Endothelial Dysfunction in Obesity and Therapeutic Targets.

Parallel to the increasing prevalence of obesity in the world, the mortality from cardiovascular disease has also increased. Low-grade chronic inflammation in obesity disrupts vascular homeostasis, and the dysregulation of adipocyte-derived endocrine and paracrine effects contributes to endothelial dysfunction. Besides the adipose tissue inflammation, decreased nitric oxide (NO)-bioavailability, insulin resistance (IR), and oxidized low-density lipoproteins (oxLDLs) are the main factors contributing to endothelial dysfunction in obesity and the development of cardiorenal metabolic syndrome. While normal healthy perivascular adipose tissue (PVAT) ensures the dilation of blood vessels, obesity-associated PVAT leads to a change in the profile of the released adipo-cytokines, resulting in a decreased vasorelaxing effect. Higher stiffness parameter ß, increased oxidative stress, upregulation of pro-inflammatory cytokines, and nicotinamide adenine dinucleotide phosphate (NADP) oxidase in PVAT turn the macrophages into pro-atherogenic phenotypes by oxLDL-induced adipocyte-derived exosome-macrophage crosstalk and contribute to the endothelial dysfunction. In clinical practice, carotid ultrasound, higher leptin levels correlate with irisin over-secretion by human visceral and subcutaneous adipose tissues, and remnant cholesterol (RC) levels predict atherosclerotic disease in obesity. As a novel therapeutic strategy for cardiovascular protection, liraglutide improves vascular dysfunction by modulating a cyclic adenosine monophosphate (cAMP)-independent protein kinase A (PKA)-AMP-activated protein kinase (AMPK) pathway in PVAT in obese individuals. Because the renin-angiotensin-aldosterone system (RAAS) activity, hyperinsulinemia, and the resultant IR play key roles in the progression of cardiovascular disease in obesity, RAAS-targeted therapies contribute to improving endothelial dysfunction. By contrast, arginase reciprocally inhibits NO formation and promotes oxidative stress. Thus, targeting arginase activity as a key mediator in endothelial dysfunction has therapeutic potential in obesity-related vascular comorbidities. Obesity-related endothelial dysfunction plays a pivotal role in the progression of type 2 diabetes (T2D). The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone (thiazolidinedione), is a popular drug for treating diabetes; however, it leads to increased cardiovascular risk. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin (EMPA) significantly improves endothelial dysfunction and mortality occurring through redox-dependent mechanisms. Although endothelial dysfunction and oxidative stress are alleviated by either metformin or EMPA, currently used drugs to treat obesity-related diabetes neither possess the same anti-inflammatory potential nor simultaneously target endothelial cell dysfunction and obesity equally. While therapeutic interventions with glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide or bariatric surgery reverse regenerative cell exhaustion, support vascular repair mechanisms, and improve cardiometabolic risk in individuals with T2D and obesity, the GLP-1 analog exendin-4 attenuates endothelial endoplasmic reticulum stress.

Ultrasound molecular imaging for early detection of acute renal ischemia-reperfusion injury.

Background: Microcirculatory perfusion disorder and inflammatory response are critical links in acute kidney injury (AKI). We aim to construct anti-vascular cell adhesion molecule-1(VCAM-1) targeted microbubbles (TM) to monitor renal microcirculatory perfusion and inflammatory response. Methods: TM carrying VCAM-1 polypeptide was constructed by biological coupling. The binding ability of TM to human umbilical vein endothelial cells (HUVECs) was detected. Bilateral renal ischemia-reperfusion injury (IRI) models of mice were established to evaluate microcirculatory perfusion and inflammatory response using TM. Thirty-six mice were randomly divided into six groups according to the different reperfusion time (0.5, 2, 6, 12, and 24 h) and sham-operated group (Sham group). The correlation of TM imaging with serum and histopathological biomarkers was investigated. Results: TM has advantages such as uniform distribution, regular shape, high stability, and good biosafety. TM could bind specifically to VCAM-1 molecule expressed by tumor necrosis factor-alpha (TNF-α)-treated HUVECs. In the renal IRI-AKI model, the area under the curve (AUC) of TM significantly decreased both in the renal cortical and medullary after 2 h of reperfusion compared with the Sham group (p < 0.05). Normalized intensity difference (NID) of TM at different reperfusion time was all higher than that of blank microbubbles (BM) and the Sham group (p < 0.05). Ultrasound molecular imaging of TM could detect AKI early before commonly used renal function markers, histopathological biomarkers, and BM imaging. AUC of TM was negatively correlated with serum creatinine (Scr), blood urea nitrogen (BUN), and Cystatin C (Cys-C) levels, and NID of TM was linearly correlated with VCAM-1, TNF-α, and interleukin-6 (IL-6) expression (p < 0.05). Conclusions: Ultrasound molecular imaging based on TM carrying VCAM-1 polypeptide can accurately evaluate the changes in renal microcirculatory perfusion and inflammatory response, which might be a promising modality for early diagnosis of AKI.

In Vivo PET Detection of Lung Micrometastasis in Mice by Targeting Endothelial VCAM-1 Using a Dual-Contrast PET/MRI Probe.

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.

Effect of pentoxifylline on endothelial dysfunction, oxidative stress and inflammatory markers in STEMI patients.

Aim: ST-elevation myocardial infarction (STEMI) patients suffer higher mortality and adverse outcomes linked to endothelial dysfunction (ED). Methods: 43 patients were randomized to pentoxifylline (PTX) 400 mg thrice daily (n = 22) or placebo (n = 21). Soluble vascular cell adhesion molecule-1, malondialdehyde, interleukin-1 (IL-1), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor-α (TNF-α) were assessed at baseline and 2 months. Results: After 2 months, no significant difference was observed in markers' levels between the 2 groups. However, a within-group comparison revealed a statistically significant change in hs-CRP in the PTX group (10.057 (9.779-10.331) versus 9.721 (6.102-10.191)), p = 0.032. Conclusion: PTX for 2 months in STEMI patients was safe and well-tolerated but had no significant detectable effect on ED, oxidative stress or inflammatory markers. Clinical Trial Registration: NCT04367935 (ClinicalTrials.gov).

This study examined the effect and the safety of a drug called pentoxifylline in patients who have recently had a heart attack. Pentoxifylline can possibly reduce inflammation and is used for patients with blood flow issues. The study involved 43 participants, 22 receiving pentoxifylline and 21 receiving a placebo for 2 months. We measured different markers related to inflammation and heart health before and after. Overall, there was no significant difference between the groups, but patients who received pentoxifylline experienced less inflammation according to only one of the markers measured. This study concluded that the prescription of pentoxifylline after a heart attack is safe, well-tolerated and without notable side effects. Still, we recommend larger and longer studies to be sure of its effect.

Serum Levels of Intercellular Adhesion Molecule 1 and Vascular Cell Adhesion Molecule 1 as Biomarkers to Predict Radiotherapy Sensitivity in Cervical Cancer.

Background: Cervical cancer is a significant global health burden, and individualized treatment approaches are necessary due to its heterogeneity. Radiotherapy is a common treatment modality; however, the response varies among patients. The identification of reliable biomarkers to predict radiotherapy sensitivity is crucial. Methods: A cohort of 189 patients with stage IB2-IVA cervical cancer, treated with radiotherapy alone or concurrent chemoradiotherapy, was included. Serum samples were collected before treatment, and intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) concentrations were determined. Patients were categorized into radiotherapy-sensitive (RS) and radiotherapy-resistant (RR) groups based on treatment response. Clinicopathological characteristics and survival rates were analyzed. Results: The analysis of clinicopathological characteristics showed that age, family history of cervical cancer and post-menopausal status did not significantly differ between RS and RR groups. Tumor size demonstrated a borderline significant association with radiotherapy response, while differentiation degree was significantly associated. Serum ICAM-1 and VCAM-1 concentrations were significantly higher in the RR group compared to the RS group. Combined detection of ICAM-1 and VCAM-1 improved the predictive ability for radiotherapy sensitivity. Higher serum ICAM-1 and VCAM-1 levels were observed in patients with lower tumor differentiation. Five-year overall survival rates differed significantly between patients with high and low ICAM-1 and VCAM-1 levels. Conclusion: Serum ICAM-1 and VCAM-1 levels show potential as predictive biomarkers for radiotherapy sensitivity in cervical cancer.

In vivo tracking of mesenchymal stem cell dynamics and therapeutics in LPS-induced acute lung injury models.

Mesenchymal stem cells (MSCs) have been widely used to treat various inflammatory and immune-related diseases in preclinical and clinical settings. Intravital microscopy (IVM) is considered the gold standard for investigating pathophysiological conditions in living animals. However, the potential for real-time monitoring of MSCs in the pulmonary microenvironment remains underexplored. In this study, we first constructed a lung window and captured changes in the lung at the cellular level under both inflammatory and noninflammatory conditions with a microscope. We further investigated the dynamics and effects of MSCs under two different conditions. Meanwhile, we assessed the alterations in the adhesive capacity of vascular endothelial cells in vitro to investigate the underlying mechanisms of MSC retention in an inflammatory environment. This study emphasizes the importance of the "lung window" for live imaging of the cellular behavior of MSCs by vein injection. Moreover, our results revealed that the upregulation of vascular cell adhesion molecule 1 (VCAM1) in endothelial cells post-inflammatory injury could enhance MSC retention in the lung, further ameliorating acute lung injury. In summary, intravital microscopy imaging provides a practical method to investigate the therapeutic effects of MSCs in acute lung injury.

Differentiation-inducing factor-1 reduces lipopolysaccharide-induced vascular cell adhesion molecule-1 by suppressing mTORC1-S6K signaling in vascular endothelial cells.

AIMS: Differentiation-inducing factor-1 (DIF-1), a compound in Dictyostelium discoideum, exhibits anti-cancer effects by inhibiting cell proliferation and motility of various mammalian cancer cells in vitro and in vivo. In addition, DIF-1 suppresses lung colony formation in a mouse model, thus impeding cancer metastasis. However, the precise mechanism underlying its anti-metastatic effect remains unclear. In the present study, we aim to elucidate this mechanism by investigating the adhesion of circulating tumor cells to blood vessels using in vitro and in vivo systems. MAIN METHODS: Melanoma cells (1.0 × 105 cells) were injected into the tail vein of 8-week-old male C57BL/6 mice after administration of DIF-1 (300 mg/kg per day) and/or lipopolysaccharide (LPS: 2.5 mg/kg per day). To investigate cell adhesion and molecular mechanisms, cell adhesion assay, western blotting, immunofluorescence staining, and flow cytometry were performed. KEY FINDINGS: Intragastric administration of DIF-1 suppressed lung colony formation. DIF-1 also substantially inhibited the adhesion of cancer cells to human umbilical vein endothelial cells. Notably, DIF-1 did not affect the expression level of adhesion-related proteins in cancer cells, but it did decrease the expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells by suppressing its mRNA-to-protein translation through inhibition of mTORC1-p70 S6 kinase signaling. SIGNIFICANCE: DIF-1 reduced tumor cell adhesion to blood vessels by inhibiting mTORC1-S6K signaling and decreasing the expression of adhesion molecule VCAM-1 on vascular endothelial cells. These findings highlight the potential of DIF-1 as a promising compound for the development of anti-cancer drugs with anti-metastatic properties.

Compound Kushen Injection inhibits epithelial-mesenchymal transition of gastric carcinoma by regulating VCAM1 induced by the TNF signaling pathway.

BACKGROUND: Gastric carcinoma (GC) treatment needs to be developed rapidly. Compound Kushen Injection (CKI), a formula from traditional Chinese medicine, has been used clinically in combination with chemotherapy to treat GC with satisfactory results. However, the molecular mechanism by which CKI acts to cure GC is still unclear. METHODS: In the present study, in vivo and in vitro experiments were used to assess the efficacy of CKI. Using ceRNA microarray and TMT technologies, the molecular mechanism of CKI was further investigated at the transcriptional and protein levels, and a bioinformatics approach was employed to investigate and functionally validate key CKI targets in GC. RESULTS: When combined with cisplatin (DDP), CKI significantly increased its efficacy in preventing the proliferation and metastasis of GC cells and malignant-looking tumors in mice. High-throughput sequencing data and bioinformatics analysis showed that CKI regulated the TNF signaling pathway, epithelial-mesenchymal transition (EMT), with VCAM1 as a key target. The transcription factors CEBPB, JUN, RELA, NFKB1, the EMT mesenchymal-like cell markers N-cadherin and vimentin, as well as the expression of VCAM1 and its upstream signaling driver TNF, were all downregulated by CKI. In contrast, the expression of the EMT epithelial-like cell marker E-cadherin was upregulated. CONCLUSION: CKI can effectively inhibit GC growth and metastasis, improve body's immunity, and protect normal tissues from damage. The molecular mechanism by which CKI inhibits metastasis of GC is by regulating VCAM1 induced by the TNF signaling pathway to inhibit EMT of GC. Our results provide an important clue to clarify precisely the multi-scale molecular mechanism of CKI in the treatment of GC.

Anthocyanin supplementation improves obesity-related inflammatory characteristics: A systematic review and meta-analysis of randomized controlled trials.

The relationship between anthocyanin intake and obesity-related inflammatory markers remains unclear in existing research. To investigate this, we hypothesized that anthocyanin supplementation could reduce plasma concentrations of inflammatory markers, including C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), vascular cell adhesion molecule-1, and other cytokines in obesity. We conducted a systematic search of PubMed, Web of Science, Scopus, SinoMed, and other related literature and identified 16 randomized controlled trials that met our inclusion criteria. Our findings showed that anthocyanin intake was significantly associated with a reduction in vascular cell adhesion molecule-1 mean plasma concentrations (-53.56 ng/mL; 95% confidence interval [CI], -82.10 to -25.03). We also observed a modest decrease in CRP (-0.27 ng/mL; 95% CI, -0.58 to 0.05), TNF-α (-0.20 ng/mL; 95% CI, -0.54 to 0.15), and IL-6 (-0.53 ng/mL; 95% CI, -1.16 to 0.10) mean plasma concentrations. Subgroup analysis revealed that anthocyanin intake tended to decrease CRP and IL-6 concentrations in overweight or dyslipidemic individuals. Additionally, the intervention duration subgroup analysis showed that anthocyanin supplementation had a stronger effect on plasma IL-6 and TNF-α in participants after 8 to 12 weeks of intervention. In conclusion, our meta-analysis indicated that anthocyanin supplementation can effectively reduce obesity-related inflammatory markers associated with chronic low-grade inflammation.

Tp47-Induced Monocyte-Derived Microvesicles Promote the Adherence of THP-1 Cells to Human Umbilical Vein Endothelial Cells via an ERK1/2-NF-κB Signaling Cascade.

The Treponema pallidum membrane protein Tp47 induces immunocyte adherence to vascular cells and contributes to vascular inflammation. However, it is unclear whether microvesicles are functional inflammatory mediators between vascular cells and immunocytes. Microvesicles that were isolated from Tp47-treated THP-1 cells using differential centrifugation were subjected to adherence assays to determine the adhesion-promoting effect on human umbilical vein endothelial cells (HUVECs). Intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) levels in Tp47-induced microvesicle (Tp47-microvesicle)-treated HUVECs were measured, and the related intracellular signaling pathways of Tp47-microvesicle-induced monocyte adhesion were investigated. Tp47-microvesicles promoted THP-1 cell adhesion to HUVECs (P < 0.01) and upregulated ICAM-1 and VCAM-1 expression in HUVECs (P < 0.001). The adhesion of THP-1 cells to HUVECs was inhibited by anti-ICAM-1 and anti-VCAM-1 neutralizing antibodies. Tp47-microvesicle treatment of HUVECs activated the extracellular signal-regulated kinase 1/2 (ERK1/2) and NF-κB signaling pathways, whereas ERK1/2 and NF-κB inhibition suppressed the expression of ICAM-1 and VCAM-1 and significantly decreased the adhesion of THP-1 cells to HUVECs. IMPORTANCE Tp47-microvesicles promote the adhesion of THP-1 cells to HUVECs through the upregulation of ICAM-1 and VCAM-1 expression, which is mediated by the activation of the ERK1/2 and NF-κB pathways. These findings provide insight into the pathophysiology of syphilitic vascular inflammation.