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Frontiers in Oncology 2023Angiogenic growth factors (AGFs) are a class of secreted cytokines related to angiogenesis that mainly include vascular endothelial growth factors (VEGFs),... (Review)
Review
Angiogenic growth factors (AGFs) are a class of secreted cytokines related to angiogenesis that mainly include vascular endothelial growth factors (VEGFs), stromal-derived factor-1 (SDF-1), platelet-derived growth factors (PDGFs), fibroblast growth factors (FGFs), transforming growth factor-beta (TGF-β) and angiopoietins (ANGs). Accumulating evidence indicates that the role of AGFs is not only limited to tumor angiogenesis but also participating in tumor progression by other mechanisms that go beyond their angiogenic role. AGFs were shown to be upregulated in the glioma microenvironment characterized by extensive angiogenesis and high immunosuppression. AGFs produced by tumor and stromal cells can exert an immunomodulatory role in the glioma microenvironment by interacting with immune cells. This review aims to sum up the interactions among AGFs, immune cells and cancer cells with a particular emphasis on glioma and tries to provide new perspectives for understanding the glioma immune microenvironment and in-depth explorations for anti-glioma therapy.
PubMed: 37790751
DOI: 10.3389/fonc.2023.1254694 -
CNS Neuroscience & Therapeutics Jan 2024Dynamic changes in ischemic pathology after stroke suggested a "critical window" of enhanced neuroplasticity immediately after stroke onset. Although physical exercise...
OBJECTIVE
Dynamic changes in ischemic pathology after stroke suggested a "critical window" of enhanced neuroplasticity immediately after stroke onset. Although physical exercise has long been considered a promising strategy of stroke rehabilitation, very early physical exercise may exacerbate brain injury. Since remote ischemic conditioning (RIC) promotes neuroprotection and neuroplasticity, the present study combined RIC with sequential exercise to establish a new rehabilitation strategy for a better rehabilitative outcome.
METHODS
A total of 120 adult male Sprague-Dawley rats were used and divided into five groups: (1) sham, (2) stroke, (3) stroke with exercise, (4) stroke with RIC, and (5) stroke with RIC followed by exercise. Brain damage was evaluated by infarct volume, neurological deficit, cell death, and lactate dehydrogenase (LDH) activity. Long-term functional outcomes were determined by grid walk tests, rotarod tests, beam balance tests, forelimb placing tests, and the Morris water maze. Neuroplasticity was evaluated through measurements of both mRNA and protein levels of synaptogenesis (synaptophysin [SYN], post-synaptic density protein-95 [PSD-95], and brain-derived neurotrophic factor [BDNF]) and angiogenesis (vascular endothelial growth factor [VEGF], angiopoietin-1 [Ang-1], and angiopoietin-2 [Ang-2]). Inflammasome activation was measured by concentrations of interleukin-18 (IL-18) and IL-1β detected by enzyme-linked immunosorbent assay (ELISA) kits, mRNA expressions of NLR pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), IL-18 and IL-1β, and protein quantities of NLRP3, ASC, cleaved-caspase-1, gasdermin D-N (GSDMD-N), and IL-18 and IL-1β. Stress granules (SGs), including GTPase-activating protein-binding protein 1 (G3BP1), T cell-restricted intracellular antigen-1 (TIA1), and DEAD-box RNA helicase 3X (DDX3X) were evaluated at mRNA and protein levels. The interactions between DDX3X with NLRP3 or G3BP1 were determined by immunofluorescence and co-immunoprecipitation.
RESULTS
Early RIC decreased infarct volumes, neurological deficits, cell death, and LDH activity at post-stroke Day 3 (p < 0.05). All treatment groups showed significant improvement in functional outcomes, including sensory, motor, and cognitive functions. RIC and exercise, as compared to RIC or physical exercise alone, had improved functional outcomes after stroke (p < 0.05), as well as synaptogenesis and angiogenesis (p < 0.05). RIC significantly reduced mRNA and protein expressions of NLRP3 (p < 0.05). SGs formation peaked at 0 h after ischemia, then progressively decreased until 24 h postreperfusion, which was reversed by RIC (p < 0.05). The assembly of SGs consumed DDX3X and then inhibited NLRP3 inflammasome activation.
CONCLUSIONS
RIC followed by exercise induced a better rehabilitation in ischemic rats, while early RIC alleviated ischemia-reperfusion injury via stress-granule-mediated inhibition of NLRP3 inflammasome.
Topics: Humans; Rats; Male; Animals; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Interleukin-18; Rats, Sprague-Dawley; Stroke Rehabilitation; DNA Helicases; Stress Granules; Vascular Endothelial Growth Factor A; Poly-ADP-Ribose Binding Proteins; RNA Helicases; RNA Recognition Motif Proteins; Brain Injuries; Stroke; Infarction; RNA, Messenger
PubMed: 37580991
DOI: 10.1111/cns.14405 -
Journal of Orthopaedic Surgery and... Sep 2023Osteoarthritis (OA) is defined as a degenerative joint disease that can affect all tissues of the joint, including the articular cartilage, subchondral bone, ligaments... (Review)
Review
Osteoarthritis (OA) is defined as a degenerative joint disease that can affect all tissues of the joint, including the articular cartilage, subchondral bone, ligaments capsule, and synovial membrane. The conventional nonoperative treatments are ineffective for cartilage repair and induce only symptomatic relief. Platelet-rich plasma (PRP) is a platelet concentrate derived from autologous whole blood with a high concentration of platelets, which can exert anti-inflammatory and regenerative effects by releasing multiple growth factors and cytokines. Recent studies have shown that PRP exhibits clinical benefits in patients with OA. However, high operational and equipment requirements greatly limit the application of PRP to OA treatment. Past studies have indicated that high-concentration PRP growth factors and cytokines may be applied as a commercial replacement for PRP. We reviewed the relevant articles to summarize the feasibility and mechanisms of PRP-based growth factors in OA. The available evidence suggests that transforming growth factor-α and β, platelet-derived growth factors, epidermal growth factor, insulin-like growth factor-1, and connective tissue growth factors might benefit OA, while vascular endothelial growth factor, tumor necrosis factor-α, angiopoietin-1, and stromal cell derived factor-1α might induce negative effects on OA. The effects of fibroblast growth factor, hepatocyte growth factor, platelet factor 4, and keratinocyte growth factor on OA remain uncertain. Thus, it can be concluded that not all cytokines released by PRP are beneficial, although the therapeutic action of PRP has a valuable potential to improve.
Topics: Humans; Vascular Endothelial Growth Factor A; Epidermal Growth Factor; Chemokine CXCL12; Tumor Necrosis Factor-alpha; Osteoarthritis
PubMed: 37735688
DOI: 10.1186/s13018-023-04119-3 -
Biomedicines Dec 2023Aggressive hepatocellular carcinoma (HCC) overexpressing Angiopoietin-2 (ANG-2) (a protein linked with angiogenesis, proliferation, and epithelial-mesenchymal transition...
Angiopoietin-2 and the Vascular Endothelial Growth Factor Promote Migration and Invasion in Hepatocellular Carcinoma- and Intrahepatic Cholangiocarcinoma-Derived Spheroids.
Aggressive hepatocellular carcinoma (HCC) overexpressing Angiopoietin-2 (ANG-2) (a protein linked with angiogenesis, proliferation, and epithelial-mesenchymal transition (EMT)), shares 95% of up-regulated genes and a similar poor prognosis with the proliferative subgroup of intrahepatic cholangiocarcinoma (iCCA). We analyzed the pro-invasive effect of ANG-2 and its regulator vascular endothelial growth factor (VEGF) on HCC and CCA spheroids to uncover posUsible common ways of response. Four cell lines were used: Hep3B and HepG2 (HCC), HuCC-T1 (iCCA), and EGI-1 (extrahepatic CCA). We treated the spheroids with recombinant human (rh) ANG-2 and/or VEGF and then observed the changes at the baseline, after 24 h, and again after 48 h. Proangiogenic stimuli increased migration and invasion capability in HCC- and iCCA-derived spheroids and were associated with a modification in EMT phenotypic markers (a decrease in E-cadherin and an increase in N-cadherin and Vimentin), especially at the migration front. Inhibitors targeting ANG-2 (Trebananib) and the VEGF (Bevacizumab) effectively blocked the migration ability of spheroids that had been stimulated with rh-ANG-2 and rh-VEGF. Overall, our findings highlight the critical role played by ANG-2 and the VEGF in enhancing the ability of HCC- and iCCA-derived spheroids to migrate and invade, which are key processes in cancer progression.
PubMed: 38255193
DOI: 10.3390/biomedicines12010087 -
Biomolecules Aug 2023Inflammatory, vasculogenic, and profibrogenic factors have been previously reported in vitreous (VH) and aqueous (AH) humors in myopic patients who underwent cataract...
Inflammatory, vasculogenic, and profibrogenic factors have been previously reported in vitreous (VH) and aqueous (AH) humors in myopic patients who underwent cataract surgery. In light of this, we selected some mediators for AH and anterior-capsule-bearing lens epithelial cell (AC/LEC) analysis, and AH expression was correlated with LEC activation (epithelial-mesenchymal transition and EMT differentiation) and axial length (AL) elongation. In this study, AH (97; 41M/56F) and AC/LEC samples (78; 35M/43F) were collected from 102 patients who underwent surgery, and biosamples were grouped according to AL elongation. Biomolecular analyses were carried out for AH and LECs, while microscopical analyses were restricted to whole flattened AC/LECs. The results showed increased levels of interleukin (IL)-6, IL-8, and angiopoietin-2 (ANG)-2 and decreased levels of vascular endothelium growth factor (VEGF)-A were detected in AH depending on AL elongation. LECs showed EMT differentiation as confirmed by the expression of smooth muscle actin (α-SMA) and transforming growth factor (TGF)-βR1/TGFβ isoforms. A differential expression of IL-6R/IL-6, IL-8R/IL-8, and VEGF-R1/VEGF was observed in the LECs, and this expression correlated with AL elongation. The higher VEGF-A and lower VEGF-D transcript expressions were detected in highly myopic LECs, while no significant changes were monitored for VEGF-R transcripts. In conclusion, these findings provide a strong link between the AH protein signature and the EMT phenotype. Furthermore, the low VEGF-A/ANG-2 and the high VEGF-A/VEGF-D ratios in myopic AH might suggest a specific inflammatory and profibrogenic pattern in high myopia. The highly myopic AH profile might be a potential candidate for rating anterior chamber inflammation and predicting retinal distress at the time of cataract surgery.
Topics: Humans; Aqueous Humor; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor A; Interleukin-8; Biomarkers; Epithelial Cells; Interleukin-6; Cataract
PubMed: 37759728
DOI: 10.3390/biom13091328 -
Journal of Korean Medical Science Sep 2023Despite the well-established benefits of statin treatments in lowering low-density lipoprotein cholesterol (LDL-C), a significant residual risk for atherosclerotic... (Review)
Review
Despite the well-established benefits of statin treatments in lowering low-density lipoprotein cholesterol (LDL-C), a significant residual risk for atherosclerotic cardiovascular disease (ASCVD) remains. Triglycerides (TGs) have long been recognized as potential residual risk factors in this context, but recent studies now disclose the substantial role of TG-rich lipoproteins (TRLs) and cholesterol components of metabolized TRLs (commonly referred to as remnant cholesterol) in atherogenesis, not just TGs alone. Evidence derived through diverse sources, including preclinical studies of pathogenic mechanisms, epidemiologic investigations, and genetic research, has consistently supported the considerable contribution of TRLs and remnant cholesterol in predicting occurrences of ASCVD. As emerging biomarkers for predicting atherosclerosis, they have thus become prioritized therapeutic targets, meant to augment LDL-C lowering efforts in individuals at high risk of ASCVD. However, routine clinical testing for remnant cholesterol and TRLs is still in question, necessitating further research into appropriate treatment plans if levels are elevated. New therapies targeting proteins in TG metabolic pathways, particularly angiopoietin-like protein 3 and apolipoprotein C-III, have shown potential advantages in patients with mild-to-moderate hypertriglyceridemia by reducing blood levels of TGs and remnant cholesterol. The aim of this review is to summarize existing evidence linking elevated TRLs and remnant cholesterol with development of ASCVD and to explore additional guidance for clinical therapy.
Topics: Humans; Cardiovascular Diseases; Cholesterol, LDL; Cholesterol; Triglycerides; Lipoproteins; Atherosclerosis
PubMed: 37750369
DOI: 10.3346/jkms.2023.38.e295 -
Current Opinion in Lipidology Dec 2023The aim of this study was to discuss the potential mechanisms and implications of the opposing liver safety results from recent angiopoietin-like 3 (ANGPTL3) inhibition... (Review)
Review
PURPOSE OF REVIEW
The aim of this study was to discuss the potential mechanisms and implications of the opposing liver safety results from recent angiopoietin-like 3 (ANGPTL3) inhibition studies.
RECENT FINDINGS
The clinical development of vupanorsen, a N-acetylgalactosamine (GalNAc) antisense targeting hepatic ANGPTL3, was recently discontinued due to a significant signal of liver transaminase increase. Vupanorsen elicited a dose-dependent increase in hepatic fat fraction up to 75%, whereas the small interfering RNA (siRNA) ARO-ANG3, has reported preliminary evidence of a dose-dependent decrease in hepatic fat fraction up to 30%.
SUMMARY
ANGPTL3 inhibition is an attractive therapeutic target to reduce all apoB-containing lipoproteins. The discrepancy in liver signal results between the antisense and siRNA approach may be explained by the level of target inhibition. An alternative explanation may relate to off-target effects of vupanorsen, which have a molecule- and/or platform-specific origin. For intrahepatic strategies, highly potent ANGPTL3 inhibition will for now require special attention for liver safety.
Topics: Humans; Angiopoietin-like Proteins; Angiopoietin-Like Protein 3; Liver; RNA, Small Interfering; Angiopoietins
PubMed: 37820081
DOI: 10.1097/MOL.0000000000000898 -
Arteriosclerosis, Thrombosis, and... Aug 2023Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by arteriovenous malformations and blood vessel enlargements. However, there are no...
BACKGROUND
Hereditary hemorrhagic telangiectasia (HHT) is a vascular disorder characterized by arteriovenous malformations and blood vessel enlargements. However, there are no effective drug therapies to combat arteriovenous malformation formation in patients with HHT. Here, we aimed to address whether elevated levels of ANG2 (angiopoietin-2) in the endothelium is a conserved feature in mouse models of the 3 major forms of HHT that could be neutralized to treat brain arteriovenous malformations and associated vascular defects. In addition, we sought to identify the angiogenic molecular signature linked to HHT.
METHODS
Cerebrovascular defects, including arteriovenous malformations and increased vessel calibers, were characterized in mouse models of the 3 common forms of HHT using transcriptomic and dye injection labeling methods.
RESULTS
Comparative RNA sequencing analyses of isolated brain endothelial cells revealed a common, but unique proangiogenic transcriptional program associated with HHT. This included a consistent upregulation in cerebrovascular expression of ANG2 and downregulation of its receptor Tyr kinase with Ig and EGF homology domains (TIE2/TEK) in HHT mice compared with controls. Furthermore, in vitro experiments revealed TEK signaling activity was hampered in an HHT setting. Pharmacological blockade of ANG2 improved brain vascular pathologies in all HHT models, albeit to varying degrees. Transcriptomic profiling further indicated that ANG2 inhibition normalized the brain vasculature by impacting a subset of genes involved in angiogenesis and cell migration processes.
CONCLUSIONS
Elevation of ANG2 in the brain vasculature is a shared trait among the mouse models of the common forms of HHT. Inhibition of ANG2 activity can significantly limit or prevent brain arteriovenous malformation formation and blood vessel enlargement in HHT mice. Thus, ANG2-targeted therapies may represent a compelling approach to treat arteriovenous malformations and vascular pathologies related to all forms of HHT.
Topics: Animals; Mice; Telangiectasia, Hereditary Hemorrhagic; Endothelial Cells; Angiopoietin-2; Arteriovenous Malformations; Phenotype
PubMed: 37288572
DOI: 10.1161/ATVBAHA.123.319385 -
EBioMedicine Sep 2023Children with SARS-CoV-2 related Multisystem Inflammatory Syndrome in Children (MIS-C) often present with clinical features that resemble Kawasaki disease (KD). Disease...
Transient anti-cytokine autoantibodies superimpose the hyperinflammatory response in Kawasaki disease and multisystem inflammatory syndrome in children: a comparative cohort study on correlates of disease.
BACKGROUND
Children with SARS-CoV-2 related Multisystem Inflammatory Syndrome in Children (MIS-C) often present with clinical features that resemble Kawasaki disease (KD). Disease severity in adult COVID-19 is associated to the presence of anti-cytokine autoantibodies (ACAAs) against type I interferons. Similarly, ACAAs may be implicated in KD and MIS-C. Therefore, we explored the immunological response, presence of ACAAs and disease correlates in both disorders.
METHODS
Eighteen inflammatory plasma protein levels and seven ACAAs were measured in KD (n = 216) and MIS-C (n = 56) longitudinally by Luminex and/or ELISA. Levels (up to 1 year post-onset) of these proteins were related to clinical data and compared with healthy paediatric controls.
FINDINGS
ACAAs were found in both patient groups. The presence of ACAAs lagged behind the inflammatory plasma proteins and peaked in the subacute phase. ACAAs were mostly directed against IFN-γ (>80%) and were partially neutralising at best. KD presented with a higher variety of ACAAs than MIS-C. Increased levels of anti-IL-17A (P = 0·02) and anti-IL-22 (P = 0·01) were inversely associated with ICU admission in MIS-C. Except for CXCL10 in MIS-C (P = 0·002), inflammatory plasma proteins were elevated in both KD and MIS-C. Endothelial angiopoietin-2 levels were associated with coronary artery aneurysms in KD (P = 0·02); and sCD25 (P = 0·009), angiopoietin-2 (P = 0·001), soluble IL-33-receptor (ST2, P = 0·01) and CXCL10 (P = 0·02) with ICU admission in MIS-C.
INTERPRETATION
Markers of endothelial activation (E-selectin, angiopoietin-2), and innate and adaptive immune responses (macrophages [CD163, G-CSF], neutrophils [lipocalin-2], and T cells [IFN-γ, CXCL10, IL-6, IL-17]), are upregulated in KD and MIS-C. ACAAs were detected in both diseases and, although only partly neutralising, their transient presence and increased levels in non-ICU patients may suggest a dampening role on inflammation.
FUNDING
The Kawasaki study is funded by the Dutch foundation Fonds Kind & Handicap and an anonymous donor. The sponsors had no role in the study design, analysis, or decision for publication.
Topics: Adult; Humans; Child; Cytokines; Mucocutaneous Lymph Node Syndrome; Angiopoietin-2; COVID-19; Cohort Studies; SARS-CoV-2; Autoantibodies
PubMed: 37524002
DOI: 10.1016/j.ebiom.2023.104736 -
Theranostics 2023Multigene mutations in colorectal cancer (CRC), including KRAS, BRAF, and p53, afford high metastatic ability and resistance to EGFR-targeting therapy. Understanding...
Multigene mutations in colorectal cancer (CRC), including KRAS, BRAF, and p53, afford high metastatic ability and resistance to EGFR-targeting therapy. Understanding the molecular mechanisms regulating anti-EGFR-resistant CRC metastasis can improve CRC therapy. This study aimed to investigate the effects of IL-8 and the activation of KRAS on reactive oxygen species (ROS) production and metastasis of hyperlipidemia-associated CRC harboring mutations of KRAS and p53. The cytokine array analysis determined the up-expression of secreted factors, including IL-8. The clinical relevance of the relationship between IL-8 and angiopoietin-like 4 (ANGPTL4) was examined in CRC patients from National Cheng Kung University Hospital and TCGA dataset. Expressions of IL-8, ANGPTL4, NADPH oxidase 4 (NOX4), and epithelial-mesenchymal transition (EMT) markers in free fatty acids (FFAs)-treated KRAS/p53 mutant CRC cells were determined. The hyperlipidemia-triggered metastatic ability of CRC cells under treatments of antioxidants, statin, and cetuximab or knockdown of IL-8, KRAS, and EGFR was evaluated in vitro and in vivo. In addition, the effects of antioxidants and depletion of IL-8 and KRAS on the correlation between ROS production and hyperlipidemia-promoted CRC metastasis were also clarified. In this study, we found that free fatty acids promoted KRAS/p53-mutant but not single-mutant or non-mutant CRC cell metastasis. IL-8, the most abundant secreted factor in KRAS/p53-mutant cells, was correlated with the upregulation of NOX4 expression and ROS production under oleic acid (OA)-treated conditions. In addition, the metastasis of KRAS/p53-mutant CRC relies on the ANGPTL4/IL-8/NOX4 axis and the activation of KRAS. The antioxidants and inactivation of KRAS also inhibited OA-induced EMT and metastasis. Although KRAS mediated EGF- and OA-promoted CRC cell invasion, the inhibition of EGFR did not affect OA-induced ANGPTL4/IL-8/NOX4 axis and CRC metastasis. The high-fat diet mice fed with vitamin E and statin or in IL-8-depleted cells significantly inhibited tumor extravasation and metastatic lung growth of CRC. The antioxidants, statins, and targeting IL-8 may provide better outcomes for treating metastatic CRC that harbors multigene mutations and anti-EGFR resistance.
Topics: Animals; Mice; Antibodies; Antioxidants; Colonic Neoplasms; Fatty Acids, Nonesterified; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Interleukin-8; Oleic Acids; Proto-Oncogene Proteins p21(ras); Reactive Oxygen Species; Tumor Suppressor Protein p53; Humans
PubMed: 37649607
DOI: 10.7150/thno.85855