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Lymphoma growth, progression, and dissemination require tumor cell interaction with supporting vessels and are facilitated through tumor-promoted angiogenesis, lymphangiogenesis, and/or lymphoma vessel co-option. Vessel co-option has been shown to be responsible for tumor initiation, metastasis, and resistance to anti-angiogenic treatment but is largely uncharacterized in the setting of lymphoma. We developed an in vitro model to study lymphoma–vessel interactions and found that mantle cell lymphoma (MCL) cells co-cultured on Matrigel with human umbilical vein (HUVEC) or human lymphatic (HLEC) endothelial cells migrate to and anneal with newly formed capillary-like (CLS) or lymphatic-like (LLS) structures, consistent with lymphoma–vessel co-option. To inhibit this interaction, we constructed an antibody fusion protein, αCD20-EndoP125A, linking mutant anti-angiogenic endostatin (EndoP125A) to an αCD20-IgG1-targeting antibody. αCD20-EndoP125A inhibited both CLS and LLS formation, as well as MCL migration and vessel co-option. Lymphoma vessel co-option requires cell migration, which is regulated by chemokine–chemokine receptor interactions. CXCL12 and its receptor, CXCR4, are highly expressed by both endothelial cells forming CLS and by MCL cells during vessel co-option. αCD20-EndoP125A suppressed expression of both CXCL12 and CXCR4, which were required to facilitate CLS assembly and vessel co-option. We also tested αCD20-EndoP125A effects in vivo using an aggressive murine B cell lymphoma model, 38c13-hCD20, which demonstrated rapid growth and dissemination to tumor-draining lymph nodes (TDLNs) and the spleen, lung, and brain. The pattern of lymphoma distribution and growth within the lung was consistent with vessel co-option. As predicted by our in vitro model, αCD20-EndoP125A treatment inhibited primary tumor growth, angiogenesis, and lymphangiogenesis, and markedly reduced the number of circulating tumor cells and lymphoma dissemination to TDLNs and the lungs, spleen, and brain. αCD20-EndoP125A inhibited lymphoma vessel co-option within the lung. Marked inhibition of MCL primary tumor growth and dissemination were also seen using an MCL xenograft model. The ability of αCD20-EndoP125A to inhibit angiogenesis, lymphangiogenesis, and lymphoma vessel co-option provides a novel therapeutic approach for inhibition of lymphoma progression and dissemination. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease is one of the most leading public health problems worldwide. Increased endostatin accelerates the development and progression of CKD. Present study was aimed to estimate serum Endostatin levels and to correlate the serum endostatin levels with eGFR in chronic kidney disease patients in a tertiary care hospital. Material and Methods: Present study was an observational case control study, conducted in patients of age group 45-65 years, both genders. Patients were divided as Group A (Known case of chronic kidney disease with eGFR <60ml/min/1.73m2), Group B (Known case of chronic kidney disease with eGFR 60 - 90 ml/min/1.73m2) & Group C (Age and sex matched healthy control of both genders). Results: There was a significant mean difference in endostatin between Group 1 and Group 2; Group 2 and Group 3; Group 1 and Group 3 (p = 0.000; 0.000; 0.000). There was a significant positive strong correlation of endostatin with systolic BP, diastolic BP, FBS, serum urea, creatinine, uric acid, PCR, total cholesterol, TGL, LDL and VLDL with correlation coefficient of r = 0.872; 0.715; 0.899; 0.992;0.811;0.918; 0.947; 0.882; 0.864; 0.923 and 0.864 respectively. There was a significant negative strong correlation between endostatin and serum protein, albumin and HDL with a correlation coefficient r = -0.899; -0.920 and -0.780 respectively. The sensitivity (true positives) was found to be 86.7% and specificity (true negative) was found to be 81.7%. Area under the curve was 96.2. The significant cut off value is 397.65. Endostatin above 397.65 ng/mL was considered to be chronic kidney disease. Conclusion: Serum Endostatin levels increases as eGFR decreases. Serum Endostatin levels strongly correlate with eGFR and hence with the severity of the chronic kidney disease. Serum Endostatin negatively correlated with HDL and positively correlated with LDL and triglyceride levels which indicates the risk for the development of atheromatous complications. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitor rechallenge has emerged as a prominent study area in non-small cell lung cancer (NSCLC). β-glucan was reported to reverse resistance to anti-PD-1/PD-L1 inhibitors by regulating the tumor microenvironment. In this self-initiated clinical trial (ChiCTR2100054796), NSCLC participants who have previously failed anti-PD-1 therapy received β-glucan (500 mg, bid, d1-21), Envafolimab (300 mg, d1) and Endostar (210 mg, civ72h) every 3 weeks until disease progression or unacceptable toxicity. The clinical efficacy and adverse events were observed, while serum samples were collected for proteomic analysis. Results: Twenty Three patients were enrolled from January 2022 to March 2023 (median age, 65 years; male, n = 18 [78.3%]; squamous NSCLC, n = 9 [39.1%]; mutant type, n = 13 [56.5%]). The overall response rate (ORR) was 21.7% and disease control rate (DCR) was 73.9%. Median progression-free survival (mPFS) and median overall survival (mOS) was 4.3 months [95% CI: 2.0–6.6] and 9.8 months [95% CI: 7.2–12.4], respectively. The mPFS between PD-L1 positive and negative subgroup has significant difference (6.3 months vs. 2.3 months, p = 0.002). Treatment-related adverse events (TRAEs) occurred in 52.2% of patients. The most common TRAEs were hypothyroidism (26.1%) and fatigue (26.1%). 2 (8.7%) grade 3 adverse events were reported. No adverse reaction related deaths have been observed. Proteomic analysis revealed that the levels of CASP-8, ARG1, MMP12, CD28 and CXCL5 correlated with resistance to the treatment while the levels of CD40-L and EGF related to the favorable response. Conclusion: β-glucan combined with Envafolimab and Endostar has considerable efficacy and safety for immune rechallenge in metastatic NSCLC patients who failed of anti-PD-1 treatment previously, especially for PD-L1 positive patients. [ABSTRACT FROM AUTHOR]

Background: Myocardial infraction is one of the main causes of death in today's society. Rehabilitation changes some markers in this disease. The aim of this research is to investigate the reaction of factor derived from fibroblasts and endostatin to the acute rehabilitation of physical activity along with electrical stimulation in infarcted rats. Materials and Methods: In this controlled experimental study with a control group, 50 Wistar rats (8weeks old, 220±15g) were induced with isoproterenol (150mg/kg) to infarction. Then they were randomly divided into 5 groups of 10 healthy, infarct, rehabilitation, electrical stimulation and rehabilitation with electrical stimulation. The intervention groups underwent increasing rehabilitation (with a speed of 10 to 18m/min and duration of 50m) and electrical stimulation (a foot shock with an intensity of 0.5 M/A and duration of 20m) for one session. After exercise and anesthesia, venous blood samples were collected for FGF-2 and Ens serum levels and evaluated by ELISA method. ANOVA was used for data analysis at a significance level of P<0.05. Results: Induction of rats with isoproterenol led to a significant increase in the serum levels of FGF-2 and Ens in all groups (P=0.0001). ANOVA showed that a session of rehabilitation led to a significant increase (P=0.040) of serum FGF-2 levels and a non-significant decrease (P=0.547) of Ens in all groups compared to infarction. Conclusion: It seems that increasing acute rehabilitation by creating positive angiogenic changes in infarcted rats can play an important role in improving myocardial damage and replacing closed capillaries. [ABSTRACT FROM AUTHOR]

Glycosaminoglycans (GAGs) play a key role in a variety of biological processes in the extracellular matrix (ECM) via interactions with their protein targets. Due to their high flexibility, periodicity and electrostatics-driven interactions, GAG-containing complexes are very challenging to characterize both experimentally and in silico. In this study, we, for the first time, systematically analyzed the interactions of endostatin, a proteolytic fragment of collagen XVIII known to be anti-angiogenic and anti-tumoral, with heparin (HP) and representative heparan sulfate (HS) oligosaccharides of various lengths, sequences and sulfation patterns. We first used conventional molecular docking and a docking approach based on a repulsive scaling–replica exchange molecular dynamics technique, as well as unbiased molecular dynamic simulations, to obtain dynamically stable GAG binding poses. Then, the corresponding free energies of binding were calculated and the amino acid residues that contribute the most to GAG binding were identified. We also investigated the potential influence of Zn2+ on endostatin–HP complexes using computational approaches. These data provide new atomistic details of the molecular mechanism of HP's binding to endostatin, which will contribute to a better understanding of its interplay with proteoglycans at the cell surface and in the extracellular matrix. [ABSTRACT FROM AUTHOR]

Radiation induced changes (RIC) are the most common complications observed post Gamma Knife radiosurgery (GKRS) and may be observed within 6–18 months post procedure. It has been observed that almost one-third of RICs are symptomatic and half of them are persistent. There is no way to predict which patients will develop these changes and to what extent. This was a prospective analytical pilot study with the aim of understanding the role of serum vascular endothelial growth factor (VEGF) and endostatin as predictive factors for clinically symptomatic RIC in intracranial arteriovenous malformations (AVMs) of Spetzler Martin (SM) grade 3 being managed with primary GKRS. A total of 15 patients were analyzed; 60% of them had a history of bleed. The median volume of AVM nidus was 4.36 mL. One-third of the patients had no imaging changes suggestive of RIC at 1 year follow-up and 2 of the patients had symptomatic RIC needing intervention. Before GKRS, the median values of serum concentration of endostatin and VEGF were 34.98 ng/mL and 168.37 pg/mL, respectively. The serum values of VEGF at 1 month post GKRS was much lower than the pre-GKRS values but not found to be predictive of RIC. No correlation could be observed with the levels of serum endostatin and RIC. Some patients may develop resistant edema and necrosis post GKRS for intracranial AVMs, which may warrant medical and surgical intervention. Serum biomarkers like VEGF and endostatin may vary in the post GKRS period and can be used to identify at-risk cases, however more studies are needed to decide on appropriate time of sampling and identify clinically relevant predictive factors. [ABSTRACT FROM AUTHOR]

Numerous studies have demonstrated that endostatin (ES), a potent angiostatic peptide derived from collagen type XVIII α 1 chain and encoded by COL18A1, is elevated in pulmonary arterial hypertension (PAH). It is important to note that elevated ES has consistently been associated with altered hemodynamics, poor functional status, and adverse outcomes in adult and pediatric PAH. This study used serum samples from patients with Group I PAH and plasma and tissue samples derived from the Sugen/hypoxia rat pulmonary hypertension model to define associations between COL18A1/ES and disease development, including hemodynamics, right ventricle (RV) remodeling, and RV dysfunction. Using cardiac magnetic resonance imaging and advanced hemodynamic assessments with pressure–volume loops in patients with PAH to assess RV–pulmonary arterial coupling, we observed a strong relationship between circulating ES levels and metrics of RV structure and function. Specifically, RV mass and the ventricular mass index were positively associated with ES, whereas RV ejection fraction and RV–pulmonary arterial coupling were inversely associated with ES levels. Our animal data demonstrate that the development of pulmonary hypertension is associated with increased COL18A1/ES in the heart as well as the lungs. Disease-associated increases in COL18A1 mRNA and protein were most pronounced in the RV compared with the left ventricle and lung. COL18A1 expression in the RV was strongly associated with disease-associated changes in RV mass, fibrosis, and myocardial capillary density. These findings indicate that COL18A1/ES increases early in disease development in the RV and implicates COL18A1/ES in pathologic RV dysfunction in PAH. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate the effectiveness and safety of recombinant human endostatin (Rh-endostatin) plus programmed cell death 1 (PD-1) inhibitors and chemotherapy as first-line treatment for advanced or metastatic non-small cell lung cancer (NSCLC) in a real-world setting. Methods: This was a retrospective study on patients with EGFR/ALK-negative, advanced or metastatic NSCLC. Patients received Rh-endostatin plus PD-1 inhibitors and chemotherapy every three weeks for 4 to 6 cycles. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: A total of 68 patients were included in this retrospective analysis. As of data cutoff (December 13, 2022), the median follow-up of 21.4 months (interquartile range [IQR], 8.3-44.4 months). The median PFS and OS was 22.0 (95% confidence interval [CI]: 16.6-27.4) and 31.0 months (95% CI: 23.4-not evaluable [NE]), respectively. The ORR was 72.06% (95% CI: 59.85-82.27%), and DCR was 95.59% (95% CI: 87.64-99.08%). Patients with stage IIIB/IIIC NSCLC had significantly longer median PFS (23.4 vs. 13.2 months), longer median OS (not reached vs. 18.0 months), and higher ORR (89.2% vs. 51.6%) than those with stage IV NSCLC (all p ≤ 0.001). The ORR was higher in patients with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%) than in those with low PD-L1 expression or positive PD-L1 expression (75% vs. 50%, p = 0.025). All patients experienced treatment-related adverse events (TRAEs), and ≥ grade 3 TRAEs occurred in 16 (23.53%) patients. Conclusions: Rh-endostatin combined with PD-1 inhibitors plus chemotherapy as first-line treatment yielded favorable effectiveness with a manageable profile in patients with advanced or metastatic NSCLC, representing a promising treatment modality. [ABSTRACT FROM AUTHOR]

Background: This study aims to assess the efficacy and safety of Endostar in the management of locally advanced cervical cancer. Methods: This retrospective, 2-center study enrolled 41 patients with locally advanced cervical cancer between June 2017 and December 2020. The patients were subjected to a combination of Endostar and chemoradiotherapy until they experienced disease progression or an unacceptable level of toxicity. The patients in the Endostar combined chemoradiotherapy (E + CRT) and CRT groups were matched 1:1 based on clinical features, including age, disease stage, and pathological type. The therapeutic efficacy and safety outcomes were compared between the 2 groups. Results: Early treatment response: the CR rates in E + CRT and CRT groups were 48.8% and 26.8%, respectively (χ 2 = 4.20, P <.05). The ORR and DCR were not significantly different between the 2 groups. Long-term efficacy: there was no significant difference in the 1-year and 2-year PFS rates and OS rates between 2 groups. However, in patients with stage IIB, subgroup analyses revealed a significant difference in PFS between the 2 groups (P <.05). Prognostic factors: stage, Eastern Cooperative Oncology Group (ECOG) score, and tumor size were independent predictive factors for PFS, while ECOG score and tumor size were those of OS in patients with locally advanced cervical cancer. Safety: The incidence of grade III-IV myelosuppression was significantly lower in E + CRT group than in CRT group (P <.05). Conclusions: The combination of Endostar and concurrent CRT exhibited greater efficacy in treating locally advanced cervical cancer with no severe adverse reactions, when compared to simple CRT. It is expected that this approach will evolve into a new treatment alternative for patients with locally advanced cervical cancer. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a condition initiated by the assimilation of β-amyloid plaques (Aβ) and tau tangles, leading to neurodegeneration. It involves frequently cognitive decline as well as memory impairment in patients. Efforts in therapeutic interventions are currently facing challenges in identifying targets within this scaffold that can significantly alter the clinical course for individuals with AD. Moreover, in AD, neurons release a protein called endostatin, which accumulates in Aβ plaques and enhances AD. This accumulation of Aβ in the triggers a cascade of events leading to synaptic dysfunction, neuroinflammation, and ultimately neuronal death. Environmental factors nowadays increase the risk of AD with prolonged exposure of heavy metals such as copper (Cu), lead (Pb), mercury (Hg), cadmium (Cd), and other pesticides. It has been observed that these factors can cause the aggregation of Aβ and tau which initiates the plaque formation and hence leads to enhanced pathogenesis of AD. This review summarizes the interlinking between heavy metals, environmental factors, pesticides, endostatin, and progression of AD has been deliberated with recent findings. [ABSTRACT FROM AUTHOR]

Angiogenesis is critical for rheumatoid arthritis (RA) progression. The effects of tofacitinib, a JAK-STAT inhibitor used for RA treatment, on angiogenesis in RA are unclear. We, therefore, evaluated the levels of angiogenic factors in two systems of a human co-culture of fibroblast (HT1080) and monocytic (U937) cell lines treated with tofacitinib and in serum samples from RA patients before and after six months of tofacitinib treatment. Tofacitinib reduced CD147 levels, matrix metalloproteinase-9 (MMP-9) activity, and angiogenic potential but increased endostatin levels and secreted proteasome 20S activity. In vitro, tofacitinib did not change CD147 mRNA but increased miR-146a-5p expression and reduced STAT3 phosphorylation. We recently showed that CD147 regulates the ability of MMP-9 and secreted proteasome 20S to cleave collagen XVIIIA into endostatin. We show here that tofacitinib-enhanced endostatin levels are mediated by CD147, as CD147-siRNA or an anti-CD147 antibody blocked proteasome 20S activity. The correlation between CD147 and different disease severity scores supported this role. Lastly, tofacitinib reduced endostatin' s degradation by inhibiting cathepsin S activity and recombinant cathepsin S reversed this in both systems. Thus, tofacitinib inhibits angiogenesis by reducing pro-angiogenic factors and enhancing the anti-angiogenic factor endostatin in a dual effect mediated partly through CD147 and partly through cathepsin S. [ABSTRACT FROM AUTHOR]

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Peritoneal adhesions commonly occur following abdominal or pelvic surgery and can cause serious complications. Currently, physical barriers are the primary approach used in clinical practice to prevent adhesion, although their effectiveness is frequently inadequate. In this study, we developed an injectable peptide-loaded hydrogel with multiple functions, including self-fusion, tissue-adhesiveness, anti-inflammation, anti-cell adhesion and anti-angiogenesis. To assess the effectiveness of these hydrogels, which are stabilized by dynamic imine bonds and acetal connections, in preventing postoperative abdominal adhesions, we utilized both a rat abdominal adhesion model and a rat model simulating repeated-injury adhesions. In comparison to the commercially available HA hydrogel, as-prepared hydrogels exhibited significant reductions in inflammation, fibrosis, and angiogenesis, leading to an obvious decrease in peritoneal adhesions. Moreover, this peptide-loaded hydrogel demonstrated an ideal degradation time, maintaining an in vivo viability for about 10 days. We believe this peptide-loaded hydrogel presents a promising solution for the challenging clinical issue of postoperative abdominal adhesions.

Backgroud: The study aimed to analyze the efficacy and safety of PD-1 inhibitors plus chemotherapy with or without endostatin for stage IV lung squamous cell carcinoma (LUSC). Methods: A total of 219 patients with stage IV LUSC were included. 120 received PD-1 inhibitors plus chemotherapy with or without endostatin (IC ± A), of which 39 received endostatin (IC+A) and 81 did not receive endostatin (IC-A). 99 received chemotherapy with or without endostatin (C ± A). Endpoints included overall survival (OS), progression-free survival (PFS), adverse events (AEs), and immune-related adverse events (irAEs). Results: The median PFS in the IC ± A group versus the C ± A group was 8 and 4 months (P < 0.001), and the median OS was 17 and 9 months (P < 0.001). There was no significant difference in any grade AEs between the IC ± A and C ± A groups (P > 0.05). The median PFS in the IC+A group versus the IC-A group was 11 and 7 months (P = 0.024), and the median OS was 34 and 15 months (P = 0.01). There was no significant difference between the IC+A group and the IC-A group for all grade AEs and irAEs (P > 0.05). The subgroup analysis showed that patients with LIPI = 0 had significant OS and PFS benefits in IC+A group, while for patients with LIPI = 1–2, there was no significant difference in OS and PFS benefits between the IC+A group and IC-A group. Conclusions: PD-1 inhibitors plus chemotherapy with endostatin might be first-line treatment for patients with stage IV LUSC. [ABSTRACT FROM AUTHOR]

PEGylation is a commonly used approach to prolong the blood circulation time of cationic liposomes. However, PEGylation is associated with the "PEG dilemma", which hinders binding and uptake into tumor cells. The cleavable PEG products are a possible solution to this problem. In the current research, doxorubicin-loaded cationic liposomes (Dox-CLs) surface-conjugated with a matrix metalloproteinase-2 (MMP-2)-sensitive octapeptide linker-PEG derivative were prepared and compared to non-PEGylated and PEGylated CLs in terms of size, surface charge, drug encapsulation and release, uptake, in vivo pharmacokinetics, and anticancer efficacy. It was postulated that PEG deshielding in response to the overexpressed MMP-2 in the tumor microenvironment increases the interaction of protected CLs with cellular membranes and improves their uptake by tumor cells/vasculature. MMP2-responsive Dox-CLs had particle sizes of ∼115-140 nm, surface charges of ∼+25 mV, and encapsulation efficiencies of ∼85-95%. In vitro cytotoxicity assessments showed significantly enhanced uptake and cytotoxicity of PEG-cleavable CLs compared to their non-cleavable PEG-coated counterparts or Caelyx®. Also, the chick chorioallantoic membrane assay showed great antiangiogenesis ability of Dox-CLs leading to target and prevent tumor neovascularization. Besides, in vivo studies showed an effective therapeutic efficacy of PEG-cleavable Dox-CLs in murine colorectal cancer with negligible hematological and histopathological toxicity. Altogether, our results showed that MMP2-responsive Dox-CLs could be served as a promising approach to improve tumor drug delivery and uptake. [ABSTRACT FROM AUTHOR]

Recent research suggests that photobiomodulation therapy (PBMT) positively impacts the vascular function associated with various cerebrovascular diseases. Nevertheless, the specific mechanisms by which PBMT improves vascular function remain ambiguous. Since endothelial nitric oxide synthase (eNOS) is crucial in regulating vascular function following cerebral ischemia, we investigated whether eNOS is a key element controlling cerebrovascular function and the senescence of vascular endothelial cells following PBMT treatment. Both rat photothrombotic (PT) stroke and in vitro oxygen–glucose deprivation (OGD)-induced vascular endothelial injury models were utilized. We demonstrated that treatment with PBMT (808 nm, 350 mW/cm2, 2 min/day) for 7 days significantly reduced PT-stroke-induced vascular permeability. Additionally, PBMT inhibited the levels of endothelial senescence markers (senescence green and p21) and antiangiogenic factor (endostatin), while increasing the phospho-eNOS (Ser1177) in the peri-infarct region following PT stroke. In vitro study further indicated that OGD increased p21, endostatin, and DNA damage (γH2AX) levels in the brain endothelial cell line, but they were reversed by PBMT. Intriguingly, the beneficial effects of PBMT were attenuated by a NOS inhibitor. In summary, these findings provide novel insights into the role of eNOS in PBMT-mediated protection against cerebrovascular senescence and endothelial dysfunction following ischemia. The use of PBMT as a therapeutic is a promising strategy to improve endothelial function in cerebrovascular disease. [ABSTRACT FROM AUTHOR]

The combination of anti-angiogenesis agents with immune-checkpoint inhibitors is a promising treatment for patients with advanced hepatocellular carcinoma (HCC); however, therapeutic resistance caused by cancer stem cells present in tumor microenvironments remains to be overcome. In this study, we report for the first time that the Kringle 1 domain of human hepatocyte growth-factor α chain (HGFK1), a previously described anti-angiogenesis peptide, repressed the sub-population of CD90+ cancer stem cells (CSCs) and promoted their differentiation and chemotherapy sensitivity mainly through downregulation of pre-Met protein expression and inhibition of Wnt/β-catenin and Notch pathways. Furthermore, we showed that the i.p. injection of PH1 (a tumor-targeted and biodegradable co-polymer), medicated plasmids encoding Endostatin (pEndo), HGFK1 genes (pEndo), and a combination of 50% pEndo + 50% pHGFK1 all significantly suppressed tumor growth and prolonged the survival of the HCC-bearing mice. Importantly, the combined treatment produced a potent synergistic effect, with 25% of the mice showing the complete clearance of the tumor via a reduction in the microvessel density (MVD) and the number of CD90+ CSCs in the tumor tissues. These results suggest for the first time that HGFK1 inhibits the CSCs of HCC. Furthermore, the combination of two broad-spectrum anti-angiogenic factors, Endo and HGFK1, is the optimal strategy for the development of effective anti-HCC drugs. [ABSTRACT FROM AUTHOR]

Aims The pathophysiology of orthostatic hypotension (OH), a common clinical condition, associated with adverse outcomes, is incompletely understood. We examined the relationship between OH and circulating endostatin, an endogenous angiogenesis inhibitor with antitumour effects proposed to be involved in blood pressure (BP) regulation. Methods and results We compared endostatin levels in 146 patients with OH and 150 controls. A commercial chemiluminescence sandwich immunoassay was used to measure circulating levels of endostatin. Linear and multivariate logistic regressions were conducted to test the association between endostatin and OH. Endostatin levels were significantly higher in OH patients (59 024 ± 2513 pg/mL) vs. controls (44 090 ± 1978pg/mL, P < 0.001). A positive linear correlation existed between endostatin and the magnitude of systolic BP decline upon standing (P < 0.001). Using multivariate analysis, endostatin was associated with OH (adjusted odds ratio per 10% increase of endostatin in the whole study population = 1.264, 95% confidence interval 1.141–1.402), regardless of age, sex, prevalent cancer, and cardiovascular disease, as well as traditional cardiovascular risk factors. Conclusion Circulating endostatin is elevated in patients with OH and may serve as a potential clinical marker of increased cardiovascular risk in patients with OH. Our findings call for external validation. Further research is warranted to clarify the underlying pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

Malignant pleural effusion (MPE) is one of the common complications of lung cancer. The quality of life and prognoses for MPE patients are significantly compromised. Controlling the production of MPE can relieve patients' symptoms, improve their quality of life, and prolong their survival. This article presents a case of advanced non-small cell lung cancer (NSCLC) with MPE and negative driver genes. The patient received envafolimab and Endostar in combination, resulting in a complete reduction of MPE and durable clinical benefits. The exploratory use of this treatment method improved the quality of life of this patient and has the potential to prolong the survival of this patient. [ABSTRACT FROM AUTHOR]

The endothelial glycocalyx, located at the luminal surface of the endothelium, plays an important role in the regulation of leukocyte adhesion, vascular permeability, and vascular homeostasis. Endomucin (EMCN), a component of the endothelial glycocalyx, is a mucin-like transmembrane glycoprotein selectively expressed by venous and capillary endothelium. We have previously shown that knockdown of EMCN impairs retinal vascular development in vivo and vascular endothelial growth factor 165 isoform (VEGF165)-induced cell migration, proliferation, and tube formation by human retinal endothelial cells in vitro and that EMCN is essential for VEGF165-stimulated clathrin-mediated endocytosis and signaling of VEGF receptor 2 (VEGFR2). Clathrin-mediated endocytosis is an essential step in receptor signaling and is of paramount importance for a number of receptors for growth factors involved in angiogenesis. In this study, we further investigated the molecular mechanism underlying EMCN's involvement in the regulation of VEGF-induced endocytosis. In addition, we examined the specificity of EMCN's role in angiogenesis-related cell surface receptor tyrosine kinase endocytosis and signaling. We identified that EMCN interacts with AP2 complex, which is essential for clathrin-mediated endocytosis. Lack of EMCN did not affect clathrin recruitment to the AP2 complex following VEGF stimulation, but it is necessary for the interaction between VEGFR2 and the AP2 complex during endocytosis. EMCN does not inhibit VEGFR1 and FGFR1 internalization or their downstream activities since EMCN interacts with VEGFR2 but not VEGFR1 or FGFR1. Additionally, EMCN also regulates VEGF121-induced VEGFR2 phosphorylation and internalization. [ABSTRACT FROM AUTHOR]

Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target techniques, with a specific emphasis on targeting the vascular endothelial growth factor, but have not reached ideal therapeutic efficacy. In response to this issue, our study introduced a novel nanoparticle system known as CSsiRNA/PEITC&L-cRGD NPs. These chitosan-based nanoparticles have been recognized for their excellent biocompatibility and ability to deliver genes. To enhance their targeted delivery capability, they were combined with a cyclic RGD peptide (cRGD). Targeted codelivery of gene and chemotherapeutic agents was achieved through the use of a negatively charged lipid shell and cRGD, which possesses high affinity for integrin αv β3 overexpressed in tumor cells and neovasculature. In this multifaceted approach, co-delivery of VEGF siRNA and phenethyl isothiocyanate (PEITC) was employed to target both tumor vascular endothelial cells and tumor cells simultaneously. The co-delivery of VEGF siRNA and PEITC could achieve precise silencing of VEGF, inhibit the accumulation of HIF-1 α under hypoxic conditions, and induce apoptosis in tumor cells. In summary, we have successfully developed a nanoparticle delivery platform that utilizes a dual mechanism of action of antitumor angiogenesis and pro-tumor apoptosis, which provides a robust and potent strategy for the delivery of anti-cancer therapeutics. [ABSTRACT FROM AUTHOR]

Recombinant proteins are gaining increasing popularity for treating human diseases. The clinical effectiveness of recombinant proteins is directly related to their biological activity, which is an important indicator in drug development and quality control. However, certain recombinant proteins have unclear or complex signal pathways, making detecting their activity in vitro difficult. For instance, recombinant human endostatin (endostatin), a new antitumor drug developed in China, lacks a sensitive and stable assay for its biological activity since being market approval. To address this issue, we performed a genome‐wide screening of immortalized human umbilical vein endothelial cells (HUVECs) using a CRISPR/Cas9 knockout library containing 20,000 targeted genes. We identified two potential endostatin‐resistant genes, NEPSPP and UTS2, and successfully constructed a highly sensitive cell line, HUVEC‐UTS2‐3#, by knocking down the UTS2 gene. Based on the optimized parameters of HUVEC‐UTS2‐3# cells, we established a new method for detecting the biological activity of endostatin. The method was validated, and it produced results consistent with primary HUVEC cells but with higher sensitivity and more stable data. The use of gene‐editing technology provides a novel solution for detecting the biological activity of recombinant proteins that other methods cannot detect. [ABSTRACT FROM AUTHOR]

Tumor angiogenesis, the formation of new blood vessels within the tumor microenvironment, is considered a hallmark of cancer progression and represents a crucial target for therapeutic intervention. The tumor microenvironment is characterized by a complex interplay between proangiogenic and antiangiogenic factors, regulating the vascularization necessary for tumor growth and metastasis. The study of angiogenesis involves a spectrum of techniques, spanning from biomarker assessment to advanced imaging modalities. This comprehensive review aims to provide insights into the molecular intricacies, regulatory dynamics, and clinical implications of tumor angiogenesis. By delving into these aspects, we gain a deeper understanding of the processes driving vascularization in tumors, paving the way for the development of novel and effective antiangiogenic therapies in the fight against cancer. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is one of the highly vascularized childhood solid tumors, and understanding the molecular mechanisms underlying angiogenesis in NB is crucial for developing effective therapeutic strategies. B-cell receptor-associated protein 31 (BAP31) has been implicated in tumor progression, but its role in angiogenesis remains unexplored. This study investigated BAP31 modulation of pro-angiogenic factors in SH-SY5Y NB cells. Through protein overexpression, knockdown, antibody blocking, and quantification experiments, we demonstrated that overexpression of BAP31 led to increased levels of vascular endothelial growth factor A (VEGFA) and Galectin-3 (GAL-3), which are known to promote angiogenesis. Conditioned medium derived from BAP31-overexpressing neuroblastoma cells stimulated migration and tube formation in endothelial cells, indicating its pro-angiogenic properties. Also, we demonstrated that BAP31 enhances capillary tube formation by regulating hypoxia-inducible factor 1 alpha (HIF-1α) and its downstream target, GAL-3. Furthermore, GAL-3 downstream proteins, Jagged 1 and VEGF receptor 2 (VEGFR2), were up-regulated, and blocking GAL-3 partially inhibited the BAP31-induced tube formation. These findings suggest that BAP31 promotes angiogenesis in NB by modulating GAL-3 and VEGF signaling, thereby shaping the tumor microenvironment. This study provides novel insights into the pro-angiogenic role of BAP31 in NB. [ABSTRACT FROM AUTHOR]

Previously, we demonstrated that the expression of THBS1 is increased in esophageal squamous cell carcinoma (ESCC) tissues and is correlated with lymph node metastasis and poor prognosis, indicating that THBS1 might be a candidate oncogene in ESCC. In this study, we future studied the specific role of THBS1 in ESCC and its molecular mechanism. Silencing THBS1 expression resulted in inhibition of cell migration and cell invasion of ESCC cells, the decrease of colony formation and proliferation. Tube formation of human umbilical vein endothelial cells (HUVECs) in vitro was decreased when cultured with conditioned medium from THBS1‐silenced cells. The expression of CD31, a marker for blood vessel endothelial cells, was decreased in tumor tissues derived from THBS1‐silenced tumors in vivo. Silencing THBS1 leaded the decreased of hypoxia‐inducible factor‐1α (HIF‐1α), HIF‐1β, and VEGFA protein. The expression of p‐ERK and p‐AKT were declined in HUVECs following incubation with conditioned medium from THBS1‐silenced ESCC cells compared conditioned medium from control cells. Furthermore, the treatment with bevacizumab boosted the decrease of the p‐ERK and p‐AKT levels in HUVECs incubated with the conditioned medium from THBS1‐silenced ESCC cells. THBS1 silencing combined with bevacizumab blocked VEGF, inhibited to the tube formation, colony formation and migration of HUVECs, which were superior to that of bevacizumab alone. We presumed that THBS1 can enhance HIF‐1/VEGF signaling and subsequently induce angiogenesis by activating the AKT and ERK pathways in HUVECs, resulting in bevacizumab resistance. THBS1 would be a potential target in tumor antiangiogenesis therapies. [ABSTRACT FROM AUTHOR]

Aims: Inflammation and angiogenesis play an important role in the development of early diabetic kidney disease. We investigated the association of soluble Tumour Necrosis Factor Receptor 1 (sTNF‐R1), sTNF‐R2 and endostatin with new onset microalbuminuria in normoalbuminuric patients with diabetes mellitus type 2. Methods: We conducted a case control study to assess serum levels of sTNF‐R1, sTNF‐R2 and endostatin in 169 patients with new onset microalbuminuria and in 188 matched normoalbuminuric, diabetic controls. Baseline serum samples from participants of the ROADMAP (Randomized Olmesartan and Diabetes Microalbuminuria Prevention) and observational follow‐up (ROADMAP‐OFU) studies were used. Results: Endostatin and sTNF‐R1 but not sTNF‐R2 were increased at baseline in patients with future microalbuminuria. In the multivariate analysis, each log2 increment in endostatin levels was associated with an increase of only 6% in the risk of development of microalbuminuria (adjusted HR (95% CI) 1.006 (1.001–1011). sTNF‐R1 and sTNF‐R2 levels were conversely associated with microalbuminuria, but the results did not reach statistical significance. The respective adjusted HRs (95% CI) were 1.305 (0.928–1.774) and 0.874 (0.711–1.074). Conclusions: sTNF‐R1 and sTNF‐R2 failed to predict the occurrence of microalbuminuria in normoalbuminuric patients with type 2 diabetes. Likewise, the utility of endostatin in predicting new onset proteinuria is limited. [ABSTRACT FROM AUTHOR]

Background: CCRT is presently the standard treatment for LA-NSCLC. RP is one of the main obstacles to the completion of thoracic radiation therapy, resulting in limited survival benefits in NSCLC patients. This research aims to explore the role of Endostar in the occurrence of grade≥2 RP and clinical curative effect in LA-NSCLC patients. Methods: This study retrospectively analyzed 122 patients with stage III NSCLC who received CCRT from December 2008 to December 2017, or Endostar intravenous drip concurrently with chemoradiotherapy (Endostar + CCRT group). Standard toxicity of the pneumonitis endpoint was also collected by CTCAE V5.0. We further summarized other available studies on the role of Endostar in the prognosis of NSCLC patients and the incidence of RP. Results: There were 76 cases in the CCRT group and 46 cases in the CCRT+ Endostar group. In the CCRT+ Endostar group, the occurrence of grade ≥2 RP in patients with V20Gy ≥25% was significantly higher than that in patients with V20Gy < 25% (p = 0.001). In the cohorts with V20Gy < 25%, 0 cases of 29 patients treated with Endostar developed grade ≥2 RP was lower than in the CCRT group (p = 0.026). The re-analysis of data from other available studies indicated that Endostar plus CCRT could be more efficient and safely in the occurrence of grade≥2 RP with LA-NSCLC. Conclusions: When receiving CCRT for LA-NSCLC patients, simultaneous combination of Endostar is recommended to enhance clinical benefit and reduce pulmonary toxicity. [ABSTRACT FROM AUTHOR]

During progression of rheumatoid arthritis (RA), angiogenesis provides oxygen and nutrients for the cells' increased metabolic demands and number. To turn on angiogenesis, pro-angiogenic factors must outweigh anti-angiogenic factors. We have previously shown that CD147/extracellular matrix metalloproteinase inducer (EMMPRIN) can induce the expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and matrix metallopeptidase 9 (MMP-9) in a co-culture of the human HT1080 fibrosarcoma and U937 monocytic-like cell lines. However, whether CD147 influences anti-angiogenic factors was not known. We now show that relative to single cultures, the co-culture of these cells not only enhanced pro-angiogenic factors but also decreased the anti-angiogenic factors endostatin and thrombospondin-1 (Tsp-1), generally increasing the angiogenic potential as measured by a wound assay. Using anti-CD147 antibody, CD147 small interfering RNA (siRNA), and recombinant CD147, we demonstrate that CD147 hormetically regulates the generation of endostatin but has no effect on Tsp-1. Since endostatin is cleaved from collagen XVIII (Col18A), we applied different protease inhibitors and established that MMP-9 and proteasome 20S, but not cathepsins, are responsible for endostatin generation. MMP-9 and proteasome 20S collaborate to synergistically enhance endostatin generation, and in a non-cellular system, CD147 enhanced MMP-9 activity and hormetically regulated proteasome 20S activity. Serum samples obtained from RA patients and healthy controls mostly corroborated these findings, indicating clinical relevance. Cumulatively, these findings suggest that secreted CD147 mediates a possibly allosteric effect on MMP-9 and proteasome 20S activities and can serve as a switch that turns angiogenesis on or off, depending on its ambient concentrations in the microenvironment. [ABSTRACT FROM AUTHOR]

Angiogenesis plays a significant role in the human body, from wound healing to tumor progression. "Angiogenic switch" indicates a time-restricted event where the imbalance between pro- and antiangiogenic factors results in the transition from prevascular hyperplasia to outgrowing vascularized tumor, which eventually leads to the malignant cancer progression. In the last decade, molecular players, i.e., angiogenic biomarkers and underlying molecular pathways involved in tumorigenesis, have been intensely investigated. Disrupting the initiation and halting the progression of angiogenesis by targeting these biomarkers and molecular pathways has been considered as a potential treatment approach for tumor angiogenesis. This review discusses the currently known biomarkers and available antiangiogenic therapies in cancer, i.e., monoclonal antibodies, aptamers, small molecular inhibitors, miRNAs, siRNAs, angiostatin, endostatin, and melatonin analogues, either approved by the U.S. Food and Drug Administration or currently under clinical and preclinical investigations. [ABSTRACT FROM AUTHOR]

Rosmarinus officinalis L. compounds, especially its main polyphenolic compounds, carnosic acid (CA) and rosmarinic acid (RA), influence various facets of cancer biology, making them valuable assets in the ongoing fight against cancer. These two secondary metabolites exhibit formidable antioxidant properties that are a pivotal contributor against the development of cancer. Their antitumor effect has been related to diverse mechanisms. In the case of CA, it has the capacity to induce cell death of cancer cells through the rise in ROS levels within the cells, the inhibition of protein kinase AKT, the activation of autophagy-related genes (ATG) and the disrupt mitochondrial membrane potential. Regarding RA, its antitumor actions encompass apoptosis induction through caspase activation, the inhibition of cell proliferation by interrupting cell cycle progression and epigenetic regulation, antioxidative stress-induced DNA damage, and interference with angiogenesis to curtail tumor growth. To understand the molecular interaction between rosemary compounds (CA and RA) and a protein that is involved in cancer and inflammation, S100A8, we have performed a series of molecular docking analyses using the available three-dimensional structures (PDBID: 1IRJ, 1MR8, and 4GGF). The ligands showed different binding intensities in the active sites with the protein target molecules, except for CA with the 1MR8 protein. [ABSTRACT FROM AUTHOR]

Angiogenesis is the physiological process that results in the formation of new blood vessels develop from pre-existing vasculature and plays a significant role in several physiological and pathological processes. Inhibiting angiogenesis, a crucial mechanism in the growth and metastasis of cancer, has been proposed as a potential anticancer therapy. Different studies showed the beneficial effects of angiogenesis inhibitors either in patients suffering from different cancers, alone or in combination with conventional therapies. Even though there are currently a number of efficient anti-angiogenic drugs, including monoclonal antibodies and kinase inhibitors, the associated toxicity profile and their affordability constraints are prompting researchers to search for a safe and affordable angiostatic agent for cancer treatment. Endostatin is one of the endogenous anti-angiogenic candidates that have been extensively pursued for the treatment of cancer, but even over three decades after its discovery, we have not made much advancement in employing it as an anticancer therapeutic despite of its remarkable anti-angiogenic effect with low toxicity profile. A recombinant human endostatin (rh-Es) variant for non-small cell lung cancer was approved by China in 2006 and has since been used effectively. Several other successful clinical trials related to endostatin for various malignancies are either ongoing or have already been completed with promising results. Thus, in this review, we have provided an overview of existing anti-angiogenic drugs developed for cancer therapy, with a summary of tumour angiogenesis in the context of Endostatin, and clinical status of rh-Es in cancer treatment. Furthermore, we briefly discuss the various strategies to improve endostatin features (poor pharmacokinetic properties) for developing rh-Es as a safe and effective agent for cancer treatment. [ABSTRACT FROM AUTHOR]

Abstract Recombinant proteins are gaining increasing popularity for treating human diseases. The clinical effectiveness of recombinant proteins is directly related to their biological activity, which is an important indicator in drug development and quality control. However, certain recombinant proteins have unclear or complex signal pathways, making detecting their activity in vitro difficult. For instance, recombinant human endostatin (endostatin), a new antitumor drug developed in China, lacks a sensitive and stable assay for its biological activity since being market approval. To address this issue, we performed a genome‐wide screening of immortalized human umbilical vein endothelial cells (HUVECs) using a CRISPR/Cas9 knockout library containing 20,000 targeted genes. We identified two potential endostatin‐resistant genes, NEPSPP and UTS2, and successfully constructed a highly sensitive cell line, HUVEC‐UTS2‐3#, by knocking down the UTS2 gene. Based on the optimized parameters of HUVEC‐UTS2‐3# cells, we established a new method for detecting the biological activity of endostatin. The method was validated, and it produced results consistent with primary HUVEC cells but with higher sensitivity and more stable data. The use of gene‐editing technology provides a novel solution for detecting the biological activity of recombinant proteins that other methods cannot detect.

Glycosaminoglycans (GAGs) play a key role in a variety of biological processes in the extracellular matrix (ECM) via interactions with their protein targets. Due to their high flexibility, periodicity and electrostatics-driven interactions, GAG-containing complexes are very challenging to characterize both experimentally and in silico. In this study, we, for the first time, systematically analyzed the interactions of endostatin, a proteolytic fragment of collagen XVIII known to be anti-angiogenic and anti-tumoral, with heparin (HP) and representative heparan sulfate (HS) oligosaccharides of various lengths, sequences and sulfation patterns. We first used conventional molecular docking and a docking approach based on a repulsive scaling–replica exchange molecular dynamics technique, as well as unbiased molecular dynamic simulations, to obtain dynamically stable GAG binding poses. Then, the corresponding free energies of binding were calculated and the amino acid residues that contribute the most to GAG binding were identified. We also investigated the potential influence of Zn2+ on endostatin–HP complexes using computational approaches. These data provide new atomistic details of the molecular mechanism of HP’s binding to endostatin, which will contribute to a better understanding of its interplay with proteoglycans at the cell surface and in the extracellular matrix.

During progression of rheumatoid arthritis (RA), angiogenesis provides oxygen and nutrients for the cells’ increased metabolic demands and number. To turn on angiogenesis, pro-angiogenic factors must outweigh anti-angiogenic factors. We have previously shown that CD147/extracellular matrix metalloproteinase inducer (EMMPRIN) can induce the expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and matrix metallopeptidase 9 (MMP-9) in a co-culture of the human HT1080 fibrosarcoma and U937 monocytic-like cell lines. However, whether CD147 influences anti-angiogenic factors was not known. We now show that relative to single cultures, the co-culture of these cells not only enhanced pro-angiogenic factors but also decreased the anti-angiogenic factors endostatin and thrombospondin-1 (Tsp-1), generally increasing the angiogenic potential as measured by a wound assay. Using anti-CD147 antibody, CD147 small interfering RNA (siRNA), and recombinant CD147, we demonstrate that CD147 hormetically regulates the generation of endostatin but has no effect on Tsp-1. Since endostatin is cleaved from collagen XVIII (Col18A), we applied different protease inhibitors and established that MMP-9 and proteasome 20S, but not cathepsins, are responsible for endostatin generation. MMP-9 and proteasome 20S collaborate to synergistically enhance endostatin generation, and in a non-cellular system, CD147 enhanced MMP-9 activity and hormetically regulated proteasome 20S activity. Serum samples obtained from RA patients and healthy controls mostly corroborated these findings, indicating clinical relevance. Cumulatively, these findings suggest that secreted CD147 mediates a possibly allosteric effect on MMP-9 and proteasome 20S activities and can serve as a switch that turns angiogenesis on or off, depending on its ambient concentrations in the microenvironment.

Simple Summary: Tibial dyschondroplasia (TD) is an avian metabolic disease characterized by rapid apoptosis and reduced angiogenesis with compromised chondrocyte activity at the growth plate and, ultimately, poor osteogenesis. Thiram, a widely recognized fungicide used to preserve fruits and grains, is considered among one of the potential predisposing factors of TD through sonic hedgehog, notch-gridlock, and ephrin-B2/EphB4 pathways of angiogenesis. Current literature provides a comprehensive overview regarding the involvement of pro and anti-angiogenic proteins in the mechanism of TD development. Precise coupling of two fundamental mechanisms, chondrogenesis and osteogenesis via angiogenesis, plays a crucial role during rapid proliferation of growth plates, and alteration in their balance might lead to pathogenic conditions. Tibial dyschondroplasia (TD) is characterized by an avascular, non-mineralized, jade-white "cartilaginous wedge" with impaired endochondral ossification and chondrocyte proliferation at the proximal end of a tibial bone in rapidly growing poultry birds. Developing vascular structures are dynamic with cartilage growth and are regulated through homeostatic balance among pro and anti-angiogenic proteins and cytokines. Pro-angiogenic factors involves a wide spectrum of multifactorial mitogens, such as vascular endothelial growth factors (VEGF), platelet-derived growth factors (PDGF), basic fibroblast growth factor (bFGF), placental growth factors, transforming growth factor-β (TGF-β), and TNF-α. Considering their regulatory role via the sonic hedgehog, notch-gridlock, and ephrin-B2/EphB4 pathways and inhibition through anti-angiogenic proteins like angiostatin, endostatin, decoy receptors, vasoinhibin, thrombospondin, PEX, and troponin, their possible role in persisting inflammatory conditions like TD was studied in the current literature review. Balanced apoptosis and angiogenesis are vital for physiological bone growth. Any homeostatic imbalance among apoptotic, angiogenetic, pro-angiogenic, or anti-angiogenic proteins ultimately leads to pathological bone conditions like TD and osteoarthritis. The current review might substantiate solid grounds for developing innovative therapeutics for diseases governed by the disproportion of angiogenesis and anti-angiogenesis proteins. [ABSTRACT FROM AUTHOR]

Antiangiogenic therapy with sorafenib (SF) alone is ineffective in eradicating tumors, and its long-term application can exacerbate tumor hypoxia, which in turn restricts SF's therapeutic efficacy. Here, a redox-responsive fluorinated peptide (DEN-TAT-PFC) consisting of dendritic poly-lysine, cell-penetrating peptide TAT, and perfluorocarbon was designed and synthesized to co-load siRNA-targeting hypoxia-inducible factors (siHIF-1α) and SF. The unique architecture of the peptide and fluorinated modifications enhanced the siRNA delivery efficiency, including increased siRNA binding, GSH-responsive release, cellular uptake, endosomal escape, and serum resistance. Simultaneously, the DEN-TAT-PFC/SF/siHIF-1α co-delivery system achieved efficient knockdown of HIF-1α at mRNA and protein levels, thus alleviating hypoxia and further substantially reducing VEGF expression. Additionally, the excellent oxygen-carrying ability of DEN-TAT-PFC may facilitate relief of the hypoxic microenvironment. As a result of these synergistic effects, DEN-TAT-PFC/SF/siHIF-1α exhibited considerable anti-tumor cell proliferation and anti-angiogenesis effects. Therefore, DEN-TAT-PFC can be a versatile platform for fabricating fluorine-containing drugs/siRNA complex nano-systems. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the applicability of perfusion-weighted imaging (PWI) in evaluating the curative effect of endostar (EN) combined with neoadjuvant chemotherapy (NAC) in advanced cervical cancer. Methods: Between January 2021 and December 2022, 85 patients from Gansu Provincial Maternity and Child-care Hospital, China with advanced cervical cancer received NAC intravenously and underwent pre and post-chemotherapy PWI. Neoadjuvant chemotherapy (NAC) consisted of paclitaxel (135 - 175 mg/m²) and carboplatin (300 - 400 mg/m²). The NAC regimen comprised three courses, with each course lasting three weeks. General data, gross tumor volume (GTV), maximum signal intensity loss rate (MSILR), tumor regression rate (TRR), and post-chemotherapy MSILR reduction were compared between effective and non-effective groups. Results: There was a significant difference in International Federation of Gynecology and Obstetrics (FIGO) staging, pathological types and proportion of lymph node metastasis between effective and noneffective groups (p < 0.05). At the end of 3 cycles of chemotherapy, ORR was 72.94 %. After treatment with EN combined with NAC, GTV and MSILR in effective group were significantly lower compared to non-effective group (p < 0.05). After chemotherapy, the mean relative ratio (MRR) and MSILR in effective group were significantly higher compared to non-effective group (p < 0.05). Also, MSILR before treatment (EN combined with NAC) was positively correlated with TRR after chemotherapy in patients with advanced cervical cancer (p < 0.05). Conclusion: Perfusion-weighted imaging effectively changes tumor volume in patients with advanced cervical cancer after treatment with EN combined with NAC, and this has high application in evaluating the drug's curative effect. [ABSTRACT FROM AUTHOR]

Non-small Cell Lung Cancer (NCLC) is the predominant form of lung cancer, representing the primary cause of cancer-related mortality on a global scale. In recent decades, significant research has been conducted on tumor angiogenesis in treating NCLC, owing to its pivotal role in advancing cancer. Numerous anti-angiogenic pharmaceuticals, including Recombinant Endostatin (RE), have undergone extensive assessment in preclinical and clinical settings, yielding varied outcomes that frequently fall short of expectations. Nevertheless, there is a growing fascination with RE owing to its capacity to induce a circulatory normalizing window, thereby potentially enhancing the therapeutic effectiveness of the conventional treatment for NCLC. This work aimed to assess the potential benefits of RE in enhancing the effectiveness and safety of Platinumbased Radiotherapy (PRT) when administered through intravenous and pulmonary infusions for patients with stage IIIA/B-NCLC. This paper presents a comprehensive review of both experimental and clinical investigations that have examined the combined administration of REPRT as a therapeutic approach for NCLC treatment. Out of the total sample size of 14 individuals who were assessed, the treatment's combined effectiveness is 77.6%. This percentage indicates a substantial proportion of positive results about the therapeutic intervention. The disease control rate, encompassing patients who display complete or partial responses, exhibits a noteworthy rise of 89.6%. The results underscores the effectiveness of RE-PRT in successfully arresting or reversing the advancement of the NCLC [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) have become the standard second-line treatment for advanced non-small cell lung cancer (NSCLC). Recent findings indicating an intertwined regulation of vascular endothelial growth factor (VEGF) signaling and immunosuppression in the tumor microenvironment suggest that the combination of ICIs and angiogenesis inhibitors could have synergistic antitumor activity, along with favorable tolerability. However, ICIs plus anti-angiogenesis therapy has not been widely evaluated. The purpose of this pilot study was to evaluate the efficacy and safety of ICIs plus recombinant human (rh)-endostatin as second-line treatment in advanced NSCLC with negative driver gene. Method: Prospectively evaluated the efficacy and safety of ICIs plus rh-endostain as second-line treatment in advanced NSCLC with negative driver gene. The primary endpoints of the study were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were objective response rate (ORR), disease control rate (ORR), and safety. Results: A total of 34 patients were recruited in this study. 18 patients received ICIs plus anti-angiogenesis therapy (ICIs combination therapy), and 16 patients received ICIs monotherapy. DCR was 88.9% vs 43.8% (P = 0.009). Median PFS (mPFS) was 8.3 months vs. 3.7 months (HR = 0.276, 95% CI 0.125-0.607, P = 0.001). Median OS (mOS) was 18.0 months vs 9.6 months (HR=0.364, 95% CI 0.147-0.902, P=0.009). In multivariate Cox regression analysis, ICI combination therapy prolonged PFS (HR = 0.069, 95% CI 0.019-0.185, P < 0.001) and OS (HR = 0.044, 95% CI 0.011-0.185, P < 0.001). We did not observe a significant difference in the incidence of adverse events (AEs) between the two groups (P > 0.05). Conclusions: Compared with ICIs monotherapy, ICIs combination therapy improves clinical response in patients with advanced NSCLC with negative driver gene, significantly prolongs PFS and OS, and does not significantly difference the incidence of AEs. [ABSTRACT FROM AUTHOR]

Background: Endostar is a strong angiogenesis inhibitor that is effective in treating non-small cell lung cancer (NSCLC), but the effect of Endostar in the treatment of patients with EGFR-TKI-resistant NSCLC remains unclear. We evaluated the clinical efficacy and safety of Endostar in EGFR-mutant NSCLC patients resistant to EGFR inhibition treatment. Methods: From January 1, 2016 to June 30, 2018, 68 patients were selected from the 4 institutions for the study. Patients with NSCLC received Endostar plus chemotherapy every 21-day cycle. Chemotherapy types included platinum-containing dual drugs and platinum-free single drugs. Endostar was administered by intermittent intravenous infusion or continuous microinfusion pump infusion. The overall response rate (ORR), disease control rate (DCR) and adverse events were analyzed. Survival of patients was also evaluated. Results: For all patients, the median progression-free survival (PFS) was 2.8 months, and the median overall survival (OS) was 14.2 months. PFS and OS in the Endostar pump continuous group were better than those in the Endostar intravenous infusion group. The disease control rate (DCR) was 79.4%. A total of 28 (41.2%) patients experienced varying grades of adverse events during treatment. No treatment-associated deaths were observed. The grade 3 treatment-emergent adverse events (TEAEs) were myelosuppression, weakness, and nausea/vomiting. Conclusions: Endostar was effective and well tolerated in advanced NSCLC patients. Endostar treatment showed promising survival results in EGFR-mutant NSCLC patients. [ABSTRACT FROM AUTHOR]

To observe the lesion characteristics of vertebral subchondral bone by establishing a rat model of intervertebral disc degeneration. Thirty-two Sprague--Dawley rats were randomly divided into four groups of eight rats each, and one group served as the control group without any treatment. The rats in the experimental group were injected with 30 μl of anhydrous alcohol under the endplate (sub-endplate) above the Co6 vertebrae and 30 μl of phosphate buffered saline buffer under the endplate above the Co8 vertebrae. Eight rats were randomly taken for follow-up testing at 2, 4, and 8 w after establishment of models. The rats underwent imaging X-rays and magnetic resonance imaging to assess vertebral subchondral bone and intervertebral disc degeneration grades; then serum enzyme-linked immunosorbent assay was performed to measure tumor necrosis factoralpha, interleukin-1 beta, type I procollagen amino-terminal peptide, type I collagen carboxy-terminal peptide, vascular endothelial growth factor A and endostatin. The Co5/Co6 and Co7/Co8 motion segments (including the adjacent vertebrae and intervertebral disc) were used to perform micro-computed tomography, histological staining with hematoxylin and eosin, sapphire green, and toluidine blue, as well as for detecting the expression of collagen type II, and vascular endothelial growth factor A expression. Collagen type II, aggregated proteoglycan (aggrecan), sox-9, vascular endothelial growth factor A by immunohistochemical tests. Imaging, histologic staining and immunohistochemistry confirmed the successful establishment of intervertebral disc degeneration model. Histological observations and immunohistochemical analysis showed progressive degeneration of major intervertebral disc structures. Blocking the intervertebral disc trophic pathway in the vertebral subchondral bone region can successfully establish intervertebral disc degeneration rat model, and the possible main lesion characteristics of the vertebral subchondral bone during this process include abnormal bone remodeling, destruction of blood vessels and enhanced inflammatory response. [ABSTRACT FROM AUTHOR]

The balance of angiogenic factors, including vascular endothelial growth factor (VEGF), and angiostatic factors, like thrombospondin-1 (TSP-1) and endostatin, controls striated muscle angiogenic responses to exercise training. The effect of age on circulating levels of these factors following a bout of exercise is unclear. The authors hypothesized that older adults would have lower circulating VEGF but higher TSP-1 and endostatin after exercise compared with young adults. Ten young and nine older participants cycled for 45 min at 60% estimated HRmax. Serum [VEGF], [TSP-1], and [endostatin] obtained before (PREX), immediately after (POSTX0), and 3 hr after (POSTX3) exercise were analyzed. [VEGF] increased in older adults only from PREX to POSTX0 (p <.05). [TSP-1] increased in both age groups (p <.05). There was no effect of age or exercise on [endostatin]. In conclusion, immediately after exercise, both groups had a similar increase in [TSP-1], but [VEGF] increased in older adults only. [ABSTRACT FROM AUTHOR]

Background: Increased microvascular density correlates with more advanced disease and unfavorable overall survival in non-Hodgkin lymphoma (NHL), suggesting that angiogenesis is important for disease progression. However, studies of anti-angiogenic agents in NHL patients, have generally not shown favorable outcomes. The aim of this study was to investigate whether plasma levels of a subset of angiogenesis-associated proteins are increased in indolent B-cell derived NHL (B-NHL) and to investigate whether the levels differ between patients with asymptomatic versus symptomatic disease. Methods: Plasma levels of growth differentiation factor 15 (GDF15), endostatin, matrix metalloproteinase 9 (MMP9), neutrophil gelatinase-associated lipocalin (NGAL), long pentraxin 3 (PTX3), and galectin 3 (GAL-3) were measured by ELISA in 35 patients with symptomatic indolent B-NHL, 41 patients with asymptomatic disease, and 62 healthy controls. Bootstrap t-tests were used to assess the relative differences in biomarker levels between groups. Group differences were visualized using a principal component plot. Results: Mean plasma endostatin and GDF15 levels were significantly higher in symptomatic and asymptomatic lymphoma patients than in controls. Symptomatic patients had higher mean MMP9 and NGAL than controls. Conclusions: The finding of increased plasma endostatin and GDF15 in patients with asymptomatic indolent B-NHL suggests that increased angiogenic activity is an early event in indolent B-NHL disease progression.

Background: There is evidence of pre-established vulnerability in individuals that increases the risk of their progression to severe disease or death, although the mechanisms causing this are still not fully understood. Previous research has demonstrated that a urinary peptide classifier (COV50) predicts disease progression and death from SARS-CoV-2 at an early stage, indicating that the outcome prediction may be partly due to vulnerabilities that are already present. The aim of this study is to examine the ability of COV50 to predict future non-COVID-19-related mortality, and evaluate whether the pre-established vulnerability can be generic and explained on a molecular level by urinary peptides. Methods: Urinary proteomic data from 9193 patients (1719 patients sampled at intensive care unit (ICU) admission and 7474 patients with other diseases (non-ICU)) were extracted from the Human Urinary Proteome Database. The previously developed COV50 classifier, a urinary proteomics biomarker panel consisting of 50 peptides, was applied to all datasets. The association of COV50 scoring with mortality was evaluated. Results: In the ICU group, an increase in the COV50 score of one unit resulted in a 20% higher relative risk of death [adjusted HR 1.2 (95% CI 1.17–1.24)]. The same increase in COV50 in non-ICU patients resulted in a higher relative risk of 61% [adjusted HR 1.61 (95% CI 1.47–1.76)], consistent with adjusted meta-analytic HR estimate of 1.55 [95% CI 1.39–1.73]. The most notable and significant changes associated with future fatal events were reductions of specific collagen fragments, most of collagen alpha I (I). Conclusion: The COV50 classifier is predictive of death in the absence of SARS-CoV-2 infection, suggesting that it detects pre-existing vulnerability. This prediction is mainly based on collagen fragments, possibly reflecting disturbances in the integrity of the extracellular matrix. These data may serve as a basis for proteomics-guided intervention aiming towards manipulating/ improving collagen turnover, thereby reducing the risk of death. [ABSTRACT FROM AUTHOR]

The tumor extracellular matrix (ECM) critically regulates cancer progression and treatment response. Expression of the basement membrane component collagen XVIII (ColXVIII) is induced in solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII was markedly upregulated in human breast cancer (BC) and was closely associated with a poor prognosis in high-grade BCs. We discovered a role for ColXVIII as a modulator of epidermal growth factor receptor tyrosine kinase (ErbB) signaling and show that it forms a complex with ErbB1 and -2 (also known as EGFR and human epidermal growth factor receptor 2 [HER2]) and a6-integrin to promote cancer cell proliferation in a pathway involving its N-terminal portion and the MAPK/ERK1/2 and PI3K/AKT cascades. Studies using Col18a1 mouse models crossed with the mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT) mammary carcinogenesis model showed that ColXVIII promoted BC growth and metastasis in a tumor cell-autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in the MMTV-PyMT and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII substantially improved the efficacy of ErbB-targeting therapies in both preclinical models. In summary, ColXVIII was found to sustain the stemness properties of BC cells and tumor progression and metastasis through ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have important therapeutic potential. [ABSTRACT FROM AUTHOR]

Background: Several common retinal diseases that cause blindness are characterised by pathological neovascularisation accompanied by inflammation and neurodegeneration, including retinopathy of prematurity (ROP), diabetic retinopathy (DR), age-related macular degeneration (AMD), and retinal vein occlusion (RVO). The current treatment strategies for these diseases have limited benefits. Thus, safer and more effective alternative approaches are required. In this study, we loaded small extracellular vesicles (sEVs) derived from mesenchymal stem cell (MSC) with pigment epithelium-derived factor (PEDF), and tested the therapeutic effect of PEDF-loaded sEVs (PEDF-sEVs) using an oxygen induced retinopathy (OIR) mouse model, aiming to establish a new therapy strategy for the treatment of retinal pathological angiogenesis. Results: We formulated PEDF-loaded sEVs (PEDF-sEVs) containing high concentrations of PEDF and evaluated their effects through in vivo and in vitro experiments. In OIR mice, PEDF-sEVs showed significantly better effects on retinal avascular areas, inflammation, and neuronal degeneration compared with the anti-vascular endothelial growth factor (VEGF) drug, which may indicate a possible advantage of PEDF-sEVs over anti-VEGF drugs in the treatment of pathological neovascularisation. In vitro, PEDF-sEVs greatly inhibited endothelial cell (EC) proliferation, migration, and tube formation by suppressing the VEGF-induced phosphorylation of extracellular signal-regulated kinase (ERK) and AKT (also known as Protein Kinase B). All experiments and analyses were performed in triplicate. PEDF-sEVs were more effective than PEDF or sEVs alone, both in vitro and in vivo. Furthermore, to determine the distribution of PEDF-sEVs, we used DiD-labelled sEVs and FITC-labelled PEDF to track the sEVs and PEDF, respectively. We found that PEDF-sEVs effectively reduced the degradation of PEDF. Conclusions: Loading PEDF on sEVs effectively enhanced the anti-angiogenic, anti-inflammatory, and neuroprotective effects of PEDF by increasing the stability and penetrability. These results suggest a potential role for PEDF-sEVs in retinal pathological neovascularisation. [ABSTRACT FROM AUTHOR]

Angiogenesis refers to the formation of new blood vessels from existing ones, which can occur in both physiologic and pathologic conditions. Lack of tissue oxygen is the main stimulator of angiogenesis accompanied by increasing in HIF-1α-(hypoxia-inducible factor-1α) expression as a nuclear transcription factor. Other factors such as VEGF (vascular endothelial growth factor), FGF2 (fibroblast growth factor2), and TGF (transforming growth factor) are involved in angiogenesis, too. To control diabetes and tumoral disease, abnormal angiogenesis inhibition can be useful besides stimulation that can be helpful in cardiovascular disease. In this study, we have reviewed the mechanisms and stimulators of angiogenesis and its influential factors. The most important angiogenic factors are MMP, Ang, FGF, and VEGF. Ang is not directly involved in the process of angiogenesis but sometimes destabilize the arteries. In contrast to angiostatin, endostatin TIMP and TSP1 act as the most important angiostatic factors. Many attempts have been made to identify the mechanisms and factors involved in this process but angiogenic inhibitors that inhibit the growth of cancerous masses or tumors in the body have not yet been adequately investigated. [ABSTRACT FROM AUTHOR]