Qingre Huoxue Decoction, A Traditional Chinese Herbal Formulation, Impacts Angiogenesis in Psoriasis-Like Skin Through the HIF-1α/Flt-1/VEGF Pathway

Background: Qingre Huoxue Decoction (QHD), a traditional Chinese medicine (TCM) formulation, could alleviate psoriasis in our previous studies. The present work aimed to assess QHD’s effects on psoriasis and the underpinning mechanism in cultured cells and experimental animals.Methods: The CCK-8 assay was carried out for cell viability assessment. HUVEC migration was assessed by transwell and wound healing assays. QHD-induced suppression of capillary tube formation in HUVECs was detected by tube formation assay. In addition, the imiquimod (IMQ)-induced male BALB/c mouse model of psoriasis was established to examine the Psoriasis Area and Severity Index (PASI) after QHD administration. HIF-1α, Flt-1 and VEGF expression levels in vivo were assessed by immunoblot, qPCR and immunofluorescence. Results: The results showed that QHD dose-dependently reduced viability in HUVECs. In addition, QHD suppressed tube formation in HUVECs at levels below those needed to inhibit HUVECs. Upon QHD administration, HUVEC migration was markedly decreased; QHD effectively prevented the migratory ability of HUVECs, as determined by wound areas at 0h, 12h and 24h, respectively. Finally, QHD starkly downregulated HIF-1α, Flt-1 and VEGF in the IMQ-induced mouse model, at the protein and mRNA levels.Conclusions: In summary, QHD inhibits angiogenesis in cultured cells and mice. HIF-1α/Flt-1/VEGF signaling is important in angiogenesis and psoriasis development. These findings provide a rationale for developing QHD for clinical use against psoriasis.

IL-17 Promotes Nitric Oxide Production in Non-Small-Cell Lung Cancer

Introduction: Lung cancer is the second most frequent malignancy worldwide, but its aetiology is still unclear. Inflammatory cytokines and Th cells, including Th17, are now emerging as being involved in NSCLC pathways, thus postulating a role of IL-17 in tumour angiogenesis by stimulating the vascular endothelial growth factor and the release of nitric oxide. Despite the fact that many biomarkers are used for chest malignancy diagnosis, data on FeNO levels and inflammatory cytokines in NSCLC are still few. Our study aimed to evaluate the relationship between pulmonary nitric oxide production and VEGF and Th17-related cytokines in the EBC of patients affected by early-stage NSCLC. Methods: FeNO measurement and lung function tests were performed in both patients affected by NCSLC and controls; EBC samples were also taken, and Th1 (IL-1, IL-6, IL-12, IFN-g, TNF-a), Th17 (IL-17, IL-23) and Th2 (IL-4, IL-5, IL-13) related cytokines were measured. Results: Th1 and Th17-related cytokines in EBC, except for IFN-gamma and TNF-alpha, were significantly higher in patients than in healthy controls, whereas no differences were seen for Th2-related cytokines. FeNO at the flow rate of 50 mL/s, JawNO and CalvNO levels were significantly higher in patients affected by NSCLC compared to controls. Significant correlations were found between FeNO 50 mL/s and IL-17, IL-1 and VEGF. JawNO levels positively correlated with IL-6, IL-17 and VEGF. No correlations were found between FeNO and Th2-related cytokines. Conclusion: This is the first report assessing a relationship between FeNO levels and Th17-related cytokines in the EBC of patients affected by early-stage NSCLC. IL-17, which could promote angiogenesis through the VEGF pathway, might be indirectly responsible for the increased lung production of NO in patients with NSCLC.

Treatment-free survival after discontinuation of immune checkpoint inhibitors in metastatic renal cell carcinoma: a systematic review and meta-analysis

While immune checkpoint inhibitors (ICI) can lead to sustained responses in metastatic renal cell carcinoma (mRCC), the optimal duration of therapy remains unknown. We aimed to examine treatment-free survival (TFS) in objective responders who discontinued ICI and to explore factors that may impact objective response rate (ORR) and TFS. MEDLINE/PubMed, Embase, and the Cochrane Library were searched for prospective studies reporting individual outcomes after ICI discontinuation in patients with mRCC. Pooled ORR and TFS were estimated using random-effects meta-analyses, and associations between ICI regimen type or treatment line and ORR or TFS were evaluated. Sixteen cohorts comprising 1833 patients treated with ICI were included. The pooled ORR was 43% (95% CI 33% to 53%), and significant differences in summary estimates existed among patients who received ICI monotherapy (22%, 95% CI 18% to 26%), ICI plus a vascular endothelial growth factor (VEGF) pathway inhibitor (57%, 95% CI 48% to 65%), and dual ICI (40%, 95% CI 36% to 44%). Of 572 responders who had available data, 327 stopped ICI, with 86 (26%) continuing to respond off-treatment. Pooled TFS rates at 6 and 12 months were 35% (95% CI 20% to 50%) and 20% (95% CI 8% to 35%), respectively, and were highest for responders treated with dual ICI and lowest for those treated with ICI plus a VEGF pathway inhibitor. Thus, a subset of patients with mRCC who are treated with ICI-based therapy can have durable TFS after therapy discontinuation. Prospective clinical trials and biomarkers are needed to identify patients who can discontinue ICI therapy without compromising clinical outcomes.

miR-3156-5p Enhances Hypoxia-Induced Angiogenesis in Hepatocellular Carcinoma via Modulating the SOCS5/HIF-1α/VEGF Pathway

Background: MicroRNAs (miRNAs) are dysregulated in hypoxia-induced hepatocellular carcinoma (HCC). This study probed the regulatory mechanism of miR-3156-5p on HCC under hypoxia. Methods: HCC cells (HepG2) were exposed to normoxia or hypoxia, and the conditioned medium (CM) of HepG2 was applied. Quantitative reverse transcription PCR (qRT-PCR) was implemented to analyze the miR-3156-5p profile. The cell counting kit-8 (CCK-8) assay and the colony formation experiment were conducted to measure cell proliferation, colony formation, and angiogenesis. Results: The results manifested that miR-3156-5p was up-regulated in HCC cells and endothelial cells under hypoxia, and up-regulating miR-3156-5p boosted HCC cell proliferation, endothelial cell angiogenesis, and HIF-1α/VEGF expression. Conclusions: miR-3156-5p activates the HIF-1α/VEGF pathway by hampering SOCS5, thereby enhancing the angiogenic potential of hypoxia-induced endothelial cells in HCC cells.

Endothelial Semaphorin 3fb regulates Vegf pathway-mediated angiogenic sprouting

Vessel growth integrates diverse extrinsic signals with intrinsic signaling cascades to coordinate cell migration and sprouting morphogenesis. The pro-angiogenic effects of Vascular Endothelial Growth Factor (VEGF) are carefully controlled during sprouting to generate an efficiently patterned vascular network. We identify crosstalk between VEGF signaling and that of the secreted ligand Semaphorin 3fb (Sema3fb), one of two zebrafish paralogs of mammalian Sema3F. The sema3fb gene is expressed by endothelial cells in actively sprouting vessels. Loss of sema3fb results in abnormally wide and stunted intersegmental vessel artery sprouts. Although the sprouts initiate at the correct developmental time, they have a reduced migration speed. These sprouts have persistent filopodia and abnormally spaced nuclei suggesting dysregulated control of actin assembly. sema3fb mutants show simultaneously higher expression of pro-angiogenic (VEGF receptor 2 (vegfr2) and delta-like 4 (dll4)) and anti-angiogenic (soluble VEGF receptor 1 (svegfr1)/ soluble Fms Related Receptor Tyrosine Kinase 1 (sflt1)) pathway components. We show increased phospho-ERK staining in migrating angioblasts, consistent with enhanced Vegf activity. Reducing Vegfr2 kinase activity in sema3fb mutants rescues angiogenic sprouting. Our data suggest that Sema3fb plays a critical role in promoting endothelial sprouting through modulating the VEGF signaling pathway, acting as an autocrine cue that modulates intrinsic growth factor signaling.

Endothelial Semaphorin 3fb regulates Vegf pathway-mediated angiogenic sprouting

Vessel growth integrates diverse extrinsic signals with intrinsic signaling cascades to coordinate cell migration and sprouting morphogenesis. The pro-angiogenic effects of Vascular Endothelial Growth Factor (VEGF) are carefully controlled during sprouting to generate an efficiently patterned vascular network. We identify crosstalk between VEGF signaling and that of the secreted ligand Semaphorin 3fb (Sema3fb), one of two zebrafish paralogs of mammalian Sema3F. The sema3fb gene is expressed by endothelial cells in actively sprouting vessels. Loss of sema3fb results in abnormally wide and stunted intersegmental vessel artery sprouts. Although the sprouts initiate at the correct developmental time, they have a reduced migration speed. These sprouts have persistent filopodia and abnormally spaced nuclei suggesting dysregulated control of actin assembly. sema3fb mutants show simultaneously higher expression of pro-angiogenic (VEGF receptor 2 (vegfr2) and delta-like 4 (dll4)) and anti-angiogenic (soluble VEGF receptor 1 (svegfr1)/ soluble Fms Related Receptor Tyrosine Kinase 1 (sflt1)) pathway components. We show increased phospho-ERK staining in migrating angioblasts, consistent with enhanced Vegf activity. Reducing Vegfr2 kinase activity in sema3fb mutants rescues angiogenic sprouting. Our data suggest that Sema3fb plays a critical role in promoting endothelial sprouting through modulating the VEGF signaling pathway, acting as an autocrine cue that modulates intrinsic growth factor signaling.