This service exclusively searches for literature that cites resources. Please be aware that the total number of searchable documents is limited to those containing RRIDs and does not include all open-access literature.
CCAAT/Enhancer Binding Proteindelta (C/EBPdelta) is a member of the highly conserved C/EBP family of leucine zipper (bZIP) proteins. C/EBPdelta is highly expressed in G0 growth arrested mammary epithelial cells (MECs) and "loss of function" alterations in C/EBPdelta have been associated with impaired contact inhibition, increased genomic instability and increased cell migration. Reduced C/EBPdelta expression has also been reported in breast cancer and acute myeloid leukemia (AML). C/EBPdelta functions as a transcriptional activator, however, only a limited number of C/EBPdelta target genes have been reported. As a result, the role of C/EBPdelta in growth control and the potential mechanisms by which "loss of function" alterations in C/EBPdelta contribute to tumorigenesis are poorly understood. The goals of the present study were to identify C/EBPdelta target genes using Chromatin Immunoprecipitation coupled with a CpG Island (HCG12K) Array gene chip ("ChIP-chip") assay and to assess the expression and potential functional roles of C/EBPdelta target genes in growth control.
The switch between quiescence and proliferation is central for neurogenesis and its alteration is linked to neurodevelopmental disorders such as microcephaly. However, intrinsic mechanisms that reactivate Drosophila larval neural stem cells (NSCs) to exit from quiescence are not well established. Here we show that the spindle matrix complex containing Chromator (Chro) functions as a key intrinsic regulator of NSC reactivation downstream of extrinsic insulin/insulin-like growth factor signalling. Chro also prevents NSCs from re-entering quiescence at later stages. NSC-specific in vivo profiling has identified many downstream targets of Chro, including a temporal transcription factor Grainy head (Grh) and a neural stem cell quiescence-inducing factor Prospero (Pros). We show that spindle matrix proteins promote the expression of Grh and repress that of Pros in NSCs to govern their reactivation. Our data demonstrate that nuclear Chro critically regulates gene expression in NSCs at the transition from quiescence to proliferation.The spindle matrix proteins, including Chro, are known to regulate mitotic spindle assembly in the cytoplasm. Here the authors show that in Drosophila larval brain, Chro promotes neural stem cell (NSC) reactivation and prevents activated NSCs from entering quiescence, and that Chro carries out such a role by regulating the expression of key transcription factors in the nucleus.
Compounds 10 (ND-322) and 15 (ND-364) are potent selective inhibitors for gelatinases, matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9). However, both of them are racemates. Herein we report facile synthesis of optically active (R)- and (S)-enantiomers of compounds 10 and 15. And the sulfonyl of 15 was transformed to sulfinyl to obtain four epimeric mixtures. All synthesized thiirane-based compounds were evaluated in MMP2 and MMP9 inhibitory assays. Our results indicated that the configuration of thiirane moiety had little effects on gelatinase inhibition, but the substitution of sulfinyl for sulfonyl was detrimental to gelatinase inhibition. Besides, all target compounds exhibited no inhibition against other two Zn(2+) dependant metalloproteases, aminopeptidase N (APN) and histone deacetylases (HDACs), which confirmed the unique Zn(2+) chelation mechanism of thiirane moiety against gelatinases.
Currently, no therapeutic options exist for castration-resistant prostate cancer (CRPC) patients who have developed resistance to the second generation anti-androgen receptor (AR) axis therapy. Here we report that co-deletion of Pten and p53 in murine prostate epithelium, often observed in human CRPC, leads to AR-independent CRPC and thus confers de novo resistance to second generation androgen deprivation therapy (ADT) in multiple independent yet complementary preclinical mouse models. In contrast, mechanism-driven co-targeting hexokinase 2 (HK2)-mediated Warburg effect with 2-deoxyglucose (2-DG) and ULK1-dependent autophagy with chloroquine (CQ) selectively kills cancer cells through intrinsic apoptosis to cause tumor regression in xenograft, leads to a near-complete tumor suppression and remarkably extends survival in Pten-/p53-deficiency-driven CRPC mouse model. Mechanistically, 2-DG causes AMPK phosphorylation, which in turn inhibits mTORC1-S6K1 translation signaling to preferentially block anti-apoptotic protein MCL-l synthesis to prime mitochondria-dependent apoptosis while simultaneously activates ULK1-driven autophagy for cell survival to counteract the apoptotic action of anti-Warburg effect. Accordingly, inhibition of autophagy with CQ sensitizes cancer cells to apoptosis upon 2-DG challenge. Given that 2-DG is recommended for phase II clinical trials for prostate cancer and CQ has been clinically used as an anti-malaria drug for many decades, the preclinical results from our proof-of-principle studies in vivo are imminently translatable to clinical trials to evaluate the therapeutic efficacy by the combination modality for a subset of currently incurable CRPC harboring PTEN and TP53 mutations.
There is increasing interest in discovering HDAC6 selective inhibitors as chemical probes to elucidate the biological functions of HDAC6 and ultimately as new therapeutic agents. Small-molecular fluorescent probes are widely used to detect target protein location and function, identify protein complex composition in biological processes of interest. In the present study, structural modification of the previously reported compound 4MS leads to two novel fluorescent HDAC inhibitors, 6a and 6b. Determination of IC50 values against the panel of Zn2+ dependent HDACs (HDAC1-11) reveals that 6b is a HDAC6 selective inhibitor, which can induce hyperacetylation of tubulin but not histone H4. Importantly, fluorescent and immunofluorescent analyses of cells treated with the proteasome inhibitor MG132 demonstrates that 6b can selectively target and image HDAC6 within the inclusion body, the aggresome. These results identify 6b not only as a HDAC6 selective inhibitor but also as a fluorescent probe for imaging HDAC6 and investigating the roles of HDAC6 in various physiological and pathological contexts.
Mutations of the Integrator subunits are associated with neurodevelopmental disorders and cancers. However, their role during neural development is poorly understood. Here, we demonstrate that the Drosophila Integrator complex prevents dedifferentiation of intermediate neural progenitors (INPs) during neural stem cell (neuroblast) lineage development. Loss of intS5, intS8, and intS1 generated ectopic type II neuroblasts. INP-specific knockdown of intS8, intS1, and intS2 resulted in the formation of excess type II neuroblasts, indicating that Integrator prevents INP dedifferentiation. Cell-type-specific DamID analysis identified 1413 IntS5-binding sites in INPs, including zinc-finger transcription factor earmuff (erm). Furthermore, erm expression is lost in intS5 and intS8 mutant neuroblast lineages, and intS8 genetically interacts with erm to suppress the formation of ectopic neuroblasts. Taken together, our data demonstrate that the Drosophila Integrator complex plays a critical role in preventing INP dedifferentiation primarily by regulating a key transcription factor Erm that also suppresses INP dedifferentiation.
Objective: To investigate the effect of anatomic and technical parameters on the incidental internal mammary lymph node (IMN) irradiation (IIMNI) dose among postmastectomy patients. Methods: We retrospectively delineated the IMN on planning CT images from 138 patients who had undergone postmastectomy radiotherapy (PMRT). We analyzed the IIMNI dose coverage and its relationship with anatomic and technical parameters. Results: The IIMNI mean dose was 32.85 ± 9.49 Gy, and 10 of 138 patients (7.25%) treated with PMRT received ≥45 Gy. In univariate analysis, the body weight, body mass index, body surface area, thoracic transverse diameter (DT), ratio of DT to the thoracic anteroposterior diameter (DAP)(RT/AP), planning target volume of IMN (PTVIMN) included in PTV (IMNin) and the ratio of IMNin to PTVIMN (RIMNin) and PTV posterior border were the parameters affecting IIMNI dose. In multivariate analysis, body weight, RT/AP, and RIMNin were correlative factors that affected IIMNI dose. Conclusions: For patients who underwent PMRT without IMN irradiation (IMNI), there was a wide variety in IIMNI doses. A minority of patients had adequate IIMNI dose coverage, and the higher IIMNI doses were associated with the less body weights and more RIMNin.
With five histone deacetylase (HDAC) inhibitors approved for cancer treatment, proteolysis-targeting chimeras (PROTACs) for degradation of HDAC are emerging as an alternative strategy for HDAC-targeted therapeutic intervention. Herein, three bestatin-based hydroxamic acids (P1, P2 and P3) were designed, synthesized and biologically evaluated to see if they could work as HDAC degrader by recruiting cellular inhibitor of apoptosis protein 1 (cIAP1) E3 ubiquitin ligase. Among the three compounds, the bestatin-SAHA hybrid P1 exhibited comparable even more potent inhibitory activity against HDAC1, HDAC6 and HDAC8 relative to the approved HDAC inhibitor SAHA. It is worth noting that although P1 could not lead to intracellular HDAC degradation after 6 h of treatment, it could dramatically decrease the intracellular levels of HDAC1, HDAC6 and HDAC8 after 24 h of treatment. Intriguingly, the similar phenomenon was also observed in the HDAC inhibitor SAHA. Cotreatment with proteasome inhibitor bortezomib could not reverse the HDAC decreasing effects of P1 and SAHA, confirming that their HDAC decreasing effects were not due to protein degradation. Moreover, all three bestatin-based hydroxamic acids P1, P2 and P3 exhibited more potent aminopeptidase N (APN, CD13) inhibitory activities than the approved APN inhibitor bestatin, which translated to their superior anti-angiogenic activities. Taken together, a novel bestatin-SAHA hybrid was developed, which worked as a potent APN and HDAC dual inhibitor instead of a PROTAC.
Purified vitexin compound 1 (VB1, a neolignan isolated and extracted from the seed of Chinese herb Vitex negundo) is an effective antitumor agent and exhibits promising clinical activity against various cancers including colorectal cancer. However, it remains unknown about the precise underlying mechanism associated with the antitumor effect of VB1 and how it triggers apoptosis in cancer cells. Here, we demonstrated that VB1 promoted apoptosis via p53-dependent induction of p53 upregulated modulator of apoptosis (PUMA) and further to induce Bax (Bcl-2-associated X protein) activation and mitochondrial dysfunction in colon cancer HCT-116 and LoVo cells. Deficiency in p53, PUMA, or Bax abrogated VB1-induced apoptosis and promoted cell survival in HCT-116 cells. Furthermore, the combination of VB1 with chemotherapeutic drugs 5-fluorouracil (5-FU) or NVP-BZE235 resulted in a synergistic antitumor effect via PUMA induction in HCT-116 cells. VB1 significantly suppressed the cell proliferation of wild-type (WT) HCT-116 and LoVo cells in vitro and tumor growth in vivo. The results indicate that p53/PUMA/Bax axis plays a critical role in VB1-induced apoptosis and VB1 may have valuable clinical applications in cancer therapy as a novel anticancer agent used alone or in combination with other chemotherapeutic drugs.
Objective: Increasing evidence has uncovered the roles of lncRNA-miRNA-mRNA regulatory networks in cardiovascular diseases. However, the crosstalk between ceRNA networks and development of heart failure (HF) remains unclear. This study was to investigate the role of lncRNA-mediated ceRNA networks in the pathophysiological process of HF and its potential regulatory functions on programmed cell death. Methods: We firstly screened the GSE77399, GSE52601 and GSE57338 datasets in the NCBI GEO database for screening differentially expressed lncRNAs, miRNAs and mRNAs. lncRNA-miRNA-mRNA regulatory networks based on the ceRNA theory were subsequently constructed. GO and KEGG enrichment analysis was conducted to predict potential biological functions of mRNAs in ceRNA networks. Differentially expressed mRNAs were then interacted with programmed cell death related genes. lncRNA-mediated ceRNA regulatory pathways on programmed cell death were validated with qRT-PCR testing. Results: Based on our bioinformatic analysis, two lncRNAs, eight miRNAs and 65 mRNAs were extracted to construct two lncRNAs-mediated ceRNA networks in HF. Biological processes and pathways were enriched in extracellular matrix. Seven lncRNA-mediated ceRNA regulatory pathways on programmed cell death, GAS5/miR-345-5p/ADAMTS4, GAS5/miR-18b-5p/AQP3, GAS5/miR-18b-5p/SHISA3, GAS5/miR-18b-5p/C1orf105, GAS5/miR-18b-5p/PLIN2, GAS5/miR-185-5p/LPCAT3, and GAS5/miR-29b-3p/STAT3, were finally validated. Conclusions: Two novel ceRNA regulatory networks in HF were discovered based on our bioinformatic analysis. Based on the interaction and validation analysis, seven lncRNA GAS5-mediated ceRNA regulatory pathways were hypothesized to impact programmed cell death including seven for apoptosis, three for ferroptosis, and one for pyroptosis. Upon which, we provided novel insights and potential research plots for bridging ceRNA regulatory networks and programmed cell death in HF.
"Loss of function" alterations in CCAAT/Enhancer Binding Proteindelta (C/EBPdelta) have been reported in a number of human cancers including breast, prostate and cervical cancer, hepatocellular carcinoma and acute myeloid leukemia. C/EBPdelta gene transcription is induced during cellular quiescence and repressed during active cell cycle progression. C/EBPdelta exhibits tumor suppressor gene properties including reduced expression in cancer cell lines and tumors and promoter methylation silencing. We previously reported that C/EBPdelta expression is inversely correlated with c-Myc (Myc) expression. Aberrant Myc expression is common in cancer and transcriptional repression is a major mechanism of Myc oncogenesis. A number of tumor suppressor genes are targets of Myc transcriptional repression including C/EBPalpha, p15INK4, p21CIP1, p27KIP1 and p57KIP2. This study investigated the mechanisms underlying Myc repression of C/EBPdelta expression.
Inactivation of Dickkopf-3 (DKK3) is closely associated with a poor prognosis in various solid tumor and hematologic malignancies. Promoter hypermethylation is one potential cause of DKK3 inactivation. However, whether other mechanisms lead to DKK3 inactivation and the subsequent effects of these inactivations on cell proliferation and the Wnt signaling pathway in adult B acute lymphoblastic leukemia (B-ALL) remain unclear. In the present study, we found that low DKK3 expression levels were associated with high miR-708 expression and promoter hypermethylation in adult B-ALL. miR-708 was confirmed to directly decrease DKK3 expression in Nalm-6 and BALL-1 cells. Additionally, a miR-708 inhibitor decreased cell proliferation mainly through apoptosis and cell cycle arrest at the G1 phase, and these effects were eliminated by DKK3 siRNA treatment. Moreover, the demethylating agent 5-aza-2'-deoxycytidine (5-aza) decreased the methylation state of the DKK3 promoter based on methylation-specific PCR (MSP) and bisulfite genomic sequencing PCR (BSP), although this demethylation effect was not enhanced by the miR-708 inhibitor. The miR-708 inhibitor or 5-aza significantly increased DKK3 expression and decreased p-GSK3β, cyclin D1 and nuclear and cytoplasmic β-catenin protein expression, indicating that the Wnt/β-catenin signaling pathway was inhibited. These effects became more pronounced when the miR-708 inhibitor and 5-aza were used simultaneously. These findings provide greater insights into the mechanisms that increase DKK3 expression and suggest that a miR-708 inhibitor and 5-aza might be useful as targeted therapies for adult B-ALL.
Age-related macular degeneration (AMD) is associated with the dysfunction and death of the retinal pigment epithelium (RPE). Recently, there has been increasing interest in stem cell-derived RPE cells for cell replacement therapies, such as those for AMD. The present study investigated whether RPE-conditioned medium (RPECM) could promote the differentiation of human adipose tissue-derived mesenchymal stromal cells (hADSCs) into RPE cells, and enhance the proliferation and migration of these cells. Reverse-transcription quantitative polymerase chain reaction analysis demonstrated that RPECM induced hADSCs to differentiate into cells expressing RPE markers, including retinoid isomerohydrolase (RPE65), cytokeratin (CK8) and Bestrophin, which were identified to be significantly upregulated by ~10-fold, 3.5-fold and 2.4-fold, respectively, compared with the control group [hADSCs cultured in ADSC-conditioned medium (ADSCCM)]. The immunocytochemistry and western blot analysis results demonstrated that the protein levels of RPE65, CK8 and Bestrophin were significantly increased in RPECM-treated hADSCs. In addition, Cell Counting Kit-8 analysis demonstrated that RPECM promoted the proliferation of induced cells. RPECM also increased the expression level of the cell proliferative marker Ki-67. Furthermore, to evaluate the migration potential, cell migration assays were performed. These assays demonstrated that following RPECM treatment hADSCs migrated more quickly compared with the control group. The results of the present study suggest that RPECM induces hADSCs to differentiate into RPE cells with higher proliferative and migratory potentials, which may aid in applications for hADSCs in RPE regenerative therapy.
The ability of neural stem cells (NSCs) to transit between quiescence and proliferation is crucial for brain development and homeostasis. Drosophila Hippo pathway maintains NSC quiescence, but its regulation during brain development remains unknown. Here, we show that CRL4Mahj, an evolutionarily conserved E3 ubiquitin ligase, is essential for NSC reactivation (exit from quiescence). We demonstrate that damaged DNA-binding protein 1 (DDB1) and Cullin4, two core components of Cullin4-RING ligase (CRL4), are intrinsically required for NSC reactivation. We have identified a substrate receptor of CRL4, Mahjong (Mahj), which is necessary and sufficient for NSC reactivation. Moreover, we show that CRL4Mahj forms a protein complex with Warts (Wts/large tumor suppressor [Lats]), a kinase of the Hippo signaling pathway, and Mahj promotes the ubiquitination of Wts. Our genetic analyses further support the conclusion that CRL4Mahj triggers NSC reactivation by inhibition of Wts. Given that Cullin4B mutations cause mental retardation and cerebral malformation, similar regulatory mechanisms may be applied to the human brain.
The aim of this study was to evaluate whether a patented single-channel applicator, which was modified from the traditional tandem applicator and wrapped with an oval-shield alloy around the source channel, has the same clinical efficacy and safety as the standard Fletcher-type applicator in high dose rate (HDR) brachytherapy for carcinoma of the cervix. Between December 2011 and February 2017, 299 patients with pathologically confirmed International Federation of Gynecology and Obstetrics (2009) stage Ib2-IVa cervical cancer were recruited to the trial and finished the allocated intervention. Of the first 151 patients, 71 were allocated to the Fletcher group and 80 to the single-channel group, satisfying the criteria for a preliminary analysis. All but 3 patients were treated with concurrent cisplatin chemotherapy and external beam radiotherapy followed by HDR brachytherapy. The 2-year overall survival, progression-free survival, and locoregional failure-free survival was 80.3%, 77.5%, and 78.9%, respectively, for the Fletcher group, and 86.3%, 82.5%, and 83.8%, respectively, for the single-channel group. The seriousness of acute treatment-related toxicities was similar in the 2 groups. The cumulative rate of late rectal complications of grade 3-4 in the Fletcher group and the single-channel group was 2.8% and 2.5%, respectively. The cumulative rate of grade 3 bladder complications was 2.8% for the Fletcher group and 1.3% for the single-channel group. The preliminary results of our study show that the patented single-channel intracavitary applicator might be able to provide protection for the rectum and bladder and seems to have the same clinical efficacy as the standard Fletcher-type 3-channel applicator in HDR brachytherapy for carcinoma of the cervix. This trial was registered with the Chinese Clinical Trial Registry (registration no. ChiCTR-TRC-12002321).
In our previous study, we designed and synthesized a novel series of N-hydroxycinnamamide-based HDAC inhibitors (HDACIs), among which the representative compound 14a exhibited promising HDACs inhibition and antitumor activity. In this current study, we report the development of a more potent class of N-hydroxycinnamamide-based HDACIs, using 14a as lead, among which, compound 11r gave IC50 values of 11.8, 498.1, 3.9, 2000.8, 5700.4, 308.2, and 900.4 nM for the inhibition of HDAC1, HDAC2, HDAC3, HDAC8, HDAC4, HDAC6, and HDAC11, exhibiting dual HDAC1/3 selectivity. Compounds 11e, 11r, 11w, and 11y showed excellent growth inhibition in multiple tumor cell lines. In vivo antitumor assay in U937 xenograft model identified compound 11r as a potent, orally active HDACI. To the best of our knowledge, this work constitutes the first report of oral active N-hydroxycinnamamide-based HDACIs with dual HDAC1/3 selectivity.
Clinically, many esophageal cancer patients who planned for radiation therapy have already undergone diagnostic Positron-emission tomography/computed tomography (PET/CT) imaging, but it remains unclear whether these imaging results can be used to delineate the gross target volume (GTV) of the primary tumor for thoracic esophageal cancer (EC).
Matrine has been demonstrated to exert anticancer effects on acute myeloid leukemia (AML) cell lines. However, the mechanisms of matrine in AML remain largely unknown. The present study investigated the anticancer effects and underlying mechanisms of matrine on human AML cells in vitro. THP-1 cell lines were cultured and treated with different doses of matrine (0.4, 0.8, 1.2, 1.6 and 2.0 g/l). The effects of matrine on the cell proliferation were assessed by the Cell Counting Kit-8 assay. The apoptotic effects were evaluated by DAPI and annexin V/propidium iodide staining assays. The effects of the drug on phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/ mechanistic target of rapamycin kinase (mTOR) protein expression were studied by western blot analysis. The results of the present study demonstrated that matrine suppressed the viability of THP-1 cells. The anticancer effects were identified to be dose-dependent and the IC50 value was 1.2 g/l in THP-1 cells. Matrine inhibited cell viability and induced cell apoptosis of AML cell lines in a dose- and time-dependent manner. In addition, it was observed that matrine decreased the expression of phosphorylated (p)-PI3K, p-Akt and p-mTOR in a concentration-dependent manner. However, the expression levels of PI3K, Akt and mTOR remained almost unaltered. These findings indicated that matrine may inhibit cell proliferation and induce apoptosis of AML cells and may be a novel effective chemotherapeutic agent against AML.
Welcome to the FDI Lab - SciCrunch.org Resources search. From here you can search through a compilation of resources used by FDI Lab - SciCrunch.org and see how data is organized within our community.
You are currently on the Community Resources tab looking through categories and sources that FDI Lab - SciCrunch.org has compiled. You can navigate through those categories from here or change to a different tab to execute your search through. Each tab gives a different perspective on data.
If you have an account on FDI Lab - SciCrunch.org then you can log in from here to get additional features in FDI Lab - SciCrunch.org such as Collections, Saved Searches, and managing Resources.
Here is the search term that is being executed, you can type in anything you want to search for. Some tips to help searching:
You can save any searches you perform for quick access to later from here.
We recognized your search term and included synonyms and inferred terms along side your term to help get the data you are looking for.
If you are logged into FDI Lab - SciCrunch.org you can add data records to your collections to create custom spreadsheets across multiple sources of data.
Here are the facets that you can filter your papers by.
From here we'll present any options for the literature, such as exporting your current results.
If you have any further questions please check out our FAQs Page to ask questions and see our tutorials. Click this button to view this tutorial again.
Year:
Count: