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International Journal of Molecular... Aug 2023The early identification of women with an increased risk of preeclampsia (PE) is desirable, but apart from soluble fms-like tyrosine kinase-1 (sFlt-1), few biomarkers... (Meta-Analysis)
Meta-Analysis Review
The early identification of women with an increased risk of preeclampsia (PE) is desirable, but apart from soluble fms-like tyrosine kinase-1 (sFlt-1), few biomarkers have previously been identified as relevant for predicting preeclampsia. Since kinases and phosphatases regulate critical biological processes and previous evidence suggests a potential role of these molecules in preeclampsia, we performed this systematic review and metanalysis. The objective was to determine if there are kinases and phosphatases whose serum levels are different between women with and without PE, being relevant biomarkers of PE. We followed the recommendations of Cochrane and the Preferred Reported Items for Systematic Reviews and Metanalysis (PRISMA) to perform this study. The MESH terms preeclampsia, kinases, phosphatases, angiopoietins, soluble tyrosine protein kinase receptor (sTIE2), and cellular-mesenchymal-epithelial transition factor (c-MET) were combined to find relevant articles in the PubMed, PROSPERO, and Cochrane databases. Then, a qualitative and quantitative analysis was performed in R Studio software. From 580 abstracts identified, 37 were included in the final analysis, which comprised 24,211 pregnant women (2879 with PE and 21,332 women without PE [HP]. The pooled analysis showed that serum creatine kinase (CK) (SMD: 2.43, CI 95% 0.25-4.62) was significantly higher in PE, whereas sTIE2 and anti-angiogenic factor soluble c-Met (sMet)were significantly lower in PE than in HP (SMD: -0.23, CI95% -0.37 to -0.09; and SMD:0.24, CI95% 0.01-0.47, respectively). Adenosine monophosphate-activated protein kinase (AMPK), angiopoietin-1 (ANG-1), angiopoietin-2 (ANG-2), the ratio angiopoietin-1/angiopoietin-2, acid phosphatase, and alkaline phosphatase were not different between women with PE and HP. In summary CK, sTIE2, and c-MET are relevant biomarkers of PE. It is desirable to incorporate them into current models for PE prediction to evaluate their utility as biomarkers.
Topics: Pregnancy; Female; Humans; Phosphoric Monoester Hydrolases; Angiopoietin-1; Angiopoietin-2; Pre-Eclampsia; Antibodies; Receptor, trkA
PubMed: 37629025
DOI: 10.3390/ijms241612842 -
Transactions of the American Clinical... 2023Microvascular endothelial activation/dysfunction has emerged as an important mechanistic pathophysiological process in the development of morbidity and mortality in...
Microvascular endothelial activation/dysfunction has emerged as an important mechanistic pathophysiological process in the development of morbidity and mortality in life-threatening infections. The angiopoietin-Tie2 system plays an integral role in the regulation of microvascular endothelial integrity. Angiopoietin-1 (Ang-1), produced by platelets and pericytes, is the cognate agonistic ligand for Tie2, promoting endothelial quiescence and inhibiting microvascular leak. Angiopoietin-2 (Ang-2), released from activated endothelial cells in Weibel-Palade bodies, competes with Ang-1 for binding to Tie-2, thereby promoting endothelial activation/dysfunction and microvascular leak. In healthy homeostasis, levels of Ang-1 far exceed Ang-2 in circulating serum/plasma. In diseases associated with systemic inflammation, Ang-1 falls and Ang-2 rises (i.e., Ang-1/2 dysregulation). Our research has shown that Ang-1/2 dysregulation is a prominent feature in a number of life-threatening infections and critical illnesses, including sepsis, cerebral malaria, COVID-19, streptococcal toxic shock syndrome (STSS), hemolytic-uremic syndrome (HUS), dengue, and CAR T-cell-associated neurotoxicity. Further work has implicated Ang-1/2 dysregulation in the development of end-organ injury, including acute lung injury/ARDS, acute kidney injury (AKI), and blood-brain-barrier (BBB) breakdown. Current studies are focused in three areas: (a) translation of Ang-1 and -2 as clinically informative prognostic and "theranostic" biomarkers in critically ill individuals; (b) incorporation of Ang-1/2 assays in a point of care device for clinical triage decision making; and (c) development of an engineered Ang-1 super agonist nanoparticle as a novel pathogen-agnostic therapeutic to prevent and/or mitigate end-organ dysfunction in individuals with life-threatening infections and critical illnesses associated with systemic inflammation.
Topics: Humans; Angiopoietins; COVID-19; Critical Illness; Endothelial Cells; Inflammation
PubMed: 37701588
DOI: No ID Found -
Open Biology Apr 2016Lipoprotein lipase (LPL) is a rate-limiting enzyme for hydrolysing circulating triglycerides (TG) into free fatty acids that are taken up by peripheral tissues.... (Review)
Review
Lipoprotein lipase (LPL) is a rate-limiting enzyme for hydrolysing circulating triglycerides (TG) into free fatty acids that are taken up by peripheral tissues. Postprandial LPL activity rises in white adipose tissue (WAT), but declines in the heart and skeletal muscle, thereby directing circulating TG to WAT for storage; the reverse is true during fasting. However, the mechanism for the tissue-specific regulation of LPL activity during the fed-fast cycle has been elusive. Recent identification of lipasin/angiopoietin-like 8 (Angptl8), a feeding-induced hepatokine, together with Angptl3 and Angptl4, provides intriguing, yet puzzling, insights, because all the three Angptl members are LPL inhibitors, and the deficiency (overexpression) of any one causes hypotriglyceridaemia (hypertriglyceridaemia). Then, why does nature need all of the three? Our recent data that Angptl8 negatively regulates LPL activity specifically in cardiac and skeletal muscles suggest an Angptl3-4-8 model: feeding induces Angptl8, activating the Angptl8-Angptl3 pathway, which inhibits LPL in cardiac and skeletal muscles, thereby making circulating TG available for uptake by WAT, in which LPL activity is elevated owing to diminished Angptl4; the reverse is true during fasting, which suppresses Angptl8 but induces Angptl4, thereby directing TG to muscles. The model suggests a general framework for how TG trafficking is regulated.
Topics: Angiopoietins; Animals; Biological Transport; Humans; Lipoprotein Lipase; Models, Biological; Signal Transduction; Triglycerides
PubMed: 27053679
DOI: 10.1098/rsob.150272 -
Asia-Pacific Journal of Ophthalmology... 2018Diabetic retinopathy and diabetic macular edema comprise a major source of visual disability throughout the developed world. The etiology and pathogenesis of macular... (Review)
Review
Diabetic retinopathy and diabetic macular edema comprise a major source of visual disability throughout the developed world. The etiology and pathogenesis of macular edema is intricate and multifactorial, in which the hyperglycemic state in diabetes induces a microangiopathy. Through several inflammatory and vasogenic mediators, including vascular endothelial growth factor (VEGF) upregulation and inflammatory cytokines and chemokines, pathologic changes are induced in the vascular endothelium triggering breakdown of the blood retinal barrier, causing extravasation of fluid into the extracellular space and manifesting clinically as macular edema, resulting in visual loss. The advent of medications targeting the VEGF pathway has led to great clinical improvements compared with the previous standard of care of laser therapy alone, as shown in studies such as RISE, RIDE, VIVID, VISTA, and DRCR. However, analyses have shown that many patients have inadequate response or are nonresponders to anti-VEGF therapy, demonstrating the need for additional therapies to more comprehensively treat this disease. Although corticosteroid treatments and implants have demonstrated some efficacy in adjunctive and supplemental treatment, the need to more adequately treat macular edema remains. Our knowledge of diabetic macular edema continues to grow, leading to new currently available and emerging pharmacotherapies to further enhance our treatment and restore vision in those affected by diabetic macular edema. This review will discuss the pathogenesis of diabetic macular edema and the pharmacologic therapies available for its treatment, including anti-VEGF, steroids, and newer therapies still in development, such as angiopoietin antagonists, Tie2 agonists, kallikrein inhibitors, interleukin inhibitors, and others.
Topics: Adrenal Cortex Hormones; Angiogenesis Inhibitors; Angiopoietins; Anti-Inflammatory Agents; Diabetic Retinopathy; Humans; Kallikrein-Kinin System; Macular Edema; Protein Kinase Inhibitors; Vascular Endothelial Growth Factor A
PubMed: 29473719
DOI: 10.22608/APO.2017529 -
Proceedings of the National Academy of... Mar 1999The angiopoietins have recently joined the members of the vascular endothelial growth factor family as the only known growth factors largely specific for vascular...
The angiopoietins have recently joined the members of the vascular endothelial growth factor family as the only known growth factors largely specific for vascular endothelium. The angiopoietins include a naturally occurring agonist, angiopoietin-1, as well as a naturally occurring antagonist, angiopoietin-2, both of which act by means of the Tie2 receptor. We now report our attempts to use homology-based cloning approaches to identify new members of the angiopoietin family. These efforts have led to the identification of two new angiopoietins, angiopoietin-3 in mouse and angiopoietin-4 in human; we have also identified several more distantly related sequences that do not seem to be true angiopoietins, in that they do not bind to the Tie receptors. Although angiopoietin-3 and angiopoietin-4 are strikingly more structurally diverged from each other than are the mouse and human versions of angiopoietin-1 and angiopoietin-2, they appear to represent the mouse and human counterparts of the same gene locus, as revealed in our chromosomal localization studies of all of the angiopoietins in mouse and human. The structural divergence of angiopoietin-3 and angiopoietin-4 appears to underlie diverging functions of these counterparts. Angiopoietin-3 and angiopoietin-4 have very different distributions in their respective species, and angiopoietin-3 appears to act as an antagonist, whereas angiopoietin-4 appears to function as an agonist.
Topics: Amino Acid Sequence; Angiopoietin-1; Angiopoietin-Like Protein 1; Angiopoietin-like Proteins; Angiopoietins; Animals; Chromosome Mapping; Chromosomes, Human, Pair 20; Chromosomes, Human, Pair 8; Evolution, Molecular; Female; Genetic Variation; Growth Substances; Humans; Intercellular Signaling Peptides and Proteins; Membrane Glycoproteins; Mice; Molecular Sequence Data; Organ Specificity; Pregnancy; Proteins; Receptor Protein-Tyrosine Kinases; Receptor, TIE-2; Sequence Alignment; Sequence Homology, Amino Acid
PubMed: 10051567
DOI: 10.1073/pnas.96.5.1904 -
Circulation Journal : Official Journal... Dec 2009Recent major increases in obesity and related metabolic diseases (known as the metabolic syndrome (MetS)) because of sedentary lifestyles and overnutrition in developed... (Review)
Review
Recent major increases in obesity and related metabolic diseases (known as the metabolic syndrome (MetS)) because of sedentary lifestyles and overnutrition in developed and developing countries, are an exploding medical and social problem. These conditions are associated with increased risk of cardiovascular disease (CVD), the leading cause of death. Thus, it is necessary to understand the molecular basis underlying MetS and develop effective preventive and therapeutic approaches against CVD. To date, 7 angiopoietin-like proteins (Angptls) that are structurally similar to angiopoietins have been identified. However, none binds to the angiopoietin receptor, Tie2, or to the closely related Tie1 receptor, suggesting that these ligands function differently from angiopoietins. Some Angptls potently regulate angiogenesis, similar to angiopoietins, whereas others have pleiotropic activity other than angiogenesis and function in lipid and energy metabolism. In this review, we focus on the roles of Angptl2 and Angptl6/angiopoietin-like growth factor (AGF) in the development of MetS and CVD, and discuss the potential for Angptl2 and Angptl6/AGF to function as molecular targets for the prevention and treatment of both conditions.
Topics: Angiogenesis Modulating Agents; Angiopoietin-Like Protein 2; Angiopoietin-Like Protein 6; Angiopoietin-like Proteins; Angiopoietins; Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Cardiovascular Agents; Cardiovascular Diseases; Drug Design; Humans; Hypolipidemic Agents; Metabolic Syndrome; Signal Transduction
PubMed: 19875897
DOI: 10.1253/circj.cj-09-0710 -
Journal of Orthopaedic Research :... May 2017Recent evidence suggests that common factor(s) or molecule(s) might regulate lipid and glucose metabolism, inflammation, and bone and cartilage degeneration. These... (Review)
Review
Recent evidence suggests that common factor(s) or molecule(s) might regulate lipid and glucose metabolism, inflammation, and bone and cartilage degeneration. These findings may be particularly relevant for cases of rheumatoid arthritis, in which chronic inflammation occurs in an autoimmune context and causes the degradation of articular joints as well as insulin resistance and cardiovascular complications. Candidates for this common regulatory system include signals mediated by peroxisome proliferator-activated regulator and its response factor, angiopoietin-like 4. The expression and bioactivity of angiopoietin-like 4, an adipocytokine that was originally reported to have an angiogenic function, have been detected not only in the vascular system and adipose tissue but also in rheumatoid joints. An essential role for angiopoietin-like 4 has been established in dyslipidemia, and recent reports indicate that it may modulate bone and cartilage catabolism in rheumatoid arthritis. The enhanced expression of angiopoietin-like 4 in rheumatoid arthritis may explain the occurrence of insulin resistance, cardiovascular risk, and joint destruction, thereby suggesting that this molecule could be a potential target for anti-rheumatoid arthritis strategies. This review describes recent research on the role of angiopoietin-like 4 in chronic inflammatory conditions and rheumatoid arthritis, as well as potential therapeutic candidates. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:939-943, 2017.
Topics: Angiopoietin-Like Protein 4; Angiopoietins; Arthritis, Rheumatoid; Chronic Disease; Humans; Inflammation; Insulin Resistance
PubMed: 28004425
DOI: 10.1002/jor.23507 -
Arteriosclerosis, Thrombosis, and... May 2024ANGPTL3 (angiopoietin-like protein 3) is a circulating protein with a key role in maintaining lipoprotein homeostasis. A monoclonal antibody against ANGPTL3 is an...
BACKGROUND
ANGPTL3 (angiopoietin-like protein 3) is a circulating protein with a key role in maintaining lipoprotein homeostasis. A monoclonal antibody against ANGPTL3 is an approved and well-tolerated treatment to reduce lipoproteins in familial hypercholesterolemia homozygotes. However, the reduction of hepatic ANGPTL3 synthesis using an antisense oligonucleotide unexpectedly resulted in a dose-dependent increase in liver lipid content and circulating transaminases, resulting in the termination of the clinical trial. Meanwhile, the use of silencing RNAs remains an area of active investigation. Our study sought to investigate whether intracellular downregulation of ANGPTL3 may lead to a primary increase in neutral lipids within the hepatocyte.
METHODS
We downregulated by silencing RNA in primary human hepatocytes 3-dimensional spheroids, HepG2/LX-2 3-dimensional spheroids, and in HepG2, Hep3B2, and Huh7 cultured in 2 dimensions.
RESULTS
ANGPTL3 downregulation increased neutral lipids in all models investigated. Interestingly, ANGPTL3 induced lower intracellular deiodinase type 1 protein levels resulting in a reduction in beta-oxidation and causing an increase in triglycerides stored in lipid droplets.
CONCLUSIONS
In conclusion, intracellular downregulation by silencing RNA led to an increase in triglycerides content due to a reduction in energy substrate utilization resembling a primary intracellular hepatocyte hypothyroidism.
Topics: Humans; Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Angiopoietins; Down-Regulation; Energy Metabolism; Hep G2 Cells; Hepatocytes; Lipid Metabolism; RNA Interference; Transfection; Triglycerides
PubMed: 38385290
DOI: 10.1161/ATVBAHA.123.319789 -
The American Journal of Pathology Jun 2000The angiopoietins are recently described growth factors for vascular endothelium. The Tie1 and Tie2 receptors are expressed by endothelium. Acquired immune deficiency...
The angiopoietins are recently described growth factors for vascular endothelium. The Tie1 and Tie2 receptors are expressed by endothelium. Acquired immune deficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS) and cutaneous angiosarcoma are malignancies of endothelial origin. KS involves primarily the skin and mucosal surfaces and is common in AIDS patients. In an effort to determine whether the angiopoietins and Tie receptors play a role in the pathobiology of angiosarcoma and KS, we studied the expression of angiopoietin-1, angiopoietin-2, angiopoietin-4, Tie1, and Tie2 mRNAs in biopsies of KS from 12 AIDS patients, in biopsies of cutaneous angiosarcoma from two patients, and in control biopsies of normal skin from three volunteers by in situ hybridization. Strong expression of angiopoietin-2, Tie1, and Tie2 mRNAs was detected in the tumor cells of KS and cutaneous angiosarcomas, in contrast to the focal low-level expression in normal skin biopsies. Focal low-level expression of angiopoietin-1 was seen in KS, cutaneous angiosarcomas, and in normal skin. Focal low-level expression of angiopoietin-4 was identified in a minority of KS lesions. These findings suggest that the angiopoietins and Tie receptors may play an important role in the pathobiology of KS and cutaneous angiosarcoma and identify additional potential targets for therapeutic intervention in these vascular malignancies.
Topics: Acquired Immunodeficiency Syndrome; Angiopoietin-1; Angiopoietin-2; Angiopoietins; Growth Substances; Hemangiosarcoma; Humans; Intercellular Signaling Peptides and Proteins; Membrane Glycoproteins; Neoplasm Proteins; Proteins; Proto-Oncogene Proteins; RNA, Messenger; Receptor Protein-Tyrosine Kinases; Receptor, TIE-1; Receptor, TIE-2; Receptors, Cell Surface; Receptors, TIE; Reference Values; Sarcoma, Kaposi; Skin Neoplasms
PubMed: 10854238
DOI: 10.1016/S0002-9440(10)65088-2 -
BioMed Research International 2019Angiopoietin-like proteins (Angptls) play critical roles in biological processes, primarily in lipid metabolism. The functional state of the thyroid has a profound...
PURPOSE
Angiopoietin-like proteins (Angptls) play critical roles in biological processes, primarily in lipid metabolism. The functional state of the thyroid has a profound influence on metabolism in the human body. Therefore, the aim of this study was to investigate possible changes in serum Angptl3, 4, and 8 levels in hypothyroid patients.
METHODS
The study included 29 patients with clinical hypothyroidism, 30 patients with subclinical hypothyroidism, and 29 healthy subjects. Baseline clinical indices, including serum thyroid function tests, were recorded and serum Angptl3, 4, and 8 levels were measured across the three groups.
RESULTS
Serum Angptl3 and 8 levels were significantly higher in the hypothyroid groups compared to the control group ( < 0.05). There were no differences in Angptl4 levels among the three groups ( > 0.05). Positive correlations were identified between Angptl3 and high-density lipoprotein cholesterol (r = 0.431, < 0.001), and there was a negative correlation between Angptl3 and total tri-iodothyronine (TT3) (r = -0.220, = 0.047) and free tri-iodothyronine (r = - 0.279, = 0.013) levels. Angptl8 was positively correlated with triglyceride (r = 0.267, = 0.012) and cholesterol levels (r= 0.235, = 0.028) but was negatively correlated with tri-iodothyronine (r = -0.24, = 0.031). Furthermore, we used receiver operating characteristic curve analysis to evaluate the diagnostic performance of Angptl3 and 8 in discriminating thyroid dysfunction. The area under curve for detecting thyroid dysfunction based on Angptl3 and Angptl8 was 0.763.
CONCLUSIONS
Our data show that serum Angptl3 and 8 levels are increased in clinical and subclinical hypothyroid patients and that Angptl3 and 8 may serve as possible biomarkers of hypothyroid disease.
Topics: Adult; Angiopoietin-Like Protein 3; Angiopoietin-Like Protein 8; Angiopoietin-like Proteins; Angiopoietins; Biomarkers; Female; Humans; Hypothyroidism; Lipid Metabolism; Male; Middle Aged; Peptide Hormones; Triglycerides
PubMed: 31380419
DOI: 10.1155/2019/3814687