The establishment of a vascular supply is required for organ development and differentiation as well as for tissue repair and reproductive functions in the adult1 Neovascularization (angiogenesis) is also implicated in the pathogenesis of a number of disorders These include: proliferative retinopathies, age-related macular degeneration, tumors, rheumatoid arthritis, and psoriasis1,2 A strong correlation has been noted between density of microvessels in primary breast cancers and their nodal metastases and patient survival3 Similarly, a correlation has been reported between vascularity and invasive behavior in several other tumors4–6

The biology of vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen in vitro and an angiogenic inducer in a variety of in vivo models. Hypoxia has been shown to be a major inducer of VEGF gene transcription. The tyrosine kinases Flt-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2) are high-affinity VEGF receptors. The role of VEGF in developmental angiogenesis is emphasized by the finding that loss of a single VEGF allele results in defective vascularization and early embryonic lethality. VEGF is critical also for reproductive and bone angiogenesis. Substantial evidence also implicates VEGF as a mediator of pathological angiogenesis. In situ hybridization studies demonstrate expression of VEGF mRNA in the majority of human tumors. Anti-VEGF monoclonal antibodies and other VEGF inhibitors block the growth of several tumor cell lines in nude mice. Clinical trials with various VEGF inhibitors in a variety of malignancies are ongoing. Very recently, an anti-VEGF monoclonal antibody (bevacizumab; Avastin) has been approved by the Food and Drug Administration as a first-line treatment for metastatic colorectal cancer in combination with chemotherapy. Furthermore, VEGF is implicated in intraocular neovascularization associated with diabetic retinopathy and age-related macular degeneration.

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Vascular endothelial growth factor: basic science and clinical progress.

New blood vessel formation (angiogenesis) is a fundamental event in the process of tumor growth and metastatic dissemination. Hence, the molecular basis of tumor angiogenesis has been of keen interest in the field of cancer research. The vascular endothelial growth factor (VEGF) pathway is well established as one of the key regulators of this process. The VEGF/ VEGF-receptor axis is composed of multiple ligands and receptors with overlapping and distinct ligand-receptor binding specificities, cell-type expression, and function. Activation of the VEGF-receptor pathway triggers a network of signaling processes that promote endothelial cell growth, migration, and survival from pre-existing vasculature. In addition, VEGF mediates vessel permeability, and has been associated with malignant effusions. More recently, an important role for VEGF has emerged in mobilization of endothelial progenitor cells from the bone marrow to distant sites of neovascularization. The well-established role of VEGF in promoting tumor angiogenesis and the pathogenesis of human cancers has led to the rational design and development of agents that selectively target this pathway. Studies with various anti-VEGF/VEGF-receptor therapies have shown that these agents can potently inhibit angiogenesis and tumor growth in preclinical models. Recently, an anti-VEGF antibody (bevacizumab), when used in combination with chemotherapy, was shown to significantly improve survival and response rates in patients with metastatic colorectal cancer and thus, validate VEGF pathway inhibitors as an important new treatment modality in cancer therapy.

Role of the Vascular Endothelial Growth Factor Pathway in Tumor Growth and Angiogenesis

The existence of factors that stimulate blood vessel growth, thereby recruiting a neovascular supply to nourish a growing tumour, was postulated many decades ago, although the identification and isolation of these factors proved elusive. Now, vascular endothelial growth factor (VEGF), which was identified in the 1980s, is recognized as an essential regulator of normal and abnormal blood vessel growth. In 1993, it was shown that a monoclonal antibody that targeted VEGF results in a dramatic suppression of tumour growth in vivo, which led to the development of bevacizumab (Avastin; Genentech), a humanized variant of this anti-VEGF antibody, as an anticancer agent. The recent approval of bevacizumab by the US FDA as a first-line therapy for metastatic colorectal cancer validates the ideas that VEGF is a key mediator of tumour angiogenesis and that blocking angiogenesis is an effective strategy to treat human cancer.

Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer

Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis

To investigate the relationship between angiogenesis and hepatic tumorigenesis, we examined the expression of vascular endothelial growth factor (VEGF) in 8 human colon carcinoma cell lines and in 30 human colorectal cancer liver metastases. Abundant message for VEGF was found in all tumors, localized to the malignant cells within each neoplasm. Two receptors for VEGF, KDR and flt1, were also demonstrated in most of the tumors examined. KDR and flt1 mRNA were limited to tumor endothelial cells and were more strongly expressed in the hepatic metastases than in the sinusoidal endothelium of the surrounding liver parenchyma. VEGF monoclonal antibody administration in tumor-bearing athymic mice led to a dose- and time-dependent inhibition of growth of subcutaneous xenografts and to a marked reduction in the number and size of experimental liver metastases. In hepatic metastases of VEGF antibody-treated mice, neither blood vessels nor expression of the mouse KDR homologue flk-1 could be demonstrated. These data indicate that VEGF is a commonly expressed angiogenic factor in human colorectal cancer metastases, that VEGF receptors are up-regulated as a concomitant of hepatic tumorigenesis, and that modulation of VEGF gene expression or activity may represent a potentially effective antineoplastic therapy in colorectal cancer.

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Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis.

Induction of Vascular Endothelial Growth Factor by Insulin-like Growth Factor 1 in Colorectal Carcinoma

Pulmonary fibrosis in general is the final common outcome of various interstitial lung diseases. In recent years, the incidence of pulmonary fibrosis has been rising with poor prognosis. 6-gingerol is deemed as a functional polyphenol of ginger. The aim of the present study was to investigate the effect of 6-gingerol, on pulmonary fibrosis. Mice were randomly divided into four groups: control, bleomycin, bleomycin + 6-gingerol 100 mg/kg, bleomycin + 6-gingerol 250 mg/kg, and the survival rates of the groups were recorded. Pathological and fibrotic changes in the lungs were identified by H&E and Masson staining, respectively. The levels of hydroxyproline and protein deposited in lung tissues were then, respectively, determined by colorimetry and western blotting. Subsequently, the proportion of cells and inflammatory factors in the alveolar lavage fluid were estimated. Following the identification of the possibility of Sirtuin1 (SIRT1) in the pharmacological mechanism through molecular docking and western blotting, human embryonic lung fibroblasts MRC-5 were treated with TGF-β1 and SIRT1 inhibitor to study the role of SIRT1 in the regulatory effect of 6-gingerol. From the results, 6-gingerol was found to increase the survival rate of mice and reduce lung pathology and fibrosis in mice. And, it significantly reduced the levels of hydroxyproline and the proteins deposited in lung tissues. Moreover, the number of neutrophils, basophils, monocytes, and the levels of inflammatory factors in the alveolar lavage fluid were also reduced. SIRT1 inhibitor blocked the function of 6-gingerol to inhibit fibrosis. To sum up, 6-gingerol relieves pulmonary fibrosis via activating SIRT1. This finding expands the pharmacological effect of 6-gingerol, and it is expected to advance the development of treatments for pulmonary fibrosis.

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6-Gingerol, a functional polyphenol of ginger, reduces pulmonary fibrosis by activating Sirtuin1.

Background Autoimmune encephalomyelitis is a clinical condition in which memory and cognition is affected badly and is also associated with lower levels of consciousness or even coma in worse scenarios. It is a noninfectious condition which involves immune oriented inflammation. Objective The study's goal was to figure out what was causing the problem HMGB1 involved in regulating the autoimmune encephalomyelitis by regulating NF-κB. Materials and Methods The expressions of HMGB1, miR-129-5p, and TLR4/NF-κB signalling pathway-related proteins were measured by qRT-PCR. To explore the differences among its control, models, and all groups, histopathology, immunohistochemistry, and immunofluorescence tests were performed. Results According to the findings, miR-129-5p is in charge of suppressing HMGB1 production and inhibiting the TLR4/NF-κB signalling pathway. On development of autoimmune encephalomyelitis, neurons in the hippocampus area got injured in the miR-129-5p inhibitors class. In the miR-129-5p inhibitor class, expression of miR-129-5p reduced and HMGB1 elevated, increasing neuronal inflammation and damage. Impairment in the hippocampus, on the either side, was shown to be reduced in HMGB1 shRNA, miR-129-5p mimics, and TLR4/NF-κB classes. Conclusion According to the study's findings, there is indeed a link among increased miR-129-5p and decreased HMGB1 expression and also suppression of the TLR4/NF-κB signal transduction pathway in autoimmune encephalomyelitis in the miR-129-5p inhibitors group. As a result, we may assume the autoimmune disease illness has progressed once concentrations of HMGB1, TLR4/NF-κB, and miR-129-5p have decreased.

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Research on the Mechanism of HMGB1 Regulating Autoimmune Encephalomyelitis by Regulating NF-κB

Abstract In view of the association between long noncoding RNA OIP5-AS1 and osteoarthritis (OA) pathology, the corresponding potential mechanism is worthy of exploration. Primary chondrocytes were identified by morphological observation and immunohistochemical staining of collagen II. The association between OIP5-AS1 and miR-338-3p was analyzed by StarBase and dual-luciferase reporter assay. After the expression of OIP5-AS1 or miR-338-3p in interleukin (IL)-1β-stimulated primary chondrocytes and CHON-001 cells was manipulated, cell viability, proliferation, apoptosis rate, apoptosis-related protein (cleaved caspase-9, Bax) expressions, extracellular matrix (ECM) (matrix metalloproteinase (MMP)-3, MMP-13, aggrecan, and collagen II), PI3K/AKT pathway, and mRNA expressions of inflammatory factors (IL-6 and IL-8), OIP5-AS1, and miR-338-3p were determined by cell counting kit-8, EdU, flow cytometry, Western blot, and quantitative reverse transcription-polymerase chain reaction. As a result, the expression of OIP5-AS1 was downregulated in IL-1β-activated chondrocytes, while miR-338-3p was overexpressed. OIP5-AS1 overexpression reversed the effects of IL-1β on viability, proliferation, apoptosis, ECM degradation, and inflammation in chondrocytes. However, OIP5-AS1 knockdown exhibited opposite effects. Interestingly, the effects of OIP5-AS1 overexpression were partially offset by miR-338-3p overexpression. Furthermore, OIP5-AS1 overexpression blocked the PI3K/AKT pathway by modulating miR-338-3p expression. In sum, OIP5-AS1 promotes viability and proliferation, and inhibits apoptosis and ECM degradation in IL-1β-activated chondrocytes by targeting miR-338-3p through blocking the PI3K/AKT pathway, indicating an attractive strategy for OA treatment.

Hui Yuan

Papers

Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis.

Induction of Vascular Endothelial Growth Factor by Insulin-like Growth Factor 1 in Colorectal Carcinoma

6-Gingerol, a functional polyphenol of ginger, reduces pulmonary fibrosis by activating Sirtuin1.

Research on the Mechanism of HMGB1 Regulating Autoimmune Encephalomyelitis by Regulating NF-κB

lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes