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Objectives To investigate the prognostic utility of 28 serum biomarkers in systemic sclerosis (SSc), SSc-associated interstitial lung disease (SSc-ILD) and clinically relevant disease subgroups. Methods Participants with sera, high-resolution CT and lung function within 12 months of baseline were identified from the Australian Scleroderma Cohort Study. Baseline was the time of serum collection. Twenty-seven of the prespecified 28 serum biomarkers were analysed and biomarker associations with mortality and ILD progression were investigated in univariable and multivariable analyses, including within disease subgroups and combined with established risk factors for poorer prognosis in SSc. Results A total of 407 participants were identified, 252 (61.9%) with SSc-ILD. The median (interquartile range) follow-up after biomarker measurement was 6.31 (3.11–9.22) years. Sixteen biomarkers were associated with increased mortality. High levels of VCAM-1 were most strongly associated with mortality [hazard ratio (HR) 3.55; 95% CI 2.37–5.33; P <  0.001]. Five additional biomarkers had an HR >2: SP-D (2.28, 1.57–3.31; P <  0.001), E-selectin (2.19, 1.53–3.14; P <  0.001), IL-6 (2.15, 1.50–3.09; P <  0.001), MMP-3 (2.05, 1.42–2.95; P <  0.001) and ET-1 (2.03, 1.40–2.92; P <  0.001). Eleven biomarkers were independently associated with mortality following adjustment for sex, age and baseline forced vital capacity (FVC%predicted). Three biomarkers were associated with ILD progression at 1-year follow-up: CXCL4 (odds ratio 2.67, 1.46–4.88; P  = 0.001), MMP-1 (2.56, 1.43–4.59; P =  0.002) and ET-1 (2.18, 1.24–3.83; P =  0.007). Conclusion Multiple biomarkers, especially VCAM-1, E-selectin, SP-D and CXCL4, provide prognostic utility beyond that of established risk factors for patients with SSc. [ABSTRACT FROM AUTHOR]

Growing body of evidence suggests that cardiovascular risk factor, asymmetric dimethylarginine (ADMA), can be implicated in the pathogenesis of neurodegenerative and psychiatric disorders. In part, ADMA can affect brain health negatively modulating critical functions of the blood-brain barrier (BBB). The precise mechanisms and consequences of ADMA action on the cerebral vasculature remains unexplored. Here, we evaluated ADMA-induced maladaptation of BBB functions by analyzing real time electrical cell-substrate impedance, paracellular permeability, immune-endothelial interactions, and inflammatory cytokines production by primary human brain microvascular endothelial cells (hBMVEC) treated with ADMA. We found that ADMA disrupted physical barrier function as evident by significant decrease in electrical resistance and increase in paracellular permeability of hBMVEC monolayers. Next, ADMA triggered immune-endothelial interactions since adhesion of primary human monocytes and their extravasation across the endothelialmonolayer both were significantly elevated upon treatment with ADMA. Increased levels of cell adhesion molecules (VCAM-1 and RANTES), VEGF-A and inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-10, IL-4, IL-2, IL-13, IL-12p70) characterize ADMA-induced hBMVEC dysfunction as inflammatory. Overall, our data suggest that ADMA can impair BBB functions disrupting the endothelial barrier and eliciting neuroinflammatory and neuroimmune responses. [ABSTRACT FROM AUTHOR]

Studies in animal models have suggested a linkage between the inflammatory response to injury and subsequent nephron loss during the acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Failure of normal repair during the CKD transition correlates with de novo expression of vascular cell adhesion protein-1 (VCAM-1) by a subset of injured proximal tubule cells. This study identified the role of VCAM-1 expression in promoting the failed repair state. Single-cell transcriptome analysis of patients with AKI and CKD and whole kidney RNA and protein analyses of mouse models of CKD confirmed a marked increase of VCAM-1 expression in the proximal tubules of injured kidneys. In immortalized mouse proximal tubular cells and primary cultured renal cells (PCRCs), VCAM-1 expression was induced by proinflammatory cytokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Analyses of bulk RNA sequencing of TNF-α-treated primary cultured renal cells or pseudo-bulk RNA sequencing of biopsies from Kidney Precision Medicine Project datasets indicated activation of NF-κB and an enrichment of inflammatory response and cell adhesion pathways in VCAM-1-positive cells. Pharmacological inhibition of NF-κB signaling or genetic deletion of myeloid differentiation factor 88 and TIR domain-containing adapter-inducing interferon-β suppressed TNF-α- and IL-1β-induced VCAM-1 expression in vitro. TNF-α stimulation or overexpression of VCAM-1 significantly increased splenocyte adhesion to the mouse proximal tubular monolayer in culture. These results demonstrate that persistence of proinflammatory cytokines after AKI can induce NF-κB-dependent VCAM-1 expression by proximal tubule cells, mediating increased immune cell adhesion to the tubule and thus promoting further tubule injury and greater risk of progression from AKI to CKD. NEW & NOTEWORTHY: We demonstrated the induction of VCAM-1 and its biological function in proximal tubules. We found that proinflammatory cytokines (TNF-α and IL-1β) significantly induced VCAM-1 expression via NF-κB signaling pathway. TNF-α treatment or overexpression of VCAM-1 in immortalized MPT cells increased CD45+ splenocyte adhesion. Pharmacological inhibition of NF-κB or genetic deletion of Vcam1 suppressed TNF-α-induced splenocyte adhesion in vitro, suggesting that VCAM-1 mediates proximal tubular-immune cell cross talk in failed tubule recovery during AKI-to-CKD transition. [ABSTRACT FROM AUTHOR]

Intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin are cell adhesion molecules that play a significant role in inflammation and are implicated in the pathophysiology of preeclampsia development and HIV infection. More specifically, the immune expression of ICAM-1, VCAM-1, and E-selectin within cyto- and syncytiotrophoblast cells are dysregulated in preeclampsia, indicating their role in defective placentation. This study investigates the associations of ICAM-1, VCAM-1, and E-selectin gene variants (rs3093030, rs3783605, and rs1805193, respectively) with preeclampsia comorbid with HIV infection in women of African ancestry. It also examines the susceptibility to preeclampsia development and the effect of highly active antiretroviral therapy (HAART). A total of 405 women were enrolled in this study. Out of these women, 204 were preeclamptic and 201 were normotensive. Clinical characteristics were maternal age, weight, blood pressure (systolic and diastolic), and gestational age. Whole blood was collected, DNA was extracted, and genotyping of the ICAM-1 (rs3093030 C>T), VCAM-1(rs3783605 A>G), and E-selectin (rs1805193 A>C) gene polymorphisms was performed. Comparisons were made using the Chi-squared test. Our results demonstrated that preeclamptic women exhibited a higher frequency of analyzed variants, in contrast to those with the duality of preeclampsia and HIV infection. Additionally, the C allele of the ICAM-1 (rs3093030 C>T) and G allele of the VCAM-1 (rs3783605 A>G) genes were found to have a greater role in the co-morbidity and may be considered as a risk factor for preeclampsia development in women of African ancestry. In contrast, the SNP of rs1805193 of the E-selectin gene indicated that A>C was only significantly associated with HIV infection and not with preeclampsia. These findings highlight a strong association of the rs3093030 SNP of the ICAM-1 gene and of the VCAM-1 rs3783605 gene with the development of preeclampsia, indicating their role in the defective trophoblast invasion of preeclampsia. Sub-group analysis further reveals an association of the AA genotype with late-onset preeclampsia, a less severe form of disease indicating differing genetic predispositions between early and late-onset forms. [ABSTRACT FROM AUTHOR]

Background: The mechanism involved in HBO2 preconditioning in preventing inflammation in diving is still unclear. Syndecan-1, which is an important part of glycocalyx, has never been studied for its involvement in HBO2 preconditioning to prevent inflammation in decompression diving. This study aims to determine how HBO2 preconditioning impacts inflammation through Syndecan-1, MDA, and IL-1a markers. Method: This study is a true experimental post-test design. Forty male 12- to 14-year-old Sprague Dawley rats were divided into four groups. HBO2 and decompression diving were carried out in an animal hyperbaric chamber. All data were collected 12 and 24 hours after the decompression diving. Result: The incidence of decompression sickness was less frequent in the HBO2 preconditioning treatment group as opposed to the control group (4 vs 9) but did not reach a significant level (p > 0.05). All parameters showed no difference between the control and treatment groups 12 hours after the dive (p > 0.05). Twenty-four hours after diving, the treatment group demonstrated substantially elevated IL-1a levels in comparison to the control group (p = 0.030), and the increase of IL-1a in the treatment group is significant (p = 0.001). Although MDA levels did not reach significant, the treatment group's increase in MDA levels 24 hours after diving was greater than that of the control group. Meanwhile, The treatment group had a smaller reduction in Syndecan-1 levels in comparison to the control group following diving 24 hours later. Conclusion: HBO2 preconditioning prolongs the inflammation, as evidenced by increased levels of MDA, Syndecan-1, and IL-1a, even though it can prevent decompression sickness. Further research is needed to find the right time and dose of HBO2 preconditioning to shorten the inflammation time. [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]

Abstract Ibrutinib (IB) is a tyrosine kinase inhibitor (TKI) that has immunomodulatory action and can be used as second-line therapy for steroid-refractory or steroid-resistant chronic Graft versus Host Disease (cGVHD). Mesenchymal stromal cells (MSCs) are distributed throughout the body and their infusion has also been explored as a second-line therapeutic alternative for the treatment of cGVHD. Considering the currently unknown effects of IB on endogenous MSCs, as well as the possible combined use of IB and MSCs for cGVHD, we investigated whether adipose tissue-derived MSCs present IB-targets, as well as the consequences of treating MSCs with this drug, regarding cell viability, proliferation, phenotype, and anti-inflammatory potential. Interestingly, we show for the first time that MSCs express several IB target genes. Also of note, the treatment of such cells with this TKI elevated the levels of CD90 and CD105 surface proteins, as well as VCAM-1. Furthermore, IB-treated MSCs presented increased mRNA expression of the anti-inflammatory genes PD-L1, TSG-6, and IL-10. However, continued exposure to IB, even at low doses, compromised the viability of MSCs. These data indicate that the use of IB can stimulate an anti-inflammatory profile in MSCs, but also that a continued exposure to IB can compromise MSC viability over time.

الملخص: أهداف البحث: تم مؤخرا اقتراح مشاركة البروتين المفرز الناجم عن ونت-1 (ويسب1/سي سي إن 4) في العديد من التفاعلات مع الالتهاب. ومع ذلك، فإن دوره في التهاب المفاصل الروماتويدي لا يزال موضع جدل. تم الإبلاغ عن الارتباطات بين التهاب المفاصل الروماتويدي الذي تم تشخيصه بشكل سيئ وعدد من العلامات الكلاسيكية المستمدة من الديموغرافيا والكيمياء الحيوية. تهدف هذه الدراسة للبحث في موثوقية وفعالية تركيزات مصل ''سي سي إن 4''، وجزيء التصاق الخلايا الوعائية -1، وماتريكس ميلوبروتيناز-3، وعامل تحفيز مستعمرة الخلايا المحببة في المراقبة والتقييم لتوقع التهاب المفاصل الروماتويدي وتلف العظام وارتباطهما بمسار المرض. طريقة البحث: قامت الدراسة بتحليل 128 مريضا مصابا بالتهاب المفاصل الروماتويدي، بما في ذلك 68 تم تشخيصهم حديثا، و60 تم تشخيصهم مسبقا، و60 كمجموعة مراقبة. تم قياس مستويات العلامات الحيوية باستخدام مقايسة الممتص المناعي المرتبط بالإنزيم، وتم قياس المعلمات المخبرية الروتينية مثل المعلمات المصلية والسريرية والكيميائية الحيوية والدموية. تم جمع بيانات الديموغرافيا والقياسات البشرية والأعراض السريرية من خلال المقابلات والاستبيان، وتم استخدام درجة نشاط المرض المشترك 28 لتحديد نشاط المرض. النتائج: أشارت النتائج إلى ارتفاع معنوي في تراكيز أربعة مؤشرات حيوية في مجموعة التهاب المفاصل الروماتويدي مقارنة بالعينة السليمة. كما تم تسجيل تراكيز مرتفعة في المرضى الذين يعانون من ارتفاع، مقارنة مع المرضى المعتدلين والمنخفضين، وفقا لحالة نشاط ''المرض المشترك 28 إي إس آر''، باستثناء عدد الوحيدات، ونسبة الهيماتوكريت، ومستوى اليوريا. علاوة على ذلك، تم تسجيل ارتباط إيجابي بين مستوى ''سي سي إن 4'' وقيم جزيء التصاق الخلايا الوعائية -1، ماتريكس ميلوبروتيناز-3، عامل تحفيز مستعمرة الخلايا المحببة، درجة نشاط ''المرض المشترك 28 سي آر بي'' ودرجة نشاط ''المرض المشترك 28 إي إس آر''. مستويات العلامات التنبؤية الثلاثة (''سي سي إن 4'' وجزيء التصاق الخلايا الوعائية -1 وماتريكس ميلوبروتيناز-3) كانت مرتفعة في المرضى غير المعالجين، في حين أن مستوى عامل تحفيز مستعمرة الخلايا المحببة لم يظهر أي فرق. الاستنتاجات: تشير هذه البيانات إلى أنه يمكن استخدام ''سي سي إن 4'' بشكل موثوق لتحديد النشاط والاستجابة العلاجية المتعلقة بالتهاب المفاصل الروماتويدي، مما يؤدي إلى تشخيص التهاب المفاصل الروماتويدي مبكرا. Abstract: Background: The involvement of Wnt-1-induced secreted protein-1 (WISP1/CCN4) in several inflammatory reaction has recently been proposed. Nevertheless, this protein's involvement in rheumatoid arthritis (RA) remains debated. Associations between poorly diagnosed RA and several classical markers derived from demography and biochemistry have been reported. Aim: We sought to investigate the reliability and effectiveness of serum concentrations of CCN4, vascular cell adhesion molecule-1 (VCAM-1), matrix melloprotenase-3 (MMP-3), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in monitoring and predicting RA and bone damage, and their correlation with RA disease course. Methods: The study analyzed 128 patients with RA, comprising 68 newly diagnosed and 60 previously diagnosed patients, as well as 60 controls. Biomarker levels were measured with enzyme linked immuno-sorbent assays. Routine laboratory parameters such as serological, clinical, biochemical, and hematological parameters were additionally measured. Demography, anthropometry, and clinical symptom data were collected through interviews and a questionnaire. The joint disease activity score 28 (DAS28) was used to determine disease activity. Results: Concentrations of four biomarkers were significantly higher in the RA group than the healthy controls. Elevated biomarker concentrations were also observed in patients with high, rather than moderate or low, DAS28-ESR activity status, except for monocyte count, hematocrit (%), and urea level. Furthermore, CCN4 level positively correlated with VCAM-1, MMP-3, and GM-CSF levels, DA-S28-CRP and DAS28-ESR. The levels of three predictive markers, CCN4, VCAM-1, and MMP-3, were elevated in non-treated patients, whereas GM-CSF level showed no difference. The highest area under the curve was 73.3% for CCN4, with 93.3% sensitivity and 64.7% specificity. Conclusion: Our data suggest that CCN4 can be reliably used to indicate activity and therapeutic response associated with RA, thus facilitating earlier RA diagnosis.

Ibrutinib (IB) is a tyrosine kinase inhibitor (TKI) that has immunomodulatory action and can be used as second-line therapy for steroid-refractory or steroid-resistant chronic Graft versus Host Disease (cGVHD). Mesenchymal stromal cells (MSCs) are distributed throughout the body and their infusion has also been explored as a second-line therapeutic alternative for the treatment of cGVHD. Considering the currently unknown effects of IB on endogenous MSCs, as well as the possible combined use of IB and MSCs for cGVHD, we investigated whether adipose tissue-derived MSCs present IB-targets, as well as the consequences of treating MSCs with this drug, regarding cell viability, proliferation, phenotype, and anti-inflammatory potential. Interestingly, we show for the first time that MSCs express several IB target genes. Also of note, the treatment of such cells with this TKI elevated the levels of CD90 and CD105 surface proteins, as well as VCAM-1. Furthermore, IB-treated MSCs presented increased mRNA expression of the anti-inflammatory genes PD-L1, TSG-6, and IL-10. However, continued exposure to IB, even at low doses, compromised the viability of MSCs. These data indicate that the use of IB can stimulate an anti-inflammatory profile in MSCs, but also that a continued exposure to IB can compromise MSC viability over time. [ABSTRACT FROM AUTHOR]

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Tumor blood vessels are highly leaky in structure and have poor blood perfusion, which hampers infiltration and function of CD8T cells within tumor. Normalizing tumor vessels is thus thought to be important in promoting the flux of immune T cells and enhancing ant-tumor immunity. However, how tumor vasculature is normalized is poorly understood. Metformin (Met) combined with ant-PD-1 therapy is known to stimulate proliferation of and to produce large amounts of IFNγ from tumor-infiltrating CD8T lymphocytes (CD8TILs). We found that the combination therapy promotes the pericyte coverage of tumor vascular endothelial cells (ECs) to improve blood perfusion and that it suppresses the hyperpermeability through the increase of VE-cadherin. Peripheral node addressin(PNAd) and vascular cell adhesion molecule (VCAM)-1, both implicated to promote tumor infiltration of CD8T cells, were also increased. Importantly, tumor vessel normalization, characterized as the reduced 70-kDa dextran leakage and the enhancement ofVE-cadherin and VCAM-1, were canceled by anti-CD8 Ab or anti-IFNγ Ab injection to mice. The increased CD8TILs were also abrogated by anti-IFNγ Ab injection. In vascular ECs, flow cytometry analysis revealed that pSTATl expression was found to be associated with VE-cadherin expression. Moreover, in vitro treatment with Met and IFNγ enhanced VE-cadherin and VCAM-1 on human umbilical vein endothelial cells (HUVECs). The Kaplan-Meier method revealed a correlation of VE-cadherin or VCAM-1 levels with overall survival in patients treated with immune checkpoint inhibitors. These data indicate that IFNγ-mediated cross talk of CD8TILs with tumor vessels is important for creating a better tumor microenvironment and maintaining sustained antitumor immunity. [ABSTRACT FROM AUTHOR]

Background: Acute appendicitis is a common abdominal emergency observed in emergency departments (ED). Distinguishing between uncomplicated and complicated appendicitis is important in determining a treatment strategy. Serum soluble vascular cell adhesion molecule-1 (VCAM-1) is an inflammatory biomarker. We aimed to determine the role of VCAM-1 in predicting complicated appendicitis in children. Methods: Pediatric patients with suspected appendicitis admitted to the ED were enrolled in this prospective study. Pre-surgical serum VCAM-1 was tested in children with acute appendicitis within 72 h of symptoms (from day 1 to day 3). Serum VCAM-1 levels were further analyzed and compared between patients with and without complicated appendicitis. Results: Among the 226 pediatric appendicitis patients, 70 had uncomplicated appendicitis, 138 had complicated appendicitis, and 18 had normal appendices. The mean serum VCAM-1 levels in patients with perforated appendicitis were higher than in those with simple appendicitis (p < 0.001). On day 1 to day 3, the mean VCAM-1 levels in patients with complicated appendicitis were all significantly higher than in those with uncomplicated appendicitis (all p < 0.001). Conclusion: Serum VCAM-1 levels may be helpful in differentiating uncomplicated and complicated appendicitis in children and could predict appendiceal perforation. [ABSTRACT FROM AUTHOR]

Purpose: This study was designed to explore the effects of interleukin 33 (IL-33) on the progression of atherosclerosis and the possible mechanism. Methods: The adhesion assay was performed on isolated peripheral blood mononuclear cells (PBMCs) and human umbilical vein endothelial cells (HUVEC). The expression of proteins and messenger RNA (mRNA) were detected by western blot and quantitative real-time polymerase chain reaction (PCR), including intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and P-selectin. The effect of IL-33 on the interaction of growth stimulation expressed gene 2 (ST2) with myeloid differentiation factor 88 (MyD88) and interleukin-1 receptor-associated kinase (IRAK) 1/4 were investigated using co-immunoprecipitation assay. An apolipoprotein (Apo) E-/- mice model was used to confirm the effect of IL-33 on atherosclerosis progression. Area of plaques was recorded by hematoxylin-eosin (H&E) staining. The severity of atherosclerosis plaque was evaluated using immunohistochemistry assay, and lipid accumulation was measured by an oil red O staining. In contrast, western blot was performed to detect the expression levels of VCAM-1, extracellular signal-regulated kinase (ERK) 1/2, and interferon regulatory factor 1 (IRF1). Results: Our study observed that IL-33 suppressed cell adhesion and the expression of VCAM-1 in tumor necrosis factor-α (TNF-α) exposed HUVEC. Moreover, the addition of IL-33 significantly inhibited the expression of IRF1 and the binding level of IRF1 to VCAM-1 and also promoted the phosphorylation level of IRAK1/4 and ERK1/2 compared to TNF-α-stimulated HUVEC. The ST2 neutralizing antibody or ERK pathway inhibitor SCH772984 reversed the regulatory effects of IL-33 on HUVEC, suggesting that IL-33 suppressed IRF1 and VCAM-1 dependent on binding to ST2 and activating the ERK1/2 signaling pathway. Further investigation in vivo confirmed that IL-33 decreased the expressions of IRF1 and VCAM-1 by activating the phosphorylation of ERK1/2 in the thoracic aorta of Apo E-/- mice. Conclusion: In conclusion, our results demonstrated that IL-33 plays a protective role in the progression of atherosclerosis by inhibiting cell adhesion via the ERK1/2-IRF1-VCAM-1 pathway. This study may provide a potential therapeutic way to prevent the development of atherosclerosis. [ABSTRACT FROM AUTHOR]

Growing body of evidence suggests that cardiovascular risk factor, asymmetric dimethylarginine (ADMA), can be implicated in the pathogenesis of neurodegenerative and psychiatric disorders. In part, ADMA can affect brain health negatively modulating critical functions of the blood-brain barrier (BBB). The precise mechanisms and consequences of ADMA action on the cerebral vasculature remains unexplored. Here, we evaluated ADMA-induced maladaptation of BBB functions by analyzing real time electrical cell-substrate impedance, paracellular permeability, immune-endothelial interactions, and inflammatory cytokines production by primary human brain microvascular endothelial cells (hBMVEC) treated with ADMA. We found that ADMA disrupted physical barrier function as evident by significant decrease in electrical resistance and increase in paracellular permeability of hBMVEC monolayers. Next, ADMA triggered immune-endothelial interactions since adhesion of primary human monocytes and their extravasation across the endothelial monolayer both were significantly elevated upon treatment with ADMA. Increased levels of cell adhesion molecules (VCAM-1 and RANTES), VEGF-A and inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-10, IL-4, IL-2, IL-13, IL-12p70) characterize ADMA-induced hBMVEC dysfunction as inflammatory. Overall, our data suggest that ADMA can impair BBB functions disrupting the endothelial barrier and eliciting neuroinflammatory and neuroimmune responses.

Objective: Endometriosis is an estrogen-dependent chronic inflammatory disease in women of reproductive age. A review of the literature revealed that cytokines and inflammatory factors are associated with endometriosis-associated infertility. Interleukin 33 (IL-33) is a strong inducer of other pro-inflammatory cytokines. Vascular cell adhesion molecule-1 (VCAM-1) plays a central role in recruiting inflammatory cells, whose expression facilitates leukocyte adhesion and is rapidly induced by pro-inflammatory cytokines. Many studies have indicated that VCAM-1 expression is high in endometriosis; however, whether the expression of VCAM-1 is related to IL-33 is unclear. Materials and methods: Human ovarian endometriotic stromal cells (hOVEN-SCs) were treated with IL-33 to enable investigation of cell characterization, gene and protein expression, and signal pathways. Proliferation potential was measured using an MTT assay. Gene expression was analyzed using reverse transcription-polymerase chain reaction. Protein expression assay was performed using western blot analysis. Results: This study investigated the effects of IL-33 on VCAM-1 and COX-2 expression in hOVEN-SCs. First, the results revealed that the IL-33/ST2/mitogen-activated protein kinase (MAPK) signaling pathway could increase the expression of VCAM-1 and COX-2 in hOVEN-SCs. Second, we discovered that COX-2 expression was essential for IL-33-induced VCAM-1 expression because the effects could be negated through NS398, a selective COX-2 inhibitor. Finally, treatment of IL-33-treated hOVEN-SCs with celecoxib significantly and dose-responsively decreased VCAM-1 expression. Conclusion: Taken together, these results indicate that IL-33 can upregulate VCAM-1 expression in hOVEN-SCs through the IL-33/ST2/MAPK/COX-2 signaling pathway and thereby contribute to endometriosis.

ObjectiveChronic inflammation and vascular dysfunction (e.g., chronic endothelial activation) are related yet dissociable mechanisms of HIV-associated neurocognitive impairment (NCI), even among those on antiretroviral therapy (ART). However, how these mechanisms differentially contribute to domain-specific deficits in people with and without HIV (PWH, PWoH) is unclear. We empirically-derived profiles of NCI and examined relationships with peripheral inflammatory and vascular biomarkers.MethodsParticipants were 84 virally-suppressed PWH and 126 PWoH who underwent neuropsychological testing and blood draw. Cluster analysis identified subgroups based on domain deficit scores. ANOVAs examined HIV serostatus and cluster group differences in composite plasma biomarker z-scores of inflammation (IL-6, CXCL10/IP-10, CCL2/MCP-1) and vascular injury (VCAM-1, ICAM-1, uPAR). Confirmatory regressions examined the interaction of HIV and biomarker z-scores on domain-specific T-scores, controlling for cardiovascular disease (CVD) risk and psychosocial factors.ResultsCluster analysis identified three groups: Unimpaired (n = 129), Learning/Recall (n = 52, isolated learning/recall deficits), Dysexecutive/Slow (n = 29, executive function, working memory, processing speed, and motor deficits). PWH had higher odds of Dysexecutive/Slow membership, which related to CVD risk and higher vascular dysfunction, but not inflammation, in PWH. Vascular biomarkers moderated adverse HIV effects on executive function, processing speed, and working memory such that PWH had lower T-scores only when vascular dysfunction was high.ConclusionsIn PWH with controlled disease, peripheral markers of endothelial dysfunction and vascular permeability are selectively associated with an empirically-derived subgroup that exhibits domain deficits commonly impacted by cerebrovascular disease. Findings support the presence of a vascular NCI subgroup of PWH who may benefit from interventions that directly target the neurovascular unit.

The primary inflammatory process in atherosclerosis, a major contributor to cardiovascular disease, begins with monocyte adhering to vascular endothelial cells. Actinidia arguta (kiwiberry) is an edible fruit that contains various bioactive components. While A. arguta extract (AAE) has been recognized for its anti-inflammatory characteristics, its specific inhibitory effect on early atherogenic events has not been clarified. We used tumor necrosis factor-α (TNF-α)–stimulated human umbilical vein endothelial cells (HUVECs) for an in vitro model. AAE effectively hindered the attachment of THP-1 monocytes and reduced the expression of vascular cell adhesion molecule-1 (VCAM-1) in HUVECs. Transcriptome analysis revealed that AAE treatment upregulated phosphatase and tensin homolog (PTEN), subsequently inhibiting phosphorylation of AKT and glycogen synthase kinase 3β (GSK3β) in HUVECs. AAE further hindered phosphorylation of AKT downstream of the nuclear factor kappa B (NF-κB) signaling pathway, leading to suppression of target gene expression. Oral administration of AAE suppressed TNF-α–stimulated VCAM-1 expression, monocyte-derived macrophage infiltration, and proinflammatory cytokine expression in C57BL/6 mouse aortas. Myo-inositol, identified as the major compound in AAE, played a key role in suppressing THP-1 monocyte adhesion in HUVECs. These findings suggest that AAE could serve as a nutraceutical for preventing atherosclerosis by inhibiting its initial pathogenesis. [ABSTRACT FROM AUTHOR]

In the aftermath of acute kidney injury (AKI), surviving proximal tubule epithelia repopulate injured tubules to promote repair. However, a portion of cells fail to repair [termed failed-repair proximal tubule cells (FR-PTCs)] and exert ongoing proinflammatory and profibrotic effects. To better understand the molecular drivers of the FR-PTC state, we reanalyzed a mouse ischemia-reperfusion injury single-nucleus RNA-sequencing (snRNA-seq) atlas to identify Traf2 and Nck interacting kinase (Tnik) to be exclusively expressed in FR-PTCs but not in healthy or acutely injured proximal tubules after AKI (2 and 6 wk) in mice. We confirmed expression of Tnik protein in injured mouse and human tissues by immunofluorescence. Then, to determine the functional role of Tnik in FR-PTCs, we depleted TNIK with siRNA in two human renal proximal tubule epithelial cell lines (primary and immortalized hRPTECs) and analyzed each by bulk RNA-sequencing. Pathway analysis revealed significant upregulation of inflammatory signaling pathways, whereas pathways associated with differentiated proximal tubules such as organic acid transport were significantly downregulated. TNIK gene knockdown drove reduced cell viability and increased apoptosis, including differentially expressed poly(ADP-ribose) polymerase (PARP) family members, cleaved PARP-1 fragments, and increased annexin V binding to phosphatidylserine. Together, these results indicate that Tnik upregulation in FR-PTCs acts in a compensatory fashion to suppress inflammation and promote proximal tubule epithelial cell survival after injury. Modulating TNIK activity may represent a prorepair therapeutic strategy after AKI. [ABSTRACT FROM AUTHOR]

Vascular cell adhesion molecule-1 (VCAM-1) was identified over 2 decades ago as an endothelial adhesion receptor involved in leukocyte recruitment and cell-based immune responses. In atherosclerosis, a chronic inflammatory disease of the blood vessels that is the leading cause of death in the USA, endothelial VCAM-1 is robustly expressed beginning in the early stages of the disease. The interactions of circulating immune cells with VCAM-1 on the activated endothelial cell surface promote the uptake of monocytes and the progression of atherosclerotic lesions in susceptible vessels. Herein, we review the role of VCAM-1 in atherosclerosis and the use of VCAM-1 binding peptides, antibodies and aptamers as targeting agents for nanoplatforms for early detection and treatment of atherosclerotic disease. [ABSTRACT FROM AUTHOR]

Endothelial inflammation is a multifaceted physiological process that plays a pivotal role in the pathogenesis and progression of diverse diseases, encompassing but not limited to acute lung infections like COVID-19, coronary artery disease, stroke, sepsis, metabolic syndrome, certain malignancies, and even psychiatric disorders such as depression. This inflammatory response is characterized by augmented expression of adhesion molecules and secretion of pro-inflammatory cytokines. In this study, we discovered that saponins from Allium macrostemon bulbs (SAMB) effectively inhibited inflammation in human umbilical vein endothelial cells induced by the exogenous inflammatory mediator lipopolysaccharide or the endogenous inflammatory mediator tumor necrosis factor-α, as evidenced by a significant reduction in the expression of pro-inflammatory factors and vascular cell adhesion molecule-1 (VCAM-1) with decreased monocyte adhesion. By employing the NF-κB inhibitor BAY-117082, we demonstrated that the inhibitory effect of SAMB on VCAM-1 expression may be attributed to the NF-κB pathway's inactivation, as characterized by the suppressed IκBα degradation and NF-κB p65 phosphorylation. Subsequently, we employed a murine model of lipopolysaccharide-induced septic acute lung injury to substantiate the potential of SAMB in ameliorating endothelial inflammation and acute lung injury in vivo. These findings provide novel insight into potential preventive and therapeutic strategies for the clinical management of diseases associated with endothelial inflammation. [ABSTRACT FROM AUTHOR]

Background: Cell adhesion molecules are protein entities that are located on the cell surface. The vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression is related to type 2 diabetes mellitus (T2DM) with dyslipidemia. Objectives: To determine the levels of VCAM-1 and ICAM-1 in T2DM patients with dyslipidemia and to explore the relationship between VCAM-1 and ICAM-1 and the development of dyslipidemia in T2DM patients. Patients and methods: The study included 150 individuals with an age range of (35-55) years. Patients with diabetes for more than 5 years were excluded. Fifty healthy individuals constituted Group 1 (G1), fifty patients with T2DM constituted Group 2 (G2), and fifty T2DM patients with dyslipidemia constituted Group 3 (G3). Whole blood samples were drawn to measure HbA1c based on fluorescence immunoassay technology. The serum was separated to measure fasting blood glucose (FBG), triglycerides (TG), total cholesterol (TC), and high-density lipoproteins (HDL) by manual methods, while VCAM-1, and ICAM-1 were determined using the ELISA test. The study was conducted between November 2022 and April 2023 at the National Center for Diabetes Treatment and Research, Baghdad, Iraq. Results: Significantly higher levels of FSG and HbA1c were detected in G2 and G3 compared to G1, but non-significantly so when G3 was compared to G2. Significant higher levels of TG and TC levels were detected for G3 when compared to G1 and G2, but non-significantly so when G2 was compared to G1. HDL levels were significantly lower in G3 compared to G2 and G1, but non-significantly so when G2 was compared to G1. VCAM-1, and ICAM-1 were significantly higher in G2 compared to G1, and VCAM-1 level was significantly higher in G3 compared to G2. Non-significant differences in ICAM-1 levels were found between G3 and G2. Conclusion: VCAM-1 and ICAM-1 are potentially significant factors in the development of dyslipidemia in diabetes patients. They might serve as biomarkers to accurately predict the progression of cardiovascular disease.

Aim. To assess endothelial function and arterial stiffness over time in patients after hospitalization with coronavirus disease 2019 (COVID-19) and compare them with a control group.Material and methods. A total of 53 patients over 18 years of age were hospitalized for COVID-19 in June — August 2021 was examined at two visits: the first — 10-16 months, the second — 14-23 months after discharge from the hospital. Control group included 53 patients from the ESSE-RF epidemiological study of a St. Petersburg population who did not have COVID-19, selected by sex, status of smoking, hypertension and type 2 diabetes. Endothelial function was assessed by the levels of vascular cell adhesion molecule 1 (VCAM-1) and von Willebrand factor (vWF) in plasma and the reactive hyperemia index (lnRHI) on the EndoPAT 2000 system. Carotid-femoral pulse wave velocity (cfPWV) was determined using the SphygmoCor device, while cardio-ankle vascular index (CAVI) and ankle-brachial index (ABI) — using the VaSera device.Results. The prevalence of endothelial vasomotor function disorders at the first and second visits in the active group did not differ significantly as follows: lnRHI £0,51 — 21% and 21%, cfPWV >10 m/s — 17% and 14%, and SLSI >9 — 28% and 34%, respectively. Plasma VCAM-1 levels were significantly higher during hospitalization than at the first and second visits — no differences were found between visits. The levels of lnRHI, vWF, cfPWV, CAVI, ABI at the first and second visits did not differ significantly. Post-COVID-19 patients differed from the control group only by a significantly higher ABI level at the second visit. According to the analysis of covariance, COVID-19 is associated with a CAVI increase at the first visit, as well as with an increase in ABI at both visits.Conclusion. The 1,5-2-year follow-up of patients after COVID-19, which required hospitalization, showed a decrease in the plasma endothelial dysfunction parameter VCAM-1. There is no changes in endothelial function and arterial stiffness over a period of time from 10-16 months to 14-23 months after hospitalization with COVID-19.

Abstract Glaucoma is a complex neurodegenerative disorder characterized by the progressive loss of retinal ganglion cells (RGC) and optic nerve axons, leading to irreversible visual impairment. Despite its clinical significance, the underlying mechanisms of glaucoma pathogenesis remain poorly understood. In this study, we aimed to unravel the multifaceted nature of glaucoma by investigating the interaction between T cells and retinas. By utilizing clinical samples, murine glaucoma models, and T cell transfer models, we made several key findings. Firstly, we observed that CD4+ T cells from glaucoma patients displayed enhanced activation and a bias towards T helper (Th) 1 responses, which correlated with visual impairment. Secondly, we identified the infiltration of Th1 cells into the retina, where they targeted RGC and integrated into the pro-inflammatory glial network, contributing to progressive RGC loss. Thirdly, we discovered that circulating Th1 cells upregulated vascular cell adhesion protein 1 (VCAM-1) on retinal microvessels, facilitating their entry into the neural retina. Lastly, we found that Th1 cells underwent functional reprogramming before reaching the retina, acquiring a phenotype associated with lymphocyte migration and neurodegenerative diseases. Our study provides novel insights into the role of peripheral CD4+ T cells in glaucoma pathogenesis, shedding light on the mechanisms underlying their infiltration into the retina and offering potential avenues for innovative therapeutic interventions in this sight-threatening disease. Graphical Abstract

Iis Inayati Rakhmat,1– 3 Gaga Irawan Nugraha,3,4 Eko Fuji Ariyanto,3,4 Yuni Susanti Pratiwi,3,4 Desy Linasari,5 Siti Nur Fatimah,3,6 Mohammad Ghozali,3,4 Mas Rizky AA Syamsunarno,3,4 Mohammad Rizki Akbar,3,7 Tri Hanggono Achmad3,4 1Doctoral Study Program Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 2Department of Biochemistry, Faculty of Medicine, Universitas Jenderal Achmad Yani, Cimahi, West Java, Indonesia; 3Cardiometabolic Working Group Study, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 4Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 5Department of Community Medicine, Faculty of Medicine, Universitas Jenderal Achmad Yani, Cimahi, West Java, Indonesia; 6Department of Public Health, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 7Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Padjadjaran-Hasan Sadikin General Hospital, Bandung, West Java, IndonesiaCorrespondence: Gaga Irawan Nugraha, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Eycmann 38, Bandung, West Java, 40161, Indonesia, Tel/Fax +6222 2032170, Email gaga@unpad.ac.idBackground: Metabolic syndrome (MetS) is a risk factor for cardiovascular disease and is linked to obesity. Subjects with MetS who have normo-weight potentially show higher mortality and morbidity.Purpose: This study aims to reveal the critical essential metabolic parameters associated with endothelial dysfunction in MetS subjects with normo-weight compared to obese.Patients and Methods: The study was designed using a case–control approach. Ninety-nine MetS subjects (34 Normo-weight and 65 obese) from the urban population were enrolled in this study. The components of MetS are based on NCEP/ATP III criteria. Asymmetric dimethylarginine (ADMA) and vascular cell adhesion molecule 1 (VCAM-1) as markers for endothelial dysfunction were measured in both groups.Results: Fasting blood glucose (FBG) levels were higher in the normo-weight group (143.38 ± 79.8 mg/dL) compared to the obese group (120.89 ± 46.5 mg/dL). High-density lipoprotein cholesterol (HDL-c) levels in the normo-weight group were lower (42.82 ± 10.1 mg/dL) compared to obesity (45.74 ± 9.3 mg/dL), while triacylglycerol (TAG) levels were higher in the obese (197.25 ± 110.5 mg/dL) compared to the normo-weight group (167.03 ± 98.4 mg/dL), although the differences were statistically not significant (all p > 0.05). The difference between ADMA and VCAM-1 levels was statistically not significant in both groups. Correlation between MetS components with endothelial dysfunction parameters shows that metabolic parameters correlate strongly. Interestingly, a stronger correlation between FBG and ADMA was observed in normo-weight (r = 0.519) compared to obese groups (r = 0.445). In addition, TAG consistently shows a significant correlation with ADMA and VCAM-1 in normo-weight groups.Conclusion: Metabolic parameters, especially FBG and TAG, correlate strongly with endothelial dysfunction parameters in normo-weight subjects with metabolic syndrome.Keywords: ADMA, normal-weight metabolically unhealthy, VCAM-1

Intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin are cell adhesion molecules that play a significant role in inflammation and are implicated in the pathophysiology of preeclampsia development and HIV infection. More specifically, the immune expression of ICAM-1, VCAM-1, and E-selectin within cyto- and syncytiotrophoblast cells are dysregulated in preeclampsia, indicating their role in defective placentation. This study investigates the associations of ICAM-1, VCAM-1, and E-selectin gene variants (rs3093030, rs3783605, and rs1805193, respectively) with preeclampsia comorbid with HIV infection in women of African ancestry. It also examines the susceptibility to preeclampsia development and the effect of highly active antiretroviral therapy (HAART). A total of 405 women were enrolled in this study. Out of these women, 204 were preeclamptic and 201 were normotensive. Clinical characteristics were maternal age, weight, blood pressure (systolic and diastolic), and gestational age. Whole blood was collected, DNA was extracted, and genotyping of the ICAM-1 (rs3093030 C>T), VCAM-1(rs3783605 A>G), and E-selectin (rs1805193 A>C) gene polymorphisms was performed. Comparisons were made using the Chi-squared test. Our results demonstrated that preeclamptic women exhibited a higher frequency of analyzed variants, in contrast to those with the duality of preeclampsia and HIV infection. Additionally, the C allele of the ICAM-1 (rs3093030 C>T) and G allele of the VCAM-1 (rs3783605 A>G) genes were found to have a greater role in the co-morbidity and may be considered as a risk factor for preeclampsia development in women of African ancestry. In contrast, the SNP of rs1805193 of the E-selectin gene indicated that A>C was only significantly associated with HIV infection and not with preeclampsia. These findings highlight a strong association of the rs3093030 SNP of the ICAM-1 gene and of the VCAM-1 rs3783605 gene with the development of preeclampsia, indicating their role in the defective trophoblast invasion of preeclampsia. Sub-group analysis further reveals an association of the AA genotype with late-onset preeclampsia, a less severe form of disease indicating differing genetic predispositions between early and late-onset forms.

Glaucoma is a complex neurodegenerative disorder characterized by the progressive loss of retinal ganglion cells (RGC) and optic nerve axons, leading to irreversible visual impairment. Despite its clinical significance, the underlying mechanisms of glaucoma pathogenesis remain poorly understood. In this study, we aimed to unravel the multifaceted nature of glaucoma by investigating the interaction between T cells and retinas. By utilizing clinical samples, murine glaucoma models, and T cell transfer models, we made several key findings. Firstly, we observed that CD4+ T cells from glaucoma patients displayed enhanced activation and a bias towards T helper (Th) 1 responses, which correlated with visual impairment. Secondly, we identified the infiltration of Th1 cells into the retina, where they targeted RGC and integrated into the pro-inflammatory glial network, contributing to progressive RGC loss. Thirdly, we discovered that circulating Th1 cells upregulated vascular cell adhesion protein 1 (VCAM-1) on retinal microvessels, facilitating their entry into the neural retina. Lastly, we found that Th1 cells underwent functional reprogramming before reaching the retina, acquiring a phenotype associated with lymphocyte migration and neurodegenerative diseases. Our study provides novel insights into the role of peripheral CD4+ T cells in glaucoma pathogenesis, shedding light on the mechanisms underlying their infiltration into the retina and offering potential avenues for innovative therapeutic interventions in this sight-threatening disease. [ABSTRACT FROM AUTHOR]

Inflammation is a physiological response to a damaging stimulus but sometimes can be the cause of the onset of neurodegenerative diseases, atherosclerosis, and cancer. These pathologies are characterized by the overexpression of inflammatory markers like endothelial adhesion molecules, such as Vascular Cell Adhesion Molecule-1 (VCAM-1). In the present work, the development of liposomes for therapeutic targeted delivery to inflamed endothelia is described. The idea is to exploit a three-step pretargeting system based on the biotin–avidin high-affinity interaction: the first step involves a previously described biotin derivative bearing a VCAM-1 binding peptide; in the second step, the avidin derivative NeutrAvidinTM, which strongly binds to the biotin moiety, is injected; the final step is the administration of biotinylated liposomes that would bind to NeutravidinTM immobilized onto VCAM-1 overexpressing endothelium. Stealth biotinylated liposomes, prepared via the thin film hydration method followed by extrusion and purification via size exclusion chromatography, have been thoroughly characterized for their chemico-physical and morphological features and loaded with metformin hydrochloride, a potential anti-inflammatory agent. The three-step system, tested in vitro on different cell lines via confocal microscopy, FACS analysis and metformin uptake, has proved its suitability for therapeutic applications. [ABSTRACT FROM AUTHOR]

Objective: It is aimed to be a technique that can be used for diagnosis and to prevent maternal deaths in cases where the serum levels of cell adhesion molecules are different in patients with abnormal placentation compared to healthy pregnant women. Materials and methods: Patients between March 2020 and September 2021 were included in the study. While 56 patients, out of 153 cases formed the placental adhesion and/or localization anomaly group, 55 cases without placental adhesion anomaly (placental invasion anomaly and/or previa pathology) constituted the cesarean section group and 42 cases constituted the vaginal birth control group. Demographic characteristics and histories of 153 patients were questioned. I-CAM-1, V-CAM-1, E-Selectin, P-Selectin, LRG-1 levels were studied. The parameters measured by the ELISA method were studied in the Thermo Fisher Scientific Multiscan Go (Finland) device at the Hatay Mustafa Kemal University Medical Faculty Medical Biochemistry USA ELISA Laboratory. Wholehouse and One Way Anova analysis methods were used to compare the results. Results: There were significant differences in E-Selectin, P-Selectin, ICAM-1 and LRG-1 values between the groups (p < 0.05). There was a significant difference between the vaginal birth (VB) and previa/percreata (PP) groups in terms of E-Selectin (p = 0.038). In terms of P-Selectin, there was a significant difference between the C/S and previa/percreata (PP) groups (p < 001). P-Selectin was higher in the previa/percreata (PP) group. There was a significant difference between the Vaginally birth (VB), C/S group (p = 0.041) and the vaginal birth (VB), previa/percreata (PP) group (p = 0.013) in terms of ICAM-1, but there was no significant difference between the C/S and previa/percreata (PP) groups. In terms of LRG-1, there was a significant difference between all 3 groups (p < 0.05). Discussion: A recent study investigated the potential modulatory effects of trans-resveratrol (RSV), arginase and endothelial dysfunction biomarkers in patients with PE. Another reflection of endothelial dysfunction in PE is increased endothelial activation biomarkers such as intercellular adhesion molecule-1 (ICAM-1), von Willebrand factor (vWF), and Caspase-3 (CASP-3). The study, regarding vWF expression, the preeclampsia (PE) group showed higher levels compared to endothelial cells incubated with healty pregnant (HP) plasma [Bueno-Pereira et al 2022 Antioxidants 2111]. From this and similar studies, the hypothesis that the role of cell adhesion molecules in endothelial damage may be the underlying cause of invasion and location anomalies emerges. This hypothesis is the starting point of our study. Conclusions: In our study, all adhesion molecules except V-CAM-1 were found to be significantly higher in the previa/percreata (PP) group. E-Selectin and LRG-1 adhesion molecules were found to be significantly higher even in C/S patients compared to normal delivery. As a result; these adhesion molecules can be studied as a marker in previa/percreata (PP) patients. [ABSTRACT FROM AUTHOR]

(1) Background: Although obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity, the link between OSA and cardiovascular disease (CVD) is not completely elucidated. Thus, we aim to assess cardiovascular risk (CVR) using SCORE 2 and SCORE 2 for older persons (SCORE 2OP), and to evaluate the association between the endothelial biomarkers VCAM-1, ICAM-1, epicardial fat, and sleep study parameters in order to improve current clinical practices and better understand the short-and long-term CVRs in OSA patients. (2) Methods: 80 OSA patients and 37 healthy volunteers were enrolled in the study. SCORE2 and SCORE 2 OP regional risk charts (validated algorithms to predict the 10-year risk of first-onset CVD) were used for the analysis of CVR. Two-dimensional echocardiography was performed on all patients and epicardial fat thickness was measured. VCAM-1 and ICAM-1 serum levels were assessed in all patients. (3) Results: OSA patients were classified as being at high CVR, regardless of the type of score achieved. Increased EFT was observed in the OSA group. VCAM-1 was associated with a high CVR in OSA patients, but no significant correlation was observed between adhesion molecules and epicardial fat thickness. (4) Conclusions: OSA patients have a high CVR according to the SCORE 2 and SCORE 2OP risk scores. VCAM-1 may be associated with a high CVR in OSA patients. Extending conventional risk stratification scores by adding other potential biomarkers improves the risk stratification and guide treatment eligibility for CVD prevention in the OSA population. [ABSTRACT FROM AUTHOR]

We previously reported that proinflammatory cytokines, particularly tumor necrosis factor (TNF)-α, promoted tumor migration, invasion, and proliferation, thus worsening the prognosis of glioblastoma (GBM). Urolithins, the potent metabolites produced by the gut from pomegranate polyphenols, have anticancer properties. To develop an effective therapy for GBM, this study aimed to study the effects of urolithins against GBM. Urolithin A and B significantly reduced GBM migration, reduced epithelial–mesenchymal transition, and inhibited tumor growth. Moreover, urolithin A and B inhibited TNF-α-induced vascular cell adhesion molecule (VCAM)-1 and programmed death ligand 1 (PD-L1) expression, thereby reducing human monocyte (HM) binding to GBM cells. Aryl hydrocarbon receptor (AhR) level had higher expression in patients with glioma than in healthy individuals. Urolithins are considered pharmacological antagonists of AhR. We demonstrated that the inhibition of AhR reduced TNF-α-stimulated VCAM-1 and PD-L1 expression. Furthermore, human macrophage condition medium enhanced expression of PD-L1 in human GBM cells. Administration of the AhR antagonist attenuated the enhancement of PD-L1, indicating the AhR modulation in GBM progression. The modulatory effects of urolithins in GBM involve inhibiting the Akt and epidermal growth factor receptor pathways. The present study suggests that urolithins can inhibit GBM progression and provide valuable information for anti-GBM strategy. [ABSTRACT FROM AUTHOR]

Objective(s): Cisplatin (CP) is frequently used in various types of cancers. The cardiotoxic effects of this agent limit its usage. Our study seeks to investigate the protective effects of Irbesartan (IRB) on CP-induced cardiotoxicity. Materials and Methods: The following four groups comprised thirty-two rats: control, CP, CP+IRB, and IRB. On the fourth day of the experiment, 5 mg/kg of CP was given to CP and CP+IRB groups intraperitoneally, and for seven days, water or IRB 50 mg/kg (orally) was administered. Vascular endothelial growth factor (VEGF), caspase-3 (Cas-3), vascular cell adhesion molecule-1 (VCAM-1), NADPH oxidase-1 (NOX-1), creatine kinase MB (CK-MB), and lactate dehydrogenase (LDH) were measured. Results: The levels of VCAM-1, NOX-1, VEGF, Cas-3, and LDH were increased in the CP group. The treatment with IRB decreased VCAM-1, NOX-1, VEGF, Cas-3, and LDH levels significantly (P

Abstract Background Nitric oxide is produced by different nitric oxide synthases isoforms. NO activates two signaling pathways, one dependent on soluble guanylate cyclase and protein kinase G, and other where NO post-translationally modifies proteins through S-nitrosylation, which is the modification induced by NO in free-thiol cysteines in proteins to form S-nitrosothiols. High levels of NO have been detected in blood of breast cancer patients and increased NOS activity has been detected in invasive breast tumors compared to benign or normal breast tissue, suggesting a positive correlation between NO biosynthesis, degree of malignancy and metastasis. During metastasis, the endothelium plays a key role allowing the adhesion of tumor cells, which is the first step in the extravasation process leading to metastasis. This step shares similarities with leukocyte adhesion to the endothelium, and it is plausible that it may also share some regulatory elements. The vascular cell adhesion molecule-1 (VCAM-1) expressed on the endothelial cell surface promotes interactions between the endothelium and tumor cells, as well as leukocytes. Data show that breast tumor cells adhere to areas in the vasculature where NO production is increased, however, the mechanisms involved are unknown. Results We report that the stimulation of endothelial cells with interleukin-8, and conditioned medium from breast tumor cells activates the S-nitrosylation pathway in the endothelium to induce leukocyte adhesion and tumor cell extravasation by a mechanism that involves an increased VCAM-1 cell surface expression in endothelial cells. We identified VCAM-1 as an S-nitrosylation target during this process. The inhibition of NO signaling and S-nitrosylation blocked the transmigration of tumor cells through endothelial monolayers. Using an in vivo model, the number of lung metastases was inhibited in the presence of the S-nitrosylation inhibitor N-acetylcysteine (NAC), which was correlated with lower levels of S-nitrosylated VCAM-1 in the metastases. Conclusions S-Nitrosylation in the endothelium activates pathways that enhance VCAM-1 surface localization to promote binding of leukocytes and extravasation of tumor cells leading to metastasis. NAC is positioned as an important tool that might be tested as a co-therapy against breast cancer metastasis.

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.

Background: Acute appendicitis is a common abdominal emergency observed in emergency departments (ED). Distinguishing between uncomplicated and complicated appendicitis is important in determining a treatment strategy. Serum soluble vascular cell adhesion molecule-1 (VCAM-1) is an inflammatory biomarker. We aimed to determine the role of VCAM-1 in predicting complicated appendicitis in children. Methods: Pediatric patients with suspected appendicitis admitted to the ED were enrolled in this prospective study. Pre-surgical serum VCAM-1 was tested in children with acute appendicitis within 72 h of symptoms (from day 1 to day 3). Serum VCAM-1 levels were further analyzed and compared between patients with and without complicated appendicitis. Results: Among the 226 pediatric appendicitis patients, 70 had uncomplicated appendicitis, 138 had complicated appendicitis, and 18 had normal appendices. The mean serum VCAM-1 levels in patients with perforated appendicitis were higher than in those with simple appendicitis (p < 0.001). On day 1 to day 3, the mean VCAM-1 levels in patients with complicated appendicitis were all significantly higher than in those with uncomplicated appendicitis (all p < 0.001). Conclusion: Serum VCAM-1 levels may be helpful in differentiating uncomplicated and complicated appendicitis in children and could predict appendiceal perforation.

Introduction. Damage to the vascular endothelium and hypercoagulation are two of the main causes of post-­COVID-19 complications. The aim of our study was to evaluate endothelial dysfunction and thrombotic complications at different periods after COVID-19 in patients with type 2 diabetes mellitus. Patients and methods. We conducted a cross-­sectional study of 135 patients with type 2 diabetes mellitus who applied for inpatient treatment at the RSSPMCE clinic (Tashkent, Uzbekistan) in the period from 3 to 24 months after the acute period of COVID-19. The following laboratory parameters were assessed: fibrinogen, INR, APTT, D-dimer, von Willebrand factor, and cell adhesion molecules (VCAM-1, ICAM-1). Results. Despite normal or near-normal INR, APTT and fibrinogen levels, many patients had elevated levels of D-dimer (41.4 % of cases), von Willebrand factor (27.6 % of cases) and vascular cell molecules up to 24 months after infection. The concentrations of ICAM-1 and VCAM-1 did not have statistically significant correlations with the degree of compensation of diabetes mellitus (HbA1c level). At various times after COVID-19, cases of ischemic forms of diabetic foot syndrome and thrombosis affecting the cavernous sinus and upper extremities were recorded. Conclusion. Taking into account the results obtained, patients with type 2 diabetes mellitus after SARS-CoV-2 infection require careful monitoring, and, in addition to assessing standard coagulation parameters, determining the level of cell adhesion molecules may have diagnostic value.

Objectives: Heart disease, caused by atherosclerosis, is the leading cause of death. Maintaining vascular integrity is crucial to reducing atherosclerosis risk. Mangos are rich in fiber, vitamins, minerals, and phytochemicals that may offer cardioprotective and immune-boosting benefits. However, their effects on the vasculature and immune system in adults with overweight and obesity remain unclear. The objective of this study was to investigate the effects of mango consumption on vascular health and immune function in adults with overweight and obesity. Methods: In a 12-week, crossover study, 27 overweight and obese participants consumed either 100 kcals of mangos daily or isocaloric low-fat cookies daily. Fasting blood samples were collected at baseline, week 4, and week 12 and analyzed for vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), P-selectin, E-selectin, sCD4, sCD8, sCD3E, and sCD45, tumor necrosis factor-alpha (TNF-α), catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD). Results: Mango consumption significantly decreased VCAM-1 between baseline and week 4 (P = 0.046) and week 12 (P = 0.004). CAT increased between baseline and week 12 (P = 0.035) with mango consumption. GPx increased at week 12 compared to baseline and week 4 (P 0.05 for all non-significant results). Conclusions: This study suggests that 100 kcals of mangos may benefit the integrity of the vasculature by reducing VCAM-1 and increasing SOD, CAT, and GPx levels. Mangos can be an alternative snack for improving atherosclerosis and oxidative stress risk factors.

Diabetes is a major cause of mortality and morbidity worldwide, leading to various complications, including diabetic retinopathy (DR), which can result in vision impairment and blindness. DR involves the disruption of the blood retinal barrier (BRB) and the development of neovascularization due to high blood sugar levels. Inflammatory cytokines and cell adhesion molecules play a role in this process, with NF-κB and its down regulators, such as ICAM-1 and VCAM-1, being key players. Moringa oleifera (MO), a plant with medicinal properties, is being investigated for its prospective effect in preventing and treating DR. This study explores the effects of Moringa oleifera extract on streptozotocin (STZ) induced diabetic rats with DR. Molecular docking studies indicate that components of Moringa oleifera extract, namely Quercetin and Myrecetin, strongly bind to key targets involved in DR. To induce DR, rats were given STZ, and after 8 weeks, various factors were evaluated. The results show that MO extract significantly reduces blood glucose levels compared to the diabetes group. Additionally, the extract decreases the expression of VEGF, an angiogenic mediator, and reduces the levels of TNF-α and Total Antioxidant Capacity (TAC), markers of inflammation, in the retinas of diabetic rats. Histopathological analyses reveal improvements in the retinal blood vessels of MO -treated animals compared to the diabetes group. The extract also reduces the overexpression of NF-κB and VCAM-1 in the retina. These findings suggest that MO may be useful in managing diabetic retinopathy by inhibiting angiogenic mediators and regulating NF-κB and VCAM-1. [Display omitted] • Effect of Moringa oleifera (MO) against diabetic retinopathy. • In-vitro biochemical study of MO was done for the treatment of diabetic retinopathy. • In-silico study also has proven the hypothesis of MO phytoconstituents against diabetic retinopathy targets. [ABSTRACT FROM AUTHOR]

Objective(s): Cisplatin (CP) is frequently used in various types of cancers. The cardiotoxic effects of this agent limit its usage. Our study seeks to investigate the protective effects of Irbesartan (IRB) on CP-induced cardiotoxicity. Materials and Methods: The following four groups comprised thirty-two rats: control, CP, CP+IRB, and IRB. On the fourth day of the experiment, 5 mg/kg of CP was given to CP and CP+IRB groups intraperitoneally, and for seven days, water or IRB 50 mg/kg (orally) was administered. Vascular endothelial growth factor (VEGF), caspase-3 (Cas-3), vascular cell adhesion molecule-1 (VCAM-1), NADPH oxidase-1 (NOX-1), creatine kinase MB (CK-MB), and lactate dehydrogenase (LDH) were measured. Results: The levels of VCAM-1, NOX-1, VEGF, Cas-3, and LDH were increased in the CP group. The treatment with IRB decreased VCAM-1, NOX-1, VEGF, Cas-3, and LDH levels significantly (P<0.05). Histopathological examination revealed normal heart architecture in Control and IRB groups. While marked hyperemia and myocardial cell degeneration were noticed in the CP group, significant amelioration was observed in the CP+IRB group. Aortas in the CP group showed endothelial damage and desquamation. IRB treatment markedly ameliorated histopathological findings in the CP+IRB group. Cardiac and aortic damage caused by CP was attenuated by IRB treatment owing to the antiinflammatory and antiapoptotic effects of IRB. Conclusion: IRB may help reduce the severity of CP-induced cardiac injury by limiting leukocyte migration and reducing inflammation and apoptosis. [ABSTRACT FROM AUTHOR]

Mesenchymal stem/stromal cells (MSCs) are spindle-like heterogeneous cell populations with advantageous bidirectional immunomodulatory and hematopoietic support effects. Vascular cellular adhesion molecule-1 (VCAM-1)+ MSCs have been reported to exhibit immunoregulatory and proangiogenic capacities. Here, we studied the effects of VCAM-1+ human umbilical cord (hUC)-MSCs on neuroprotection against cerebral infarction. Sprague–Dawley rats were subjected to middle cerebral artery occlusion (MCAO), and VCAM-1− and VCAM-1+ hUC-MSCs were intravenously injected into the rat 4 h post-MCAO surgery. Thereafter, modified neurological severity scores (mNSS) were determined, and the Morris water maze test, 2,3,5-triphenyltetrazolium chloride (TTC), hematoxylin and eosin (H&E), Nissl, TUNEL staining, and qRT-PCR were conducted. Following induction of oxygen–glucose deprivation/reoxygenation (OGD/R), SH-SY5Y cells were co-cultured with VCAM-1− and VCAM-1+ hUC-MSCs. CCK-8, flow cytometry, ELISA, and western blot analyses were performed in vitro. Compared with VCAM-1− hUC-MSCs, administration of VCAM-1+ hUC-MSCs revealed improved therapeutic efficacy against cerebral infarction in rats, as confirmed by lower mNSS scores and infarct volumes, as well as improved learning and memory capacities. In addition, VCAM-1+ hUC-MSCs exhibited improved efficacy against neurological defects in rats with cerebral infarction, accompanied by inhibition of the NLRP3-mediated inflammatory response. VCAM-1+ hUC-MSC co-culture improved the viability and diminished NLRP3-mediated inflammatory response in OGD/R-treated SH-SY5Y cells. Moreover, NLRP3 overexpression in SH-SY5Y cells prevented the beneficial effects of VCAM-1+ hUC-MSC co-culture. Overall, our findings demonstrated the relevance of VCAM-1+ hUC-MSC-based cytotherapy for preclinical neuroprotection against cerebral infarction. [ABSTRACT FROM AUTHOR]

Background: Dupilumab, a monoclonal anti‐IL‐4Rα antibody, is approved for several type 2 mediated inflammatory diseases like asthma, atopic dermatitis, and diffuse type 2 chronic rhinosinusitis (CRS). Clinical studies had reported a transient increase in blood eosinophils during dupilumab therapy. This study aimed to assess the impact of elevated blood eosinophils on clinical outcome and to investigate the cause of high blood eosinophil levels under dupilumab therapy. Methods: Patients suffering from diffuse type 2 CRS treated with dupilumab were examined on days 0, 28, 90, and 180 after therapy start. Sino‐Nasal‐Outcome‐Test Score (SNOT‐22), Total Nasal Polyp Score (TNPS), and blood samples were collected. Cytokine measurements and proteomics analysis were conducted. Flow cytometry analysis measured receptor expression on eosinophils. Results: Sixty‐eighty patients were included. Baseline eosinophilia ≥0.3G/L was observed in 63.2% of patients, and in 30.9% of patients, eosinophils increased by ≥0.5G/L under dupilumab. Subjects with eosinophilia ≥0.3G/L at baseline had the best SNOT‐22 mean change compared to no eosinophilia. Eosinophil elevation during dupilumab therapy had no impact on clinical scores. The eosinophil adhesion molecule VCAM‐1 decreased significantly during therapy in all patients. The chemokine receptor CXCR4 was significantly down‐ and IL‐4 upregulated in subjects with eosinophil increase. Conclusion: Our findings suggest that increased eosinophils in type 2 CRS are associated with a good clinical response to dupilumab. Patients with elevated IL‐4 at baseline developed dupilumab‐induced transient eosinophilia. We identified the downregulation of VCAM‐1 and surface markers CD49d and CXCR4 on eosinophils as possible explanations of dupilumab‐induced eosinophilia. [ABSTRACT FROM AUTHOR]

Background: Nitric oxide is produced by different nitric oxide synthases isoforms. NO activates two signaling pathways, one dependent on soluble guanylate cyclase and protein kinase G, and other where NO post-translationally modifies proteins through S-nitrosylation, which is the modification induced by NO in free-thiol cysteines in proteins to form S-nitrosothiols. High levels of NO have been detected in blood of breast cancer patients and increased NOS activity has been detected in invasive breast tumors compared to benign or normal breast tissue, suggesting a positive correlation between NO biosynthesis, degree of malignancy and metastasis. During metastasis, the endothelium plays a key role allowing the adhesion of tumor cells, which is the first step in the extravasation process leading to metastasis. This step shares similarities with leukocyte adhesion to the endothelium, and it is plausible that it may also share some regulatory elements. The vascular cell adhesion molecule-1 (VCAM-1) expressed on the endothelial cell surface promotes interactions between the endothelium and tumor cells, as well as leukocytes. Data show that breast tumor cells adhere to areas in the vasculature where NO production is increased, however, the mechanisms involved are unknown. Results: We report that the stimulation of endothelial cells with interleukin-8, and conditioned medium from breast tumor cells activates the S-nitrosylation pathway in the endothelium to induce leukocyte adhesion and tumor cell extravasation by a mechanism that involves an increased VCAM-1 cell surface expression in endothelial cells. We identified VCAM-1 as an S-nitrosylation target during this process. The inhibition of NO signaling and S-nitrosylation blocked the transmigration of tumor cells through endothelial monolayers. Using an in vivo model, the number of lung metastases was inhibited in the presence of the S-nitrosylation inhibitor N-acetylcysteine (NAC), which was correlated with lower levels of S-nitrosylated VCAM-1 in the metastases. Conclusions: S-Nitrosylation in the endothelium activates pathways that enhance VCAM-1 surface localization to promote binding of leukocytes and extravasation of tumor cells leading to metastasis. NAC is positioned as an important tool that might be tested as a co-therapy against breast cancer metastasis. [ABSTRACT FROM AUTHOR]

Vascular cell adhesion molecule-1 (VCAM-1) has been well established as a critical contributor to atherosclerosis and consequently as an attractive therapeutic target for anti-atherosclerotic drug candidates. Many publications have demonstrated that disrupting the VCAM-1 function blocks monocyte infiltration into the sub-endothelial space, which effectively prevents macrophage maturation and foam cell transformation necessary for atherosclerotic lesion formation. Currently, most VCAM-1-inhibiting drug candidates in pre-clinical and clinical testing do not directly target VCAM-1 itself but rather down-regulate its expression by inhibiting upstream cytokines and transcriptional regulators. However, the pleiotropic nature of these regulators within innate immunity means that optimizing dosage to a level that suppresses pathological activity while preserving normal physiological function is extremely challenging and oftentimes infeasible. In recent years, highly specific pharmacological strategies that selectively inhibit VCAM-1 function have emerged, particularly peptide- and antibody-based novel therapeutics. Studies in such VCAM-1–directed therapies so far remain scarce and are limited by the constraints of current experimental atherosclerosis models in accurately representing the complex pathophysiology of the disease. This has prompted the need for a comprehensive review that recounts the evolution of VCAM-1–directed pharmaceuticals and addresses the current challenges in novel anti-atherosclerotic drug development. [ABSTRACT FROM AUTHOR]

Epidemiological studies suggest that the severity of periodontitis is higher in people with diabetes than in healthy individuals. Insulin resistance might play a crucial role in the pathogenesis of multiple diabetic complications and is reportedly induced in the gingiva of rodents with type 2 diabetes; however, the molecular mechanisms underlying the pathogenesis of diabetes-related periodontitis remain unclear. Therefore, we aimed to investigate whether endothelial insulin resistance in the gingiva may contribute to the pathogenesis of periodontitis as well as elucidate its underlying molecular mechanisms. We demonstrated that insulin treatment downregulated lipopolysaccharide (LPS)–induced or tumor necrosis factor α (TNFα)–induced VCAM1 expression in endothelial cells (ECs) via the PI3K/Akt activating pathway, resulting in reduced cellular adhesion between ECs and leukocytes. Hyperglycemia-induced selective insulin resistance in ECs diminished the effect of insulin on LPS- or TNFα-stimulated VCAM1 expression. Vascular endothelial cell–specific insulin receptor knockout (VEIRKO) mice exhibited selective inhibition of the PI3K/Akt pathway in the gingiva and advanced experimental periodontitis-induced alveolar bone loss via upregulation of Vcam1, Tnf α, Mcp-1, Rankl, and neutrophil migration into the gingiva compared with that in the wild-type (WT) mice despite being free from diabetes. We also observed that insulin-mediated activation of FoxO1, a downstream target of Akt, was suppressed in the gingiva of VEIRKO and high-fat diet (HFD)–fed mice, hyperglycemia-treated ECs, and primary ECs from VEIRKO. Further analysis using ECs transfected with intact and mutated FoxO1, with mutations at 3 insulin-mediated phosphorylation sites (T24A, S256D, S316A), suggested that insulin-mediated regulation of VCAM1 expression and cellular adhesion of ECs with leukocytes was attenuated by mutated FoxO1 overexpression. These results suggest that insulin resistance in ECs may contribute to the progression of periodontitis via dysregulated VCAM1 expression and cellular adhesion with leukocytes, resulting from reduced activation of the PI3K/Akt/FoxO1 axis. [ABSTRACT FROM AUTHOR]

Evidence suggests cholesterol accumulation in pro-inflammatory endothelial cells (EC) contributes to triggering atherogenesis and driving atherosclerosis progression. Therefore, inhibiting miR-33a-5p within inflamed endothelium may prevent and treat atherosclerosis by enhancing apoAI-mediated cholesterol efflux by upregulating ABCA1. However, it is not entirely elucidated whether inhibition of miR-33a-5p in pro-inflammatory EC is capable of increasing ABCA1-dependent cholesterol efflux. In our study, we initially transfected LPS-challenged, immortalized mouse aortic EC (iMAEC) with either pAntimiR33a5p plasmid DNA or the control plasmid, pScr. We detected significant increases in both ABCA1 protein expression and apoAI-mediated cholesterol efflux in iMAEC transfected with pAntimiR33a5p when compared to iMAEC transfected with pScr. We subsequently used polymersomes targeting inflamed endothelium to deliver either pAntimiR33a5p or pScr to cultured iMAEC and showed that the polymersomes were selective in targeting pro-inflammatory iMAEC. Moreover, when we exposed LPS-challenged iMAEC to these polymersomes, we observed a significant decrease in miR-33a-5p expression in iMAEC incubated with polymersomes containing pAntimR33a5p versus control iMAEC. We also detected non-significant increases in both ABCA1 protein and apoAI-mediated cholesterol in iMAEC exposed to polymersomes containing pAntimR33a5p when compared to control iMAEC. Based on our results, inhibiting miR-33a-5p in pro-inflammatory EC exhibits atheroprotective effects, and so precisely delivering anti-miR-33a-5p to these cells is a promising anti-atherogenic strategy. [ABSTRACT FROM AUTHOR]

Background: The incidence and clinical importance of nonalcoholic fatty liver disease (NAFLD) has emerged. However, effective therapeutic strategies for NAFLD have yet to be found. Panax ginseng (P. ginseng) is a traditional herb in Eastern Asia with therapeutic effects in many chronic disorders. However, the precise effects of ginseng extract on NAFLD are currently unknown. In present study, the therapeutic effects of Rg3-enriched red ginseng extract (Rg3-RGE) on the progression of NAFLD were explored. Methods: Twelve-week-old C57BL/6 male mice were fed a chow or western diet supplemented with high sugar water solution with or without Rg3-RGE. Histopathology, immunohistochemistry, immunofluorescence, serum biochemistry, western blot analysis, and quantitative RT-PCR were used for in vivo experiment. Conditionally immortalized human glomerular endothelial cell (CiGEnC) and primary liver sinusoidal endothelial cells (LSECs) were used for in vitro experiments. Results: Eight weeks of Rg3-RGE treatment significantly attenuated the inflammatory lesions of NAFLD. Furthermore, Rg3-RGE inhibited the inflammatory infiltrate in liver parenchyma and the expression of adhesive molecules to LSECs. Moreover, the Rg3-RGE exhibited similar patterns on the in vitro assays. Conclusion: The results demonstrate that Rg3-RGE treatment ameliorates NAFLD progression by inhibiting chemotaxis activities in LSECs.

Background: Annona muricata leaves are used as traditional tea drink that is currently being studied on the developing effort of treating some types of cancers because they are known as anti-cancer. Motivated by that usage, this study aims to analyse the potential of A. muricata leaves extract to be an anti-colon cancer by investigating the extract capability in reducing blood intercellular cell-adhesion molecule-1 (ICAM-1) and vascular cell-adhesion molecule-1 (VCAM-1). Method: The research was conducted in Faculty of Medicine Universitas Indonesia with an ex­perimental design. A. muricata leaves extract was tested in vivo. In vivo test was conducted to Swiss Webster mice induced with 10 mg/kg azoxymethane (AOM) and dextran sodium sulfate 1% (DSS). Statistical analysis used was SPSS. Results: EIFAM reduce the serum level of ICAM-1 and VCAM-1. EIFAM significantly reduce serum level of VCAM compare to ESFAM. Conclusion: Ethanol insoluble fraction of Annona muricata leaves water extract of is potential to be an anti-colon cancer proven by the extract capability to reduce ICAM-1 and VCAM-1.

Background. Cigarette smoking could induce endothelial dysfunction and the increase of circulating markers of inflammation by activation of monocytes. This can lead to increased intima media thickness (IMT) of entire blood vessels and result in acceleration of the atherosclerosis process. However, to our knowledge, little is known about the role of cigarette smoking in this atherosclerotic inflammatory process. The aim of this study is to explore the link between cigarette smoking and its effect on endothelial nitric oxide synthase (e-NOS) and vascular cell adhesion molecule 1 (VCAM-1). Methods. An experimental study with a post-test only controlled group design was used. We used 18 Wistar rats ( Rattus norvegicus) randomly subdivided into two groups: group K (-) were not exposed to tobacco smoke, whereas group K (+) were exposed to smoke equivalent of more than 40 cigarettes for 28 days daily. After 28 days, samples were analyzed for e-NOS, VCAM-1 and aortic IMT. Results . Our results indicate that tobacco smoke can enhance the expression of VCAM-1 on rat cardiac vascular endothelial cells, resulting in a decreased expression of e-NOS level and increase of aortic IMT. Linear regression model found that eNOS level negatively correlated wiith aortic IMT ( r 2 = 0.584, β = -0.764, p < 0.001), whereas VCAM-1 expression did not correlate with aortic IMT ( r 2 = 0.197, p = 0.065). Conclusion. Low e-NOS level and high VCAM-1 level observed after cigarette smoke exposure which may increase aortic IMT.

Endothelial inflammation is a multifaceted physiological process that plays a pivotal role in the pathogenesis and progression of diverse diseases, encompassing but not limited to acute lung infections like COVID-19, coronary artery disease, stroke, sepsis, metabolic syndrome, certain malignancies, and even psychiatric disorders such as depression. This inflammatory response is characterized by augmented expression of adhesion molecules and secretion of pro-inflammatory cytokines. In this study, we discovered that saponins from Allium macrostemon bulbs (SAMB) effectively inhibited inflammation in human umbilical vein endothelial cells induced by the exogenous inflammatory mediator lipopolysaccharide or the endogenous inflammatory mediator tumor necrosis factor-α, as evidenced by a significant reduction in the expression of pro-inflammatory factors and vascular cell adhesion molecule-1 (VCAM-1) with decreased monocyte adhesion. By employing the NF-κB inhibitor BAY-117082, we demonstrated that the inhibitory effect of SAMB on VCAM-1 expression may be attributed to the NF-κB pathway’s inactivation, as characterized by the suppressed IκBα degradation and NF-κB p65 phosphorylation. Subsequently, we employed a murine model of lipopolysaccharide-induced septic acute lung injury to substantiate the potential of SAMB in ameliorating endothelial inflammation and acute lung injury in vivo. These findings provide novel insight into potential preventive and therapeutic strategies for the clinical management of diseases associated with endothelial inflammation.