Endothelial Growth Factor Signaling Pathway Research Articles

MiRNome-transcriptome analysis unveils the key regulatory pathways involved in the tumorigenesis of tongue squamous cell carcinoma.

Tongue squamous cell carcinoma (TSCC) is considered the most common malignant tumor among the oral squamous cell carcinomas with a poor prognosis. Understanding the underlying molecular mechanisms that underpin TSCC and its treatments is the focus of the research. Deregulated expression of microRNAs (miRNAs) has recently been implicated in various biological processes linked to cancer. Therefore, in this study, we attempted to investigate miRNAs and their targets expressed in TSCC, which could be involved in its oncogenesis. We performed next-generation sequencing of small RNAs and transcriptomes in H357 TSCC cell line and human oral keratinocytes as a control to find miRNAs and mRNAs that are differentially expressed (DE), which were then supplemented with additional expression datasets from databases, yielding 269 DE miRNAs and 2094 DE genes. The target prediction followed by pathway and disease function analysis revealed that the DE targets were significantly associated with the key processes and pathways, such as apoptosis, epithelial-mesenchymal transition, endocytosis and vascular endothelial growth factor signaling pathways. Furthermore, the top 12 DE targets were chosen based on their involvement in more than one cancer-related pathway, of which 6 genes are targeted by miR-128-3p. Real-time quantitative PCR validation of this miRNA and its targets in H357 and SCC9 TSCC cells confirmed their possible targeting from their reciprocal expression, with MAP2K7 being a critical target that might be involved in oncogenesis and progression of TSCC by acting as a tumor suppressor. Further research is underway to understand how miR-128-3p regulates oncogenesis in TSCC via MAP2K7 and associated pathways.

Molecular and haemodynamic interplay in bicuspid aortic valve aortopathy: segmental differences across the aortic circumference

Abstract Background Bicuspid aortic valve (BAV) patients develop ascending aortic (AAo) dilation. The pathogenesis of BAV-aortopathy (genetic vs. hemodynamic) remains unclear. Purpose To identify regional changes around the AAo wall in BAV patients with aortopathy integrating clinical imaging and molecular data. Methods BAV patients with aortopathy (n=20) were recruited prospectively to surgically collect aortic tissue and perform four-dimensional cardiac magnetic resonance (CMR) scans. Molecular markers were measured analysing the tissue biopsies (n=15) and wall shear stress (WSS) across the AAo circumference was calculated from the 4D CMR data (n=11 patients, and n=7 additional healthy volunteers for comparison). Dilated (anterior/right) vs. non-dilated (posterior/left) circumferential segments were profiled for whole genomic microRNAs (Next Generation RNA-Sequencing, miRCURY LNA PCR), proteins content (Tandem Mass Spectrometry) and elastin fragmentation and degeneration (histomorphometric analysis). Picture 1 summarises the study approach (including a map of the AAo divided in the following segments: A=anterior, AR=anterior-right, PR=posterior-right, P=posterior, PL=posterior-left, AL=anterior-left). Results Integrated bioinformatic analyses of RNA-sequencing and proteomic datasets identified 5 microRNAs (miR-128-3p, miR-210-3p, miR-150-5p, miR-199b-5p, and miR-21-5p) differentially expressed across the AAo circumference. Among them, three miRNAs (miR-128-3p, miR-150-5p, and miR-199b-5p) were predicted to have an effect on eight common target genes, whose expression was dysregulated according to proteomic analyses and involved in vascular endothelial growth factor signalling, hippo signaling and arachidonic acid pathway. Decreased elastic fibre levels and elastic layer thickness were observed in the dilated segments in the histomorphometric analysis. Increased WSS and flow-velocity, helical streamlines and asymmetrical flow were observed at the anterior/right wall in asymmetrically and symmetrically dilated patients (the latter exhibiting higher WSS), compared to healthy volunteers. Conclusion This study has newly revealed concomitant expressional dysregulation of miRNAs, proteins, and elastic fibres on the anterior/right wall in dilated BAV patients, corresponding to regions of elevated WSS, contributing to advance the understanding of the interplay of genetic and hemodynamic factors underpinning BAV aortopathy. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation and Above & Beyond

Treatment Activity of Ho(III)-Based Coordination Polymer on Liver Cancer by the Inhibition of Vascular Endothelial Growth Factor Signaling Pathway Activity

A new 0D dinuclear coordination polymer [Ho2(L)6(phen)2] (1) was hydrothermally synthesized based on HoCl3·6H2O, organic ligand HL = 3-hydroxybenzoic acid, and the auxiliary ligand phen = 1,10-phenanthroline (L− is the fully deprotonated organic ligand), and full characterization of the structure was performed via the X-ray single-crystal diffraction data. Once this newly synthesized novel compound was achieved, the way it acted inside the liver cancer was examined, and the corresponding mechanism was determined. First, the Cell Counting Kit-8 (CCK-8) method was conducted to analyze the compound activity after the treatment of liver cancer cells. In addition, real-time reverse-transcription polymerase chain reaction (RT-PCR) method was used to examine the in-cell vascular endothelial growth factor (VEGF) signaling pathway activity. The molecular docking simulation showed that the carboxyl and phenol groups contained active binding receptor sites, indicating that Ho complex has excellent biological activity.

Iron-based metal–organic framework as a dual cooperative release system for enhanced vascularization and bone regeneration

Vascularization and bone regeneration are closely related in the process of bone remodeling, and designing a bioactive scaffold with pro-angiogenic and osteogenic properties may accelerate the repair of bone defects. In this work, an iron-based metal–organic framework (MIL-88) was developed as a carrier for loading a pro-angiogenic small molecular drug (dimethyloxallyl glycine, DMOG), and then embedded into the PLGA nanofibrous scaffolds to repair cranial defects in rats. Imaging and histological evaluation indicated that PLGA/MIL@D scaffold markedly enhanced vascularization and bone regeneration in vivo. Moreover, in vitro assay showed that co-delivery system significantly promoted angiogenesis by stimulating endothelial cell migration, tube formation, and enhanced osteogenesis by promoting expression of osteoblast related proteins. In addition, PLGA/MIL@D scaffold promotes angiogenesis by activating the hypoxia-inducible factor-1 (HIF-1)/vascular endothelial growth factor (VEGF) signaling pathway. Altogether, this bioactive PLGA/MIL@D scaffold can combine angiogenesis with osteogenesis, and will be a bright strategy for the repair of bone defects.

Pharmacological effects of the Cassia Seed on atherosclerosis: A meta-analysis based on network pharmacology.

The aim of this study was to shed light on the active ingredients and potential targets of Cassia Seed about anti-atherosclerosis based on network pharmacology. The active ingredients and potential targets of Cassia Seed were obtained from traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) and SwissTargetPrediction database. Then, atherosclerosis-related targets were screened via GeneCards, online mendelian inheritance in man, therapeutic target database and DrugBank database. The common targets and protein-protein interaction (PPI) network was later identified and built. Furthermore, we used the database for annotation, visualization and integrated discovery (DAVID) database server to accomplish the enrichment analysis. The compounds-targets-pathways network was ultimately constructed by Cytoscape. A total of 14 active ingredients and 475 related targets were sifted from Cassia Seed. Among 574 potential atherosclerotic targets, there were 99 targets overlapped with those of Cassia Seed. Topological analysis with Cytoscape revealed that proto-oncogene tyrosine-protein kinase proto-oncogene tyrosine-protein kinase Src, transcription factor AP-1 (JUN), mitogen-activated protein kinase 8 (MAPK8), mitogen-activated protein kinase 14 (MAPK14) and catenin beta-1 were considered as the hub gene. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis suggested that the Cassia Seed had the potential to influence varieties of biological processes and pathways, including positive regulation of smooth muscle cell proliferation, inflammatory response, tumor necrosis factor (TNF) signaling pathway, vascular endothelial growth factor (VEGF) signaling pathway and arachidonic acid (ARA) metabolism. Taken together, our findings support that anti-atherosclerosis effects of Cassia Seed are characterized by multi-component, multi-target and multi-path mechanism of action.

Comprehensive analysis of the lncRNAs, mRNAs, and miRNAs implicated in the immune response of Pinctada fucata martensii to Vibrio parahaemolyticus

Non-coding RNAs (ncRNAs) have been implicated in a variety of biological processes. However, most ncRNAs are of unknown function and are as-yet unannotated. The immune-related functions of ncRNAs in the pearl oyster Pinctada fucata martensii were explored based on transcriptomic differences in the expression levels of long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) in the hemocytes of P.f. martensii after challenge by the pathogenic bacterium Vibrio parahaemolyticus. Across the challenged and control pearl oysters, 144 miRNAs and 14,571 lncRNAs were identified. In total, 13,375 ncRNAs were differentially expressed between the challenged and control pearl oysters; in the challenged pearl oysters as compared to the controls, 15 miRNAs and 5147 lncRNAs were upregulated, while 51 miRNAs and 8162 lncRNAs were downregulated. The sequencing results were validated using quantitative real-time polymerase chain reaction (qRT-PCR) analysis. GO and KEGG pathway analysis showed that genes targeted by the differentially expressed ncRNAs were associated with the vascular endothelial growth factor (VEGF) signaling pathway and the nuclear factor kappa-B (NF-κB) signaling pathway. An lncRNA-mRNA-miRNA network that was developed based on the transcriptomic results of this study suggested that lncRNAs may compete with miRNAs for mRNA binding sites. This study may provide a useful framework for the detection of additional novel ncRNAs, as well as new insights into the pathogenic mechanisms underlying the response of P.f. martensii to V. parahaemolyticus.

Investigation of the pharmacological effect and mechanism of mountain-cultivated ginseng and garden ginseng in cardiovascular diseases based on network pharmacology and zebrafish experiments.

Ginseng (Panax ginseng C.A. Mey) is a kind of perennial herb of the Panax genus in the Araliaceae family. The secondary metabolites of mountain-cultivated ginseng (MCG) and garden ginseng (GG) vary greatly due to their different growth environments. To date, the differences in their pharmacological effects on cardiovascular diseases (CVDs) and their clinical applications remain unclear. To distinguish between the components of MCG and GG, ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS) was performed. Next, the relationship between the expression of metabolites and the categories of the sample were analyzed using supervised partial least squares discriminant analysis and orthogonal partial least squares discriminant analysis. A network-based pharmacology approach was developed and applied to determine the underlying mechanism of different metabolites in CVD. In the present study, the role of MCG and GG in angiogenesis and their protective effects on damaged blood vessels in a vascular injury model of zebrafish were investigated. Using UPLC-Q-TOF/MS, 11 different metabolites between MCG and GG were identified. In addition, 149 common target genes associated with the metabolites and CVD were obtained; these targets were related to tumor protein P53, proto-oncogene tyrosine-protein kinase Src, human ubiquitin-52 amino acid fusion protein, ubiquitin-40S ribosomal protein S27a, polyubiquitin B, signal transducer and activator of transcription 3, isocitrate dehydrogenase 1, vascular endothelial growth factor A, glycose synthase kinase-3B, and coagulation factor II and were associated with the regulation of the phosphoinositide 3-kinase-Akt signaling pathway, the tumor necrosis factor signaling pathway, and the hypoxia-inducible factor-1 (HIF-1) signaling pathway, which play important roles in the curative effect in CVD treatment. Both types of ginseng can promote the growth of the subintestinal vessel plexus and protect injured intersegmental vessels through the HIF-1α/vascular endothelial growth factor signaling pathway in a dose-dependent manner. In addition, MCG has a stronger impact than GG. This is the first time metabolomics and network pharmacology methods were combined to study the difference between MCG and GG on CVDs, which provides a significant theoretical basis for the clinical treatment of CVD with two kinds of ginseng.

The Study on the Action Mechanism of the Jinyingzi (Rosae Laevigatae Fructus)–Qianshi (Euryales Semen) Couplet Herbs on Membranous Nephropathy Based on Network Pharmacology

Abstract Objective Our objective was to explore the action mechanism of the Jinyingzi (Rosae Laevigatae Fructus)–Qianshi (Euryales Semen) couplet herbs in the treatment of membranous nephropathy (MN) based on network pharmacology. Methods The active ingredients and targets of Jinyingzi (Rosae Laevigatae Fructus) and Qianshi (Euryales Semen) were screened by systematic pharmacology database and analysis platform. Online Human Mendelian Genetic database and GeneCards database were used to retrieve MN-related targets. The active ingredient-related targets and MN disease targets were introduced into Venny 2.1, and Wayne diagram was drawn. The intersection targets were the potential targets of the Jinyingzi (Rosae Laevigatae Fructus)–Qianshi (Euryales Semen) couplet herbs in the treatment of MN. The protein interaction network of potential targets was constructed, and the core targets were screened with String platform. Metascape platform was used for functional enrichment analysis of gene ontology (GO) and pathway enrichment analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG). The “herb-active ingredient-target-pathway” networks were drawn by using Cytoscape software, and the key components, targets, and signaling pathways were screened. Results A total of 8 active ingredients and 193 related targets in Jinyingzi (Rosae Laevigatae Fructus) and Qianshi (Euryales Semen) were screened out; a total of 1,621 targets of MN disease and 105 potential targets for the treatment of MN were obtained in the treatment with Jinyingzi (Rosae Laevigatae Fructus)–Qianshi (Euryales Semen) couplet herbs; 40 core targets were screened by protein–protein interaction network topology analysis; a total of 1,978 results were obtained by GO function enrichment analysis, and 206 signal pathways were obtained by KEGG pathway enrichment analysis and screening. The network topology analysis of “herb-active ingredient-target-pathway” showed that the key components included quercetin, kaempferol, β-sitosterol, etc.; the key targets included protein kinase Bα (AKT), mitogen-activated protein kinase 1 (MAPK1), B-cell lymphoma-2 (BCL2), prostaglandin-endoperoxide synthase 2 (PTGS2), etc.; the key pathways included advanced glycation end product/receptor of AGE signaling pathway, phosphatidyl inositol 3-kinase (PI3K)/AKT signaling pathway, MAPK signaling pathway, hypoxia-inducible factor-1 signaling pathway, Ras signaling pathway, nuclear factor kappa-B (NF-κB) signaling pathway, Toll-like receptors signaling pathway, p53 signaling pathway and vascular endothelial growth factor signaling pathway in the late stage of diabetic complications. Conclusion The Jinyingzi (Rosae Laevigatae Fructus)–Qianshi (Euryales Semen) couplet herbs can regulate PI3K/AKT, MAPK, NF-κB signaling pathways in MN by targeting proteins of AKT1, MAPK8, PTGS2 through key components of quercetin, β-sitosterol, and kaempferol, so as to inhibit the overexpression of inflammatory factors in renal tissues, regulate inflammatory response, and improve renal function.

Circulating microRNA associated with future relapse status in major depressive disorder.

Major depressive disorder (MDD) is an episodic condition with relapsing and remitting disease course. Elucidating biomarkers that can predict future relapse in individuals responding to an antidepressant treatment holds the potential to identify those patients who are prone to illness recurrence. The current study explored relationships between relapse risk in recurrent MDD and circulating microRNAs (miRNAs) that participate in RNA silencing and post-transcriptional regulation of gene expression. Serum samples were acquired from individuals with a history of recurrent MDD who were followed longitudinally in the observational study, OBSERVEMDD0001 (ClinicalTrials.gov Identifier: NCT02489305). Circulating miRNA data were obtained in 63 participants who relapsed (“relapsers”) and 154 participants who did not relapse (“non-relapsers”) during follow-up. The miRNA was quantified using the ID3EAL™ miRNA Discovery Platform from MiRXES measuring 575 circulating miRNAs using a patented qPCR technology and normalized with a standard curve from spike-in controls in each plate. The association between miRNAs and subsequent relapse was tested using a linear model, adjusting for age, gender, and plate. Four miRNAs were nominally associated with relapse status during the observational follow-up phase with a false discover rate adjusted p-value < 0.1. Enrichment analysis of experimentally validated targets revealed 112 significantly enriched pathways, including neurogenesis, response to cytokine, neurotrophin signaling, vascular endothelial growth factor signaling, relaxin signaling, and cellular senescence pathways. These data suggest these miRNAs putatively associated with relapse status may have the potential to regulate genes involved in multiple signaling pathways that have previously been associated with MDD. If shown to be significant in a larger, independent sample, these data may hold potential for developing a miRNA signature to identify patients likely to relapse, allowing for earlier intervention.

Anti-Angiogenic Therapy in ALK Rearranged Non-Small Cell Lung Cancer (NSCLC).

The management of advanced lung cancer has been transformed with the identification of targetable oncogenic driver alterations. This includes anaplastic lymphoma kinase (ALK) gene rearrangements. ALK tyrosine kinase inhibitors (TKI) are established first-line treatment options in advanced ALK rearranged non-small cell lung cancer (NSCLC), with several next-generation ALK TKIs (alectinib, brigatinib, ensartinib and lorlatinib) demonstrating survival benefit compared with the first-generation ALK TKI crizotinib. Still, despite high objective response rates and durable progression-free survival, drug resistance inevitably ensues, and treatment options beyond ALK TKI are predominantly limited to cytotoxic chemotherapy. Anti-angiogenic therapy targeting the vascular endothelial growth factor (VEGF) signaling pathway has shown efficacy in combination with platinum-doublet chemotherapy in advanced NSCLC without a driver alteration, and with EGFR TKI in advanced EGFR mutated NSCLC. The role for anti-angiogenic therapy in ALK rearranged NSCLC, however, remains to be elucidated. This review will discuss the pre-clinical rationale, clinical trial evidence to date, and future directions to evaluate anti-angiogenic therapy in ALK rearranged NSCLC.

Study on the mechanism of Qiju Dihuang pill in the treatment of ophthalmic diseases based on systems pharmacology.

Qiju Dihuang pill is one of the common Traditional Chinese Medicine to treat ophthalmic diseases. In vivo studies have suggested that Qiju Dihuang pill can be used for treating glaucoma, and it can also be used clinically to treat cataract patients. However, the bioactive ingredients and the therapeutic mechanism of Qiju Dihuang pill on treating these ophthalmic diseases remained unclear. Presently, a systems pharmacology approach which combines pharmacokinetic screening, targeted fishing, biological function enrichment, network pharmacology, and molecular docking analysis, was employed. A total of 134 active ingredients with 72 corresponding targets are identified from Qiju Dihuang pill. Additionally, 3 core targets including CHRM1, ESR1, and AR are obtained from the ingredients and drug targets network analysis. Besides, gen ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis reveal 3 important biological pathways, that is, calcium signaling pathway, insulin signaling pathway and Vascular endothelial growth factor signaling pathway. In final, a molecular docking model was constructed to study the interaction mechanism between active components and drug targets at the molecular level. All the findings show that Qiju Dihuang pill achieves therapeutic effects on treating ophthalmic diseases by regulating the crucial targets of the compounds in it. This work not only provides insight into the therapeutic mechanism of herbal medicine in the treatment of ophthalmic diseases from a multiscale perspective, but also offers an effective approach for drug discovery and development of Traditional Chinese Medicine.

A bilayer collagen scaffold with bevacizumab stabilizes chondrogenesis and promotes osteochondral regeneration

Stem cell-based tissue engineering represents a promising therapeutic for osteochondral restoration. A bilayer scaffold with an appropriate niche can simultaneously induce stem cells for cartilage and bone regeneration. However, the engineered cartilage derived from stem cells tends to ossify due to vascular invasion. Bevacizumab possesses pronounced anti-angiogenic activity by inhibiting the vascular endothelial growth factor (VEGF) signaling pathway. Here, we prepared a bilayered collagen-based scaffold with bevacizumab loaded in the upper layer (Bev/collagen) to promote stable osteochondral regeneration. We show that this Bev/collagen scaffold possesses suitable bevacizumab release kinetics (nearly 100% at 7 weeks) to achieve the anti-angiogenic activity and prevents vascular invasion. When colonized with bone marrow stem cells, it also exhibited cytocompatibility to support in vitro cartilage regeneration. The engineered cartilage successfully maintained cartilaginous property in the upper layer after subcutaneous implantation in nude mice for 4 weeks and in situ transplantation in a rabbit osteochondral defect model for 8 weeks, resulting in satisfactory osteochondral regeneration. This study highlights a new avenue for osteochondral regeneration by leveraging anti-angiogenesis activity.

Network pharmacology identification and in Vivo validation of key pharmacological pathways of Phyllanthus reticulatus (Euphorbiaceae) leaf extract in liver cancer treatment

Ethnopharmacological relevancePhyllanthus reticulatus (Euphorbiaceae) is a medicinal plant that has been used in Zhuang medicine since ancient times. Traditionally, it has the effect of removing toxins and detumescence and can be used to treat hepatitis in China and India. Our previous studies have proved that the ethyl acetate extract of its leaves (PRPE) has an anti-hepatoma effect. Aim of the studyTo predict targets of an ethyl acetate extract of Phyllanthus reticulatus leaves (PRPE) in hepatoma treatment via network pharmacology and verify the predictions in a mouse model of liver cancer. Materials and methodsChemical constituents and therapeutic targets of P. reticulatus (PRP) were searched and predicted via public databases. A protein-protein interaction network comprising common targets was constructed, and the key gene targets were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used for biological function and pathway enrichment analyses. The effects of PRP on BEL-7404 and HepG2 cells were determined by MTT assay, apoptosis was measured by flow cytometry and hoechst44432/PI. And a nude mouse xenograft model was established to verify the anti-tumour effect in vivo. The histopathology of tumours was observed by staining with haematoxylin and eosin (H&E). Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry were used to determine the gene and protein expression levels of phosphoinositide 3-kinase (PI3K), Akt1, p53, caspase-3, Bcl-2 and Bax, respectively. ResultsTwenty-seven chemical components and 567 potential therapeutic targets of PRP were identified. GO analysis indicated that these targets are mainly associated with peptidyl-tyrosine phosphorylation and steroid metabolic process. KEGG analysis showed that the targets are mainly located in the PI3K/Akt, apoptosis, mitogen-activated protein kinase (MAPK), Ras and vascular endothelial growth factor (VEGF) signalling pathways. According to the p-adjust value, the PI3K/Akt pathway is the core pathway. In vitro, PRPE could inhibit proliferation and induce apoptosis in hepatoma cells. IC50 values of PRPE were 2.48 and 6.34 mg/mL for BEL-7404 and hepG2 cells, respectively. PRPE significantly reduced tumour volume and weight. H&E results showed that PRPE repaired necrotic areas in hepatoma cells. PRPE reduced the protein expression of PI3K, Akt1 and Bcl-2 and increased the protein expression of p53 and Bax. Meanwhile, PRPE reduced the mRNA expression of PI3K, AKT1 and BCL2 and increased the mRNA expression of TP53, CASP3 and BAX. ConclusionThe targets of PRPE are the PI3K/Akt, apoptosis, MAPK, Ras and VEGF signalling pathways. Passing through the PI3K/Akt pathway to induce apoptosis is the main mechanism of PRPE.

Chlorinated benzothiadiazines inhibit angiogenesis through suppression of VEGFR2 phosphorylation

Angiogenesis inhibitors are a critical pharmacological tool for the treatment of solid tumors. Suppressing vascular permeability leads to inhibition of tumor growth, invasion, and metastatic potential by blocking the supply of oxygen and nutrients. Disruption of the vascular endothelial growth factor (VEGF) signaling pathway is a validated target for the design of antiangiogenic agents. Several VEGFR2 inhibitors have been clinically approved over the past years. Structural analysis of these clinical VEGFR2 inhibitors highlighted key functional group overlap with the benzothiadiazine core contained in a library of in-house compounds. Herein we ascribe anti-angiogenic activity to a series of chlorinated benzothiadiazines. Selected compounds show significant activity to completely ameliorate VEGF-induced endothelial cell proliferation by suppression of VEGFR2 phosphorylation. The scaffold is devoid of activity to inhibit carbonic anhydrases and generally lacks cytotoxicity across a range of cancer and non-malignant cell lines. Assay of activity at 468 kinases shows remarkable selectivity with only four kinases inhibited > 65% at 10 µM concentration, and with significant activity to inhibit TNK2/ACK1 and PKRD2 by > 90%. All four identified kinase targets are known modulators of angiogenesis, thus highlighting compound 17b as a novel angiogenesis inhibitor for further development.

Endothelial Regulation of Microvascular Growth and Stability by Ang‐Tie and VEGF Signaling Pathways: A Mechanistic Computational Systems Biology Model

The Angiopoietin‐Tie (Ang‐Tie) pathway is a key signaling pathway regulating vascular stability and permeability, and it significantly intersects and crosstalk with the vascular endothelial growth factor (VEGF) signaling pathway, a major signaling pathway regulating angiogenesis and vascular permeability. Disrupted Ang‐Tie and VEGF signaling is linked to vascular dysfunction related to cancer, systemic inflammation, cardiovascular disease, and diabetic macular edema. Ang‐Tie pathway is regulated by various molecular mechanisms, including ligand‐receptor interactions, receptor multimerization, binding of co‐receptor Tie1, inhibition by vascular endothelial protein tyrosine phosphatase (VE‐PTP), receptor extracellular domain shedding, junctional localization, trafficking, and turnover. VEGF pathway is regulated by ligand binding, homo‐ and heterodimerization of VEGF receptors VEGFR1 and VEGFR2, interaction with neuropilin, thrombospondin‐1/CD47, receptor internalization, recycling, and degradation. Ang‐Tie and VEGF signaling pathways also share crosstalk mechanisms and integrative downstream signaling through phosphoinositide 3‐kinases (PI3K)/Akt, sphingosine‐dependent Erk activation, Src sequestration via RhoA/mDia, and calcium cycling, forming a complex reaction network that requires an integrative model to study the signaling outcomes on a systems level. The present study uses a mechanistic computational model of the Ang‐Tie and VEGF signaling pathways, their regulatory mechanisms, crosstalk, and integrative downstream signaling to quantitatively characterize the molecular control of vascular growth, permeability, and stability by endothelial cells. The model captures and reproduces key experimental observations of the Ang‐Tie/VEGF signaling network with detailed molecular mechanisms. The model significantly expands our previous computational models of the Ang‐Tie signaling pathway [1,2] and integrates our systems biology understanding of the VEGF pathway and their crosstalk. The model serves as a platform for quantitatively predicting the signaling outcome of varying ligand concentrations and receptor expressions in physiological and pathological conditions, identifying molecular mechanisms and targets for therapeutic interventions targeting the signaling network, and simulating the effects of drugs and their combinations on the signaling outcome on a network level.

Eugenol suppresses the proliferation and invasion of TNF-α-induced fibroblast-like synoviocytes via regulating NF-κB and COX-2

Eugenol (4-allyl -2- methoxyphenol), reportedly, a native compound that widely exists in a variety of plants, shows diverse biological activities such as anti-bacteria, anti-inflammation and anti-oxidation. This work was to delve into the effects and molecular mechanisms of eugenol on the phenotypes of fibroblast-like synovial cells from rheumatoid arthritis (RA). Fibroblast-like synovial cells treated with tumor necrosis factor-α (TNF-α) for 24 h received eugenol treatment. In this study, we found eugenol could inhibit TNF-α-induced proliferation, migration, invasion, angiogenesis and inflammatory response of fibroblast-like synovial cells, and promote apoptosis. Eugenol's target genes were significantly associated with vascular endothelial growth factor (VEGF) and NF-kappaB (NF-κB) signaling pathway. Eugenol reversed the promoting effect of TNF-α on the expression of NF-κB signaling pathway-related proteins as well as prostaglandin-endoperoxide synthase 2 (PTGS2, also known as COX-2) protein. In addition, the NF-κB pathway inhibitor Bay11-7082 markedly restrained the viability, migration, aggressiveness, and angiogenic and inflammatory responses of TNF-α-induced fibroblast-like synovial cells and promoted apoptosis. In conclusion, eugenol may represent a novel drug to suppress the progression of RA by inhibiting NF-κB signaling pathway and COX-2 expression in fibroblast-like synovial cells.

MiR-155 regulates physiological angiogenesis but an miR-155-rich microenvironment disrupts the process by promoting unproductive endothelial sprouting.

Angiogenesis involves cell specification orchestrated by regulatory interactions between the vascular endothelial growth factor and Notch signaling pathways. However, the role of microRNAs in these regulations remains poorly explored. Here we show that a controlled level of miR-155 is essential for proper angiogenesis. In the mouse retina angiogenesis model, antimiR-155 altered neovascularization. In vitro assays established that endogenous miR-155 is involved in podosome formation, activation of the proteolytic machinery and cell migration but not in morphogenesis. The role of miR-155 was explored using miR-155 mimics. In vivo, exposing the developing vasculature to miR-155 promoted hypersprouting, thus phenocopying defects associated with Notch deficiency. Mechanistically, miR-155 overexpression weakened Notch signaling by reducing Smad1/5 expression, leading to the formation of tip cell-like cells which did not reach full invasive capacity and became unable to undergo morphogenesis. These results identify miR-155 as a novel regulator of physiological angiogenesis and as a novel actor of pathological angiogenesis.

Therapeutic Effect of Cu(II) Complex with Photocatalytic Property on Gastric Cancer by Inhibiting the Proliferation of Tumor Cells

In situ hydrolysis of 1,4,5,8-naphthalenetetracarboxylic dianhydride (L) and simultaneous self-assembly with Cu(II) ions afforded a new Cu(II) compound formulated as [Cu(L) (4,4′-bpy)0.5(H2O)]n (1), which is structurally determined by a series of characterization techniques, such as powder X-ray diffraction (PXRD), thermogravimetric Analysis (TGA), and elemental analysis. It is noteworthy that compound 1 can catalyze the degradation of methylene blue (MB) in aqueous solution under UV irradiation. This paper also investigated and evaluated its application value and research mechanism in gastric cancer. However, we also used real-time reverse transcription-polymerase chain reaction (RT-PCR) to detect the activation of vascular endothelial growth factor (VEGF) signaling pathway, and Cell Counting Kit-8 (CCK-8) method was used to calculate the inhibition activity of 1 on gastric cancer cell viability.

Mechanisms of the Jian Pi Tiao Gan Yin in the treatment of simple obesity revealed by network pharmacology.

BackgroundThis study sought to examine the mechanism of the Jian Pi Tiao Gan Yin in the treatment of obesity by network pharmacology.MethodsThe active components and corresponding targets of the Jian Pi Tiao Gan Yin were identified using the traditional Chinese medicine systems pharmacology database and analysis platform, and the obesity-related targets were acquired from the Online Mendelian Inheritance in Man database. The drug and disease targets were also identified. Cytoscape software was used to construct the “active component target” network diagram. The protein-protein interaction network was drawn using the Search Tool for the Retrieval of Interacting Genes/Proteins platform, and the Cytoscape MCODE plugin was used to find clusters for the protein cluster analysis. The gene annotation and analysis were performed with the Metascape database via functional databases, such as the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), and Autodock and PyMOL were used for the molecular docking.ResultsThe GO analysis identified 244 target genes of the Jian Pi Tiao Gan Yin, 1,378 targets of obesity, and 123 targets of drug and disease. Additionally, 208 biological process items, 38 molecular function items, and 33 cell component items were also identified. The KEGG pathway analysis identified the hypoxia-inducible factor, forkhead box O, cyclic adenosine monophosphate, and vascular endothelial growth factor signaling pathways. The results of the molecular docking showed that the main active components of the Jian Pi Tiao Gan Yin in the treatment of obesity were quercetin, kaempferol, stigmasterol, luteolin, isorhamnetin, β-sitosterol, sapogenin, tanshinone, and formononetin, all of which have been proven to bind to core obesity-related proteins, such as AKT1, interleukin-6 (IL-6), vascular endothelial growth factor A (VEGFA), tumor necrosis factor (TNF), tumor protein 53 (TP53), prostaglandin-endoperoxide synthase 2 (PTGS2), caspase-3 (CASP3), mitogen-activated protein kinase 1 (MAPK1), JUN, and epidermal growth factor (EGF). Thus, our study revealed the potential mechanism of the Jian Pi Tiao Gan Yin as a multi-component, multi-target, and multi-channel treatment for obesity. These findings lay the foundation for further studies on the mechanism of the Jian Pi Tiao Gan Yin in obesity treatment.ConclusionsThe Jian Pi Tiao Gan Yin can be used as a multi-component, multi-target, and multi-channel treatment for obesity.

Efficacy and safety of aflibercept plus chemotherapy in metastatic colorectal cancer: A systematic review and PRISMA-Compliant single-arm Meta-Analysis of noncomparative clinical studies and randomized controlled trials.

Aflibercept, a recombinant protein designed to suppress the vascular endothelial growth factor (VEGF) signalling pathway, has been used in patients with metastatic colorectal cancer (mCRC). We conducted the first meta-analysis to systematically review the efficacy and safety ofaflibercept in mCRC. PubMed Central/Medline, Embase and cochrane library were systematically searched for randomized controlled trials and single-arm clinical trials on aflibercept plus chemotherapy for the treatment of mCRC through 9 September 2021. Ten studies comprising 2049 patients met the inclusion criteria. The pooled estimate rates were 16.0% for 12mPFS, 64.4% for 12mOS, 32.5% for ORR, 83.5% for DCR, while the rates of III/IV AEs rate were 80.2% respectively. The pooled estimate rates were 16.8% for III/IV diarrhoea, 22.3% for III/IV hypertension, 29.5% for III/IV neutropenia, 7.3% for III/IV proteinuria and 8.6% for III/IV oral mucositis. Analysis of data from randomized controlled trials(RCT) and single-arm clinical trials confirmed the good efficacy of aflibercept plus chemotherapy in mCRC, while the safety of the treatment is concerning.