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2022 ◽  
Vol 12 (5) ◽  
pp. 1040-1045
Jingfang Zhu ◽  
Jianglin Hu

Preeclampsia (PE) causes serious harm to the health of mothers and infants. PTEN regulates cell biological behaviors, but its role in preeclampsia have not been reported. Real time PCR and Western blot detected PTEN level in the placenta of PE patients and controls. Placental trophoblastderived cell line HTR8 was assigned into NC group, PTEN group and si-PTEN inhibitor group followed by measuring PTEN level, cell proliferation by MTT assay, cell invasion by Transwell, Caspase 3 activity, Beclin-1 and Atg-5 expression as well as PI3K/Akt/HIF-1α/VEGF signaling protein by Western blot. PTEN in PE patients was significantly downregulated (P < 0.05). Transfection of PTEN siRNA significantly down-regulated PTEN, promoted cell proliferation and invasion, reduced Caspase 3 activity, increased Beclin-1 and Atg-5, and PI3K/Akt/HIF-1α/VEGF protein expression (P < 0.05). Transfection of pcDNA 3.0-PTEN up-regulated PTEN and significantly reversed the above changes (P < 0.05). In conclusion, PTEN is reduced in PE and it can regulate pre-eclampsia trophoblast autophagy possibly through PI3K/Akt/HIF-1α/VEGF signaling, suggesting that PTEN can be a potential target for PE therapy.

2022 ◽  
Vol 12 (5) ◽  
pp. 1065-1070
Jin Song ◽  
Jiahan Chang ◽  
Xue Lin ◽  
Cibo Fan ◽  
Lili Han ◽  

Triple-negative breast cancer (TNBC) remains a threat to women’s life with a lack of targeted therapy. This study aimed to explore the role of PTEN derived from BMSCs in TNBC. We carried out a retrospective analysis of 65 TNBC patients and 30 healthy subjects from October 2016 to January 2021 with a 10-year follow up. PTEN expression in TNBC tissues and cells was determined by RTqPCR. Functional experiments were conducted to evaluate PTEN’s effect on TNBC cell biological behaviors using MTT assay and Transwell assay, as well as on PI3K-Akt-HIF-1α-VEGF signaling transduction. PTEN was up-regulated in TNBC tissues relative to healthy controls and it was negatively associated with the survival rate. In in vitro experiments, PTEN overexpression increased cell viability and invasion and knocking down of PTEN exerted opposite effect. The expression of PI3K was directly regulated by PTEN. Up-regulation of PTEN resulted in a decline in HIF-1α, Akt and VEGF expressions, which were elevated after knocking down of PTEN. In conclusion, PTEN derived from BMSCs promotes TNBC cell development through blocking PI3K-Akt-HIF-1α-VEGF signaling pathway, providing a new theoretical basis for targeted therapy of TNBC.

2022 ◽  
Vol 2022 ◽  
pp. 1-14
Rongrong Zhou ◽  
De Jin ◽  
Yuqing Zhang ◽  
Liyun Duan ◽  
Yuehong Zhang ◽  

Objective. To explore the main bioactive compounds and investigate the underlying mechanism of Pollen Typhae (PT) against diabetic retinopathy (DR) by network pharmacology and molecular docking analysis. Methods. Bioactive ingredients and the target proteins of PT were obtained from TCMSP, and the related target genes were acquired from the SwissTargetPrediction database. The target genes of DR were obtained from GeneCards, TTD database, DisGeNET database, and DrugBank. The compound-target interaction network was established based on Cytoscape 3.7.2. The protein-protein interaction (PPI) network was constructed via STRING database and Cytoscape 3.7.2. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were visualized through DAVID database and Bioinformatics. Ingredient-gene-pathway network analysis was conducted to further screen the ingredients, target proteins, and pathways closely related to the biological mechanism on PT for DR, and molecular docking analysis was performed by SYBYL-X 2.1.1 software. Finally, the mechanism and underlying targets of PT in the treatment of DR were predicted. Results. A total of 8 compounds and 171 intersection targets were obtained based on the online network database. 7 main compounds were screened from compound-target network, and 53 targets including the top six key targets (PTGS2, AKT1, VEGFA, MAPK3, TNF, and EGFR) were further acquired from PPI analysis. The 53 key targets covered 80 signaling pathways, among which PI3K-Akt signaling pathway, focal adhesion, Rap1 signaling pathway, VEGF signaling pathway, and HIF-1 signaling pathway were closely connected with the biological mechanism involved in the alleviation of DR by PT. Ingredient-gene-pathway network shows that AKTI, EGFR, and VEGFA were core genes, kaempferol and isorhamnetin were pivotal ingredients, and VEGF signaling pathway and Rap1 signaling pathway were closely involved in anti-DR. The docking results indicated that five main compounds (arachidonic acid, isorhamnetin, quercetin, kaempferol, and (2R)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one) had good binding activity with EGFR and AKT1 targets. Conclusion. The active ingredients in PT may regulate the levels of inflammatory factors, suppress the oxidative stress, and inhibit the proliferation, migration, and invasion of retinal pericytes by acting on PTGS2, AKT1, VEGFA, MAPK3, TNF, and EGFR targets through VEGF signaling pathway, PI3K-Akt signaling pathway, Rap1 signaling pathway, and HIF-1 signaling pathway to play a therapeutic role in diabetic retinopathy.

2021 ◽  
Wen Li ◽  
Xiang He ◽  
Jiong Zhu ◽  
Huimin Zhang

Abstract 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.

2021 ◽  
Vol 9 ◽  
Aniket Ramshekar ◽  
M. Elizabeth Hartnett

Retinopathy of prematurity (ROP) is a leading cause of blindness in children worldwide. Blindness can occur from retinal detachment caused by pathologic retinal angiogenesis into the vitreous, termed intravitreal neovascularization (IVNV). Although agents that interfere with the bioactivity of vascular endothelial growth factor (VEGF) are now used to treat IVNV, concerns exist regarding the identification of optimal doses of anti-VEGF for individual infants and the effect of broad VEGF inhibition on physiologic angiogenesis in external organs or in the retina of a preterm infant. Therefore, it is important to understand VEGF signaling in both physiologic and pathologic angiogenesis in the retina. In this manuscript, we review the role of receptors that interact with VEGF in oxygen-induced retinopathy (OIR) models that represent features of ROP pathology. Specifically, we discuss our work regarding the regulation of VEGFR2 signaling in retinal endothelial cells to not only reduce severe ROP but also facilitate physiologic retinal vascular and neuronal development.

2021 ◽  
Vol 13 (1) ◽  
Qing Xiao ◽  
Yinu Zhao ◽  
Hongjing Sun ◽  
Jia Xu ◽  
Wenjie Li ◽  

Abstract Background Diabetic retinopathy (DR) is a diabetic complication and the primary cause of blindness in the world. However, the treatments of DR are challenging given its complicated pathogenesis. Here, we investigated the molecular mechanisms of DR by focusing on the function of E2F1/miR-423-5p/HIPK2/HIF1α/VEGF axis. Methods Cultured retinal endothelial cells (hRMECs, hRECs) were treated with 25 mM glucose to mimic the high glucose-induced DR in vitro. Streptozotocin (STZ) was injected into mice to induce DR in mice. qRT-PCR, western blotting, immunohistochemistry, and ELISA were employed to measure levels of E2F1, miR-423-5p, HIPK2, HIF1α, and VEGF. H&E staining was utilized to examine retinal neovascularization. CCK-8 assay, transwell assay, and vascular tube formation assay were used to assess the cell viability, migration, and angiogenesis. Dual luciferase assay was performed to validate interactions between E2F1 and miR-423-5p, miR-423-5p and HIPK2. Results HG treatment increased the cell viability, migration, and angiogenesis accompanied by upregulation of E2F1, miR-423-5p, HIF1α, and VEGF levels, but reduction in HIPK2 expression. Knockdown of E2F1 or miR-423-5p suppressed the HG-induced increases in cell viability, migration, and angiogenesis. E2F1 transcriptionally activated miR-423-5p expression and miR-423-5p mimics blocked the effects of E2F1 knockdown on angiogenesis. Moreover, miR-423-5p directly targeted HIPK2 to disinhibit HIF1α/VEGF signaling. Knockdown of HIPK2 reversed the effects of miR-423-5p inhibitor on cell viability, migration, and angiogenesis. Knockdown of E2F1 suppressed neovascularization during DR in vivo. Conclusions E2F1 activates miR-423-5p transcription during DR to promote angiogenesis via suppressing HIPK2 expression to disinhibit HIF1α/VEGF signaling. Strategies targeting E2F1/miR-423-5p/HIPK2 axis could be potentially used for DR treatment.

2021 ◽  
pp. 147752
Umadevi V. Wesley ◽  
Ian Sutton ◽  
Paul A. Clark ◽  
Katelin Cunningham ◽  
Carolina Larrain ◽  

Gene Reports ◽  
2021 ◽  
pp. 101483
Eskandar Taghizadeh ◽  
Khalil Tazik ◽  
Forough Taheri ◽  
Ghazal Shayankia ◽  
Seyed Mohammad Gheibi Hayat ◽  

2021 ◽  
Vol 66 (11) ◽  
pp. 650-654
Elena Sergeyevna Gershtein ◽  
E. A. Korotkova ◽  
A. P. Petrosyan ◽  
E. A. Suleymanov ◽  
I. S. Stilidi ◽  

Analysis of long-term treatment results of 77 primary gastric cancer patients at stage I-IV of the tumor process followed during 1 - 41 months (median - 6.4 months) from the onset of specific treatment are presented depending on the basal levels of VEGF, soluble forms of its receptors (sVEGFR1, sVEGFR2) and matrix metalloproteinases (MMP-2, 7, 9) in blood serum. Overall survival assessed by Kaplan-Meyer analysis and with the help of Cox multiparametric regression model was applied as the criterion of prognostic value. It was found that at high (≥ 420 pg/ml) serum VEGF, the overall survival of patients with gastric cancer was statistically significantly lower than at the marker’s levels below 420 pg/ml (p<0.011): 3-year’s survival comprised 46,3±12,5% and 88,2±7,8% respectively. Median survival of patients with high VEGF level comprised 21.7 months, of those with low VEGF was not achieved during the whole follow-up period. Serum sVEGFR1, sVEGFR2, MMP-2, 7 and 9 levels were not significantly associated with the overall survival of patients included in this study. Only index M of TNM system and serum VEGF level demonstrated an independent prognostic value in multiparametric model (p=0.036). Thus, it was confirmed that VEGF signaling pathway plays an important role in gastric cancer, and its components - in the first place, VEGF A - are substantial factors of disease prognosis, and can also be useful for monitoring of treatment efficiency.

2021 ◽  
Vol 11 ◽  
Baoling Liu ◽  
Quanping Su ◽  
Bolian Xiao ◽  
Guodong Zheng ◽  
Lizhong Zhang ◽  

Angiogenesis plays an important role in tumor initiation and progression of glioma. Seeking for biomarkers associated with angiogenesis is important in enhancing our understanding of glioma biologically and identifying its new drug targets. RNA-sequencing (RNA-seq) data and matched clinical data were downloaded from the CGGA database. A series of filtering analyses were performed to screen for reliable genes: survival, multivariate Cox, ROC curve filtration, and clinical correlation analyses. After immunohistochemical verification, RAB42 was identified as a reliable gene for further single gene analysis. Afterwards, we performed gene set enrichment analysis (GSEA) and co-expression analysis to establish the related molecular mechanisms and signal pathways in glioma. Finally, the gene functions and the mechanisms were investigated in vitro experiments. A total of 23270 mRNA expression and 1018 glioma samples were included in this study. After the three filtering analyses, we selected ten genes for immunohistochemical verification: KLHDC8A, IKIP, HIST1H2BK, HIST1H2BJ, GNG5, FAM114A1, TMEM71, RAB42, CCDC18, and GAS2L3. Immunostaining demonstrated that RAB42 was significantly expressed on the membrane of glioma tissues but not in normal tissues. These results were verified and validated in GEPIA datasets, and the association between RAB42 with clinical features was also evaluated. Analysis of gene functions indicated that RAB42 activated VEGF signaling pathways and the mechanism was associated with natural killer cell mediated cytotoxicity, JAK-STAT signaling pathway and apoptosis pathways by PI3K/AKT in gliomas. Experiments in vitro suggested that the proliferation and invasion of glioma cells might be inhibited after downregulating of RAB42. And the tumorigenesis promotion of RAB42 may relate to the activation of VEGF signaling pathway. Taken together, this study shows that the overexpression of RAB42 is an independent prognostic factor of adverse prognosis. Its pro-oncogenic mechanism may be associated with the activation of VEGF signaling pathways.

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