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Pathology, Research and Practice Nov 2023Oxysterols and oxysterol-metabolizing enzymes have been implicated in the pathogenesis of various cancers. However, the distinct function of the oxysterol-metabolizing...
Oxysterols and oxysterol-metabolizing enzymes have been implicated in the pathogenesis of various cancers. However, the distinct function of the oxysterol-metabolizing enzyme cytochrome P450 family 39 Subfamily A Member 1 (CYP39A1) in colorectal cancer (CRC) remains unclear. The aims of the current study were to evaluate whether CYP39A1 affects the oncogenic behaviors of CRC cells and to investigate the prognostic value of its expression in CRC. A CYP39A1 small-interfering RNA was used to block CYP39A1 gene expression in DLD1 and SW480 cells. The expression of CYP39A1 in CRC tissues was investigated by immunohistochemistry. Tumor angiogenesis and lymphangiogenesis were assessed by CD34 and D2-40 immunohistochemical staining, respectively. CYP39A1 knockdown inhibited tumor cell migration and invasion in DLD1 and SW480 cells. Angiogenesis was also inhibited through the decreased expression of vascular endothelial growth factor (VEGF)-A and hypoxia-inducible factor (HIF)-1α, and angiostatin and endostatin expression increased. In addition, CYP39A1 knockdown inhibited the lymphangiogenesis by decreasing the expression of VEGF-C. CYP39A1 expression was increased in CRC tissues compared with normal colorectal mucosa. CYP39A1 expression was associated with tumor stage, depth of invasion, lymph node metastasis, distant metastasis, and poor survival. The microvessel and lymphatic vessel density values of CYP39A1-positive tumors were significantly higher than those of CYP39A1-negative tumors. These results indicate that CYP39A1 is associated with tumor progression by influencing tumor cell angiogenesis and lymphangiogenesis in CRC.
Topics: Humans; Vascular Endothelial Growth Factor A; Oxysterols; Prognosis; Lymphatic Vessels; Lymphangiogenesis; Colorectal Neoplasms; Steroid Hydroxylases
PubMed: 37820439
DOI: 10.1016/j.prp.2023.154875 -
International Journal of Molecular... Aug 2023Chronic venous disease (CVD) is a condition characterized by functional disturbances in the microcirculation of the superficial and deep veins, affecting up to 30% of...
Chronic venous disease (CVD) is a condition characterized by functional disturbances in the microcirculation of the superficial and deep veins, affecting up to 30% of the global population. Diosmin, a phlebotropic drug, is commonly used in the treatment of CVD, and its beneficial effects have been described in numerous clinical studies. However, the precise molecular mechanism underlying the activity of diosmin is not yet fully understood. Therefore, the objective of our study was to investigate whether diosmin has an impact on oxygen management, as cardiovascular diseases are often associated with hypoxia. In our study, patients were administered a daily dosage of 2 × 600 mg of diosmin for 3 months, and we evaluated several factors associated with oxygen management, angiogenesis, and inflammation using biochemical assays. Our findings indicate that diosmin reduced the levels of fibroblast growth factors (FGF) and vascular endothelial growth factor (VEGF-C), while increasing endostatin and angiostatin levels, suggesting a potential influence on angiogenesis regulation. Furthermore, diosmin exhibited anti-inflammatory properties by suppressing the levels of tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β), and interleukin 6 (IL-6), while promoting the production of interleukin 12 (IL-12). Additionally, diosmin significantly decreased the levels of hypoxia-inducible factor (HIF), anion gap (AG), and lactate, indicating its potential influence on the hypoxia-inducible factor pathway. These findings suggest that diosmin may play a crucial role in modulating oxygen management and inflammation in the context of chronic venous disease.
Topics: Humans; Diosmin; Vascular Endothelial Growth Factor A; Interleukin-12; Cardiovascular Diseases; Fibroblast Growth Factors; Hypoxia; Inflammation; Interleukin-6; Lactic Acid; Homeostasis; Oxygen
PubMed: 37629098
DOI: 10.3390/ijms241612917 -
Phytomedicine : International Journal... Sep 2023A proprietary Chinese herbal product called Dan-Deng-Tong-Nao softgel capsule (DDTNC) is used to treat ischemic stroke. However, the preventive mechanisms of DDTNC...
Dan-Deng-Tong-Nao softgel capsule promotes angiogenesis of cerebral microvasculature to protect cerebral ischemia reperfusion injury via activating HIF-1α-VEGFA-Notch1 signaling pathway.
BACKGROUND
A proprietary Chinese herbal product called Dan-Deng-Tong-Nao softgel capsule (DDTNC) is used to treat ischemic stroke. However, the preventive mechanisms of DDTNC against cerebral ischemia reperfusion injury (CIRI) haven not been characterized.
OBJECTIVE
To explore the mechanisms of protective effects of DDTNC against CIRI from both internal and external levels.
METHODS
Chemical characterization was performed using UPLC. The potential protective mechanisms of DDTNC against CIRI were predicted using network pharmacology. Model of middle cerebral artery occlusion/reperfusion (MCAO/R) was established in rats. An model of brain microvascular endothelial cells (BMECs) induced by oxygen-glucose deprivation/reoxygenation (OGD/R) was also established. We evaluated neurological deficits, cerebral infarct volume, cortical neuron damage, and mitochondrial swelling in vivo. We evaluated the expression of VEGFR2, VEGFA, HIF-1α, CD31, and CD34 in ischemic cortex, and VEGF, bFGF, BDNF, angiostatin, and endostatin in serum of rats and in BMEC supernatants. We also evaluated cell viability, cytotoxicity, intracellular ROS, apoptosis, and migration ability in vitro.
RESULTS
Seven components were detected in DDTNC. KEGG enrichment analysis showed that DDTNC may modulate angiogenesis via the HIF-1 signaling pathway. DDTNC treatment reduced neurological score and infarct volume, and improved cell morphology of damaged neurons. Transmission electron microscopy showed that DDTNC reduced mitochondria swelling in cortical neurons. Furthermore, DDTNC reduced intracellular ROS and inhibited apoptosis. DDTNC boosted the expression of CD31, CD34, VEGFR2, VEGFA and HIF-1α, highlighting its involvement in angiogenesis, according to immunofluorescence studies. Furthermore, DDTNC enhanced tube formation and migration of BMECs in vitro. ELISA and western blotting indicated that DDTNCCSF induced the expression of VEGF, BDNF and bFGF, reduced the level of angiostatin and endostatin, increased the protein expression of VEGFA, Notch1 and HIF-1α in vitro and in vivo.
CONCLUSIONS
DDTNC promoted angiogenesis to protect brain tissue against MCAO/R, and exerted protective effects against OGD/R in BMECs via activating HIF-1α-VEGFA-NOTCH1 signal transduction pathway.
Topics: Rats; Animals; Endothelial Cells; Vascular Endothelial Growth Factor A; Angiostatins; Brain-Derived Neurotrophic Factor; Endostatins; Reactive Oxygen Species; Signal Transduction; Brain Ischemia; Infarction, Middle Cerebral Artery; Reperfusion Injury; Microvessels; Receptor, Notch1
PubMed: 37487254
DOI: 10.1016/j.phymed.2023.154966 -
Experimental Animals Nov 2023Epilepsy is the most common chronic disorder in the nervous system, mainly characterized by recurrent, periodic, unpredictable seizures. Post-translational modifications...
Epilepsy is the most common chronic disorder in the nervous system, mainly characterized by recurrent, periodic, unpredictable seizures. Post-translational modifications (PTMs) are important protein functional regulators that regulate various physiological and pathological processes. It is significant for cell activity, stability, protein folding, and localization. Phosphoglycerate kinase (PGK) 1 has traditionally been studied as an important adenosine triphosphate (ATP)-generating enzyme of the glycolytic pathway. PGK1 catalyzes the reversible transfer of a phosphoryl group from 1, 3-bisphosphoglycerate (1, 3-BPG) to ADP, producing 3-phosphoglycerate (3-PG) and ATP. In addition to cell metabolism regulation, PGK1 is involved in multiple biological activities, including angiogenesis, autophagy, and DNA repair. However, the exact role of PGK1 succinylation in epilepsy has not been thoroughly investigated. The expression of PGK1 succinylation was analyzed by Immunoprecipitation. Western blots were used to assess the expression of PGK1, angiostatin, and vascular endothelial growth factor (VEGF) in a rat model of lithium-pilocarpine-induced acute epilepsy. Behavioral experiments were performed in a rat model of lithium-pilocarpine-induced acute epilepsy. ELISA method was used to measure the level of S100β in serum brain biomarkers' integrity of the blood-brain barrier. The expression of the succinylation of PGK1 was decreased in a rat model of lithium-pilocarpine-induced acute epilepsy compared with the normal rats in the hippocampus. Interestingly, the lysine 15 (K15), and the arginine (R) variants of lentivirus increased the susceptibility in a rat model of lithium-pilocarpine-induced acute epilepsy, and the K15 the glutamate (E) variants, had the opposite effect. In addition, the succinylation of PGK1 at K15 affected the expression of PGK1 succinylation but not the expression of PGK1total protein. Furthermore, the study found that the succinylation of PGK1 at K15 may affect the level of angiostatin and VEGF in the hippocampus, which also affects the level of S100β in serum. In conclusion, the mutation of the K15 site of PGK1 may alter the expression of the succinylation of PGK1 and then affect the integrity of the blood-brain barrier through the angiostatin / VEGF pathway altering the activity of epilepsy, which may be one of the new mechanisms of treatment strategies.
Topics: Rats; Animals; Phosphoglycerate Kinase; Vascular Endothelial Growth Factor A; Blood-Brain Barrier; Lithium; Pilocarpine; Angiostatins; Seizures; Epilepsy; Adenosine Triphosphate
PubMed: 37258131
DOI: 10.1538/expanim.23-0019 -
Mathematical Biosciences and... Jan 2023Anti-angiogenesis as a treatment strategy for normalizing the microvascular network of tumors is of great interest among researchers, especially in combination with...
Anti-angiogenesis as a treatment strategy for normalizing the microvascular network of tumors is of great interest among researchers, especially in combination with chemotherapy or radiotherapy. According to the vital role that angiogenesis plays in tumor growth and in exposing the tumor to therapeutic agents, this work develops a mathematical framework to study the influence of angiostatin, a plasminogen fragment that shows the anti-angiogenic function, in the evolutionary behavior of tumor-induced angiogenesis. Angiostatin-induced microvascular network reformation is investigated in a two-dimensional space by considering two parent vessels around a circular tumor by a modified discrete angiogenesis model in different tumor sizes. The effects of imposing modifications on the existing model, i.e., the matrix-degrading enzyme effect, proliferation and death of endothelial cells, matrix density function, and a more realistic chemotactic function, are investigated in this study. Results show a decrease in microvascular density in response to the angiostatin. A functional relationship exists between angiostatin's ability to normalize the capillary network and tumor size or progression stage, such that capillary density decreases by 55%, 41%, 24%, and 13% in tumors with a non-dimensional radius of 0.4, 0.3, 0.2, and 0.1, respectively, after angiostatin administration.
Topics: Humans; Angiostatins; Angiogenesis Inhibitors; Endothelial Cells; Neoplasms; Neovascularization, Pathologic; Microvessels
PubMed: 36896553
DOI: 10.3934/mbe.2023252 -
Scientific Reports Feb 2023Although several angiogenesis-related factors are reportedly involved in the pathogenesis of ulcerative colitis (UC), the mechanisms by which they contribute to disease...
Although several angiogenesis-related factors are reportedly involved in the pathogenesis of ulcerative colitis (UC), the mechanisms by which they contribute to disease are unclear. We first examined the expression of angiogenesis-related factors in inflamed colorectal tissue of UC patients using antibody array, and identified the 5 factors with highest expression, which included matrix metalloproteinase-8, urokinase-type plasminogen activator (uPA), angiostatin/plasminogen, hepatocyte growth factor and endoglin. Subsequent real-time PCR experiments using additional colorectal tissues revealed that uPA mRNA levels were significantly higher in inflamed tissues than in non-inflamed tissues, and significantly correlated with the severity of UC. Mirror section immunohistochemistry revealed that uPA was expressed in the neutrophils of inflamed colorectal tissues. We administered dextran sulfate sodium (DSS) in drinking water to uPA knockout (uPA) mice, and found that the disease activity index in uPA mice was marginally lower and the histological score in uPA mice was significantly lower than those in wild-type mice, suggesting the importance of uPA in colitis. When an uPA-selective inhibitor, UK122, was administered to DSS-treated C57BL6J mice, the disease activity index and histological score in those mice were significantly lower compared with control mice. Multiple cytokine/chemokine assay using colorectal tissues from uPA and UK122-treated mice revealed significantly lowered level of RANTES. In conclusion, uPA was highly expressed in neutrophils of the inflamed mucosa of UC patients, and the expression level correlated with the severity of UC. Genetic uPA deletion or pharmacological uPA blockade significantly ameliorated colitis in mice, concomitant with downregulation of RANTES.
Topics: Animals; Mice; Urokinase-Type Plasminogen Activator; Colitis; Colitis, Ulcerative; Serine Proteases; Colorectal Neoplasms
PubMed: 36806262
DOI: 10.1038/s41598-023-29824-1 -
Neoplasma Feb 2023Zerumbone had been verified as a potential anti-cancer agent. Our research aimed to investigate the effect of zerumbone combined with gefitinib in lung cancer. Human...
Zerumbone had been verified as a potential anti-cancer agent. Our research aimed to investigate the effect of zerumbone combined with gefitinib in lung cancer. Human pulmonary alveolar epithelial cells (HPAEpiC), A549, and H460 cell lines were used to detect the efficacy of zerumbone. BALB/c nude mice were randomly divided into five groups, including model, gefitinib (Gef, 10 mg/kg), low dose zerumbone (L-Zer, 20 mg/kg), high dose zerumbone (H-Zer, 40 mg/kg), and H-Zer + Gef groups, and the tumor growth in each group was monitored. TdT-mediated dUTP Nick-End Labeling (TUNEL) was used to detect cell apoptosis. Immunohistochemistry (IHC), immunofluorescence, and western blot were used to analyze the protein expressions in tumor tissues. Glutathione (GSH) and malondialdehyde (MAD) were detected by special kits. Zerumbone inhibited the proliferation of lung cancer cells in vitro. Tumor volume and weight were reduced after gefitinib or zerumbone treatment. Gefitinib and zerumbone treatment significantly promoted the apoptosis of tumor cells. The expression of Bcl-2, Bax, and P53 proteins confirmed cell apoptosis. IHC results indicated that zerumbone and gefitinib treatment decreased tumor angiogenesis. Consistent with this result, the expression of EGFR, VEGFR2, and Ki-67 proteins decreased, while the expression of angiostatin and endostatin proteins increased. Interestingly, zerumbone treatment increased the level of MDA while decreasing GSH. Next, the levels of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) decreased after zerumbone and gefitinib treatment. Our study suggested that zerumbone combined with gefitinib could effectively inhibit lung cancer for multi-model therapies, including the inhibition of tumor growth, angiogenesis, induce cell apoptosis, and ferroptosis.
Topics: Animals; Humans; Mice; Amino Acid Transport System y+; Apoptosis; Cell Line, Tumor; Cell Proliferation; Gefitinib; Lung Neoplasms; Mice, Nude; Proto-Oncogene Proteins c-akt; STAT3 Transcription Factor
PubMed: 36637083
DOI: 10.4149/neo_2022_220418N423 -
Allergy Jun 2023
Topics: Humans; Angiostatins; Angiomotins; Airway Remodeling; Microfilament Proteins; Intercellular Signaling Peptides and Proteins; Asthma; Inflammation; Biomarkers
PubMed: 36602260
DOI: 10.1111/all.15637 -
The Journal of Thoracic and... Jul 2023Our recent studies using a porcine model of metabolic syndrome (MS) and chronic myocardial ischemia show that extracellular vesicle (EV) therapy improves blood flow and...
OBJECTIVE
Our recent studies using a porcine model of metabolic syndrome (MS) and chronic myocardial ischemia show that extracellular vesicle (EV) therapy improves blood flow and arteriogenesis in ischemic myocardium, although mechanisms of these changes are unclear. We hypothesized that in the setting of MS, EV therapy would decrease antiangiogenic signaling to mediate increased blood flow to chronically ischemic myocardium.
METHODS
Yorkshire swine were fed a high-fat diet for 4 weeks to induce MS, then underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs underwent intramyocardial injection of vehicle (control, n = 6) or human bone marrow-derived EVs (n = 8). Five weeks later, left ventricular myocardium in ischemic territory was harvested. Protein expression was measured using immunoblot analysis, and data were analyzed using Wilcoxon rank sum test. Myocardial perfusion was measured with isotope-labeled microspheres, and correlation data were analyzed using Spearman rank correlation coefficient.
RESULTS
EV treatment was associated with decreased expression of antiangiogenic proteins, angiostatin (P < .001) and endostatin (P = .043) in ischemic myocardium compared with control. In EV-treated pigs, there was a negative correlation between blood flow to ischemic myocardium and angiostatin (r = -0.76; P = .037), but not endostatin expression (r = .02; P = .98). EV treatment was also associated with decreased cathepsin D, which cleaves precursors to produce angiostatin and endostatin, in ischemic myocardium (P = .020).
CONCLUSIONS
In the setting of MS and chronic myocardial ischemia, EV therapy is associated with decreased expression of antiangiogenic proteins, which might contribute to increased blood flow to chronically ischemic myocardium.
Topics: Swine; Humans; Animals; Metabolic Syndrome; Angiostatins; Disease Models, Animal; Myocardial Ischemia; Myocardium; Extracellular Vesicles; Coronary Circulation
PubMed: 36244819
DOI: 10.1016/j.jtcvs.2022.09.019 -
Journal of Oral Pathology & Medicine :... Nov 2022Head and neck vascular malformation (HNVM) is a highly complex congenital condition that is difficult to diagnose, monitor and treat. Therefore, it is critical to...
BACKGROUNDS
Head and neck vascular malformation (HNVM) is a highly complex congenital condition that is difficult to diagnose, monitor and treat. Therefore, it is critical to explore serum cytokines that may be related to its pathology and prognosis.
METHODS
An antibody-based microarray was used to examine the expression of 31 angiogenic cytokines in 11 HNVM patients relative to 11 healthy subjects. ELISA was used to verify the results. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses of the differentially expressed cytokines (DECs). Additionally, we explored the function of DECs in human umbilical vein endothelial cells (HUVECs) in vitro via CCK-8, wound healing, transwell and tube formation assays.
RESULTS
Expression of interleukin (IL)-10, matrix metallopeptidase-9 (MMP-9) and vascular endothelial growth factor receptor 2 (VEGF-R2) in HNVM patients was significantly higher, whereas levels of IL-12p40 and angiostatin were significantly lower in HNVM patients relative to healthy controls (p < 0.05). However, ELISA only verified that IL-10, MMP-9, VEGF-R2 and IL-12p40 had significant expression changes. Functional enrichment analysis revealed DECs mainly participated in the RAS signalling pathway. Functional studies demonstrated that IL-10, MMP-9 and VEGF-R2 promote cell proliferation, migration, invasion and tube formation, while IL-12p40 inhibited these processes in HUVECs.
CONCLUSIONS
The present study not only indicates that IL-10, MMP-9, VEGF-R2 and IL-12p40 may participate in the development of HNVMs but also provides a theoretical basis for the discovery of new targeted molecules in the treatment of HNVMs.
Topics: Humans; Vascular Endothelial Growth Factor A; Interleukin-10; Cell Movement; Matrix Metalloproteinase 9; Interleukin-12 Subunit p40; Human Umbilical Vein Endothelial Cells; Vascular Malformations; Cytokines
PubMed: 35854627
DOI: 10.1111/jop.13335