Process Of Angiogenesis Research Articles

Mitochondrial-targeting antioxidant MitoQ modulates angiogenesis and promotes functional recovery after spinal cord injury

BackgroundIn traumatic spinal cord injury (SCI), secondary injuries, including cellular death, mitochondrial dysfunction, and vascular injury, have been considered as important causes of impaired functional recovery after SCI. Postinjury angiogenesis has been considered to be a potential strategy for SCI treatment. New-born vessels may play a key role in nerve regeneration, which indicates the importance of angiogenesis in nerve regeneration. Recent studies have revealed the crosstalk between reactive oxygen species (ROS) and angiogenesis. As the main source of cellular ROS, mitochondria have been proven to be essential to the angiogenesis process. MethodsSCI was established in a T10 clip-compression animal model. Then, the animals received an intraperitoneal injection of MitoQ (5 mg/kg/d) on Days 0, 1, and 2 after surgery. The Basso Mouse Scale (BMS) score and footprint analysis (CatWalk analysis) were performed to evaluate functional recovery after SCI. Immunofluorescence and fluorescence assays (LEL-FITC/CD31/Iba-1/Neurofilament) were performed to evaluate angiogenesis, microglia activation and neural regeneration. RT-qPCR (VEGFR-1, VEGFR-2 and VEGFA) was performed to evaluate angiogenesis-related factor in injured spinal cord. ATP production assay and western-blotting assay (Mfn-1 and Drp-1) were performed to evaluate mitochondrial function in the injured spinal cord. BV2 cells were used as in vitro cell model. After receiving TBHP or TBHP-MitoQ treatment, ELISA and immunofluorescence assays were used to evaluate the level of VEGFA secretion from BV2 cells. A coculture system of HUVECs and BV2 cells was established. Tube formation assays and immunofluorescence assays (CD31) were performed on HUVECs in a coculture system to evaluate angiogenesis promotion. ATP production assays were performed to evaluate mitochondrial function in BV2 cells. MitoSOX Red and DCFH-DA staining were performed to evaluate mitochondrial and cellular ROS. ResultsIn vitro MitoQ promoted the secretion of VEGFA from BV2 cells, which was verified through ELISA and immunofluorescence assays. The angiogenic promotion of MitoQ-treated BV2 cells was evaluated by tube formation and immunofluorescence assays (CD31) in a coculture system of BV2 cells and HUVECs. MitoQ inhibited cellular and mitochondrial-derived ROS in TBHP-treated BV2 cells. ATP production was increased in MitoQ-treated BV2 cells. To verify MitoQ’s effect in vivo, a T10 clip-compression animal model was established successfully. MitoQ significantly promoted functional recovery, as shown by the BMS assay and gait analysis. The promotion of neural regeneration was identified through immunofluorescence assay of neurofilament. Immunofluorescence and fluorescence assays (LEL-FITC/CD31/Iba-1) and RT-qPCR (VEGFR-1, VEGFR-2 and VEGFA) indicated that MitoQ could promote angiogenesis and inhibit macrophage/microglia activation in lesion-site after SCI. Enhanced ATP production and increased Mfn-1 with decreased Drp-1 protein expression showed MitoQ could promote mitochondrial function in SCI. ConclusionThe mitochondrial-specific antioxidant MitoQ promotes functional recovery and tissue preservation through the enhancement of angiogenesis with the modification of mitochondrial function after SCI.

A Pan-cancer Analysis Reveals the Abnormal Expression and Drug Sensitivity of CSF1.

Colony-stimulating factor-1 (CSF1) is a cytokine that is closely related to normal organ growth and development as well as tumor progression. We aimed to summarize and clarify the reasons for the abnormal expression of CSF1 in tumors and explore the role of CSF1 in tumor progression. Furthermore, drug response analysis could provide a reference for clinical medication. The expression of CSF1 was analyzed by TCGA and CCLE. Besides, cBioPortal and MethSurv databases were used to conduct mutation and DNA methylation analyses. Further, correlations between CSF1 expression and tumor stage, survival, immune infiltration, drug sensitivity and enrichment analyses were validated via UALCAN, Kaplan-Meier plotter, TIMER, CTRP and Coexperia databases. CSF1 is expressed in a variety of tissues; meaningfully, it can be detected in the blood. Compared with normal tissues, CSF1 expression was significantly decreased in most tumors. The missense mutation and DNA methylation of CSF1 might cause the downregulated expression. Moreover, decreased CSF1 expression was related to higher tumor stage and worse survival. Further, the promoter DNA methylation level of CSF1 was prognostically significant in most tumors. Besides, CSF1 was closely related to immune infiltration, especially macrophages. Importantly, CSF1 expression was associated with a good response to VEGFRs inhibitors, which may be due to the possible involvement of CSF1 in tumor angiogenesis and metastasis processes. The abnormal expression of CSF1 could serve as a promising biomarker of tumor progression and prognosis in pan-cancer. Significantly, angiogenesis and metastasis inhibitors may show a good response to CSF1-related tumors.

Comparative transcriptome analysis of human and murine choroidal neovascularization identifies fibroblast growth factor inducible-14 as phylogenetically conserved mediator of neovascular age-related macular degeneration.

Visual outcome of patients with neovascular age-related macular degeneration has significantly improved during the last years following the introduction of anti-vascular endothelial growth factor (VEGF) therapy. However, about one third of patients show persistent exudation and decreasing visual acuity despite recurrent anti-VEGF treatment, which implies a role of other, still unknown proangiogenic mediators. The present study applied transcriptional profiling of human and mouse (C57BL/6J wildtype) choroidal neovascularization (CNV) membranes each with reference to healthy control tissue to identify yet unrecognized mediators of CNV formation. Key factors were further investigated by immunohistochemistry as well as by intravitreal inhibition experiments and multiplex protein assays in the laser-induced CNV mouse model. Transcriptional profiles of CNV membranes were characterized by enhanced activation of blood vessel development, cytoskeletal organization, and cytokine production, with angiogenesis and wound healing processes predominating in humans and activation of immune processes in mice. Besides several species-specific factors, 95 phylogenetically conserved CNV-associated genes were detected, among which fibroblast growth factor inducible-14 (FN14), a member of the tumor necrosis factor (TNF) receptor family, was identified as a key player of CNV formation. Blocking the pathway by intravitreal injection of a FN14 decoy receptor modulated the cytokine profile - most notably IL-6 - and led to a significant reduction of CNV size in vivo. This study characterizes the transcriptome of human and mouse CNV membranes in an unprejudiced manner and identifies FN14 as a phylogenetically conserved mediator of CNV formation and a promising new therapeutic target for neovascular AMD. This study was funded by the Helmut Ecker Foundation and the Volker Homann Foundation.

Elucidating the role of hypoxia-inducible factor in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic multifactorial disease, provocative, and degenerative autoimmune condition that impacts millions of individuals around the globe. As a result of this understanding, anti-inflammatory drugs have been created, perhaps widely effective (like steroids) and highly specialized methods (including anti-TNF antibody) using biological therapies (including TNF inhibitors). Despite this, the connections between inflammatory response, articular development, and intracellular responsiveness to changes in oxygen concentration are undervalued in rheumatoid arthritis. Hypoxia, or a lack of oxygen, is thought to cause enhanced synovial angiogenesis in RA, which is mediated by some of the hypoxia-inducible factors like vascular endothelial growth factor (VEGF). Substantial genetic alterations occur when the HIF regulatory factors signaling cycle is activated, allowing organelles, tissues, and species to acclimatize to decreasing oxygen saturation. The most well-characterized hypoxia-responsive transcripts are the angiogenic stimulant VEGF, whose production is greatly elevated by hypoxia in several types of cells, especially RA synovium fibroblasts. Blocking vascular endothelial growth factors has been demonstrated to be helpful in murine models of rheumatism, indicating how hypoxia could trigger the angiogenesis process, resulting in the progression of RA. These mechanisms highlight the intimate affiliation amongst hypoxia, angiogenesis, and inflammation in rheumatoid arthritis. This review will look at how hypoxia activates molecular pathways and how other pathways involving inflammatory signals develop and sustain synovitis in rheumatoid arthritis.

Bioactive anti-inflammatory antibacterial metformin-contained hydrogel dressing accelerating wound healing.

Highly efficient wound healing and skin regeneration remain a challenge. Long-term inflammation and bacterial infection can inhibit the healing process and lead to the scar formation. Here, we report a hydrogel (FEM) formed by self-assembly of ε-poly-l-lysine-F127-ε-poly-l-lysine (EPL-F127-EPL) and metformin for wound repair. Especially, the role of metformin-based antibacterial hydrogel in wound healing and repair was investigated for the first time. FEM has inherent multifunctional properties, including controlled metformin release, anti-inflammatory and antibacterial activity, temperature responsiveness, injectable and self-healing capabilities. The in vivo results showed that FEM dressings accelerated the wound healing by stimulating the angiogenesis process of the wound tissue and anti-inflammation. This study shows that the multifunctional metformin-contained hydrogel scaffolds could enhance the wound repair through the anti-inflammation and accelerated angiogenesis, which could also expand the biomedical applications of metformin-based biomaterials.

Malaysian Tualang Honey Suppresses the Angiogenic Events in Endothelial Cells Induced by Vascular Endothelial Growth Factor

Anti-VEGF therapy has been used as the anti-angiogenic agent in cancer treatment. However, the treatment often couples with severe complications. Complementary natural products that offer similar anti-angiogenic potency with less side effects are sought as alternatives. Study showed that Malaysian Tualang Honey (MTH) can inhibit inflammation-induced vascular hyperpermeability in vitro and in vivo, but the effect on the angiogenesis process remains unclear. Thus, this study aims to determine the anti-angiogenic effects of MTH. Effects of MTH ranging from 0.3% to 0.9% on VEGF-induced human umbilical vein endothelial cells (HUVEC) angiogenesis was determined by proliferation, migration and tube-formation assays. Matrix metalloproteinase-2 (MMP-2) secretion from HUVEC and VEGF production from MCF7 cancer cells in response to MTH were also quantified by using ELISA kits. Suramin, an angio-suppressive agent was used as positive control. MTH significantly suppressed HUVEC proliferation (from 155% proliferation rate to 54%); migration (~ 50% inhibition rate) and tube-formation (69% reduction) induced by VEGF. These findings were explained by the significant reduction (p < 0.05) of VEGF-induced MMP-2 secretion in HUVEC with 39% suppression exhibited by 0.9% of MTH. MTH also significantly (p < 0.05) reduced VEGF secretion (19% reduction compared to control) in MCF7 breast cancer cells. Our findings suggest that the anti-angiogenic effects of MTH mainly targets endothelial cell through inhibition cell proliferation, migration and tube formation capacity, via suppression of MMP-2 secretion by the endothelial cells. However, MTH has less prominent effect on suppressing VEGF secretion by the MCF7 cancer cells.

The absence of cellular glucose triggers oncogene AEG-1 that instigates VEGFC in HCC: A possible genetic root cause of angiogenesis

Background and ObjectiveAstrocyte Elevated Gene-1 (AEG-1) is the master and multi-regulator of the various transcriptional factor primarily regulating chemoresistance, angiogenesis, metastasis, and invasion under the pathological condition, including liver cancer. This study was focused on investigating the process of tumor angiogenesis in liver carcinoma by studying the role of AEG-1 under GD/2DG conditions. Method and resultsThe PCR and western blot analysis revealed that glucose depletion (GD) induces the overexpression of AEG-1. Further, it leads to the constant expression of VEGFC through the activation of HIF-1α/CCR7 via the stimulations of PI3K/Akt signaling pathways. GLUT2 is the major transporter of a glucose molecule that is highly participating under GD through the expression of AEG-1 and constantly expresses glucokinase (GCK). The obtained data suggest that AEG-1 act as an angiogenesis and glycolysis regulator by modulating the expression of GCK through HIF-1α and GLUT2. 2-deoxy-D-glucose (2DG) is a glycolysis inhibitor that induces impaired glycolysis and cellular apoptosis by cellular oxidative stress. The administration of 2DG has led to the chemoresistance of AEG-1. ConclusionThe total findings of the study judged that disruption of cellular energy metabolism induced by the absence of glucose or the presence of mutant glucose moiety (2DG) promotes the overexpression of AEG-1. The GD/2DG activates the VEGFC by inducing the HIF-1α and CCR7. Moreover, AEG-1 induces the expression of OPN, which regulates metastasis, angiogenesis, and actively participates in protective autophagy by promoting LC3 a/b.

Exploring the pharmacological components and effective mechanism of Mori Folium against periodontitis using network pharmacology and molecular docking

ObjectivesTo investigate the main active components, potential targets of action and analyze the potential molecular mechanisms of Mori Folium in preventing and treating periodontitis using network pharmacology and molecular docking methods. Materials and methodsThe main components and action targets of Mori Folium were obtained in TCMSP and ETCM databases, and then the action targets of Mori Folium components were inversing screening using Swiss Target Prediction and BATMAN-TCM databases. Targets associated with periodontitis were retrieved from OMIM, Genecard, DrugBank, NCBI Gene and DisGeNET databases. Intersectional targets of Mori Folium and periodontitis were obtained by Venn analysis. Construction of an "active components-targets" network to prevent and treat periodontitis in Mori Folium using Cytoscape 3.8.0. The STRING database was used to construct the protein-protein interaction (PPI) network of intersecting targets, and the core network was screened using CytoNCA and MCODE plug-ins. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were performed using the ClusterProfile package of R software, and then the "Mori Folium active components-targets-signaling pathway" network was constructed using Cytoscape software. Molecular docking was performed using AutoDock Vina software, and Pymol and LigPlus visualized the results. ResultsSixteen active components and 1048 targets were screened from Mori Folium, of which 164 were intersectional with periodontitis targets and were considered potential therapeutic targets. The "Mori Folium active components-action targets" network identified Quercetin, Moracin D, Moracin E, Moracin G, Moracin H and Moracin B as the main active ingredients of Mori Folium for the prevention and treatment of periodontitis. PPI network analysis revealed interleukin 6 (IL6), albumin (ALB), tumor necrosis factor (TNF), vascular endothelial growth factor A (VEGFA), RAC-alpha serine/threonine-protein kinase (AKT1), cellular tumor antigen p53 (TP53), prostaglandin G/H synthase 2 (PTGS2), pro-epidermal growth factor (EGF), matrix metalloproteinase 9 (MMP9) and interleukin 6 (IL10) as the top 10 core potential targets. GO and KEGG enrichment analyses showed that the action targets of Mori Folium against periodontitis were mainly related to the response to bacterium and their lipopolysaccharide, angiogenesis and reactive oxygen species metabolic process, as well as through signaling pathways that regulate processes related to the accumulation of advanced glycation end products (AGEs), response to oxidative stress, response to inflammatory, and osteoclast differentiation during the development of the disease. Molecular docking revealed that Quercetin, Moracin D, Moracin E, Moracin G, Moracin H and Moracin B were able to bind stably to AKT1, PTGS2 and ESR1 targets, with Moracin E showing the most stable structure after binding to AKT1. ConclusionsIn conclusion, this study revealed the active components, potential targets of action and the potential molecular mechanisms and pharmacological activities involved in the prevention and treatment of periodontitis in Mori Folium, providing a reference for the development of drugs from Mori Folium for the prevention and treatment of periodontitis.

Inner nuclear membrane protein TMEM201 maintains endothelial cell migration and angiogenesis by interacting with the LINC complex

The nuclear envelope comprises the outer nuclear membrane, inner nuclear membrane (INM), and nucleopore. Although ∼60 INM proteins have been identified, only a few of them have been well characterized, revealing their crucial roles. Our group focused on the INM protein transmembrane protein 201 (TMEM201), whose role in cellular function remains to be defined. In this study, we investigated the role of TMEM201 in endothelial cell migration and angiogenesis. Depletion of TMEM201 expression by short hairpin RNA-mediated interference impeded human umbilical vein endothelial cell (HUVEC) angiogenic behavior in tube formation and fibrin gel bead sprouting assays. Meanwhile, TMEM201-deficient HUVECs exhibited impaired migration ability. We next explored the underlying mechanism and found that the N-terminal of TMEM201 interacted with the linker of nucleoskeleton and cytoskeleton complex and was required for regulating endothelial cell migration and angiogenesis. These in vitro findings were further confirmed by using in vivo models. In Tmem201-knockout mice, retinal vessel development was arrested and aortic ring sprouting was defective. In addition, loss of tmem201 impaired zebrafish intersegmental vessel development. In summary, TMEM201 was shown to regulate endothelial cell migration and control the process of angiogenesis. This study is the first to reveal the role of INM proteins in the vascular system and angiogenesis.

Assessment of the Concentration of Endogenous Factors Regulating Angiogenesis, VASH-1 and VEGF-A, in the Blood Serum of Patients with Neuroendocrine Neoplasms.

Neuroendocrine neoplasms (NENs) constitute about 2% of all malignant neoplasms, and the angiogenesis process in these tumors is still of a great interest. Vasohibin-1 (VASH-1) is an angiogenesis inhibitor, while vascular endothelial growth factor A (VEGF-A) is one of the main factors promoting vascular formation. The subject of this study was to assess serum concentration of these factors in patients with diagnosed NEN and in control group. Methods. The study group consisted of 120 patients with diagnosed NENs, while the control group consisted of 69 healthy volunteers. The concentrations of VASH-1 and VEGF-A in serum were tested using the ELISA. We also analyzed the association of the concentration of these factors with demographic data (e.g., age and gender), body mass index (BMI), primary tumor location, histological grade, metastasis, clinical staging, selected biochemical parameters and markers of NENs, and information on smoking habits. Results. The mean concentration of VASH-1 was 218.8 ± 359.8 pg/ml in the study group and 973.1 ± 1239.4 pg/ml in the control group, that difference was statistically significant (p < 0.05). In the NEN group, the highest concentration of VASH-1 was in patients with pancreatic NENs in relation to NENs with different location of the primary tumor (p < 0.05). Negative correlation was found between the concentration of VASH-1 and serotonin (rS = −0.19, p < 0.05). No statistically significant differences were observed for VEGF-A (p = 0.658). Conclusions. Patients with NENs showed lower serum level of VASH-1 in comparison to healthy volunteers. The highest level of VASH-1 was observed in tumors localized in pancreas. This might reflect the relevant function of VASH-1 in NENs and requires further evaluation to further knowledge of angiogenesis in NENs. Furthermore, the serum concentration of VEGF-A showed no statistical differences and probably does not have diagnostic value in this group of patients.

Study of Angiogenesis in Experiment

The creation of new blood vessels is referred to as angiogenesis. Endothelial cells, which line the inside wall of blood arteries, migrate, proliferate, and differentiate during this process. Chemical cues in the body influence the process of angiogenesis. This study intends to highlight the expression of various angiogenic indicators throughout various diseases, the involvement of pro-angiogenic and anti-angiogenic factors during angiogenesis, and the use of angiogenic inhibitors during antiangiogenic therapy, particularly in cancer.

Key Role of Astrocytes in Postnatal Brain and Retinal Angiogenesis.

Angiogenesis is a key process in various physiological and pathological conditions in the nervous system and in the retina during postnatal life. Although an increasing number of studies have addressed the role of endothelial cells in this event, the astrocytes contribution in angiogenesis has received less attention. This review is focused on the role of astrocytes as a scaffold and in the stabilization of the new blood vessels, through different molecules release, which can modulate the angiogenesis process in the brain and in the retina. Further, differences in the astrocytes phenotype are addressed in glioblastoma, one of the most devastating types of brain cancer, in order to provide potential targets involved in the cross signaling between endothelial cells, astrocytes and glioma cells, that mediate tumor progression and pathological angiogenesis. Given the relevance of astrocytes in angiogenesis in physiological and pathological conditions, future studies are required to better understand the interrelation between endothelial and astrocyte signaling pathways during this process.

Peroxisome Proliferator-Activated Receptor Alpha (PPAR-α) as a Regulator of the Angiogenic Profile of Endometriotic Lesions.

Endometriosis is a disease that affects a significant proportion of women and its infiltrative pattern is entirely dependent on the vascular supply of lesions. Several factors seem to trigger the process of angiogenesis in endometriotic lesions. During the last years, peroxisome proliferator-activated receptors (PPARs), a group of nuclear proteins that regulate gene transcription and that seem to regulate energy consumption and expenditure, have been also implicated in the pathophysiology of angiogenesis. Their ability to regulate the course of cancer and improve the survival rates of patients has been extensively studied and seems to be partially dependent on alteration of the vascular supply of malignant lesions. Research in the field of endometriosis is scarce in the international literature and mainly focused on PPAR-gamma. However, indirect evidence suggests that PPAR-alpha (PPAR-α) may also regulate the vascular supply of endometriotic lesions as well. Specifically, PPAR-α agonists seem to downregulate angiogenesis by increasing the expression of several anti-angiogenic molecules, including thrombospondin-1 (TSP-1) and gypenoside 140 (gp140), as well as factors that are involved in the mitogen-activated protein kinase cascade. In the present article, we summarize existing indirect and direct evidence that indicates the existence of an association between the expression of PPAR-α and endometriosis to help future research in this field.

Dynamics of Endothelial Engagement and Filopodia Formation in Complex 3D Microscaffolds

The understanding of endothelium–extracellular matrix interactions during the initiation of new blood vessels is of great medical importance; however, the mechanobiological principles governing endothelial protrusive behaviours in 3D microtopographies remain imperfectly understood. In blood capillaries submitted to angiogenic factors (such as vascular endothelial growth factor, VEGF), endothelial cells can transiently transdifferentiate in filopodia-rich cells, named tip cells, from which angiogenesis processes are locally initiated. This protrusive state based on filopodia dynamics contrasts with the lamellipodia-based endothelial cell migration on 2D substrates. Using two-photon polymerization, we generated 3D microstructures triggering endothelial phenotypes evocative of tip cell behaviour. Hexagonal lattices on pillars (“open”), but not “closed” hexagonal lattices, induced engagement from the endothelial monolayer with the generation of numerous filopodia. The development of image analysis tools for filopodia tracking allowed to probe the influence of the microtopography (pore size, regular vs. elongated structures, role of the pillars) on orientations, engagement and filopodia dynamics, and to identify MLCK (myosin light-chain kinase) as a key player for filopodia-based protrusive mode. Importantly, these events occurred independently of VEGF treatment, suggesting that the observed phenotype was induced through microtopography. These microstructures are proposed as a model research tool for understanding endothelial cell behaviour in 3D fibrillary networks.

The microenvironment of pituitary adenomas: biological, clinical and therapeutical implications.

The microenvironment ofpituitary adenomas (PAs) includes a range of non-tumoral cells, such as immune and stromal cells, as well as cell signaling molecules such as cytokines, chemokines and growth factors, which surround pituitary tumor cells and may modulate tumor initiation, progression, invasion, angiogenesis and other tumorigenic processes. The microenvironment of PAs has been actively investigated over the last years, with several immune and stromal cell populations, as well as different cytokines, chemokines and growth factors being recently characterized in PAs. Moreover, key microenvironment-related genes as well as immune-related molecules and pathways have been investigated, with immune check point regulators emerging as promising targets for immunotherapy. Understanding the microenvironment of PAs will contribute to a deeper knowledge of the complex biology of PAs, as well as will provide developments in terms of diagnosis, clinical management and ultimately treatment of patients with aggressive and/or refractory PAs.

MTA-Enriched Polymeric Scaffolds Enhanced the Expression of Angiogenic Markers in Human Dental Pulp Stem Cells.

Revascularization of the pulp tissue is one of the fundamental processes and challenges in regenerative endodontic procedures (REPs). In this regard, the current study is aimed at synthesizing the mineral trioxide aggregate- (MTA-) based scaffolds as a biomaterial for REPs. Poly (ε-caprolactone) (PCL)/chitosan (CS)/MTA scaffolds were constructed and evaluated by FTIR, SEM, XRD, and TGA analyses. Proliferation and adhesion of human dental pulp stem cells (hDPSCs) were assessed on these scaffolds by scanning electron microscopy (SEM) and MTT assays, respectively. The expression of angiogenic markers was investigated in gene and protein levels by real-time PCR and western blotting tests. Our results indicated that the obtained appropriate physicochemical characteristics of scaffolds could be suitable for REPs. The adhesion and proliferation level of hDPSCs were significantly increased after seeding on PCL/CS/MTA scaffolds. The expression levels of VEGFR-2, Tie2, and Angiopoietin-1 genes were statistically increased on the PCL/CS/MTA scaffold. In support of these findings, western blotting results showed the upregulation of these markers at protein levels in PCL/CS/MTA scaffold (P < 0.05). The current study results suggested that PCL/CS/MTA scaffolds provide appropriate structures for the adhesion and proliferation of hDPSCs besides induction of the angiogenesis process in these cells.

Recent advances in targeted therapy for ovarian cancer

Abstract The global burden of ovarian cancer is gradually increasing while patients still suffer from relatively limited treatment options. With recent advances in the decoding of the molecular landscape of ovarian cancer, more options in targeted strategy were offered and can therefore be tailored in different clinical settings for individual patient. Targeting of the abnormal angiogenesis process is the first significant clinical breakthrough which revolutionized the treatment of advanced ovarian cancer, followed by the advent of poly-(ADP)-ribose polymerase (PARP) inhibitors. These two strategies represented by bevacizumab and olaparib respectively underwent tests of numerous clinical trials. In recent years, immune checkpoint inhibitors (ICIs) have been incorporated into the blueprint of ovarian cancer treatment though the effectiveness still left much to be desired. Herein, we systematically outlined recent advances in targeted therapy for ovarian cancer and summarized the landmark clinical trials for each targeted therapy including angiogenesis inhibitors, PARP inhibitors and ICIs.

Angiogenin promotes angiogenesis via the endonucleolytic decay of miR-141 in colorectal cancer

Mature microRNA (miRNA) decay is a key step in miRNA turnover and gene expression regulation. Angiogenin (ANG), the first human tumor-derived angiogenic protein and also a member of the RNase A superfamily, can promote tumor growth and metastasis by regulating rRNA biogenesis and tiRNA production. However, its effect on miRNA has not been explored. In this study, we find that ANG exclusively downregulates mature miR-141 in human umbilical endothelial cells (HUVECs) via its ribonuclease activity and preferably cleaves single-stranded miR-141 at the A5/C6, U7/G8, and U14/A15 sites via endonucleolytic digestion. By downregulating miR-141, ANG promotes HUVECs proliferation, migration, tube formation, and angiogenesis both in vitro and in vivo. Conversely, downregulated ANG inhibits ANG-mediated miR-141 decay, thus decreasing the angiogenesis process of HUVECs. We also find an inverse correlation between ANG and miR-141 expression in colorectal cancer (CRC) tissues. Our study indicates that ANG regulates CRC progression by disrupting miR-141 and its regulation on angiogenesis-related target genes, not only revealing a new mechanism of ANG action but also newly identifying miR-141 as a substrate of ANG. This study suggests that targeting ANG nuclease activity might be valuable in treating angiogenesis-related diseases through coordinately regulating the metabolism of rRNA, tiRNA, and miRNA.

Studi In Silico Senyawa Cendawan Endofit Sebagai Kandidat Obat Antiangiogenesis Hemangioma

Increasing levels of angiogenic factors such as gamma interferon (Y-IF), tumor necrosis factor-beta (TNF-β), and transforming growth factor-beta (TGF-β) are thought to be the cause of the angiogenesis process in hemangiomas. Endophytic fungi are potential in searching for new drug sources due to their antimicrobial, antifungal, and anticancer compounds. This study aimed to determine the potential and interactions of endophytic fungi as candidates for vascular endothelial growth factor receptor-2 (VEGFR-2) angiogenesis hemangiomas and apply Lipinski's rule of five to differentiate drug-like and non-drug-like molecules and in-line toxicity using in silico test. The research method was molecular docking using several programs, namely Autodock Vina (PyRx), PyMol, and Discovery Studio 2019, and tethering five ligands from the endophytic fungus Trichoderma sp. and Aspergillus sp. with 2 VEGFR-2 target proteins (protein codes were 3VHE and 1Y6A). The best binding affinity of the ligands was tested by Lipinski's rule of five and toxicity test using Toxtree. The results showed that benzyl benzoate is potentially an antiangiogenesis inhibitor for VEGFR-2 protein based on its binding affinity value, which is close to the control ligand value of -8.7 kcal/mol (3VHE) and -7.4 kcal/mol (1Y6A). Therefore, benzyl benzoate, chloromycetin, and 1-hexyl-3-nitrobenzene compounds comply with Lipinski's rule of five. Based on the results of the toxicity test and the parameters of the Kroes TTC decision tree, benzyl benzoate and chloromycetin are categorized as safe compounds for consumption.&#x0D; &#x0D; Keywords: angiogenesis, benzyl benzoate, endophytic fungi, molecular docking, VEGFR-2

Optimization of human umbilical cord blood-derived mesenchymal stem cell isolation and culture methods in serum- and xeno-free conditions

BackgroundAlthough umbilical cord blood (UCB) is identified as a source of mesenchymal stem cells (MSCs) with various advantages, the success in cell isolation is volatile. Therefore, it is necessary to optimize methods of cord blood-derived MSC (UCB-MSC) isolation and culture. In this study, we evaluated the efficiency of UCB-MSC isolation and expansion using different commercially available serum- and xeno-free media and investigated the capacity of autologous serum and plasma as a supplement to support cell proliferation. Additionally, we defined the presence of multilineage-differentiating stress-enduring (Muse) cells in the UCB-MSC population. Functions of UCB-MSC in in vitro angiogenesis processes and anti-cancer were also verified.MethodsMononuclear cells were isolated using density gradient separation and cultured in four commercial media kits, as well as four surface coating solutions. UCB-MSCs were characterized and tested on tube formation assay, and co-cultured with SK-MEL cells in a transwell system.ResultsThe results showed that only StemMACS™ MSC Expansion Media is more appropriate to isolate and culture UCB-MSCs. The cells exhibited a high cell proliferation rate, CFU forming capability, MSC surface marker expression, trilineage differentiate potential, and chromosome stability. In addition, the culture conditions with autologous serum coating and autologous plasma supplement enhanced cell growth and colony forming. This cell population contained Muse cells at rate of 0.3%. Moreover, UCB-MSCs could induce the tube formation of human umbilical vein endothelial cells and inhibit more than 50% of SK-MEL cell growth.ConclusionsUCB-MSCs could be high-yield isolated and expanded under serum- and xeno-free conditions by using the StemMACS™ MSC Expansion Media kit. Autologous serum coating and plasma supplement enhanced cell proliferation. These UCB-MSCs had effected the tube formation process and an anti-cancer impact.