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1.
Nucleic Acids Res ; 48(D1): D320-D327, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31906602

RESUMO

Liquid-liquid phase separation (LLPS) leads to a conversion of homogeneous solution into a dense phase that often resembles liquid droplets, and a dilute phase. An increasing number of investigations have shown that biomolecular condensates formed by LLPS play important roles in both physiology and pathology. It has been suggested the phase behavior of proteins would be not only determined by sequences, but controlled by micro-environmental conditions. Here, we introduce LLPSDB (http://bio-comp.ucas.ac.cn/llpsdb or http://bio-comp.org.cn/llpsdb), a web-accessible database providing comprehensive, carefully curated collection of proteins involved in LLPS as well as corresponding experimental conditions in vitro from published literatures. The current release of LLPSDB incorporates 1182 entries with 273 independent proteins and 2394 specific conditions. The database provides a variety of data including biomolecular information (protein sequence, protein modification, nucleic acid, etc.), specific phase separation information (experimental conditions, phase behavior description, etc.) and comprehensive annotations. To our knowledge, LLPSDB is the first available database designed for LLPS related proteins specifically. It offers plenty of valuable resources for exploring the relationship between protein sequence and phase behavior, and will enhance the development of phase separation prediction methods, which may further provide more insights into a comprehensive understanding of LLPS in cellular function and related diseases.

3.
Food Chem ; 306: 125629, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31629298

RESUMO

To understand the mechanism of the color formation of pepper fruit, integrative analysis of the metabolome and transcriptome profiles was performed in pepper varieties with 4 different fruit colors. A total of 188 flavonoids were identified, and most of the anthocyanins, flavonols and flavones showed markedly higher abundances in purple variety than in other varieties, which was linked to the high expression of flavonoid synthesis and regulatory genes. Using weighted gene co-expression network analyses, modules related to flavonoid synthesis and candidate genes that regulate flavonoid synthesis and transport were identified. Furthermore, the analysis of 12 carotenoids showed that the content of xanthophylls at 50 days after anthesis was significantly different between the four pepper varieties, which was resulted from the differential expressions of genes downstream of the carotenoid pathway. Our results provide new insights into the understanding of the synthesis and accumulation of flavonoids and carotenoids in pepper fruit.


Assuntos
Capsicum/metabolismo , Capsicum/química , Carotenoides/metabolismo , Cor , Flavonoides/metabolismo , Metaboloma , Transcriptoma , Verduras/química , Verduras/metabolismo
4.
Mol Genet Genomics ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31745640

RESUMO

Dwarfing is the development trend of pepper breeding. It is of great practical and scientific value to generate new dwarf germplasms, and identify new genes or alleles conferring dwarf traits in pepper. In our previous study, a weakly BR-insensitive dwarf mutant, E29, was obtained by EMS mutagenesis of the pepper inbred line 6421. It can be used as a good parent material for breeding new dwarf varieties. Here, we found that this dwarf phenotype was controlled by a single recessive gene. Whole-genome resequencing, dCAPs analysis, and VIGs validation revealed that this mutation was caused by a nonsynonymous single-nucleotide mutation (C to T) in CaBRI1. An enzyme activity assay, transcriptome sequencing, and BL content determination further revealed that an amino-acid change (Pro1157Ser) in the serine/threonine protein kinase and catalytic (S_TKc) domain of CaBRI1 impaired its kinase activity and caused the transcript levels of two important genes (CaDWF4 and CaROT3) participating in BR biosynthesis to increase dramatically in the E29 mutant, accompanied by significantly increased accumulation of brassinolide (BL). Therefore, we concluded that the novel single-base mutation in CaBRI1 conferred the dwarf phenotype and resulted in brassinosteroid (BR) accumulation in pepper. This study provides a new allelic variant of the height-regulating gene CaBRI1 that has theoretical and practical values for the breeding of the plants suitable for the facility cultivation and mechanized harvesting of pepper varieties.

5.
Phys Chem Chem Phys ; 21(36): 19795-19804, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31482888

RESUMO

Allostery plays important roles in the regulation of many biological processes, such as signal transduction and transcriptional regulation. Although great advances have been achieved in understanding the allosteric mechanism through experimental and theoretical investigations, the details of the allosteric process are still not clear. Here, using the N-terminal domain of calmodulin (nCaM) as the model protein, we reported the atomic level characterization of the allosteric process induced by Ca2+ binding through extensive and unbiased molecular dynamics simulations. In two trajectories, it was found that Ca2+ first binds to EF-hand 2 and then induces the conformational transformation of nCaM from the Apo to Holo state assisted by second Ca2+ binding to EF-hand 1 completely. The binding order was consistent with a recent experimental result. The simulations also indicated that the two EF-hands changed conformations synergistically and the EF-hand 2 showed an earlier and more gradual conformational transition. Meanwhile, the allosteric process of nCaM triggered by Ca2+ binding might be completed within hundreds of nanoseconds in a two-state-like manner. This was validated by biased simulations, in which the Ca2+ ions were restrained near the binding sites. This work provides the molecular details of the conformational transition of nCaM triggered by Ca2+ binding.


Assuntos
Cálcio/química , Calmodulina/química , Íons/química , Simulação de Acoplamento Molecular , Domínios Proteicos , Ligação Proteica , Conformação Proteica
6.
Nanotechnology ; 30(47): 475701, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31430734

RESUMO

In this work, we first report Au nanoclusters/porous silica particles nanocomposites as fluorescence enhanced sensors for selective and sensitive detection of Cu (II). As red-emitting GSH-protected Au nanoclusters (Au NCs) were self-assemble into porous silica particles (PSPs) after ultrasonic treatment. As a result, the Au NCs can be immobilized in the nano-channels of PSPs, which leads to the observation of an immobilized induced emission enhancement phenomenon. The photoluminscence (PL) intensity of the nanocomposites can enhance dozens of times compared with Au NCs. As a result, we obtain a novel PL enhanced sensor of Au NCs/PSPs nanocomposites with excellent PL properties. The as-prepared Au NCs/PSPs nanocomposites show good water-solubility, high stability, low toxicity, and exhibit a high PL quenching for reliable, sensitive and selective detection of Cu2+. The limit of detection can reach as low as 1 ppb. What is more, the Au NCs/PSPs nanocomposites also show sensitive detection of Cu2+ in living cells. These properties provide the Au NCs/PSPs nanocomposites with promising PL sensors for Cu2+ detection in various environmental and biological systems.

7.
Eur J Med Chem ; 180: 171-190, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31306905

RESUMO

p300 is an important histone acetyltransferase in epigenetics, and its overexpression is closely related to various diseases such as cancers. C646 is one of the most representative p300 inhibitors and used in various studies of p300. However, its intrinsic drawbacks such as containing potentially toxic groups prevent it from further development. In order to find potent p300 inhibitors with good drug-like properties, C646 was chosen as the lead compound and a series of new p300 inhibitors were designed based on the principle of bioisosterism and reasonable scaffold hopping, and the structure-activity relationship was systematically explored. Ten of them were found to show comparable inhibitory activity as C646. The most potent compound, 1r (IC50 = 0.16 µM), showed better p300 inhibitory activity than C646 with improved drug-like properties. Western blotting experiment confirmed that 1r could reduce the level of H3K27 acetylation more significantly than C646. Further cellular assay indicated that it could inhibit the proliferation of human breast ductal carcinoma cell T47D and human breast cancer cell MCF7 with the IC50 values of 5.08 µM and 22.54 µM, respectively. Docking study of 1r with p300 protein showed the possible reasons for its higher inhibition activity. Thus, compound 1r might be with potential for development as a novel epigenetic agent targeting p300.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Pirazolonas/farmacologia , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazolonas/síntese química , Pirazolonas/química , Relação Estrutura-Atividade , Fatores de Transcrição de p300-CBP/metabolismo
8.
J Biomol Struct Dyn ; : 1-11, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31248328

RESUMO

Phosphorylation of protein is critical for various cell processes, which preferentially happens in intrinsically disordered proteins (IDPs). How phosphorylation modulates structural ensemble of disordered peptide remains largely unexplored. Here, using replica exchange molecular dynamics (REMD) and Markov state model (MSM), the conformational distribution and kinetics of p53 N-terminal transactivation domain (TAD) 2 as well as its dual-site phosphorylated form (pSer46, pThr55) were simulated. It reveals that the dual phosphorylation does not change overall size and secondary structure element fraction, while a change in the distribution of hydrogen bonds induces slightly more pre-existing bound helical conformations. MSM analysis indicates that the dual phosphorylation accelerates conformation exchange between disordered and order-like states in target-binding region. It suggests that p53 TAD2 after phosphorylation would be more apt to bind to both the human p62 pleckstrin homology (PH) domain and the yeast tfb1 PH domain through different binding mechanism, where experimentally it exhibits an extended and α-helix conformation, respectively, with increased binding strength in both complexes. Our study implies except binding interface, both conformation ensemble and kinetics should be considered for the effects of phosphorylation on IDPs. Abbreviations IDPs intrinsically disordered proteins REMD replica exchange molecular dynamics MSM Markov state model TAD transactivation domain PH pleckstrin homology PRR proline-rich region DBD DNA-binding domain TET Tetramerization domain REG regulatory domain MD molecular dynamics PME particle-mesh Ewald TICA time-lagged independent component analysis CK Chapman-Kolmogorov GMRQ generalized matrix Rayleigh quotient SARW self-avoiding random walk KID kinase-inducible domain MFPT mean first passage time DSSP definition of secondary structure of proteins RMSD root mean square deviation Rg radius of gyration Ree end to end distance Communicated by Ramaswamy H. Sarma.

9.
J Med Chem ; 62(11): 5414-5433, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31117515

RESUMO

PRMT4 is a type I protein arginine methyltransferase and plays important roles in various cellular processes. Overexpression of PRMT4 has been found to be involved in several types of cancers. Selective and in vivo effective PRMT4 inhibitors are needed for demonstrating PRMT4 as a promising therapeutic target. On the basis of compound 6, a weak dual PRMT4/6 inhibitor, we constructed a tetrahydroisoquinoline scaffold through a cut-and-sew scaffold hopping strategy. The subsequent SAR optimization efforts employed structure-based approach led to the identification of a novel PRMT4 inhibitor 49. Compound 49 exhibited prominently high potency and selectivity, moderate pharmacokinetic profiles, and good antitumor efficacy in acute myeloid leukemia xenograft model via oral administration, thus demonstrating this compound as a useful pharmacological tool for further target validation and drug development in cancer therapy.

10.
J Proteome Res ; 18(3): 982-994, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30650966

RESUMO

Pepper ( Capsicum annuum L.) fruit development is a complex and genetically programmed process. In this study, we conducted integrative analysis of transcriptome and proteome profiles during pepper fruit development. A total of 23 349 transcripts and 5455 protein groups were identified in four fruit developmental stages of two pepper varieties. The numbers of transcripts and proteins identified were decreased gradually across fruit development, and the most significant changes in transcript and protein levels happened from the mature green (MG) to breaker (Br) stages. Poor correlation between differentially expressed transcript and differentially expressed protein profiles was observed during pepper fruit development. We then analyzed expression profiles of transcripts and proteins involved in cell wall metabolism, and capsanthin, tocopherol, and ascorbate biosynthetic pathways during fruit development, and identified key regulatory proteins in these pathways. We presented a dynamic picture of pepper fruit development via comprehensive analysis of transcriptome and proteome profiles at different fruit developmental stages and in different varieties, revealing the temporal specificity of key protein expression. Our report provides insight into the transcription and translation dynamics of pepper fruit development and a reference for other nonclimacteric species.

11.
Acta Pharmacol Sin ; 40(5): 677-688, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30224636

RESUMO

Pancreatic adenocarcinoma is a highly malignant cancer that often involves a deregulation of c-Myc. It has been shown that c-Myc plays a pivotal role in the regulation of a variety of physiological processes and is involved in early neoplastic development, resulting in poor progression. Hence, suppression of c-Myc overexpression is a potential strategy for pancreatic cancer therapy. CUDC-907 is a novel dual-acting inhibitor of phosphoinositide 3-kinase (PI3K) and histone deacetylase (HDAC). It has shown potential efficiency in patients with lymphoma, multiple myeloma, or thyroid cancer, as well as in solid tumors with c-Myc alterations, but the evidence is lacking for how CUDC-907 regulates c-Myc. In this study, we investigated the effect of CUDC-907 on human pancreatic cancer cells in vitro and in vivo. Our results showed that CUDC-907 potently inhibited the proliferation of 9 pancreatic cancer cell lines in vitro with IC50 values ranging from 6.7 to 54.5 nM. Furthermore, we revealed the antitumor mechanism of CUDC-907 in Aspc-1, PANC-1, and Capan-1 pancreatic cancer cells: it suppressed the HDAC6 subunit, thus downregulating c-Myc protein levels, which was a mode of action distinct from the existing mechanisms. Consistently, the extraordinary antitumor activity of CUDC-907 accompanied by downregulation of c-Myc and Ki67 expression in tumor tissue was observed in a human pancreatic cancer Aspc-1 xenograft nude mouse model in vivo. Our results suggest that CUDC-907 can be a valuable therapeutic option for treating pancreatic adenocarcinoma.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Desacetilase 6 de Histona/antagonistas & inibidores , Morfolinas/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Pirimidinas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Antígeno Ki-67/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Morfolinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Acta Neurol Belg ; 118(4): 617-627, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30306461

RESUMO

A 29-year-old male with a 4-month history of binocular temporal visual field defect, 1-month history of memory loss and 5-day history of headache was admitted to our hospital. Brain MRI showed progressive signal abnormalities in the brain parenchyma. His laboratory tests showed elevated serum IgG4 and liver dysfunction. Abdominal CT, ultrasound and liver biopsy showed chronic liver disease. According to the diagnostic criteria of IgG4-related disease, IgG4-related inflammatory pseudotumor of brain parenchyma was considered. After methylprednisolone treatment, his symptoms improved and brain lesion reduced. This is the second reported case of a tumefactive lesion of the brain with serum IgG4 elevation, which was responsive to steroid treatment. Coincidentally, his mother had similar medical history and imaging findings, and was subspecialty diagnosed with the same disease, but without pathological and immunohistochemical confirmation. This suggests that the disease may be hereditary. It is important to recognize IgG4-related inflammatory pseudotumors of the brain parenchyma so that patients do not undergo unnecessary surgical or other procedures.


Assuntos
Encefalopatias/diagnóstico por imagem , Granuloma de Células Plasmáticas/diagnóstico por imagem , Imunoglobulina G/sangue , Adulto , Encefalopatias/sangue , Granuloma de Células Plasmáticas/sangue , Humanos , Imagem por Ressonância Magnética , Masculino , Tecido Parenquimatoso/diagnóstico por imagem
14.
Cancer Lett ; 431: 150-160, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29857126

RESUMO

Targeting WT MLL for the treatment of MLL-r leukemia, which is highly aggressive and resistant to chemotherapy, has been shown to be a promising strategy. However, drug treatments targeting WT MLL are lacking. We used an in vitro histone methyltransferase assay to screen a library consists of 592 FDA-approved drugs for MLL1 inhibitors by measuring alterations in HTRF signal and found that Piribedil represented a potent activity. Piribedil specifically inhibited the proliferation of MLL-r cells by inducing cell-cycle arrest, apoptosis and myeloid differentiation with little toxicity to the non-MLL cells. Mechanism study showed Piribedil blocked the MLL1-WDR5 interaction and thus selectively reduced MLL1-dependent H3K4 methylation. Importantly, MLL1 depletion induced gene expression that was similar to that induced by Piribedil and rendered the MLL-r cells resistant to Piribedil-induced toxicity, revealing Piribedil exerted anti-leukemia effects by targeting MLL1. Furthermore, both the Piribedil treatment and MLL1 depletion sensitized the MLL-r cells to doxorubicin-induced apoptosis. Our study support the hypothesis that Piribedil could serve as a new drug for the treatment of MLL-r AML and provide new insight for further optimization of targeting MLL1 HMT activity.


Assuntos
Apoptose , Doxorrubicina/farmacologia , Histona-Lisina N-Metiltransferase/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Proteína de Leucina Linfoide-Mieloide/metabolismo , Piribedil/farmacologia , Animais , Antineoplásicos/farmacologia , Ciclo Celular , Diferenciação Celular , Proliferação de Células/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Regulação para Baixo , Sinergismo Farmacológico , Regulação Leucêmica da Expressão Gênica , Histonas/química , Humanos , Células K562 , Camundongos , Camundongos Nus , Transplante de Neoplasias , RNA Interferente Pequeno/metabolismo
15.
Phys Chem Chem Phys ; 20(13): 8676-8684, 2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29537020

RESUMO

Intrinsically disordered regions (IDRs) or proteins (IDPs), which play crucial biological functions in essential biological processes of life, do not have well-defined secondary or tertiary structures when isolated in solution. The highly dynamic properties and conformational heterogeneity of IDPs make them challenging to study with traditional experimental techniques. As a powerful complementary tool for experiments, all-atom molecular dynamics simulation can obtain detailed conformational information on IDPs, but the limitation of force field accuracy is a challenge for reproducing IDP conformers. Here, we compared five empirical all-atom force fields AMBER03, AMBER99SB-ILDN, CHARMM27, OPLS-AA/L and CHARMM36m in modeling the conformational ensembles of wild-type peptide TAD2(41-62) from the human p53 tumor suppressor. Our results show that for the model peptide, the newest force field CHARMM36m produces more expanded coil ensemble followed by AMBER99SB-ILDN; CHARMM27 displays a predominant propensity for a helical structure; whereas OPLS-AA/L exhibits a apparent preference for a ß-sheet structure and yields the most compact conformation. In the comparison of the simulated dimensions with theoretical prediction and the back-calculated chemical shifts with experimental measurements, AMBER99SB-ILDN gives a more consistent agreement than the other force fields. In addition, the region from residues 47 to 55, which commonly forms an amphipathic α-helix upon binding target proteins according to experimental observation, could form a helical structure with a different probability population in our simulations with different force fields. This implies that the binding process might be conducted by, or partly by "conformation selection" for this peptide. This work indicates that force field development for modeling general IDPs accurately has a long way to go, and more detailed experimental data of IDPs are also in demand.

16.
ACS Appl Mater Interfaces ; 9(38): 32756-32766, 2017 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-28880075

RESUMO

High-performance active materials for energy-storage and energy-conversion applications require a novel class of electrodes: ones with a structure conducive to conductivity, large specific surface area, high porosity, and mechanical robustness. Herein, we report the design and fabrication of a new ternary hybrid aerogel. The process entails an in situ assembly of 2D WSe2 nanosheets and NiFe-LDH nanosheets on a 3D N,S-codoped graphene framework, accomplished by a facile hydrothermal method and electrostatic self-assembly technology. The obtained nanocomposite architecture maximizes synergistic effects among its three 2D-layer components. To assess the performance of this hybrid material, we deployed it as an advanced electrode in overall water splitting and in a supercapacitor. Results in both scenarios attest to its excellent electrochemical properties. Specifically, serving as a catalyst in an oxygen evolution reaction, our nanocomposite requires overpotentials of 1.48 and 1.59 V to obtain current densities of 10 and 100 mA cm-2, respectively. The hybrid material also efficiently electrocatalyzes hydrogen evolution reactions in base solution, necessitating overpotentials of -50 and -237 mV for current densities of 1.0 and 100 mA cm-2, respectively. The 3D hybrid, when applied to a symmetric supercapacitor device, achieves 125.6 F g-1 capacitance at 1 A g-1 current density. In summary, our study elucidates a new strategy to maximize efficiency via synergetic effects that is likely applicable to other 2D materials.

17.
Phys Chem Chem Phys ; 19(33): 22321-22328, 2017 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-28805214

RESUMO

Experimental studies indicate that the A39V/N53P/V55L Fyn SH3 domain folds from the unfolded state to the native state via a low-populated on-pathway intermediate, whereas the folding of the wildtype is two-state-like. To get insights into the biophysical basis of their different folding mechanisms, we used native-centric models with and without additional transferrable, sequence-dependent nonnative hydrophobic interactions to study the folding behaviors of the Fyn SH3 domain and its mutant. The pure native-centric model predicts that both the wildtype and the mutant fold in a two-state manner, without any detectable intermediate. However, in the simulated trajectories based on the model with sequence-dependent nonnative hydrophobic interactions, a low populated on-pathway intermediate was identified for the mutant, but not for the wild type, although it is not sufficient to induce chevron rollover. In the modelling intermediate, the topology of strands ß1 to ß4 followed by the helix turn is native-like, while strand ß5 is mostly unstructured, which is in good agreement with experiments. Meanwhile, the nonnative contacts in the intermediate overlapped largely with those identified experimentally. Further investigation implies that different folding mechanisms between the wildtype and the mutant might arise from the distinction of the nonnative contact patterns at the transition states. In addition, we predicted that nonnative interactions led to deceleration or acceleration of the folding largely depending on whether they could destabilize or stabilize the transition state relative to the unfolded state. This study implies that the simple native-centric model augmented by sequence-dependent nonnative hydrophobic interactions should be useful in general to predict the folding of proteins with a low-populated intermediate.

18.
Phys Chem Chem Phys ; 19(27): 18102, 2017 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-28675224

RESUMO

Correction for 'A critical comparison of coarse-grained structure-based approaches and atomic models of protein folding' by Jie Hu et al., Phys. Chem. Chem. Phys., 2017, 19, 13629-13639.

19.
Medicine (Baltimore) ; 96(30): e7630, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28746225

RESUMO

RATIONALE: Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease, are associated with a large number of extraintestinal manifestations. Pulmonary manifestations are infrequently seen in patients with IBD. Moreover, serositis including pleural and pericardial manifestations in UC is rare. PATIENT CONCERNS: We report a case of UC with acute pleurisy in a 43-year-old man; review literature; and discuss the diagnosis, differential diagnosis, and treatment. DIAGNOSES: Active duodenal ulcer was found using gastroscopy. Multiple ulcers in segmented pattern were noticed in the left hemi-colon using colonoscopy. An UC in active stage was confirmed subsequently by histology. INTERVENTION: The patient was treated with bifidobacterium tetravaccine tablets, oral mesalazine and mesalazine enemas. The omeprazole and mucosal protective agents were given to treat the duodenal ulcer. OUTCOMES: As follow-up, the therapy including oral mesalazine and infliximab regularly was continued and the patient condition was stabilized. MAIN LESSON: Pulmonary involvement should be considered in patients who develop pleurisy in UC. Infliximab is considered the better available treatment for patients presenting with pleurisy in UC.


Assuntos
Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Pleurisia/complicações , Pleurisia/diagnóstico , Adulto , Colite Ulcerativa/terapia , Diagnóstico Diferencial , Humanos , Masculino , Pleurisia/terapia
20.
Acta Pharmacol Sin ; 38(10): 1381-1393, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28504248

RESUMO

The flavonoid quercetin exhibits significant anticancer activities with few side effects. In the current study, we characterized TL-2-8, a quercetin derivative, as a novel anticancer agent in vitro and in vivo. Cell proliferation and viability were assessed using Cell Counting Kit-8 and CellTiter-Blue assay, respectively. Cell death was examined using PI staining or a TUNEL assay. Mitophagy was determined by measuring autophagic flux and by confocal imaging. Protein expression was examined by Western blotting. We found that TL-2-8 selectively inhibited the proliferation and decreased the viability of various cancer cells (the anti-proliferation IC50 values in MDA-MB-231, MDA-MB-468 and MCF-7 breast cancer cells at 72 h were 8.28, 8.56, and 9.58 µmol/L, respectively), and it displayed only slight cytotoxicity against normal MCF-10A and HEK-293 cells. In MDA-MB-231 and MDA-MB-468 breast cancer cells, TL-2-8 treatment induced the degradation of multiple Hsp90 client proteins without inducing Hsp70. TL-2-8 (3, 6, 12 µmol/L) dose-dependently inhibited the expression of AHA1, an activator of Hsp90 ATPase, and decreased Hsp90-AHA1 complex formation, leading to decreased Hsp90 chaperone function and reduced polo-like kinase 1 (PLK1) signaling. Consequently, impaired mitophagy was induced via the downregulation of lysosomal-associated membrane protein 2 (LAMP2). The in vivo anticancer effects of TL-2-8 were evaluated in an MDA-MB-231 breast cancer xenograft model, which was treated with TL-2-8 (25, 50, 100 mg·kg-1·d-1, po). Administration of TL-2-8 resulted in tumor growth inhibition rates of 37.9%, 58.9% and 70.9%, respectively, whereas quercetin treatment (100 mg·kg-1·d-1, po) produced only a lower tumor growth inhibition rate (49.5%). Furthermore, TL-2-8 treatment significantly extended the lifespan of mice bearing MDA-MB-231 breast cancer cell xenografts. Our results demonstrate that TL-2-8 induces significant cell death and immature mitophagy in breast cancer cells in vitro and in vivo via AHA1 abrogation.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Flavonoides/farmacologia , Animais , Antineoplásicos/administração & dosagem , Neoplasias da Mama/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo , Feminino , Células HEK293 , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Marcação In Situ das Extremidades Cortadas , Concentração Inibidora 50 , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Chaperonas Moleculares/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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