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Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify DYRK1A/PPARG/EGR1 pathway is responsible for Down syndrome-associated pulmonary hypertension.

Down syndrome (DS) is the most prevalent chromosomal disorder associated with a higher incidence of pulmonary arterial hypertension (PAH). The dysfunction of vascular endothelial cells (ECs) is known to cause pulmonary arterial remodeling in PAH, although the physiological characteristics of ECs harboring trisomy 21 (T21) are still unknown. In this study, we analyzed the human vascular ECs by utilizing the isogenic pairs of T21-induced pluripotent stem cells (iPSCs) and corrected disomy 21 (cDi21)-iPSCs. In T21-iPSC-derived ECs, apoptosis and mitochondrial reactive oxygen species (mROS) were s

Signaling metabolite succinylacetone activates HIF-1α and promotes angiogenesis in GSTZ1-deficient hepatocellular carcinoma.

Aberrant angiogenesis in hepatocellular carcinoma (HCC) is associated with tumor growth, progression, and local or distant metastasis. Hypoxia-inducible factor 1α (HIF-1α) is a transcription factor that plays a major role in regulating angiogenesis during adaptation of tumor cells to nutrient-deprived microenvironments. Genetic defects in Krebs cycle enzymes, such as succinate dehydrogenase and fumarate hydratase, result in elevation of oncometabolites succinate and fumarate, thereby increasing HIF-1α stability and activating the HIF-1α signaling pathway. However, whether other metabolites reg

Valproic acid enhances the viability of random pattern skin flaps: involvement of enhancing angiogenesis and inhibiting oxidative stress and apoptosis.

BACKGROUND: Random skin flaps are commonly applied during plastic surgery, but distal flap necrosis limits their clinical applications. Valproic acid (VPA), a histone deacetylase inhibitor and a traditional antiepileptic agent, may promote flap survival. MATERIALS AND METHODS: Sprague-Dawley rats were randomly divided into VPA-treated and control groups. All rats received VPA or saline by intraperitoneal injections once daily for 7 days after the modified McFarlane flap model was established. On postoperative day 7, flap survival, laser Doppler blood flow, and water content were examined for

Apatinib-loaded nanoparticles suppress vascular endothelial growth factor-induced angiogenesis and experimental corneal neovascularization.

Pathological angiogenesis is one of the major symptoms of severe ocular diseases, including corneal neovascularization. The blockade of vascular endothelial growth factor (VEGF) action has been recognized as an efficient strategy for treating corneal neovascularization. In this study, we aimed to investigate whether nanoparticle-based delivery of apatinib, a novel and selective inhibitor of VEGF receptor 2, inhibits VEGF-mediated angiogenesis and suppresses experimental corneal neovascularization. Water-insoluble apatinib was encapsulated in nanoparticles composed of human serum albumin (HSA)-

Temsirolimus targets multiple hallmarks of cancer to impede mesothelioma growth in vivo.

BACKGROUND AND OBJECTIVE: The mechanistic target of rapamycin (mTOR) promotes cancer cell proliferation and survival, transduces pro-angiogenic signals and regulates immune cell differentiation and function. We hypothesized that temsirolimus, an mTOR inhibitor, would curtail experimental mesothelioma progression in vivo by limiting tumour cell growth, abrogating tumour angiogenesis and modulating immune/inflammatory tumour milieu. METHODS: We produced flank and pleural syngeneic murine mesotheliomas by delivering AE17 and AB1 murine mesothelioma cells into the right flank or the pleural space

MT1-MMP silencing by an shRNA-armed glioma-targeted conditionally replicative adenovirus (CRAd) improves its anti-glioma efficacy in vitro and in vivo.

MMP14 (MT1-MMP) is a cell membrane-associated proteinase of the extracellular matrix, whose biological roles vary from angiogenesis to cell proliferation and survival. We recently found a direct correlation between MMP14 expression levels in brain tumors of glioma patients and the disease progression. By using gene silencing as an experimental approach we found that MMP14 knockdown decreases production of pro-angiogenic factors such as VEGF and IL8 and thereby suppresses angiogenesis in glioma tumors. Although the clinical relevance of MMP14 down-regulation and its possible implications for gl

Specific involvement of SRC family kinase activation in the pathogenesis of retinal neovascularization.

PURPOSE: Src family kinases (SFKs) are membrane-attached nonreceptor protein tyrosine kinases that link a variety of extracellular cues to intracellular signal pathways. The purpose of this study was to characterize the roles of SFKs in vascular endothelial growth factor (VEGF)-mediated retinal angiogenesis. METHODS: Primary rat retinal glial Müller cells and bovine and human retinal microvascular endothelial cells (RMECs) were used in the in vitro studies. A rat model of retinopathy of prematurity (ROP) was used in the in vivo studies. RESULTS: In vitro, SFKs were essential for hypoxia-indu

A ribonuclease inhibitor expresses anti-angiogenic properties and leads to reduced tumor growth in mice.

Our experiments were designed to determine whether recombinant ribonuclease inhibitor (RNasin) could inhibit angiogenesis and reduce tumor growth in adult mice. We used the Fajardo disc angiogenesis assay as the primary means of measuring new blood vessel growth. This assay measures the penetration of cells into a polyvinyl alcohol sponge with a central core of ELVAX-coated sponge containing test substances. Cell penetration was reduced to 29.3% of control (phosphate-buffered saline; heat-inactivated RNasin) values. Endothelial cell influx was measured by lectin staining and confirmed by cultu

Hypoxia-Inducible Factors in Rheumatoid Arthritis: Central Pathogenic Roles and Therapeutic Opportunities.

Rheumatoid arthritis (RA) joints are characterized by a persistently hypoxic microenvironment that drives activation of hypoxia-inducible factors (HIFs). In RA synovium, both HIF-1α and HIF-2α accumulate across key cellular compartments (fibroblast-like synoviocytes, macrophages, endothelial cells, and chondrocytes) and correlate with disease activity, positioning HIF signaling as a central node linking hypoxic stress to inflammation, metabolic rewiring, angiogenesis, and joint destruction. Notably, HIF-1α primarily regulates inflammatory responses and metabolic adaptation, whereas HIF-2α play

Pathogenesis of Neovascular Glaucoma in Diabetic Retinopathy: A Review.

Neovascular glaucoma (NVG) secondary to diabetic retinopathy (DR) is a severe complication driven by ischemia-induced angiogenesis. Current evidence indicates that the pathogenesis begins with retinal hypoxia caused by hyperglycemia-induced capillary occlusion, which stabilizes hypoxia-inducible factor-1α (HIF-1α) and upregulates vascular endothelial growth factor (VEGF). VEGF-A and placental growth factor (PlGF) drive abnormal angiogenesis in the retina, iris, and anterior chamber angle. Downregulation of endogenous inhibitors such as pigment epithelium-derived factor (PEDF) may exacerbate th

Realization of Osteolysis, Angiogenesis, Immunosuppression, and Drug Resistance by Extracellular Vesicles: Roles of RNAs and Proteins in Their Cargoes and of Ectonucleotidases of the Immunosuppressive Adenosinergic Noncanonical Pathway in the Bone Marrow Niche of Multiple Myeloma.

Angiogenesis and immunosuppression promote multiple myeloma (MM) development, and osteolysis is a primary feature of MM. Although immunomodulatory drugs and proteasome inhibitors (PIs) markedly improve the survival of patients with MM, this disease remains incurable. In the bone marrow niche, a chain of ectoenzymes, including CD38, produce immunosuppressive adenosine, inhibiting T cell proliferation as well as immunosuppressive cells. Therefore, anti-CD38 antibodies targeting myeloma cells have the potential to restore T cell responses to myeloma cells. Meanwhile extracellular vesicles (EVs) c

HIF-1-VEGF-Notch mediates angiogenesis in temporomandibular joint osteoarthritis.

Angiogenesis has been reported participated in temporomandibular joint osteoarthritis (TMJ-OA). While the pathogenesis is unclear, recent studies indicate that hypoxia is important in TMJ-OA. In order to induce osteoarthritis-like lesions in mandibular condyles, rats were sleep deprived experimentally. An increased number of blood vessels were observed in the rats' condyles of SD and SR group compared with controls. Protein and mRNA levels of related factors including VEGF, HIF-1 and Notch were investigated by means of immunohistochemical staining, western blot and real-time PCR, which were hi

Galectin Targeted Therapy in Oncology: Current Knowledge and Perspectives.

The incidence and mortality of cancer have increased over the past decades. Significant progress has been made in understanding the underpinnings of this disease and developing therapies. Despite this, cancer still remains a major therapeutic challenge. Current therapeutic research has targeted several aspects of the disease such as cancer development, growth, angiogenesis and metastases. Many molecular and cellular mechanisms remain unknown and current therapies have so far failed to meet their intended potential. Recent studies show that glycans, especially oligosaccharide chains, may play a

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… Scheduling of radiation with angiogenesis inhibitors anginex and avastin improves therapeutic outcome via vessel normalization. Clin. Cancer Res. 2007;13:3395–3402. doi: 10.1158/1078-0432.CCR-06-2441. 36. … Antiangiogenesis therapy using a novel angiogenesis inhibitor, anginex, following radiation causes tumor growth delay. Int. J. Clin. Oncol. 2007;12:42–47. doi: 10.1007/s10147-006-0625-y. 52. …

[Nephrotoxicity--proteinuria and hypertension--].

Targeted and biological therapies have been investigated as methods of improving anticancer therapy. One approach to targeted therapy is to inhibit tumor angiogenesis, which has a critical role in the development of cancer. However, the potential for further improvement in outcomes is likely to be limited by its nephrotoxic side effects such as urinary protein and hypertension. Among the anti-angiogenesis inhibitors, the humanized monoclonal antibody, bevacizumab, directed against VEGF(vascular endothelial growth factor), is the first anti-angiogenic agent to be approved for cancer therapy, bu…

Aspects of human fetoplacental vasculogenesis and angiogenesis. I. Molecular regulation.

Patterns of fetoplacental angiogenesis vary during gestation and in association with certain pregnancy pathologies. In a set of three linked reviews, we provide a survey of current knowledge about the molecular regulation, cellular players, qualitative and quantitative morphological features of the vascularization of human placental villi. Here, an account is given of the role played by hypoxia-inducible factor in mediating the effects of oxygen on production of growth factor ligands and receptors which regulate angiogenesis and vessel maturation. However, it should be noted that, for the huma

Exploring potential VEGF receptor 2 inhibitors: a molecular modeling and pharmacophore-based screening approach.

The vascular endothelial growth factor (VEGF) receptor 2, a membrane tyrosine kinase receptor activated by VEGF-A, triggers endothelial cell proliferation, migration, survival, and angiogenesis. With the aim of identifying additional new ligands or acquiring novel information to craft potent drugs, the focus of this study was to point to this macromolecule as to a possible target for selective modulators or inhibitors. Using the Pharmit server, pharmacophore-based screening of about 450 million compounds was performed, yielding candidate ligands evaluated through molecular modeling tools such

ERO1α as a Potential Drug Target for Breast Cancer: A Systematic Review of Current Evidence.

Hypoxia, oxidative stress, and impaired protein folding contribute to tumor progression and therapy resistance. Endoplasmic Reticulum Oxidoreductin 1 Alpha (ERO1α) is a key enzyme regulating redox homeostasis in the endoplasmic reticulum by reoxidizing protein disulfide isomerase, facilitating disulfide bond formation, and generating reactive oxygen species. Elevated ERO1α levels are associated with increased tumor aggressiveness, metastasis, and poor clinical outcomes. Despite growing evidence of its tumor-promoting functions, no clinically approved ERO1α inhibitors exist. This systematic rev

Design and synthesis of novel sulfanilamide derivatives as aminopeptidase N inhibitors.

Guided by the structural architecture of the aminopeptidase N (APN) active site, we designed and synthesized a series of novel APN inhibitors featuring sulfanilamide scaffold coupled with hydroxamate zinc-binding motifs. Among the series, compound 2k exhibited the inhibitory activity (IC50 = 4.3 μM) as effectively as a positive control drug Bestatin. Notably, our compounds exhibited pronounced selectivity against zinc-dependent metallopeptidase MMP-2. The SAR research indicated that ortho-disubstitution in the phenyl group could lead to an order of magnitude improvement. A molecular docking st

Surufatinib-induced renal thrombotic microangiopathy: first case report and review of literature.

Angiogenesis inhibitors such as tyrosine kinase inhibitors (TKIs) are common therapeutics currently used to treat oncologic disease. Surufatinib is a novel, small-molecule multiple receptor TKI approved by the National Medical Products Administration (NMPA) for the treatment of progressive, advanced, and well-differentiated pancreatic and extrapancreatic neuroendocrine tumours (NETs). Thrombotic microangiopathy (TMA) is a well-documented complication of TKIs targeting the VEGF-A/VEGFR2 signalling pathway. Here, we describe a 43-year-old female patient with biopsy-proven TMA and nephrotic syndr…

Development of a Selective Dual Discoidin Domain Receptor (DDR)/p38 Kinase Chemical Probe.

Discoidin domain receptors 1 and 2 (DDR1/2) play a central role in fibrotic disorders, such as renal and pulmonary fibrosis, atherosclerosis, and various forms of cancer. Potent and selective inhibitors, so-called chemical probe compounds, have been developed to study DDR1/2 kinase signaling. However, these inhibitors showed undesired activity on other kinases such as the tyrosine protein kinase receptor TIE or tropomyosin receptor kinases, which are related to angiogenesis and neuronal toxicity. In this study, we optimized our recently published p38 mitogen-activated protein kinase inhibitor