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Journal of Clinical Medicine May 2024Complications from diabetic retinopathy such as diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) constitute leading causes of preventable vision... (Review)
Review
Complications from diabetic retinopathy such as diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) constitute leading causes of preventable vision loss in working-age patients. Since vascular endothelial growth factor (VEGF) plays a major role in the pathogenesis of these complications, VEGF inhibitors have been the cornerstone of their treatment. Anti-VEGF monotherapy is an effective but burdensome treatment for DME. However, due to the intensive and burdensome treatment, most patients in routine clinical practice are undertreated, and therefore, their outcomes are compromised. Even in adequately treated patients, persistent DME is reported anywhere from 30% to 60% depending on the drug used. PDR is currently treated by anti-VEGF, panretinal photocoagulation (PRP) or a combination of both. Similarly, a number of eyes, despite these treatments, continue to progress to tractional retinal detachment and vitreous hemorrhage. Clearly there are other molecular pathways other than VEGF involved in the pathogenesis of DME and PDR. One of these pathways is the angiopoietin-Tie signaling pathway. Angiopoietin 1 (Ang1) plays a major role in maintaining vascular quiescence and stability. It acts as a molecular brake against vascular destabilization and inflammation that is usually promoted by angiopoietin 2 (Ang2). Several pathological conditions including chronic hyperglycemia lead to Ang2 upregulation. Recent regulatory approval of the bi-specific antibody, faricimab, may improve long term outcomes in DME. It targets both the Ang/Tie and VEGF pathways. The YOSEMITE and RHINE were multicenter, double-masked, randomized non-inferiority phase 3 clinical trials that compared faricimab to aflibercept in eyes with center-involved DME. At 12 months of follow-up, faricimab demonstrated non-inferior vision gains, improved anatomic outcomes and a potential for extended dosing when compared to aflibercept. The 2-year results of the YOSEMITE and RHINE trials demonstrated that the anatomic and functional results obtained at the 1 year follow-up were maintained. Short term outcomes of previously treated and treatment-naive eyes with DME that were treated with faricimab during routine clinical practice suggest a beneficial effect of faricimab over other agents. Targeting of Ang2 has been reported by several other means including VE-PTP inhibitors, integrin binding peptide and surrobodies.
PubMed: 38792322
DOI: 10.3390/jcm13102778 -
Biomedicines Apr 2024Angiopoietins are crucial growth factors for maintaining a healthy, functional endothelium. Patients with type 2 diabetes (T2D) exhibit significant levels of angiogenic...
Angiopoietins are crucial growth factors for maintaining a healthy, functional endothelium. Patients with type 2 diabetes (T2D) exhibit significant levels of angiogenic markers, particularly Angiopoietin-2, which compromises endothelial integrity and is connected to symptoms of endothelial injury and failure. This report examines the levels of circulating angiopoietins in people with T2D and diabetic nephropathy (DN) and explores its link with ANGPTL proteins. We quantified circulating ANGPTL3, ANGPTL4, ANGPTL8, Ang1, and Ang2 in the fasting plasma of 117 Kuwaiti participants, of which 50 had T2D and 67 participants had DN. The Ang2 levels increased with DN (4.34 ± 0.32 ng/mL) compared with T2D (3.42 ± 0.29 ng/mL). This increase correlated with clinical parameters including the albumin-to-creatinine ratio (ACR) (r = 0.244, = 0.047), eGFR (r = -0.282, = 0.021), and SBP (r = -0.28, = 0.024). Furthermore, Ang2 correlated positively to both ANGPTL4 (r = 0.541, < 0.001) and ANGPTL8 (r = 0.41, = 0.001). Multiple regression analysis presented elevated ANGPTL8 and ACRs as predictors for Ang2's increase in people with DN. In people with T2D, ANGPTL4 positively predicted an Ang2 increase. The area under the curve (AUC) in receiver operating characteristic (ROC) analysis of the combination of Ang2 and ANGPTL8 was 0.77 with 80.7% specificity. In conclusion, significantly elevated Ang2 in people with DN correlated with clinical markers such as the ACR, eGFR, and SBP, ANGPTL4, and ANGPTL8 levels. Collectively, this study highlights a close association between Ang2 and ANGPTL8 in a population with DN, suggesting them as DN risk predictors.
PubMed: 38790911
DOI: 10.3390/biomedicines12050949 -
Current Issues in Molecular Biology May 2024Humans are persistently exposed to massive amounts of blue light via sunlight, computers, smartphones, and similar devices. Although the positive and negative effects of...
Humans are persistently exposed to massive amounts of blue light via sunlight, computers, smartphones, and similar devices. Although the positive and negative effects of blue light on living organisms have been reported, its impact on learning and memory remains unknown. Herein, we examined the effects of widespread blue light exposure on the learning and memory abilities of blue light-exposed mice. Ten-week-old male ICR mice were divided into five groups (five mice/group) and irradiated with blue light from a light-emitting diode daily for 6 months. After 6 months of blue light irradiation, mice exhibited a decline in memory and learning abilities, assessed using the Morris water maze and step-through passive avoidance paradigms. Blue light-irradiated mice exhibited a decreased expression of the clock gene brain and muscle arnt-like 1 (Bmal1). The number of microglia and levels of M1 macrophage CC-chemokine receptor 7 and inducible nitric oxide synthase were increased, accompanied by a decrease in M2 macrophage arginase-1 levels. Levels of angiopoietin-like protein 2 and inflammatory cytokines interleukin-6, tumor necrosis factor-α, and interleukin-1β were elevated. Our findings suggest that long-term blue light exposure could reduce Bmal1 expression, activate the M1 macrophage/Angptl2/inflammatory cytokine pathway, induce neurodegeneration, and lead to a decline in memory.
PubMed: 38785563
DOI: 10.3390/cimb46050295 -
Current Issues in Molecular Biology Apr 2024This study aimed to explore the correlation between Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) concentrations and the Angiopoietin-2/Angiopoietin-1 ratio...
This study aimed to explore the correlation between Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) concentrations and the Angiopoietin-2/Angiopoietin-1 ratio (Ang-2/Ang-1) with clinical outcomes, potentially serving as disease severity and survival biomarkers. A study at AHEPA University Hospital involved 90 Coronavirus Disease 2019 (COVID-19) adult patients, 30 hospitalized intensive care units (ICU), 30 inward units (non-ICU), and 30 asymptomatic non-hospitalized individuals as controls. Estimated endothelial dysfunction markers related to angiogenesis were measured. There was a statistically significant difference only between outpatient and hospitalized patients (non-ICU-ICU groups) for the Ang-1 and Ang-2 indices. The Ang-2/Ang-1 ratio has differed significantly among the individual patient groups. An ROC analysis was conducted to find an optimal threshold for distinguishing between (outpatients-non-ICU) and (non-ICU-ICU) groups. It was based on Youden's index of 0.1122 and 0.3825, respectively. The Ang-1, Ang-2 levels, and Ang-2/Ang-1 ratio were analyzed as severity indicators in COVID-19 patients. The Ang-2/Ang-1 ratio demonstrated better prognostic and diagnostic utility than individual biomarker levels. Monitoring the Ang-2/Ang-1 ratio can identify COVID-19 patients at risk and assist clinicians in tailoring treatment strategies to improve outcomes.
PubMed: 38785513
DOI: 10.3390/cimb46050245 -
JCI Insight May 2024Small cell lung cancer (SCLC) is the most aggressive lung cancer entity with an extremely limited therapeutic outcome. Most patients are diagnosed at an extensive stage....
Small cell lung cancer (SCLC) is the most aggressive lung cancer entity with an extremely limited therapeutic outcome. Most patients are diagnosed at an extensive stage. However, the molecular mechanisms driving SCLC invasion and metastasis remain largely elusive. We used an autochthonous SCLC mouse model and matched samples from patients with primary and metastatic SCLC to investigate the molecular characteristics of tumor metastasis. We demonstrate that tumor cell invasion and liver metastasis in SCLC are triggered by an Angiopoietin-2 (ANG-2)/Integrin β-1-dependent pathway in tumor cells, mediated by focal adhesion kinase/Src kinase signaling. Strikingly, CRISPR-Cas9 KO of Integrin β-1 or blocking Integrin β-1 signaling by an anti-ANG-2 treatment abrogates liver metastasis formation in vivo. Interestingly, analysis of a unique collection of matched samples from patients with primary and metastatic SCLC confirmed a strong increase of Integrin β-1 in liver metastasis in comparison with the primary tumor. We further show that ANG-2 blockade combined with PD-1-targeted by anti-PD-1 treatment displays synergistic treatment effects in SCLC. Together, our data demonstrate a fundamental role of ANG-2/Integrin β-1 signaling in SCLC cells for tumor cell invasion and liver metastasis and provide a potentially new effective treatment strategy for patients with SCLC.
Topics: Animals; Female; Humans; Male; Mice; Angiopoietin-2; Cell Line, Tumor; Integrin beta1; Liver Neoplasms; Lung Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Signal Transduction; Small Cell Lung Carcinoma
PubMed: 38775153
DOI: 10.1172/jci.insight.166402 -
Clinical and Experimental Hepatology Dec 2023Metabolic-associated fatty liver disease (MAFLD) requires close monitoring due to its increased incidence and progression to fibrosis, cirrhosis and even hepatocellular...
AIM OF THE STUDY
Metabolic-associated fatty liver disease (MAFLD) requires close monitoring due to its increased incidence and progression to fibrosis, cirrhosis and even hepatocellular carcinoma. The search for non-invasive markers to diagnose liver fibrosis is ongoing. The aim of our study was to evaluate the serum levels of growth differentiation factor-15 (GDF-15), thrombospondin-2 (TSP2), pentraxin 3 (PTX3) and angiopoietin-like protein 8 (ANGPTL8) in children with MAFLD.
MATERIAL AND METHODS
Fifty-six overweight/obese children with suspected liver disease were included in this prospective study. MAFLD was diagnosed according to the latest consensus. Vibration-controlled transient elastography (TE) was performed to detect clinically significant liver fibrosis. Serum concentrations of GDF-15, TSP2, PTX3 and ANGPTL8 were measured by enzyme-linked immunosorbent assay (ELISA).
RESULTS
Liver steatosis was diagnosed in abdominal ultrasound in 31 (55.36%) overweight/obese patients who were classified as the MAFLD group. Aspartate aminotransferase (AST)/platelet ratio (APRI) and liver stiffness measurement (LSM) values and TSP2 concentrations showed significantly higher values in patients in MAFLD than in the non-MAFLD group. TSP2 was significantly positively correlated with alanine transaminase (ALT), AST, γ-glutamyltransferase (GGT) and APRI in the study group. The receiver operating characteristics (ROC) analysis showed that the area under the curve (AUC) of LSM, APRI and serum TSP2 was significant for predicting MAFLD in obese children. In the multivariable regression model, LSM was the only significant parameter associated with the diagnosis of MAFLD in children.
CONCLUSIONS
TSP2 may be a potential biomarker of hepatocyte injury in pediatric patients with MAFLD. None of the examined biomarkers were found to be effective non-invasive markers of liver fibrosis in children.
PubMed: 38774195
DOI: 10.5114/ceh.2023.133108 -
BMC Cancer May 2024Our study was to investigate the impact of taurolactone, a novel anti-tumor and anti-angiogenic drug, on AGGF1, an angiogenic factor, and angiogenesis mimicry in...
OBJECTIVE
Our study was to investigate the impact of taurolactone, a novel anti-tumor and anti-angiogenic drug, on AGGF1, an angiogenic factor, and angiogenesis mimicry in patients diagnosed with hepatocellular carcinoma (HCC).
METHODS
A total of 120 HCC patients were enrolled from the Department of Oncology and Hepatobiliary Surgery at our hospital between May 2021 and December 2022. HCC diagnoses were confirmed through imaging or tissue biopsy for all patients. The age of patients ranged from 37 to 72 years, with an average age of 64.29 ± 4.58 years. These participants were divided equally into two groups: the control group and the observation group, each consisting of 60 individuals. While the control group received standard drug treatment, the observation group was administered taurolactone treatment. Before being included in the study, all participants or their legal representatives provided signed informed consent. Patient demographic information was collected through a questionnaire survey. ELISA was used to measure the levels of VEGF and AGGF1 in patients following treatment. Western blot was applied to assess the protein expression of PDGF, Angiopoietin, and AGGF1. MRI imaging technology was utilized to assess the perfusion characteristics of tumor blood vessels in patients. Tumor vessel density was compared between patients using ultrasonography. We also conducted a comparison between the two groups in terms of progression-free survival and overall survival.
RESULTS
General patient information between the two groups showed no significant differences (P > 0.05). Of note, the observation group exhibited greatly lower levels of VEGF and AGGF1 compared to the control group (P < 0.05). Moreover, the levels of PDGF, Angiopoietin, and AGGF1 protein expression were significantly reduced in the observation group compared to the control group (P < 0.05). In terms of tumor perfusion, the observation group displayed lower average and maximum perfusion volumes in tumor blood vessels compared to the control group (P < 0.05). Additionally, the observation group demonstrated delayed peak times and arrival times of tumor blood vessels in comparison to the control group (P < 0.05). Furthermore, the density of tumor blood vessels was notably lower in the observation group compared to the control group (P < 0.05). Patients in the observation group had longer progression-free survival and overall survival than the control group (P < 0.05).
CONCLUSION
In HCC patients, our study highlighted the potential efficacy of taurolactone treatment as it effectively inhibited angiogenic factors and angiogenesis mimicry, ultimately leading to an improved prognosis for these patients.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Middle Aged; Male; Female; Aged; Angiogenesis Inhibitors; Angiogenic Proteins; Adult; Neovascularization, Pathologic; Lactones; Antineoplastic Agents; Vascular Endothelial Growth Factor A; Angiogenesis
PubMed: 38773427
DOI: 10.1186/s12885-024-12356-w -
Scientific Reports May 2024Neonatal sepsis is a major cause of childhood mortality. Limited diagnostic tools and mechanistic insights have hampered our abilities to develop prophylactic or...
Neonatal sepsis is a major cause of childhood mortality. Limited diagnostic tools and mechanistic insights have hampered our abilities to develop prophylactic or therapeutic interventions. Biomarkers in human neonatal sepsis have been repeatedly identified as associated with dysregulation of angiopoietin signaling and altered arachidonic acid metabolism. We here provide the mechanistic evidence in support of the relevance for these observations. Angiopoetin-1 (Ang-1), which promotes vascular integrity, was decreased in blood plasma of human and murine septic newborns. In preclinical models, administration of Ang-1 provided prophylactic protection from septic death. Arachidonic acid metabolism appears to be functionally connected to Ang-1 via reactive oxygen species (ROS) with a direct role of nitric oxide (NO). Strengthening this intersection via oral administration of arachidonic acid and/or the NO donor L-arginine provided prophylactic as well as therapeutic protection from septic death while also increasing plasma Ang-1 levels among septic newborns. Our data highlight that targeting angiogenesis-associated pathways with interventions that increase Ang-1 activity directly or indirectly through ROS/eNOS provide promising avenues to prevent and/or treat severe neonatal sepsis.
Topics: Humans; Animals; Infant, Newborn; Neonatal Sepsis; Angiopoietin-1; Mice; Reactive Oxygen Species; Nitric Oxide; Arachidonic Acid; Female; Male; Arginine; Signal Transduction; Nitric Oxide Synthase Type III; Neovascularization, Pathologic; Biomarkers; Disease Models, Animal; Animals, Newborn; Angiogenesis
PubMed: 38769383
DOI: 10.1038/s41598-024-62195-9 -
Journal of Cellular and Molecular... May 2024Acute lung injury (ALI) is featured with a robust inflammatory response. Angiopoietin-like protein 2 (ANGPTL2), a pro-inflammatory protein, is complicated with various...
Acute lung injury (ALI) is featured with a robust inflammatory response. Angiopoietin-like protein 2 (ANGPTL2), a pro-inflammatory protein, is complicated with various disorders. However, the role of ANGPTL2 in ALI remains to be further explored. The mice and MH-S cells were administrated with lipopolysaccharide (LPS) to evoke the lung injury in vivo and in vitro. The role and mechanism of ANGPTL was investigated by haematoxylin-eosin, measurement of wet/dry ratio, cell count, terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling, reverse transcription quantitative polymerase chain reaction, immunofluorescence, enzyme-linked immunosorbent assay, detection of autophagic flux and western blot assays. The level of ANGPTL2 was upregulated in lung injury. Knockout of ANGPTL2 alleviated LPS-induced pathological symptoms, reduced pulmonary wet/dry weight ratio, the numbers of total cells and neutrophils in BALF, apoptosis rate and the release of pro-inflammatory mediators, and modulated polarization of alveolar macrophages in mice. Knockdown of ANGPTL2 downregulated the level of pyroptosis indicators, and elevated the level of autophagy in LPS-induced MH-S cells. Besides, downregulation of ANGPTL2 reversed the LPS-induced the expression of leukocyte immunoglobulin (Ig)-like receptor B2 (LILRB2) and triggering receptor expressed on myeloid cells 2 (TREM2), which was reversed by the overexpression of LILRB2. Importantly, knockdown of TREM2 reversed the levels of autophagy- and pyroptosis-involved proteins, and the contents of pro-inflammatory factors in LPS-induced MH-S cells transfected with si ANGPTL2, which was further inverted with the treatment of rapamycin. Therefore, ANGPTL2 silencing enhanced autophagy to alleviate alveolar macrophage pyroptosis via reducing LILRB2-mediated inhibition of TREM2.
Topics: Angiopoietin-Like Protein 2; Animals; Pyroptosis; Autophagy; Mice; Macrophages, Alveolar; Receptors, Immunologic; Membrane Glycoproteins; Acute Lung Injury; Lipopolysaccharides; Gene Knockdown Techniques; Male; Mice, Inbred C57BL; Angiopoietin-like Proteins; Mice, Knockout
PubMed: 38758159
DOI: 10.1111/jcmm.18280 -
Cureus May 2024Background Human embryo vasculogenesis (blood vessel development starting from endothelial precursors) includes the ability of mesenchymal cells and pluripotent stem...
Background Human embryo vasculogenesis (blood vessel development starting from endothelial precursors) includes the ability of mesenchymal cells and pluripotent stem cells to differentiate into endothelial cells. Quantification of endothelial progenitor cells is difficult to assess during the early steps of human embryo development due to several factors, especially due to the paucity of human embryo tissue which is usually discarded after early-stage pregnancy abortive methods. CD133 (Promimin-1) is a general marker of progenitor cells, but combined with other endothelial markers such as CD34, it may identify endothelial progenitor cells during embryonic development. CD34 immunohistochemistry was previously performed by our team to identify human embryo capillaries and comparatively assess microvessel density between different human embryonic tissues. TIE2 is an angiopoietin receptor strongly involved in the newly formed blood vessel maturation due to its expression in some mesenchymal precursors for future pericytes. CD34 assesses the presence of endothelial cells but its single use does not evaluate the endothelial progenitor state as CD133 may do nor vessel maturation as TIE2 may do. Data about the dynamics of CD133/TIE2 expression in the early stages of human embryo development are scarce. Hence, in this study, we aimed to comparatively assess the dynamic of CD133+ endothelial precursors and TIE2 expression on five and seven-week-old human embryonic tissues with a special emphasis on their expression on embryonic vascular beds. Methodology CD133 and TIE2 immunohistochemistry was performed on five and seven-week-old human embryonic tissues followed by their quantification using the Qu Path digital image analysis (DIA) automated method. Results CD133 and TIE2 showed divergent patterns of expression during the initial phases of human embryonic development, specifically in the vascular endothelium of tiny capillaries. The expression of CD133 in endothelial cells lining the perfused lumen gradually decreased from five to seven-week-old embryos. It remained expressed with greater intensity in cells located at the tip of the vascular bud that emerged into pre-existing capillaries. TIE2 was much more specific than CD133, being restricted to the level of the vascular endothelium; therefore, it was easier to quantify using digital image analysis. The endothelium of the embryonic aorta was an exception to the divergent expression, as CD133 and TIE2 were consistently co-expressed in the seven-week-old embryo. The Qu Path DIA assessment increased the accuracy of CD133 and TIE2 evaluation, being the first time they were quantified by using automated software and not manually. Conclusions High heterogeneity of CD133 and TIE2 was observed between five and seven-week-old embryonic tissues as well as between different embryonic regions from the same gestational age. The unique finding of CD133/TIE2 co-expression persistence inside aortic endothelium needs further studies to elucidate the role of this co-expression.
PubMed: 38756714
DOI: 10.7759/cureus.60353