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1.
Artigo em Inglês | MEDLINE | ID: mdl-31786240

RESUMO

Chimeric antigen receptor (CAR)-T cell therapy, a new immunotherapy for relapsed and refractory (R/R) hematologic malignancies, can be accompanied by adverse events, including coagulation disorders. Here, we performed a comprehensive analysis of coagulation parameters in 100 patients with R/R hematologic malignancies after receiving CAR-T cell therapy to illuminate the profiles of coagulation disorders and to facilitate the management of coagulation disorders. A high incidence of coagulation disorders was observed, including elevated D-dimer (50/100, 50%), increased fibrinogen degradation product (45/100, 45%), decreased fibrinogen (23/100, 23%), prolonged activated partial thromboplastin time (16/100, 16%), and prolonged prothrombin time (10/100, 10%). Coagulation disorders occurred mainly during day 6 to day 20 after CAR-T cell infusion. The changes in coagulation parameters were associated with high tumor burden in acute lymphoblastic leukemia, more lines of prior therapies, lower baseline platelet count, and especially cytokine release syndrome (CRS). Disseminated intravascular coagulation (DIC) was found in 7 patients with grade ≥3 CRS and indicated a poor prognosis. Our study suggests that coagulation disorders are manageable in most patients after CAR-T cell therapy. Coexistence of DIC and severe CRS is closely related to nonrelapsed deaths during the acute toxicity phase, and effective and timely treatment is the key to reduce nonrelapse mortality for patients with DIC and severe CRS.

2.
Chem Commun (Camb) ; 55(78): 11774-11777, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31515552

RESUMO

A copper-catalyzed 1,4-addition reaction of sulfonyl iodides with 1,3-enynes affording various allenyl halides in high yields under mild conditions has been developed. Mechanistic studies showed that the reaction proceeds through a radical mechanism.

3.
Blood ; 134(19): 1619-1631, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31409672

RESUMO

Mutations in GATA1, which lead to expression of the GATA1s isoform that lacks the GATA1 N terminus, are seen in patients with Diamond-Blackfan anemia (DBA). In our efforts to better understand the connection between GATA1s and DBA, we comprehensively studied erythropoiesis in Gata1s mice. Defects in yolks sac and fetal liver hematopoiesis included impaired terminal maturation and reduced numbers of erythroid progenitors. RNA-sequencing revealed that both erythroid and megakaryocytic gene expression patterns were altered by the loss of the N terminus, including aberrant upregulation of Gata2 and Runx1. Dysregulation of global H3K27 methylation was found in the erythroid progenitors upon loss of N terminus of GATA1. Chromatin-binding assays revealed that, despite similar occupancy of GATA1 and GATA1s, there was a striking reduction of H3K27me3 at regulatory elements of the Gata2 and Runx1 genes. Consistent with the observation that overexpression of GATA2 has been reported to impair erythropoiesis, we found that haploinsufficiency of Gata2 rescued the erythroid defects of Gata1s fetuses. Together, our integrated genomic analysis of transcriptomic and epigenetic signatures reveals that, Gata1 mice provide novel insights into the role of the N terminus of GATA1 in transcriptional regulation and red blood cell maturation which may potentially be useful for DBA patients.


Assuntos
Eritropoese/genética , Fator de Transcrição GATA1/genética , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/fisiopatologia , Animais , Cromatina/genética , Epigênese Genética/genética , Camundongos , Camundongos Mutantes , Isoformas de Proteínas
4.
Int Immunopharmacol ; 74: 105740, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301646

RESUMO

This study aims to observe the expression and role of NLRP6 in liver injury after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Allo-HSCT model was established through infusion of 5 × 106 bone marrow mononuclear cells into whole body irradiated mice. On days 7, 14, 21 and 28 after transplantation, the peripheral blood was collected to detect liver function. The liver of the mice was obtained to assess the pathological changes of liver tissues after allo-HSCT by H&E staining and Mason staining. Meanwhile, expression of NLRP6, phosphorylated p38-MAPK and IκBα, caspase-1 and NLRP3 in liver were detected by Western blot. ELISA was used for detection of the level of interleukin (IL)-1ß, IL-18, tumor necrosis factor (TNF)-α, IL-6, myeloperoxidase (MPO) and tumor growth factor (TGF)-ß1. Increased expression of NLRP6, phosphorylated Iκbα, phosphorylated p38-MAPK, pro-caspase-1, and p20, in liver tissue with injury and fibrosis in mice after allo-HSCT were observed. Meanwhile, the level of IL-1ß, IL-18, IL-6 and TNF-α was also increased. However, NLRP6-/- mice showed more severe liver damage and liver fibrosis after transplantation together with higher level of phosphorylated Iκbα, phosphorylated p38-MAPK, Pro-caspase-1, p20 expression as well as IL-1ß, IL-18, IL-6, and TNF-α secretion compared with wide-type. Interestingly, the expression of NLRP3 in the liver of NLRP6-/- mice was significantly higher than that of wild-type. In conclusion, the expression of NLRP6 in host's liver is associated with liver injury after allo-HSCT. NLRP6 deficiency in host's liver leads to more severe liver damage, indicating a protective role of NLRP6 in host's liver to liver damage after allo-HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatias/genética , Fígado/patologia , Complicações Pós-Operatórias/genética , Receptores de Superfície Celular/metabolismo , Animais , Citocinas/metabolismo , Citoproteção , Fibrose , Regulação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Fígado/metabolismo , Hepatopatias/etiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Superfície Celular/genética , Transplante Homólogo
5.
Chem Sci ; 10(25): 6316-6321, 2019 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-31341585

RESUMO

A Ru(ii)-catalyzed direct access to various functionalized allenoic acids via C-H allenylation of readily available aryl carboxylic acids with propargylic acetates is reported. Axially chiral allenoic acids could be obtained in high ee by using optically active propargylic acetates through a chirality transfer strategy.

6.
Clin Cancer Res ; 25(19): 5901-5912, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31217200

RESUMO

PURPOSE: The myeloproliferative neoplasms (MPN), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are characterized by the expansion of the erythroid, megakaryocytic, and granulocytic lineages. A common feature of these disorders is the presence of abnormal megakaryocytes, which have been implicated as causative agents in the development of bone marrow fibrosis. However, the specific contributions of megakaryocytes to MPN pathogenesis remain unclear. EXPERIMENTAL DESIGN: We used Pf4-Cre transgenic mice to drive expression of JAK2V617F in megakaryocyte lineage-committed hematopoietic cells. We also assessed the critical role of mutant megakaryocytes in MPN maintenance through cell ablation studies in JAK2V617F and MPLW515L BMT models of MPN. RESULTS: JAK2V617F -mutant presence in megakaryocytes was sufficient to induce enhanced erythropoiesis and promote fibrosis, which leads to a myeloproliferative state with expansion of mutant and nonmutant hematopoietic cells. The increased erythropoiesis was associated with elevated IL6 level, which was also required for aberrant erythropoiesis in vivo. Furthermore, depletion of megakaryocytes in the JAK2V617F and MPLW515L BMT models ameliorated polycythemia and leukocytosis in addition to expected effects on megakaryopoiesis. CONCLUSIONS: Our observations reveal that JAK/STAT pathway activation in megakaryocytes induces myeloproliferation and is necessary for MPN maintenance in vivo. These observations indicate that MPN clone can influence the behavior of the wild-type hematopoietic milieu, at least, in part, via altered production of proinflammatory cytokines and chemokines. Our findings resonate with patients who present with a clinical MPN and a low JAK2V617F allele burden, and support the development of MPN therapies aimed at targeting megakaryocytes.

7.
BMC Genomics ; 20(1): 456, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170917

RESUMO

BACKGROUND: Ricinus communis is a highly economically valuable oil crop plant from the spurge family, Euphorbiaceae. However, the available reference genomes are incomplete and to date studies on ricinoleic acid biosynthesis at the transcriptional level are limited. RESULTS: In this study, we combined PacBio single-molecule long read isoform and Illumina RNA sequencing to identify the alternative splicing (AS) events, novel isoforms, fusion genes, long non-coding RNAs (lncRNAs) and alternative polyadenylation (APA) sites to unveil the transcriptomic complexity of castor beans and identify critical genes related to ricinoleic acid biosynthesis. Here, we identified 11,285 AS-variants distributed in 21,448 novel genes and detected 520 fusion genes, 320 lncRNAs and 9511 (APA-sites). Furthermore, a total of 6067, 5983 and 4058 differentially expressed genes between developing beans of the R. communis lines 349 and 1115 with extremely different oil content were identified at 7, 14 and 21 days after flowering, respectively. Specifically, 14, 18 and 11 DEGs were annotated encoding key enzymes related to ricinoleic acid biosynthesis reflecting the higher castor oil content of 1115 compared than 349. Quantitative real-time RT-PCR further validated fifteen of these DEGs at three-time points. CONCLUSION: Our results significantly improved the existed gene models of R. communis, and a putative model of key genes was built to show the differences between strains 349 and 1115, illustrating the molecular mechanism of castor oil biosynthesis. A multi-transcriptome database and candidate genes were provided to further improve the level of ricinoleic acid in transgenic crops.


Assuntos
Ácidos Ricinoleicos/metabolismo , Ricinus/genética , Transcriptoma , Processamento Alternativo , Perfilação da Expressão Gênica , Fusão Gênica , Genes de Plantas , Sequenciamento de Nucleotídeos em Larga Escala , Poliadenilação , RNA Longo não Codificante/genética , Ricinus/metabolismo , Análise de Sequência de RNA , Fatores de Transcrição/genética
8.
Environ Sci Pollut Res Int ; 26(19): 19272-19281, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31069655

RESUMO

As cadmium levels are increasing in the environment, the adverse effects of cadmium exposure specifically associated with chronic diseases are receiving increasing attention. Several population-based studies have been conducted on the association between cadmium and diabetes mellitus (DM) but have reported controversial results. Here, we aimed to evaluate the association between cadmium exposure and DM. In this meta-analysis, a random effects model was used because there was evidence of heterogeneity among studies. A dose-response relationship was assessed through a restricted cubic spline model with three knots. The results showed a positive association between cadmium levels in the body and DM (OR = 1.27; 95% CI, 1.07-1.52). The cadmium levels in the body were defined on the basis of combined urinary and blood cadmium. Subgroup analysis further indicated a positive association between urinary cadmium levels and DM (OR = 1.31; 95% CI, 1.02-1.69). The dose-response analysis results showed a positive association between levels of urinary cadmium above 2.43 µg/g creatinine and DM, and the risk of DM increased by 16% for each l µg/g creatinine increase in urinary cadmium levels. The results from our meta-analysis indicate that cadmium levels in the body are positively associated with DM, and urinary cadmium levels above 2.43 µg/g creatinine are associated with an increased risk of DM.


Assuntos
Cádmio/urina , Diabetes Mellitus/epidemiologia , Exposição Ambiental/análise , Poluentes Ambientais/urina , Cádmio/toxicidade , Creatinina/urina , Diabetes Mellitus/induzido quimicamente , Diabetes Mellitus/urina , Relação Dose-Resposta a Droga , Exposição Ambiental/efeitos adversos , Poluentes Ambientais/toxicidade , Feminino , Humanos , Masculino
9.
Chemistry ; 25(42): 9948-9958, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31013370

RESUMO

Herein, we report the total synthesis of traumatic lactone and rhizobialide by utilizing allenoic acid to construct the lactone ring. The key starting materials, allenoic acids, could be prepared by the ATA (allenation of terminal alkynes) of a terminal alkyne with an aldehyde that contained a protected hydroxyl group followed by hydrolysis. Importantly, the asymmetric synthesis could be realized just by replacing racemic diphenylprinol with (R)- or (S)-diphenylprinol to deliver the optically active allenoate.

10.
Food Nutr Res ; 632019.
Artigo em Inglês | MEDLINE | ID: mdl-30863273

RESUMO

Background: Dietary intake of cereal fiber has been reported to benefit lipid metabolism through multiple mechanisms. The present study aimed to discover the potential mechanisms by which cereal fiber could modify the intestinal cholesterol metabolism. Design: Male C57BL/6 mice were fed a reference chow (RC) diet; high-fat, high-cholesterol (HFC) diet; HFC plus oat fiber diet; or HFC plus wheat bran fiber diet for 24 weeks. Serum lipids were measured by enzymatic methods. Western blot was used to determine the protein expressions involved in intestinal cholesterol metabolism. Results: Our results showed that HFC-induced elevations of serum triglycerides, total cholesterol, and low-density lipoprotein cholesterol were normalized in both groups that received cereal fiber. At the protein level, compared with the HFC diet group, the two cereal fibers, especially the oat fiber, significantly increased the protein expression of peroxisome proliferator-activated receptor alpha, liver X receptor alpha, sterol regulatory element-binding protein (SREBP) 2, low-density lipoprotein receptor, adenosine triphosphate (ATP)-binding cassette A1, and ATP-binding cassette G1, while decreasing the protein expression of Niemann-Pick C1-like protein 1, SREBP-1, fatty acid synthase, and acetyl-coenzyme A carboxylase, which were involved in intestinal cholesterol metabolism. Conclusion: Taken together, increased intake of cereal fiber improved blood cholesterol profiles and increased the intestinal cholesterol efflux and cholesterol clearance in C57BL/6 mice fed a HFC diet. Oat fiber had a stronger effect than wheat bran fiber on cholesterol metabolism by modulating the PPARα, LXRα, and SREBP signaling pathways.

11.
Chem Sci ; 10(7): 2228-2235, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30881648

RESUMO

A palladium-catalyzed highly regio- and chemo-selective cyclization of 2,7-alkadiynylic carbonates with functionalized alkynes to construct 1,3-dihydroisobenzofuran and isoindoline derivatives under mild conditions has been developed. Functional groups such as alcohol, sulfonamide, and indoles could be well tolerated. After careful mechanistic studies, a mechanism involving oxidative addition and regioselectivity-defined double alkyne insertions has been proposed.

12.
Org Lett ; 21(10): 3523-3527, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-30916977

RESUMO

A palladium-catalyzed highly regioselective and chemoselective intermolecular cyclization of 2,7-alkadiynylic carbonates with terminal propargyl tertiary alcohols to construct benzopolycycles containing furan and pyrrole moieties has been developed with a very broad scope. Polycycles containing spirane structures or dispirane structures could be also smoothly synthesized in moderate to good yields. The reaction enjoys excellent regioselectivity.

13.
Nat Commun ; 10(1): 507, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30705274

RESUMO

Metal-catalyzed enantioselective construction of the loosening axial allene chirality spreading over three carbon atoms using a chiral ligand is still a significant challenge. In the literature, steric effect of the substrates is the major strategy applied for such a purpose. Herein, we present a general palladium-catalyzed asymmetrization of readily available racemic 2,3-allenylic carbonates with different types of non-substituted and 2-substituted malonates using (R)-(-)-DTBM-SEGPHOS as the preferred ligand to afford 1,3-disubstituted chiral allenes with 90~96% ee. This protocol has been applied to the first enantioselective synthesis of natural product, (R)-traumatic lactone. Control experiments showed that in addition to the chiral ligand, conducting this transformation via Procedure C, which excludes the extensive prior coordination of the allene unit in the starting allene with Pd forming a species without the influence of the chiral ligand, is crucial for the observed high enantioselectivity.

15.
Cell Physiol Biochem ; 50(6): 2314-2328, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30423551

RESUMO

BACKGROUND/AIMS: Chronic Lymphocytic leukemia (CLL) is characterized by accumulation of cells in the G0/G1 phase of the cell cycle and resistance to apoptosis due to gene mutation or abnormal gene expression. In our previous study, constitutively photomorphogenic 1 (COP1) was shown to be upregulated in Binet C-phase CLL patients. Based on the negative regulation of COP1 in the repair of DNA damage, we further studied the function of COP1 in CLL cell apoptosis induced by fludarabine in vitro and in vivo. METHODS: We analyzed the sensitivity of primary CLL cells to the fludarabine by CCK-8, and detected the expression of p53 in cells after drug treatment by western blot. Next, we constructed COP1 overexrpessing CLL cell line HG3, and analyzed the effect of COP1 overexpression on the HG3 cell's apoptosis, and HG3 transplant mice survival with drug treatment. RESULTS: Here, we found that primary CLL cells with high expression of COP1 showed low sensitivity to the drug and presented delayed enrichment of p53 protein than cells with low COP1 expressed. COP1 overexpression reduced HG3 cell sensitivity to the fludarabine treatment and inhibited cell apoptosis, and also retarded itself via autoubiquitination. The further study showed that COP1 promoted ubiquitin-dependent p53 degradation, which further disrupts the formation of the p53-Brn-3a complex and activation of Bcl-2 transcription. Moreover, mice engrafted with cells overexpressing COP1 showed a shortened survival, increased tumor cells burden in spleen and bone marrow (BM), and reduced tumor cell apoptosis even when fludarabine combined cyclophosphamide (F+C) therapy was administered. CONCLUSION: This study demonstrates that COP1 contributes to drug resistance of CLL cells to the fludarabine treatment in vitro and in vivo.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Leucemia Linfocítica Crônica de Células B/patologia , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Vidarabina/análogos & derivados , Animais , Antineoplásicos/uso terapêutico , Medula Óssea/patologia , Linhagem Celular Tumoral , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Camundongos , Camundongos Endogâmicos NOD , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Baço/patologia , Taxa de Sobrevida , Fator de Transcrição Brn-3A/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Vidarabina/farmacologia , Vidarabina/uso terapêutico
16.
Nanoscale ; 10(25): 11750-11759, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29923583

RESUMO

Magnetoelectric multiferroic fluids composed of BaTiO3@CoFe2O4 composite nanoparticles dispersed in a highly insulating nonpolar oleic acid/silicone oil mixture have been developed. The effects of the particle volume fraction and a magnetic field, as well as an electric field, on the ferroelectric and magnetic properties, as well as the magnetoelectric coupling effect, have been systematically studied and discussed in this paper. Magnetic characterization shows an approximation to superparamagnetism, and both the remanent magnetization (Mr) and the coercive field (Hc) increase with increases in the volume fraction and applied electric field. Similarly, a superparaelectric state has been observed in the multiferroic fluids, in which both the remanent polarization (Pr) and the coercive field (Ec) are near zero, whereas they increase with increases in the applied magnetic field and volume fraction. High converse and direct magnetoelectric coupling coefficients are estimated to be αH = 8.16 × 10-4 (Oe cm) V-1 and αE = 1.58 × 104 V (cm Oe)-1, respectively. Further analysis indicates that the composite particles can be aligned under an external magnetic/electric field so that their magnetic/electric moments can be parallel to the external field, which in turn results in changes in the magnetization/polarization directions. These results imply that besides magnetoelectric fluids that consist of core/shell-structured nanoparticles, conventional multiferroic fluids based on composite particles may provide an opportunity to gain electrical control of magnetization and vice versa, which implies potential applications.

17.
Org Lett ; 20(10): 2831-2834, 2018 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-29745672

RESUMO

Rhodium-catalyzed green synthesis of isoindolin-1-ones via a sequential C-H activation/allene formation/cyclization pathway by applying water as solvent is reported. The reaction is highly regioselective, tolerating some potentially useful functional groups.

18.
Nat Commun ; 9(1): 1654, 2018 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-29695784

RESUMO

γ-(E)-Vinylic and γ-alkylic γ-butyrolactones are two different types of lactones existing extensively in animals and plants and many of them show interesting biological activities. Nature makes alkylic γ-butyrolactones by many different enzymatic lactonization processes. Scientists have been mimicking the natural strategy by developing new catalysts. However, direct and efficient access to γ-(E)-vinylic γ-butyrolactones is still extremely limited. Here, we wish to present our modular allene approach, which provides an efficient asymmetric approach to (E)-vinylic γ-butyrolactones from allenoic acids by identifying a new gold complex as the catalyst. Based on this cycloisomerization strategy, the first syntheses of racemic xestospongiene and xestospongienes E, F, G, and H have been realized and the absolute configurations of the chiral centers in xestospongienes E and F have been revised. In addition, by applying a C-O bond cleavage-free hydrogenation, the syntheses of naturally occurring γ-alkylic γ-lactones, (R)-4-tetradecalactone, (S)-4-tetradecalactone, (R)-γ-palmitolactone, and (R)-4-decalactone, have also been achieved.

19.
Leukemia ; 32(7): 1587-1597, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29467488

RESUMO

Deregulation of key regulators of histone modification is important in the initiation and progression of human leukemia. Acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) participates in histone acetylation and its role in acute myeloid leukemia remains unclear. Here we observed significant upregulation of ANP32A in primary AML cells, which was essential for AML cell proliferation, survival, and colony formation. Integrative analysis of the genome-wide histone H3 acetylation and gene expression demonstrated that ANP32A deficiency reduced histone H3 acetylation, in accordance with changes in gene expression. Notably, significant histone H3 acetylation enrichment was associated with mRNA changes in lipid-related genes, including APOC1, PCSK9, P2RX1, and LPPR3. Indeed, over-expression of APOC1 partially compensated the proliferation-defect phenotype in ANP32A deficient AML cells while APOC1 knockdown alone mimicked the effect of ANP32A deficiency. Collectively, our data indicate that ANP32A is a novel regulator of histone H3 acetylation and promotes leukemogenesis.


Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Histonas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Acetilação , Animais , Apolipoproteína C-I/metabolismo , Apoptose , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/genética , Regulação Leucêmica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Metabolismo dos Lipídeos/genética , Camundongos , RNA Mensageiro/genética , Proteínas de Ligação a RNA , Ensaio Tumoral de Célula-Tronco
20.
Exp Hematol ; 60: 63-72, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29305109

RESUMO

Multiple myeloma (MM) is an extremely serious plasma cell malignancy. Despite the recent introduction of chemotherapies such as bortezomib and lenalidomide, it remains an incurable disease due to the high rate of relapse and the development of drug resistance. Epigenetic regulation is closely related to MM progression, but the epigenetic modification mechanism of MM cell apoptosis has remained unclear. As a novel histone deacetylase inhibitor (HDACi), Scriptaid's possible roles in MM progression have not been explored. Herein, we found that Scriptaid decreased several human MM cell viabilities in a dose-dependent manner. Scriptaid was also able to dose dependently and significantly induce MM cell cycle arrest at the G2/M phase. Moreover, Scriptaid facilitates p21 transcriptional activities by mediating H3Ac gene-activated modification, eventually leading to MM cell apoptosis. Overall, our results show that Scriptaid is an inducer of MM cell death, suggesting the possibility for Scriptaid-mediated therapeutics to cure refractory/relapsed MM.


Assuntos
Apoptose/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Epigênese Genética/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hidroxilaminas/farmacologia , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Quinolinas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/genética , Células HEK293 , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia
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