Vascular Endothelial Growth Factor Levels Research Articles

Disturbance of gut microbiota aggravates the inflammatory response and damages the vascular endothelial function in patients with preeclampsia.

To investigate the influence of intestinal flora imbalance on inflammatory factors in the serum and vascular endothelial functionality in individuals with preeclampsia (PE). From January 2022 to December 2023, a total of 58 individuals with PE (PE group) and 60 healthy controls (CON group) were included in this study; they were matched for age and pre-pregnancy Body Mass Index (BMI). A comparison was made between the two groups in terms of the general data and the number of unique intestinal flora. Additionally, clinical blood measures, serum inflammatory factors, and vascular endothelial function were also assessed and compared between the groups. Age, gestational age, and pre-pregnancy BMI were similar between the PE and control group. However, diastolic and systolic blood pressure were significantly higher in the PE group. The abundance of Lactobacillus, Bifidobacterium, Enterobacter, and Enterococcus. Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were considerably higher in the PE group compared to the CON group, but Interleukin-4 (IL-4) was noticeably lower, and the amount of White blood cells (WBC), neutrophil count (N) and lymphocyte count (L) in the PE group were significantly higher than those in the CON group. In the PE group, serum vascular endothelin (ET) and soluble endoglin (sEng) were higher than in the CON group, vascular endothelial growth factor (VEGF) and nitric oxide (NO) levels were considerably lower than in the CON group, and the levels of TC, TG, LDL-C and HDL-C were significantly higher in the PE group than in the CON group. The presence of Lactobacillus and Bifidobacterium was inversely associated with levels of TNF-α, IL-6, Interleukin-10 (IL-10), ET, and sEng, and positively associated with levels of IL-4, VEGF, and NO. Nevertheless, there was a positive correlation between the abundance of Enterobacterium and Enterococcus with the levels of TNF-α, IL-6, IL-10, ET, and sEng. Conversely, there was a negative correlation between the abundance of Enterobacterium and Enterococcus and the levels of IL-4, VEGF, and NO. Patients with PE exhibited dysbiosis of intestinal flora, characterized by altered gut microbiota diversity, increased serum pro-inflammatory factors, and impaired vascular endothelial function.

Serum Vitamin D Levels and Vascular Endothelial Growth Factor in Patients with Type 2 Diabetes Mellitus: A Cross-sectional Study

Introduction: Diabetes Mellitus (DM) is the most common noncommunicable disease and the fifth leading cause of death worldwide. Recent research has demonstrated that low Vitamin D levels and high Vascular Endothelial Growth Factor (VEGF) in middle-aged and elderly populations represent a risk factor for Type 2 Diabetes Mellitus (T2DM). Aim: To estimate the Vitamin D and VEGF levels in study subjects with T2DM and healthy controls and to correlate the Vitamin D level and VEGF with HbA1c % in study subjects with T2DM. Materials and Methods: A cross-sectional study was undertaken from October 2014 to November 2016 at the Department of Medicine in collaboration with the Department of Biochemistry, Bangalore Medical College and Research Institute, Bangalore. The study included 50 T2DM subjects on oral hypoglycaemic agents for five years and 50 age and sexmatched healthy controls selected randomly from the general population. In all the study subjects, Random Blood Glucose (RBG), LFT, Renal Function Test (RFT), HBA1c, serum Vitamin D, and serum VEGF were estimated. Student t-test and Chisquare/Fisher-Exact test were used to find the significance of study parameters between cases and controls. Multivariate logistic regression analysis was done to assess the risk factors for DM. Results: The mean age of the cases was 50.9±9.7 years and of controls was 49.76±7.7 years. Among the 50 cases, 19 (38%) were men and 31 (62%) were women. Among the 50 controls, 27 (54%) were men and 23 (46%) were women. The mean Body Mass Index (BMI) among cases was 27.21±4.59 and in controls was 24.82±2.63 (p-value=0.0016). The mean serum 25(OH) Vitamin D levels in cases were 11.39±3.32 ng/mL and in controls were 28.06±11.14 ng/mL (p-value <0.001). The mean serum VEGF levels in cases were 97.52±16.96 pg/mL and in controls were 56.37±17.74 pg/mL (p-value <0.001). Conclusion: The present study found that subjects with T2DM have lower serum 25(OH) Vitamin D levels and higher serum VEGF levels than those without T2DM. Serum Vitamin D decreases and serum VEGF-A levels increase with increasing HbA1c%, correlating with vascular complications.

Nrf2 and HuR/ELAV1 as determinant factors for VEGF expression and secretion in ARPE‐19 cells under stress stimuli

Aims/Purpose: The transcription nuclear factor E2‐related factor 2 (Nrf2) pathway is a key antioxidant system in the RPE, protecting it from oxidative stress and inflammation. Its dysfunction is a renowned aspect of Age‐related Macular Degeneration (AMD). As previously documented, RNA‐binding protein HuR/ELAVL1 interacts with Nrf2 mRNA, as well as many of its targets at the post‐transcriptional level. Among them, vascular endothelial growth factor (VEGF) is a crucial one, being involved in both physiological maintenance of vasculature and pathological angiogenesis. Purposes of our study were disclosing the crosstalk between Nrf2 and HuR in RPE cells subjected to stressful stimuli and understanding their regulatory effect on VEGF.Methods: Wild type, Nrf2‐ or HuR‐deficient ARPE‐19 cells were used. As stressful stimuli, MG132 (5 μM) and Bafilomycin (50 nM) for 24 h, or 4‐Hydroxynonenal (4‐HNE; 50 or 100 μM) for 6 h, were used. Cell viability was assayed by enzymatic fluorescence analysis; VEGF expression and extracellular secretion were evaluated by RT‐qPCR and ELISA, respectively.Results: When subjected to intense toxic stimuli, HuR‐deficient cells display impaired viability, although to a lesser extent compared to Nrf2‐deficient cells. In these silenced cell models, 4‐HNE seems to be more harmful than the autophagy inhibitors. Nrf2 or HuR deficiency markedly affects VEGF levels and secretion, even more than stressful conditions. Furthermore, distinctive effects of silencing either Nrf2 or HuR on the level of the other factor have been disclosed.Conclusions: Both HuR and Nrf2 are involved in the constitutive regulation of VEGF levels; contexts characterized by oxidative stress or impaired clearance induce more significant changes in RPE featured by an impairment of Nrf2 than of HuR levels. Further elucidations in how the crosstalk between these two factors regulate common targets (e.g., VEGF) may improve our understanding of RPE homeostasis and alteration, and consequently AMD pathophysiology.

The Effect of Riboflavin on Neurological Rehabilitation after Traumatic Brain Injury in Children.

Traumatic brain injury (TBI), which is the brain impairment and lesion caused by the external force injuring the head and the underlying brain, can cause pediatric death, disability, neurological disorders, and even lifelong disability. This study was to explore the effect of riboflavin (RF) on neurological rehabilitation and functional recovery after TBI. The rat models of TBI were constructed by treating rats with controlled cortical impact (CCI). By treating TBI rats with RF, we investigated whether the administration of RF would affect the sensorimotor function and cognitive ability recovery through adhesive removal test, modified neurological severity score (mNSS), corner test, wire-grip test and the Morris water maze. The effects of RF on lesion volume and water content were investigated using hematoxylin and eosin (H&E) staining and wet-dry method. The Nissl staining and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) staining were used to demonstrate the effect of RF on neural apoptosis. Inflammation-related cytokines of interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β1 were measured by enzyme-linked immunosorbent assay (ELISA) to evaluate the effect of RF on neuroinflammation. The impact of RF on oxidative stress was assessed by measuring malondialdehyde (MDA) content and superoxide dismutase (SOD) activity, and the platelet endothelial cell adhesion molecule-1 (CD31) staining for observing vessel density, the reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) for measuring vascular endothelial growth factor (VEGF) mRNA expression and western blot for VEGF protein expression were used for evaluated angiogenesis. The administration of RF could facilitate the recovery of neurological function by promoting the recovery of sensorimotor function and cognitive ability (p < 0.05). Furthermore, RF could reduce the lesion volume and water content after TBI and ameliorate neural apoptosis, neuroinflammation, and oxidative stress (p < 0.05). Finally, RF increased vessel density (p < 0.01) and VEGF levels (p < 0.01) in brain tissues after TBI, promoting angiogenesis. RF benefits neurological rehabilitation after TBI by promoting neurological function recovery, ameliorating the pathogenesis after TBI, and facilitating brain vascular remodeling. These findings provide a novel mechanism for RF treating pediatric TBI.

Systemic allopurinol administration reduces malondialdehyde, interleukin 6, tumor necrosis factor α, and increases vascular endothelial growth factor in random flap Wistar rats exposed to nicotine.

Smoking poses a risk to flap viability, with nicotine being a major contributor to the formation of free radicals. Allopurinol, known for its antioxidant properties, has been shown to enhance tissue survival in ischemic conditions by reducing the production of reactive oxygen species (ROS). This study aims to assess the impact of allopurinol on the viability and success of skin flaps in Wistar rats exposed to nicotine. This study examined skin flap survival in nicotine-exposed rats treated with allopurinol. Twenty-eight rats were separated into two groups. During 1 month of nicotine exposure, the treatment group received systemic allopurinol 7 days before and 2 days after the flap procedure, while the control group received no allopurinol. Pro-angiogenic factors, proinflammatory factors, anti-inflammatory factors, and oxidative markers were assessed on the 7th day after the flap procedure using enzyme-linked immunosorbent assay method. Macroscopic flap viability was evaluated on the 7th day using Image J photos. As an oxidative marker, malondialdehyde levels were significantly lower in rats given allopurinol than in controls (P &lt; 0.001). The levels of interleukin 6 and tumor necrosis factor α, as markers of inflammatory factors, were significantly lower in the group of rats given allopurinol compared to controls (P &lt; 0.001). The level of angiogenesis in rats given allopurinol, measured by vascular endothelial growth factor levels, was also higher in the treatment group compared to controls (P &lt; 0.001). Macroscopically, the percentage of distal flap necrosis in Wistar rats given allopurinol was lower and statistically significant compared to controls (P &lt; 0.001). Xanthine oxidoreductase is part of a group of enzymes involved in reactions that produce ROS. Allopurinol, as an effective inhibitor of the xanthine oxidase enzyme, can reduce oxidative stress by decreasing the formation of ROS. This reduction in oxidative stress mitigates the risk of ischemic-reperfusion injury effects and significantly increases the viability of Wistar rat flaps exposed to nicotine.

A Randomized Controlled Study of Enhanced External Counterpulsation with Cardiac Rehabilitation in Patients with Nonobstructive Coronary Artery Disease and Coronary Microvascular Dysfunction.

Treatment with enhanced external counterpulsation (EECP) or cardiac rehabilitation (CR) benefits patients with coronary heart disease; this paper intends to explore the feasibility of EECP combined with CR in patients with nonobstructive coronary heart disease (NOCAD) and coronary microcirculation disorders (CMD).In January 2021-2022 month June our income NOCAD patients as the research object, the line of cardiac magnetic resonance (CMR), myocardial perfusion reserve (MPR) < 2.0 coronary microcirculation disorders (CMD, 80 cases). Random indicator method 80 CMD patients divided into two groups, 40 cases in each. Usual treatment group: conventional drugs and CR therapy. EECP treatment group: on the basis of standard treatment group, employ EECP therapy. Comparing the two groups before and after the treatment curative effect cardiac function index, endothelial unction index, adverse cardiovascular events, etc.After EECP treatment, the treatment group showed a higher effective rate compared to the usual treatment group (P < 0.05). EECP group curative effect, left ventricular ejection fraction,plasma NO and vascular endothelial growth factor levels higher than the usual group, the incidence of adverse cardiovascular events is lower than the usual group. The difference was statistically significant (P < 0.05).EECP combined with cardiac rehabilitation in patients with CMD symptoms has better effect and safety and provides reference for treatment of CMD patients.

Association of Vascular Endothelial Growth Factor Levels with Risk of Alzheimer's Disease: A Systematic Review and Meta-Analysis.

Alzheimer's disease (AD) is a progressive neurodegenerative illness that leads to impairment of cognitive functions and memory loss. Even though there is a plethora of research reporting the abnormal regulation of VEGF expression in AD pathogenesis, whether the CSF and serum VEGF are increased in AD is an open question yet. In this study, the association of CSF and serum VEGF concentrations with the risk of Alzheimer's disease was investigated using systematic review and meta-analysis. A systematic literature search was carried out using online specialized biomedical databases of Web of Science, Pubmed, Scopus, Embase, and Google Scholar until Feb 2023 without restriction to the beginning time. The meta-analysis was performed using the random-effects model and only case-control publications describing VEGF concentrations in Alzheimer's patients were considered for calculating the pooled effect size. In the systematic literature search, 6 and 13 studies met the inclusion criteria to evaluate CSF and serum VEGF concentrations of Alzheimer's patients, respectively. This meta-analysis retrieved a total number of 2380 Alzheimer's patients and 5368 healthy controls. Under the random-effects model in the meta-analysis, the pooled SMD for CSF and serum VEGF concentrations of Alzheimer's patients were -0.13 (95%CI,-0.42-0.16) and 0.23 (95%CI,-0.27-0.73), respectively. Results of meta-regression analysis showed that the quality scores of papers and female sex ratios of participants did not affect the associations of VEGF concentrations with the risk of Alzheimer's disease. However, the age average of patients significantly affects the associations of CSF VEGF concentrations with the risk of Alzheimer's disease (P=0.051). There was a statistically significant subgroup effect for the disease severity of Alzheimer's patients which modifies the associations of serum VEGF concentrations with the risk of Alzheimer's disease (P<0.01) and subgroup analysis shows that study location modifies the associations of CSF and serum VEGF concentrations with the risk of Alzheimer's disease (P<0.01). The results show that the serum VEGF concentrations increased for Alzheimer's patients in accordance with the increased expression of VEGF and the VEGF levels of Alzheimer's patients decreased by increasing their disease severities. Therefore, in addition to detecting AD in the earliest stages of the disease, serum VEGF could be a promising biomarker to follow up on the disease and evaluate the clinical course of the disease.

Relationship between angiogenic growth factors and atherosclerosis in renal transplantation recipients: a cross-sectional study.

Accelerated development of atherosclerosis has been observed in renal transplant recipients (RTRs). Angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) are vascular enzymes that play important roles in vascular development and angiogenesis. This study aimed to investigate the relationship between Ang-2 and VEGF and atherosclerosis in RTRs. This study was conducted at Ankara City Hospital, Turkey. This cross-sectional study included 36 (37.5%) female and 60 (62.5%) male RTRs. All findings were compared with those of 70 healthy controls. Ultrasonographic measurements of the carotid artery intima-media thickness (CA-IMT) and renal resistive index (RRI) were used as indicators of atherosclerosis. Log10 Ang-2, log10 VEGF, CA-IMT, and RRI levels were significantly higher in patients than in healthy controls. No significant differences were detected in CA-IMT and RRI between those with log10 Ang-2 ≥ 3.53 pg/mL and those with < 3.53 pg/mL. No significant differences were detected in CA-IMT and RRI between those with log10 VEGF ≥ 1.98 pg/mL and those with < 1.98 pg/mL. No correlation was detected between log10 Ang-2 and log10 VEGF, CA-IMT, or RRI. Increased serum angiogenic growth factor levels and increased atherosclerosis development were detected in RTRs compared to healthy individuals. No relationship was observed between angiogenic growth factors and atherosclerosis. This may be due to the decreased synthesis and effect of angiogenic growth factor receptors synthesized from atherosclerotic plaques due to atherosclerosis, which improves after renal transplantation.

Silencing of transient receptor potential canonical channel 4 inhibits endothelial progenitor cell angiogenesis by suppressing VEGF and SDF-1.

Endothelial progenitor cells (EPCs) play a crucial role in acquired angiogenesis and endothelial injury repair. Transient receptor potential canonical channel 4 (TRPC4), a key component of store-operated calcium channels, is essential for EPC function. While the role of TRPCs has been clarified in vascular diseases, the relationship between TRPC4 and EPC function, along with the underlying molecular mechanisms, remains unclear and requires further elucidation. EPCs were isolated from canine bone marrow and identified by morphology and flow cytometry. TRPC4 was transfected into EPCs using lentivirus or negative control, and its expression was assessed using real-time polymerase chain reaction (RT-PCR). Proliferation, migration, and tube formation were evaluated using Cell Counting Kit-8 (CCK-8), Transwell, and Matrigel assays, respectively. Levels of vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) were measured using enzyme-linked immunosorbent assay (ELISA). TRPC4 mRNA expression was significantly reduced in TRPC4-short hairpin RNA (shRNA) transfected EPCs compared to the normal control (NC)-shRNA groups. Migration and tube formation were significantly decreased after TRPC4 silencing, while proliferation showed no difference. Additionally, levels of SDF-1 and VEGF in EPCs were markedly reduced following TRPC4 silencing. TRPC4 plays a crucial role in regulating angiogenesis in EPCs. Silencing of TRPC4 can lead to decreased angiogenesis by inhibiting VEGF and SDF-1 expression, suggesting that TRPC4 knockdown might be a novel therapeutic strategy for vascular diseases.

Mechanism of mingjing granules in treating wet age-related macular degeneration based on network pharmacology and experimental verification

Objective: To analyze the potential mechanism of Mingjing granules in the treatment of wet age-related macular degeneration (wAMD) based on the research methods of network pharmacology and molecular docking approach and to provide a new reference for the currently limited treatment of wAMD. Materials and Methods: We searched TCMSP, GeneCards, OMIM, PharmGkb, TTD, and DrugBank database to screen the main active ingredients of Mingjing granules and their therapeutic targets of wAMD. The network of active components and targets was constructed using Cytoscape3.6.1 software, which was also used for the topological analysis of target genes. The network of Protein-Protein Interactions (PPI) was mapped using the String platform. We also used R language to do the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway for additional analysis. Molecular docking studies were finished by Chemoffice, Autodock, and Pymol. Finally, the efficacy of the Mingjing granules was examined in animal experiments, in which we used enzyme-linked immunosorbent assay to the contents of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) levels in peripheral blood. Results: Active compounds, including quercetin, lignocaine, and kaempferol, were found. PPI network analysis showed that tumor necrosis factor (TNF), MMP-9, epidermal growth factor (EGF), prostaglandin-endoperoxide synthase 2 (PTGS2), and caspase-3 (CASP3) were related to both Mingjing granules and wAMD. GO and KEGG pathway analysis showed that these targets were mainly involving lipids and atherosclerosis, TNF, and interleukin-17 (IL-17) signaling pathways. Docking studies suggested that quercetin and luteolin can fit in the binding pocket of four target proteins (CASP3, EGF, PTGS2, and TNF). In the vivo experiment, the Mingjing granules were found to be effective on the expression of VEGF and MMP-9 in peripheral blood. Conclusions: This study initially reveals the multi-constituent, multi-target, and multi-pathway mechanism of action of Mingjing granules in the treatment of wAMD and implies the inhibition of choroidal neovascularization may be related to the expression of VEGF and MMP-9.

Gut microbiota-derived acetate promotes long-term recovery through angiogenesis guided by lymphatic ingrowth in older adults with stroke.

Ischemic stroke is a leading cause of morbidity and mortality in older adults. Therefore, in this study, we sought to understand the interplay between the microbiota, gut, and brain in the context of stroke in older adults. To determine whether gut microbiota from younger individuals promotes recovery through angiogenesis in both elderly stroke patients and aged stroke mice, we explored the changes in gut microbiota and the correlation between short-chain fatty acids (SCFAs) and angiogenesis in the aged stroke population. Then, we altered the gut microbiome in aged mice by transplanting microbiota from younger donors before inducing experimental stroke to explore the mechanism by which gut microbiota-derived SCFAs promote angiogenesis. Part I: We conducted a single-center, double-blind trial to compare gut microbiota diversity and SCFA levels in fecal samples from older stroke patients with those from younger stroke patients. Additionally, we measured levels of vascular endothelial growth factor (VEGF) and VEGFC levels in plasma to assess their correlation with SCFA levels. Part II: We performed fecal microbiota transplantation (FMT) 3 days before inducing ischemic stroke in aged male mice (16-18) via distal middle cerebral artery occlusion (dMCAO). The FMT was conducted using gut microbiomes from either young donors (2-3 months) or aged donors (16-18 months). In older stroke patients, gut microbiota diversity was significantly reduced compared to that in younger stroke patients. Furthermore, levels of acetate, a bacterially derived SCFA, were lower and positively correlated with angiogenesis markers (VEGF and VEGF-C). In aged stroke mice, transplantation of young microbiota improved stroke outcomes by promoting angiogenesis, which was facilitated by lymphatic ingrowth into the cortex. This protective effect was linked to gut microbiota-derived acetate, which enhanced lymphangiogenesis by replenishing acetyl coenzyme A. (a) Gut microbiota-derived acetate promotes angiogenesis post-stroke and (b) lymphatic ingrowth into the cerebral cortex was observed in post-dMCAO mice. These findings suggest that selectively promoting SCFA-producing bacteria, particularly acetate-producers, could be a promising therapeutic strategy to reduce functional impairments in older stroke subjects.

Circulating VEGF and inflammatory bowel disease: a bidirectional mendelian randomization.

Introduction: Prior observational studies have suggested an association between circulating vascular endothelial growth factor (VEGF) levels and inflammatory bowel disease (IBD). This study sought to demonstrate the directionality of the association between circulating VEGF and particular forms of IBD as well as if there is a causal relationship between them. Methods: We collected summary data from relevant genome-wide association studies (GWASs) to assess the validity of causality, and a two-sample bidirectional Mendelian randomization (MR) study and sensitivity testing were performed to assess the causal relationship between circulating VEGF and IBD risk, including Crohn's disease and ulcerative colitis. Results: Our findings revealed a direct causal link between circulating VEGF and Crohn's disease (b 0.195, se 0.078, p < 0.013). However, neither circulating VEGF nor ulcerative colitis were shown to be causally linked (p > 0.025), nor was there proof of a reverse causal relationship from IBD to VEGF. Discussion: In conclusion, circulating VEGF shows a cause-and-effect relationship with Crohn's disease.

Efficacy of Lenvatinib in Combination With PD-1 Monoclonal Antibody and Interventional Treatment for Intermediate-Stage Hepatocellular Carcinoma: Impact on Serum Vascular Endothelial Growth Factor and Matrix Metalloproteinase-9 Levels: A Retrospective Study.

Objectives: To scrutinize the therapeutic efficiency and safety profile of lenvatinib, accompanied by the programmed cell death protein-1 (PD-1) monoclonal antibody, and interventional treatment in managing intermediate-stage hepatocellular carcinoma. Methods: Retrospective analysis was performed on clinical data from 93 patients suffering from intermediate to advanced hepatocellular carcinoma, treated at our institution from May 2018 to April 2020. Patients were divided based on the therapeutic regimen: 43 cases constituted the control group receiving lenvatinib plus transhepatic artery chemoembolization (TACE), while the remaining 50 cases in the study group were managed with lenvatinib, PD-1 monoclonal antibody, and TACE. Outcome measures included therapeutic efficacy, tumor markers (carcinoembryonic antigen [CEA], alpha-fetoprotein [AFP], α-L-fucosidase [AFU], carbohydrate antigen 199 [CA199]), immune response indices (CD3+, CD4+, CD8+, CD4+/CD8+ ratio), pertinent cytokine levels (vascular endothelial growth factor [VEGF], matrix metalloproteinase-9 [MMP-9], basic fibroblast growth factor [aFGF], acidic fibroblast growth factor [bFGF]), quality of life (as per Quality of Life Assessment Scale for Cancer Patients [QOL-LC] scores), adverse effects, and survival rates. Results: The study group exhibited a significantly enhanced total effective rate compared to the control group (74.00% vs 53.49%, P < .05). Post-treatment levels of CEA, AFP, AFU, CA199, CD8+, VEGF, MMP-9, aFGF, and bFGF were notably lower in both groups, particularly in the study group. Contrastingly, CD3+, CD4+, CD4+/CD8+ratios, and QOL-LC scores were substantially elevated in the study group (P < .05). Adverse reaction prevalence was analogous between 2 groups (27.91% vs 26.00%; P > .05). Moreover, the study group reported significantly higher 1-, 2-, and 3-year survival rates than the control group (P < .05). Conclusion: The combined use of lenvatinib, PD-1 monoclonal antibody, and interventional treatment for intermediate to advanced hepatocellular carcinoma may have a definitive therapeutic efficacy. This regimen is effective in reducing tumor marker levels, enhancing immune function, modulating VEGF, MMP-9, and other related cytokine levels, and improving patients' quality of life without significantly augmenting adverse effects. This treatment paradigm also contributes to increased survival rates and promises favorable prognosis.

Tetramethylpyrazine regulates angiogenesis of endothelial cells in cerebral ischemic stroke injury via SIRT1/VEGFA signaling pathway

This study aims to investigate whether tetramethylpyrazine(TMP) can stimulate angiogenesis in cerebral microvascular endothelial cells and alleviate cerebral ischemic stroke(CIS) and to explore the underlying mechanisms. In the animal study, adult Sprague-Dawley rats(n=15) were assigned into sham surgery(sham), middle cerebral artery occlusion/reperfusion(MCAO/R), and MCAO/R+TMP(intraperitoneal injection of 20 mg·kg~(-1)) groups. The neurological function was evaluated by the Z-Longa method. The cerebral infarction volume was detected by TTC staining. Enzyme-linked immunosorbent assay(ELISA) was employed to detect the expression of vascular endothelial growth factor(VEGF), angiopoietin(Ang), and platelet-derived growth factor(PDGF). Immunofluorescence staining was employed to detect Ki67 and the expression of vascular endothelial growth factor A(VEGFA) and slient information regulator 1(SIRT1). Western blot was employed to determine the expression levels of VEGFA, SIRT1, angiopoietin-2(Ang-2), and platelet-derived growth factor B(PDGFB). In the cell study, mouse brain-derived endothelial cells(Bend.3) were cultured, and the optimal concentration of TMP was determined. Then, VEGF, Ang, and PDGF were detected by ELISA after the addition of cabozantinib. Western blot was employed to measure the expression of VEGFA, Ang-2, and PDGFB. Immunofluorescence staining was used to detect CD31, CD34, and Ki67, and the proliferation, migration, and tube formation ability of Bend.3 cells were observed in vitro. Western blot and immunofluorescence staining were performed to measure the expression of SIRT1 and VEGFA after addition of the SIRT1-specific inhibitor selisistat(EX-527). The results showed that compared with the sham group, the MCAO/R group had severe neurological function damage, increased infarction volume, up-regulated expression of VEGF, VEGFA, Ang, Ang-2, PDGF, and PDGFB, and down-regulated expression of Ki67 and SIRT1(P&lt;0.01). Compared with the MCAO/R group, the MCAO/R+TMP group presented alleviated neurological function damage, reduced infarction volume, and activated expression of VEGF, VEGFA, Ang, Ang-2, PDGF, PDGFB, Ki67, and SIRT1(P&lt;0.01). The cell experiments showed that compared with the normal group, Bend.3 cells were activated by oxygen glucose deprivation/reoxygenation(OGD/R) treatment(P&lt;0.05, P&lt;0.01). Compared with the OGD/R group, the OGD/R+TMP group upregulated the expression levels of VEGF, VEGFA, Ang, Ang-2, PDGF, PDGFB, SIRT1, Ki67, CD31, and CD34, enhanced the angiogenic ability of Bend.3 cells without being inhibited by BMS or EX-527(P&lt;0.05, P&lt;0.01, P&lt;0.001). The results suggest that TMP can activate the SIRT1/VEGFA signaling pathway to stimulate angiogenesis and alleviate CIS injury.

Chronic spontaneous urticaria: Evidence of systemic microcirculatory changes.

Chronic spontaneous urticaria (CSU) is a chronic inflammatory skin disease where activation of endothelial cells (ECs) at sites of skin lesions leads to increased blood flow, leakage of fluid into the skin, cellular infiltration, and vascular remodeling. To understand the disease duration and the sometimes vague systemic symptoms accompanying flares, the objective of this study was to examine if CSU comes with systemic vascular changes at the microcirculatory level. We investigated CSU patients (n=49) and healthy controls (HCs, n=44) for microcirculatory differences by nailfold videocapillaroscopy (NVC) and for blood levels of the soluble EC biomarkers serum vascular endothelial growth factor (VEGF), soluble E-selectin, and stem cell factor (SCF). Patients were also assessed for clinical characteristics, disease activity, and markers of autoimmune CSU (aiCSU). CSU patients had significantly lower capillary density, more capillary malformations, and more irregular capillary dilations than HCs on NVC. Serum levels of VEGF, soluble E selectin and SCF were similar in CSU patients and HCs. CSU patients with higher VEGF levels had significantly more abnormal capillaries. Patients with markers of aiCSU, that is, low IgE levels or increased anti-TPO levels, had significantly more capillaries and less capillary dilations than those without. Our results suggest that CSU comes with systemic microcirculatory changes, which may be driven, in part, by VEGF.

Underlying anti-cancer mechanisms of histone deacetylase (HDAC) inhibitors in tamoxifen-resistant breast cancer cells.

Breast cancer is an important women's malignancy with high cancer-related deaths worldwide. Drug resistance lowers the treatment efficacy in this malignancy. This study aimed to explore the underlying mechanisms of histone deacetylase (HDAC) inhibitor trichostatin A (TSA) to overcome resistance to tamoxifen in breast cancer cells. Tamoxifen-resistance in MCF-7 breast cancer cells was simulated. MTT assay was used to detect the cytotoxic effects of HDAC inhibitor and PI3K inhibitor on the cancer cells. Trans-well assay was applied to evaluate the invasion and migration of the treated cancer cells. Flow cytometer assay was also applied to evaluate cell cycle phases in the treated cancer cells. Finally, expression of vascular endothelial growth factor (VEGF), E-cadherin, Vimentin, phosphorylated phosphatidylinositol kinase (p-PI3k), phosphorylated protein kinase B (p-AKT), and phosphorylated mammalian target protein of rapamycin (p-mTOR) was evaluated by western blotting. The obtained results indicated that HDAC inhibitor treatments significantly decreased viability, migration, and invasion in the cancer cells. Furthermore, the frequency of the treated cancer cells significantly increased in the S phase as well as significantly decreasing in the G2/M phase of the cell cycle. Moreover, HDAC inhibitor modified levels of VEGF, E-cadherin, Vimentin, p-PI3k, p-AKT, and p-mTOR proteins. However, HDAC inhibitor combined with PI3K inhibitor exerts more profound effects on the cancer cells as compared to HDAC inhibitor monotherapy. HDAC inhibitors inhibited the survival of breast cancer drug-resistant cells, invasion, migration, and angiogenesis by inhibiting the PI3k/Akt/mTOR signaling pathway.

Эндотелиальная дисфункция сосудов как возможный предиктор тяжелого течения COVID-19

Objective. To study the role of the main marker of endothelial dysfunction VEGF-A as a possible predictor of severe COVID-19 formation. Patients and methods. On the basis of the clinic of the Republican Specialized Scientific and Practical Medical Center of Epidemiology, Microbiology, Infectious and Parasitic Diseases (RSSPMCEMIPD) and Samarkand Regional Specialized Medical Center, 210 patients with coronavirus infection were examined during 2020–2022. Patients were divided into 2 groups comparable by main characteristics: I consisted of 98 (47%) patients with a moderate form of COVID-19, II – 112 (53%) with a severe form of the disease. All patients were fully examined at admission to the hospital and at discharge from it. The level of medium molecular peptides (MMP) in blood plasma was determined by the method of N.I.Gabrielyan on spectrophotometer SF-46 in ultraviolet spectrum; the levels of vascular endothelial growth factor (VEGF-A) – in 163 patients – and interleukins 1 and 6 (IL-1, IL-6) in blood serum – by enzyme immunoassay (test systems of Cytokin LLC and Vector-Best JSC). The level of C-reactive protein (CRP) was determined using the immunoenzyme analyzer "MINDRAY MR-96A"; procalcitonin and D-dimer values were determined using an automatic ELISA analyzer mini-VIDAS. The obtained results were processed by methods of descriptive and variation statistics. Differences were considered reliable at (p &lt; 0.05). Results. The clinical picture of COVID-19 complicated by pneumonia was characterized by pronounced symptoms of intoxication, respiratory tract damage, respiratory failure. In group II patients, such comorbidities as ischemic heart disease (23.5 vs. 41.1%), arterial hypertension (9.2 vs. 25.4%), and diabetes mellitus (2.0 vs. 12.5%) were recorded significantly more often. In 119 (56.7%) cases (mostly in the group with severe coronavirus infection), there was a combination of several comorbidities. In 36 (17.1%) patients with elevated blood sugar level before hospitalization for COVID-19 neither clinical nor laboratory signs of diabetes ellitus were present; in group II stable elevated blood sugar level against the background of therapy of the main disease was recorded 2 times more often (23.2 vs. 10.2%, respectively). In the same group, the level of CPR was 1.5 times higher. A significant correlation (p &lt; 0.05) of elevated levels of CRP and D-dimer with the severity of COVID-19 course was established. In 163 patients the mean values of VEGF-A on admission were elevated; in patients from group II this index was significantly (p &lt; 0.01) higher: 303.02 ± 21.47 vs. 390.52 ± 29.05 pg/mL. At discharge, this index increased to 466.56 ± 37.59 pg/mL in group II patients and decreased to 237.60 ± 17.03 pg/mL in group I patients (differences were significant; p &lt; 0.01). In group I, this index returned to normal after 1 month, and in group II, it decreased to 205.05 ± 15.90 pg/mL only 2 months after discharge. A reliable correlation (p &lt; 0.05) of elevated levels of D-dimer, CRP, MMP with high VEGF-A levels, as well as with the severity of the disease and increasing respiratory failure was established. Positive results of bacteriologic study of upper respiratory tract secretions were found in 63 (64.3%) patients of group I and in 78 (69.6%) patients of group II; Staphylococcus aureus predominated in patients from group II (11.1 vs. 38.5%) and Candida spp (85.7 vs. 28.2%) from group I. Conclusion. The relationship between blood levels of VEGF-A and standard inflammatory markers allows us to propose this factor of endothelial dysfunction as a predictor of inflammation and disease progression, as well as to use it to assess the efficacy of therapy. Key words: bacterial pneumonia, novel coronavirus infection, procalcitonin, C-reactive protein, vascular endothelial growth factor, endothelial dysfunction

The role of PEDF, VEGF, and Ki-67 in tissue invasion and tumor angiogenesis of medullary thyroid carcinoma

Objective: This study investigated the role of pigment epithelium-derived factor (PEDF), vascular endothelial growth factor (VEGF), nuclear factor kappa B (NF-kB), and Ki-67 proliferation index (PI) factors in Medullary thyroid carcinoma (MTC) tissue progression and their relationship with tumor angiogenesis. Immunohistochemical (IHC) analyses of PEDF expression in various human tumor samples and healthy tissues have shown that high levels of PEDF expression are associated with a positive prognosis, and low levels of PEDF suggest a poorer prognosis. With the completion of further studies showing the antitumor effects of PEDF on different types of cancer, PEDF’s potential as a therapeutic agent has become increasingly promising. To the best of our knowledge, the role of PEDF in tumor angiogenesis in MTC has not been previously investigated. Material and Methods: Thirty-seven tissue samples were retrospectively analyzed and sent/removed for pathology after total or subtotal thyroidectomy and archived between 01.01.2000 and 31.12.2015 in the Pathology Department of Hacettepe University. Relationships between categorical variables are analyzed using Pearson Chi-squared or Fisher’s Exact tests.The correlation between two numerical variables is analyzed using Spearman’s Rho correlation coefficient, and a comparison of numerical variables between two groups is made using the Mann-Whitney U test. Results: The clinicopathological features of the patients were evaluated as sporadic or hereditary, tumor node metastasis (TNM) staging, single or multifocal focus, recurrence or regional or distant metastasis, progression-free survival time (PFS), and appropriate pathology tissue samples were determined as PEDF, VEGF, NF-kB, Ki-67 staining was compared. As a result of this comparison, a moderate negative correlation was found between VEGF expression level and PFS (rho = - 0,407, p = 0,019). No statistically significant correlation was found between single or multifocal groups and Ki-67 proliferation index (PI) expression levels (p = 0.070), but this is a small p value, a variable that is likely to find significant differences in studies with larger sample groups.The relationship between PEDF, VEGF, NF- kB, Ki-67 PI factors and tumor angiogenesis as reflected by microvessel density (MVD) was also investigated. To this end, we correlated the expression levels of PEDF, VEGF, NF-kB, and Ki-67 staining of suitable pathology tissue samples of the patients with the results obtained from the staining with CD 31. As a result of this comparison, no statistically significant relationship was found. Conclusions: We demonstrated and described for the first time PEDF expression patterns in MTC tumor tissues. A direct relationship between PEDF expression level and angiogenesis, angiogenetic and clinicopathological factors does not seem to exist, at least as it pertains to the group studied. Further studies are required to fully elucidate mechanisms for tumor angiogenesis and invasion in MTC.

Anti-inflammatory, antioxidant, antiangiogenic, and therapeutic efficacy of neroli oil in rats with endometriotic lesions.

Endometriosis is a serious health problem among women of reproductive age, with pelvic pain and infertility. Given the limited success of current treatments, this study explores Neroli oil (N.O.) effects on inflammation, oxidation, angiogenesis, and tissue remodeling implicated in endometriosis. Albino Wistar female rats were used to simulate an endometriosis model. Groups were established for comparison: a control, an endometriosis model, a N.O.-treated group, and a N.O.-treated group postendometriosis induction. The study focused on Tumor necrosis factor-alpha (TNF-α), Interleukin 6, Interleukin 8, vascular endothelial growth factor (VEGF), myeloperoxidase, Matrix metalloproteinase-1 (MMP-1), nitric oxide, superoxide dismutase, catalase, and anti-mullerian hormone values, as well as histopathological evaluations of endometriotic foci. AMH values showed a significant increase in the endometriosis group treated with N.O. compared with the endometriosis group (p < 0,01).A statistically significant decrease was found in MMP-1 level in the endometriosis group that underwent N.O. (p < 0.001). Increased CAT (p < 0.0001) and decrease in nitric oxide (p < 0.01) are found in N.O.-treated endometriosis group. TNF-α levels in the endometriosis group showed a statistically significant increase in the endometriosis group when compared with the control and sham group (p < 0.001, p < 0.01 respectively). In our study, a statistically significant increase was observed in VEGF levels (p < 0.001) in endometriosis group and significant decrease in the N.O. administered endometriosis model group. Groups treated with N.O. showed decreased inflammation and congestion scores. Histopathological assessments demonstrated reduced inflammation and tissue remodeling signs in endometriotic foci. This study highlights the potential of N.O. in the treatment of endometriosis, owing to its anti-inflammatory, antioxidant, and antiangiogenic properties that can disrupt chronic processes. Our findings lend support to utilization of herbal remedies for the management of endometriosis, thereby emphasizing the necessity for additional comprehensive investigations in the future.

Accumulation of Inflammatory Mediators in the Normal Pericardial Fluid.

There is paucity of studies that focus on the composition of pericardial fluid under resting conditions. The purpose of this study is to determine the levels of inflammatory mediators in pericardial fluid and their correlation with plasma levels in patients undergoing elective cardiac surgery. We conducted a prospective cohort study on candidates for elective aortic valve replacement surgery. Pericardial fluid and peripheral venous blood samples were collected after opening the pericardium. Levels of interleukin 1α (IL-1α); interleukin 1β (IL-1β); interleukin 2 (IL-2) interleukin 4 (IL-4); interleukin 6 (IL-6); interleukin 8 (IL8); interleukin 10 (IL10); tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1) epidermal growth factor (EGF), soluble E-selectin, L-selectin, P-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) were determined in both pericardial fluid and serum samples. A total of 45 patients with a mean age of 74 years were included of which 66% were males. Serum levels of all study mediators were within normal limits. Serum and pericardial levels of IL-1 α, IL-1 β, IL-2, IL-4, and IL-10 were similar. Levels of VEGF, EGF, VCAM-2, ICAM 1, E-selectin, P-selectin, and L-selectin were significantly lower in pericardial fluid than in serum. However, levels of IL-6, IL-8, TNF-α, IFN-γ, MCP-1, and MCP-1 were significantly higher in the pericardial fluid than in serum. Under normal conditions, the pattern of distribution of different inflammatory mediators in the pericardial fluid does not reflect serum levels. This may either reflect the condition of the underlying myocardium and epicardial fat or the activity of the mesothelial and mononuclear cells present in pericardial fluid.