Baicalein is a novel TLR4-targeting therapeutics agent that inhibits TLR4/HIF-1α/VEGF signaling pathway in colorectal cancer.
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ABSTRACT:
SUBMITTER: Chen M
PROVIDER: S-EPMC8567042 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Vascular endothelial growth factor (VEGF) is correlated with angiogenesis and early relapse of colorectal cancer (CRC). This study investigated the role of miR-148a in the regulation of VEGF/angiogenesis and early relapse of CRC. We established a stable clone with miR-148a expression in HCT116 and HT29 cell lines and created a hypoxic condition by using CoCl2 to determine the underlying mechanism of miR-148a. The effects of miR-148a on the phosphoryl-ERK (pERK)/hypoxia-inducible factor-1α (HIF-1α)/VEGF pathway were evaluated through Western blotting and the inhibitory effect of miR-148a on angiogenesis was demonstrated through a tube formation assay. Sixty-three CRC tissues (28 early relapse and 35 non-early relapse) were analysed to assess the relationship between miR-148a and HIF-1α/VEGF. The protein expression of pERK/HIF-1α/VEGF in HCT116 and HT29 cells was significantly decreased by miR-148a (all P < 0.05). The protein expression of VEGF/HIF-1α was strongly inversely associated with the expression of miR-148a in the 63 CRC tissue samples (all P < 0.05). Tube formation assay demonstrated that miR-148a significantly obliterated angiogenesis. miR-148a suppresses VEGF through down-regulation of the pERK/HIF-1α/VEGF pathway and might lead to the inhibition of angiogenesis; miR-148a down-regulation increased the early relapse rate of CRC. This demonstrates that miR-148a is a potential diagnostic and therapeutic target.
| S-EPMC6484316 | biostudies-literature
Project description:Retinopathy of prematurity (ROP), which is characterized by retinal neovascularization (RNV), is a major cause of neonatal blindness. The primary treatment for ROP is anti-vascular endothelial growth factor (VEGF) therapy, which is costly and can rapidly lead to desensitization. Celastrol, a bioactive compound extracted from Tripterygium wilfordii Hook F. ("Thunder of God Vine"), has been shown to exert anticancer and anti-inflammatory effects. However, whether celastrol has antiangiogenic activity and can suppress inflammation to inhibit ROP progression is unclear. This was investigated in the present study in vitro as well as in vivo using a mouse model of oxygen-induced retinopathy (OIR). Our results showed that celastrol treatment reduced neovascular and avascular areas in the retina and inhibited microglia activation and inflammation in OIR mice. Celastrol also inhibited proliferation, migration, and tube formation in cultured human retinal microvascular endothelial cells, and reversed the activation of the microRNA (miR)-17-5p/hypoxia-inducible factor (HIF)-1α/VEGF pathway in the retina of OIR mice. These results indicate that celastrol alleviates pathologic RNV in the retina by protecting neuroglia and suppressing inflammation via inhibition of miR-17-5p/HIF-1α/VEGF signaling, and thus has therapeutic potential for the prevention and treatment of ROP.Abbreviations: BSA, bovine serum albumin; COX2, cyclooxygenase 2; ECM, endothelial cell medium; FBS, fetal bovine serum; HDAC, histone deacetylase; HIF-1, hypoxia-inducible factor 1; HRMEC, human retinal microvascular endothelial cell; Hsp70, heat shock protein; IB4, isolectin B4; ICAM-1, intercellular adhesion molecule 1; IL-1β/6, interleukin 1 beta/6; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein 1; miRNA, microRNA; MMP, matrix metalloproteinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-kappa B; OIR, oxygen-induced retinopathy; PBS, phosphate-buffered saline; PCNA, proliferating cell nuclear antigen; PI3K, phosphatidylinositol-3-kinase; qRT-PCR, quantitative real-time PCR; RNV, retinal neovascularization; ROP, retinopathy of prematurity; RTCA, real-time cell analyzer; RVO, retinal vaso-obliteration; TNF-α, tumor necrosis factor alpha; VCAM-1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor.
| S-EPMC9467611 | biostudies-literature
Project description:Pre-eclampsia is a complication that occurs during pregnancy, the pathological feature of which is a change in vascular endothelial homeostasis. microRNA (miR)-646 is an anti-angiogenic miRNA that has been indicated to exhibit potential anti-angiogenic effects in endothelial cells cultured in vitro and in ischemia-induced angiogenesis. However, whether miR-646 has therapeutic potential in placental angiogenesis in pre-eclampsia remains to be determined. In the current study, human peripheral blood-derived endothelial progenitor cells (EPCs) were isolated to study the coordination between miR-646, vascular endothelial growth factor (VEGF)-A and hypoxia-inducible factor (HIF)-1α expression in preeclampsia EPCs. EPCs were isolated from human peripheral blood to demonstrate a potential interaction between miR-646 and targets (VEGF-A) in vitro. The number of EPCs and the expression of miR-646 in patients with preeclampsia was detected, and the effects of miR-646 on EPC function and preeclampsia angiogenesis was assessed. Clinical specimens demonstrated that miR-646 expression was enhanced in pregnancy with preeclampsia. The results indicated that miR-646 suppressed EPCs multiplication, differentiation and migration. miR-646 was observed to exert an anti-angiogenic function by suppressing the expression of angiogenic cytokines VEGF-A and HIF-1α. Additionally, luciferase results displayed that miR-646 downregulated VEGF-A expression by directly binding to a specific sequence in its 3'-untranslated region. The results of the current study demonstrated that the miR-646/VEGF-A/HIF-1α axis is significant for angiogenic properties of EPCs in vitro and in vivo placental vasculogenesis. The results of the present study provide a new insight into microRNA regulation of vessel homeostasis and angiogenesis, and a basis for alternative treatments for patients with pre-eclampsia.
| S-EPMC7401288 | biostudies-literature
Project description:Nature has a nearly infinite inventory of unexplored phytochemicals and biomolecules that have the potential to treat a variety of diseases. Safranal exhibits anti-cancer property and the present study explores its antiangiogenic property. Hepatocellular carcinoma (HCC) ranks as the sixth deadliest among all cancer types. Targeting the non-tumor vasculature supporting system is very promising as it has less plasticity, unlike malignant cells that are often associated with issues like drug resistance, poor prognosis, and relapse. In this study, we successfully inhibited the proliferation of primary human umbilical vein endothelial cells (HUVEC) with an IC50 of 300μM and blocked VEGF secretion in HepG2 cells. Furthermore, safranal inhibited VEGF-induced angiogenesis in vitro and ex vivo via scratch wound assay, tube formation assay, transmembrane assay, and aortic ring assay. In addition, safranal downregulated the in vitro expression of HIF-1α, VEGF, VEGFR2, p-AKT, p-ERK1/2, MMP9, p-FAK, and p-STAT3. The present study is the first to reveal the antiangiogenic potential of safranal and propose its possible underlying mechanism in HCC.
| S-EPMC8862147 | biostudies-literature
Project description:Advancement in novel target detection using improved molecular cancer biology has opened up new avenues for promising anti-cancer drug development. In the past two decades, the mechanism of tumor hypoxia has become more understandable with the discovery of hypoxia-inducible factor-1α (HIF-1α). It is a major transcriptional regulator that coordinates the activity of various transcription factors and their downstream molecules involved in tumorigenesis. HIF-1α not only plays a crucial role in the adaptation of tumor cells to hypoxia but also regulates different biological processes, including cell proliferation, survival, cellular metabolism, angiogenesis, metastasis, cancer stem cell maintenance, and propagation. Therefore, HIF-1α overexpression is strongly associated with poor prognosis in patients with different solid cancers. Hence, pharmacological targeting of HIF-1α has been considered to be a novel cancer therapeutic strategy in recent years. In this review, we provide brief descriptions of natural and synthetic compounds as HIF-1α inhibitors that have the potential to accelerate anticancer drug discovery. This review also introduces the mode of action of these compounds for a better understanding of the chemical leads, which could be useful as cancer therapeutics in the future.
| S-EPMC9413992 | biostudies-literature
Project description:Erianin is a natural compound found in Dendrobium chrysotoxum Lindl. Diabetic retinopathy (DR) is a serious and common microvascular complication of diabetes. This study aims to investigate the inhibitory mechanism of erianin on retinal neoangiogenesis and its contribution to the amelioration of DR. Erianin blocked high glucose (HG)-induced tube formation and migration in choroid-retinal endothelial RF/6A cells. Erianin inhibited HG-induced vascular endothelial growth factor (VEGF) expression, hypoxia-inducible factor 1-alpha (HIF-1α) translocation into nucleus and ERK1/2 activation in RF/6A and microglia BV-2 cells. MEK1/2 inhibitor U0126 blocked HG-induced HIF-1α and ERK1/2 activation in both above two cells. In addition, erianin abrogated VEGF-induced angiogenesis in vitro and in vivo, and also inhibited VEGF-induced activation of VEGF receptor 2 (VEGFR2) and its downstream cRaf-MEK1/2-ERK1/2 and PI3K-AKT signaling pathways in RF/6A cells. Furthermore, erianin reduced the increased retinal vessels, VEGF expression and microglia activation in streptozotocin (STZ)-induced hyperglycemic and oxygen-induced retinopathy (OIR) mice. In conclusion, our results demonstrate that erianin inhibits retinal neoangiogenesis by abrogating HG-induced VEGF expression by blocking ERK1/2-mediated HIF-1α activation in retinal endothelial and microglial cells, and further suppressing VEGF-induced activation of VEGFR2 and its downstream signals in retinal endothelial cells.
| S-EPMC5039671 | biostudies-literature
Project description:Overexpression of NQO1 is associated with poor prognosis in human cancers including breast, colon, cervix, lung and pancreas. Yet, the molecular mechanisms underlying the pro-tumorigenic capacities of NQO1 have not been fully elucidated. Here we show a previously undescribed function for NQO1 in stabilizing HIF-1α, a master transcription factor of oxygen homeostasis that has been implicated in the survival, proliferation and malignant progression of cancers. We demonstrate that NQO1 directly binds to the oxygen-dependent domain of HIF-1α and inhibits the proteasome-mediated degradation of HIF-1α by preventing PHDs from interacting with HIF-1α. NQO1 knockdown in human colorectal and breast cancer cell lines suppresses HIF-1 signalling and tumour growth. Consistent with this pro-tumorigenic function for NQO1, high NQO1 expression levels correlate with increased HIF-1α expression and poor colorectal cancer patient survival. These results collectively reveal a function of NQO1 in the oxygen-sensing mechanism that regulates HIF-1α stability in cancers.
| S-EPMC5171868 | biostudies-literature
Project description:BackgroundStabilization and increased activity of hypoxia-inducible factor 1-α (HIF-1α) can directly increase cancellous bone formation and play an essential role in bone modeling and remodeling. However, whether an increased HIF-1α expression in adipose-derived stem cells (ADSCs) increases osteogenic capacity and promotes bone regeneration is not known.ResultsIn this study, ADSCs transfected with small interfering RNA and HIF-1α overexpression plasmid were established to investigate the proliferation, migration, adhesion, and osteogenic capacity of ADSCs and the angiogenic ability of human umbilical vein endothelial cells (HUVECs). Overexpression of HIF-1α could promote the biological functions of ADSCs, and the angiogenic ability of HUVECs. Western blotting showed that the protein levels of osteogenesis-related factors were increased when HIF-1α was overexpressed. Furthermore, the influence of upregulation of HIF-1α in ADSC sheets on osseointegration was evaluated using a Sprague-Dawley (SD) rats implant model, in which the bone mass and osteoid mineralization speed were evaluated by radiological and histological analysis. The overexpression of HIF-1α in ADSCs enhanced bone remodeling and osseointegration around titanium implants. However, transfecting the small interfering RNA (siRNA) of HIF-1α in ADSCs attenuated their osteogenic and angiogenic capacity. Finally, it was confirmed in vitro that HIF-1α promotes osteogenic differentiation and the biological functions in ADSCs via the VEGF/AKT/mTOR pathway.ConclusionsThis study demonstrates that HIF-1α has a critical ability to promote osteogenic differentiation in ADSCs by coupling osteogenesis and angiogenesis via the VEGF/AKT/mTOR signaling pathway, which in turn increases osteointegration and bone formation around titanium implants.
| S-EPMC10405507 | biostudies-literature
Project description:Anti-angiogenesis is currently considered as one of the major antitumor strategies for its protective effects against tumor emergency and later progression. The anti-diabetic drug metformin has been demonstrated to significantly inhibit tumor angiogenesis based on recent studies. However, the mechanism underlying this anti-angiogenic effect still remains an enigma. In this study, we investigated metformin-induced inhibitory effect on tumor angiogenesis in vitro and in vivo. Metformin pretreatment significantly suppressed tumor paracrine signaling-induced angiogenic promotion even in the presence of heregulin (HRG)-β1 (a co-activator of HER2) pretreatment of HER2+ tumor cells. Similar to that of AG825, a specific inhibitor of HER2 phosphorylation, metformin treatment decreased both total and phosphorylation (Tyr 1221/1222) levels of HER2 protein and significantly reduced microvessel density and the amount of Fitc-conjugated Dextran leaking outside the vessel. Furthermore, our results of VEGF-neutralizing and -rescuing tests showed that metformin markedly abrogated HER2 signaling-induced tumor angiogenesis by inhibiting VEGF secretion. Inhibition of HIF-1α signaling by using RNAi or YC-1, a specific inhibitor of HIF-1α synthesis, both completely diminished mRNA level of VEGF and greatly inhibited endothelial cell proliferation promoted by HER2+ tumor cell-conditioned medium in both the absence and presence of HRG-β1 pretreatment. Importantly, metformin treatment decreased the number of HIF-1α nucleus positive cells in 4T1 tumors, accompanied by decreased microvessel density. Our data thus provides novel insight into the mechanism underlying the metformin-induced inhibition of tumor angiogenesis and indicates possibilities of HIF-1α-VEGF signaling axis in mediating HER2-induced tumor angiogenesis.
| S-EPMC4792577 | biostudies-literature
Project description:Epithelial-mesenchymal transition (EMT) plays a crucial role in hepatocellular carcinoma (HCC) progression. Hypoxia and excessive transforming growth factor-β (TGF-β) have been identified as inducers and target for EMT in HCC. Here, we show hypoxia inducible factor-1α (HIF-1α) and TGF-β form a feed-forward loop to induce EMT in HCC cells. Further mechanistic study indicates under both hypoxia and TGF-β stimulation, Smad and PI3K-AKT pathways are activated. We show sanguinarine, a natural benzophenanthridine alkaloid, impairs the proliferation of nine kinds of HCC cell lines and the colony formation of HCC cells. In hypoxic and TGF-β cell models, sanguinarine inhibits HIF-1α signaling and the expression of EMT markers, translocation of Snail and activation of both Smad and PI3K-AKT pathways. Sanguinarine could also inhibit TGF-β-induced cell migration in HCC cells. In vivo studies reveal that the administration of sanguinarine inhibits tumor growth and HIF-1α signaling, inhibits the expression changes of EMT markers as well as Smad and PI3K-AKT pathway proteins. Our findings suggest that sanguinarine is a promising candidate targeting HIF-1α/TGF-β signaling to improve the treatment for HCC patients.
| S-EPMC6901539 | biostudies-literature