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Nuclear factor-erythroid 2-related factor 2 (Nrf2) is persistently activated in many human tumors including acute myeloid leukemia (AML). Therefore, inhibition of Nrf2 activity may be a promising target in leukemia therapy. Here, we used an antioxidant response element-luciferase reporter system to identify a novel pyrazolyl hydroxamic acid derivative, 1-(4-(tert-Butyl)benzyl)-3-(4-chlorophenyl)-N-hydroxy-1H pyrazole-5-carboxamide (4f), that inhibited Nrf2 activity. 4f had a profound growth-inhibitory effect on three AML cell lines, THP-1, HL-60 and U937, and a similar anti-growth effect in a chick embryo model. Moreover, flow cytometry of AML cells revealed increased apoptosis with 4f (10 μM) treatment for 48 h. The protein levels of cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase were enhanced in all three AML cell types. Furthermore, Nrf2 protein level was downregulated by 4f. Upregulation of Nrf2 by tert-butylhydroquinone (tBHQ) or Nrf2 overexpression could ameliorate 4f-induced growth inhibition and apoptosis. Treatment with 4f reduced both B-cell lymphoma-2 (Bcl-2) expression and Bcl-2/Bcl-2-associated X protein (Bax) ratio, which indicated that 4f induced apoptosis, at least in part, via mitochondrial-dependent signaling. Therefore, as an Nrf2 inhibitor, the pyrazolyl hydroxamic acid derivative 4f may be a promising agent in AML therapy.
Annexin A7 (ANXA7) is a suppressor of tumorigenesis and metastasis in prostate cancer. Activated ANXA7 GTPase promotes prostate cancer cell apoptosis. However, the role and underlying mechanism of ANXA7 GTPase in prostate cancer metastasis have not been established. RKIP is a metastatic suppressor and downregulated in prostate cancer metastases. The binding of RKIP and its target proteins could inhibit the activation of its interactive partners. However, the effect of RKIP on ANXA7 GTPase activation is not clear. Here, we report that activation of ANXA7 GTPase by a small molecule SEC ((S)-ethyl 1-(3-(4-chlorophenoxy)-2-hydroxypropyl)-3- (4-methoxyphenyl)-1H-pyrazole-5-carboxylate) effectively inhibited prostate cancer metastasis. Mechanistically, activated ANXA7 promoted AMPK phosphorylation, leading to decreased mTORC1 activity, suppressed STAT3 nuclear translocation, and downregulation of pro-metastatic genes, including CCL2, APLN, and IL6ST. Conversely, RKIP interacted with ANXA7 and impaired activation of ANXA7 GTPase by SEC and its downstream signaling pathway. Notably, SEC treatment suppressed metastasis of prostate cancer cells in in vivo orthotopic analysis. Together, our findings provide a novel insight into how metastasis of prostate cancer with low RKIP expression is suppressed by SEC-induced activation of ANXA7 GTPase via the AMPK/mTORC1/STAT3 signaling pathway.
In vascular strips, the adjacent endothelial cells modulate the contraction of vascular smooth muscle cells (VSMCs) induced by sphingosylphosphorylcholine (SPC) through nitric oxide (NO). The aim of this study was to elucidate the mechanisms by which vascular endothelial cells (VECs) reduce the SPC-induced contraction of VSMCs in a co-culture system.
Chromatin modulators are emerging as attractive drug targets, given their widespread implication in human cancers and susceptibility to pharmacological inhibition. Here we establish the histone methyltransferase G9a/EHMT2 as a selective regulator of fast proliferating myeloid progenitors with no discernible function in hematopoietic stem cells (HSCs). In mouse models of acute myeloid leukemia (AML), loss of G9a significantly delays disease progression and reduces leukemia stem cell (LSC) frequency. We connect this function of G9a to its methyltransferase activity and its interaction with the leukemogenic transcription factor HoxA9 and provide evidence that primary human AML cells are sensitive to G9A inhibition. Our results highlight a clinical potential of G9A inhibition as a means to counteract the proliferation and self-renewal of AML cells by attenuating HoxA9-dependent transcription.
Recently, the specific roles of integrin beta4 in the signaling networks that drive pathological angiogenesis and tumor progression have been revealed. Our previous study showed that integrin beta4 might be involved in neuron survival signal transduction. To further our study on the role of integrin beta4 in the survival and apoptosis of primary cultured mouse neurons, we inhibited the expression of integrin beta4 by its specific small interfering RNA. Viability of the cells remarkably declined, and neurons underwent apoptosis with down-regulation of integrin beta4. Next, we investigated the effect of siRNA-mediated down-regulation of integrin beta4 on the level of intracellular reactive oxygen species and the activities of NADPH oxidase and superoxide dismutase. The level of reactive oxygen species in the neurons was elevated significantly, the activities of manganese-dependent superoxide dismutase and copper/zinc-dependent superoxide dismutase were not altered, but the activity of NADPH oxidase was increased. Furthermore, inhibition of NADPH oxidase by its specific inhibitor dibenziodolium chloride attenuated the neuronal death induced by integrin beta4 knockdown. The data suggest that integrin beta4 is a key factor in neuron survival and apoptosis and indicate that this integrin subunit might perform its action through regulating NADPH oxidase and the level of reactive oxygen species in neuronal survival and apoptosis.
Lipopolysaccharide (LPS)-induced vascular endothelial cell (VEC) dysfunction is an important contributing factor in vascular diseases. Recently, we found that LPS impaired VEC by inducing autophagy. Our previous researches showed that a butyrolactone derivative, 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO) selectively protected VEC function. The objective of the present study is to investigate whether and how 3BDO inhibits LPS-induced VEC autophagic injury. Our results showed that LPS induced autophagy and led to increase of reactive oxygen species (ROS) and decrease of mitochondrial membrane potential (MMP) in Human umbilical vein vascular endothelial cells (HUVECs). Furthermore, LPS significantly increased p8 and p53 protein levels and the nuclear translocation of p53. All of these effects of LPS on HUVECs were strongly inhibited by 3BDO. Importantly, the ROS scavenger N-acetylcysteine (NAC) could inhibited LPS-induced autophagy and knockdown of p8 by RNA interference inhibited the autophagy, p53 protein level increase, the translocation of p53 into nuclei and the ROS level increase induced by LPS in HUVECs. The data suggested that 3BDO inhibited LPS-induced autophagy in HUVECs through inhibiting the ROS overproduction, the increase of p8 and p53 expression and the nuclear translocation of p53. Our findings provide a potential tool for understanding the mechanism underlying LPS-induced autophagy in HUVECs and open the door to a novel therapeutic drug for LPS-induced vascular diseases.
Heat shock protein 90 (HSP90) inhibition has aroused increasing enthusiasm in antitumor strategies in recent years. According to our previous studies, we synthesized a series of coumarin pyrazoline compounds HCP1-HCP6 that might be HSP90 inhibitors. Interactions between HCP1-HCP6 and HSP90 were examined and antitumor activities of them were investigated in A549 lung cancer cells. Results showed that all the six derivatives could interact with HSP90, in which HCP1 exhibited the best binding ability and inhibited the activity of HSP90. Meanwhile, HCP1-HCP6 reduced the cell viability of A549 cells and HCP1 possessed the lowest IC50 value. Above all HCP1 exerted better HSP90 inhibitory and anticancer effects than our initially identified HSP90 inhibitor DPB. As to the underlying mechanism, HCP1-HCP6 not only induced apoptosis as DPB but also blocked autophagic flux in A549 cells. Therefore, we discovered a novel HSP90 inhibitor HCP1 that had better biological activity and provided us a useful tool to explore the underlying mechanism of lung cancer therapy.
The development of cell therapy for repairing damaged or diseased skeletal muscle has been hindered by the inability to significantly expand immature, transplantable myogenic stem cells (MuSCs) in culture. To overcome this limitation, a deeper understanding of the mechanisms regulating the transition between activated, proliferating MuSCs and differentiation-primed, poorly engrafting progenitors is needed. Here, we show that methyltransferase Setd7 facilitates such transition by regulating the nuclear accumulation of β-catenin in proliferating MuSCs. Genetic or pharmacological inhibition of Setd7 promotes in vitro expansion of MuSCs and increases the yield of primary myogenic cell cultures. Upon transplantation, both mouse and human MuSCs expanded with a Setd7 small-molecule inhibitor are better able to repopulate the satellite cell niche, and treated mouse MuSCs show enhanced therapeutic potential in preclinical models of muscular dystrophy. Thus, Setd7 inhibition may help bypass a key obstacle in the translation of cell therapy for muscle disease.
Despite significant process in ubiquitin modification by using traditional genetic methods, chemical small molecules that directly target and modify ubiquitin are little reported. Here, we find that a fluorescigenic pyrazoline derivative (FPD5) could do so effectively. Molecule docking revealed that lysine 11 of ubiquitin was the key contact residue. FPD5, with stronger fluorescence, elevated the ubiquitination of beclin 1 (BECN1) and promoted autophagy. This study highlights that targeting ubiquitin by chemical small molecules enables us to modulate ubiquitination and the downstream signaling in the ubiquitin system.
Although manufactured magnetic nanoparticles (NPs) are currently used in many fields, NPs have potential toxicity on cardiovascular system especially atherosclerosis. In our previous study, we prepared novel Fe3O4 nanoparticles surface-coated with aminoguanidine (Fe3O4-AG NPs) which could remove acid dyes from aqueous solution efficiently. To understand its biocompatibility to atherosclerotic plaque vulnerability, we investigated the effects of the nanoparticles on human umbilical vein endothelial cells (HUVECs) in vitro and plaque stability in vivo. Fe3O4-AG NPs were taken up by HUVECs and induced HUVEC apoptosis. Fe3O4-AG NP injection remarkably promoted plaque vulnerability at low-dose (0.5 mg/kg) but not high-dose (5.0 mg/kg) in apolipoprotein E-/- (ApoE-/-) mice. Further study indicated that Fe3O4-AG NP-induced atherosclerotic plaque vulnerability was tightly linked to bioactivity of nitric oxide (NO). A significant decrease in NO production was induced which coincided with the inhibition of endothelial nitric oxide synthase (eNOS) activity in serum and endothelium of plaque in ApoE-/- mice injected with low-dose Fe3O4-AG NPs in vivo and HUVECs treated with low-dose Fe3O4-AG NPs in vitro. Thus, the low concentration of Fe3O4-AG NPs presented toxicity to atherosclerosis. Our results indicated that the use of Fe3O4-AG NPs to improve aqueous solution pollution should be cautious due to the potential toxicity.
Oxidized low-density lipoprotein (oxLDL) inhibits mammalian target of rapamycin (mTOR) and induces autophagy and apoptosis in vascular endothelial cells (VECs) that play very critical roles for the cardiovascular homostasis. We recently defined 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO) as a new activator of mTOR. Therefore, we hypothesized that 3BDO had a protective role in VECs and thus stabilized atherosclerotic lesions in apolipoprotein E(-/-) (apoE(-/-)) mice. Our results showed that oxLDL inhibited the activity of mTOR and increased the protein level of autophagy-related 13 (ATG13) and its dephosphorylation, thus inducing autophagy in human umbilical vein endothelial cells (HUVECs). All of these effects were strongly inhibited by 3BDO. In vivo experiments confirmed that 3BDO activated mTOR and decreased the protein level of ATG13 in the plaque endothelium of apoE(-/-) mice. Importantly, 3BDO did not affect the activity of mTOR and autophagy in macrophage cell line RAW246.7 and vascular smooth muscle cells of apoE(-/-) mice, but suppressed plaque endothelial cell death and restricted atherosclerosis development in the mice. 3BDO protected VECs by activating mTOR and thus stabilized atherosclerotic lesions in apoE(-/-) mice.
Increased integrin β4 (ITGB4) level is accompanied by malignant progression of multiple carcinomas. However, selective therapeutic strategies against cancer cells expressing a high level of ITGB4 have not been reported. Here, for the first time, we report that a chiral small molecule, SEC, selectively promotes apoptosis in cancer cells expressing a high level of ITGB4 by inducing ITGB4 nuclear translocation. Nuclear ITGB4 can bind to the ATF3 promoter region and activate the expression of ATF3, then upregulate the downstream pro-apoptosis genes. Furthermore, SEC promoted the binding of annexin A7 (ANXA7) to ITGB4 and increased ANXA7 GTPase activity. Activated ANXA7 promoted ITGB4 nuclear translocation by triggering ITGB4 phosphorylation at Y1494. SEC also inhibited the growth of xenograft tumors in the avian embryo model. We identified a small molecule, SEC, with selective pro-apoptosis effects on cancer cells with high expression of ITGB4, both in vitro and in vivo, by triggering the binding of ITGB4 and ANXA7, ITGB4 nuclear trafficking, and pro-apoptosis gene expression.
Allium fistulosum L. has good nutritional value and is cultivated worldwide as an efficacious traditional medicinal plant. Its biological activities are attributable to its phytochemicals. Nitrogen is an essential nutrient for plant growth and development; however, the effect of nitrogen levels on the level of active components in this species is not well understood.
Targeting the endothelial-to-mesenchymal transition (EndoMT) may be a novel therapeutic strategy for cancer and various diseases induced by fibrosis. We aimed to identify a small chemical molecule as an inducer of EndoMT and find a new signal pathway by using the inducer. Safrole oxide (SFO), 50 µg/ml, could most effectively induce EndoMT within 12 h. To understand the underlying molecular mechanism, we performed microarray, quantitative real-time PCR and western blot analysis to find key factors involved in SFO-induced EndoMT and demonstrated the involvement of the factors by RNAi. The expression of activating transcription factor 4 (ATF4), p75 neurotrophin receptor (p75NTR), and interleukin 8 (IL-8) was greatly increased in SFO-induced EndoMT. Knockdown of ATF4 inhibited the SFO-induced EndoMT completely, and knockdown of p75NTR or IL-8 partially inhibited the EndoMT, which suggests that all three factors were involved in the process. Furthermore, knockdown of p75NTR inhibited the SFO-increased IL-8 expression and secretion, and knockdown of ATF4 inhibited SFO-increased p75NTR level significantly. The ATF4/p75NTR/IL-8 signal pathway may have an important role in EndoMT induced by SFO. Our findings support potential novel targets for the therapeutics of cancer and fibrosis disease.
Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) are key regulators of multiple biological processes by altering gene expression at various levels. Apoptosis in vascular endothelial cells (VECs) is closely linked to numerous cardiovascular diseases, such as arteriosclerosis, thrombus formation and plaque erosion. However, studies on lncRNAs in the cardiovascular system are just beginning. And thus far, no anti-apoptosis lncRNAs have been identified in VECs. Here, we focused on the anti-apoptosis roles of lncRNAs in the serum and FGF-2 starvation-induced apoptosis of VECs. Using microarray analysis, we found a novel lncRNA LOC100129973 which acted as an apoptosis inhibitor in VECs. Through sponging miR-4707-5p and miR-4767, lncRNA LOC100129973 upregulated the expression of two apoptosis repressors gene, Apoptosis Inhibitor 5 (API5) and BCL2 like 12 (BCL2L12), and thus alleviated the serum and FGF-2 starvation-induced apoptosis in VECs. This evidence suggests that lncRNA LOC100129973 is an attractive target to improve endothelial function and for therapy of apoptosis related cardiovascular diseases.
The objective of this study was to observe the effect of Jagged1/Notch pathway-mediated angiogenesis on the in vitro proliferation of hepatocellular carcinoma cells, and the effect and possible mechanism of the spleen-invigorating and blood stasis-removing recipe. Spleen-invigorating and blood stasis-removing recipe serum from SPF grade nude mice was prepared, and the fingerprint of the drugs of the spleen-invigorating and blood stasis-removing recipe and drug serum were identified by HPLC. SMMC-7721 human hepatocellular carcinoma cells were divided into the normal control group, DAPT inhibitor control group, and drug serum group according to the different treatments. The Cell Counting Kit-8 (CCK-8) method was used to determine cell proliferation ability, and angiogenesis was observed under an inverted microscope. The expression of Jagged1, Notch1, and VEGF was measured by qPCR and western blot analysis. The interaction of Jagged1 and Notch1 was detected by Co-IP. The CCK-8 assay indicated that cell proliferation was inhibited in response to drug treatment (P<0.01). The expression of Jagged1, Notch1, and VEGF in the drug serum group was significantly lower than in the normal control group (P<0.01). Compared with the control group, the new vascular area of the DAPT inhibitor control group and drug serum group was smaller, and the blood vessels of the DAPT inhibitor control group and drug serum group were more sparse. The levels of Jagged1, Notch1, VEGF protein and the interaction between Jagged1 and Notch1 in the DAPT inhibitor control group and drug serum group were significantly lower than in the control serum group (P<0.01). In conclusion, the spleen-invigorating and blood stasis-removing recipe can inhibit the proliferation of hepatocellular carcinoma cells, and tumor angiogenesis in vitro. The function is related to the reduced expression of Jagged1, reduced interaction between Jagged1 and Notch1, and the reduced expression and activity of VEGF.
Demyelination occurs widely in neurodegenerative diseases. Progesterone has neuroprotective effects, is known to reduce the clinical scores and the inflammatory response. Progesterone also promotes remyelination in experimental autoimmune encephalomyelitis and cuprizone-induced demyelinating brain. However, it still remains unclear whether progesterone can alleviate neural behavioral deficits and demyelination with degeneration of oligodendroglial cells in cuprizone-induced mice. In this study, mice were fed with 0.2% cuprizone to induce demyelination, and treated with progesterone to test its potential protective effect on neural behavioral deficits, demyelination and degeneration of oligodendroglial cells. Our results showed noticeable alleviation of neural behavioral deficits following progesterone treatment as assessed by changes in average body weight, and activity during the open field and Rota-rod tests when compared with the vehicle treated cuprizone group. Progesterone treatment alleviated demyelination as shown by Luxol fast blue staining, MBP immunohistochemical staining, and electron microscopy. There was an obvious decrease in TUNEL and Caspase-3-positive apoptotic cells, and an increase in the number of oligodendroglial cells staining positive for PDGFRα, Olig2, Sox10 and CC-1 antibody in the brains of cuprizone-induced mice after progesterone administration. These results indicate that progesterone can alleviate neural behavioral deficits and demyelination against oligodendroglial cell degeneration in cuprizone-induced mice.
Current systemic therapies have little curative benefit for synovial sarcoma. Histone deacetylase (HDAC) inhibitors and the heat shock protein 90 (Hsp90) inhibitor 17-AAG have recently been shown to inhibit synovial sarcoma in preclinical models. We tested combinations of 17-AAG with the HDAC inhibitor MS-275 for synergism by proliferation and apoptosis assays. The combination was found to be synergistic at multiple time points in two synovial sarcoma cell lines. Previous studies have shown that HDAC inhibitors not only induce cell death but also activate the survival pathway NF-kappaB, potentially limiting therapeutic benefit. As 17-AAG inhibits activators of NF-kappaB, we tested if 17-AAG synergizes with MS-275 through abrogating NF-kappaB activation. In our assays, adding 17-AAG blocks NF-kappaB activation by MS-275 and siRNA directed against histone deacetylase 3 (HDAC3) recapitulates the effects of MS-275. Additionally, we find that the NF-kappaB inhibitor BAY 11-7085 synergizes with MS-275. We conclude that agents inhibiting NF-kappaB synergize with HDAC inhibitors against synovial sarcoma.
With the increased incidence and recognition, ulcerative colitis (UC) has become a global public health problem in the world. Although many immunosuppressant and biological drugs have been used for UC treatment, the cure rate is still very low. It is necessary to find some safe and long-term used medicine for UC cure. Recently, the Chinese traditional herb Danshen has been investigated in the treatment of UC. However, it is a limitation of Danshen that many of the active components in Danshen are not easily absorbed by the human body. Probiotics could convert macromolecules into smaller molecules to facilitate absorption. Thus, Lactobacillus rhamnosus (F-B4-1) and Bacillus subtillis Natto (F-A7-1) were screened to ferment Danshen in this study. The fermented Danshen products were gavaged in the dextran sulfate sodium (DSS)-induced UC model mice. Danshen had better results to attenuate symptoms of DSS-induced UC after fermented with F-B4-1 and F-A7-1. Loss of body weight and disease activity index (DAI) were reduced. The abnormally short colon lengths and colonic damage were recovered. And fermented Danshen had the better inhibitory effect than Danshen itself on pro-inflammatory cytokine expression during DSS-induced UC. The results indicated that compared with Danshen, fermented Danshen relieved DSS-induced UC in mice more effectively. Danshen fermented by probiotics might be an effective treatment to UC in clinic stage in the future.
Increasing evidence indicates that Nrf-2, named the nuclear factor-erythroid 2-related factor, may perform anticancer function. In this study, a series of novel substituted phenyl- (3-methyl-1H-indol-2-yl)-prop-2-en-1-one (indolyl-chalcone) derivatives were synthesized and their effects on Nrf-2 activity were observed. We found that compounds 3a-3d and 6c elevated Nrf-2 activity. Then we evaluated their anticancer activities in vitro and in vivo by utilizing human lung cancer cell line A549. The in vitro results showed that among the compounds, 3d performed effectively anti-growth activity by inducing A549 lung cancer cell apoptosis and activating Nrf-2/HO-1 (heme oxygenase-1) pathway. In vivo, we proved that compound 3d inhibited the tumor growth effectively through inducing cell apoptosis without affecting CAM normal angiogenesis. These data suggest that our discovery of a novel Nrf-2 activator compound 3d would provide a new point of human lung cancer treatment.
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