Process Of Angiogenesis Research Articles

Participation of Selected Soluble BMP-2 and BMP-7 Bone Morphogenetic Proteins and Their Soluble Type I ALK-1 and Type II BMPR2 Receptors in Formation and Development of Endometriosis.

Angiogenesis is considered to be one of the key stages in the development of endometriosis. Recent studies indicate that bone morphogenetic proteins (BMPs) and their receptors (BMPR) may play an important role in the angiogenesis process. In the literature, however, there is a lack of publications concerning binding BMPs and their receptors with the pathogenesis of endometriosis. The aim of the study was to determine the role of soluble bone morphogenetic proteins, BMP-2 and BMP-7, and their receptors, ALK-1 and BMPR2, in the process of the formation and development of endometriosis. Peritoneal fluid was collected in the proliferative phase of the menstrual cycle, from 80 women aged 21–49 years (mean age 31.3 ± 6.7 years) undergoing laparoscopy to determine the causes of primary infertility. The study involved 60 women in the I, II, III, and IV stages of the disease. The reference group consisted of 20 women who did not have endometriosis or other lesions in the pelvic area. The concentration in the peritoneal fluid of women with endometriosis was compared to the concentration of this parameter in the reference group, and a statistically significant reduction in the concentration of the BMP-2 molecule was found, as well as increasing concentrations of BMP-7, ALK-1, and BMPR2. BMP-2 and BMP-7 and their soluble receptors, ALK-1 and BMPR2, are involved in the formation of endometriosis. The changes in the concentrations of most of the tested parameters demonstrated in the study, especially in the early stages of the disease, may indicate the more effective formation of new blood vessels in this period.

Next-generation immunotherapy: regulatory T-cells

Regulatory T lymphocytes (Treg) control the activity of immune cells and suppress the development of inflammation, maintaining the immune balance necessary for the body. Dysfunctions of Tregs are associated with the pathogenesis of autoimmune and oncological diseases. With systemic and organ-specific autoimmune reactions, as well as organ transplantation, a decrease in the function of Tregs is observed. While in the course of oncogenesis, the activity of Tregs prevents the development of an adequate immune response to tumor antigens, promotes the processes of angiogenesis and uncontrolled growth of transformed cells. Taking into account the important function of Tregs in the control of autoimmunity and oncogenesis, approaches to immunotherapy of inflammatory pathologies based on autologous and donor Tregs, as well as methods of activating an antitumor immune response as a result of selective blockade of the functional activity of Tregs, are being actively developed. The review provides an overview of technologies for modulating the activity of Tregs for the treatment of cancer, autoimmunity and adverse reactions after transplantation.

Nanodrugs as a New Approach in the Therapy of Cardiovascular Diseases and Cancer with Tumor-associated Angiogenesis.

Cancer, along with cardiovascular diseases, is globally defined as the leading cause of death. Importantly, some risk factors are common to these diseases. The process of angiogenesis and platelet aggregation is observed in cancer development and progression. In recent years, studies have been conducted on nanodrugs for these diseases that have provided important information on the biological and physicochemical properties of nanoparticles. Their attractive features are that they are made of biocompatible, well-characterized, and easily functionalized materials. Unlike conventional drug delivery, sustained and controlled drug release can be obtained by using nanomaterials. In this article, we review the latest research to provide comprehensive information on nanoparticle-based drugs for the treatment of cancer, cardiovascular disease associated with abnormal haemostasis, and the inhibition of tumor-associated angiogenesis. The results of the analysis of data based on drugs with nanoparticles confirm their improved pharmaceutical and biological properties, which give promising antiplatelet, anticoagulant, and antiangiogenic effects. Moreover, the review included in vitro, in vivo research and presented nanodrugs with chemotherapeutics approved by Food and Drug Administration. By the optimization of nanoparticle size and surface properties, nanotechnology is able to deliver drugs with enhanced bioavailability in treatment of cardiovascular disease, cancer and inhibition of cancer-related angiogenesis. Thus, nanotechnology can improve the therapeutic efficacy of the drug, but there is a need for a better understanding of the nanodrugs interaction in the human body because this is a key factor in the success of potential nanotherapeutics.

STUDY OF THE PHARMACOLOGICAL ACTIVITY OF NOVEL EPOR/CD131 HETERORECEPTOR AGONISTS IN MICE WITH ENDOTHELIAL-SPECIFIC EXPRESSION OF MUTANT POLG GENE

The aim of the research was to study antiatherosclerotic and endothelial kinds of a protective activity of peptides mimicking an erythropoietin a-helix B tertiary structure with laboratory codes EP-11-1 (UEHLERALNSS), EP-11-2. (UEQLERALNCS), EP-11-3 (UEQLERALNTS).Materials and methods. The study was conducted on 96 C57Bl/6J male double transgenic Polgmut/mut/Cdh5-CRE mice. Atherosclerosis was induced by a balloon injury accompanied by Western diet. Then, for 27 days, the drugs under study were administered once per 3 days at the dose of 20 μg/kg. On the 28th day, the animals were euthanized and the area of atherosclerotic plaques was collected for an assessment. The expression of genes associated with the processes of inflammation, apoptosis, and angiogenesis was determined in the tissues of the aorta. In addition, the endothelial protective effect of peptides in isolated segments of the thoracic aorta of wild and transgenic ransgenic Polgmut/mut mice was studied.Results. The assessment of the plaque size in the animals with the Polgmut/mut/Cdh5-CRE genotype against the background of the peptides under study did not reveal statistically significant differences in comparison to control. However, a quantitative PCR showed a statistically significant decreased expression of pro-apoptotic factors p-53 and Bax, and also increase the expression of anti-apoptotic factor Bcl-2 against the background of the peptides EP-11-1 and EP-11-2 administration. The administration of EP-11-1 and the original peptide pHBSP resulted in a statistically significant decrease in the Bax/Bcl-2 ratio. Compounds EP-11-1, EP-11-2, and EP-11-3 were more effective than the original peptide pHBSP, in reducing the increased expression of genes for inflammatory markers iNos, intercellular adhesion molecules Icam-1, Vcam-1 and E-selectin. The use of EP-11-1 led to a more efficient, in comparison with pHBSP, restoration of endothelial-dependent vasodilation of the aortic segments in mice with endothelial-specific overexpression of the mutant Polg gene.Conclusion. The study carried out on a murine model of the endothelial-specific expression of mutant gamma polymerase has shown that derivatives of the pHBSP peptide with laboratory codes EP-11-1, EP-11-2, EP-11-3, obtained by BLAST-searching for groups of pHBSP related peptides, have atheroprotective and endothelial protective kinds of a protective activity, which is more pronounced in comparison with the original peptide pHBSP.

Blood Vessels and Peripheral Nerves as Key Players in Cancer Progression and Therapy Resistance.

Simple SummaryThe interactions between cancer cells and the surrounding blood vessels and peripheral nerves are critical in all the phases of tumor development. Accordingly, therapies that specifically target vessels and nerves represent promising anticancer approaches. The first aim of this review is to document the importance of blood vessels and peripheral nerves in both cancer onset and local or distant growth of tumoral cells. We then focus on the state-of-the-art therapies that limit cancer progression through the impairment of blood vessels and peripheral nerves. The mentioned literature is helpful for the scientific community to appreciate the recent advances in these two fundamental components of tumors.Cancer cells continuously interact with the tumor microenvironment (TME), a heterogeneous milieu that surrounds the tumor mass and impinges on its phenotype. Among the components of the TME, blood vessels and peripheral nerves have been extensively studied in recent years for their prominent role in tumor development from tumor initiation. Cancer cells were shown to actively promote their own vascularization and innervation through the processes of angiogenesis and axonogenesis. Indeed, sprouting vessels and axons deliver several factors needed by cancer cells to survive and proliferate, including nutrients, oxygen, and growth signals, to the expanding tumor mass. Nerves and vessels are also fundamental for the process of metastatic spreading, as they provide both the pro-metastatic signals to the tumor and the scaffold through which cancer cells can reach distant organs. Not surprisingly, continuously growing attention is devoted to the development of therapies specifically targeting these structures, with promising initial results. In this review, we summarize the latest evidence that supports the importance of blood vessels and peripheral nerves in cancer pathogenesis, therapy resistance, and innovative treatments.

Abstract P168: Promising Diagnostic Biomarkers For Congenital Vascular Malformations

Background: Congenital vascular malformations (CVMs) are vascular lesions that result from developmental errors during embryogenesis. They can occur anywhere in the body, causing pain, bleeding, ulcers, disfiguration, organ failure or limb loss. Depending on intralesional blood flow dynamics, CVMs can be broadly classified into low-flow (LF), which involve veins, lymphatics, capillaries or a mixture, and high-flow (HF), which involve arteries and veins. Accurate diagnosis and monitoring of LF and HF CVMs remains challenging and requires a wide range of imaging modalities. Aim: We sought to identify potential diagnostic serum biomarkers, particularly those pertaining to the processes of inflammation and angiogenesis. Methods: Sera were isolated from the peripheral bloods of consented healthy controls ( n = 10) and patients diagnosed as having either LF ( n = 10) or HF ( n = 10) CVMs. Various mediators of inflammation and angiogenesis were analysed in the sera using the Inflammation 20-Plex and Angiogenesis 18-Plex Human ProcartaPlex™ Panels. The levels of these mediators in patients with LF or HF CVMs were compared with those in healthy controls using the Kruskall-Wallis test and correlated with lesion volumes and visual analogue scores for pain using the Spearman rank correlation test. Results: Compared to healthy controls, the inflammatory mediators E-selectin, IFNα, IFNγ, IL1β, IL4, IL12, IL17, MIP1α, MIP1β and TNFα were elevated in the sera of LF CVM patients, whereas only MIP1α was raised in the sera of HF CVM patients. None of the angiogenic mediators were altered in the sera of patients with LF or HF CVMs. Serum IFNα, IFNγ, IL4, IL12, TNFα, VEGFA, VEGFD and syndecan correlated positively with pain scores in patients with LF CVMs, whereas only IP10 did in patients with HF CVMs. Serum Ang1 and leptin correlated negatively with lesion volumes in patients with LF or HF CVMs, respectively. Conclusion: Serum inflammatory mediators could be used as biomarkers to distinguish LF from HF CVMs and their expression seemed to be associated with pain severity in patients with LF CVMs. The angiogenic mediators Ang1 and leptin were associated with lesion volumes in patients with LF or HF CVMs, respectively.

The role of VEGF, PDGF and IL-6 on diabetic foot ulcer after Platelet Rich Fibrin + hyaluronic therapy

BackgroundCurrent standard management of diabetic foot ulcers (DFUs) consists of surgical debridement followed by soak NaCl 0.9% gauzes tight infection and glycaemic control. Nowadays the use of advanced platelet-rich fibrin (A-PRF) has emerged as an adjunctive method for treating DFUs. This study was conducted to demonstrate the ability of combine A-PRF + HA as a complementary therapy in DFUs healing related with angiogenesis,inflammation and granulation index process. MethodsThis open label randomized controlled trial was conducted in Koja District Hospital and Gatot Soebroto Hospital Jakarta, Indonesia on July 2019–April 2020. DFUs patients with wound duration of three months, Wagner-2, with size of ulcer less than 40 cm2 were included in the study. The number of subjects was calculated based on the rule of thumb and allocated randomly into three groups, namely topical A-PRF + HA, A-PRF and Sodium Chloride 0.9% as a control, for each of 10 subjects. A-PRF made by 10 mL venous blood, centrifuge 200 G in 10 min, meanwhile A-PRF + HA though mix both them with vertex machine around 5 min. Biomarker such as VEGF, PDGF and IL-6 examined from DFU taken by cotton swab and analysis using ELISA. Granulation Index was measured using ImageJ. Biomarkers and granulation index were evaluated on day 0, 3, 7 and 14. Data were analysed using SPSS version 20 with Anova and Kruskal Wallis test to compare the angiogenesis and inflammation effect between the three groups. ResultIn topical dressing A-PRF + HA, there is an increase in delta VEGF on day-3 (43.1 pg/mg protein) and day-7 (275,8 pg/mg protein) compared to A-PRF on day-3 (1.8 pg/mg protein) and day-7 (104.7 pg/mg protein), also NaCl (control) on day-3 (-4.9 pg/mg protein) and day-7 (28.3 pg/mg protein). So that the delta VEGF of A-PRF + HA group increase significantly compared with others on day-3 (p = 0.003) and day- 7 (p < 0.001). Meanwhile A-PRF + AH group, there is also a decrease in delta IL-6 after therapy on day-3 (-10.9 pg/mg protein) and day-7 (-18.3 pg/mg protein) compared to A-PRF in delta IL-6 on day- 3 (-3.7 pg/mg protein) and on day-7 (-7.8 pg/mg protein). In NaCl (control) group there is a increase delta IL-6 on day-3 (4.3 pg/mg protein) and on day-7 (35.5 pg/mg protein). So that the delta IL-6 of A-PRF + HA group decrease significantly compared with others only on day- 7 (p = 0.015). In PDGF le level analysis, A-PRF + HA group increase significantly (p = 0.012) only in day -7 compare with other group (5.5 pg/mg protein). ConclusionThe study shows the superior role of combined A-PRF + HA in the treatment DFU though increase angiogenesis and decrease inflammation pathway. The advantage of using A-PRF + HA is that it accelerates wound healing by increasing granulation tissue compared to A-PRF alone.

Gene expression of angiogenesis and apoptotic factors in female BALB/c mice with breast cancer after eight weeks of aerobic training.

Objective(s):Breast cancer is the most common cancer in women, caused by a disorder in the angiogenesis and apoptosis process. Exercise can affect the process of angiogenesis and apoptosis in the tumor tissue. Thus, the aim of the present study was to investigate the changes in angiogenesis and apoptotic factors in mice with breast cancer after 8 weeks of exercise training.Materials and Methods:Sixteen females BALB/c mice (age: 3-5 weeks and weight: 17.1 ± 0.1 g) with breast cancer were randomly divided into two groups of aerobic training and control. The aerobic training included 8 weeks and 5 sessions per week of running with an intensity of 14-20 m.min-1. HIF-1α, VEGF, miR-21 and cytochrome C, Apaf-1, caspase-9, and caspase-3 gene expressions were examined by real-time PCR. Repeated measures ANOVA, Bonferroni’s post hoc test, and independent samples t-test were used to analyze the data (P<0.05).Results:The results showed that aerobic training reduced the growth of tumor volume and significantly reduced miR-21 gene expression. Aerobic training also significantly increased the gene expression of HIF-1α, cytochrome C, Apaf-1, caspase-9, and caspase-3, while changes in VEGF gene expression were not statistically significant.Conclusion:It appears that aerobic exercise training reduces tumor size and ameliorates breast cancer by reducing miR-21 gene expression, suppressing the apoptosis process, and reducing angiogenesis.

Folate Conjugated Solid Lipid Nanoparticle: Formulation Development, Optimization, and Characterization

Objective: The current paper represents the development, optimization, and characterization of paclitaxel-loaded folate conjugated solid lipid nanoparticles (FA-SLNs). Methods: The ligand (FA-SLNs) conjugated and non-conjugated SLNs (PTX-SLNs) were prepared by hot homogenization method. Both of the formulations (FA-SLNs and PTX-SLNs) were optimized with various parameters i.e. drug loading, stirring time, stirring speed, particle size, and polydispersity index, and characterized. The in-vitro drug release study was performed in different pH environments by using the dialysis bag method. The surface morphology and particle size were determined through scanning electron micorscopy and Transmission Electron Microscopy respectively, The SLNs formulations were also evaluated for the stability study. Result: The particle size of PTX-SLNs and FA-SLNs was determined and found to be 190.1±1.9 and 231.3±2.3 nm respectively. The surface morphology of the SLNs indicates that the prepared formulations are round-shaped and show smooth surfaces. The TEM study indicated that particles were in the range of 100-300 nm. The entrapment efficiency and drug loading capacity of FA-SLNs were found to be 79.42±1.6% and 17.3±1.9%, respectively. In-vitro drug release study data, stated that the optimum drug release was found in an acidic environment at pH 4.0, that showed 94.21% drug release after 16 hours and it proves that optimized formulation FA-SLNs will gave the sustained and better release in tumor tissue that owing acidic environment because of the angiogenesis process. Conclusion: In this research paper, different formulation parameters, found to influence fabrication of drug into Solid lipid nanoparticles, were optimized for high entrapment efficiency and drug loading. The most important parameters were drug:lipid ratio, drug:polymer ratio and lipid: surfactant ratio. Higher in-vitro drug release was observed in pH 4 as compared to the pH 7.4. These result data concludes that FA-SLNs formulation was successfully prepared, optimized and characterized.

Pathomorphological manifestations of vascular remodeling in the perifocal areas of ischemic cerebral infarction

Abstract. Acute disorders of cerebral circulation remain one of the leading causes of death of patients throughout the world. Tissue recovery after a stroke is directly related to active revascularization, which is intensified in the peri-infarction area. Newly formed vessels contribute to the restoration of cellular metabolism in surviving neurons. The processes of vascular remodeling after stroke have been at the center of many clinical and morphological studies in recent years. The aim of the study. To study the processes of vascular remodeling and neoplasm of vessels in the perifocal areas of ischemic cerebral infarctions. Material and methods. The study researched the brain of 29 deceased patients with hemispheric infarctions with different periods of the disease: up to 3 days (n = 5), 6 days (n = 5), 9-12 (n = 10), 30 (n = 5), 45 days (n = 4). The object of the study was perifocal areas of cerebral infarction, as well as areas outside ischemic lesions. The studies were carried out using histological, morphometric and statistical techniques. Results. Studies have shown that in the perifocal areas of cerebral infarction within 3 days from the onset of the disease, the morpho-functional state of the microvasculature was characterized by circulatory and hemocoagulation disorders. Along with destructive changes in blood vessels, processes are directed to improve blood circulation in ischemic areas of the brain. Collateral blood flow increases, dilation of pial vessels is noted with a decrease in the Kernogan index. On the 6th day, the processes of angiogenesis and vasculogenesis are activated, which intensify in the subsequent stages of the disease. In the long term, the efficiency of collateral blood flow in the pial vessels decreases, reduction in the capillary network, and the lumen of large arteries is recalibrated. Conclusions. In the early stages of cerebral stroke (up to 3 days), increased blood circulation in the ischemic areas of the brain occurs due to increased collateral blood flow. From the 6th day, the processes of angiogenesis in the form of capillary budding and the processes of vasculogenesis intensify. In large arterioles, recalibration processes take place. After 30-45 days in the perifocal areas of cerebral infarction, a significant reduction of the capillary network is recorded, which is regarded as a reaction to a decrease in blood supply to the areas of organized infarction.

GDF15 and Cardiac Cells: Current Concepts and New Insights.

Growth and differentiation factor 15 (GDF15) belongs to the transforming growth factor-β (TGF-β) superfamily of proteins. Glial-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL) is an endogenous receptor for GDF15 detected selectively in the brain. GDF15 is not normally expressed in the tissue but is prominently induced by “injury”. Serum levels of GDF15 are also increased by aging and in response to cellular stress and mitochondrial dysfunction. It acts as an inflammatory marker and plays a role in the pathogenesis of cardiovascular diseases, metabolic disorders, and neurodegenerative processes. Identified as a new heart-derived endocrine hormone that regulates body growth, GDF15 has a local cardioprotective role, presumably due to its autocrine/paracrine properties: antioxidative, anti-inflammatory, antiapoptotic. GDF15 expression is highly induced in cardiomyocytes after ischemia/reperfusion and in the heart within hours after myocardial infarction (MI). Recent studies show associations between GDF15, inflammation, and cardiac fibrosis during heart failure and MI. However, the reason for this increase in GDF15 production has not been clearly identified. Experimental and clinical studies support the potential use of GDF15 as a novel therapeutic target (1) by modulating metabolic activity and (2) promoting an adaptive angiogenesis and cardiac regenerative process during cardiovascular diseases. In this review, we comment on new aspects of the biology of GDF15 as a cardiac hormone and show that GDF15 may be a predictive biomarker of adverse cardiac events.

The role of endothelial dysfunction and subclinical inflammation in the development of obstetric and perinatal complications in diabetes mellitus patients

Diabetes mellitus in pregnant women is one of the topical problems of modern medicine. Recently, there has been an increase in cases of type 2 diabetes, especially an increase in the frequency of early onset in children and adolescents, respectively, in the fertile age, in a few years; they will enter with the burden of pathology. This is particularly problematic and important during pregnancy, since type 1 and type 2 diabetes are accompanied by a high risk of adverse obstetric and perinatal complications, which are detected in most women with type 1 and type 2 diabetes. The purpose of this review was to assess the role of vascular endothelial dysfunction and subclinical inflammation in the genesis of placental insufficiency causing the development of a number of pregnancy complications in diabetes mellitus, to search for biological markers of these processes, which may reveal some pathogenetic mechanisms for the formation and diagnosis of these disorders. The review shows changes in the content of a number of biological markers, primarily such as pro-inflammatory cytokines (IL-1, TNFα, IL-6); CRP, for certain pregnancy complications in diabetes mellitus women. It is the imbalance of cytokines that very often determines the development of gestational complications and disrupts immunological tolerance in the mother-placenta-fetus system. The degree of severity of angiogenesis processes depends on the level of hyperglycemia, manifestations of subclinical inflammation and is reflected in the increase in the VEGF expression level and its receptors in terminal and stem villi of the placenta. Thus, the review shows the role of endothelial dysfunction and subclinical inflammation in the development of obstetric and perinatal complications in diabetes mellitus patients, which is indicated by the changes in a range of proinflammatory cytokines and other biologically active markers.

PHENOTYPIC EXPRESSION OF MESENCHYMAL STEM CELLS: COMPARING SELECTIVE TISSUEENGINEERED PHOTOSTIMULATION TECHNIQUE AND CONVENTIONAL LIPOSUCTION TECHNIQUE.

Introduction: Adipose-derived stem cells (ASCs) show some membrane markers that enable cell identification by flow cytometry. One of them which is essential during the angiogenesis process is CD105 (Endoglin). This is very important for various pathologies where it is required angiogenesis to regenerate tissues or organs affected by various acquired or congenital noxae. To determine the phenotypic expression, CD105 angiogenesis factor, of ASCs obtain Objective: ed by Selective Tissue Engineering Photostimulation (STEP ) with infrared light of 1210 nm compared to those obtained by TM Gold Standard Suction assisted lipectomy/conventional liposuction technique (SAL). ASCs obtained by Results: STEP™ technique with 1210 nm laser were found to be highly viable (&gt; 97%) and showed increased CD105 expression (90%) and only &lt;5% with the SAL. ASC had been obtained after application of the STEP™ technique is highly Conclusion: viable and show higher expression of specific marker CD105 than the ASC obtained by SAL.

Study of genes involved in angiogenesis and metabolic processes of peripheral blood lymphocytes in patients with chronic endometritis

Objective. To study the polymorphisms of the genes involved in angiogenesis and in metabolic processes, to assess the level of lymphocytes in patients with chronic endometritis and practically healthy women of reproductive period.&#x0D; Materials and methods. 86 patients were examined; DNA regions of the genes eNOS 1799983 (Glu298Asp), PPARA (G2528C), ApoE rs429358 (Cys130Arg), MTHFR (C677T, A1298C) were used as primers; blood lymphocytes (CD3+, CD4+, CD8+, CD19+, CD95+) were assessed.&#x0D; Results. Statistically significant differences in gynecological and chronic somatic pathology were obtained in patients with chronic endometritis; they more often than practically healthy women had polymorphisms of the genes ApoE rs429358, eNOS1799983, PPARA (G2528C); patients with chronic endometritis more often had dysregulation of the immune system in the form of insufficiency of the cellular effector link of immunity and changes in the PPARA, ApoE, eNOS gene. Attention was drawn to the obtained relationships of polymorphic genes and clinical manifestations in patients with chronic endometritis, in particular, with a history of non-developing pregnancy in anamnesis, there was more often detected polymorphism of the ApoE gene, with abnormal uterine bleeding polymorphism of PPARA, with chronic inflammatory pathology of the gallbladder polymorphism of the MTHFR gene.&#x0D; Conclusions. The prevalence of polymorphism of the genes eNOS 1799983 (Glu298Asp), PPARA (G2528C), ApoE rs429358 (Cys130Arg), MTHFR (C677T, A1298C) was obtained in patients with chronic endometrial inflammation compared with practically healthy participants in the study. Insufficiency of the cellular effector link of immunity was revealed in the majority of patients with ChE and an association with allele C genotypes G/C and C/C of PPARA 4253778 gene, with allele C genotypes G/C and C/C of ApoE42935 gene, with allele C genotypes G/C and C/C of eNOS 1799983 gene and G/C genotype of MTHFR gene (C677T, A1298C).

Screening and identification of key biomarkers of papillary renal cell carcinoma by bioinformatic analysis

BackgroundPapillary renal cell carcinoma (PRCC) is the most common type of renal cell carcinoma after clear cell renal cell carcinoma (ccRCC). Its pathological classification is controversial, and its molecular mechanism is poorly understood. Therefore, the identification of key genes and their biological pathways is of great significance to elucidate the molecular mechanisms of PRCC occurrence and progression.MethodsThe PRCC-related datasets GSE7023, GSE48352 and GSE15641 were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified, and gene ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed. Cytoscape and STRING were used to construct the protein-protein interaction network (PPI) and perform module analysis to identify hub genes and key pathways. A heatmap of hub genes was constructed using the UCSC cancer genomics browser. Overall survival and recurrence-free survival of patients stratified by the expression levels of hub genes were analysed using Kaplan-Meier Plotter. The online database UALCAN was applied to analyse gene expression based on tissue type, stage, subtype and race.ResultsA total of 214 DEGs, specifically, 205 downregulated genes and 9 upregulated genes, were identified. The DEGs were mainly enriched in angiogenesis, kidney development, oxidation-reduction process, metabolic pathways, etc. The 17 hub genes identified were mainly enriched in the biological processes of angiogenesis, cell adhesion, platelet degranulation, and leukocyte transendothelial migration. Survival analysis showed that EGF, KDR, CXCL12, REN, PECAM1, CDH5, THY1, WT1, PLAU and DCN might be related to the carcinogenesis, metastasis or recurrence of PRCC. UALCAN analysis showed that low expression of PECAM1 and PLAU in PRCC tissues was related to stage, subtype and race.ConclusionsThe DEGs and hub genes identified in the present study provide insight into the specific molecular mechanisms of PRCC occurrence and development and may be potential molecular markers and therapeutic targets for the accurate classification and efficient diagnosis and treatment of PRCC.

The canonical smooth muscle cell marker TAGLN is present in endothelial cells and is involved in angiogenesis.

Elongation of vascular endothelial cells (ECs) is an important process in angiogenesis; however, the molecular mechanisms remain unknown. The actin-crosslinking protein TAGLN (transgelin, also known as SM22 or SM22α) is abundantly expressed in smooth muscle cells (SMCs) and is widely used as a canonical marker for this cell type. In the course of studies using mouse embryonic stem cells (ESCs) carrying an Tagln promoter-driven fluorescence marker, we noticed activation of the Tagln promoter during EC elongation. Tagln promoter activation co-occurred with EC elongation in response to vascular endothelial growth factor A (VEGF-A). Inhibition of phosphoinositide 3-kinase (PI3K)-Akt signaling and mTORC1 also induced EC elongation and Tagln promoter activation. Human umbilical vein endothelial cells (HUVECs) elongated, activated the TAGLN promoter and increased TAGLN transcripts in an angiogenesis model. Genetic disruption of TAGLN augmented angiogenic behaviors of HUVECs, as did the disruption of TAGLN2 and TAGLN3 genes. Tagln expression was found in ECs in mouse embryos. Our results identify TAGLN as a putative regulator of angiogenesis whose expression is activated in elongating ECs. This finding provides insight into the cytoskeletal regulation of EC elongation and an improved understanding of the molecular mechanisms underlying the regulation of angiogenesis.

Glycosaminoglycans are implicated in CXCL-12 induced angiogenesis

Background and Aims: Ischemia refers to reduction of blood flow and oxygen in tissue due to the obstruction of vessels and it can lead to necrosis. Pro-angiogenic treatment is a potential approach for ischemia therapy. In angiogenesis processes, the chemokines (CXCL12, CCL5) binds to their specific receptors but also to co-receptors that are proteoglycans, containing the

High Immunoexpression of COX-2 as a Metastatic Risk Factor in ccRCC without PD-L1 Involvement.

IntroductionClear cell renal cell carcinoma (ccRCC) is the most lethal type of malignancy of the urinary tract system as it is resistant to chemotherapy and radiation and has a survival rate of less than 5% in cases of metastasis. Inflammation plays an essential role in the metastasis of ccRCC. Cyclooxygenase-2 (COX-2) is an inflammatory protein that affects the processes of carcinogenesis, invasion, migration, metastasis, and angiogenesis. COX-2 can modulate programmed death ligand-1 (PD-L1) expression and play a role in immune evasion, meaning that tumor cells are able to escape the body’s immune response and more easily metastasize.PurposeThis study aims to determine the role of COX-2 and PD-L1 in the occurrence of ccRCC metastases.Materials and MethodsThis study is an observational analytical study, which employed a cross-sectional approach to examine the paraffin block samples of 40 ccRCC cases from Dr. Hasan Sadikin Hospital Bandung, Indonesia, between 2014 and 2021. Immunoexpression was measured using immunohistochemical staining for COX-2 in tumor cells and for PD-L1 in immune cells. PD-L1 calculation was measured using Qupath 0.2.3. digital software. Metastatic data were obtained using radiological imaging and pathological examinations. Meanwhile, the data were analyzed using the chi-square test for COX-2 and Fischer’s exact test for PD-L1.ResultsThe research results revealed a significant association between COX-2 and the occurrence of metastases in ccRCC (p=0.001) with a prevalence odds ratio of 10.28. Positive PD-L1 immunoexpression of the immune cells (≥1%) was found in 14% (3/21) of the metastatic group and 5% (1/19) of the non-metastatic group (p=0.607). There was no association between COX-2 and PD-L1 immunoexpression (p=0.278).ConclusionThis study shows that metastases in ccRCC patients are ten times as likely to be associated with high COX-2 immunoexpression than low COX-2 immunoexpression. COX-2 plays a role in the process of ccRCC metastasis without PD-L1 involvement.

The relationship between interleukin-13 and angiogenin in patients with bladder cancer.

Participation of anti-inflammatory interleukin-13 (IL-13) in the process of carcinogenesis was well studied. Angiogenesis plays a key role in the process of tumour growth and metastasis. Higher expression of angiogenin (ANG) have been proven in many types of cancers. The aim of the study was to more fully understand the significance of plasma IL-13 as an immunomodulator and ANG as a stimulator of the angiogenesis process in patients with bladder cancer (BC) and to investigate the relationship between parameters. These parameters were examined in the group of BC patients and in subgroups of BC depending on clinical stage: non-muscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC), histopathologic malignancy low grade (LG), high grade (HG) and in primary and recurrent BC. The level of IL-13 and ANG in the plasma of BC patients and controls were measured by enzyme-linked immunosorbent assay. All calculations were done using the STATISTICA 13.3 (TIBCO software Inc.). Plasma levels of IL-13 and ANG were significantly higher in BC patients and in all patient subgroups examined than in the controls (p < 0.001). A negative significant correlation was found between ANG and IL-13 levels in BC-patients. Based on the receiver operating characteristic curves (ROC), IL-13 had good diagnostic value in BC. The presented results may suggest a relationship between angiogenesis and inflammation in the pathogenesis of bladder cancer and the development of this disease. With the increase of IL-13 level in BC-patients plasma, the ANG level decreased.

Modulation of Nrf2 and NF-κB Signaling Pathways by Naturally Occurring Compounds in Relation to Cancer Prevention and Therapy. Are Combinations Better Than Single Compounds?

Nrf2 (nuclear factor erythroid 2-related factor 2) and NF-κB (nuclear factor–kappa B) signaling pathways play a central role in suppressing or inducing inflammation and angiogenesis processes. Therefore, they are involved in many steps of carcinogenesis through cooperation with multiple signaling molecules and pathways. Targeting both transcription factors simultaneously may be considered an equally important strategy for cancer chemoprevention and therapy. Several hundreds of phytochemicals, mainly edible plant and vegetable components, were shown to activate Nrf2 and mediate antioxidant response. A similar number of phytochemicals was revealed to affect NF-κB. While activation of Nrf2 and inhibition of NF-κB may protect normal cells against cancer initiation and promotion, enhanced expression and activation in cancer cells may lead to resistance to conventional chemo- or radiotherapy. Most phytochemicals, through different mechanisms, activate Nrf2, but others, such as luteolin, can act as inhibitors of both Nrf2 and NF-κB. Despite many experimental data confirming the above mechanisms currently, limited evidence exists demonstrating such activity in humans. Combinations of phytochemicals resembling that in a natural food matrix but allowing higher concentrations may improve their modulating effect on Nrf2 and NF-κB and ultimately cancer prevention and therapy. This review presents the current knowledge on the effect of selected phytochemicals and their combinations on Nrf2 and NF-κB activities in the above context.