Type 2 Diabetes Mellitus (T2DM) is linked to multiple complications, including cognitive impairment, and the prevalence of memory-related neurodegenerative diseases is higher in T2DM patients. One possible theory is the alteration of the microvascular and macrovascular environment of the blood-brain barrier (BBB). In this study, we employed different approaches, including RT-PCR, functional pharmacokinetic studies using sodium fluorescein (NaFL), and confocal microscopy, to characterize the functional and molecular integrity of the BBB in a T2DM animal model, leptin receptor-deficient mutant mice (Leprdb/db mice). As a result, VCAM-1, ICAM-1, MMP-9, and S100b (BBB-related markers) dysregulation was observed in the Leprdb/db animal model compared to littermate wild-type mice. The brain concentration of sodium fluorescein (NaFL) increased significantly in Leprdb/db untreated mice compared to insulin-treated mice. Therefore, the permeability of NaFL was higher in Leprdb/db control mice than in all remaining groups. Identifying the factors that increase the BBB in Leprdb/db mice will provide a better understanding of the BBB microvasculature and present previously undescribed findings of T2DM-related brain illnesses, filling knowledge gaps in this emerging field of research.

Increased immune-inflammatory activation has been repeatedly linked to etiopathogenesis and the progression of both major depressive disorder (MDD) and bipolar depression (BD). We explore the role of soluble intercellular cell adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in diagnostic differentiation and disorder progression in patients with MDD and BD. Serum levels of sICAM-1 and sVCAM-1 were measured in 137 patients (MDD = 93 and BD = 44) and compared with 73 healthy controls. The severity of psychopathology was assessed using the Hamilton Depression Rating Scale and Clinical Global Impression Scale. After adjustment for multiple confounders, we noticed significant downregulation of sVCAM-1 and upregulation of sICAM-1 levels in both patient groups. Decreased sVCAM-1 levels were detected in patients with acute episodes of BD when compared to MDD. Immune mediators were related to indicators of progression in both mood disorders. They also followed different post-treatment normalization patterns in MDD and BD and in relation to the stage of each disorder. Adhesion molecules could potentially be useful in discriminating between patients with MDD and BD and determining the possible progression of the disorders. Future nosological methods should include time-dependent pathoplasticity and biological correlates, at least for affective disorders.

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 of VE-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 pSTAT1 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.

In systemic sclerosis (SSc), fibrosis of the myocardium along with ongoing autoimmune inflammation can alter the electric function of the cardiac myocytes, which may increase the risk for ventricular arrhythmias and sudden cardiac death. We analyzed the electrocardiographic (ECG) variables describing ventricular repolarization such as QT interval, QT dispersion (QTd), T wave peak-to-end interval (Tpe), and arrhythmogeneity index (AIX) of 26 patients with SSc and 36 healthy controls. Furthermore, echocardiographic and laboratory parameters were examined, with a focus on inflammatory proteins like C-reactive ptotein (CRP), soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), and progranulin (PGRN). The CRP, sICAM-1, and sVCAM-1 levels were positively correlated with the length of the QT interval. Although the serum PGRN levels were not increased in the SSc group compared to the controls, in SSc patients, the PGRN levels were positively correlated with the QT interval and the AIX. According to our results, we conclude that there may be a potential association between autoimmune inflammation and the risk for ventricular arrhythmias in patients with SSc. We emphasize that the measurement of laboratory parameters of inflammatory activity including CRP, PGRN, sVCAM-1, and sICAM-1 could be helpful in the prediction of sudden cardiac death in patients with SSc.

Endothelial dysfunction plays a key role in the development of liver cirrhosis. Among the biomarkers of endothelial dysfunction, the soluble form of Vascular Adhesion Protein-1 (sVAP-1) is an unconventional and less known adhesion molecule endowed also with amine oxidase activity. The aim of this study was to explore and correlate the behavior of sVAP-1 with that of the soluble vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) and with the severity of liver cirrhosis. A cross-sectional study was carried out by enrolling 28 controls, 59 cirrhotic patients without hepatocellular carcinoma, and 56 patients with hepatocellular carcinoma (HCC), mainly caused by alcohol abuse. The levels of adhesion molecules and of the pro-inflammatory cytokines (IL-6 and TNF-αα) were determined by immunoassay and the enzymatic activity of sVAP-1 by a fluorometric assay. In non-diabetic patients without HCC, a specific behavior of sVAP-1 was highlighted. Differently from sVCAM-1, sICAM-1, and cytokines, the sVAP-1 level was significantly increased only in the early stage of disease, and then, it decreased in the last stage (866 ± 390 ng/mL vs. 545 ± 316 ng/mL, in Child-Pugh class A vs. C, respectively, p < 0.05). Bivariate analysis correlates sVAP-1 to sVCAM-1, in the absence of HCC (Spearman\'s rho = 0.403, p < 0.01). Multiple linear regression analysis revealed that sVCAM-1 appears to be a predictor of sVAP-1 (β coefficient = 0.374, p = 0.021). In conclusion, in non-diabetic and non-HCC cirrhotic patients, sVAP-1 may be a potential prognostic biomarker that, together with sVCAM-1 and pro-inflammatory cytokines, may provide information on the progression of sinusoidal liver endothelium damage.

Current clinical diagnostic imaging methods for lung metastases are sensitive only to large tumours (1-2 mm cross-sectional diameter), and early detection can dramatically improve treatment. We have previously demonstrated that an antibody-targeted MRI contrast agent based on microparticles of iron oxide (MPIO; 1 μm diameter) enables the imaging of endothelial vascular cell adhesion molecule-1 (VCAM-1). Using a mouse model of lung metastasis, upregulation of endothelial VCAM-1 expression was demonstrated in micrometastasis-associated vessels but not in normal lung tissue, and binding of VCAM-MPIO to these vessels was evident histologically. Owing to the lack of proton MRI signals in the lungs, we modified the VCAM-MPIO to include zirconium-89 (89Zr, t1/2 = 78.4 h) in order to allow the in vivo detection of lung metastases by positron emission tomography (PET). Using this new agent (89Zr-DFO-VCAM-MPIO), it was possible to detect the presence of micrometastases within the lung in vivo from ca. 140 μm in diameter. Histological analysis combined with autoradiography confirmed the specific binding of the agent to the VCAM-1 expressing vasculature at the sites of pulmonary micrometastases. By retaining the original VCAM-MPIO as the basis for this new molecular contrast agent, we have created a dual-modality (PET/MRI) agent for the concurrent detection of lung and brain micrometastases.

Metastatic tumours in the brain now represent one of the leading causes of death from cancer. Current treatments are largely ineffective owing to the combination of late diagnosis and poor delivery of therapies across the blood-brain barrier (BBB). Conjugating magnetic resonance imaging (MRI) contrast agents with a monoclonal antibody for VCAM-1 (anti-VCAM1) has been shown to enable detection of micrometastases, two to three orders of magnitude smaller in volume than those currently detectable clinically. The aim of this study was to exploit this targeting approach to enable localised and temporary BBB opening at the site of early-stage metastases using functionalised microbubbles and ultrasound. Methods: Microbubbles functionalised with anti-VCAM1 were synthesised and shown to bind to VCAM-1-expressing cells in vitro. Experiments were then conducted in vivo in a unilateral breast cancer brain metastasis mouse model using Gadolinium-DTPA (Gd-DTPA) enhanced MRI to detect BBB opening. Following injection of Gd-DTPA and targeted microbubbles, the whole brain volume was simultaneously exposed to ultrasound (0.5 MHz, 10% duty cycle, 0.7 MPa peak negative pressure, 2 min treatment time). T1-weighted MRI was then performed to identify BBB opening, followed by histological confirmation via immunoglobulin G (IgG) immunohistochemistry. Results: In mice treated with targeted microbubbles and ultrasound, statistically significantly greater extravasation of Gd-DTPA and IgG was observed in the left tumour-bearing hemisphere compared to the right hemisphere 5 min after treatment. No acute adverse effects were observed. There was no investigation of longer term bioeffects owing to the nature of the study. Conclusion: The results demonstrate the feasibility of using targeted microbubbles in combination with low intensity ultrasound to localise opening of the BBB to metastatic sites in the brain. This approach has potential application in the treatment of metastatic tumours whose location cannot be established a priori with conventional imaging methods.

The most serious long-term effects of diabetes is peripheral artery disease (PAD) which increases the chance of developing diabetic foot ulcers, gangrene and even lower limb amputation. The clinical manifestations of PAD which are typically not revealed until symptoms like intermittent claudication, rest pain and ischemic gangrene develop, are not present in majority of diabetes mellitus patients with PAD due to diabetic peripheral neuropathy. Therefore, current study is aimed to evaluate the inflammatory and endothelial dysfunction markers with their correlation to biomarkers that can help for in-time diagnosis and efficient prognosis of developing diabetes-associated PAD. Enzyme-linked immunosorbent assay was used to evaluate the interlukin-6, interlukin-8, intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) in PAD with diabetes group, diabetic group and healthy individual group while biomarkers were measured by kit method. It was observed that serum IL-6, IL-8, ICAM and VCAM levels in type II diabetes mellitus (T2DM) with PAD patients were increased significantly (85.93, 597.08, 94.80 and 80.66) as compared to T2DM patients (59.52, 231.34, 56.88 and 50.19) and healthy individuals (4.81, 16.93, 5.55 and 5.16). The overall means for the parameters, IL-6, IL-8, ICAM, VCAM, urea, S/creatinine, CK-MB, AST, ALT, cholesterol, triglyceride, HDL, LDL, PT, aPTT, INR, HbA1C, and CRP within all groups were significantly (P < 0.05) different from each other. Therefore, it was concluded that the change in IL-6, IL-8, ICAM and VCAM can serve as an accurate diagnostic indicator and successful treatment.

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).
CONCLUSIONS: Serum VCAM-1 levels may be helpful in differentiating uncomplicated and complicated appendicitis in children and could predict appendiceal perforation.

Substance P (SP), encoded by the Tac1 gene, has been shown to promote leukocyte infiltration and organ impairment in mice with sepsis. Neurokinin-1 receptor (NK1R) is the major receptor that mediates the detrimental impact of SP on sepsis. This investigation studied whether SP affects the expression of adhesion molecules, including intercellular cell adhesion molecule-1 (ICAM1) and vascular cell adhesion molecule-1 (VCAM1) on vascular endothelial cells in the liver and lungs, contributing to leukocyte infiltration in these tissues of mice with sepsis. Sepsis was induced by caecal ligation and puncture (CLP) surgery in mice. The actions of SP were inhibited by deleting the Tac1 gene, blocking NK1R, or combining these two methods. The activity of myeloperoxidase and the concentrations of ICAM1 and VCAM1 in the liver and lungs, as well as the expression of ICAM1 and VCAM1 on vascular endothelial cells in these tissues, were measured. The activity of myeloperoxidase and the concentration of ICAM1 and VCAM1 in the liver and lungs, as well as the expression of ICAM1 and VCAM1 on vascular endothelial cells in these tissues, increased in mice with CLP surgery-induced sepsis. Suppressing the biosynthesis of SP and its interactions with NK1R attenuated CLP surgery-induced alterations in the liver and lungs of mice. Our findings indicate that SP upregulates the expression of ICAM1 and VCAM1 on vascular endothelial cells in the liver and lungs, thereby increasing leukocyte infiltration in these tissues of mice with CLP surgery-induced sepsis by activating NK1R.