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Journal of Clinical and Diagnostic... Jun 2015Angiogenesis is a complex process depending on the coordination of many regulators and there by activating angiogenic switch. Recent advances in understanding of... (Review)
Review
Angiogenesis is a complex process depending on the coordination of many regulators and there by activating angiogenic switch. Recent advances in understanding of angiogenic mechanism have lead to the development of several anti-angiogenic and anti-metastatic agents that use the strategy of regulation of angiogenic switch. Antiangiogenic therapy is a form of treatment not cure for cancer and represents a highly effective strategy for destroying tumour because vascular supply is the fundamental requirement for growth of tumour. Because of the quiescent nature of normal adult vasculature, angiogenic inhibitors are expected to confer a degree of specificity when compared to nonspecific modalities of chemo and radiotherapy, so it has the advantage of less toxicities, does not induce drug resistance and deliver a relatively non toxic, long term treatment of tumour.
PubMed: 26266204
DOI: 10.7860/JCDR/2015/12016.6135 -
International Journal of Rheumatic... Feb 2015In 1983, Graham Hughes first described the concept of antiphospholipid syndrome (APS). In 1984, we described the enzyme-linked immunosorbent assay (ELISA) system which... (Review)
Review
In 1983, Graham Hughes first described the concept of antiphospholipid syndrome (APS). In 1984, we described the enzyme-linked immunosorbent assay (ELISA) system which directly detected circulating aCL in patients with systemic lupus erythematosus (SLE) who revealed biological false positive serological test for syphilis. In 1990, three groups, including our group, independently reported the necessity of a cofactor for the binding of autoimmune anticardiolipin antibodies (aCL) to the solid phase phospholipids. β2-glycoprotein I (β2GPI) was identified as this cofactor. In 1994,the epitope for aCL was shown to develop when β2GPI is adsorbed on polyoxygenated polystyrene plates. In 2000, we described antiprothrombin antibodies bind to prothrombin exposed to immobilized phosphatidylserine and established a phosphatidylserine dependent monoclonal antiprothrombin antibody. In 2004, a novel role of nicked β2GPI was identified in the negative feedback pathway of extrinsic fibrinolysis. Nicked β2GPI was found to bind angiostatin 4.5 and to attenuate its antiangiogenic property. In 2004, we demonstrated that the p38 MAPK pathway mediates induction of the TF gene in stimulated with human monoclonal anti- β2GPI antibodies. Very recently, β2GPI was identified as a complement regulator. The cross-link between complement activation and prothrombotic status in patients with APS has been drawn much attention. Genetic factors are hypothesized to play a role in the susceptibility to APS based on several family studies in patients with antiphospholipid antibodies (aPL) and/or clinical manifestations of APS. The genetics of β2GPI has been extensively studied. 247 Val/Leu polymorphism can affect the conformational change of β2-GPI and the exposure of the epitopes for aCL. We found that 247 Val was correlated with anti-β2-GPI production in patients with primary APS, and 247 Val may be important for β2-GPI antigenicity. STAT4 SNP in Japanese patients with SLE and/or APS. T allele frequencies in SLE and APS were significantly elevated compared with that in healthy controls. When analyzed only in primary APS patients, T allele frequency was further higher. BANK1, BLK and SNP in 1q25.1 region were associated with not only SLE but also APS in Japanese population. These results suggest that APS and SLE, in part, share a common genetic background.
Topics: Animals; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Complement Activation; Enzyme-Linked Immunosorbent Assay; Female; Genetic Predisposition to Disease; Humans; Lupus Erythematosus, Systemic; Male; Mice; Prognosis; Risk Assessment; beta 2-Glycoprotein I
PubMed: 25524556
DOI: 10.1111/1756-185X.12438 -
Oxidative Medicine and Cellular... 2019Angiogenesis is the process of new vessel formation, which sprouts from preexisting vessels. This process is highly complex and primarily involves several key steps,... (Review)
Review
Angiogenesis is the process of new vessel formation, which sprouts from preexisting vessels. This process is highly complex and primarily involves several key steps, including stimulation of endothelial cells by growth factors, degradation of the extracellular matrix by proteolytic enzymes, migration and proliferation of endothelial cells, and capillary tube formation. Currently, it is considered that multiple cytokines play a vital role in this process, which consist of proangiogenic factors (e.g., vascular endothelial growth factor, fibroblast growth factors, and angiopoietins) and antiangiogenic factors (e.g., endostatin, thrombospondin, and angiostatin). Angiogenesis is essential for most physiological events, such as body growth and development, tissue repair, and wound healing. However, uncontrolled neovascularization may contribute to angiogenic disorders. In physiological conditions, the above promoters and inhibitors function in a coordinated way to induce and sustain angiogenesis within a limited period of time. Conversely, the imbalance between proangiogenic and antiangiogenic factors could cause pathological angiogenesis and trigger several diseases. With insights into the molecular mechanisms of angiogenesis, increasing reports have shown that a close relationship exists between angiogenesis and oxidative stress (OS) in both physiological and pathological conditions. OS, an imbalance between prooxidant and antioxidant systems, is a cause and consequence of many vascular complains and serves as one of the biomarkers for these diseases. Furthermore, emerging evidence supports that OS and angiogenesis play vital roles in many dermatoses, such as psoriasis, atopic dermatitis, and skin tumor. This review summarizes recent findings on the role of OS as a trigger of angiogenesis in skin disorders, highlights newly identified mechanisms, and introduces the antiangiogenic and antioxidant therapeutic strategies.
Topics: Humans; Neovascularization, Pathologic; Oxidation-Reduction; Oxidative Stress; Skin Diseases
PubMed: 31178954
DOI: 10.1155/2019/2304018 -
Scientific Reports Feb 2023Although several angiogenesis-related factors are reportedly involved in the pathogenesis of ulcerative colitis (UC), the mechanisms by which they contribute to disease...
Although several angiogenesis-related factors are reportedly involved in the pathogenesis of ulcerative colitis (UC), the mechanisms by which they contribute to disease are unclear. We first examined the expression of angiogenesis-related factors in inflamed colorectal tissue of UC patients using antibody array, and identified the 5 factors with highest expression, which included matrix metalloproteinase-8, urokinase-type plasminogen activator (uPA), angiostatin/plasminogen, hepatocyte growth factor and endoglin. Subsequent real-time PCR experiments using additional colorectal tissues revealed that uPA mRNA levels were significantly higher in inflamed tissues than in non-inflamed tissues, and significantly correlated with the severity of UC. Mirror section immunohistochemistry revealed that uPA was expressed in the neutrophils of inflamed colorectal tissues. We administered dextran sulfate sodium (DSS) in drinking water to uPA knockout (uPA) mice, and found that the disease activity index in uPA mice was marginally lower and the histological score in uPA mice was significantly lower than those in wild-type mice, suggesting the importance of uPA in colitis. When an uPA-selective inhibitor, UK122, was administered to DSS-treated C57BL6J mice, the disease activity index and histological score in those mice were significantly lower compared with control mice. Multiple cytokine/chemokine assay using colorectal tissues from uPA and UK122-treated mice revealed significantly lowered level of RANTES. In conclusion, uPA was highly expressed in neutrophils of the inflamed mucosa of UC patients, and the expression level correlated with the severity of UC. Genetic uPA deletion or pharmacological uPA blockade significantly ameliorated colitis in mice, concomitant with downregulation of RANTES.
Topics: Animals; Mice; Urokinase-Type Plasminogen Activator; Colitis; Colitis, Ulcerative; Serine Proteases; Colorectal Neoplasms
PubMed: 36806262
DOI: 10.1038/s41598-023-29824-1 -
Cell and Tissue Research Mar 2018Neutrophils, constituting the first line of defense, perform vital functions during immune surveillance. A key feature that assists in their prompt response to an... (Review)
Review
Neutrophils, constituting the first line of defense, perform vital functions during immune surveillance. A key feature that assists in their prompt response to an inflammatory signal is rapid migration to the affected site. They are normally short-lived but can be activated to live longer under the influence of an inflammatory stimulus. They can, thereby, release their toxic granule contents that are differentially housed inside the cytoplasm. Although these events are well characterized in the peripheral circulation, we are still far from fully understanding their recruitment in lungs. Lungs are a reservoir of neutrophils under steady-state. In the event of an infection or injury, they promptly activate and recruit to the alveolar compartment as well as the airways. Lung intravital microscopy has revealed that neutrophils display novel features during steady- and activated-state highlighting key differences in the lung vasculature compared to peripheral sites. This review will discuss neutrophil biology in lung inflammation and will highlight the role of angiostatin, an anti-angiogenic molecule, as well as vitronectin, an acute phase secreted plasma protein, in lung neutrophil recruitment.
Topics: Animals; Cell Movement; Humans; Lung; Models, Biological; Neutrophil Activation; Neutrophils; Pneumonia
PubMed: 29250746
DOI: 10.1007/s00441-017-2748-z -
Experimental Animals Nov 2023Epilepsy is the most common chronic disorder in the nervous system, mainly characterized by recurrent, periodic, unpredictable seizures. Post-translational modifications...
Epilepsy is the most common chronic disorder in the nervous system, mainly characterized by recurrent, periodic, unpredictable seizures. Post-translational modifications (PTMs) are important protein functional regulators that regulate various physiological and pathological processes. It is significant for cell activity, stability, protein folding, and localization. Phosphoglycerate kinase (PGK) 1 has traditionally been studied as an important adenosine triphosphate (ATP)-generating enzyme of the glycolytic pathway. PGK1 catalyzes the reversible transfer of a phosphoryl group from 1, 3-bisphosphoglycerate (1, 3-BPG) to ADP, producing 3-phosphoglycerate (3-PG) and ATP. In addition to cell metabolism regulation, PGK1 is involved in multiple biological activities, including angiogenesis, autophagy, and DNA repair. However, the exact role of PGK1 succinylation in epilepsy has not been thoroughly investigated. The expression of PGK1 succinylation was analyzed by Immunoprecipitation. Western blots were used to assess the expression of PGK1, angiostatin, and vascular endothelial growth factor (VEGF) in a rat model of lithium-pilocarpine-induced acute epilepsy. Behavioral experiments were performed in a rat model of lithium-pilocarpine-induced acute epilepsy. ELISA method was used to measure the level of S100β in serum brain biomarkers' integrity of the blood-brain barrier. The expression of the succinylation of PGK1 was decreased in a rat model of lithium-pilocarpine-induced acute epilepsy compared with the normal rats in the hippocampus. Interestingly, the lysine 15 (K15), and the arginine (R) variants of lentivirus increased the susceptibility in a rat model of lithium-pilocarpine-induced acute epilepsy, and the K15 the glutamate (E) variants, had the opposite effect. In addition, the succinylation of PGK1 at K15 affected the expression of PGK1 succinylation but not the expression of PGK1total protein. Furthermore, the study found that the succinylation of PGK1 at K15 may affect the level of angiostatin and VEGF in the hippocampus, which also affects the level of S100β in serum. In conclusion, the mutation of the K15 site of PGK1 may alter the expression of the succinylation of PGK1 and then affect the integrity of the blood-brain barrier through the angiostatin / VEGF pathway altering the activity of epilepsy, which may be one of the new mechanisms of treatment strategies.
Topics: Rats; Animals; Phosphoglycerate Kinase; Vascular Endothelial Growth Factor A; Blood-Brain Barrier; Lithium; Pilocarpine; Angiostatins; Seizures; Epilepsy; Adenosine Triphosphate
PubMed: 37258131
DOI: 10.1538/expanim.23-0019 -
Biological & Pharmaceutical Bulletin Mar 2022Anti-angiogenic gene therapy is a promising strategy in treating cancer. Endostatin and angiostatin are widely used in tumor anti-angiogenesis therapy. Our previous...
Anti-angiogenic gene therapy is a promising strategy in treating cancer. Endostatin and angiostatin are widely used in tumor anti-angiogenesis therapy. Our previous studies have shown that the BDS-hEA, a baculovirus long-term expressing the fusion protein of human endostatin and angiostatin, has a favorable effect in inhibiting the growth and angiogenesis of hepatocellular carcinoma. The purpose of this study was to further investigate its synergistic antitumor efficiency in combination with low-dose chemotherapeutic gemcitabine (GEM) on the subcutaneous hepatocellular carcinoma xenograft model in nude mice. The results showed that the combined group significantly inhibited (p < 0.05 or p < 0.01 or p < 0.001) the growth of tumor weight and volume, reduced the expression of ki67 (cell proliferation marker), CD31 (angiogenic marker) and Matrix metalloproteinase 9 (MMP-9, tumor invasion and metastasis marker) and increased the apoptosis of tumor cells compared with the monotherapy and control groups, respectively. Synergistic index results showed that BDS-hEA combined with GEM had a synergistic effect in inhibiting tumor volume, proliferation, microvessel density, metastasis and promoting tumor apoptosis. Furthermore, there were no metastatic nodules and obvious pathological changes in liver tissue of the combined group, and the serum liver function indicators aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T-BIL), alkaline phosphatase (ALP) and glutamyl transpeptidase (GGT) were significantly reduced (p < 0.05 or p < 0.01 or p < 0.001) in the BDS-hEA or GEM groups compared with the control group. Notably, the combined therapy showed lower levels of liver function indicators than the GEM group. These data support the view that the combination of BDS-hEA and GEM has a synergistic anti-tumor properties and can reduce the damage of liver to certain extent.
Topics: Angiogenesis Inhibitors; Angiostatins; Animals; Baculoviridae; Carcinoma, Hepatocellular; Deoxycytidine; Endostatins; Humans; Liver Neoplasms; Mice; Mice, Nude; Gemcitabine
PubMed: 34937830
DOI: 10.1248/bpb.b21-00857 -
Rheumatology (Oxford, England) Apr 2017SLE, a multisystem heterogeneous disease, is characterized by production of antibodies to cellular components, with activation of both the innate and the adaptive immune... (Review)
Review
SLE, a multisystem heterogeneous disease, is characterized by production of antibodies to cellular components, with activation of both the innate and the adaptive immune system. Decades of investigation of blood biomarkers has resulted in incremental improvements in the understanding of SLE. Owing to the heterogeneity of immune dysregulation, no single biomarker has emerged as a surrogate for disease activity or prediction of disease. Beyond identification of surrogate biomarkers, a multitude of clinical trials have sought to inhibit elevated SLE biomarkers for therapeutic benefit. Armed with new -omics technologies, the necessary yet daunting quest to identify better surrogate biomarkers and successful therapeutics for SLE continues with tenacity.
Topics: Angiostatins; Antibodies, Antinuclear; Autoantibodies; Biomarkers; Chemokine CCL2; Complement System Proteins; Cytokine TWEAK; Cytokines; DNA; Ferritins; Humans; Insulin-Like Growth Factor Binding Proteins; Lipocalin-2; Lupus Erythematosus, Systemic; Tumor Necrosis Factors; Vascular Cell Adhesion Molecule-1
PubMed: 28013203
DOI: 10.1093/rheumatology/kew407 -
Arthritis Research & Therapy Jan 2018The aim was to study urinary angiostatin, CXC chemokine ligand 4 (CXCL4) and vascular cell adhesion molecule-1 (VCAM-1) as biomarkers of renal disease in systemic lupus...
BACKGROUND
The aim was to study urinary angiostatin, CXC chemokine ligand 4 (CXCL4) and vascular cell adhesion molecule-1 (VCAM-1) as biomarkers of renal disease in systemic lupus erythematosus (SLE).
METHOD
Patients who fulfilled ≥ 4 American College of Rheumatology (ACR) criteria for SLE with active renal, active non-renal or inactive disease, and a group of healthy controls were studied. Urine samples were assayed for angiostatin, CXCL4 and VCAM-1 by ELISA, and normalized by creatinine. Receiver operating characteristic analysis was performed to obtain the best cutoff values to calculate the performance of these markers in differentiating the different groups of patients as compared to anti-double-stranded DNA (anti-dsDNA) and complement C3. Correlation between these urinary biomarkers and various renal parameters was also tested.
RESULTS
Patients with SLE (n = 227; 80 with inactive SLE, 67 with active non-renal disease and 80 with active renal disease; 94% women; age 39.2 ± 13.8 years) and 53 controls (96% women) were studied. All were ethnic Chinese. Urinary angiostatin, CXCL4 and VCAM-1 (normalized for creatinine) were significantly higher in patients with active renal disease than in patients with active non-renal disease, patients with inactive SLE and controls. These markers correlated significantly with total SLE disease activity index (SLEDAI) and renal SLEDAI scores, and with the urinary protein-to-creatinine ratio. Urine angiostatin exhibited higher specificity and sensitivity in differentiating active renal from active non-renal SLE (area under the curve (AUC) 0.87) than serum anti-dsDNA/C3. Urine CXCL4 (AUC 0.64) and VCAM-1 (AUC 0.73), on the other hand, performed similarly to anti-dsDNA/C3. All three markers performed comparably to anti-dsDNA/C3 in distinguishing active from inactive SLE. In a subgroup of 68 patients with paired renal biopsy, the urinary levels of these proteins did not differ significantly between the proliferative and non-proliferative types of lupus nephritis. Urinary CXCL4 and VCAM-1 correlated significantly with the histologic activity score, and urinary angiostatin correlated significantly with proteinuria in this subgroup.
CONCLUSIONS
Urinary angiostatin, CXCL4 and VCAM-1 are potential biomarkers for SLE, in particular lupus nephritis. Further longitudinal studies are necessary to delineate the performance of these markers in predicting renal flares and prognosis in SLE patients.
Topics: Adult; Angiostatins; Biomarkers; Female; Humans; Kidney Function Tests; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Platelet Factor 4; Sensitivity and Specificity; Vascular Cell Adhesion Molecule-1; Young Adult
PubMed: 29325582
DOI: 10.1186/s13075-017-1498-3 -
Current Medicinal Chemistry 2021Lupus nephritis (LN) is severe renal comorbidity associated with systemic lupus erythematosus (SLE), a complex autoimmune disorder with high morbidity and mortality.... (Review)
Review
Lupus nephritis (LN) is severe renal comorbidity associated with systemic lupus erythematosus (SLE), a complex autoimmune disorder with high morbidity and mortality. Diagnosis and monitoring of LN patients still rely on renal biopsy, a procedure that exposes patients to a variety of risks and is not capable of providing longitudinally information about disease prognosis. In this review, we summarized current data of recent promising biomarkers developed in the precision medicine era, particularly under genomic, transcriptomic, proteomic, and metabolomic techniques. Genome-wide association studies have been evaluating the role of endogenous elements beyond the autoimmunity in LN. Transcriptomic methods, including single-cell sequencing, are potential tools in identifying inflammatory signatures, miRNAs, and gene expression. Proteomic measures, including anti-C1q antibodies, cytokines, TLRs, VCAM-1, NGAL osteopontin, angiostatin, have been considered helpful to provide a more profound comprehension of the disease pathogenic processes. Metabolomic approaches may identify several abnormal metabolite profiles related to the impairment of cellular functions. Together, these accurate, non-invasive, and moderate-cost propedeutic resources may be the novel tools for recognizing, distinguishing, and predicting LN progression and prognosis. Furthermore, omics evaluation may also predict responsiveness to treatment and, consequently, change the way we manage LN cases in the near future.
Topics: Biomarkers; Genome-Wide Association Study; Humans; Lupus Erythematosus, Systemic; Lupus Nephritis; MicroRNAs; Proteomics
PubMed: 33583367
DOI: 10.2174/0929867328666210212102438