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Acta Histochemica Dec 2023Idiopathic pulmonary fibrosis (IPF) is considered as a chronic interstitial lung disease with underlying mechanism of IPF remaining unclear, while there are no...
OBJECTIVE
Idiopathic pulmonary fibrosis (IPF) is considered as a chronic interstitial lung disease with underlying mechanism of IPF remaining unclear, while there are no definitive treatment options. In recent years, scientists have gradually paid attention to the influence of angiogenesis on IPF. Because IPF is a progressive with microvascular remodeling disorder, scientists have postulated that angiogenesis may also be one of the initiating and contributing factors of the disease. Bupleurum is a common natural Chinese herbal medicine with antibacterial, anti-inflammatory, anti-tumor and other pharmacological effects. As the most important active monomer of Bupleurum, Saikosaponin-d (SSd) is a new discovery with anti-pulmonary fibrosis (PF) activity. This study attempts to investigate the role of SSd in the interference of PF through regulation of angiogenesis in IPF through Angiopoietin (Angpt) /Tie receptor 2 (Tie2) pathway.
METHODS
Randomly, we allocated C57BL/6 mice into four groups (n = 20 in each group). Afterwards, establishment of IPF model was accomplished via intratracheal administration of bleomycin (BLM, 5 mg/kg), while corresponding drug intervention was given accordingly. On 3rd, 7th, 14th and 28th days after modeling, we performed histopathological examination through staining. Meanwhile, immunohistochemistry (IHC) of PF and the expression of related factors were observed, while Ang/Tie2 pathway was assessed by ELISA with the effect of SSd on angiogenesis related proteins in IPF being explored with IHC and Western Blot technique.
RESULTS
Our results showed that SSd could reduce inflammation and PF levels in lung tissue of experimental mice, while levels of angiogenesis-related factors, namely Tie-2, Ang-1 and ANGPT2 (Ang-2), fibrosis- associated factors like Alpha-smooth muscle actin (α-SMA), collagen-I and hydroxyproline in SSd and dexamethasone (DXM) mice were significantly reduced at each time point compared to BLM (p < 0.01). Additionally, we discovered substantial decreased expressions of Ang-1, Ang-2, Tie-2, α-SMA and collagen-I at protein level in SSd and DXM mice at each time point compared to BLM (p < 0.05). Besides, insignificant differences were observed between SSd and DXM groups (p > 0.05).
CONCLUSION
This study has demonstrated that SSd could down-regulate the expression of ANG-1, Ang-2 and Tie2 in the Ang/Tie2 pathway, and may reduce lung inflammation and PF in BLM-induced mice via inhibition of angiogenesis.
Topics: Mice; Animals; Angiopoietins; Mice, Inbred C57BL; Lung; Idiopathic Pulmonary Fibrosis; Collagen Type I; Bleomycin
PubMed: 37837833
DOI: 10.1016/j.acthis.2023.152100 -
Best Practice & Research. Clinical... May 2023ANGPTL3 has emerged as a therapeutic target whose inhibition results in profound reductions of plasma lipids, including atherogenic triglyceride-rich lipoproteins and... (Review)
Review
ANGPTL3 has emerged as a therapeutic target whose inhibition results in profound reductions of plasma lipids, including atherogenic triglyceride-rich lipoproteins and low-density lipoprotein cholesterol. The identification of ANGPTL3 deficiency as a cause of familial combined hypolipidemia in humans hastened the development of anti-ANGPTL3 therapeutic agents, including evinacumab (a monoclonal antibody inhibiting circulating ANGPTL3), vupanorsen (an antisense oligonucleotide [ASO] targeting hepatic ANGPTL3 mRNA for degradation), and others. Advances have also been made in ANGPTL3 vaccination and gene editing strategies, with the former still in preclinical phases and the latter in preparation for Phase 1 trials. Here, we review the discovery of ANGPTL3 as an important regulator of lipoprotein metabolism, molecular characteristics of the protein, mechanisms by which it regulates plasma lipids, and the clinical development of anti-ANGPTL3 agents. The clinical success of therapies inhibiting ANGPTL3 highlights the importance of this target as a novel approach in treating refractory hypertriglyceridemia and hypercholesterolemia.
Topics: Humans; Angiopoietin-like Proteins; Angiopoietin-Like Protein 3; Lipoproteins; Triglycerides; Angiopoietins
PubMed: 35999139
DOI: 10.1016/j.beem.2022.101688 -
Mediators of Inflammation 2015The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial... (Review)
Review
The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial processes associated with a proinflammatory environment, to which tumour microenvironment and other tissues from the tumour bearing individuals contribute. The aim of the present review is to address the role of ghrelin, myostatin, leptin, HIF, IL-6, TNF-α, and ANGPTL-4 in the regulation of energy balance, tumour development, and tumoural cell invasion. Hypoxia induced factor plays a prominent role in tumour macro- and microenvironment, by modulating the release of proinflammatory cytokines.
Topics: Angiopoietin-Like Protein 4; Angiopoietins; Animals; Cachexia; Cytokines; Ghrelin; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Inflammation; Interleukin-6; Leptin; Myostatin; Neoplasm Metastasis; Neoplasms; Prognosis; Syndrome; Tumor Microenvironment; Tumor Necrosis Factor-alpha
PubMed: 26508818
DOI: 10.1155/2015/791060 -
Virulence Aug 2013Dynamic changes in microvascular endothelial structure and function are pivotal in the acute inflammatory response, the body's rapid, coordinated effort to localize,... (Review)
Review
Dynamic changes in microvascular endothelial structure and function are pivotal in the acute inflammatory response, the body's rapid, coordinated effort to localize, sequester, and eliminate microbial invaders at their portal of entry. To achieve this, the endothelium becomes leaky and inflamed, providing innate immune cells and humoral effector molecules access to the site of infection. During sepsis this locally adaptive response becomes manifest throughout the body, leading to dangerous host consequences. Increased leakiness in the pulmonary circulation contributes to acute respiratory distress syndrome (ARDS), a complication of sepsis associated with 40% mortality. Understanding the molecular governance of vascular leak and inflammation has major diagnostic, prognostic, and potentially therapeutic implications for this common and pernicious disease. This review summarizes results from cell-based experiments, animal models, and observational human studies; together, these studies suggest that an endothelial receptor called Tie2 and its ligands, called angiopoietins, form a signaling axis key to the vascular dyshomeostasis that underlies sepsis.
Topics: Angiopoietin-1; Angiopoietin-2; Animals; Endothelium, Vascular; Humans; Receptor, TIE-2; Respiratory Distress Syndrome; Sepsis
PubMed: 23652985
DOI: 10.4161/viru.24906 -
Journal of the American Society of... Nov 2014Nephrotic syndrome is recognized by the presence of proteinuria in excess of 3.5 g/24 h along with hypoalbuminemia, edema, hyperlipidemia (hypertriglyceridemia and... (Review)
Review
Nephrotic syndrome is recognized by the presence of proteinuria in excess of 3.5 g/24 h along with hypoalbuminemia, edema, hyperlipidemia (hypertriglyceridemia and hypercholesterolemia), and lipiduria. Each component has been investigated individually over the past four decades with some success. Studies published recently have started unraveling the molecular basis of proteinuria and its relationship with other components. We now have improved understanding of the threshold for nephrotic-range proteinuria and the pathogenesis of hypertriglyceridemia. These studies reveal that modifying sialylation of the soluble glycoprotein angiopoietin-like 4 or changing key amino acids in its sequence can be used successfully to treat proteinuria. Treatment strategies on the basis of fundamental relationships among different components of nephrotic syndrome use naturally occurring pathways and have great potential for future development into clinically relevant therapeutic agents.
Topics: Angiopoietin-Like Protein 4; Angiopoietins; Drug Design; Humans; Hyperlipidemias; N-Acetylneuraminic Acid; Nephrotic Syndrome
PubMed: 24854282
DOI: 10.1681/ASN.2014030267 -
Cells Feb 2020Angiopoietin/tyrosine protein kinase receptor Tie-2 signaling in endothelial cells plays an essential role in angiogenesis and wound healing. Angiopoietin-1 (Ang-1) is... (Review)
Review
Angiopoietin/tyrosine protein kinase receptor Tie-2 signaling in endothelial cells plays an essential role in angiogenesis and wound healing. Angiopoietin-1 (Ang-1) is crucial for blood vessel maturation while angiopoietin-2 (Ang-2), in collaboration with vascular endothelial growth factor (VEGF), initiates angiogenesis by destabilizing existing blood vessels. In healthy people, the Ang-1 level is sustained while Ang-2 expression is restricted. In cancer patients, Ang-2 level is elevated, which correlates with poor prognosis. Ang-2 not only drives tumor angiogenesis but also attracts infiltration of myeloid cells. The latter rapidly differentiate into tumor stromal cells that foster tumor angiogenesis and progression, and weaken the host's anti-tumor immunity. Moreover, through integrin signaling, Ang-2 induces expression of matrix metallopeptidases (MMPs) to promote tumor cell invasion and metastasis. Many oncogenic viruses induce expression of Ang-2 to promote development of neoplasia associated with viral infection. Multiple Ang-2 inhibitors exhibit remarkable anti-tumor activities, further highlighting the importance of Ang-2 in cancer development.
Topics: Angiopoietins; Animals; Humans; Mice; Mice, Nude; Neoplasms; Signal Transduction; Virus Diseases
PubMed: 32085414
DOI: 10.3390/cells9020457 -
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 -
Diabetes Dec 2022Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Prognostic biomarkers reflective of underlying molecular mechanisms are critically...
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of DKD. A three-marker panel was derived from a proteomics analysis of plasma samples by an unbiased machine learning approach from participants (N = 58) in the Clinical Phenotyping and Resource Biobank study. In combination with standard clinical parameters, this panel improved prediction of the composite outcome of ESKD or a 40% decline in glomerular filtration rate. The panel was validated in an independent group (N = 68), who also had kidney transcriptomic profiles. One marker, plasma angiopoietin 2 (ANGPT2), was significantly associated with outcomes in cohorts from the Cardiovascular Health Study (N = 3,183) and the Chinese Cohort Study of Chronic Kidney Disease (N = 210). Glomerular transcriptional angiopoietin/Tie (ANG-TIE) pathway scores, derived from the expression of 154 ANG-TIE signaling mediators, correlated positively with plasma ANGPT2 levels and kidney outcomes. Higher receptor expression in glomeruli and higher ANG-TIE pathway scores in endothelial cells corroborated potential functional effects in the kidney from elevated plasma ANGPT2 levels. Our work suggests that ANGPT2 is a promising prognostic endothelial biomarker with likely functional impact on glomerular pathogenesis in DKD.
Topics: Humans; Angiopoietin-1; Receptor, TIE-2; Diabetic Nephropathies; Cohort Studies; Endothelial Cells; Angiopoietin-2; Angiopoietins; Signal Transduction; Biomarkers; Kidney Failure, Chronic; Disease Progression; Diabetes Mellitus
PubMed: 36331122
DOI: 10.2337/db22-0169 -
The Turkish Journal of Pediatrics 2017Mimaroğlu E, Çıtak EÇ, Kuyucu N, Eskendari G. The diagnostic and prognostic value of angiopoietins compared with C-reactive protein and procalcitonin in children...
Mimaroğlu E, Çıtak EÇ, Kuyucu N, Eskendari G. The diagnostic and prognostic value of angiopoietins compared with C-reactive protein and procalcitonin in children with febrile neutropenia. Turk J Pediatr 2017; 59: 418-425. In this study, we aimed to determine serum angiopoetin (Ang) levels and compare them with levels of C-reactive protein (CRP) and procalcitonin (PCT). Cancer patients (aged 0-18 years) who experienced febrile neutropenia attacks were included in the study. Ang-1, Ang-2, CRP, and PCT were analyzed at admission and 2nd day. Ninety-four episodes of febrile neutropenia that developed in 62 patients were analyzed in this study. The mean age of the patients was 7.56 ± 4.8 (0.5-17) years. The patients had lymphoma (33.9%), solid tumors (48.4%), and other cancer (17.7%). The percentages of the patients with fever of unknown origin (FUO), clinically documented infection (CDI), and microbiologically documented infection (MDI) categories were 45.7%, 22.3%, and 31.9%, respectively. During the study period 11 patients were lost to follow-up. The levels of CRP, PCT and Ang-2 were significantly higher; and that of Ang-1 was significantly lower, compared to the controls. The differentiation cannot be made between the groups by CRP and PCT levels. The level of Ang-1 was the lowest in MDI group; the level of Ang-2 and the ratio of Ang-2/Ang-1 were high in each group. Ang-1, Ang-2 and the ratio of Ang-2/Ang-1 were significantly associated with mortality. Angs correlated with the severity of infection.
Topics: Adolescent; Angiopoietins; Biomarkers; C-Reactive Protein; Child; Child, Preschool; Febrile Neutropenia; Female; Humans; Infant; Male; Neoplasms; Procalcitonin; Prognosis; Survival Rate
PubMed: 29624222
DOI: 10.24953/turkjped.2017.04.008 -
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