Vascular Growth Factor Research Articles

Encephalopathies Associated With Severe COVID-19 Present Neurovascular Unit Alterations Without Evidence for Strong Neuroinflammation.

ObjectiveCoronavirus disease (COVID-19) has been associated with a large variety of neurologic disorders. However, the mechanisms underlying these neurologic complications remain elusive. In this study, we aimed at determining whether neurologic symptoms were caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) direct infection or by either systemic or local proinflammatory mediators.MethodsIn this cross-sectional study, we checked for SARS-CoV-2 RNA by quantitative reverse transcription PCR, SARS-CoV-2–specific antibodies, and 49 cytokines/chemokines/growth factors (by Luminex) in the CSF +/− sera of a cohort of 22 COVID-19 patients with neurologic presentation and 55 neurologic control patients (inflammatory neurologic disorder [IND], noninflammatory neurologic disorder, and MS).ResultsWe detected anti–SARS-CoV-2 immunoglobulin G in patients with severe COVID-19 with signs of intrathecal synthesis for some of them. Of the 4 categories of tested patients, the CSF of IND exhibited the highest level of cytokines, chemokines, and growth factors. By contrast, patients with COVID-19 did not present overall upregulation of inflammatory mediators in the CSF. However, patients with severe COVID-19 (intensive care unit patients) exhibited higher concentrations of CCL2, CXCL8, and vascular endothelium growth factor A (VEGF-A) in the CSF than patients with a milder form of COVID-19. In addition, we could show that intrathecal CXCL8 synthesis was linked to an elevated albumin ratio and correlated with the increase of peripheral inflammation (serum hepatocyte growth factor [HGF] and CXCL10).ConclusionsOur results do not indicate active replication of SARS-CoV-2 in the CSF or signs of massive inflammation in the CSF compartment but highlight a specific impairment of the neurovascular unit linked to intrathecal production of CXCL8.

Development of a recombinant anti-VEGFR2-EPCAM bispecific antibody to improve antiangiogenic efficiency

Tumor progression and metastasis, especially in invasive cancers (such as triple-negative breast cancer [TNBC]), depend on angiogenesis, in which vascular epithelial growth factor (VEGF)/vascular epithelial growth factor receptor [1] has a decisive role, followed by the metastatic spread of cancer cells. Although some studies have shown that anti-VEGFR2/VEGF monoclonal antibodies demonstrated favorable results in the clinic, this approach is not efficient, and further investigations are needed to improve the quality of cancer treatment. Besides, the increased expression of epithelial cell adhesion molecule (EpCAM) in various cancers, for instance, invasive breast cancer, contributes to angiogenesis, facilitating the migration of tumor cells to other parts of the body. Thus, the main goal of our study was to target either VEGFR2 or EpCAM as pivotal players in the progression of angiogenesis in breast cancer. Regarding cancer therapy, the production of bispecific antibodies is easier and more cost-effective compared to monoclonal antibodies, targeting more than one antigen or receptor; for this reason, we produced a recombinant antibody to target cells expressing EpCAM and VEGFR2 via a bispecific antibody to decrease the proliferation and metastasis of tumor cells. Following the cloning and expression of our desired anti-VEGFR2/EPCAM sequence in E. coli, the accuracy of the expression was confirmed by Western blot analysis, and its binding activities to VEGFR2 and EPCAM on MDA-MB-231 and MCF-7 cell lines were respectively indicated by flow cytometry. Then, its anti-proliferative potential was indicated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and apoptosis assay to evaluate inhibitory effects of the antibody on tumor cells. Subsequently, the data indicated that migration, invasion, and angiogenesis were inhibited in breast cancer cell lines via the bispecific antibody. Furthermore, cytokine analysis indicated that the bispecific antibody could moderate interleukin 8 (IL-8) and IL-6 as key mediators in angiogenesis progression in breast cancer. Thus, our bispecific antibody could be considered as a promising candidate tool to decrease angiogenesis in TNBC.

Glycosaminoglycans: From Vascular Physiology to Tissue Engineering Applications.

Cardiovascular diseases represent the number one cause of death globally, with atherosclerosis a major contributor. Despite the clinical need for functional arterial substitutes, success has been limited to arterial replacements of large-caliber vessels (diameter > 6 mm), leaving the bulk of demand unmet. In this respect, one of the most challenging goals in tissue engineering is to design a “bioactive” resorbable scaffold, analogous to the natural extracellular matrix (ECM), able to guide the process of vascular tissue regeneration. Besides adequate mechanical properties to sustain the hemodynamic flow forces, scaffold’s properties should include biocompatibility, controlled biodegradability with non-toxic products, low inflammatory/thrombotic potential, porosity, and a specific combination of molecular signals allowing vascular cells to attach, proliferate and synthesize their own ECM. Different fabrication methods, such as phase separation, self-assembly and electrospinning are currently used to obtain nanofibrous scaffolds with a well-organized architecture and mechanical properties suitable for vascular tissue regeneration. However, several studies have shown that naked scaffolds, although fabricated with biocompatible polymers, represent a poor substrate to be populated by vascular cells. In this respect, surface functionalization with bioactive natural molecules, such as collagen, elastin, fibrinogen, silk fibroin, alginate, chitosan, dextran, glycosaminoglycans (GAGs), and growth factors has proven to be effective. GAGs are complex anionic unbranched heteropolysaccharides that represent major structural and functional ECM components of connective tissues. GAGs are very heterogeneous in terms of type of repeating disaccharide unit, relative molecular mass, charge density, degree and pattern of sulfation, degree of epimerization and physicochemical properties. These molecules participate in a number of vascular events such as the regulation of vascular permeability, lipid metabolism, hemostasis, and thrombosis, but also interact with vascular cells, growth factors, and cytokines to modulate cell adhesion, migration, and proliferation. The primary goal of this review is to perform a critical analysis of the last twenty-years of literature in which GAGs have been used as molecular cues, able to guide the processes leading to correct endothelialization and neo-artery formation, as well as to provide readers with an overall picture of their potential as functional molecules for small-diameter vascular regeneration.

Reduced plasma level of basic fibroblast growth factor is associated with incomplete device endothelialization at six months following left atrial appendage closure

ObjectivesTo investigate whether inflammatory and growth factors (IGFs) were associated with incomplete device endothelialization (IDE) at 6 months after successful left atrial appendage closure (LAAC).BackgroundIDE after LAAC is correlated with device-related thrombus (DRT) formation and subsequent thromboembolic events. However, biomarkers for early detection of IDE remain lacking.MethodsPlasma levels of IGFs including basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF), stromal cell derived factor (SDF)-1a, transforming growth factor (TGF)-β1, vascular growth factor receptor-1 (VEGF-R1) and von Willebrand factor (vWF) were determined using ELISA kits in 55 consecutive patients with atrial fibrillation (AF) at 6 months after LAAC with Watchman devices. The status of device endothelialization was assessed by transesophageal echocardiography and cardiac CT.ResultsIDE and complete device endothelialization(CDE)were detected in 38 and 17 patients, respectively. Among the six IGFs, only plasma level of bFGF was significantly lower in patients with IDE compared to those with CDE (303.49 ± 246.84 vs. 556.31 ± 197.84 pg/ml, p < 0.001). C-statistics of plasma bFGF for discriminating patients with IDE from those with CDE was 0.785 (95 % CI: 0.663–0.907, p < 0.001), with a cut-off value of 440.52pg/ml (sensitivity 0.765; specificity 0.789). Multivariate logistic regression model showed that lower bFGF was an independent factor for IDE (OR: 11.752, 95 % CI: 2.869–48.144, P = 0.001). bFGF improved the classification of patients (NRI: 0.677,95 % CI: 0.320–1.033, p = 0.004).ConclusionsReduced plasma bFGF level confers an increased risk for IDE after LAAC. Further prospective studies are warranted to examine if bFGF could serve as a biomarker for IDE post LAAC.

Vascular growth factors as potential new treatment in cardiorenal syndrome in diabetes.

Cardiorenal syndrome in diabetes is characterised by alterations of the cardiovascular system paralleled by kidney disease with progressive renal function decline. In diabetes, chronic metabolic and haemodynamic perturbations drive endothelial dysfunction, inflammation, oxidative stress and progressive tissue fibrosis which, in turn, lead to heart and renal anatomo-functional damage. In physiology, vascular growth factors have been implicated in vascular homeostasis; their imbalance, in disease setting such as diabetes, leads to vascular dysfunction and cardiorenal damage. To define the role of vascular growth factors and angiopoietins in cardiorenal syndrome. We will focus on the two most studied vascular growth factors, vascular endothelial growth factor (VEGF) and angiopoietins (Angpt). The balance and crosstalk between these growth factors are important in organ development and in the maintenance of a healthy vasculature, heart and kidney. The observed alterations in expression/function of these vascular growth factors, as seen in diabetes, are a protective response against external perturbations. The chronic insults driving diabetes-mediated cardiorenal damage results in a paradoxical situation, whereby the vascular growth factors imbalance becomes a mechanism of disease. Studies have explored the possibility of modulating the expression/action of vascular growth factors to improve disease outcome. Experimental work has been conducted in animals and has been gradually translated in humans. Difficulties have been encountered especially when considering the magnitude, timing and duration of interventions targeting a selective vascular growth factor. Targeting VEGF in cardiovascular disease has been challenging, while modulation of the Angpt system seems more promising. Future studies will establish the translatability of therapies targeting vascular growth factors for heart and kidney disease in patients with diabetes.

Research of changes in the level of vascular endothelial growth factor in experimental diabetic retinopathy. comparison of methods of correction

The aim of work to investigate the changes in the vascular endothelium growth factor in experimental animals, which were simulated diabetic retinopathy and against the background of its correction.&#x0D; The results of the analysis of the vascular growth factor in the 2nd group confirm the development of diabetic retinopathy, a particularly pronounced increase in the marker was detected on the 180th day of the development of the pathological process. It was established analyzing the data of group No. 3 that the correction of the pathological condition with hypoglycemic agents has partial positive effect but requires the involvement of additional means of correction in addition to the normalization of the level of glycemia. The results of the 4th group indicate that the involvement of a nitric oxide donor and aflibercept in the correction of diabetic retinopathy has positive effect on the reduction of the level of vascular growth factor, more pronounced compared to the 3rd group, but it does not reach normative values. It is observed that the correction of the simulated pathological condition by reducing hyperglycemia, administration of aflibercept and bromfenac (group No. 5) gives positive results, but less pronounced, compared to the data of the 4th group.&#x0D; It was found that in rats in which diabetic retinopathy was modeled with subsequent correction of hyperglycemia, administration of aflibercept, L-carnitine and bromfenac (group No. 6) at the first stage, there is a pronounced effectiveness of the proposed method of correction in comparison with the previously considered methods, the established positive trend is being followed also at the 2nd and 3rd stages of the experiment, which indicates the effectiveness of this correction method.&#x0D; The most pronounced positive effect of normalizing the level of vascular growth factor is observed when using a hypoglycemic drug in combination with the administration of aflibercept, a solution of L-arginine and citicoline (in group No. 7).

Inhibition effects of 7-phloro-eckol from Ecklonia cava on metastasis and angiogenesis induced by hypoxia through regulation of AKT/mTOR and ERK signaling pathways

As one of the malignant tumors with high mortality, liver cancer has the characteristics of early invasion and metastasis, and lacks effective treatment methods. Therefore, it is urgent to find new safe, efficient and low-toxic anti-liver cancer drugs. In this study, the evaluated mechanism of Ecklonia cava polyphenols (7PE, 7-phloro-eckol) as a potential active substance for inhibiting liver cancer metastasis (HepG2 cell) and angiogenesis (HUVEC cell). The results have shown that 7PE can inhibit the expression of hypoxia-inducible factors (HIF-1α) protein by regulating the PI3K/AKT/mTOR and Ras/MEK/ERK/MNK signaling pathways under hypoxic conditions in HepG2 cells, thereby blocking the secretion of vascular growth factor (VEGF) protein. At the same time, 7PE can significantly inhibit the conduction of AKT and MAPK signaling pathways in HUVEC by suppressing the activation of VEGFR-2 protein, which verifies the prediction of molecular docking. Therefore, the results of this study provide a research basis for 7PE to inhibit metastasis and angiogenesis of liver cancer cells, and provide a theoretical basis for the high-value utilization of Ecklonia cava.

Tissue distribution of epirubicin after severe extravasation in humans

PurposeAs critical parameter after extravasation of cytotoxic vesicants, anthracyclines were determined in removed tissue from patients requiring surgical intervention due to tissue necrosis. We monitored their distribution within the affected lesion to establish a possible dose–toxicity relation.MethodsFrom six patients scheduled for surgery, removed tissue flaps were systematically analysed by HPLC (epirubicin: 5 subjects; doxorubicin: 1 subject).ResultsAfter extravasation, tissue concentrations were highly variable with an individual anthracycline distribution pattern ranging from a few nanograms up to 17 µg per 100 mg tissue, which indicated a substantial difference in tissue sensitivity among patients. The resection borders coincided with the extension of the erythema and guided the surgical intervention after demarcation of the lesion, which occurred usually 2 or 3 weeks after extravasation. At that time, drug was hardly detected at the resection borders. Wound drains were negative for the extravasated drugs while showing a time profile of vascular growth factors and inflammatory cytokines, which was highly similar to routine surgery. In all six patients, surgical debridement with immediate wound closure led to healing within approximately 2 weeks, when therapy was resumed in all patients with reasonable time delay.ConclusionSurgical intervention after demarcation of the extravasation lesion allows for almost uninterrupted continuation of treatment independent of the amount of extravasated anthracycline. As even minor amounts of the vesicants may trigger tissue necrosis, preventive measures merit the highest priority.

DCE-MRI in Glioma, Infiltration Zone and Healthy Brain to Assess Angiogenesis: A\xa0Biopsy Study

PurposeTo explore the focal predictability of vascular growth factor expression and neovascularization using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in glioma.Methods120 brain biopsies were taken in vital tumor, infiltration zone and normal brain tissue of 30 glioma patients: 17 IDH(isocitrate dehydrogenase)-wildtype glioblastoma (GBM), 1 IDH-wildtype astrocytoma °III (together prognostic group 1), 3 IDH-mutated GBM (group 2), 3 anaplastic astrocytomas IDH-mutated (group 3), 4 anaplastic oligodendrogliomas and 2 low-grade oligodendrogliomas (together prognostic group 4). A mixed linear model evaluated the predictabilities of microvessel density (MVD), vascular area ratio (VAR), mean vessel size (MVS), vascular endothelial growth factor and receptors (VEGF-A, VEGFR‑2) and vascular endothelial-protein tyrosine phosphatase (VE-PTP) expression from Tofts model kinetic and model-free curve parameters.ResultsAll kinetic parameters were associated with VEGF‑A (all p < 0.001) expression. Ktrans, kep and ve were associated with VAR (p = 0.006, 0.004 and 0.01, respectively) and MVS (p = 0.0001, 0.02 and 0.003, respectively) but not MVD (p = 0.84, 0.74 and 0.73, respectively). Prognostic groups differed in Ktrans (p = 0.007) and ve (p = 0.004) values measured in the infiltration zone. Despite significant differences of VAR, MVS, VEGF‑A, VEGFR‑2, and VE-PTP in vital tumor tissue and the infiltration zone (p = 0.0001 for all), there was no significant difference between kinetic parameters measured in these zones.ConclusionThe DCE-MRI kinetic parameters show correlations with microvascular parameters in vital tissue and also reveal blood-brain barrier abnormalities in the infiltration zones adequate to differentiate glioma prognostic groups.

Isatin-Hydrazones with Multiple Receptor Tyrosine Kinases (RTKs) Inhibitory Activity and In-Silico Binding Mechanism

Recently, we have reported a series of isatin hydrazone, two of them, namely, 3-((2,6-dichlorobenzylidene)hydrazono)indolin-2-one (1) and 3-((2-chloro-6-fluorobenzylidene)hydrazono)indolin-2-one (2) having potent cytotoxicity, showing cyclin-dependent kinases (CDK2) inhibitory activity and bearing recommended drug likeness properties. Since both compounds (1 and 2) showed inhibitory activity against CDK2, we assumed it would also have multiple receptor tyrosine kinases (RTKs) inhibitory activity. Considering those points, here, above-mentioned two isatin hydrazone 1 and 2 were synthesized using previously reported method for further investigation of their potency on RTKs (EGFR, VEGFR-2 and FLT-3) inhibitory activity. As expected, Compound 1 exhibited excellent inhibitory activity against epidermal growth factor receptor (EGFR, IC50 = 0.269 µM), vascular epidermal growth factor receptor 2 (VEGFR-2, IC50 = 0.232 µM) and FMS-like tyrosine kinase-3 (FLT-3, IC50 = 1.535 µM) tyrosine kinases. On the other hand, Compound 2 also exhibited excellent inhibitory activity against EGFR (IC50 = 0.369 µM), VEGFR-2 (IC50 = 0.266 µM) and FLT-3 (IC50 = 0.546 µM) tyrosine kinases. A molecular docking study with EGFR, VEGFR-2 and FLT-3 kinase suggested that both compounds act as type I ATP competitive inhibitors against EGFR and VEGFR-2, and type II ATP non-competitive inhibitors against FLT-3.

Systemic inflammatory response to non-surgical treatment in hypertensive patients with periodontal infection.

Hypertension is associated with chronic inflammation in the tissues and organs that are involved in the regulation of arterial pressure, such as kidneys and blood vessels. Periodontal disease affects systemic inflammatory markers, leading to endothelial dysfunction, atherosclerotic plaque instability, dyslipidaemia, and insulin resistance. These conditions can also cause an increase in the blood pressure. Nonsurgical periodontal therapies, such as scaling and root planning, can affect systemic markers of inflammation. We evaluated the effect of scaling and root planning on serum levels of inflammation biomarkers in hypertensive patients. The sample consisted of 19 hypertensive patients with Periodontitis. The patients underwent laboratory tests that included glycaemia, cholesterol, triglycerides and blood count. Blood pressure was measured before periodontal therapy, and the second blood pressure recording was obtained at the re-evaluation appointment. Quantification of peripheral blood cytokines was performed using the Milliplex Inflammation Human Cytokine kit (Interleukin 1-β, Interleukin-4, Interleukin-6, Interleukin-8, Interleukin-10, Interleukin-12 P70, Interleukin-17A, vascular endothelial growth factor and tumor necrosis factor-alpha). All cytokine levels decreased from the initial examination to reassessment. Cytokines that reflected a statistically significant difference included Interleukin-1β and endothelial vascular growth factor (P = .04 and P = .004). Hypertensive patients with periodontitis undergoing non-surgical periodontal treatment exhibited a decrease in proinflammatory cytokine levels. Non-surgical periodontal treatment decreases the levels of systemic proinflammatory cytokines in controlled hypertensive patients.

The rate of aerobic glycolysis is a pivotal regulator of tumor progression.

Cancer cells depend on glucose metabolism via exclusive glycolysis pathway is named Aerobic glycolysis or Warburg effect. The aim of this study was investigation of different glucose accessibility conditions on the rate of Warburg effect and its impact on Hypoxia inducible factors-1 α (HIF-1 α)/vascular endothelium growth factor (VEGF) pathway in breast cancer cells lines. MDA-MB-231 (Warburg phenomenon) and MCF-7 (oxidative) cell lines were cultured in DMEM and exposed to three different glucose accessibility medium for 48h (5.5mM as normal glucose (NG), 25mM as high glucose (HG) and 2-Deoxyglucose (2-DG) as restricted glucose accessibility). Glucose uptake, intra/extracellular lactate and pyruvate, HIF-1α accumulation and vascular endothelium growth factor (VEGF) expression were evaluated by standard methods. Our results showed in NG condition both of cell lines produce lactate, but it was higher in MDA-MB-231. HG condition increased extracellular lactate in both cell lines especially in MCF-7 cells whereas intracellular lactate and pyruvate raised only in MCF-7. 2-DG decreased extracellular and intracellular lactate and pyruvate in both cell lines especially in MDA-MB-231. HIF-1α accumulation was detectable in NG condition in both cell lines. HG condition increased HIF-1α accumulation in MCF-7 cells but not in MDA-MB-231 and 2-DG decreased it in both call lines, especially in MDA-MB-231. Expression of VEGF had similar pattern with HIF-1α in different conditions. Our findings revealed the rate of Warburg effect is an important indicator for tumor promotion and invasion due to its impacts on important transcription factors like HIF-1α.

VEGF gene polymorphism in periodontitis

INTRODUCTION: Since subjects affected by periodontitis might present an enhanced expression of the vascular endothelium growth factor (VEGF) gene, the aim of this study was to evaluate if polymorphic variants of the VEGF 936C/T gene polymorphism were associated with the periodontitis. MATERIALS AND METHODS: Oral mucosa cells were collected from 43 individuals diagnosed with periodontitis stages III and IV, and from periodontally healthy subjects. Once DNA was extracted from the cells, specific primers were used for PCR testing. The amplified gene products were submitted to electrophoresis in polyacrylamide gel and the bands were evidenced with silver nitrate. Products were subsequently submitted to digestion by the Hin1II restriction enzyme. RESULTS: Although some differences were observed in the percentages of genotypes 936 C/C (stage III periodontitis – 61%; stage IV periodontitis – 8%; periodontally healthy subjects – 31%) and C/T (stage III periodontitis – 40%; stage IV periodontitis – 33%; periodontally healthy subjects – 27%) in the groups assessed, this variation was not statistically significant (p&gt; 0.05; Fisher’s Exact Test). CONCLUSION: The results of this study indicate that VEGF 936C/T gene polymorphism was not associated with the presence or severity of periodontitis. Additional studies involving larger samples, as well as the investigation of different polymorphisms of the same gene or other genes, should be conducted in order to broaden the understanding about the role of polymorphisms in periodontal disease.

The timing of venous thromboembolism in ovarian cancer patients: A nationwide Danish cohort study

Background and aimVenous thromboembolism (VTE) is associated with excess mortality and morbidity in cancer, and is influenced by patient‐, tumor‐, and treatment‐related factors. We aimed to investigate the impact of such factors in a national cohort of patients with epithelial ovarian cancer (EOC). MethodsPatients in the Danish Gynecologic Cancer Database (DGCD) with EOC from 2005 to 2014 were followed from time of diagnosis to VTE, or censoring. Surgery, chemotherapy, and vascular epithelial growth factor (VEGF)‐inhibitors were included as time‐varying exposures in Cox proportional hazard regression models. ResultsA total of 551 VTE events were registered in 4991 EOC patients. Median follow‐up time was 2.9 years. The 2‐year cumulative incidence of VTE was 7.2%. Patients were at highest risk during the first year after EOC diagnosis. Previous VTE was associated with a hazard ratio (HR) of 3.26 (95% confidence interval [CI] 2.42–4.39). Exposure to major pelvic surgery was associated with a HR of 3.21 (95% CI 2.29–4.50). Exposure to chemotherapy or (VEGF)‐inhibitors were associated with HRs of 1.91 (95% CI 1.56–2.33) and 1.05 (95% CI 0.57–1.93), respectively. Hazard ratios for patients with clear cell histopathology was 1.46 (95% CI 0.97–2.20) and 2.42 for International Federation of Gynaecology and Obstetrics stage III‐‐IV (95% CI 1.93–3.03). ConclusionsEOC is associated with a high risk of VTE, particularly within the first year after diagnosis. Major pelvic surgery and chemotherapy were strongly associated with VTE. Person‐related risk factors were increasing age and previous VTE. Advanced stage was an independent tumor‐related risk factor. These findings support the indication for thrombosis prophylaxis during chemotherapy.

Sevoflurane inhibits cell proliferation and migration of glioma by targeting the miR‑27b/VEGF axis.

Poor prognosis in patients with glioma is primarily due to rapid tumor growth and cell invasion and migration. In addition, microRNA (miR)-27b is decreased in metastatic glioma. The present study investigated whether sevoflurane inhibited glioma cell progression by targeting miR-27b. Cell proliferation was analyzed using a Cell Counting Kit-8 assay and a wound healing assay was used to detect cell migration. Western blotting and reverse transcription-quantitative PCR analysis were performed to determine the protein and mRNA expression levels. A dual luciferase assay was used to determine the relationship between vascular epithelial growth factor (VEGF) and miR-27b. VEGF was identified to be a direct target of miR-27b. Moreover, sevoflurane treatment increased the expression of miR-27b and decreased the expression of VEGF in U251 and U87 cells. Compared with the control group, sevoflurane inhibited the proliferation and migration of U251 and U87 cells, as well as the expression of matrix metalloproteinase (MMP)-2 and MMP-9, which were subsequently abolished by pre-treatment with an miR-27b inhibitor. The present results indicated the potential use of sevoflurane by anesthesiologists for the surgical resection of glioma, which may improve patient outcomes in the clinical setting.

Racial differences in the limb skeletal muscle transcriptional programs of patients with critical limb ischemia.

Critical limb ischemia (CLI) is the most severe manifestation of peripheral artery disease (PAD) and is characterized by high rates of morbidity and mortality. As with most severe cardiovascular disease manifestations, Black individuals disproportionately present with CLI. Accordingly, there remains a clear need to better understand the reasons for this discrepancy and to facilitate personalized therapeutic options specific for this population. Gastrocnemius muscle was obtained from White and Black healthy adult volunteers and patients with CLI for whole transcriptome shotgun sequencing (WTSS) and enrichment analysis was performed to identify alterations in specific Reactome pathways. When compared to their race-matched healthy controls, both White and Black patients with CLI demonstrated similar reductions in nuclear and mitochondrial encoded genes and mitochondrial oxygen consumption across multiple substrates, indicating a common bioenergetic paradigm associated with amputation outcomes regardless of race. Direct comparisons between tissues of White and Black patients with CLI revealed hemostasis, extracellular matrix organization, platelet regulation, and vascular wall interactions to be uniquely altered in limb muscles of Black individuals. Among traditional vascular growth factor signaling targets, WTSS revealed only Tie1 to be significantly altered from White levels in Black limb muscle tissues. Quantitative reverse transcription polymerase chain reaction validation of select identified targets verified WTSS directional changes and supports reductions in MMP9 and increases in NUDT4P1 and GRIK2 as unique to limb muscles of Black patients with CLI. This represents a critical first step in better understanding the transcriptional program similarities and differences between Black and White patients in the setting of amputations related to CLI and provides a promising start for therapeutic development in this population.

Psoriatic mesenchymal stem cells stimulate the angiogenesis of human umbilical vein endothelial cells in vitro

ObjectiveTo investigate the regulation of psoriatic dermal mesenchymal stem cells (p-DMSCs) in the expression of vascular growth factor (VEGF), and migration and angiogenesis of human umbilical vein endothelial cells (HUVECs) in vitro. MethodsA co-culture model of HUVECs and dermal mesenchymal stem cells (DMSCs)was used in this study. After 7-day co-culture, changes in expression levels of VEGF mRNA and protein in HUVECs were assessed using RT-PCR and Western Blotting, respectively. Migration and tubular formation of HUVECs were also assessed following co-culture of DMSCs and HUVECs. ResultsIn comparison to either HUVECs alone or co-culture of n-DMSCs and HUVECs, co-culture of HUVECs and p-DMSCs significantly increased expression levels of both VEGF mRNA (p < 0.01 vs. HUVECs alone) and protein in HUVECs (p < 0.001 vs. both HUVECs alone and HUVECs co-cultured with n-DMSCs). Moreover, p-DMSCs stimulated HUVEC migration and vascular formation (p < 0.05 vs. both HUVECs alone and co-culture of n-DMSCs and HUVECs). ConclusionPsoriatic DMSCs can upregulate VEGF expression, and stimulate migration and angiogenesis of HUVECs, suggesting a pathogenic role of p-DMSCs in psoriasis.

Nanomaterials for Antiangiogenic Therapies for Cancer: A Promising Tool for Personalized Medicine.

Angiogenesis is one of the hallmarks of cancer. Several studies have shown that vascular endothelium growth factor (VEGF) plays a leading role in angiogenesis progression. Antiangiogenic medication has gained substantial recognition and is commonly administered in many forms of human cancer, leading to a rising interest in cancer therapy. However, this treatment method can lead to a deteriorating outcome of resistance, invasion, distant metastasis, and overall survival relative to its cytotoxicity. Furthermore, there are significant obstacles in tracking the efficacy of antiangiogenic treatments by incorporating positive biomarkers into clinical settings. These shortcomings underline the essential need to identify additional angiogenic inhibitors that target numerous angiogenic factors or to develop a new method for drug delivery of current inhibitors. The great benefits of nanoparticles are their potential, based on their specific properties, to be effective mechanisms that concentrate on the biological system and control various important functions. Among various therapeutic approaches, nanotechnology has emerged as a new strategy for treating different cancer types. This article attempts to demonstrate the huge potential for targeted nanoparticles and their molecular imaging applications. Notably, several nanoparticles have been developed and engineered to demonstrate antiangiogenic features. This nanomedicine could effectively treat a number of cancers using antiangiogenic therapies as an alternative approach. We also discuss the latest antiangiogenic and nanotherapeutic strategies and highlight tumor vessels and their microenvironments.

Dexamethasone-induced intrauterine growth restriction modulates expression of placental vascular growth factors and fetal and placental growth.

Prenatal exposure to glucocorticoids (GC) is a central topic of interest in medicine since GCs are essential for the maturation of fetal organs and intrauterine growth. Synthetic glucocorticoids, which are used in obstetric practice, exert beneficial effects on the fetus, but have also been reported to lead to intrauterine growth retardation (IUGR). In this study, a model of growth restriction in mice was established through maternal administration of dexamethasone during late gestation. We hypothesised that GC overexposure may adversely affect placental angiogenesis and fetal and placental growth. Female BALB/c mice were randomly assigned to control or dexamethasone treatment, either left to give birth or euthanised on days 15, 16, 17 and 18 of gestation followed by collection of maternal and fetal tissue. The IUGR rate increased to 100% in the dexamethasone group (8 mg/kg body weight on gestational days 14 and 15) and pups had clinical features of symmetrical IUGR at birth. Dexamethasone administration significantly decreased maternal body weight gain and serum corticosterone levels. Moreover, prenatal dexamethasone treatment not only induced fetal growth retardation but also decreased placental weight. In IUGR placentas, VEGFA protein levels and mRNA expression of VEGF receptors were reduced and NOS activity was lower. Maternal dexamethasone administration also reduced placental expression of the GC receptor, αGR. We demonstrated that maternal dexamethasone administration causes fetal and placental growth restriction. Furthermore, we propose that the growth retardation induced by prenatal GC overexposure may be caused, at least partially, by an altered placental angiogenic profile.

Anlotinib as a promising inhibitor on tumor growth of oral squamous cell carcinoma through cell apoptosis and mitotic catastrophe

BackgroundOral squamous cell carcinoma (OSCC) has been one of the most malignant cancers in head and neck region. Anlotinib is a tyrosine kinase inhibitor targeting several receptors such as vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and c-Kit. Here we investigated whether Anlotinib have any antitumor effect on oral cancer and tried to explore and explain the possible mechanism.MethodsData from The Cancer Genome Atlas and the Gene Expression Omnibus and Gene Expression Omnibus database was collected to analyze the relationship between the expression of vascular epithelial growth factor receptor 2 and the overall survival rate of OSCC. Oral cancer cell lines Cal-27 and SCC-25 were cultured to conduct all the experiments. In vitro experiments such as CCK-8, colony formation, cell cycle assay and cell apoptosis assay were conducted to detect cell proliferation ability and the change of cell phase and apoptosis. Proteins concerning cell cycle and cell apoptosis were visualized via western blot. α-Tubulin were visualized via immunofluorescence to detect cells undergoing mitotic catastrophe.ResultsHigher expression of VEGFR-2 was significantly related to poorer prognosis. Experiment in vitro demonstrated that cell proliferation was significantly inhibited(p < 0.05) after Anlotinib administration and G2/M arrest and apoptosis were both detected in both cell lines. Cycle-related proteins promoting cell cycle progression and proteins related to cell survival were downregulated in Anlotinib group compared to the control group. Cell-death-related biomarker and phosphorylated histone 3 were upregulated in expression in Anlotinib group. Abnormal spindle apparatus was observed in cells undergoing mitotic catastrophe.ConclusionsAnlotinib could exert an antitumor effect on oral cancer cell lines via apoptotic pathway and mitotic catastrophe pattern, presenting a promising potential therapy for patients with OSCC.