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Nature Aging May 2021The plasma proteomic changes that precede the onset of dementia could yield insights into disease biology and highlight new biomarkers and avenues for intervention. We...
The plasma proteomic changes that precede the onset of dementia could yield insights into disease biology and highlight new biomarkers and avenues for intervention. We quantified 4,877 plasma proteins in nondemented older adults in the Atherosclerosis Risk in Communities cohort and performed a proteome-wide association study of dementia risk over five years (n = 4,110; 428 incident cases). Thirty-eight proteins were associated with incident dementia after Bonferroni correction. Of these, 16 were also associated with late-life dementia risk when measured in plasma collected nearly 20 years earlier, during mid-life. Two-sample Mendelian randomization causally implicated two dementia-associated proteins (SVEP1 and angiostatin) in Alzheimer's disease. SVEP1, an immunologically relevant cellular adhesion protein, was found to be part of larger dementia-associated protein networks, and circulating levels were associated with atrophy in brain regions vulnerable to Alzheimer's pathology. Pathway analyses for the broader set of dementia-associated proteins implicated immune, lipid, metabolic signaling and hemostasis pathways in dementia pathogenesis.
Topics: Humans; Aged; Proteomics; Alzheimer Disease; Brain; Proteome
PubMed: 37118015
DOI: 10.1038/s43587-021-00064-0 -
Biomedicine & Pharmacotherapy =... Jun 2020Angiogenesis is considered as a major progenitor in the progression of obesity. The current manuscript enumerates the extrinsic role of angiogenesis in obesity. (Review)
Review
PURPOSE
Angiogenesis is considered as a major progenitor in the progression of obesity. The current manuscript enumerates the extrinsic role of angiogenesis in obesity.
RESULT
High caloric diet and lack of physical exercise are the most common causes of obesity and related metabolic conditions. A grossly elevated levels of fat in adipose tissue escalate certain complications which further worsen the state of obesity. Enlargement of white adipose tissue (WAT), deposition of fat mass, proliferation of endothelial cells, production of inflammatory cytokines induces the formation of denovo capillaries from parent microvasculature. Also, several intracellular signaling pathways precipitate obesity. Though, angiostatic molecules (endostatin, angiostatin and TNP-470) have been designed to combat obesity and associated complications.
CONCLUSION
Adipose tissue trigger growth of blood capillaries, and in turn adipose tissue endothelial cells promote pre-adipocyte proliferation. Modulation of angiogenesis and treatment with angiostatic substances may have the potential to impair the progression of obesity.
Topics: Adipocytes; Adipose Tissue; Animals; Biomarkers; Humans; Neovascularization, Pathologic; Neovascularization, Physiologic; Obesity; Receptors, Notch; Vascular Endothelial Growth Factor A
PubMed: 32200253
DOI: 10.1016/j.biopha.2020.110103 -
Translational Psychiatry May 2022Angiostatin, an endogenous angiogenesis inhibitor generated by the proteolytic cleavage of plasminogen, was recently reported to contribute to the development of...
Angiostatin, an endogenous angiogenesis inhibitor generated by the proteolytic cleavage of plasminogen, was recently reported to contribute to the development of Alzheimer's disease (AD). However, whether there are pathological changes in angiostatin levels in individuals with AD dementia is unclear, and whether plasma angiostatin has a relationship with major AD pathological processes and cognitive impairment remains unknown. To examine plasma angiostatin levels in patients with AD dementia and investigate the associations of angiostatin with blood and cerebrospinal fluid (CSF) AD biomarkers, we conducted a cross-sectional study including 35 cognitively normal control (CN) subjects and 59 PiB-PET-positive AD dementia patients. We found that plasma angiostatin levels were decreased in AD dementia patients compared to CN subjects. Plasma angiostatin levels were negatively correlated with plasma Aβ42 and Aβ40 levels in AD dementia patients and positively correlated with CSF total tau (t-tau) levels and t-tau/Aβ42 in AD dementia patients with APOE-ε4. In addition, plasma angiostatin levels had the potential to distinguish AD from CN. These findings suggest a link between angiostatin and AD pathogenesis and imply that angiostatin might be a potential diagnostic biomarker for AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Angiostatins; Biomarkers; Cognitive Dysfunction; Cross-Sectional Studies; Humans; Peptide Fragments; tau Proteins
PubMed: 35538065
DOI: 10.1038/s41398-022-01962-6 -
American Journal of Translational... 2021Dyslipidemia aggravates kidney injury distal to atherosclerotic renal artery stenosis (ARAS). Besides dyslipidemia, metabolic syndrome (MetS) also involves development...
BACKGROUND
Dyslipidemia aggravates kidney injury distal to atherosclerotic renal artery stenosis (ARAS). Besides dyslipidemia, metabolic syndrome (MetS) also involves development of obesity and insulin-resistance (IR). We hypothesized that concurrent obesity and IR magnify swine stenotic-kidney damage beyond dyslipidemia.
METHODS
Pigs with unilateral RAS were studied after 16 weeks of atherogenic diets without (ARAS) or with (MetS + RAS) development of obesity/IR (n=6 each). Additional pigs on normal diet served as normal or non-dyslipidemic RAS controls (n=6 each). Stenotic-kidney renal blood flow (RBF), glomerular filtration rate (GFR), and microvascular architecture were studied using CT, and oxygenation was studied using blood oxygen level-dependent magnetic-resonance-imaging. We further compared kidney adiposity, oxidative stress, inflammation, apoptosis, fibrosis, and systemic levels of oxidative and inflammatory cytokines.
RESULTS
ARAS and MetS + RAS developed hypertension and dyslipidemia, and MetS + RAS also developed obesity and IR. RBF and GFR were similarly decreased in all post-stenotic pig kidneys compared to normal pig kidneys, yet MetS + RAS aggravated and expanded medullary hypoxia and microvascular loss. RAS and ARAS increased systemic levels of tumor necrosis factor (TNF)-α, which were further elevated in MetS + RAS. Renal oxidative stress and TNF-α expression increased in ARAS and further in MetS + RAS, which also upregulated expression of anti-angiogenic angiostatin, and magnified apoptosis, tubular injury, and fibrosis.
CONCLUSION
Beyond dyslipidemia, obesity and insulin-resistance aggravate damage in the post-stenotic kidney in MetS, despite relative hyperfiltration-related preservation of renal function. These observations underscore the need to control systemic metabolic disturbances in order to curb renal damage in subjects with ischemic kidney disease.
PubMed: 34540008
DOI: No ID Found -
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 -
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 -
The Journal of Thoracic and... Jul 2023Our recent studies using a porcine model of metabolic syndrome (MS) and chronic myocardial ischemia show that extracellular vesicle (EV) therapy improves blood flow and...
OBJECTIVE
Our recent studies using a porcine model of metabolic syndrome (MS) and chronic myocardial ischemia show that extracellular vesicle (EV) therapy improves blood flow and arteriogenesis in ischemic myocardium, although mechanisms of these changes are unclear. We hypothesized that in the setting of MS, EV therapy would decrease antiangiogenic signaling to mediate increased blood flow to chronically ischemic myocardium.
METHODS
Yorkshire swine were fed a high-fat diet for 4 weeks to induce MS, then underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs underwent intramyocardial injection of vehicle (control, n = 6) or human bone marrow-derived EVs (n = 8). Five weeks later, left ventricular myocardium in ischemic territory was harvested. Protein expression was measured using immunoblot analysis, and data were analyzed using Wilcoxon rank sum test. Myocardial perfusion was measured with isotope-labeled microspheres, and correlation data were analyzed using Spearman rank correlation coefficient.
RESULTS
EV treatment was associated with decreased expression of antiangiogenic proteins, angiostatin (P < .001) and endostatin (P = .043) in ischemic myocardium compared with control. In EV-treated pigs, there was a negative correlation between blood flow to ischemic myocardium and angiostatin (r = -0.76; P = .037), but not endostatin expression (r = .02; P = .98). EV treatment was also associated with decreased cathepsin D, which cleaves precursors to produce angiostatin and endostatin, in ischemic myocardium (P = .020).
CONCLUSIONS
In the setting of MS and chronic myocardial ischemia, EV therapy is associated with decreased expression of antiangiogenic proteins, which might contribute to increased blood flow to chronically ischemic myocardium.
Topics: Swine; Humans; Animals; Metabolic Syndrome; Angiostatins; Disease Models, Animal; Myocardial Ischemia; Myocardium; Extracellular Vesicles; Coronary Circulation
PubMed: 36244819
DOI: 10.1016/j.jtcvs.2022.09.019 -
Cellular and Molecular Life Sciences :... Jan 2022In the cartilage matrix, complex interactions occur between angiogenic and anti-angiogenic components, growth factors, and environmental stressors to maintain a proper... (Review)
Review
In the cartilage matrix, complex interactions occur between angiogenic and anti-angiogenic components, growth factors, and environmental stressors to maintain a proper cartilage phenotype that allows for effective load bearing and force distribution. However, as seen in both degenerative disease and tissue engineering, cartilage can lose its vascular resistance. This vascularization then leads to matrix breakdown, chondrocyte apoptosis, and ossification. Research has shown that articular cartilage inflammation leads to compromised joint function and decreased clinical potential for regeneration. Unfortunately, few articles comprehensively summarize what we have learned from previous investigations. In this review, we summarize our current understanding of the factors that stabilize chondrocytes to prevent terminal differentiation and applications of these factors to rescue the cartilage phenotype during cartilage engineering and osteoarthritis treatment. Inhibiting vascularization will allow for enhanced phenotypic stability so that we are able to develop more stable implants for cartilage repair and regeneration.
Topics: Aggrecans; Angiogenesis Inhibitors; Angiostatins; Animals; Apoptosis; Cartilage; Chondrocytes; Cytokines; Endostatins; Humans; Inflammation; Low Density Lipoprotein Receptor-Related Protein-1; Mice; Osteoarthritis; Osteogenesis; Regeneration; Serine Proteinase Inhibitors; Stem Cells; Thrombospondins; Tissue Engineering; Tissue Extracts; Troponin I; Vascular Endothelial Growth Factor A
PubMed: 35029764
DOI: 10.1007/s00018-021-04105-0 -
Stem Cells International 2024Angiogenesis plays a significant role in the human body, from wound healing to tumor progression. "Angiogenic switch" indicates a time-restricted event where the... (Review)
Review
Angiogenesis plays a significant role in the human body, from wound healing to tumor progression. "Angiogenic switch" indicates a time-restricted event where the imbalance between pro- and antiangiogenic factors results in the transition from prevascular hyperplasia to outgrowing vascularized tumor, which eventually leads to the malignant cancer progression. In the last decade, molecular players, i.e., angiogenic biomarkers and underlying molecular pathways involved in tumorigenesis, have been intensely investigated. Disrupting the initiation and halting the progression of angiogenesis by targeting these biomarkers and molecular pathways has been considered as a potential treatment approach for tumor angiogenesis. This review discusses the currently known biomarkers and available antiangiogenic therapies in cancer, i.e., monoclonal antibodies, aptamers, small molecular inhibitors, miRNAs, siRNAs, angiostatin, endostatin, and melatonin analogues, either approved by the U.S. Food and Drug Administration or currently under clinical and preclinical investigations.
PubMed: 38213742
DOI: 10.1155/2024/9077926 -
Nutrients Jun 2021The aim of our study was to evaluate if endothelial-dysfunction (ED) occurs in patients with primary Sjogren syndrome (pSS) and whether it is associated with the disease...
The aim of our study was to evaluate if endothelial-dysfunction (ED) occurs in patients with primary Sjogren syndrome (pSS) and whether it is associated with the disease characteristics and activity. A total of 46 patients with pSS and 30 controls, without known cardiovascular disease, were enrolled in this study. A flow-mediated-dilation (FMD) of the brachial artery, plasma concentrations of the nitric oxide (NO) metabolic pathway (ADMA, L-arginine, SDMA, cGMP), and markers of endothelial inflammatory function (PAI-1, sE-selectin) and angiogenesis (angiostatin, VEGF) were analyzed. The FMD was significantly lower in pSS patients (7.56 ± 3.08 vs. 10.91 ± 1.02%, = 0.043) and positively correlated with the Ro/SS-A-antibodies ( = 0.34, = 0.03), pulmonary involvement ( = 0.52, = 0.001) and inversely with ADMA ( = -0.35, = 0.04). Plasma ADMA, L-arginine and angiostatin levels were significantly higher in pSS patients (0.39 ± 0.08 vs. 0.36 ± 0.06 µmol/L, = 0.05; 29.07 ± 6.7 vs. 25.4 ± 5.23 µmol/L, = 0.01; 152.25 ± 60.99 vs. 120.07 ± 38.7 pg/mL, = 0.0, respectively). ADMA was associated with ESSDAI ( = 0.33, = 0.02), SCORE ( = 0.57, = 0.00003) and focus score ( = 0.38, = 0.04). In the multiple regression analysis, the ESSDAI was significantly and independently associated with plasma ADMA levels ( = 0.24, = 0.04). Moreover, plasma cGMP concentrations were negatively correlated with the disease duration ( = -0.31, = 0.03). Endothelial function is impaired in patients with pSS and associated with the measures of disease activity, which supports the key-role of inflammation in developing and maintaining accelerated atherosclerosis.
Topics: Adult; Arginine; Biomarkers; Brachial Artery; Cardiovascular Diseases; Endothelium, Vascular; Female; Heart Disease Risk Factors; Humans; Inflammation; Male; Middle Aged; Regression Analysis; Sjogren's Syndrome; Vascular Diseases
PubMed: 34204342
DOI: 10.3390/nu13062072