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Eye (London, England) Jun 2022Diabetic retinopathy is a major complication of diabetes mellitus, where in its most advanced form ischemic changes lead to the development of retinal... (Review)
Review
BACKGROUND
Diabetic retinopathy is a major complication of diabetes mellitus, where in its most advanced form ischemic changes lead to the development of retinal neovascularization, termed proliferative diabetic retinopathy (PDR). While the development of PDR is often associated with angiogenic and inflammatory cytokines, studies differ on which cytokines are implicated in disease pathogenesis and on the strength of these associations. We therefore conducted a systematic review and meta-analysis to quantitatively assess the existing body of data on intraocular cytokines as biomarkers in PDR.
METHODS
A comprehensive search of the literature without year limitation was conducted to January 18, 2021, which identified 341 studies assessing vitreous or aqueous cytokine levels in PDR, accounting for 10379 eyes with PDR and 6269 eyes from healthy controls. Effect sizes were calculated as standardized mean differences (SMD) of cytokine concentrations between PDR and control patients.
RESULTS
Concentrations (SMD, 95% confidence interval, and p-value) of aqueous IL-1β, IL-6, IL-8, MCP-1, TNF-α, and VEGF, and vitreous IL-2, IL-4, IL-6, IL-8, angiopoietin-2, eotaxin, erythropoietin, GM-CSF, GRO, HMGB-1, IFN-γ, IGF, IP-10, MCP-1, MIP-1, MMP-9, PDGF-AA, PlGF, sCD40L, SDF-1, sICAM-1, sVEGFR, TIMP, TNF-α, and VEGF were significantly higher in patients with PDR when compared to healthy nondiabetic controls. For all other cytokines no differences, failed sensitivity analyses or insufficient data were found.
CONCLUSIONS
This extensive list of cytokines speaks to the complexity of PDR pathogenesis, and informs future investigations into disease pathogenesis, prognosis, and management.
PubMed: 35672457
DOI: 10.1038/s41433-022-02127-x -
Clinics and Research in Hepatology and... May 2022
Meta-Analysis
Topics: Angiopoietin-2; Biomarkers, Tumor; Carcinoma, Hepatocellular; Diagnostic Tests, Routine; Humans; Liver Neoplasms; alpha-Fetoproteins
PubMed: 35318139
DOI: 10.1016/j.clinre.2022.101909 -
Wiener Klinische Wochenschrift Jan 2022The relationship between acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) and levels of certain inflammatory factors remains controversial. The purpose... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The relationship between acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) and levels of certain inflammatory factors remains controversial. The purpose of this meta-analysis was to summarize the available studies evaluating the association between levels of inflammatory factors and ARDS/ALI incidence.
METHODS
We searched the PubMed, EmBase, and Cochrane databases for studies published up to July 2017. For each inflammatory factor, a random effects model was employed to pool results from different studies.
RESULTS
We identified 63 studies that included 6243 patients in our meta-analysis. Overall, the results indicated that the levels of angiopoietin (ANG)-2 (standard mean difference, SMD: 1.34; P < 0.001), interleukin (IL)-1β (SMD: 0.92; P = 0.012), IL‑6 (SMD: 0.66; P = 0.005), and tumor necrosis factor (TNF)-α (SMD: 0.98; P = 0.001) were significantly higher in patients with ARDS/ALI than in unaffected individuals. No significant differences were observed between patients with ARDS/ALI and unaffected individuals in terms of the levels of IL‑8 (SMD: 0.61; P = 0.159), IL-10 (SMD: 1.10; P = 0.231), and plasminogen activator inhibitor (PAI)-1 (SMD: 0.70; P = 0.060).
CONCLUSIONS
ARDS/ALI is associated with a significantly elevated levels of ANG‑2, IL-1β, IL‑6, and TNF‑α, but not with IL‑8, IL-10, and PAI‑1 levels.
Topics: Acute Lung Injury; Biomarkers; Humans; Respiratory Distress Syndrome; Tumor Necrosis Factor-alpha
PubMed: 34860273
DOI: 10.1007/s00508-021-01971-3 -
Autoimmunity Reviews Feb 2022Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease that is common in elderly people. Its classification in the spectrum of autoinflammatory and autoimmune... (Review)
Review
BACKGROUND AND AIM
Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease that is common in elderly people. Its classification in the spectrum of autoinflammatory and autoimmune diseases is difficult because of its only partially understood immune-mediated mechanisms. The literature concerning the innate and adaptive immune system activation in PMR was systematically reviewed highlighting the relative weight of autoinflammation and autoimmunity in its pathogenesis and disease progression.
METHODS
A literature search on PubMed Central and Embase scientific databases was performed by two independent reviewers. To be eligible, the studies needed to fully satisfy our initial PICO framework: a primary diagnosis of PMR as a population, the search for immune/inflammatory cells, cytokines and autoantibodies as an intervention, a control group consisting in healthy controls, patients with other inflammatory rheumatic diseases or PMR patients in remission after treatment and as outcomes the results of the investigations in the analyzed tissue samples. The most relevant data of the included papers were extracted by using a standardized template.
RESULTS
Of the 933 screened abstracts, 52 papers were included in the systematic review and categorized depending on their primary research objectives. The hyper-activity of neutrophils and monocytes, expressing toll-like receptor 7 in active disease, an impaired phagocytosis and endothelial dysfunction, as well as an increased count of innate T cells in patients with remission emerged among the major derangements of the innate immune response in PMR. Among the cytokines profile, interleukin-6 plays a key role but other pro-inflammatory mediators and angiogenesis markers such as chemokines, B-cell activating factor, vascular endothelial growth factor and angiopoietins seem to be involved in refractory or glucocorticoid-resistant PMR. The aberrant adaptive immune response was documented by tissue and serum findings of polarized T cells towards T helper 1 and 17 phenotypes, an increased expression of immunosenescent surface markers and a downregulated immunoregulatory response. The altered distribution of peripheral B cells, detected during active disease, suggested their peripheral migration towards unidentified sites. The interaction between innate and adaptive immune response was documented by a synovial infiltrate of macrophages and T cells. Despite multiple autoantibodies have been detected in PMR patients, none proved to correlate with disease activity seeming to be reactive to the marked inflammation or antigenic determinants provided by environmental triggers or tissue/cell damage.
CONCLUSIONS
The complex network between innate and adaptive immune system in PMR is supported by findings at molecular and cellular levels. By considering both the ends of the pathophysiological spectrum of immune-mediated rheumatic diseases, PMR may be regarded as an inflammatory immune-mediated disease with mixed mechanisms in a background of genetic and epigenetic factors together with immunological and endocrine senescence.
Topics: Autoimmunity; Giant Cell Arteritis; Humans; Neutrophils; Polymyalgia Rheumatica
PubMed: 34798314
DOI: 10.1016/j.autrev.2021.102995 -
Current Medicinal Chemistry 2022Several studies have revealed the link between Coronavirus Disease 2019 (COVID-19) and endothelial dysfunction. To better understand the global pattern of this... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Several studies have revealed the link between Coronavirus Disease 2019 (COVID-19) and endothelial dysfunction. To better understand the global pattern of this relationship, we conducted a meta-analysis on endothelial biomarkers related to COVID-19 severity.
METHODS
We systematically searched the literature up to March 10, 2021, for studies investigating the association between COVID-19 severity and the following endothelial biomarkers: Intercellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule 1 (VCAM-1), E-selectin, P-selectin, Von Willebrand Factor Antigen (VWFAg), soluble Thrombomodulin (sTM), Mid-regional pro-adrenomedullin (MR-proADM), and Angiopoietin-2 (Ang-2). Pooled estimates and mean differences (PMD) for each biomarker were reported.
RESULTS
A total of 27 studies (n=2213 patients) were included. Critically ill patients presented with higher levels of MR-proADM (PMD: 0.71 nmol/L, 95% CI: 0.22 to 1.20 nmol/L, p=0.02), E-selectin (PMD: 13,32 pg/ml, 95% CI: 4,89 to 21,75 pg/ml, p=0.008), VCAM-1 (PMD: 479 ng/ml, 95% CI: 64 to 896 ng/ml, p=0.03), VWF-Ag (PMD: 110.5 IU/dl, 95% CI: 44.8 to 176.1 IU/dl, p=0.04) and Ang-2 (PMD: 2388 pg/ml, 95% CI: 1121 to 3655 pg/ml, p=0.003), as compared to non-critically ill ones. ICAM-1, P-selectin and thrombomodulin did not differ between the two groups (p>0.05).
CONCLUSION
Endothelial biomarkers display significant heterogeneity in COVID-19 patients, with higher MR-proADM, E-selectin, VCAM-1, VWF-Ag, and Ang-2 levels being associated with increased severity. These findings strengthen the evidence on the key role of endothelial dysfunction in disease progress.
Topics: Biomarkers; COVID-19; E-Selectin; Endothelium, Vascular; Humans; Intercellular Adhesion Molecule-1; Thrombomodulin; Vascular Cell Adhesion Molecule-1; Vascular Diseases; von Willebrand Factor
PubMed: 34702152
DOI: 10.2174/0929867328666211026124033 -
Lipids in Health and Disease May 2021Angiopoietin-like proteins (ANGPTLs) are closely related to insulin resistance and lipid metabolism, and may be a key in metabolic syndrome. Non-alcoholic fatty liver... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Angiopoietin-like proteins (ANGPTLs) are closely related to insulin resistance and lipid metabolism, and may be a key in metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) (newly named metabolic-associated fatty liver disease (MAFLD)) is based on metabolic dysfunction. There may be some correlation between ANGPTLs and MAFLD, but the specific correlation is unclear. This study aims to explore the predictive role of ANGPTLs in MAFLD and its progression.
METHODS
Seven databases (PubMed, EMBASE, Cochrane Library, CNKI, WANFANG, CBM and Clinicaltrials.gov ) were searched with free terms and MeSH terms. The random-effects model was used to pool the data, and Standardized Mean Difference (SMD) and 95% confidence intervals (CI) were taken as the overall outcome. No language restrictions existed in the article selection. RevMan 5.3, Stata 16 and MetaXL software were applied to analyse the data and the GRADE system was utilized to assess the certainty of evidence.
RESULTS
After reviewing 823 related articles, 13 studies (854 cases and 610 controls) met the inclusion criteria, and contributed to this meta-analysis. The results showed that circulating ANGPTL8 level was significantly elevated in the MAFLD group than in the healthy control group (SMD = 0.97 pg/mL, 95%CI: 0.77, 1.18). Conversely, there was no significant difference in the ANGPTL4 (SMD = 0.11 ng/mL, 95%CI: - 0.32, 0.54) and ANGPTL3 (SMD = - 0.95 ng/mL, 95%CI: - 4.38, 2.48) between the two groups. Subgroup analysis showed that: 1) the MAFLD group had significantly higher ANGPTL8 levels than the healthy control group in Asian and other races; 2) the ANGPTL8 levels in Body Mass Index (BMI) > 25 kg/m patients with MAFLD were higher than those in the healthy control group; 3) the higher ANGPTL8 levels were observed in moderate to severe MAFLD group than the healthy control group. Meta-regression demonstrated that BMI might effectively explain the high heterogeneity. No significant publication bias existed (P > 0.05). The certainty of evidence was assessed as very low by the GRADE system.
CONCLUSIONS
The ANGPTLs may be related to MAFLD. The increased ANGPTL8 level may be positively correlated with different situations of MAFLD, which may act as a potential indicator to monitor the development trends.
Topics: Adult; Aged; Angiopoietin-Like Protein 3; Angiopoietin-Like Protein 4; Angiopoietin-Like Protein 8; Biomarkers; Body Mass Index; Case-Control Studies; Female; Gene Expression; Humans; Lipid Metabolism; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Peptide Hormones
PubMed: 34034750
DOI: 10.1186/s12944-021-01481-1 -
The Journal of International Medical... Feb 2021Our aim was to assess the accuracy of angiopoietin-2 (Ang-2) as a prognostic marker for acute pancreatitis (AP) with organ failure (OF). (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Our aim was to assess the accuracy of angiopoietin-2 (Ang-2) as a prognostic marker for acute pancreatitis (AP) with organ failure (OF).
METHODS
We undertook a systematic search of the PubMed, Cochrane Library, Embase, Chinese Journals Full-text, Wanfang, China Biology Medicine disc, and Weipu databases to identify eligible cohort studies on the predictive value of Ang-2 for AP with OF. The main outcome measures were sensitivity and specificity. The effects were pooled using a bivariate mixed-effects model.
RESULTS
Six articles with seven case-control studies (n = 650) were included. Pooled sensitivity, specificity, and positive and negative likelihood ratios with 95% confidence intervals (CI) for AP with OF were 0.93 (95%CI: 0.75-0.99), 0.85 (95%CI: 0.75-0.92), 6.40 (95%CI: 3.36-12.19), and 0.08 (95%CI: 0.02-0.36), respectively. The area under the summary receiver operating characteristic curve was 0.95 (95%CI: 0.92-0.96), and the diagnostic odds ratio was 83.18 (95%CI: 11.50-623.17). Subgroup analysis showed that admission time of AP onset (< or ≥24 hours) was a source of overall heterogeneity. Sensitivity analysis supported this finding.
CONCLUSION
Ang-2 had high diagnostic accuracy for AP with OF; the best prediction of Ang-2 may be 24 to 72 hours after onset of AP.
Topics: Angiopoietin-2; Biomarkers; Humans; Multiple Organ Failure; Odds Ratio; Pancreatitis; Prognosis; ROC Curve; Severity of Illness Index; Time Factors
PubMed: 33527867
DOI: 10.1177/0300060520986708 -
Thrombosis Journal 2020Onset, development and progression of atherosclerosis are complex multistep processes. Many aspects of atherogenesis are not yet properly known. This study investigates...
BACKGROUND
Onset, development and progression of atherosclerosis are complex multistep processes. Many aspects of atherogenesis are not yet properly known. This study investigates the changes in vasculature that contribute to switching of vascular cells towards atherogenesis, focusing mainly on ageing.
METHODS
Databases including PubMed, MEDLINE and Google Scholar were searched for published articles without any date restrictions, involving atherogenesis, vascular homeostasis, aging, gene expression, signaling pathways, angiogenesis, vascular development, vascular cell differentiation and maintenance, vascular stem cells, endothelial and vascular smooth muscle cells.
RESULTS
Atherogenesis is a complex multistep process that unfolds in a sequence. It is caused by alterations in: epigenetics and genetics, signaling pathways, cell circuitry, genome stability, heterotypic interactions between multiple cell types and pathologic alterations in vascular microenvironment. Such alterations involve pathological changes in: Shh, Wnt, NOTCH signaling pathways, TGF beta, VEGF, FGF, IGF 1, HGF, AKT/PI3K/ mTOR pathways, EGF, FOXO, CREB, PTEN, several apoptotic pathways, ET - 1, NF-κB, TNF alpha, angiopoietin, EGFR, Bcl - 2, NGF, BDNF, neurotrophins, growth factors, several signaling proteins, MAPK, IFN, TFs, NOs, serum cholesterol, LDL, ephrin, its receptor pathway, HoxA5, Klf3, Klf4, BMPs, TGFs and others.This disruption in vascular homeostasis at cellular, genetic and epigenetic level is involved in switching of the vascular cells towards atherogenesis. All these factors working in pathologic manner, contribute to the development and progression of atherosclerosis.
CONCLUSION
The development of atherosclerosis involves the switching of gene expression towards pro-atherogenic genes. This happens because of pathologic alterations in vascular homeostasis. When pathologic alterations in epigenetics, genetics, regulatory genes, microenvironment and vascular cell biology accumulate beyond a specific threshold, then the disease begins to express itself phenotypically. The process of biological ageing is one of the most significant factors in this aspect as it is also involved in the decline in homeostasis, maintenance and integrity.The process of atherogenesis unfolds sequentially (step by step) in an interconnected loop of pathologic changes in vascular biology. Such changes are involved in 'switching' of vascular cells towards atherosclerosis.
PubMed: 33132762
DOI: 10.1186/s12959-020-00240-z -
Orphanet Journal of Rare Diseases Oct 2020Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) (HAEnCI) is associated with skin swellings, abdominal attacks, and the risk of asphyxia due to upper airway...
BACKGROUND
Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) (HAEnCI) is associated with skin swellings, abdominal attacks, and the risk of asphyxia due to upper airway obstruction. Several different gene mutations linked to the HAE phenotype have been identified. Our aim was to qualitatively assess and describe the clinical differentiators of these genetically identified HAEnCI types. To achieve this, we performed a systematic literature review of patients with angioedema symptoms and a genetically confirmed diagnosis of an HAEnCI type.
RESULTS
A systematic literature search, conducted in March 2020, returned 132 records, 43 of which describe patients with symptoms of angioedema and a genetically confirmed diagnosis of an HAEnCI type. Overall, this included 602 patient cases from 220 families. HAEnCI with a mutation in the coagulation factor XII gene (F12) (HAE-FXII) was diagnosed in 446 patients from 185 families (male:female ratio = 1:10). Estrogens (oral contraceptives, hormonal replacement therapy, and pregnancy) negatively impacted the course of disease in most female patients (252 of 277). Asphyxia occurred in 2 of 446 patients. On-demand and/or long-term prophylaxis treatment included C1-INH concentrates, icatibant, progestins, and tranexamic acid. HAEnCI with a specific mutation in the plasminogen gene (HAE-PLG) was diagnosed in 146 patients from 33 families (male:female ratio = 1:3). Estrogens had a negative influence on the course of disease in the minority of female patients (14 of 62). Tongue swelling was an important clinical feature. Asphyxia occurred in 3 of 146 patients. On-demand treatment with icatibant and C1-INH concentrate and long-term prophylaxis with progestins and tranexamic acid were effective. HAEnCI with a specific mutation in the angiopoietin-1 gene (HAE-ANGPT1) was diagnosed in 4 patients from 1 family and HAEnCI with a specific mutation in the kininogen-1 gene (HAE-KNG1) in 6 patients from 1 family.
CONCLUSIONS
A number of clinical differentiators for the different types of HAEnCI have been identified which may support clinicians to narrow down the correct diagnosis of HAEnCI prior to genetic testing and thereby guide appropriate treatment and management decisions. However, confirmation of the causative gene mutation by genetic testing will always be required.
Topics: Angioedema; Angioedemas, Hereditary; Complement C1 Inhibitor Protein; Factor XII; Female; Humans; Male; Mutation; Phenotype; Pregnancy
PubMed: 33059692
DOI: 10.1186/s13023-020-01570-x -
Journal of Extracellular Vesicles Aug 2020Severe COVID-19 infection results in bilateral interstitial pneumonia, often leading to acute respiratory distress syndrome (ARDS) and pulmonary fibrosis in survivors.... (Review)
Review
Severe COVID-19 infection results in bilateral interstitial pneumonia, often leading to acute respiratory distress syndrome (ARDS) and pulmonary fibrosis in survivors. Most patients with severe COVID-19 infections who died had developed ARDS. Currently, ARDS is treated with supportive measures, but regenerative medicine approaches including extracellular vesicle (EV)-based therapies have shown promise. Herein, we aimed to analyse whether EV-based therapies could be effective in treating severe pulmonary conditions that affect COVID-19 patients and to understand their relevance for an eventual therapeutic application to human patients. Using a defined search strategy, we conducted a systematic review of the literature and found 39 articles (2014-2020) that reported effects of EVs, mainly derived from stem cells, in lung injury models (one large animal study, none in human). EV treatment resulted in: (1) attenuation of inflammation (reduction of pro-inflammatory cytokines and neutrophil infiltration, M2 macrophage polarization); (2) regeneration of alveolar epithelium (decreased apoptosis and stimulation of surfactant production); (3) repair of microvascular permeability (increased endothelial cell junction proteins); (4) prevention of fibrosis (reduced fibrin production). These effects were mediated by the release of EV cargo and identified factors including miRs-126, -30b-3p, -145, -27a-3p, syndecan-1, hepatocyte growth factor and angiopoietin-1. This review indicates that EV-based therapies hold great potential for COVID-19 related lung injuries as they target multiple pathways and enhance tissue regeneration. However, before translating EV therapies into human clinical trials, efforts should be directed at developing good manufacturing practice solutions for EVs and testing optimal dosage and administration route in large animal models.
PubMed: 32944185
DOI: 10.1080/20013078.2020.1795365