Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 653
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Cell Physiol ; 235(2): 1090-1102, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31256427

RESUMO

Long noncoding RNAs (lncRNAs) regulate tumor development and progression by promoting proliferation, invasion, and metastasis. The oncogenic role of lncRNA SNHG16 in hepatocellular carcinoma (HCC) has not been revealed. LncRNA SNHG16 is upregulated in HCC and correlates with poorer prognosis. Patients with high SNHG16 expression showed lower rates of overall and disease-free survival than patients with low SNHG16 expression. Multivariate Cox regression revealed that SNHG16 expression was an independent predictor of poor overall and disease-free survival. In vitro, SNHG16 promoted HCC cell proliferation, migration, and invasion while inhibiting apoptosis; in vivo, it accelerated tumor development. Altering SNHG16 expression altered levels of miR-17-5p, which in turn modified expression of p62, which has been shown to regulate the mTOR and NF-κB pathways. Indeed, altering SNHG16 expression in HCC cells activated mTOR and NF-κB signaling. These results reveal a potential mechanism for the oncogenic role of SNHG16 in HCC. SNHG16 may therefore be a promising diagnostic marker as well as therapeutic target in HCC.

2.
Am J Nephrol ; : 1-10, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694015

RESUMO

BACKGROUND: Inflammation plays an important role in polycystic kidney disease (PKD). Cordyceps sinensis, a prized -Chinese medicinal herb, exerts anti-tumor, anti-inflammatory and anti-metastatic effects and benefits patients with kidney diseases. The aim of this study was to test the efficacy of FTY720, an immunosuppressant derived from C. sinensis, in a rat cystic kidney disease model, and explore its underlining mechanism. METHODS: Male wild type and Cy/+ Han:SPRD rats were treated with FTY720 at 3 and 10 mg/kg/day for 5 weeks and 12 weeks by gavage. Blood and kidney were collected for functional, morphological, RNA, and protein analysis. RESULTS: Inflammation is activated in Cy/+ Han:SPRD rats. Inflammatory cytokines including interleukin 6 and tumor necrosis factor alpha were upregulated and inflammation-related pathways were activated, such as nuclear factor κB and signal transducer and activator of transcription 3 (STAT3) pathways. Furthermore, the bioactive sphingolipid mediator sphingosine-1-phosphate (S1P), a regulator of inflammation, was accumulated in the Cy/+ Han:SPRD rats. FTY720 significantly reduced cyst growth and delayed disease progression by reducing the accumulation of S1P, thereby inhibiting inflammatory responses. CONCLUSION: FTY720 treatment reduced the expression of inflammatory cytokines and attenuated the activation of NK-κB and STAT3 pathways in Cy/+ Han:SPRD rats. It suggests that FTY720 may serve as a therapeutic agent for clinical autosomal dominant PKD treatment.

3.
Neuroimage Clin ; 24: 102081, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31734526

RESUMO

Electroconvulsive therapy (ECT) is considered a treatment option in patients with drug-resistant schizophrenia (SZ). However, approximately one-third of patients do not benefit from ECT in the clinic. Thus, it is critical to investigate differences between ECT responders and non-responders. Accumulated evidence has indicated that one region of ECT action is the hippocampus, which also plays an important role in SZ pathophysiology. To date, no studies have investigated differences in ECT effects in the hippocampus between treatment responders and non-responders. This study recruited twenty-one SZ patients treated for four weeks with ECT (MSZ, n = 21) and twenty-one SZ patients who received pharmaceutical therapy (DSZ, n = 21). The MSZ group was further categorized into responders (MSR, n = 10) or non-responders (MNR, n = 11) based on treatment outcomes by the criterion of a 50% reduction in the Positive and Negative Syndrome Scale total scores. Using structural and resting-state functional MRI, we measured the hippocampal volume and functional connectivity (FC) in all SZ patients (before and after treatment) and 23 healthy controls. In contrast to pharmaceutical therapy, ECT induced bilateral hippocampal volume increases in the MSZ. Both the MSR and MNR exhibited hippocampal expansion after ECT, whereas a lower baseline volume in one of hippocampal subfield (hippocampus-amygdala transition area) was found in the MNR. After ECT, increased FC between the hippocampus and brain networks associated with cognitive function was only observed in the MSR. The mechanism of action of ECT in schizophrenia is complex. A combination of baseline impairment level, ECT-introduced morphological changes and post-ECT FC increases in the hippocampus may jointly contribute to the post-ECT symptom improvements in patients with SZ.

4.
Theranostics ; 9(26): 8344-8361, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754401

RESUMO

High morbidity and mortality are associated with acute liver injury (ALI) for which no effective targeted drugs or pharmacotherapies are available. Discovery of potential therapeutic targets as well as inhibitors that can alleviate ALI is imperative. As excessive inflammatory cytokines released by macrophages are a critical cause of liver injury, we aimed to find novel compounds that could inhibit macrophage expression of inflammatory cytokines and alleviate liver injury. Methods: A high throughput assay was established to screen a small molecule inhibitor library of epigenetic targets. A highly selective catalytic p300/CBP inhibitor A-485 was identified as a potent hit in vitro and administrated to the lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced mice in vivo. For in vitro analysis, RAW264.7 cells and primary BMDM cells exposed to LPS were co-incubated with A-485. A model of acute liver injury induced by LPS and GalN was used for evaluation of in vivo treatment efficacy. Results: A-485 inhibited LPS-induced inflammatory cytokine expression in a concentration-dependent manner in vitro. Significantly, A-485 administration alleviated histopathological abnormalities, lowered plasma aminotransferases, and improved the survival rate in the LPS/GalN-stimulated mice. Integrative ChIP-Seq and transcriptome analysis in the ALI animal model and macrophages revealed that A-485 preferentially blocked transcriptional activation of a broad set of pathologic genes enriched in inflammation-related signaling networks. Significant inhibition of H3K27ac/H3K18ac at promoter regions of these pivotal inflammatory genes was observed, in line with their suppressed transcription after A-485 treatment. Reduced expression of these pathological pro-inflammatory genes resulted in a decrease in inflammatory pathway activation, M1 polarization as well as reduced leukocyte infiltration in ALI mouse model, which accounted for the protective effects of A-485 on liver injury. Conclusion: Using a novel strategy targeting macrophage inflammatory activation and cytokine expression, we established a high-throughput screening assay to discover potential candidates for ALI treatment. We demonstrated that A-485, which targeted pathological inflammatory signaling networks at the level of chromatin, was pharmacologically effective in vivo and in vitro. Our study thus provided a novel target as well as a potential drug candidate for the treatment of liver injury and possibly for other acute inflammatory diseases.

5.
Brain Res Bull ; 154: 116-126, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31738973

RESUMO

This study was designed to investigate whether calcium-sensing receptor (CaSR) could induce immture white matter progenitor cells proliferation and differentiation into oligodendrocyte(OL) precursor cells after oxygen-glucose deprivation (OGD) in vitro. Progenitor cells of immature white matter originating from five-day-old newborn rats were divided into control, OGD, control + CaSR silencing, OGD + CaSR silencing, control + adenosine triphosphate magnesium chloride (ATP-MgCl2) and OGD + ATP-MgCl2 groups. Immunofluorescence, real-time RT-PCR, gene silencing, Hoechst 33342/propidium iodide (PI) and Flow cytometry tests were used to examine the proliferation, differentiation and survival of the white matter progenitor cells in the different treatment groups. The results showed that normal immature white matter progenitor cells have certain ability of self-proliferation and differentiation in vitro. OGD could further induce progenitor cells proliferation and differentiation into O4 + OL precursor cells by activating CaSR, but OGD also induced more necrosis and apoptosis of newborn cells and less MBP + OL formation. The addition of ATP-MgCl2 as an activating agent of CaSR further promoted cell proliferation and differentiation both under normal and OGD conditions and reduced OGD-induced apoptosis and necrosis, while CaSR silenced resulted in minimal cell proliferation, differentiation and survival. This study suggests that CaSR plays an important role in the induction of immature white matter progenitor cells proliferation and differentiation into OL precursor cells after OGD, which may provide a new angle to further study whether CaSR initiates the intrinsic repair potential of immature white matter after ischemia in vivo.

6.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1641-1648, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607326

RESUMO

OBJECTIVE: To explore the causes and specific conditions of blood donation reaction under the collective emergency unpaid blood donation, and to provide theoretical basis and decision-making reference for drafting the collective emergency unpaid blood donation and blood donation safety. METHODS: Through a combination of prospective and retrospective models, and statistical methods were used to analyze the causes and conditions of the blood donation response of 10401 people participating in collective emergency unpaid blood donation during 2016.1-2018.8. RESULTS: A total of 10401 person-times donated blood in a sitting manner, and a total of 293 blood donation reactions occurred. By improving the blood donation services year by year, the moderate blood donation reaction during the year 2017 and 2018 was significantly lower than that in 2016 (P<0.05). In the actual blood donation group of≤100, 200, 300 and 400 ml, the incidence of blood donation reaction was statistically significant (P<0.05); the incidence of blood donation reaction in the blood donors for 1,2,3 and >3 drnations was also statistically significant (P<0.05); the blood donation reactions rate of B antigen containers was significantly different from the donors without B antigen (P<0.05); the incidence of blood donation reaction with related to the weight of the donor. CONCLUSION: The blood donation reaction of collective emergency unpaid blood donation closely relates with mental factors, blood donation service, blood donation frequency and body weight of the blood donor. The first blood donation is more likely to produce blood donation reaction. The blood donation volum≤ 100 ml from blood donors is resulted mostly from blood donation reactions.


Assuntos
Doadores de Sangue , Antígenos de Grupos Sanguíneos , Humanos , Estudos Prospectivos , Estudos Retrospectivos
7.
Stress ; : 1-11, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31591949

RESUMO

Growing evidences have shown that patients recovering from stroke experience high and unremitting stress. Chronic restraint stress (CRS) has been found to exacerbate neurological impairments in an experimental focal cortical ischemia model. However, there have been no studies reporting the effect and mechanism of CRS on intracerebral hemorrhage (ICH). This study aimed to evaluate the effect of CRS on a mouse ICH model. Adult male C57BL mice were subjected to infusion of collagenase IV (to induce ICH) or saline (for sham) into the left striatum. After ICH, animals were stressed with application of CRS protocol for 21 days. Our results showed that CRS significantly exacerbated neurological deficits (Garcia test, corner turn test, and wire grip test) and the ipsilateral brain atrophy and reduced body weight gain after ICH. Immunofluorescence staining indicated that CRS exerted significant suppressive effects on neuron, astrocyte, vascular endothelial cell and pericyte and excessively activated microglia post ICH. All of the key cellular components mentioned above are involved in the neurovascular unit (NVU) remodeling in the peri-hemorrhagic region after ICH. Western blot results showed that matrix metalloproteinase (MMP)-9 and tight junction (TJ) proteins including zonula occludens-1, occludin and claudin-5 were increased after ICH, but MMP-9 protein was further up-regulated and TJ-related proteins were down-regulated by CRS. In addition, ICH-induced activation of endoplasmic reticulum stress and apoptosis were further strengthened by CRS. Collectively, CRS exacerbates neurological deficits and disrupts the remodeling of the peri-hemorrhagic NVU after ICH, which may be associated with TJ proteins degradation and excessive activation of MMP-9 and endoplasmic reticulum stress-apoptosis. LAY SUMMARY CRS exacerbates neurological deficits and disrupts the remodeling of the NVU in the recovery stage after ICH, which suggest that monitoring chronic stress levels in patients recovering from ICH may merit consideration in the future.

8.
Eur J Med Chem ; 184: 111767, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31622854

RESUMO

Transcriptional enhancer associated domain family members (TEADs) are the most important downstream effectors that play the pivotal role in the development, regeneration and tissue homeostasis. Recent biochemical studies have demonstrated that TEADs could undergo autopalmitoylation that is indispensable for its function making the lipid-binding pocket an attractive target for chemical intervention. Herein, through structure-based virtual screen and rational medicinal chemistry optimization, we identified DC-TEADin02 as the most potent, selective, covalent TEAD autopalmitoylation inhibitor with the IC50 value of 197 ±â€¯19 nM while it showed minimal effect on TEAD-YAP interaction. Further biochemical counter-screens demonstrate the specific thiol reactivity and selectivity of DC-TEADin02 over the kinase family, lipid-binding proteins and epigenetic targets. Notably, DC-TEADin02 inhibited TEADs transcription activity leading to downregulation of YAP-related downstream gene expression. Taken together, our findings proved the validity of modulating transcriptional output in the Hippo signaling pathway through irreversible chemical interventions of TEADs autopalmitoylation activity, which may serve as a qualified chemical tool for TEADs palmitoylation-related studies in the future.

9.
J Med Chem ; 62(21): 9642-9657, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31603674

RESUMO

Glutaminase (GLS1) is a cancer energy metabolism protein which plays a predominant role in cell growth and proliferation. Because of its major involvement in malignant tumor, small-molecule GLS1 inhibitors are urgently needed to assess its therapeutic potential and for probing their underlying biology function. Recent studies showed that targeting the allosteric binding site represented a promising strategy for identifying potent and selective GLS1 inhibitors. Herein, we present the synthesis of two fluorescent probes targeting the allosteric binding site of GLS1 and their usage as mechanistic tools in multiple applicable assay platform. The fluorescence polarization (FP)-based binding assay enables easy, fast, and reliable screen of allosteric inhibitors from our in-house compound library obtained through click chemistry method. The obtained compound C147 (named as CPU-L1) has been proved to be more potent and with greater solubility than the control compound CB839, which could serve as promising leads for further optimization as novel GLS1 inhibitors.

10.
Clin Nutr ; 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31540775

RESUMO

BACKGROUND & AIMS: Drinking water and food are the major sources of strontium in human. Strontium is essential for bone metabolism, while its role in glucose and lipid metabolism is largely unknown. We aimed to investigate the association of strontium, a bone-seeking element, with type 2 diabetes mellitus (T2DM) and impaired glucose regulation (IGR) and to further explore the potential mechanisms. METHODS: The case-control study included 1448 newly diagnosed T2DM patients, 782 IGR patients, and 2230 matched controls with normal glucose tolerance. Plasma strontium and other plasma minerals were quantified via inductively coupled plasma mass spectrometry. Multivariable logistic regression analysis was used to evaluate the independent associations between plasma strontium and T2DM and IGR. RESULTS: Plasma strontium was inversely associated with T2DM and IGR. After adjustment for sociodemographic, lifestyle factors, and multiple plasma metals, the odds ratios (95% confidence intervals) of T2DM and IGR were 0.45 (0.35-0.57) and 0.55 (0.43-0.71), respectively, comparing the highest to the lowest quartile of plasma strontium levels. In spline analysis, the odds of T2DM and IGR decreased remarkably with increasing strontium concentration and followed by a plateau. Additionally, plasma strontium was negatively associated with total cholesterol, low density lipoprotein cholesterol, and lipid peroxidation (plasma malondialdehyde level). CONCLUSIONS: The current study indicated that higher plasma strontium concentration was associated with lower odds of T2DM and IGR. Further studies are warranted to confirm these findings and to clarify the underlying mechanisms.

11.
Pharmacol Res ; 149: 104440, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31479750

RESUMO

Targeting on the IKKß to discover anti-inflammatory drugs has been launched for ten years, due to its predominant role in canonical NF-κB signaling. In the current study, we identified a novel IKKß inhibitor, ellipticine (ELL), an alkaloid isolated from Ochrosia elliptica and Rauvolfia sandwicensis. We found that ELL reduced the secretion and mRNA expression of TNF-α and IL-6 and decreased the protein expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in bone marrow derived macrophages (BMDMs) stimulated with LPS. In coincided with the results, ELL suppressed PGE2 and NO production in BMDMs. Underlying mechanistic study showed that ELL inhibited IκBα phosphorylation and degradation as well as NF-κB nuclear translocation, which was attributed to suppression of IKKα/ß activation. Furthermore, kinase assay and binding assay results indicated that ELL inhibited IKKß activity via directly binding to IKKß and in turn resulted in suppression of NF-κB signaling. To identify the binding sites of ELL on IKKß, IKKßC46A plasmid was prepared and the kinase assay was performed. The results demonstrated that the inhibitory effect of ELL on IKKß activity was impaired in the mutation, implying that anti-inflammatory effect of ELL was partially attributed to binding on cysteine 46. Furthermore, ELL up-regulated LC3 II expression and reduced p62 expression, suggesting that autophagy induction contributed to the anti-inflammatory effect of ELL as well. In coincided with the in vitro results, ELL increased the survival and antagonized the hypothermia in the mice with LPS-induced septic shock. Consistently, ELL reduced TNF-α and IL-6 production in the serum of the mice treated with LPS. Collectively, our study provides evidence that ELL is an IKKß inhibitor and has potential to be developed as a lead compound for treatment inflammatory diseases in the future.

12.
Pharmacol Ther ; 204: 107406, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31521697

RESUMO

Epigenetics has emerged as an extremely exciting fast-growing area of biomedical research in post genome era. Epigenetic dysfunction is tightly related with various diseases such as cancer and aging related degeneration, potentiating epigenetics modulators as important therapeutics targets. Indeed, inhibitors of histone deacetylase and DNA methyltransferase have been approved for treating blood tumor malignancies, whereas inhibitors of histone methyltransferase and histone acetyl-lysine recognizer bromodomain are in clinical stage. However, it remains a great challenge to discover potent and selective inhibitors by targeting catalytic site, as the same subfamily of epigenetic enzymes often share high sequence identity and very conserved catalytic core pocket. It is well known that epigenetic modifications are usually carried out by multi-protein complexes, and activation of catalytic subunit is often tightly regulated by other interactive protein component, especially in disease conditions. Therefore, it is not unusual that epigenetic complex machinery may exhibit allosteric regulation site induced by protein-protein interactions. Targeting allosteric site emerges as a compelling alternative strategy to develop epigenetic drugs with enhanced druggability and pharmacological profiles. In this review, we highlight recent progress in the development of allosteric inhibitors for epigenetic complexes through targeting protein-protein interactions. We also summarized the status of clinical applications of those inhibitors. Finally, we provide perspectives of future novel allosteric epigenetic machinery modulators emerging from otherwise undruggable single protein target.

13.
Hum Brain Mapp ; 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31517428

RESUMO

An increasing number of studies in patients with generalized tonic-clonic seizures (GTCS) have reported the alteration of functional connectivity (FC) in many brain networks. However, little is known about the underlying temporal variability of FC in large-scale brain functional networks in patients. Recently, dynamic FC could provide novel insight into the physiological mechanisms in the brain. Here, we recruited 63 GTCS and 65 age- and sex-matched healthy controls. Dynamic FC approaches were used to evaluate alterations in the temporal variability of FC in patients at the region- and network-levels. In addition, two kinds of brain templates (>102 and > 103 regions) and two kinds of temporal variability FC approaches were adopted to verify the stability of the results. Patients showed increased FC variability in regions of the default mode network (DMN), ventral attention network (VAN) and motor-related areas. The DAN, VAN, and DMN illustrated enhanced FC variability at the within-network level. In addition, increased FC variabilities between networks were found between the DMN and cognition-related networks, including the VAN, dorsal attention network and frontal-parietal network in GTCS. Meanwhile, the alterations in FC variability were relatively consistent across different methods and templates. Therefore, the consistent alteration of FC variability would reflect a dynamic restructuring of the large-scale brain networks in patients with GTCS. Overly frequent information communication among cognition-related networks, especially in the DMN, might play a role in the epileptic activity and/or cognitive dysfunction in patients.

14.
Med Sci Monit ; 25: 6615-6623, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31479436

RESUMO

Primary hepatocellular carcinoma (HCC) is the fifth most frequently reported malignancy, and it is also the second most common cause of cancer-related deaths worldwide. Although most HCC cases have been reported to develop from cirrhosis, accumulating data suggest that HCC is also closely related to non-cirrhotic chronic liver disease. Traditionally, HCC was thought to develop mostly from cirrhosis; however, an increasing number of reports have found that HCC can develop directly from inflammation without cirrhosis. The incidence of HCC in non-cirrhotic liver (HCC-NCL) is high, especially in developed countries. Studies have found that the most common cause of HCC-NCL is neglected fatty liver disease. This type of HCC has unique clinical characteristics and is closely related to metabolic disorders. Unfortunately, the prevention of HCC-NCL has not received enough attention worldwide, and there is also a lack of specific screening methods and clinical guidelines. This article mainly reviews the etiology, incidence, clinical characteristics, and screening markers of HCC-NCL to improve the understanding and prevention of this disease.

15.
Cell Chem Biol ; 26(10): 1417-1426.e5, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31402318

RESUMO

DEAD-box ATP-dependent helicases (DEAH/D) are a family of conserved genes predominantly involved in gene expression regulation and RNA processing. As its prototype, eIF4AI is an essential component of the protein translation initiation complex. Utilizing a screening system based on wild-type eIF4AI and its L243G mutant with a changed linker domain, we discovered an eIF4AI inhibitor, sanguinarine (SAN) and used it to study the catalytic mechanism of eIF4AI. Herein, we describe the crystal structure of the eIF4AI-inhibitor complex and demonstrate that the binding site displays certain specificity, which can provide the basis for drug design to target eIF4AI. We report that except for competitive inhibition SAN's possible mechanism of action involves interference with eIF4AI catalytic cycling process by hindering the formation of the closed conformation of eIF4AI. In addition, our results highlight a new targetable site on eIF4AI and confirm eIF4AI as a viable pharmacological target.

16.
J Oleo Sci ; 68(9): 931-937, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31413242

RESUMO

The essential oil extracted from roots and rhizomes of Ligusticum jeholense Nakai et Kitagawa was investigated for its chemical composition by GC-MS analysis, and evaluated for its contact toxicity and repellency against Tribolium castaneum and Lasioderma serricorne, along with some of its individual components. The essential oil was rich in aromatics (65.34%) with low molecular weight. Major components included sedanolide (33.95%), 3-butylidenephthalide (18.76%), spathulenol (8.90%) and myristicin (6.76%). The results of bioassays indicated that the essential oil of L. jeholense and 3-butylidenephthalide possessed significant repellent activities against T. castaneum at 2 and 4 h post-exposure. Meanwhile, 3-butylidenephthalide had potent contact toxicity against L. serricorne (LD50 = 13.64 µg/adult). The minor component n-butylbenzene in the oil was highly toxic to T. castaneum (LD50 = 23.99 µg/adult) and L. serricorne (LD50 = 7.86 µg/adult) in contact assays, but failed to repel these beetles at all testing concentrations. Spathulenol and myristicin exerted good insecticidal and repellent effects on the two target insects. This work suggests that the essential oil of L. jeholense has promising potential for development as natural insecticide or repellent to control pest damage in warehouses.

17.
Eur J Med Chem ; 182: 111633, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31461688

RESUMO

Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.

18.
J Comput Aided Mol Des ; 33(8): 775-785, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31312965

RESUMO

Protein arginine methyltransferase 5 (PRMT5) is responsible for the mono-methylation and symmetric dimethylation of arginine, and its expression level and methyl transferring activity have been demonstrated to have a close relationship with tumorigenesis, development and poor clinical outcomes of human cancers. Two PRMT5 small molecule inhibitors (GSK3326595 and JNJ-64619178) have been put forward into clinical trials. Here, we describe the design, synthesis and biological evaluation of a series of novel, potent and selective PRMT5 inhibitors with antiproliferative activity against Z-138 mantle cell lymphoma cell line. Among them, compound C_4 exhibited the highest potency with enzymatic and cellular level IC50 values of 0.72 and 2.6 µM, respectively, and displayed more than 270-fold selectivity toward PRMT5 over several other isoenzymes (PRMT1, PRMT4 and PRMT6). Besides, C_4 demonstrated obvious cell apoptotic effect while reduced the cellular symmetric arginine dimethylation levels of SmD3 protein. The potency, small size, and synthetic accessibility of this compound class provide promising hit scaffold for medicinal chemists to further explore this series of PRMT5 inhibitors.

19.
J Hazard Mater ; 380: 120893, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31325691

RESUMO

Selective enriching low content of radionuclides from radioactive wastewater is a critical issue for environmentally benign utilization of nuclear power. Inspired by the tolerance mechanism of plants to radionuclides, we developed a pH-triggered ultraselective coordinative adsorption (CA) membrane. The as-prepared CA membrane featured the advantages of both coordinative adsorption and membrane separation, including ultrahigh selectivity coefficient of 1242, large capacity (80 L m-2) and short mass transfer distance. The adsorption isotherms of Th4+ on the CA membrane were well described by the Freundlich model (R2 > 0.99), and the adsorption kinetics have a good fitting by using the pseudo-second-order kinetic model (R2 > 0.99). In a continuous separation under gravity, the CA membrane was able to selectively enrich the low content of Th4+ (0.05 mmol L-1) in the presence of 700 folds (35 mmol L-1) of co-existing ions (Na+, Mg2+, K+, Ca2+, Sr2+, Cs+ and Ba2+). The exceptional extraction efficiency to Th4+ was 100%, superior to that (3.7%) of all co-existing ions. Notably, the Th4+ enriched on the CA membrane was facilely eluted by diluted HNO3 (0.1 mol L-1). The Th4+ in the eluents was enriched by up to 54 folds. The eluted CA membrane was further reused for selective enrichment of Th4+, which showed no obvious loss of selectivity and enrichment capability. Our strategy might open up a new strategy for realizing ultraselective and recyclable enrichment of low content of irradiation contaminants from wastewater.

20.
Acta Pharmacol Sin ; 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253937

RESUMO

The cAMP-responsive element binding protein (CREB) binding protein (CBP) and adenoviral E1A-binding protein (P300) are two closely related multifunctional transcriptional coactivators. Both proteins contain a bromodomain (BrD) adjacent to the histone acetyl transferase (HAT) catalytic domain, which serves as a promising drug target for cancers and immune system disorders. Several potent and selective small-molecule inhibitors targeting CBP BrD have been reported, but thus far small-molecule inhibitors targeting BrD outside of the BrD and extraterminal domain (BET) family are especially lacking. Here, we established and optimized a TR-FRET-based high-throughput screening platform for the CBP BrD and acetylated H4 peptide. Through an HTS assay against an in-house chemical library containing 20 000 compounds, compound DC_CP20 was discovered as a novel CBP BrD inhibitor with an IC50 value of 744.3 nM. This compound bound to CBP BrD with a KD value of 4.01 µM in the surface plasmon resonance assay. Molecular modeling revealed that DC_CP20 occupied the Kac-binding region firmly through hydrogen bonding with the conserved residue N1168. At the celluslar level, DC_CP20 dose-dependently inhibited the proliferation of human leukemia MV4-11 cells with an IC50 value of 19.2 µM and markedly downregulated the expression of the c-Myc in the cells. Taken together, the discovery of CBP BrD inhibitor DC_CP20 provides a novel chemical scaffold for further medicinal chemistry optimization and a potential chemical probe for CBP-related biological function research. In addition, this inhibitor may serve as a promising therapeutic strategy for MLL leukemia by targeting CBP BrD protein.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA