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1.
Int Immunopharmacol ; 80: 106182, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31981962

RESUMO

We previously reported that penta-acetyl geniposide ((Ac)5GP, an acetylated derivative of geniposide) exhibited better pharmacological functions than geniposide, a major active component of Gardenia jasminoides Ellis. This study demonstrated the antidepressant-like effects of (Ac)5GP and its involved mechanisms using a rat depression model caused by chronic unpredictable mild stress (CUMS). Behavioral tests including sucrose preference, open field and forced swimming were applied to evaluate depression symptoms. IL-1ß, IL-6 and TNF-α mRNA and protein levels in prefrontal cortex (PFC) were respectively measured by quantitative PCR and ELISA. The protein levels of IκBα, p-IκBα, NF-κB p65, NLRP3, pro- and mature-IL-1ß in PFC were determined by western blot. The activity of hypothalamic-pituitaryadrenal (HPA) axis was also measured. (Ac)5GP treatment alleviated the CUMS-induced depressive-like behaviors in rats, as indicated by increased sucrose intake, increased total crossing and rearing numbers, improved central activity and reduced immobility time. (Ac)5GP reversed the CUMS-induced elevations of IL-1ß, IL-6 and TNF-α mRNA and protein levels in PFC. (Ac)5GP reduced degradation and phosphorylation of IκBα and protein level of nuclear NF-κB p65 in PFC. (Ac)5GP also decreased the mRNA and protein levels of NLRP3 and reduced the ratio of mature-IL-1ß protein over total IL-1ß protein (pro-IL-1ß + mature-IL-1ß) in PFC. Moreover, (Ac)5GP reduced serum levels of adrenocorticotropic hormone/corticosterone and mRNA level of hypothalamic corticotrophin-releasing hormone. In conclusion, (Ac)5GP treatment improved the depressive-like behaviors in CUMS rats perhaps by suppressing neuroinflammation in PFC and inhibiting activations of NF-κB and NLRP3 and also attenuating HPA axis hyperactivity.

2.
Front Physiol ; 10: 1282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31680999

RESUMO

The immunological interaction between Drosophila melanogaster and its larval parasitoids has been thoroughly investigated, however, little is known about the interaction between the host and its pupal parasitoids. Pachycrepoideus vindemmiae, a pupal ectoparasitoid of D. melanogaster, injects venom into its host while laying eggs on the puparium, which regulates host immunity and interrupts host development. To resist the invasion of parasitic wasps, various immune defense strategies have been developed in their hosts as a consequence of co-evolution. In this study, we mainly focused on the host immunomodulation by P. vindemmiae and thoroughly investigated cellular and humoral immune response, including cell adherence, cell viability, hemolymph melanization and the Toll, Imd, and JAK/STAT immune pathways. Our results indicated that venom had a significant inhibitory effect on lamellocyte adherence and induced plasmatocyte cell death. Venom injection and in vitro incubation strongly inhibited hemolymph melanization. More in-depth investigation revealed that the Toll and Imd immune pathways were immediately activated upon parasitization, followed by the JAK/STAT pathway, which was activated within the first 24 h post-parasitism. These regulatory effects were further validated by qPCR. Our present study manifested that P. vindemmiae regulated the cellular and humoral immune system of host D. melanogaster in many aspects. These findings lay the groundwork for studying the immunological interaction between D. melanogaster and its pupal parasitoid.

3.
Aging (Albany NY) ; 11(15): 5705-5725, 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31400752

RESUMO

Accumulating evidence reveals the principal role of long noncoding RNAs in the progression of clear cell renal cell carcinoma (ccRCC). However, little is known about the underlying mechanism of ADAM metallopeptidase with thrombospondin type 1 motif, 9 antisense RNA 2 (ADAMTS9-AS2) in ccRCC. Here, bioinformatics analyses verified ADAMTS9-AS2 is a long noncoding RNA and its high expression was associated with better prognosis of ccRCC. ADAMTS9-AS2 was clearly downregulated in ccRCC clinical samples and cell lines. Clinical data showed low-expressed ADAMTS9-AS2 was correlated with worse overall survival in ccRCC patients. Next, miR-27a-3p was identified as an inhibitory target of ADAMTS9-AS2 by dual-luciferase reporter and RNA immunoprecipitation assays. Both overexpressed ADAMTS9-AS2 and underexpressed miR-27a-3p in ccRCC cell lines led to the inhibition of cell proliferation and the reduction of chemoresistance. Additionally, Forkhead Box Protein O1 (FOXO1) was confirmed as the inhibitory target of miR-27a-3p. Induced by ADAMTS9-AS2 overexpression, cell proliferation and chemoresistance exhibited an obvious reduction, FOXO1 expression showed an evident increase, but all were reversed after miR-27a-3p was simultaneously overexpressed. Collectively, these results suggest ADAMTS9-AS2 inhibits the progression and impairs the chemoresistance of ccRCC via miR-27a-3p-mediated regulation of FOXO1 and may serve as a prognostic biomarker and therapeutic target for ccRCC.

4.
Clin Sci (Lond) ; 133(14): 1609-1627, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31315969

RESUMO

Acute kidney injury (AKI) is a destructive clinical condition induced by multiple insults including ischemic reperfusion, nephrotoxic drugs and sepsis. It is characterized by a sudden decline in renal function, in addition to excessive inflammation, oxidative stress and programmed cell death of renal tubular epithelial cells. RIPK1-mediated necroptosis plays an important role in AKI. In the present study, we evaluated the treatment effects of Compound-71 (Cpd-71), a novel RIPK1 inhibitor, by comparing with Necrostatin-1 (Nec-1), a classic RIPK1 inhibitor, which has several drawbacks like the narrow structure-activity relationship (SAR) profile, moderate potency and non-ideal pharmacokinetic properties, in vivo and in vitro Our results showed that pretreatment of Cpd-71 attenuated cisplatin-induced renal injury, restored renal function and suppressed renal inflammation, oxidative stress and cell necroptosis. In addition, Cpd-71 inhibited renal damage while reducing the up-regulated serum creatinine (Cr) and blood urea nitrogen (BUN) levels in established AKI mice model. Consistently, we confirmed that Cpd-71 exhibited more effectively suppressive effect on cisplatin-induced renal tubular cell necroptosis than Nec-1, by physically binding to the allosteric type III ligand binding site of RIPK1, thereby reduced RIPK1 kinase activity, RIPK1/RIPK3 complex formation and phosphor-MLKL membrane translocation by molecular docking, Western blot, co-immunoprecipitation and cellular thermal shift assay (CETSA). Taken together, we currently showed that targeting RIPK1 with Cpd-71 may serve as a promising clinical candidate for AKI treatment.

5.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340456

RESUMO

The plant-specific Teosinte-branched 1/Cycloidea/Proliferating (TCP) transcription factor genes are involved in plants' development, hormonal pathways, and stress response but their evolutionary history is uncertain. The genome-wide analysis performed here for 47 plant species revealed 535 TCP candidates in terrestrial plants and none in aquatic plants, and that TCP family genes originated early in the history of land plants. Phylogenetic analysis divided the candidate genes into Classes I and II, and Class II was further divided into CYCLOIDEA (CYC) and CINCINNATA (CIN) clades; CYC is more recent and originated from CIN in angiosperms. Protein architecture, intron pattern, and sequence characteristics were conserved in each class or clade supporting this classification. The two classes significantly expanded through whole-genome duplication during evolution. Expression analysis revealed the conserved expression of TCP genes from lower to higher plants. The expression patterns of Class I and CIN genes in different stages of the same tissue revealed their function in plant development and their opposite effects in the same biological process. Interaction network analysis showed that TCP proteins tend to form protein complexes, and their interaction networks were conserved during evolution. These results contribute to further functional studies on TCP family genes.


Assuntos
Proteínas de Arabidopsis/genética , Embriófitas/genética , Regulação da Expressão Gênica de Plantas , Magnoliopsida/genética , Filogenia , Fatores de Transcrição/genética , Transcrição Genética , Sequência de Aminoácidos , Proteínas de Arabidopsis/classificação , Proteínas de Arabidopsis/metabolismo , Evolução Biológica , Sequência Conservada , Embriófitas/classificação , Embriófitas/metabolismo , Éxons , Redes Reguladoras de Genes , Íntrons , Magnoliopsida/classificação , Magnoliopsida/metabolismo , Família Multigênica , Mapeamento de Interação de Proteínas , Isoformas de Proteínas/classificação , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Alinhamento de Sequência , Fatores de Transcrição/classificação , Fatores de Transcrição/metabolismo
6.
Med Res Rev ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31361345

RESUMO

Telomere and telomerase play important roles in abnormal cell proliferation, metastasis, stem cell maintenance, and immortalization in various cancers. Therefore, designing of drugs targeting telomerase and telomere is of great significance. Over the past two decades, considerable knowledge regarding telomere and telomerase has been accumulated, which provides theoretical support for the design of therapeutic strategies such as telomere elongation. Therefore, the development of telomere-based therapies such as nucleoside analogs, non-nucleoside small molecules, antisense technology, ribozymes, and dominant negative human telomerase reverse transcriptase are being prioritized for eradicating a majority of tumors. While the benefits of telomere-based therapies are obvious, there is a need to address the limitations of various therapeutic strategies to improve the possibility of clinical applications. In this study, current knowledge of telomere and telomerase is discussed, and therapeutic strategies based on recent research are reviewed.

7.
J Enzyme Inhib Med Chem ; 34(1): 1121-1130, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31117832

RESUMO

Four series of total 35 new pyrazolo[4,3-d]pyrimidine compounds were designed, synthesized and evaluated for their inhibitory activity against LPS-induced NO production in RAW264.7 macrophages. Among them, compound 4e was found to be the most potent inhibitor, which decreased the production of cytokines in vitro, such as NO, IL-6 and TNF-α, with IC50 values of 2.64, 4.38 and 5.63 µM, respectively. Further studies showed that compound 4e inhibited cytokines secretion of macrophages through suppressing TLR4/p38 signaling pathway. Additionally, compound 4e showed in vivo anti-inflammatory activity in LPS-induced model of acute lung injury. These data suggested that compound 4e may be a promising lead structure for the treatment of ALI.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Desenho de Drogas , Pirazóis/farmacologia , Pirimidinas/farmacologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
8.
Pathol Res Pract ; 215(6): 152406, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30967300

RESUMO

BACKGROUND: Cyclin-dependent kinase 8 (CDK8) as a Mediator complex-associated transcriptional regulator has been shown to play important role in the initiation and progression of various cancers. The present study aimed to explore miR-152-3p-modulated post-transcriptional repression of CDK8 in hepatic carcinogenesis. METHODS: Eighty-nine pairs of hepatocellular carcinoma (HCC) and adjacent non-tumor tissues were collected for molecular biological analysis. Cell viability and apoptosis assays were detected using CCK8 and Annexin V-fluorescein isothiocyanate/propidium iodide (Annexinv-FITC) double staining, respectively. Bioinformatics algorithms and luciferase reporter assay were performed to validate CDK8 as a direct target of miR-152-3p. Gene and protein expression levels were monitored using RT-qPCR, western blotting or immunohistochemical (IHC) staining. RESULTS: CDK8 expression levels were up-regulated and miR-152-3p was down-regulated in HCC tissues. The correlation analysis had documented a significant negative correlation between miR-152-3p and CDK8 in the HCC tissues. Both CDK8 and miR-152-3p could serve as the independent prognostic factors for predicting the OS and DFS in HCC patients. Bioinformatics and experimental measurement revealed that CDK8 was a direct target of miR-152-3p. After co-transfection with the miR-152-3p mimics and the CDK8 overexpressed plasmids, the anti-proliferative and pro-apoptotic roles of miR-152-3p were restricted by CDK8. CONCLUSION: The present results obtained forcefully proved that miR-152-3p exhibited an antineoplastic activity via targeting CDK8 and might be served as a potential therapeutic target for the treatment of HCC.


Assuntos
Carcinogênese/genética , Carcinoma Hepatocelular/genética , Quinase 8 Dependente de Ciclina/biossíntese , Neoplasias Hepáticas/genética , MicroRNAs/genética , Adulto , Idoso , Carcinoma Hepatocelular/patologia , Quinase 8 Dependente de Ciclina/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade
9.
J Med Chem ; 62(8): 4013-4031, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-30925056

RESUMO

In order to discover novel anti-inflammatory agents for treatment of arthritis and based on preliminary structure-activity relationships, four series (A-D) of total 90 new pyrazolo[4,3- d]pyrimidine compounds were designed and synthesized. All the compounds have been tested for their anti-inflammatory activities by inhibiting of LPS-induced NO production. A clear structure-activity relationship has been concluded step by step, and finally 3,4,5-trimethoxystyryl-1 H-pyrazolo[4,3- d]pyrimidine was found to be the most active scaffold. Among them, compound D27 was discovered as the most potent anti-inflammatory agent (IC50 = 3.17 µM) with low toxicity and strong inhibitory of NO release (IR = 90.4% at 10 µM). This compound also showed potent inhibition of iNOS with IC50 value of 1.12 µM. Preliminary mechanism studies indicated that it could interfere with the stability and formation of active dimeric iNOS. The anti-inflammatory effect of this compound was determined by adjuvant-induced arthritis in rat model. We believe these findings would further support the study of rational design of more efficient iNOS inhibitors in the future.

10.
Neuropathology ; 39(3): 181-186, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30919512

RESUMO

The blood-spinal cord barrier (BSCB) changes badly after spinal cord injury (SCI), and it is an important pathophysiological basis of SCI secondary damage. Aquaporin-4 (AQP4), one of the transmembrane proteins in spinal cord, has been shown to be closely related to the development of the BSCB and edema. We established a SCI model in rats using a free-falling weight drop device to subsequently investigate AQP4 expression. AQP4 messenger RNA (mRNA) and protein expression and immunoreactivity were detected in spinal cord tissue using reverse transcription-real-time quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry and Western blot analysis. We found the water content and edema of the spinal cord were significantly higher than the control group after SCI, which was related to the growth of BSCB permeability; both reached their peak on the third day after injury. One, 3, 5, 7 days after injury, the immune response and protein expression in the model group increased from 1 to 3 days, with a plateau period from 3 to 5 days and a decline from 5 to 7 days, showing a significant difference compared with the sham group at each time point (P < 0.05), while the RT-qPCR results showed a decline of mRNA just after 3 days. In conclusion, after SCI, the water content of the spinal cord and the BSCB permeability increases, together with the excessive expression of AQP4, which reached a peak on the third day. AQP4 expression is closely relative to the permeability of BSCB and the water content of the spinal cord.


Assuntos
Aquaporina 4/biossíntese , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Animais , Aquaporina 4/genética , Barreira Hematoencefálica/patologia , Encéfalo/patologia , Permeabilidade Capilar/fisiologia , Feminino , Expressão Gênica , Ratos , Ratos Sprague-Dawley , Medula Espinal/patologia , Traumatismos da Medula Espinal/patologia
11.
Int J Mol Sci ; 19(11)2018 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-30400610

RESUMO

The plant-specific WUSCHEL-related homeobox (WOX) transcription factor gene family is important for plant growth and development but little studied in oil crops. We identified and characterized 58 putative WOX genes in Brassica napus (BnWOXs), which were divided into three major clades and nine subclades based on the gene structure and conserved motifs. Collinearity analysis revealed that most BnWOXs were the products of allopolyploidization and segmental duplication events. Gene structure analysis indicated that introns/exons and protein motifs were conserved in each subclade and RNA sequencing revealed that BnWOXs had narrow expression profiles in major tissues and/or organs across different developmental stages. The expression pattern of each clade was highly conserved and similar to that of the sister and orthologous pairs from Brassica rapa and Brassica oleracea. Quantitative real-time polymerase chain reaction showed that members of the WOX4 subclade were induced in seedling roots by abiotic and hormone stresses, indicating their contribution to root development and abiotic stress responses. 463 proteins were predicted to interact with BnWOXs, including peptides regulating stem cell homeostasis in meristems. This study provides insights into the evolution and expression of the WOX gene family in B. napus and will be useful in future gene function research.


Assuntos
Brassica napus/genética , Genes de Plantas , Família Multigênica , Reguladores de Crescimento de Planta/farmacologia , Estresse Fisiológico/genética , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Cromossomos de Plantas/genética , Sequência Conservada/genética , Meio Ambiente , Duplicação Gênica , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Íntrons/genética , Motivos de Nucleotídeos/genética , Filogenia , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Mapas de Interação de Proteínas/genética , Estresse Fisiológico/efeitos dos fármacos , Fatores de Transcrição/química , Fatores de Transcrição/genética
12.
Inflammation ; 41(6): 2184-2195, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30069664

RESUMO

Previous studies demonstrated that penta-acetyl geniposide ((Ac)5GP, an acetylated derivative of geniposide) exhibited better pharmacological functions than geniposide. This study was aimed to observe the potential effect of (Ac)5GP on adjuvant-induced arthritis (AIA) in rat and explore the involved mechanisms. Rat AIA was induced by complete Freund's adjuvant. (Ac)5GP (30, 60, 120 mg/kg) was given to AIA rats by intragastric administration. Paw swelling, polyarthritis index, serum pro-inflammatory cytokines levels, histological assessments of ankle joint, and proteoglycan expression were respectively measured to evaluate the therapeutic effect of (Ac)5GP on rat AIA. Immunohistochemistry for Ki67 and TUNEL assay were performed to reveal the anti-proliferative and pro-apoptotic effects of (Ac)5GP on AIA synoviocytes in vivo. Protein levels of Bcl-2, Bax, caspase 3, IκBα, p-IκBα, and NF-κB p65 in synovial tissues were detected by Western blot. We found that (Ac)5GP treatment could suppress secondary hind paw swelling, reduce polyarthritis index, decrease TNF-α and IL-1ß serum levels, attenuate pathological damage of ankle joint, and promote proteoglycans expression. (Ac)5GP treatment also could reduce Ki67 positive expression rate and raise the synovial apoptosis index in synovial tissues. Additionally, (Ac)5GP (120 mg/kg) could significantly decrease Bcl-2 protein level, increase Bax and cleaved caspase 3 protein levels, and normalize the ratio of Bcl-2 to Bax. Moreover, (Ac)5GP (120 mg/kg) could inhibit the degradation and phosphorylation of IκBα and reduce NF-κB p65 protein level in nuclear extracts. In conclusion, (Ac)5GP showed a potent anti-arthritic effect on AIA rats via inducing synovial apoptosis and inhibiting NF-κB activation in synovial tissues.


Assuntos
Apoptose/efeitos dos fármacos , Artrite Experimental/tratamento farmacológico , Glucosídeos Iridoides/uso terapêutico , NF-kappa B/antagonistas & inibidores , Membrana Sinovial/patologia , Animais , Glucosídeos Iridoides/farmacologia , Inibidor de NF-kappaB alfa/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/química , Fator de Transcrição RelA/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo
13.
Can J Physiol Pharmacol ; 96(11): 1104-1111, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30067070

RESUMO

Because the excessive apoptosis of articular chondrocytes contributes to extracellular matrix (ECM) loss and cartilage damage in rheumatoid arthritis (RA), inhibiting chondrocyte apoptosis might be a promising strategy for RA. Aquaporin1 (AQP1) is overexpressed in RA cartilage and synovial tissues, and play a vital pathogenic role in RA development. Particularly, we previously reported that acetazolamide (AZ) as an AQP1 inhibitor suppressed secondary inflammation and promoted ECM production in cartilage of adjuvant-induced arthritis rats. Here, we investigated the antiapoptotic effect of AZ on interleukin-1ß (IL-1ß)-induced apoptosis, a classic in vitro model of chondrocyte apoptosis. AZ treatment could inhibit IL-1ß-induced apoptosis, evidenced by increasing cell viability, relieving apoptotic nuclear morphology, decreasing apoptosis rates, and restoring mitochondrial membrane potential. Additionally, AZ reversed IL-1ß-induced decrease of Bcl-2 protein and reduced IL-1ß-induced increases of Bax and caspase 3 protein, accompanied by inhibiting IκBα degradation and phosphorylation in cytoplasm, reducing NF-κB p65 protein level in nucleus and preventing NF-κB p65 translocation from cytoplasm to nucleus. In conclusion, our findings indicated that AZ could effectively attenuate IL-1ß-induced chondrocyte apoptosis mediated by regulating the protein levels of apoptosis-related genes and inhibiting the activation of NF-κB signal pathway, suggesting that AZ might be of potential clinical interest in RA treatment.


Assuntos
Acetazolamida/farmacologia , Apoptose/efeitos dos fármacos , Inibidores da Anidrase Carbônica/farmacologia , Condrócitos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Cartilagem Articular/citologia , Células Cultivadas , Condrócitos/metabolismo , Interleucina-1beta/metabolismo , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Fator de Transcrição RelA/metabolismo
14.
Lab Invest ; 98(7): 911-923, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29581579

RESUMO

E-cadherin is a major component of tubular adherent proteins that maintain intercellular contacts and cell polarity in epithelial tissue. It is involved in pathological processes of renal cell carcinoma and fibrotic diseases via epithelial-mesenchymal transition. Although studies have shown E-cadherin is significantly downregulated in acute kidney injury (AKI), its function in AKI is unknown. Here, we evaluated cell damage and inflammation in cisplatin-stimulated tubular epithelial cell lines after disrupting E-cadherin and restoring it with PPBICA, a small molecule identified by high-throughput screening. We also determined the therapeutic potential of restoring E-cadherin in vivo. Results show cisplatin reduced E-cadherin expression both in mouse kidney and proximal tubular epithelial cell lines (mTECs). PPBICA restored E-cadherin levels, which increased cell viability while attenuating programmed cell death. This may be mediated via deactivation of the RIPK1/RIPK3 axis and decreased caspase3 cleavage. In addition, PPBICA suppressed inflammatory response in cisplatin-treated mTECs, which correlated with suppressed NF-κB phosphorylation and promoter activity. In contrast, disruption of E-cadherin promoted cell damage and inflammation. PPBICA failed to further attenuate kidney damage in E-cadherin knockdown cells, indicating that PPBICA protects against mTECs through E-cadherin restoration. We also found that peritoneal injection of PPBICA in mice prevented loss of renal function and tubular damage by suppressing NF-κB-driven renal inflammation and RIPK-regulated programmed cell death. This was driven by restoration of E-cadherin in cisplatin nephropathy. Additionally, PPBICA attenuated cisplatin-induced kidney damage in an established AKI model, indicating its therapeutic potential in the treatment of AKI. In conclusion, E-cadherin plays functional roles in tubule integrity, programmed cell death, and renal inflammation. Our results underscore the potential of E-cadherin restoration as a novel therapeutic strategy for AKI.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Caderinas/metabolismo , Cisplatino/efeitos adversos , Substâncias Protetoras/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Inflamação/metabolismo , Rim/citologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
Phys Rev Lett ; 120(4): 043201, 2018 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-29437408

RESUMO

We perform a joint experimental and theoretical study on momentum- and energy-resolved photoelectron spin polarization in multiphoton ionization of Xe atoms by circularly polarized fields. We experimentally measure the photoelectron momentum distributions of Xe atoms in circularly polarized near-infrared (800 nm) and ultraviolet (400 nm) light, respectively. We analyze the momentum- and energy-resolved photoelectron spin polarization by comparing the experimental photoelectron momentum distributions with the simulations, although we cannot derive the spin polarization solely from the experiment. We show that the use of circularly polarized ultraviolet light at 400 nm can create better than 90% spin polarization with focal volume effect considered, which enables the separation of the spin states by momentum gating. This paves the way to produce high-degree spin-polarized electron sources from strong-field multiphoton ionization.

16.
Bioorg Med Chem ; 25(24): 6623-6634, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29126741

RESUMO

A series of novel hydantoin-bridged analogues of combretastatin A-4 (CA-4) were designed, synthesized and evaluated for antiproliferative activities in vitro and in vivo. The most potent compound 8d, showed potent cytotoxicity against four human cancer cell lines with IC50 values of 0.186-0.279 µM, and possessed the efficacy of inhibiting tubulin polymerization, disrupting in vitro vascularization, blocking cell cycle in G2/M phase and inducing cell apoptosis. In the nude mice xenograft model, 8d significantly inhibited the tumor growth and showed low toxicity. Further chiral separation proved (R)-(-)-8d to be the preferential enantiomer with IC50 values of 0.081-0.157 M. These results indicated that the hydantoin derivatives merit further investigation as potential anticancer agents that inhibit tubulin polymerization.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Hidantoínas/farmacologia , Estilbenos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HeLa , Humanos , Hidantoínas/síntese química , Hidantoínas/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Estilbenos/química , Relação Estrutura-Atividade
17.
Phys Rev Lett ; 119(7): 073201, 2017 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-28949683

RESUMO

We measure photoelectron momentum distributions of Ar atoms in orthogonally polarized two-color laser fields with comparable intensities. The synthesized laser field is used to manipulate the oscillating tunneling barrier and the subsequent motion of electrons onto two spatial dimensions. The subcycle structures associated with the temporal double-slit interference are spatially separated and enhanced. We use such a spatiotemporal interferometer to reveal sub-barrier phase of strong-field tunneling ionization. This study shows that the tunneling process transfers the initial phase onto momentum distribution. Our work has the implication that the sub-barrier phase plays an indispensable role in photoelectron interference processes.

18.
PLoS One ; 11(12): e0169230, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28036386

RESUMO

PURPOSE: Gemcitabine-based chemotherapy remains one of the standards in management of metastatic breast cancer. However, intrinsic and acquired resistance to gemcitabine inevitably occurs. The aims of this study were to assess the efficacy of the combination of src inhibition and gemcitabine in gemcitabine-resistant breast cancer cells. METHODS AND RESULTS: By using colony formation, sphere forming, flow cytometry, cell counting kit-8 and transwell assays, 231/GEM-res (gemcitabine-resistant) cell line, which was 10 times more resistant, was shown to have elevated drug tolerance, enhanced proliferative and self-renewal abilities, compared with its parental cells. Inhibition of src by both saracatinib (AZD0530) and siRNA could partially reverse gemcitabine resistance and attenuate resistance-associated anti-apoptosis, migration and stem cell capacities. In addition, the combination of src inhibition and gemcitabine had synergistic antitumor effects. Western blot analysis revealed up-regulation of pro-apoptotic protein BAX, along with the down-regulation of anti-apoptotic proteins (BCL-XL, Survivin), migration associated proteins (p-FAK, MMP-3) and cancer stem cell (CSC) markers (CD44, Oct-4), which was probably mediated by AKT/c-Jun pathway. CONCLUSION: In highly gemcitabine-resistant 231 cells, src inhibition can synergize with gemcitabine, reverse drug resistance, inhibit tumor growth/metastasis/stemness of cancer stem cells, possibly via the AKT/c-Jun pathway.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Benzodioxóis/farmacologia , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores Enzimáticos/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinazolinas/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Quinases da Família src/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Feminino , Quinase 1 de Adesão Focal/biossíntese , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Hialuronatos/biossíntese , Proteínas Inibidoras de Apoptose/biossíntese , Metaloproteinase 3 da Matriz/biossíntese , Fator 3 de Transcrição de Octâmero/biossíntese , Interferência de RNA , RNA Interferente Pequeno/genética , Survivina , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas , Proteína X Associada a bcl-2/biossíntese , Proteína bcl-X/biossíntese , Quinases da Família src/genética
19.
Ren Fail ; 38(9): 1320-1327, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27498976

RESUMO

OBJECTIVE: This study aimed to systematically evaluate the effect of an angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism on type 1 diabetic nephropathy (DN). METHODS: Cochrane Library, Embase, PubMed, Science Direct, Web of science, Wanfang data, VIP database, China Knowledge Resource Integrated Database, and SinoMed were searched. A total of 17 case-control studies analyzing ACE I/D polymorphism and type 1 DN risk were included in the present meta-analysis. RESULTS: Overall, a significant increased risk was found in allele comparison (OR = 1.16, 95% CI = 1.05-1.28, p = 0.04), dominant comparison (OR = 1.56, 95% CI = 1.14-2.15, p = 0.006) and homozygote comparison (OR = 1.52, 95% CI = 1.06-2.19, p = 0.02). In subgroup analyses according to ethnicity, the risk of type 1 DN in Asian population was increased in allele comparison (OR = 1.98, 95% CI = 1.15-3.42, p = 0.01), recessive comparison (OR = 2.48, 95% CI = 1.51-4.10, p = 0.0004), dominant comparison (OR = 3.15, 95% CI = 1.90-5.23, p < 0.00001), and homozygote comparison (OR = 2.87, 95% CI = 1.02-8.06, p = 0.05). However, there was no association between the ACE I/D genetic variants and type 1 DN in Caucasian populations. CONCLUSIONS: Our meta-analysis results indicate that the ACE I/D polymorphism may contribute to type 1 DN development, especially in the Asian groups with type 1 diabetes. The current findings need to be confirmed by future well-designed and larger sample size primary studies in populations with different ethnicities.


Assuntos
DNA/genética , Diabetes Mellitus Tipo 1/genética , Nefropatias Diabéticas/genética , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Alelos , Diabetes Mellitus Tipo 1/metabolismo , Nefropatias Diabéticas/metabolismo , Frequência do Gene , Humanos , Peptidil Dipeptidase A/metabolismo
20.
Int J Biol Macromol ; 91: 1199-205, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27370747

RESUMO

A homogeneous polysaccharide (PPB) was purified from fruiting bodies of Phellinus baumii. And in vitro antitumor and immunomodulation activities were investigated on HeLa, SGC-7901 and RAW264.7 cell lines. PPB inhibited the proliferation of HeLa and SGC-7901 cells significantly, and flow cytometric studies revealed that PPB could mediate the cell cycle in the G0/G1 and S phases. Furthermore, PPB could promote the growth and phagocytosis of RAW264.7 cells, activate the secretion of cytokines such as TNF-α and IL-6, which indicated that PPB had low toxicity. The results make PPB as a candidate adjuvant in cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Basidiomycota/química , Polissacarídeos Fúngicos/farmacologia , Fatores Imunológicos/farmacologia , Animais , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Polissacarídeos Fúngicos/química , Humanos , Fatores Imunológicos/química , Interleucina-6/metabolismo , Camundongos , Fagocitose/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
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