity exercise on oxygen extraction in the gastrocnemius muscle during prolonged sitting. [Extracted from the article]

The article discusses the 32nd CEA symposium held in Würzburg, Germany, focusing on the biology of carcinoembryonic antigen cell adhesion molecules (CEACAMs). It explores the diverse roles of CEACAMs in pathogen-host interactions, immunity, cancer biology, atherogenesis, metabolism, and reproductive biology. The symposium also delves into the potential applications of CEACAMs in cancer diagnosis and therapy, liver disease, transplantation, endothelial signaling, platelet function, and pregnancy. Various laboratories presented research findings on the role of CEACAMs in different biological processes, highlighting their significance in various health and disease contexts. [Extracted from the article]

Simple Summary: CR6 interacting factor 1 (CRIF1) plays an essential role in the regulation of mitochondrial function. We provide important details to demonstrate that CRIF1 deletion-induced mitochondrial damage has an antitumor effect via TIGAR induction in BT549 breast cancer cells. CRIF1 deficiency results in OXPHOS dysfunction, which has been investigated as a potential therapeutic target for the treatment of cancer. Background/Objectives: Mitochondrial oxidative phosphorylation (OXPHOS) has been exploited as a therapeutic target in cancer treatments because of its crucial role in tumorigenesis. CR6-interacting factor 1 (CRIF1), a mitochondrial ribosomal subunit protein, is essential for the regulation of mitochondrial OXPHOS capacity. However, the mechanism of CRIF1 in triple-negative breast cancer (TNBC) cells remains unclear. Methods/Results: We showed that the downregulation of CRIF1 reduced cell proliferation in the TNBC cell lines MDA-MB-468, MDA-MB-231, and, especially, BT549. In addition, wound scratch and Transwell assays showed that CRIF1 deficiency inhibited the migration and invasion of BT549 cells. CRIF1 downregulation resulted in the suppression of mitochondrial bioenergetics in BT549 cells, specifically affecting the inhibition of OXPHOS complexes I and II. This was evidenced by a decrease in the mitochondrial oxygen consumption rate and the depolarization of the mitochondrial membrane potential. Damage to mitochondria resulted in a lower adenosine triphosphate level and an elevated production of mitochondrial reactive oxygen species. In addition, CRIF1 deficiency decreased hypoxia-inducible factor 1α accumulation, NADPH synthesis, and TP53-induced glycolysis and apoptosis regulator (TIGAR) expression in BT549 cells. These events contributed to G0/G1-phase cell cycle inhibition and the upregulation of the cell cycle protein markers p53, p21, and p16. Transfection with a TIGAR overexpression plasmid reversed these effects and prevented CRIF1 downregulation-induced proliferation and migration reduction. Conclusions: These results indicate that blocking mitochondrial OXPHOS synthesis via CRIF1 may have a therapeutic antitumor effect in BT549 TNBC cells. [ABSTRACT FROM AUTHOR]

Kidney fibrosis is the common final pathway of virtually all advanced forms of chronic kidney disease (CKD) including diabetic nephropathy (DN), IgA nephropathy (IgAN) and membranous nephropathy (MN), with complex mechanism. Comparative gene expression analysis among these types of CKD may shed light on its pathogenesis. Therefore, we conducted this study aiming at exploring the common and specific fibrosis-related genes involved in different types of CKD. Kidney biopsy specimens from patients with different types of CKD and normal control subjects were analyzed using the NanoString nCounter® Human Fibrosis V2 Panel. Genes differentially expressed in all fibrotic DN, IgAN and MN tissues compared to the normal controls were regarded as the common fibrosis-related genes in CKD, whereas genes exclusively differentially expressed in fibrotic DN, IgAN or MN samples were considered to be the specific genes related to fibrosis in DN, IgAN and MN respectively. Quantitative real-time PCR (qRT-PCR) was performed to validate the expression of the selected genes. Protein tyrosine phosphatase receptor type C (PTPRC), intercellular cell adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), interleukin 10 receptor alpha (IL10RA) and CC chemokine receptor 2 (CCR2) were identified as the potential common genes for kidney fibrosis in different types of CKD, while peroxisome proliferator-activated receptor alpha (PPARA), lactate oxidase (LOX), secreted phosphoprotein 1 (SPP1) were identified as the specific fibrosis-associated genes for DN, IgAN and MN respectively. qRT-PCR demonstrated that the expression levels of these selected genes were consistent with the NanoString analysis. There were both commonalities and differences in the mechanisms of fibrosis in different types of CKD, the commonalities might be used as the common therapeutic targets for kidney fibrosis in CKD, while the differences might be used as the diagnostic markers for DN, IgAN and MN respectively. Inflammation was highly relevant to the pathogenesis of fibrosis. This study provides further insight into the pathophysiology and treatment of fibrotic kidney disease. [ABSTRACT FROM AUTHOR]

Objective: We examine levels of candidate blood‐based biomarkers (CBBs) in patients with juvenile idiopathic arthritis (JIA) treated with tofacitinib. Methods: Patients with JIA who participated in clinical trial NCT02592434 received tofacitinib from baseline to week 18. Serial serum samples were assayed for CBBs (S100A8/9, S100A12, interleukin‐18 [IL‐18], serum amyloid A, resistin, vascular endothelial growth factor, angiopoietin‐1, angiopoietin‐2, matrix metalloproteinase 8 [MMP8], MMP2, tissue inhibitor of metalloproteinases 1, leptin, chemokine [C‐X‐C motif] ligand 9, soluble IL‐2 receptor, intercellular adhesion molecule 1, soluble tumor necrosis factor receptor, IL‐6, IL‐23, monocyte chemotactic protein 1, chemokine [C‐C motif] ligand 18 [CCL18], and CCL20). Association of CBBs with JIA response to treatment from baseline to week 18 were assessed. Results: This study included 166 patients with polyarticular‐course JIA. Paired serum samples from 143 patients were available at both baseline and week 18. Thirty‐five percent (50 of 143) of patients had a JIA‐American College of Rheumatology 90 (JIA‐ACR90) level improvement, whereas 90, 121, and 137 (63%, 85%, and 96%) achieved JIA‐ACR70, 50, and 30 improvement at week 18. Despite small numerical differences by JIA category, there were no baseline CBB values that independently predicted a decrease in Juvenile Arthritis Disease Activity Score (JADAS‐27) or JIA‐ACR90 response by week 18. Decrease in resistin level (baseline to week 18) was significantly associated with week 18 improvement in JADAS‐27 and JIA‐ACR90 response after adjusting for age, sex, JIA disease duration, and baseline resistin (r2 0.79, SE 0.070, P < 0.01, and odds ratio [95% confidence interval] 1.134 [1.018–1.264]). HLA‐B27 positivity was significantly associated with not achieving a JIA‐ACR90 response at week 18 (P = 0.0097). Conclusion: Among the CBBs included, only resistin was significantly associated with treatment response, and no CBB was identified that forecasts JIA improvement after initiation of tofacitinib. The association of HLA‐B27 positivity with lower response to tofacitinib in JIA is intriguing and merits further study. [ABSTRACT FROM AUTHOR]

Sepsis is a dysregulated systemic inflammatory response to an infection, which can lead to multiple organ dysfunction syndrome that includes the kidney. Leukocyte recruitment is an important process of the host immune defense in response to sepsis. Endothelial cells (EC) actively regulate leukocyte recruitment by expressing adhesion molecules following the activation of dedicated intracellular signal transduction pathways. Previous studies reported that the expression of adhesion molecules was associated with the activation of endothelial nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 and mitogen-activated protein kinase (MAPK) c-Jun pathways in vitro in response to conditions that mimic processes that occur in inflammation. This study aimed to investigate the spatiotemporal patterns of leukocyte recruitment, expression of adhesion molecules, and endothelial nuclear p65 and c-Jun localization in renal microvascular beds of septic mice. Here, we used a cecal ligation and puncture (CLP) sepsis mouse model and RT-qPCR and immunohistochemical staining. We showed that neutrophils, macrophages, and T lymphocytes were all present in the kidney, yet only neutrophils accumulated in a spatiotemporally discernible pattern, mainly in glomeruli at 4 h after CLP sepsis initiation. E-selectin, not vascular cell adhesion molecule-1 (VCAM-1), was expressed in glomeruli at the same time point. In a subset of mice at 72 h after CLP sepsis started, VCAM-1 expression was prominent in glomerular EC, which was not related to changes in mmu-microRNA(miR)-126a-3p levels, a short noncoding microRNA previously shown to inhibit the translation of VCAM-1 mRNA into protein. Nuclear localization of p65 and c-Jun occurred in EC of all microvascular segments at 4 and 7 h after CLP sepsis initiation. In summary, sepsis-induced recruitment of neutrophils, E-selectin expression, and NF-κB p65 and MAPK c-Jun pathway activation coincided in glomeruli at the early stage of the disease. In the other microvascular beds, sepsis led to NF-κB p65 and MAPK c-Jun pathway activation with limited expression of E-selectin and no association with VCAM-1 expression or leukocyte recruitment. [ABSTRACT FROM AUTHOR]

The editorial "Addressing Oxidative Stress and Endothelial Dysfunction in Chronic Respiratory Diseases: The Role of Exercise and Multidisciplinary Rehabilitation" discusses the prevalence of chronic respiratory diseases (CRDs) and their impact on physical, psychological, and occupational health. The article highlights the common pathogenetic mechanisms of inflammation and oxidative stress in CRDs, emphasizing the systemic nature of these processes. It also explores the role of endothelial dysfunction in CRDs and the potential benefits of exercise-based approaches in improving endothelial function and managing cardiovascular comorbidities. The study suggests that exercise and pulmonary rehabilitation may play a crucial role in restoring endothelial function and addressing the cardiovascular risk associated with CRDs. [Extracted from the article]

Type 2 diabetes mellitus (T2DM) is a global health concern, with diabetic neuropathy (DN) being a prevalent complication. Current DN treatments focus on blood glucose control and pain management, which show limited efficacy. This study explored the effects of autologous dendritic cell (DC) administration on improving DN symptoms. A quasi-experimental clinical trial was conducted on 28 DN patients at Gatot Soebroto Army Hospital. Patients received autologous DC administration, with their Toronto Clinical Neuropathy Score (TCNS), Transforming Growth Factor-β (TGF-β), and Vascular Cell Adhesion Molecule-1 (VCAM-1) levels measured before and at four weeks after treatment. The results show an average TCNS reduction from 8.93 to 7.5 (p < 0.001). TGF-β levels increased slightly from 41.16 ng/mL to 44.18 ng/mL (p > 0.05). VCAM-1 levels increased from 1389.75 ng/mL to 1403.85 ng/mL. Correlation analysis showed that TGF-β levels had a significant negative correlation with the TCNS (r = −0.353; p = 0.033) and VCAM-1 levels (r = −0.521; p = 0.002). Autologous DC administration significantly improves DN. While the changes in TGF-β and VCAM-1 levels were not statistically significant, their trends suggest that there was an anti-inflammatory effect. These findings highlight the potential of autologous DC therapy as a complementary approach to manage DN through inflammation reduction and nerve repair.

Objectives: There is a growing need to understand the potential role of soluble platelet selectin (sP-selectin) in sustained endothelial activation through increased levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular adhesion-1 (sVCAM-1) in people living with HIV (PLWH) on highly active antiretroviral therapy (HAART). Methodology: This was a cross-sectional study involving PLWH on HAART (n = 55), in comparison to PLWH not on treatment (HAART-naïve) (n = 29), and (iii) HIV negative controls (n = 48) from the Mankweng area in the Limpopo province, South Africa. We quantified serum levels of sP-selectin, together with sICAM-1 and sVCAM-1. Most of the HAART-exposed group were on treatment for <5 years. We further performed frequency distribution and descriptive statistics for categorical variables. Results: Soluble P-selectin was positively correlated with sVCAM-1 (r = 0.469; p<0.001) in PLWH on HAART, even after adjusting for confounding factor such as age, BMI, and total cholesterol (r = 0.467; p<0.001). Moreover, in PLWH on HAART sP-selecting was independently associated with the release of sVCAM-1 (β = 0.445; p<0.001), even after adjusting for confounders (β = 0.475; p = 0.001). Serum levels of low-density lipoprotein cholesterol (LDL-C) (p = 0.004) and total cholesterol (p<0.001) were significantly higher in PLWH on HAART as compared to the HAART-naïve group. Conclusion: There is a need for more studies to investigate the role of sP-selectin in promoting endothelial activation and CVD-risk in PLWH on HAART, especially within the sub-Saharan Africa region. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) poses a life-threatening risk for both mothers and babies, and its onset and progression are linked to endothelial injury. The enzyme 15-lipoxygenase-1 (15-LOX-1), critical in arachidonic acid metabolism, is implicated in various diseases, yet its specific role and precise mechanisms in PE remain largely unknown. In this study, we found that 15-LOX-1 and its main metabolite, 15-HETE, were significantly increased in both the placenta and serum of PE patients. This increase was accompanied by elevated levels of endothelial injury markers, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). A positive correlation between 15-LOX-1 and those markers in the placenta. In Alox15 −/− mice, Alox15 deficiency reduced endothelial cell injury in PE-like mice induced by L-NAME. In vitro studies showed that hypoxia-induced upregulation of 15-LOX-1 reduced the cell viability, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs), while increasing apoptosis and inflammatory cell adhesion. Mechanistically, the p38 MAPK pathway was identified as a downstream target of 15-LOX-1. Knocking down 15-LOX-1 or inhibiting p38 MAPK activation improved endothelial cell injury in hypoxia-treated HUVECs. Furthermore, downregulation of miR-26a-2-3p was found to correlate negatively and colocalize with 15-LOX-1 upregulation in the placenta of PE patients. Luciferase reporter assays further confirmed that miR-26a-2-3p directly bind to the 3′UTR of 15-LOX-1, targeting its expression. Moreover, miR-26a-2-3p agomir ameliorated the PE-like phenotype in mice through the 15-LOX-1/p38 MAPK axis, improving endothelial dysfunction. Therefore, our study provides novel insights into the pathogenesis of PE and highlight modulating the miR-26a-2-3p/15-LOX-1/p38 MAPK axis as a potential therapeutic target for PE. [Display omitted] • 15-LOX-1 and its metabolite 15-HETE was significantly increased in the serum and placenta from PE patients, accompanied by an enhanced endothelial injury factor level. • Alox15 deficiency ameliorated endothelial cell injury in PE-like mice induced by L-NAME. • Abnormal upregulation of 15-LOX-1 contributed to endothelial cell injury induced by hypoxia in cultured HUVECs though inhibiting cell viability, migration, and angiogenesis, promoting cell apoptosis and inflammatory cell adhesion. • p38 MAPK was confirmed to be the downstream of 15-LOX-1. 15-LOX-1 knockdown or inhibition of p38 MAPK activation improved endothelial cell injury in hypoxia-treated HUVECs. • 15-LOX-1 was proved to be the target gene of miR-26a-2-3p. miR-26a-2-3p agomir ameliorates PE-like phenotype in mice though 15-LOX-1/p38 MAPK axis-mediated endothelial cell injury. [ABSTRACT FROM AUTHOR]

Objective To investigate the clinical efficacy and safety of combined administration of Wuling capsule and citicoline sodium capsule in managing sudden sensorineural hearing loss among elderly patients. Methods The patients were randomly assigned to the control group (n = 72) and treatment group (n = 71) using a random number table method. Both groups received oral administration of mecobalamin at a dosage of 0.5mg three times daily, as well as oral intake of ginkgo biloba leaves at a dosage of 2 g three times daily. In addition, the control group also took citicoline sodium capsules orally at a dosage of 0.1 g three times daily. On the basis of the control group, the treatment group was additionally administered Wuling capsules orally at a dosage of 0.99 g three times daily. Both groups underwent one month of treatment for observation purposes, during which their hearing condition, blood viscosity, inner ear microcirculation, peripheral blood cytokines, clinical efficacy and adverse drug reactions were compared. Results The total effective rate of the treatment group and control group was 84.51% (60/71) and 68.06% (49/72), respectively, with a significant difference observed (P < 0.05). Following treatment, the pure tone hearing thresholds in the treatment group were measured at (40.03 ± 5.04) dB, while those in the control group were recorded as (45.25 ± 6.21) dB; for high frequency region listening levels, values of (45.27 ± 6.05) dB and (50.01 ± 7.69) dB were obtained for the treatment and control groups respectively; similarly, low frequency region listening levels were found to be (44.21 ± 5.47) dB for the treatment group and (49.32 ± 6.24) dB for the control group. Following treatment, the plasma viscosity was (1.21 ± 0.19) and (1.58 ± 0.24) mPa ⋅ s, the high tangential viscosity of whole blood was (3.59 ± 0.52) and (4.12 ± 0.61) mPa ⋅ s, the low tangential viscosity of whole blood was (5.83 ± 0.84) and (6.52 ± 0.91) mPa ⋅ s, the diameter of the internal auditory artery was (1.12 ± 0.15) and (0.96 ± 0.11) mm, the diameter of anterior inferior cerebellar artery was(1.35 ± 0.18)and( 1.19 ± 0.15)mm, calcitonin gene-related peptide concentration in plasma was(386.92 ± 40.02)and(354.21 ± 36.47)ng/mL, soluble vascular intercellular adhesion factor-1 concentration in plasma was(132.14 ± 18.96) and ( 156.34 ± 21.32) ng/mL, with statistically significant differences observed (P < 0.05). There were no adverse reactions in both groups during treatment. Conclusion The combination of Wuling capsule and citicoline sodium capsule exhibits a significant therapeutic effect in the management of senile sudden deafness, leading to improvements in hearing ability, blood viscosity, inner ear microcirculation, and peripheral blood cytokine secretion. [ABSTRACT FROM AUTHOR]

Despite advancements in treatment of sickle cell disease (SCD), hydroxyurea, a ribonucleotide reductase inhibitor, remains the cornerstone of therapy. While its primary effect is the elevation of fetal hemoglobin (HbF), hydroxyurea's mechanisms of action are multifaceted. Hydroxyurea (HU) reduces leukocyte and platelet counts, decreases the expression of endothelial adhesion molecules CD36 and CD49d, and increases nitric oxide and cyclic nucleotide levels, which may facilitate vascular dilation and further HbF induction. Numerous studies have demonstrated that hydroxyurea therapy reduces the frequency of painful episodes, acute chest syndrome, and the need for erythrocyte transfusions and hospitalizations. Long-term use of hydroxyurea leads to reduced morbidity and mortality. Hydroxyurea should be initiated in children from 9 months of age, including asymptomatic individuals, and is recommended for adults experiencing pain crises that significantly interfere with daily activities or quality of life, as well as those with severe or recurrent vaso-occlusive crises, ACS, or severe symptomatic anemia. Hydroxyurea is not recommended during pregnancy or lactation due to potential teratogenic effects and transfer into breast milk. However, its use may be considered in high-risk patients, particularly during the second and third trimesters. Concerns about secondary tumor development have not been substantiated in long-term follow-up studies. Alternative therapies, including L-glutamine, crizanlizumab, and voxelotor, are not presently approved or available for clinical use in Europe. [ABSTRACT FROM AUTHOR]

Aim To construct a diabetic atherosclerosis mouse model and study the pathological characteristics of diabetic atherosclerosis. Methods Fifty 8-week-old male LDLR-/- mice were fed with standard diet for 2 weeks and then changed to high-fat diet, they were randomly divided into two groups. The diabetic atherosclerosis group was given intraperitoneal injection of low dose streptozotocin (STZ) for 5 days continuouly to establish the model, and the atherosclerosis group was given citrate buffer injection at the same time. The body mass, blood glucose and blood lipids of the mice in the two groups were detected for many times. At the age of 23 weeks, the mice were euthanized after glucose tolerance test. HE staining and oil red O staining were used to detect the gross and aortic root atherosclerosis, immunohistochemical staining was used to detect CD4, α-smooth muscle actin (α-SMA), EGF-like module-containing mucin-like hormone receptor-like 1 (EMR1), monocyte chemotactic protein-1 (MCP-1), NOD-like receptor protein 3 (NLRP3), vascular cell adhesion molecule-1 (VCAM-1), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1), Western blot was used to detect α-SMA, CD4, tumor necrosis factor-α (TNF-α), NLPR3, intercellular adhesion molecule-1 (ICAM-1), and type Ⅰ and Ⅲ collagen. Results Compared with the atherosclerosis group, the body mass decreased, the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDLC) increased, and the levels of high density lipoprotein cholesterol (HDLC) decreased (P<0. 05) in the diabetic atherosclerosis group. Compared with the atherosclerosis group, the distribution of atherosclerotic plaques was diffuse and the area was increased in the diabetic atherosclerosis group, and the contents of lipids, T cells, macrophages, smooth muscle cells, typeⅠand Ⅲ collagen were increased (P<0. 05); the protein levels of TNF-α, MCP-1, MMP-2, NLRP3, ICAM-1 and VCAM-1 in vascular tissues were increased, while the content of TIMP-1 were decreased and MMP2/TIMP-1 were increased (P<0. 05). Conclusions LDLR-/- mouse model of diabetic atherosclerosis can be successfully established by STZ induction combined with high-fat diet, which can reflect the plaque composition and inflammatory characteristics of diabetes promoting atherosclerosis. It can be used as a relatively ideal pathological model for the study of diabetic macroangiopathy. [ABSTRACT FROM AUTHOR]

Background: Non-obstructive coronary artery disease (NOCAD) is a condition in stable patients that experience angina despite not having significant coronary obstructive lesion. Knowledge on the role of certain biomarkers in patients with NOCAD is still limited. This study aimed to evaluate the roles of inflammation and adhesion molecules in the development of NOCAD. The correlations between the peripheral and coronary levels of the inflammatory biomarkers and adhesion molecules were also investigated. Methods: In this cross-sectional study, symptomatic angina patients scheduled for coronary angiograms were recruited and separated into obstructive coronary artery disease (OCAD) and NOCAD groups based on those angiograms. Peripheral and coronary blood samples were taken to measure inflammation biomarkers [high sensitivity C-reactive protein (hsCRP) and growth differentiation factor 15 (GDF-15]), and adhesion molecules [vascular cell adhesion molecule-1 (VCAM-1)]. Subjects without angina symptoms were recruited for the control group. Results: The hsCRP, GDF-15, and VCAM-1 levels were higher in the OCAD and NOCAD groups than in the control group. VCAM-1 levels successfully predicted the incidence of NOCAD [p = 0.010, area under the curve (AUC) = 0.716]. All biomarkers' levels in the peripheral and coronary blood were correlated in OCAD and NOCAD patients (p < 0.001). Conclusion: Elevated levels of the hsCRP, GDF-15, and VCAM-1 were found with NOCAD, despite the absent of significant coronary obstruction. VCAM-1 successfully predicted NOCAD and may thus serve as an early NOCAD biomarker. Significant correlations of hsCRP, GDF-15, and VCAM-1 level in peripheral and coronary blood indicate that the peripheral levels of these biomarkers reflect the levels and changes that occur at the coronary level. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To estimate the association between maternal metformin use for the treatment of early gestational or pre-existing type 2 diabetes and preterm preeclampsia. METHODS: This is a planned secondary analysis of the MOMPOD study (Medical Optimization of Management of Overt Type 2 Diabetes in Pregnancy), a randomized trial comparing the effect of adding metformin with insulin treatment on composite neonatal outcome in singleton pregnancies with early gestational or type 2 diabetes. Participants were randomized at 11-23 weeks of gestation to 1,000 mg metformin twice daily or placebo until delivery. A subset of participants had maternal blood collected at 24-30 weeks of gestation, and serum soluble endoglin, apolipoprotein B, vascular cell adhesion molecule-1, soluble fms-like tyrosine kinase 1, placental growth factor, high-sensitivity C-reactive protein, adiponectin, and vascular endothelial growth factor levels were measured. Our primary outcome was preterm preeclampsia, defined as preeclampsia requiring delivery before 37 weeks of gestation. Secondary outcomes included preterm preeclampsia requiring delivery before 34 weeks of gestation and differences in serum biomarkers. Multivariable regression analysis was used to estimate the associations between metformin use and primary or secondary study outcomes. RESULTS: Of 831 participants, 119 (14.3%) developed preeclampsia requiring delivery before 37 weeks of gestation: 57 of 416 (13.7%) in the placebo group and 62 of 415 (14.9%) in the metformin group. Thirty-seven (4.4%) developed preeclampsia requiring delivery before 34 weeks of gestation: 15 (3.6%) receiving placebo and 22 (5.3%) receiving metformin. Compared with placebo, metformin was not associated with a significant difference in the occurrence of preeclampsia before 37 weeks of gestation (adjusted odds ratio [aOR] 1.04, 95% CI, 0.70-1.56) or before 34 weeks (aOR 1.43, 95% CI, 0.73-2.81). Similarly, there was no association between maternal metformin use and serum biomarker levels. CONCLUSION: Among parturients with early gestational or pre-existing type 2 diabetes, the addition of metformin to insulin was not associated with lower odds of preterm preeclampsia or with serum biomarkers associated with cardiovascular disease risk. [ABSTRACT FROM AUTHOR]

Polycyclic aromatic hydrocarbons (PAHs) exposure is associated with cardiovascular diseases. Toxic effects of PAHs are diverse, while cardiovascular consequences of benzo[ b ]fluoranthene (B[ b ]F) are unclear. Here, we reported the impacts of B[ b ]F on coronary artery and atherosclerosis markers both in mice and umbilical vein endothelial EAhy.926 cells. In mice, we found that B[ b ]F decreases heart-to-body weight ratio, affects aortic physiology, elevates serum low-density lipoprotein and total cholesterol, increases aortic levels of collagen fiber and atherosclerotic marker vascular cell adhesion molecule-1 (VCAM-1), and downregulates oxidative stress related nuclear factor erythroid 2-related factor 2 (Nrf2). In EAhy.926 cells, we showed that B[ b ]F inhibits cell proliferation and migration in a dose-dependent manner, induces cell cycle arrest and apoptosis, increases reactive oxygen species, upregulates VCAM-1 level, and suppresses expression of Nrf2. Taken together, our findings reveal that B[ b ]F exposure may contribute to coronary artery damage and potentially induce atherosclerosis, possibly via the Nrf2-related signaling pathways. • B[ b ]F elevates serum low-density lipoprotein and total cholesterol in mice. • B[ b ]F increases aortic collagen fiber and VCAM-1, and reduces Nrf2 in mice. • B[ b ]F inhibits proliferation and migration of EAhy.926 cells. • B[ b ]F induces cell cycle arrest and apoptosis of EAhy.926 cells. • B[ b ]F increases ROS and VCAM-1, and reduces Nrf2 in EAhy.926 cells. [ABSTRACT FROM AUTHOR]

Purpose: Soluble vascular adhesion protein-1 (sVAP-1) and adropin are 2 biomarkers of endothelial dysfunction. The main purpose of this study was to evaluate the levels of sVAP-1 in patients with moderate and severe obstructive sleep apnea (OSA) compared to healthy controls, and to further determine the relationship between sVAP-1 and adropin levels, as well as inflammatory biomarkers and sleep parameters. Methods: In this study, we included 50 male patients with OSA (25 moderate and 25 severe) and 20 age- and sex-matched control subjects. Patients with OSA underwent polysomnography. All subjects underwent fasting peripheral blood sampling for laboratory analysis. Results: Serum sVAP-1 and inflammatory biomarkers (IL-6, TNF-α, and hsCRP) levels were significantly higher in patients with severe OSA compared to those with moderate OSA and control groups, while plasma levels of adropin showed the opposite trend. Furthermore, sVAP-1 levels had a significant positive correlation with AHI, ODI, TNF-α, IL-6, and hsCRP levels and a significant negative correlation with adropin levels. The receiver operating characteristic analysis showed an Area Under Curve (AUC) of.876 (P <.001) for sVAP-1 levels predicting OSA. Serum sVAP-1 threshold of > 445.5 ng/mL had an 88% sensitivity and 80% specificity for detecting OSA status. Multivariate regression analysis demonstrated that sVAP-1 remained a significant positive predictor of OSA severity. Conclusions: Increased sVAP-1 levels in OSA patients are significantly correlated with indices of OSA severity, adropin levels, and inflammatory biomarkers, suggesting that sVAP-1 plays a vital role in the pathophysiology of OSA and may become a potential screening tool in the evaluation of OSA severity. [ABSTRACT FROM AUTHOR]

Objective To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment. Methods Patients were randomized to riociguat (n  = 60) or placebo (n  = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. α-Smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay. Results By week 14, cGMP increased by 94 (78)% with riociguat and 10 (39)% with placebo (P  < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (P  = 0.004 and P  = 0.008, respectively). There were no differences in skin collagen markers between the two groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies was associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P -values 0.004 and 0.02, respectively). Conclusion Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide–soluble guanylate cyclase–cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis. Trial registration Clinicaltrials.gov, NCT02283762. [ABSTRACT FROM AUTHOR]

Introduction : Osteoprotegerin (OPG) inhibits vascular calcification which is central to pathogenesis of arterial stiffness. However, it promotes inflammation by upregulating expression of vascular cell adhesion molecule-1(VCAM-1), thereby contributing to arterial stiffness. We investigated longitudinal association between OPG and arterial stiffness in type 2 diabetes (T2D), causality of the association and mediation by VCAM-1. Methods : This was a prospective cohort study of T2D patients (N = 1877, mean age 57.0 ± 10.8) with 10 years' follow-up. Baseline plasma OPG was measured using immunoassay. Pulse wave velocity (PWV) was assessed using applanation tonometry. We examined association between OPG and follow-up PWV using linear mixed model. One-sample Mendelian Randomization (MR) was conducted with rs1385492 as OPG-associated single nucleotide polymorphism (SNP). Results : Baseline natural log (Ln)-transformed OPG was positively associated with baseline and follow-up PWV with adjusted coefficients 0.43 (95%CI 0.05, 0.80; p =.026) and 0.51 (95%CI 0.06 to 0.97; p =.028) respectively. Genetically-predicted higher levels of plasma OPG was associated with higher last follow-up PWV with coefficient 10.81 (95%CI 2.97, 18.65; p =.007) per unit increase in LnOPG. Higher VCAM-1 accounted for 10.2% of association between LnOPG and follow-up PWV. Discussion : Baseline plasma OPG was associated with higher follow-up PWV in patients with T2D, with genetic evidence from MR. This association may be mediated, at least in part, by VCAM-1. [ABSTRACT FROM AUTHOR]

Background: Blood biomarkers predictive of the progression of idiopathic pulmonary fibrosis (IPF) would be of value for research and clinical practice. We used data from the IPF-PRO Registry to investigate whether the addition of "omics" data to risk prediction models based on demographic and clinical characteristics improved prediction of the progression of IPF. Methods: The IPF-PRO Registry enrolled patients with IPF at 46 sites across the US. Patients were followed prospectively. Median follow-up was 27.2 months. Prediction models for disease progression included omics data (proteins and microRNAs [miRNAs]), demographic factors and clinical factors, all assessed at enrollment. Data on proteins and miRNAs were included in the models either as raw values or based on clusters in various combinations. Least absolute shrinkage and selection operator (Lasso) Cox regression was applied for time-to-event composite outcomes and logistic regression with L1 penalty was applied for binary outcomes assessed at 1 year. Model performance was assessed using Harrell's C-index (for time-to-event outcomes) or area under the curve (for binary outcomes). Results: Data were analyzed from 231 patients. The models based on demographic and clinical factors, with or without omics data, were the top-performing models for prediction of all the time-to-event outcomes. Relative changes in average C-index after incorporating omics data into models based on demographic and clinical factors ranged from 1.7 to 3.2%. Of the blood biomarkers, surfactant protein-D, serine protease inhibitor A7 and matrix metalloproteinase-9 (MMP-9) were among the top predictors of the outcomes. For the binary outcomes, models based on demographics alone and models based on demographics plus omics data had similar performances. Of the blood biomarkers, CC motif chemokine 11, vascular cell adhesion protein-1, adiponectin, carcinoembryonic antigen and MMP-9 were the most important predictors of the binary outcomes. Conclusions: We identified circulating protein and miRNA biomarkers associated with the progression of IPF. However, the integration of omics data into prediction models that included demographic and clinical factors did not materially improve the performance of the models. Trial registration: ClinicalTrials.gov; No: NCT01915511; registered August 5, 2013; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Hypertension drives the development of concentric left ventricular hypertrophy (LVH). However, the relative contribution of pentraxin‐3 (PTX‐3), a novel marker for inflammatory cardiovascular disease, in the hypertrophic response to pressure overload has not been adequately elucidated. We investigated the role of PTX‐3 in the development of LVH in spontaneously hypertensive rats (SHR), untreated and treated with either captopril (an ACE inhibitor) or hydralazine (a non‐specific vasodilator). Three‐month‐old SHR received either 20 mg/kg/day hydralazine (SHR + H, n = 6), 40 mg/kg/day captopril (SHR + C, n = 6), or plain gelatine cubes (untreated SHR, n = 7) orally for 4 months. Wistar Kyoto rats (WKY, n = 7) were used as the normotensive controls. Blood pressure (BP) was measured using the tail‐cuff method. Cardiac geometry and function were determined using M‐mode echocardiography. Circulating concentrations of inflammatory markers were measured in plasma by ELISA. LV fibrosis and cardiomyocyte width were assessed by histology. Relative mRNA expression of PTX‐3 was determined in the LV by RT‐PCR. Untreated SHR exhibited greater systolic BP and relative wall thickness (RWT) compared to WKY. Captopril and hydralazine normalized BP but only captopril reversed RWT in SHR. Circulating PTX‐3 and VCAM‐1 levels were elevated in untreated SHR and reduced with captopril and hydralazine. Circulating PTX‐3 was positively associated with systolic BP but lacked independent relations with indices of LVH. LV relative mRNA expression of PTX‐3 was similar between the groups. PTX‐3 may not be involved in the development of LVH in SHR, but plausibly reflects the localized inflammatory milieu associated with hypertension. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction, which is marked by a reduction in nitric oxide (NO) production or an imbalance in relaxing and contracting factor levels, exacerbates atherosclerosis by promoting the production of cell adhesion molecules and cytokines. This study aimed to investigate the effects of Limosilactobacillus reuteri HY7503, a novel probiotic isolated from raw milk, on endothelial dysfunction. Five lactic acid bacterial strains were screened for their antioxidant, anti-inflammatory, and endothelium-protective properties; L. reuteri HY7503 had the most potent effect. In a mouse model of angiotensin II-induced endothelial dysfunction, L. reuteri HY7503 reduced vascular thickening (19.78%), increased serum NO levels (226.70%), upregulated endothelial NO synthase (eNOS) expression in the aortic tissue, and decreased levels of cell adhesion molecules (intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1]) and serum cytokines (tumor necrosis factor-alpha [TNF-α] and interleukin-6 [IL-6]). In TNF-α-treated human umbilical vein endothelial cells (HUVECs), L. reuteri HY7503 enhanced NO production and reduced cell adhesion molecule levels. In HUVECs, surface-layer proteins (SLPs) were more effective than extracellular vesicles (exosomes) in increasing NO production and decreasing cell adhesion molecule levels. These findings suggested that L. reuteri HY7503 may serve as a functional probiotic that alleviates endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Atherosclerosis, characterized by the accumulation of lipoproteins and lipids within the vascular wall, underlies a heart attack, stroke, and peripheral artery disease. Endothelial inflammation is the primary component driving atherosclerosis, promoting leukocyte adhesion molecule expression (e.g., E-selectin), inducing chemokine secretion, reducing the production of nitric oxide (NO), and enhancing the thrombogenic potential. While current therapies, such as statins, colchicine, anti-IL1β, and sodium–glucose cotransporter 2 (SGLT2) inhibitors, target systemic inflammation, none of them addresses endothelial cell (EC) inflammation, a critical contributor to disease progression. Targeting endothelial inflammation is clinically significant because it can mitigate the root cause of atherosclerosis, potentially preventing disease progression, while reducing the side effects associated with broader anti-inflammatory treatments. Recent studies highlight the potential of the APOA1 binding protein (AIBP) to reduce systemic inflammation in mice. Furthermore, its mechanism of action also guides the design of a potential targeted therapy against a particular inflammatory signaling pathway. This review discusses the unique advantages of repressing vascular inflammation or enhancing vascular quiescence and the associated benefits of reducing thrombosis. This approach offers a promising avenue for more effective and targeted interventions to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Ankylosing Spondylitis (AS) stands as a chronic inflammatory arthritis within the spondyloarthritis spectrum, notably increasing cardiovascular (CV) risk and mortality through accelerated atherosclerosis compared to the non-affected population. While evidence in some studies supports a higher cardiovascular morbidity in AS patients, results from other studies reveal no significant disparities in atherosclerotic markers between AS individuals and healthy controls. This discrepancy may arise from the complex interaction between traditional CV risk factors and AS inflammatory burden. Endothelial dysfunction, a recognized antecedent of atherosclerosis prevalent among most individuals with AS, demonstrates the synergistic impact of inflammation and conventional risk factors on endothelial injury, consequently hastening the progression of atherosclerosis. Remarkably, endothelial dysfunction can precede vascular pathology in AS, suggesting a unique relationship between inflammation, atherosclerosis, and vascular damage. The role of adhesion molecules in the development of atherosclerosis, facilitating leukocyte adherence and migration into vascular walls, underscores the predictive value of soluble intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) levels for cardiovascular events. Despite significant progress in comprehending the pathogenesis of AS and its associated cardiovascular implications, the interplay among inflammation, endothelial dysfunction, and atherosclerosis remains partially elucidated. Investigations into the efficacy of therapeutic approaches involving angiotensin receptor blockers and statins have demonstrated reduced cardiovascular risk in AS patients, underscoring the imperative for additional research in this domain. [ABSTRACT FROM AUTHOR]

This article discusses the disruption of the retinal endothelial cell barrier by direct contact with retinal Müller glial cells (RMGCs) in vitro. The inner blood-retinal barrier plays a crucial role in protecting the neural retina by restricting the passage of solutes and microbes. The study aimed to develop a model for investigating the interactions between human retinal endothelial cells (RECs) and RMGCs to understand the breakdown of the blood-retinal barrier. The results showed that direct contact between RMGCs and RECs led to an activated and leaky retinal endothelium. This model could be useful for studying diseases like diabetic retinopathy and posterior uveitis and evaluating targeted treatments. [Extracted from the article]

Objective To define the functional relevance of H19 X-linked (H19X) co-expressed long non-coding RNA (lncRNA) in endothelial cell (EC) activation as a key process in SSc vasculopathy. Methods H19X expression in SSc skin biopsies was analysed from single-cell RNA sequencing (scRNA-seq) data. Differential expression and pathway enrichment analysis between cells expressing (H19Xpos) and non-expressing H19X (H19Xneg) cells was performed. H19X function was investigated in human dermal microvascular ECs (HDMECs) by silencing. H19X and EC adhesion molecule levels were analysed by real-time quantitative PCR and western blot after stimulation with pro-inflammatory cytokines. Cytoskeletal rearrangements were analysed by fluorescent staining. Endothelial adhesion was evaluated by co-culture of HDMECs and fluorescent-labelled peripheral blood mononuclear cells (PBMCs). Shedding vascular cell adhesion protein 1 (VCAM1) was evaluated by ELISA on HDMEC supernatant. Results The scRNA-seq data showed significant upregulation of H19X in SSc compared with healthy ECs. In HDMECs, H19X was consistently induced by IFN type I and II. H19X knockdown lead to a significant decrease in the mRNA of several adhesion molecules. In particular, VCAM1 was significantly reduced at the protein and mRNA levels. Co-expression analysis of the scRNA-seq data confirmed higher expression of VCAM1 in H19Xpos ECs. ECs were also strongly associated with the 'cell adhesion molecule' pathway. Moreover, the VCAM1 downstream pathway displayed less activation following H19X knockdown. Contractility of HDMECs, PBMC adhesion to HDMECs and VCAM1 shedding were also reduced following H19X knockdown. Conclusions lncRNA H19X may contribute to EC activation in SSc vasculopathy, acting as a regulator of expression of adhesion molecules in ECs. [ABSTRACT FROM AUTHOR]

Objective To investigate the predictive value of combined detection of serum vascular cell adhesion molecule- 1(VCAM-1), platelet endothelial cell adhesion molecule-1 (PECAM-1) levels and mini mental state examination (MMSE) score for postoperative delirium (POD) in elderly patients underwent total hip arthroplasty (THA). Methods A total of 200 elderly patients with hip fracture underwent surgical treatment were selected as the research objects. Patients were divided into the POD group (n=44) and the non-POD group (n=156) according to whether POD occurred within 3 days after operation. The clinical data of patients in the two groups were collected. The preoperative cognitive status was evaluated by MMSE, and serum levels of VCAM- 1 and PECAM-1 were detected before operation and 1st and 3rd day after operation. The differences of the above indexes between the two groups were compared, and the correlation between preoperative serum VCAM-1, PECAM-1 levels and MMSE score were analyzed. Multivariate Logistic regression analysis was utilized to investigate influencing factors of POD in elderly patients underwent THA. A receiver operating characteristic (ROC) curve was constructed to assess the predictive value of preoperative serum levels of VCAM-1 and PECAM-1, as well as MMSE score, both individually and in combination for POD in elderly patients undergoing THA. Results The age, hospital anxiety and depression scale score, incidence of intraoperative hypotension and postoperative hospital stay were significantly higher or longer in the POD group than those in the non-POD group, and the MMSE score was lower than that in the non-POD group (P＜0.05). The serum levels of VCAM-1 and PECAM-1 before operation, 1st and 3rd day after operation were increased in the POD group, and which were significantly higher than those in the non-POD group (P＜0.05). The serum levels of VCAM-1 and PECAM-1 were significantly negatively correlated with MMSE score in elderly patients undergoing THA (r=-0.390, -0.501, P＜0.01). The elevated serum levels of VCAM-1 and PECAM-1 before operation and prolonged postoperative hospital stay were independent risk factors for POD in elderly patients underwent THA, and the elevated value of MMSE score was independent protective factor (P＜0.05). Preoperative serum VCAM-1 (AUC=0.793, 95%CI: 0.730-0.847), PECAM-1 (AUC=0.799, 95%CI:0.736-0.852) and MMSE score (AUC=0.805, 95%CI: 0.744-0.858) showed high predictive value for POD in elderly patients underwent THA, and the combined detection of the three indicators had higher predictive efficiency. Conclusion The elevated serum levels of VCAM-1 and PECAM-1 are related to the impairment of cognitive function in elderly patients undergoing THA, and they are independent predictors for POD in elderly patients undergoing THA, thus may be helpful for early diagnosis and prevention of POD . [ABSTRACT FROM AUTHOR]

Background: Patients with type 2 diabetes mellitus (DM) have a high prevalence of chronic kidney disease (CKD). Energy imbalance and inflammation may be involved in the pathogenesis of CKD. We examined the effects of brain-derived neurotrophic factor (BDNF) and vascular cell adhesion molecule-1 (VCAM-1) on CKD in patients with type 2 DM. Methods: Patients with type 2 DM were enrolled for this cross-sectional study. Fasting serum was prepared to measure the BDNF and VCAM-1 levels. An estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 was used as the criterion for identifying patients with CKD. Results: Of the 548 enrolled participants, 156 had CKD. Patients with CKD exhibited significantly lower BDNF (median of 21.4 ng/mL, interquartile range [IQR]: 17.0–27.0 ng/mL vs. median of 25.9 ng/mL, IQR: 21.0–30.4 ng/mL, P <0.001) and higher VCAM-1 (median of 917 ng/mL, IQR: 761–1172 ng/mL vs. median of 669 ng/mL, IQR: 552–857 ng/mL, P <0.001) levels than those without CKD. Serum BDNF levels were inversely correlated with VCAM-1 levels (Spearman’s rank correlation coefficient = -0.210, P <0.001). The patients were divided into four subgroups based on median BDNF and VCAM-1 levels (24.88 ng/mL and 750 ng/mL, respectively). Notably, patients in the high VCAM-1 and low BDNF group had the highest prevalence (50%) of CKD. Multivariate logistic regression revealed a significantly higher odds ratio (OR) of CKD in the high VCAM-1 and low BDNF group (OR = 3.885, 95% CI: 1.766–8.547, P <0.001), followed by that in the high VCAM-1 and high BDNF group (OR = 3.099, 95% CI 1.373–6.992, P =0.006) compared with that in the low VCAM-1 and high BDNF group. However, the risk of CKD in the low VCAM-1 and low BDNF group was not significantly different from that in the low VCAM-1 and high BDNF group (P =0.266). Conclusion: CKD in patients with type 2 DM is associated with low serum BDNF and high VCAM-1 levels. BDNF and VCAM-1 have a synergistic effect on CKD. Thus, BDNF and VCAM-1 can be potential biomarkers for CKD risk stratification in patients with type 2 DM. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to investigate how L1 cell adhesion molecule (L1CAM) interacting with protein tyrosine kinase 2 (PTK2) affects endometrial cancer (EC) progression and determine its association with the focal adhesion kinase (FAK)–growth factor receptor-bound protein 2 (GRB2)–son of sevenless (SOS)–rat sarcoma (RAS) pathway. EC is a female cancer of major concern in the world, and its incidence has increased rapidly in recent years. L1CAM is considered a reliable marker of poor prognosis in patients with EC. Material and Methods: A single-center and prospective study was conducted using data from the Cancer Genome Atlas and samples from normal and EC tissues to explore the differential expression of L1CAM. Additional experimental models included human immortalized endometrial epithelium cells (hEECs) and EC cell lines such as KLE, RL95-2, and Ishikawa. L1CAM expression was regulated using lentiviruses designed for either overexpression or interference, and PTK2/focal adhesion kinase (FAK) signaling was inhibited with PF431396. Transfected KLE cells were injected into mice, and tumor growth was monitored over 14 days. Cellular proliferation and survival were assessed using cell counting kit, colony formation, and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate (dUTP) nick-end labeling assays. Metastatic behavior was evaluated through Transwell assays for cell migration and invasion. The expression levels of matrix metallopeptidase (MMP) 2 and MMP9 were determined by Western blot. In addition, the activation of the FAK–GRB2–SOS–RAS pathway was examined by assessing the protein levels of FAK, GRB2, SOS, and RAS. Results: There was a significant difference in L1CAM expression between EC tumor tissues and normal tissues, and L1CAM messenger RNA (1.85-fold) and L1CAM protein (2.59-fold) were significantly more expressed in EC tissues (P < 0.01) than in normal tissues. The tumor growth of L1CAM overexpressing EC cells was faster than that of negative control EC cells (6.43 fold; P < 0.001). L1CAM promoted the expression of FAK (1.43-2.72-fold; P < 0.001); enhanced EC cell proliferation (P < 0.01), survival and motility (P < 0.001), migration (P < 0.001), and invasion (P < 0.001); and activated the FAK–GRB2–SOS–RAS pathway, all of which were reversed when FAK expression was not upregulated (P < 0.001). Conclusion: By upregulating PTK2 and its encoded protein FAK, L1CAM was found to promote tumor progression and increase the activation of the FAK–GRB2–SOS–RAS pathway. These findings establish L1CAM and PTK2 as reference genes for poor prognostic prediction in EC and as targets for EC therapy, providing a valuable basis for distinguishing between benign and malignant endometrial conditions and justifying the necessity of targeted therapeutic approaches. [ABSTRACT FROM AUTHOR]

Objective Renal function and the skeleton are classic target organs in primary hyperparathyroidism (PHPT), affected by the chronic course of the disease. Most patients diagnosed today exhibit mild PHPT, characterized by slight hypercalcemia and no or unspecific symptoms. Concerns have been raised that PHPT could promote deteriorating kidney function and increase cardiovascular risk directly. To examine the effect of parathyroidectomy (PTX) on mild PHPT on renal function and markers for bone turnover, cardiovascular disease (CVD), and vascular inflammation. Design Prospective randomized controlled trial. ClinicalTrials.gov : NCT00522028. Setting Eight Scandinavian referral centers. Participants From 1998 to 2005, 191 patients with mild PHPT were included in Sweden, Norway, and Denmark. Of these 150 were included in the present analyses. Intervention Seventy patients were randomized to PTX and 80 to observation without intervention (OBS). Measures e-GFR was calculated based on creatinine and cystatin C. Markers of CVD and systemic inflammation: osteoprotegerin, vascular cell adhesion molecule 1, soluble CD40 ligand, interleukin-1 receptor antagonist, von Willebrand factor. Bone turnover markers: C-terminal telopeptide of type 1 collagen (CTX-1) and serum Procollagen type 1 N-terminal propeptide. Results No differences in the development of renal function or vascular and systemic inflammation were detected. CTX-1 was lower in PTX after 10 years. Limitations Secondary analyses of a randomized controlled trial. Conclusion PTX does not appear to affect renal function or markers of CVD and vascular inflammation in mild PHPT in a ten-year perspective. [ABSTRACT FROM AUTHOR]

Introduction: Patients with systemic sclerosis (SSc) have an increased risk of endothelial dysfunction, atherosclerosis, and cardiovascular events compared to the general population. Therefore, the availability of robust circulating biomarkers of endothelial dysfunction and atherogenesis may facilitate early recognition and management of cardiovascular risk in SSc. We sought to address this issue by conducting a systematic review and meta-analysis of studies investigating various types of circulating cell adhesion molecules involved in endothelial dysfunction and atherogenesis (i.e., immunoglobulin-like vascular cell, VCAM-1, intercellular, ICAM-1, platelet endothelial cell, PECAM-1, neural cell, NCAM, Down syndrome cell, DSCAM, and endothelial cell-selective, ESAM, adhesion molecules, E-, L-, and P-selectin, integrins, and cadherins) in SSc patients and healthy controls. Methods: We searched PubMed, Scopus, and Web of Science from inception to 1 May 2024. Risk of bias and certainty of evidence were assessed using validated tools. Results: In 43 eligible studies, compared to controls, patients with SSc had significantly higher plasma or serum concentrations of ICAM-1 (standard mean difference, SMD=1.16, 95% CI 0.88 to 1.44, p<0.001; moderate certainty), VCAM-1 (SMD=1.09, 95% CI 0.72 to 1.46, p<0.001; moderate certainty), PECAM-1 (SMD=1.65, 95% CI 0.33 to 2.98, p=0.014; very low certainty), E-selectin (SMD=1.17, 95% CI 0.72 to 1.62, p<0.001; moderate certainty), and P-selectin (SMD=1.10, 95% CI 0.31 to 1.90, p=0.007; low certainty). There were no significant between-group differences in L-selectin concentrations (SMD=-0.35, 95% CI -1.03 to 0.32, p=0.31; very low certainty), whereas minimal/no evidence was available for cadherins, NCAM, DSCAM, ESAM, or integrins. Overall, no significant associations were observed between the effect size and various patient and study characteristics in meta-regression and subgroup analyses. Discussion: The results of this systematic review and meta-analysis suggest that specific circulating cell adhesion molecules, i.e., ICAM-1, VCAM-1, PECAM-1, E-selectin, and P-selectin, can be helpful as biomarkers of endothelial dysfunction and atherogenesis in the assessment of cardiovascular risk in SSc patients. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI) as a result of iodinated contrast media (CM) has been linked to CM-induced renal ischemia and toxic effects on endothelial cells (EC). The recombinant human C1 inhibitor (rhC1INH) has been shown to influence EC activation. Methods: Secondary analysis of 74/77 (96%) participants of a double-blind, randomized, and placebo-controlled study that assessed the effect of rhC1INH on AKI. E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM-1), and CC-chemokin-ligand-5 (CCL5) were determined in frozen blood samples over 48 h and analyzed according to the treatment group and renal outcomes. Results: The mean age was 76.7 years, and 37 patients each received rhC1INH and placebo, respectively. In the entire study population, minor differences in median EC activation markers/CCL5 concentrations during the first 48 h compared to baseline were observed (e.g., E-selectin 27.5 ng/mL at baseline vs. 29.7 ng/mL on day 1, CCL5: 17.7 ng/mL at baseline vs. 32.2 ng/mL on day 2). Absolute changes in ICAM-1/E-selectin concentrations correlated with a higher peak change in urinary NGAL concentrations. However, AKI was not associated with significant changes in EC markers/CCL5. Last, no significant differences in serum concentrations of EC activation markers/CCL5 were evident between the placebo and the rhC1INH group. Conclusions: CM administration during coronary angiography only mildly activated ECs within the first 48 h, which does not explain subsequent AKI. The administration of rhC1INH was not associated with a reduction of EC activation or CCL5. [ABSTRACT FROM AUTHOR]

The article discusses a pilot study on the effects of short-term suborbital space flight on astronauts' health. The study found that astronauts experienced a decrease in dopamine levels and an increase in cortisol and BDNF levels, leading to a pro-oxidative and inflammatory environment. Additionally, astronauts showed signs of oxidative stress, inflammation, and hormonal imbalance after returning to Earth. The study highlights the potential risks and challenges astronauts may face during and after space travel, emphasizing the need for further research in this area. [Extracted from the article]

The article discusses the acceleration of age-related impairments in vascular function in women, particularly focusing on the impact of reproductive hormones on vascular aging. Studies have shown that age-related declines in vascular function may begin earlier than previously reported, with FSH and progesterone playing a significant role in mediating these effects. The study highlights the importance of understanding the interactions between somatic and reproductive aging on vascular function to develop interventions for reducing cardiovascular risk in women. However, the lack of diversity in the sample raises questions about how factors like race, ethnicity, socioeconomic status, and lifestyle behaviors may influence vascular aging trajectories. [Extracted from the article]

Introduction: Gouty nephropathy (GN) arises from factors like excessive purine intake, metabolic disorders or abnormal synthesis, and uric acid hypersaturation in the blood, leading to urate crystal deposition in kidney tissue. DaiTongXiao (DTX) is a remedy used by the Dai people of China. It shows efficacy in lowering uric acid levels and exhibits anti-inflammatory and kidney-protective properties. Methods: A GN rat model was induced using adenine and potassium oxonate. Following DTX administration, various parameters were assessed in urine, serum, and kidney tissue. Western blot analysis evaluated TLR4/MyD88/NF-κB signaling proteins, while immunofluorescence examined NF-κB nuclear expression. Results: DTX treatment improved kidney morphology, increased body weight, and kidney index and enhanced urinary levels of blood urea nitrogen (Bun), 24-h urinary protein, uric acid (UA), and allantoin in GN rats, reducing UA, Bun, creatinine (Cre), cystatin C (CysC), serum amyloid A (SAA), α1-microglobulin (MG), and β2-MG in serum analysis. Renal tissue assessments showed decreased xanthine oxidase (XOD), hydroxyproline (Hyp), α-smooth muscle actin (α-SMA), and collage type Ⅳ (COL-Ⅳ). Kidney damage severity was notably reduced. DTX lowered serum inflammatory factors like interleukin (IL) -18, tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), transforming growth factor-β1 (TGF-β1), and IL-1β in the rat serum, reducing chemokine monocyte chemoattractant protein-1 (MCP-1) and adhesion factor vascular cell adhesion molecule-1(VCAM-1). Western blotting demonstrated the downregulation of TLR4/MyD88/NF-κB pathway proteins, and immunofluorescence revealed reduced NF-κB expression in renal tissue. Discussion: DTX exhibits significant anti-GN effects by modulating TLR4/MyD88/NF-κB pathway protein expression, reducing inflammatory factor release, and inhibiting GN progression. [ABSTRACT FROM AUTHOR]

Introduction: Snakebites are acute systemic toxic diseases caused by snake venom entering the body through wounds. Failure to use antivenom immediately and difficulty in obtaining antivenoms are frequently responsible for worsening disease. Traditional Chinese medicine is commonly used to supplement and replace antivenom in treating snakebites. The Jidesheng snake pill (JDS) is a widely used traditional Chinese medicine that has achieved good clinical therapeutic effects; however, its mechanism remains unclear. Therefore, metabolomics techniques were employed to explore the pathophysiological mechanisms of JDS treatment of Agkistrodon halys (Ah) snake venompoisoned mice. Methods: The Ah group mouse model was established by intramuscular injection of Ah venom into the hind legs of the mice. The Ah venom + JDS group model was established using JDS after the affected area was treated with Ah venom. Hematoxylin and eosin (HE) staining was used to evaluate the severity of gastrocnemius injury. Quantitative polymerase chain reaction (qPCR) was utilized to detect the mRNA expression of vascular cell adhesion molecule-1 (VCAM-1), muscle-specific creatine kinase (CKM), thrombin antithrombin complex (TAT), and tumor necrosis factor-alpha (TNF-α). Gas chromatography-mass spectrometry (GC-MS) was performed with multivariate statistical analysis to provide new insights into the global metabolic profile of Ah venom-poisoned mice. Results: HE staining revealed increased red cell necrosis, local hemorrhage, and neutrophil infiltration in the Ah venom group than in the control group. Several compounds were identified, including lipids, amino acids, peptides, and organooxygen. Eighty differential metabolites were screened between the control group and the Ah venom group, and 24 were screened between the Ah venom and JDS groups. The mechanism of Ah venom poisoning in mice may involve aminoacyl-tRNA biosynthesis, various amino acid metabolism disorders, tricarboxylic acid circulation disorders, and abnormal fatty acid metabolism. JDS may reduce symptoms by affecting longchain fatty acid and amino acid metabolism and promoting nicotinamidenicotinamide metabolism. Conclusion: Our results suggest that metabolomics has huge prospects for elucidating the pathophysiology of Agkistrodon haly venom poisoning and therapeutic mechanisms of JDS. [ABSTRACT FROM AUTHOR]

Sickle Cell Anemia (SCA), is an inherited hemoglobinopathy characterized by the presence of an abnormal hemoglobin (HbS), being the most prevalent sickle cell disease (SCD). SCA is characterized by vascular endothelial dysfunction, which contributes significantly to various clinical conditions, including but not limited to pulmonary hypertension, priapism, cutaneous leg ulceration, and stroke. The pathophysiology of endothelial dysfunction (ED) in SCA is a multifaceted process involving a chronic inflammatory and hypercoagulable state. Key factors include hemolysis-associated elements like reduced arginine and nitric oxide (NO) availability, elevated levels of vascular adhesion molecules, the uncoupling effect of NO synthase, heightened arginase activity, an environment characterized by oxidative stress with the production of reactive oxygen and nitrogen species, and occurrences of ischemia-reperfusion injury, along with apolipoprotein A-1 depletion. The urgency for novel interventions addressing ED is evident. Presently, there is a focus on investigating small molecules that disrupt the arginine-nitric oxide pathway, exhibiting anti-inflammatory and antioxidant properties while diminishing levels of cellular and vascular adhesion molecules. In this mini-review article, we delve into the progress made in strategies for treating ED in SCD with the aim of cultivating insights for drug design. [Display omitted] • ED is a vasculopathy found in SCD patients responsible for pulmonary arterial hypertension, priapism, and leg ulcers. • Low NO bioavailability, activated endothelial cells, and high levels of ROS are the main characteristics in ED. • NO-donors, sGC stimulators and activators, antioxidants, supplementation of vitamins and arginine are the focus of this review. • FDA approved drugs such as HU and l-glutamine also play an important role in ED, ameliorating the oxidant profile. [ABSTRACT FROM AUTHOR]

Aims: Endothelial inflammation is crucial in the initiation and progression of atherosclerosis, whereas cholesterol crystals (CCs) play a key role in atherogenesis. However, the effects and origination of CCs on endothelial inflammation are not well understood. Results: In the present study, we found that CCs appeared in the subendothelial space of the partially ligated carotid artery only 1 week after Western diet feeding, which was before immune cell infiltration. In vitro, CCs were generated by human aortic endothelial cells (HAECs) upon low-density lipoprotein treatment. These endothelial cell (EC)-derived CCs increased the expression of intercellular cell adhesion molecule-1 (ICAM1) and vascular cell adhesion molecule-1 (VCAM1). Mechanistic studies demonstrated that CC-induced pyroptosis was critical for endothelial inflammation. Knockdown of gasdermin D (GSDMD) inhibited CC-induced endothelial inflammation, attenuated plaque progression, and decreased macrophage content. Accordingly, the inhibition of GSDMD reduced the CC-induced increase of VCAM1 and ICAM1 in HAECs. Furthermore, CC-mediated pyroptosis was found to be caspase-1 (CASP1)-dependent. Inhibition of CASP1 also reduced endothelial inflammation and attenuated plaque progression. The expression of GSDMD was increased in human atherosclerotic plaques. These findings identify that EC-derived CCs may be an important driving force in the pathogenesis of atherosclerosis. Innovation: This study uncovered a new understanding that CC-induced pyroptosis contributes to endothelial inflammation in early atherogenesis. Conclusion: Targeting endothelial GSDMD or CASP1 contributes to the repression of vascular inflammation and atherogenesis. Antioxid. Redox Signal. 41, 201–215. [ABSTRACT FROM AUTHOR]

Cell surface marker expression is one of the criteria for defining human mesenchymal stem or stromal cells (MSC) in vitro. However, it is unclear if expression of markers including CD73 and CD90 reflects the in vivo origin of cultured cells. We evaluated expression of 15 putative MSC markers in primary cultured cells from periosteum and cartilage to determine whether expression of these markers reflects either the differentiation state of cultured cells or the self-renewal of in vivo populations. Cultured cells had universal and consistent expression of various putative stem cell markers including > 95% expression CD73, CD90 and PDPN in both periosteal and cartilage cultures. Altering the culture surface with extracellular matrix coatings had minimal effect on cell surface marker expression. Osteogenic differentiation led to loss of CD106 and CD146 expression, however CD73 and CD90 were retained in > 90% of cells. We sorted freshly isolated periosteal populations capable of CFU-F formation on the basis of CD90 expression in combination with CD34, CD73 and CD26. All primary cultures universally expressed CD73 and CD90 and lacked CD34, irrespective of the expression of these markers ex vivo indicating phenotypic convergence in vitro. We conclude that markers including CD73 and CD90 are acquired in vitro in most 'mesenchymal' cells capable of expansion. Overall, we demonstrate that in vitro expression of many cell surface markers in plastic-adherent cultures is unrelated to their expression prior to culture. [ABSTRACT FROM AUTHOR]

Vascular adhesion protein‐1 (VAP‐1) plays a dual role with its adhesive and enzymatic properties, facilitating leukocyte migration to sites of inflammation and catalyzing the breakdown of primary amines into harmful by‐products, which are linked to diabetic complications. Present in various tissues, VAP‐1 also circulates in a soluble form in the bloodstream. Diabetes is associated with several complications such as cardiovascular disease, retinopathy, nephropathy, and neuropathy, significantly contributing to disability and mortality. These complications arise from hyperglycemia‐induced oxidative stress, inflammation, and the formation of advanced glycation end‐products (AGEs). Earlier research, including our own from the 1990s and early 2000s, has underscored the critical role of VAP‐1 in these pathological processes, prompting extensive investigation into its contribution to diabetic complications. In this review, we examine the involvement of VAP‐1 in diabetes and its complications, alongside its link to other conditions related to diabetes, such as cancer and metabolic dysfunction‐associated fatty liver disease. We also explore the utility of soluble VAP‐1 as a biomarker for diabetes, its complications, and other related conditions. Since the inhibition of VAP‐1 to treat diabetic complications is a novel and promising treatment option, further studies are needed to translate the beneficial effect of VAP‐1 inhibitors observed in animal studies to clinical trials recruiting human subjects. Besides, future studies should focus on using serum sVAP‐1 levels for risk assessment in diabetic patients, identifying those who need intensive glycemic control, and determining the patient population that would benefit most from VAP‐1 inhibitor therapies. [ABSTRACT FROM AUTHOR]

Recently developed antimigraine therapeutics targeting calcitonin gene--related peptide (CGRP) signaling are effective, though their sites of activity remain elusive. Notably, the lymphatic vasculature is responsive to CGRP signaling, but whether meningeal lymphatic vessels (MLVs) contribute to migraine pathophysiology is unknown. Mice with lymphatic vasculature deficient in the CGRP receptor (CalcrliLEC mice) treated with nitroglycerin-mediated (NTG-mediated) chronic migraine exhibit reduced pain and light avoidance compared with NTG-treated littermate controls. Gene expression profiles of lymphatic endothelial cells (LECs) isolated from the meninges of Rpl22HA/+;Lyve1Cre RiboTag mice treated with NTG revealed increased MLV-immune interactions compared with cells from untreated mice. Interestingly, the relative abundance of mucosal vascular addressin cell adhesion molecule 1--interacting (MAdCAM1-interacting) CD4+ T cells was increased in the deep cervical lymph nodes of NTG-treated control mice but not in NTG-treated CalcrliLEC mice. Treatment of cultured hLECs with CGRP peptide in vitro induced vascular endothelial--cadherin (VE-cadherin) rearrangement and reduced functional permeability. Likewise, intra cisterna magna injection of CGRP caused rearrangement of VE-cadherin, decreased MLV uptake of cerebrospinal fluid (CSF), and impaired CSF drainage in control mice but not in CalcrliLEC mice. Collectively, these findings reveal a previously unrecognized role for lymphatics in chronic migraine, whereby CGRP signaling primes MLV-immune interactions and reduces CSF efflux. [ABSTRACT FROM AUTHOR]