Search Results (101)

Periodontitis and type 2 diabetes mellitus (T2DM) are linked through systemic inflammation and endothelial dysfunction, yet it remains uncertain whether periodontal inflammatory burden independently reflects early, multi-organ microvascular vulnerability beyond glycemic exposure. This study aimed to assess the independent association between periodontal inflammatory burden, measured by PISA, and retinal microvascular impairment on OCT-A, and to examine relationships with renal trajectories, small-fiber neuropathy, and inflammatory/endothelial biomarkers. This cross-sectional observational study included 285 never-smoking adults with T2DM. The primary outcome was a pre-specified OCT-A microvascular impairment composite. Secondary outcomes included eGFR slope and log(UACR) slope, corneal nerve fiber length (CNFL), and a multi-organ microvascular burden score. Biomarkers comprised hsCRP, IL-6, sICAM-1, sVCAM-1, sE-selectin, PAI-1, angiopoietin-2 (Ang-2), and vWF:Ag. Multivariable linear regression estimated associations per 1 SD higher PISA, adjusting for age, sex, diabetes duration, HbA1c, CGM time in range, CGM coefficient of variation, systolic blood pressure, LDL cholesterol, BMI, and medication classes (SGLT2 inhibitors, GLP-1 receptor agonists, ACEi/ARB, statins). False discovery rate (FDR) control (q = 0.10) was applied for secondary endpoints. Higher PISA was independently associated with worse OCT-A microvascular impairment (adjusted β = 0.138, 95% CI 0.061–0.216; p = 0.0005). Although statistically significant, the effect sizes were modest in magnitude, and their translation into clinically meaningful differences in microvascular outcomes warrants investigation in prospective settings. Higher PISA was also associated with greater multi-organ microvascular burden (β = 0.101, 95% CI 0.040–0.163; p = 0.0014; FDR q = 0.005) and lower CNFL (β = −0.224, 95% CI −0.397 to −0.052; p = 0.0113; FDR q = 0.023). PISA was associated with higher levels of inflammatory and endothelial activation/injury biomarkers (all FDR q < 0.10). In this cross-sectional study, periodontal inflammatory burden was independently associated with quantitative retinal microvascular impairment, lower corneal nerve fiber length, and a consistent pattern of endothelial activation biomarker elevations in never-smoking adults with T2DM. The clinical significance of the observed effect sizes requires further evaluation, and longitudinal studies are needed to establish temporality. Full article

The Angiopoietin–Tie2 pathway is a key regulator of postnatal vascular maintenance and remodeling, regulating vascular barrier function and integrity. While the opposing roles of the ligands Angiopoietin-1 (Ang 1) and Angiopoietin-2 (Ang 2) have been recognized for decades, the structural mechanism governing their distinct signaling outputs has only recently been elucidated. As artificial intelligence and protein design continue to develop, emerging evidence suggests that ligand valency and receptor clustering are key determinants of Tie2 pathway activation and endothelial cell function; that is, “form follows function”. This review summarizes the latest discovery in the structural biology and signaling mechanism of the Tie2 pathway using protein design to decode the ligand–receptor interactions. Probing the underlying molecular basis of Tie2 offers new therapeutic opportunities for targeting diseases, featuring vascular dysfunctions such as sepsis, traumatic brain injury, acute respiratory diseases, chronic inflammation, and cancer. This also highlights the next generation of AI-designed protein therapeutics. Full article

Background/Objectives: Lipedema is a chronic adipose tissue disorder characterized by disproportionate fat accumulation, pain, microvascular dysfunction, and low-grade inflammation. Although low-carbohydrate, high-fat (LCHF) dietary approaches are increasingly used in clinical practice, their longer-term associations with vascular, lymphatic, and immunometabolic pathways in lipedema remain insufficiently understood. This preliminary exploratory study evaluated clinical outcomes and circulating mediators during a 7-month LCHF dietary intervention. Methods: Twenty-four women with lipedema (median age: 39 years) underwent a 7-month individualized, calorie-restricted LCHF diet under medical supervision. Outcomes included body mass index (BMI), leg volume, and adipose tissue pain assessed using a visual analogue scale (VAS). Fasting serum samples collected at baseline and follow-up were analyzed for angiogenic, inflammatory, endothelial, and lipid mediators using Luminex assays and liquid chromatography–tandem mass spectrometry (LC-MS/MS). Results: The intervention was associated with significant reductions in BMI, leg volume, and adipose tissue pain (p < 0.001). These changes were accompanied by increased vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor D (VEGF-D), and angiopoietin-2 (Ang-2), together with decreased pro-inflammatory cytokines and endothelial adhesion molecules. Several endocannabinoid-related lipid mediators, including oleoyl ethanolamide (OEA), arachidonoyl ethanolamide (AEA), and palmitoyl ethanolamide (PEA), also decreased. Baseline OEA and AEA concentrations, as well as reductions in OEA over time, were associated with greater BMI reduction. Change in interleukin-8 (IL-8) showed a nominal association with leg volume reduction, while pain improvement was associated with decreases in P-selectin and VEGF-A and increases in interleukin-13 (IL-13). Conclusions: A 7-month calorie-restricted LCHF dietary intervention in women with lipedema was associated with clinical improvement and changes in circulating vascular, inflammatory, and lipid mediators. These findings reflect systemic changes accompanying the intervention; however, causal relationships and specific mechanisms cannot be established. Full article

Background and Objectives: Myopic choroidal neovascularization (mCNV) is a vision-threatening complication of pathologic myopia. While anti-VEGF monotherapy is the current standard of care, recurrence and suboptimal responses remain challenges. Faricimab is a novel bispecific antibody that targets both vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) to improve vascular stability. This study aims to evaluate the short-term efficacy and safety of a single intravitreal faricimab injection in eyes with active mCNV. Materials and Methods: This retrospective, single-center study included 27 eyes from 24 patients with active mCNV, including both treatment-naïve and previously treated cases. All eyes received a single intravitreal injection of faricimab (6.0 mg/0.05 mL). Best-corrected visual acuity (BCVA) in logMAR and central retinal thickness (CRT) via spectral-domain optical coherence tomography were assessed at baseline and one month post injection. Statistical significance was determined using paired and independent t-tests (p < 0.05). Results: The study population (mean age 55.5 ± 13.9 years; mean axial length 29.3 ± 1.6 mm) showed significant improvements at one month. Mean BCVA improved from 0.77 ± 0.71 logMAR to 0.51 ± 0.52 logMAR (p < 0.005). Mean CRT decreased from 290.2 ± 66.0 μm to 242.5 ± 45.7 μm (p < 0.005). No ocular adverse events, such as intraocular inflammation, retinal detachment, or endophthalmitis, were observed. Conclusions: A single intravitreal injection of faricimab provides significant short-term functional and anatomical improvement in this small retrospective series. Dual inhibition of VEGF-A and Ang-2 appears to be a safe and effective approach for stabilizing retinal vasculature in patients with high myopia. Larger, long-term prospective studies are needed to determine optimal treatment intervals for mCNV. Full article

Tumor-associated Tie2-expressing monocytes/macrophages (TEMs) have been implicated in promoting angiogenesis and metastasis in colorectal cancer (CRC), yet the molecular mechanisms linking TEMs infiltration to tumor metastasis and progression remain incompletely defined. This study investigated the distribution of TEMs in CRC and their association with gene expression profiles, microvessel density (MVD), and clinical outcomes. Immunohistochemistry on 30 formalin-fixed paraffin-embedded (FFPE) primary CRC samples revealed that TEMs, which characteristically express tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (Tie2) receptor and CD14, preferentially localize to perivascular regions and are associated with higher histological grade, tumor size, lymph node metastasis, and increased MVD. However, Tie2⁻/CD14⁺ macrophages and CD68⁺ tumor-associated macrophages (TAMs) showed uniform stromal distribution. Gene set enrichment analysis (GSEA) of in silico transcriptomic datasets of metastatic CRC (mCRC) identified enrichment of pathways related to cell–cell recognition, calcium signaling, transcription regulation, and metalloexopeptidase activity in Tie2⁺/CD14⁺ tumors. Subsequent qRT-PCR validation on FFPE primary CRC samples confirmed significant upregulation of C-C chemokine receptor 7 (CCR7), platelet-derived growth factor A (PDGFRA), CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2), and carboxypeptidase E (CPE) in TEMs⁺ regions. Notably, angiopoietin1 (Ang1), but not angiopoietin2 (Ang2), was significantly elevated in TEMs⁺ primary tumors. Kaplan–Meier analysis on 1336 CRC patients indicated that high expression of CITED2, CPE, and Ang2 is associated with reduced overall survival. Collectively, these findings suggest that TEM infiltration is linked to transcriptional regulation, biological processes, and enzymatic programs in CRC, potentially contributing to tumor progression and poor prognosis, and highlight CCR7, PDGFRA, CITED2, CPE, and Ang1 as candidate biomarkers for further mechanistic exploration. Full article

Background: The aim of our study was to evaluate the association of angiopoietin 2 (ANGPT2) rs2442598 and vascular endothelial growth factor A (VEGFA) rs2010963 with diabetic nephropathy (DN) in Slovenian subjects with type 2 diabetes mellitus (T2DM). Angiopoietin–endothelial tyrosine kinase receptor (Ang-Tie2) and VEGF-A signaling regulate glomerular endothelial stability and permeability and may contribute to DN susceptibility. Methods: We conducted a case–control study including 897 unrelated Slovenian subjects with T2DM (344 DN cases; 553 long-standing T2DM controls without DN). ANGPT2 rs2442598 and VEGFA rs2010963 were genotyped using TaqMan assays. Genetic associations were analysed using co-dominant, additive, dominant, and recessive genetic models with logistic regression adjusted for waist circumference, systolic blood pressure, fasting glucose, and triglycerides. Results: ANGPT2 rs2442598 was significantly associated with DN, with increased risk in carriers of the C allele, including a significant additive per allele effect (OR 1.39, 95% CI 1.10–1.74) and a dominant model effect (OR 1.47, 95% CI 1.11–1.96). In contrast, VEGFA rs2010963 showed no evidence of association across genetic models. Conclusions: In Slovenian patients with T2DM, ANGPT2 rs2442598 is associated with DN, whereas VEGFA rs2010963 is not. This association suggests that ANGPT2 genetic variation may influence DN risk and supports further functional work to define the biological effects of rs2442598. Full article

Autoimmune thyroid diseases (AITD) are based on reactivity to thyroid self-antigens, resulting in varying degrees of persistent inflammation and glandular hyperplasia. The aim of this study was to investigate the interplay between angiogenesis, inflammation, and oxidative stress in patients with AITD. The study included patients with AITD, divided into a group with Hashimoto’s thyroiditis (HT) and a group with Graves’ disease (GD), as well as healthy controls. The results showed that subjects with GD had significantly higher concentrations of angiopoietin-2 (Ang-2) compared to those with HT and the healthy controls (p < 0.001). Inflammatory parameters (C-reactive protein (CRP), the systemic inflammatory immune response index (SII), and the CRP/albumin ratio (CRP/alb)) were higher in both AITD groups (p < 0.001). Oxidative stress parameters were more pronounced in AITD, while the activity of antioxidant enzymes was reduced. Ang-2 positively correlated with H₂O₂ (r = 0.394, p = 0.006) and NO (r = 0.519, p = 0.001) in HT, as well as with O₂⁻ (r = 0.232, p = 0.009) and TBARS (r = 0.190, p = 0.038) in GD, while in GD it showed a negative correlation with SOD (r = −0.426, p = 0.012) and CAT (r = −0.534, p = 0.008). Thus, angiogenesis, inflammation, and oxidative stress are interconnected processes in AITD, which may have significance for further understanding of the disease and the development of therapeutic approaches. Full article

Background: Pneumonia contributes to post-burn morbidity and mortality. Understanding the mechanisms that predispose burn patients to pneumonia is crucial to both stratifying patients at increased risk and developing targeted interventions. Methods: A prospective observational study was conducted with 47 human patients who sustained large burn injuries with serum collected on days 2 and 3 post-burn and assessed for Angiopoietin-1 (Ang-1) and -2 (Ang-2). C57BL/6 mice were subjected to either sham injury or a 12.5% total body surface area (TBSA) scald burn injury, and plasma and lungs were assessed. Results: Patients who developed pneumonia within 30 days of injury had higher serum Ang-2 and Ang-2/1 ratio on post-injury days 2 and 3. Similar to patient findings, we observed an increase in Ang-2 in burn mice compared to sham. Within the lungs of burn mice, we found significant increases in Tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (TIE2) receptor transcript Tek, downstream mediators TNFAIP3 Interacting Protein 2 (Tnip2) and phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1), in addition to endothelial adhesion molecules intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), along with neutrophil infiltration and markers compared to sham. Conclusions: These findings suggest that burn injury increases Angiopoetin-2 and downstream signaling in the lungs, which may contribute to post-burn pulmonary dysfunction. Further studies are necessary to understand if modulating the Ang–TIE2 axis can protect against pneumonia post-burn. Full article

Alzheimer’s Disease (AD) management is challenging due to limitations in detection methods. Currently, cerebrospinal fluid (CSF) biomarkers involve assessing β-amyloid (Aβ) and phosphorylated tau proteins. The lumbar puncture procedure to obtain CSF is invasive and sometimes causes significant anxiety in patients. In contrast, plasma biomarkers would allow rapid, accurate, and cost-effective diagnosis, while minimizing invasiveness and discomfort. Using a dataset involving 120 plasma proteins from clinically diagnosed AD patients versus cognitively normal subjects, we developed classification models by applying various machine learning algorithms (EBlasso, EBEN, XGBoost, LightGBM, TabNet, and TabPFN) to plasma proteomic measurements. Gene ontology and pathway enrichment, and a literature review were used to evaluate the potential relevance of the biomarkers identified in AD-related mechanisms. Biomarkers identified were also evaluated for the enrichment of aging-related biomarkers. The models developed yielded high AUROC and accuracy, mostly >0.9. Proteins selected as predictors by all the models included Angiopoietin-2 (ANG-2), epidermal growth factor (EGF), Interleukin 1α (IL-1α), and platelet growth factor subunit B (PDGF-BB). Ample previous literature supported their relevance in AD. The pool of all the biomarkers identified was significantly enriched with known aging-related biomarkers (p = 0.040). Applying cutting-edge algorithms is expected to be advantageous for developing AD prediction models with plasma proteomic data, and future large studies to externally validate the constructed models in other populations to assess their generalizability is important. The proteins uncovered may represent novel preventative or therapeutic targets. Full article

Retinal ischemia is a key factor in the progression of vision-threatening ocular diseases, including central retinal artery/vein occlusion, exudative age-related macular degeneration (eAMD), and proliferative diabetic retinopathy. This study investigates the effects of paeoniflorin along with its related neuroprotective molecular pathways in the treatment of retinal ischemia. Free radical or ischemic-like damage was induced by incubating retinal pigment epithelium (RPE) cells for 24 h with 1 mM hydrogen peroxide (H₂O₂) or by subjecting retinal neuronal cells to 8 h of oxygen–glucose deprivation (OGD). Both treatments caused significant cell loss. Treatment with paeoniflorin significantly increased cell viability at 0.5 mM in both cell types. In a Wistar rat model of retinal ischemia and reperfusion (I/R) elicited by sustained high intraocular pressure (HIOP), pre-treatment with 0.5 mM paeoniflorin mitigated the ischemia-induced decline in ERG b-wave amplitude, reduction in whole and inner retinal thickness, loss of fluorogold-labeled retinal ganglion cells, and formation of apoptotic cells. Meanwhile, paeoniflorin effectively downregulated pro-neovascular mediators β-catenin, hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF), and the pro-inflammatory/angiogenic biomarker angiopoietin-2 (Ang-2), producing effects similar to the Wnt/β-catenin inhibitor (dickkopf-related protein 1), anti-angiogenic pigment epithelium-derived factor (PEDF), and anti-VEGF Avastin (bevacizumab). These findings suggest that paeoniflorin may protect against retinal ischemia through its anti-inflammatory, anti-neovascular/angiogenic, antioxidative, and neuroprotective properties. Full article

Neovascular age-related macular degeneration (nAMD) is a significant cause of vision loss globally, with intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents forming the cornerstone of treatment. Despite advances, the considerable treatment burden associated with frequent injections and the occurrence of suboptimal responses in some patients highlight an ongoing need for more effective and durable therapeutic options. Faricimab, a bispecific antibody that targets both VEGF-A and angiopoietin-2 (Ang-2), has been developed to address these challenges by promoting greater vascular stability and potentially offering extended treatment intervals. This review synthesizes current evidence from pivotal clinical trials (TENAYA/LUCERNE), real-world studies, meta-analyses, and case reports on the efficacy, durability, and safety of intravitreal faricimab for nAMD. Key efficacy outcomes, such as changes in best-corrected visual acuity and anatomical parameters (e.g., central subfield thickness, retinal fluid dynamics, pigment epithelial detachment morphology), are evaluated in both treatment-naïve and previously treated/treatment-resistant nAMD populations. The safety profile, including intraocular inflammation, retinal vasculitis, retinal pigment epithelium tears, and systemic adverse events, is also comprehensively addressed. Faricimab has demonstrated non-inferior visual outcomes compared to aflibercept 2 mg, alongside robust anatomical improvements and a significant potential for reduced treatment frequency, thereby lessening patient and healthcare system burden. While generally well-tolerated, ongoing monitoring for adverse events remains essential. Full article

Patients with heart failure with a reduced ejection fraction (HFrEF) are at an increased risk of developing postoperative hemodynamic instability and vasoplegia after surgery on cardiopulmonary bypass (CPB). Potentially pre-existing endothelial cell (EC) alterations due to chronic HF influence EC responses to cardiac surgery and might be responsible for the altered vascular responsiveness observed postoperatively. In this study, well-described EC activation markers were measured in blood samples collected pre- and perioperatively at four time points from HFrEF and control patients undergoing cardiac surgery on cardiopulmonary bypass (CPB). Circulating levels of Angiopoietin 2 (ANG2), von Willebrand Factor (vWF), and soluble P-selectin were measured using ELISA. Additionally, we investigated the responses of the cultured EC to patient-derived plasma through morphological profiling and mitochondrial functional assays. In total, 36 patients were included (67 (61–71) years, 78% male). HFrEF patients had higher baseline ANG2 and vWF levels when compared to controls. Both markers peaked during the first postoperative day. A pronounced increase in vWF was seen in controls after CPB. Ex vivo EC responses to patient-derived plasma showed distinct morphological differences between the two groups at baseline. A mitochondrial analysis indicated alterations in function and morphology for both groups after CPB. In conclusion, HFrEF patients exhibit a dampened EC response to cardiac surgery on CPB. Stable circulating factors in HFrEF plasma are responsible for inducing EC stress. Moreover, the mitochondrial function is highly affected postoperatively. This pre-existing mitochondrial and EC dysfunction predispose HFrEF patients to postoperative hemodynamic instability. Full article

Colorectal cancer (CRC) is a major global health burden and a leading cause of cancer-related mortality, with metastasis representing the primary cause of death. Angiogenesis plays a critical role in this process, and macrophages within the tumor microenvironment (TME) are its key regulators. Among these, Tie2-expressing macrophages (TEMs) constitute a distinct pro-angiogenic subset that localizes to perivascular regions and responds to angiopoietin2 (Ang2) signaling. Moreover, TEMs contribute to vessel destabilization and the formation of permissive niches for cancer cell intravasation, linking them to both angiogenic and non-angiogenic modes of malignant tumor progression. The significance of TEMs in CRC remains controversial. This controversy, as we noticed, stems from a confluence of methodological challenges, lack of standardized markers, small-scale studies, inconsistent findings across studies, and the inherent complexity of both CRC biology and macrophage biology. Evidence from preclinical models and patient samples highlights the correlation between Ang2/Tie2 activity, TEM infiltration, and poor prognosis in CRC. This review summarizes current knowledge on the role of TEMs and the Ang/Tie2 axis in CRC angiogenesis, metastasis, and resistance to anti-angiogenic therapies. Advancing our understanding of TEMs may enable novel macrophage-focused strategies to inhibit CRC progression and improve patient outcomes. Full article

Stroke is still considered a predominant cause of morbidity and mortality, for which research on prevention and cure has been sought to prevent neuronal damage after a stroke incident. In this research, we evaluated the protective effects of virgin coconut oil (VCO) using behavioral, morphophysiological, and gene expression parameters using an ischemic stroke surgical rat model using Sprague Dawley (SD) rats. Eight-week-old SD rats were subjected to repeated oral administration (5 mL/kg/day) of either 1% Tween 80 or VCO. For behavioral and morphophysiological parameters, surgery was performed for each group, after which neurological scoring was performed at 4 h, 24 h, 48 h, 5 d, and 10 d. Further, hematological and brain morphology assessment was performed after euthanasia and necropsy of the animals. For gene expression studies, surgery was performed with animals sacrificed at different time points (baseline, before surgery, 4 h, 24 h, and 48 h after surgery) to collect the brain. Results of the study showed that there are differences in the neurological scores between the two treatments 24 h, 48 h, and 5 d after surgery. Brain morphology assessment also showed favorable results for VCO for infarct size, edema, and hypoxic neurons. Gene expression studies also showed positive results with an increase in the relative expression of angiogenin (Ang), angiopoietin (Angpt 1), Parkin, dynamin-related protein 1 (Drp 1), mitofusin 2 (Mfn 2), and mitochondrial rho (Miro) and decreased relative expression of caspase 3, receptor for advanced glycation end-product (Rage), and glyceraldehyde-3-phosphate dehydrogenase (Gapdh). In summary, the current study shows that VCO may have protective effects on the brain after stroke, which may be explained by the results of the gene expression studies. Full article

Brain glioma is one of the most common malignant tumors of brain tissue. It is characterized by rich vascularization, which indicates the significant participation of angiogenesis in its growth and development. In its first stages, the disease is very often asymptomatic, and late diagnosis significantly limits possibilities of treatment. Tumor angiogenesis, i.e., the formation of new vessels, requires the presence of angiogenic compounds that will enable tumor progression by creating a path for the supply of nutrients. The proangiogenic compounds involved in the development of glioma include hypoxia-inducible factor 1α (HIF-1α), angiopoietin-2 (ANG-2), and interleukin-1β (IL-1β). The aim of this study was to analyze changes in the levels of these proteins in plasma samples of patients diagnosed with brain glioma in stages G1 to G4, and in a control group, using SPRi biosensors. The results obtained in plasma were compared with the concentrations obtained during the analysis of tissue homogenates from patients with glioma in stages G2 to G4. A statistically significant difference in plasma concentrations was obtained between the patient group and the control group. The concentrations of the markers in tissue homogenate samples were statistically higher than in blood plasma. There was no significant effect of gender, diet, smoking, or the patient’s general health condition (Karnofsky score) on the course of the disease. These factors do not directly increase the risk of developing brain glioma. Full article