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1.
Proc Natl Acad Sci U S A ; 116(19): 9543-9551, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-30988175

RESUMO

Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable.

2.
J Virol ; 92(18)2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-29976664

RESUMO

Mink enteritis virus (MEV), as a parvovirus, is among the smallest of the animal DNA viruses. The limited genome leads to multifunctional sequences and complex gene expression regulation. Here, we show that the expression of viral capsid protein 2 (VP2) of MEV requires its 5' untranslated regions (5' UTR) which promote VP2 gene expression at both transcriptional and translational levels. The expression of VP2 was inhibited in several common eukaryotic expression vectors. Our data showed that the 5' UTR of VP2 enhanced capsid gene transcription but not increased stability or promotes nucleocytoplasmic export of VP2 mRNA. Analysis of the functions of 5' UTR fragments showed that the proximal region (nucleotides [nt] 1 to 270; that is, positions +1 to +270 relative to the transcription initiation site, nt 2048 to 2317 of MEV-L) of 5' UTR of VP2 was necessary for VP2 transcription and also promoted the activity of P38 promoter. Unexpectedly, further analysis showed that deletion of the distal region (nt 271 to 653) of the 5' UTR of VP2 almost completely abolished VP2 translation in the presence of P38, whereas the transcription was still induced significantly. Furthermore, using a luciferase reporter bicistronic system, we identified that the 5' UTR had an internal ribosome entry site-like function which could be enhanced by NS1 via the site at nt 382 to 447. Mutation of the 5' UTR in the MEV full-length clones further showed that the 5' UTR was required for VP2 gene expression. Together, our data reveal an undiscovered function of 5' UTR of MEV VP2 in regulating viral gene expression.IMPORTANCE MEV, a parvovirus, causes acute enteritis in mink. In the present report, we describe an untranslated sequence-dependent mechanism by which MEV regulates capsid gene expression. Our results highlight the roles of untranslated sequences in regulating the transcriptional activity of P38 promoter and translation of capsid genes. These data also reveal the possibility of an unusual translation mechanism in capsid protein expression and the multiple functions of nonstructural protein. A better understanding of the gene expression regulation mechanism of this virus will help in the design of new vaccines and targets for antiviral agents against MEV.


Assuntos
Regiões 5' não Traduzidas/genética , Proteínas do Capsídeo/genética , Expressão Gênica , Vírus da Enterite do Vison/genética , Animais , Luciferases/genética , Vison , Vírus da Enterite do Vison/química , Mutação , Transcrição Genética
3.
Biochem Biophys Res Commun ; 496(2): 719-725, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29355529

RESUMO

The gene therapy of cancer, due to the limit of its efficiency and safety, has not been widely used in clinical. Recently, bacterial magnetic particles (BMPs), which are membrane-bound nanocrystals found in magnetotactic bacteria, have been exploited as a new gene delivery system. However, its application on gene therapy remains to be explored. In our previous study, we found that a combination of cecropin B (ABPs) and apoptin (VP3) could serve as an effective gene therapeutic agent. Thus, in this study, we used BMPs to deliver the co-expression plasmid of these two gene, namely pVAX1-VA, and evaluated its therapeutic effect on human hepatocellular carcinoma (HepG2). Our results showed that BMPs significantly improved the efficiency of gene transfection (almost 3-fold than Lipofectamine 2000 at 48 h, P < .001), which led to stronger apoptosis (in a peak almost 2-fold than Lipofectamine 2000-pVAX1-VA, P < .01) and growth inhibition of HepG2 cells. More importantly, compared with Lipofectamine 2000-pVAX1-VA group, BMP-pVAX1-VA strikingly inhibited tumor growth (0.60 ±â€¯0.09 g vs. 0.88 ±â€¯0.11 g, P < .05) in nude mouse tumor models and increased the tumor-infiltrating lymphocytes considerably without apparent cytotoxicity. These findings suggest that BMPs could be an attractive gene delivery system for gene therapy and provide a potential available treatment for human hepatocellular carcinoma and maybe some other kinds of tumors.


Assuntos
Proteínas do Capsídeo/genética , Carcinoma Hepatocelular/terapia , Técnicas de Transferência de Genes , Vetores Genéticos/administração & dosagem , Proteínas de Insetos/genética , Neoplasias Hepáticas/terapia , Magnetossomos/química , Magnetospirillum/química , Animais , Antineoplásicos/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Portadores de Fármacos/química , Feminino , Terapia Genética/métodos , Vetores Genéticos/genética , Vetores Genéticos/uso terapêutico , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Transfecção/métodos
4.
Transl Neurodegener ; 6: 19, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28702178

RESUMO

Alzheimer's disease (AD) is a chronic neurodegenerative disease, which is associated with learning and memory impairment in the elderly. Recent studies have found that treating AD in the way of chromatin remodeling via histone acetylation is a promising therapeutic regimen. In a number of recent studies, inhibitors of histone deacetylase (HDACs) have been found to be a novel promising therapeutic agents for neurological disorders, particularly for AD and other neurodegenerative diseases. Although HDAC inhibitors have the ability to ameliorate cognitive impairment, successful treatments in the classic AD animal model are rarely translated into clinical trials. As for the reduction of unwanted side effects, the development of HDAC inhibitors with increased isoform selectivity or seeking other directions is a key issue that needs to be addressed. The review focused on literatures on epigenetic mechanisms in recent years, especially on histone acetylation in terms of the enhancement of specificity, efficacy and avoiding side effects for treating AD.

5.
Fish Physiol Biochem ; 43(2): 517-525, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28130732

RESUMO

Zebrafish phosvitin-derived peptide Pt5, consisting of the C-terminal 55 residues of phosvitin, has been shown to have an antimicrobial-immunomodulatory activity comparable to phosvitin. Here, we showed clearly that Pt5 had the capacity to inhibit tyrosinase (TYR) activity and melanin biosynthesis, and this inhibition was independent of cell proliferation and cytotoxic effects. Incubation of fluorescein isothiocyanate (FITC)-labeled Pt5 with B16F10 melanoma cells revealed that Pt5 was localized in the cytoplasm of the cells. In addition, Pt5 inhibited the expression of TYR, tyrosinase-related protein-1 (TRP-1), tyrosinase-related protein-2 (TRP-2), and microphthalmia-associated transcription factor (MITF) in B16F10 melanoma cells and reduced the intracellular cyclic adenosine monophosphate (cAMP) concentration in the cells, but it did not affect the cellular contents of pERK1/2 and ß-catenin, suggesting that Pt5 regulates melanin biosynthesis via cAMP signaling pathway rather than Wnt and MAPK pathways. Collectively, these data indicate that Pt5 has the potential to be used as a melanogenesis inhibitor in medical and cosmetic industry, a novel role ever reported.


Assuntos
AMP Cíclico/metabolismo , Melaninas/biossíntese , Fragmentos de Peptídeos/farmacologia , Fosvitina/farmacologia , Proteínas de Peixe-Zebra/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Oxirredutases Intramoleculares/metabolismo , Camundongos , Monofenol Mono-Oxigenase/metabolismo , Oxirredutases/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos
6.
J Biol Chem ; 291(14): 7386-95, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26851285

RESUMO

The p53 tumor suppressor controls cell growth, metabolism, and death by regulating the transcription of various target genes. The target-specific transcriptional activity of p53 is highly regulated. Here we demonstrate that acetylation of p53 at Lys-120 up-regulates its transcriptional activity toward Apaf-1, a core component in the mitochondrial apoptotic pathway, and thus sensitizes caspase activation and apoptosis. We found that histone deacetylase (HDAC) inhibitors, including butyrate, augment Lys-120 acetylation of p53 and thus Apaf-1 expression by inhibiting HDAC1. In p53-null cells, transfection of wild-type but not K120R mutant p53 can restore the p53-dependent sensitivity to butyrate. Strikingly, transfection of acetylation-mimicking K120Q mutant p53 is sufficient to up-regulates Apaf-1 in a manner independent of butyrate treatment. Therefore, HDAC inhibitors can induce p53 acetylation at lysine 120, which in turn enhances mitochondrion-mediated apoptosis through transcriptional up-regulation of Apaf-1.


Assuntos
Apoptose , Fator Apoptótico 1 Ativador de Proteases/biossíntese , Mitocôndrias/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima , Acetilação/efeitos dos fármacos , Substituição de Aminoácidos , Fator Apoptótico 1 Ativador de Proteases/genética , Células HeLa , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Lisina/genética , Lisina/metabolismo , Mitocôndrias/genética , Mutação de Sentido Incorreto , Proteína Supressora de Tumor p53/genética
7.
Yao Xue Xue Bao ; 51(4): 563-72, 2016 04.
Artigo em Chinês | MEDLINE | ID: mdl-29859525

RESUMO

This study was designed to identify inducers of ATP-binding cassette transporter A1(ABCA1) and CD36 and lysosomal integral membrane protein-II analogous-1(CLA-1) and to evaluate the in vitro effect of the active compound on lipid metabolism. Among 20 000 compounds screened, E23869 was found as a positive hit using cell-based high throughput screening models. The up-regulating activities of E23869 in ABCA1p-LUC and CLA-1p-LUC Hep G2 cells were 196% and 198%, respectively. The EC(50) values of E23869 in ABCA1p- LUC and CLA-1p-LUC Hep G2 cells were 0.25 µmol·L(-1) and 0.66 µmol·L(-1), respectively. E23869 significantly upregulated the protein levels of ABCA1, scavenger receptor class B type I(SR-BI)/CLA-1 and ATP-binding cassette transporter G1(ABCG1) in both macrophages RAW264.7 and L02 cells by Western blotting analysis. Foam cell assay showed that E23869 inhibited lipids accumulations in macrophages RAW264.7. Cholesterol efflux assay showed that E23869 induced HDL-mediated cholesterol efflux in macrophages RAW264.7. Moreover, E23869 up-regulated ABCA1, SR-BI/CLA-1 and ABCG1 expressions through activation of PPARα and PPARγ. In addition, E23869 weakly promoted in vitro differentiation of mouse preadipocytes 3T3-L1. In conclusion, E23869 up-regulated ABCA1, SR-BI/CLA-1 and ABCG1 expressions to promote cholesterol efflux, which is a good leading compound for regulation of lipid metabolism.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Receptores Depuradores Classe B/metabolismo , Animais , Transporte Biológico , Antígenos CD36 , Linhagem Celular , Colesterol/metabolismo , Células Espumosas/efeitos dos fármacos , Células Hep G2 , Humanos , Macrófagos/efeitos dos fármacos , Camundongos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Células RAW 264.7 , Ativação Transcricional , Regulação para Cima
8.
Mitochondrial DNA A DNA Mapp Seq Anal ; 27(3): 1763-4, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-25259460

RESUMO

In order to further study the characteristic of Caenorhabditis, the complete mitochondrial genome (mitogenome) of a modal nematode species Caenorhabditis tropicalis n. sp. (previous species name: C. sp. 11) was determined. The results showed that the mitogenome was 13,874 bp in length, which contained 12 protein-coding genes (PCGs), 2 ribosomal RNA genes (rRNAs), 22 transfer RNA genes (tRNAs), an AT-rich region and 2 non-coding regions (NCR). The base composition of the heavy strand was 28.12% A, 47.57% T, 15.53% G, and 8.78% C. Furthermore, it is more significant that this mitogenome has two unique features: One is the AT-rich region which had 4 runs of 12 AT dinucleotides and 4 copies of directly repeated sequence (47 bp) within a pair of inverted repeat sequence (13 bp), and the other is that the NCR (130 bp) between tRNA(Arg) and tRNA(Gln) of 4 small stem-loop which was described at the first time. This paper firstly expounded the the complete mitogenome of C. tropicalis n. sp. So it can enrich the molecular resource and facilitate the further research of the population genetics and systematics for Caenorhabditis.


Assuntos
Genoma Mitocondrial/genética , Rabditídios/genética , Animais , Composição de Bases/genética , Ordem dos Genes/genética , Filogenia , RNA Ribossômico/genética , RNA de Transferência/genética , Rabditídios/classificação , Análise de Sequência de DNA
9.
J Alzheimers Dis ; 43(1): 291-302, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25079795

RESUMO

Indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme in the kynurenine pathway (KP) of tryptophan catabolism, was recently established as one of the potential players involved in the pathogenesis of Alzheimer's disease (AD). Coptisine is a main pharmacological active constituent of the traditional Chinese medicinal prescription Oren-gedoku-to (OGT) which has therapeutic potential for the treatment of AD. Our recent studies have demonstrated that OGT significantly inhibited recombinant human IDO activity, which shed light on the possible mechanism of OGT's action on AD. Here, we characterized the effects of coptisine in an AD mouse model on the basis of its IDO inhibitory ability. Coptisine was found to be an efficient uncompetitive IDO inhibitor with a Ki value of 5.8 µM and an IC50 value of 6.3 µM. In AßPP/PS1 transgenic mice, oral administration of coptisine inhibited IDO in the blood and decreased the activation of microglia and astrocytes, consequently prevented neuron loss, reduced amyloid plaque formation, and ameliorated impaired cognition. Neuronal pheochromocytoma (PC12) cells induced with amyloid-ß peptide 1-42 and interferon-γ showed reduction of cell viability and enhancement of IDO activity, while coptisine treatment increased cell viability based on its reversal effect on the enhanced activity of IDO. In conclusion, our present findings provide further evidence supporting the critical links between IDO, KP, and AD, and demonstrate coptisine, a novel IDO inhibitor, as a potential new class of drugs for AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Berberina/análogos & derivados , Transtornos Cognitivos/tratamento farmacológico , Nootrópicos/farmacologia , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Berberina/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , Modelos Animais de Doenças , Donepezila , Inibidores Enzimáticos/farmacologia , Humanos , Indanos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Masculino , Camundongos Transgênicos , Células PC12 , Piperidinas/farmacologia , Placa Amiloide/tratamento farmacológico , Placa Amiloide/patologia , Placa Amiloide/fisiopatologia , Presenilina-1/genética , Presenilina-1/metabolismo , Ratos
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