Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 57
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Cell Rep ; 36(12): 109731, 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34551290

RESUMO

TBK1 is an essential kinase for the innate immune response against viral infection. However, the key molecular mechanisms regulating the TBK1 activation remain elusive. Here, we identify PRMT1, a type I protein arginine methyltransferase, as an essential regulator of TBK1 activation. PRMT1 directly interacts with TBK1 and catalyzes asymmetric methylation of R54, R134, and R228 on TBK1. This modification enhances TBK1 oligomerization after viral infection, which subsequently promotes TBK1 phosphorylation and downstream type I interferon production. More important, myeloid-specific Prmt1 knockout mice are more susceptible to infection with DNA and RNA viruses than Prmt1fl/fl mice. Our findings reveal insights into the molecular regulation of TBK1 activation and demonstrate the essential function of protein arginine methylation in innate antiviral immunity.

2.
Cell Death Differ ; 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34584221

RESUMO

Renal fibrosis and inflammation are critical for the initiation and progression of hypertensive renal disease (HRD). However, the signaling mechanisms underlying their induction are poorly understood, and the role of tripartite motif-containing protein 31 (TRIM31), an E3 ubiquitin ligase, in HRD remains unclear. This study aimed to elucidate the role of TRIM31 in the pathogenesis of HRD, discover targets of TRIM31, and explore the underlying mechanisms. Pathological specimens of human HRD kidney were collected and an angiotensin II (AngII)-induced HRD mouse model was developed. We found that TRIM31 was markedly reduced in both human and mouse HRD renal tissues. A TRIM31-/- mice was thus constructed and showed significantly aggravated hypertension-induced renal dysfunction, fibrosis, and inflammation, following chronic AngII infusion compared with TRIM31+/+ mice. In contrast, overexpression of TRIM31 by injecting adeno-associated virus (AAV) 9 into C57BL/6J mice markedly ameliorated renal dysfunction, fibrotic and inflammatory response in AngII-induced HRD relative to AAV-control mice. Mechanistically, TRIM31 interacted with and catalyzed the K48-linked polyubiquitination of lysine 72 on Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), followed by the proteasomal degradation of MAP3K7, which further negatively regulated TGF-ß1-mediated Smad and MAPK/NF-κB signaling pathways. In conclusion, this study has demonstrated for the first time that TRIM31 serves as an important regulator in AngII-induced HRD by promoting MAP3K7 K48-linked polyubiquitination and inhibiting the TGF-ß1 signaling pathway.

3.
Autophagy ; : 1-15, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34486483

RESUMO

ABBREVIATIONS: 3-MA: 3-methyladenine; AIM2: absent in melanoma 2; ATG5: autophagy related 5; BafA1: bafilomycin A1; CASP1: caspase 1; CHX: cycloheximide; Co-IP: co-immunoprecipitation; CQ: chloroquine; DUBs: deubiquitinases; IL1B/IL-1ß: interleukin 1 beta; LAMP1: lysosomal associated membrane protein 1; LPS: lipopolysaccharide; MARCHF7/MARCH7: membrane associated RING-CH-type finger 7; NFKB/NF-κB: nuclear factor kappa B; Nig.: nigericin; NLRC4: NLR family CARD domain containing 4; NLRP3: NLR family pyrin domain containing 3; PECs: peritoneal exudate cells; PMN: polymorphonuclear; PMs: peritoneal macrophages; PYCARD/ASC: PYD and CARD domain containing; TLRs: toll like receptors; TNF/TNF-α: tumor necrosis factor; Ub: ubiquitin; USP5: ubiquitin specific peptidase 5; WT: wild type.

4.
Signal Transduct Target Ther ; 6(1): 298, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362877

RESUMO

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase, which plays an essential role in both innate and adaptive immunity. However, the key molecular mechanisms that regulate SYK activity are poorly understood. Here we identified the E3 ligase TRIM31 as a crucial regulator of SYK activation. We found that TRIM31 interacted with SYK and catalyzed K27-linked polyubiquitination at Lys375 and Lys517 of SYK. This K27-linked polyubiquitination of SYK promoted its plasma membrane translocation and binding with the C-type lectin receptors (CLRs), and also prevented the interaction with the phosphatase SHP-1. Therefore, deficiency of Trim31 in bone marrow-derived dendritic cells (BMDCs) and macrophages (BMDMs) dampened SYK-mediated signaling and inhibited the secretion of proinflammatory cytokines and chemokines against the fungal pathogen Candida albicans infection. Trim31-/- mice were also more sensitive to C. albicans systemic infection than Trim31+/+ mice and exhibited reduced Th1 and Th17 responses. Overall, our study uncovered the pivotal role of TRIM31-mediated K27-linked polyubiquitination on SYK activation and highlighted the significance of TRIM31 in anti-C. albicans immunity.

5.
J Immunol ; 207(6): 1652-1661, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34426543

RESUMO

The IκB kinase (IKK) complex plays a vital role in regulating the NF-κB activation. Aberrant NF-κB activation is involved in various inflammatory diseases. Thus, targeting IKK activation is an ideal therapeutic strategy to cure and prevent inflammatory diseases related to NF-κB activation. In a previous study, we demonstrated that IKK-interacting protein (IKIP) inhibits the phosphorylation of IKKα/ß and the activation of NF-κB through disruption of the formation of IKK complex. In this study, we identified a 15-aa peptide derived from mouse IKIP (46-60 aa of IKIP), which specifically suppressed IKK activation and NF-κB targeted gene expression via disrupting the association of IKKß and NEMO. Importantly, administration of the peptide reduced LPS-induced acute inflammation and attenuated Zymosan-induced acute arthritis in mice. These findings suggest that this IKIP peptide may be a promising therapeutic reagent in the prevention and treatment of inflammatory diseases.


Assuntos
Quinase I-kappa B/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , NF-kappa B/metabolismo , Peptídeos/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Lipopolissacarídeos/efeitos adversos , Camundongos , Camundongos Knockout , Ligação Proteica , Transdução de Sinais/genética , Zimosan/efeitos adversos
6.
Redox Biol ; 45: 102058, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34218200

RESUMO

Tripartite motif (TRIM) 31 has been implicated in diverse biological and pathological conditions. However, whether TRIM31 plays a role in ischemic stroke progression is not clarified. Here we demonstrated that TRIM31 was significantly downregulated in the ischemic brain and the deficiency of TRIM31 alleviated brain injury induced by middle cerebral artery occlusion by reducing reactive oxygen species production and maintaining mitochondrial homeostasis. Mechanistically, we found that TRIM31 is an E3 ubiquitin ligase for TP53-induced glycolysis and apoptosis regulator (TIGAR), which confers protection against brain ischemia by increasing the pentose phosphate pathway flux and preserving mitochondria function. TRIM31 interacted with TIGAR and promoted the polyubiquitination of TIGAR, consequently facilitated its degradation in a proteasome-dependent pathway. Furthermore, TIGAR knockdown effectively abolished the protective effect of TRIM31 deficiency after cerebral ischemia. In conclusion, we identified that TRIM31 was a novel E3 ubiquitin ligase for TIGAR, played a critical role in regulating its protein level, and subsequently involved in the ischemic brain injury, suggesting TRIM31 as a potential therapeutic target for ischemic stroke.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Lesões Encefálicas , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética , Animais , Apoptose , Glicólise , Masculino , Camundongos Endogâmicos C57BL , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
7.
J Phys Chem Lett ; 12(26): 6190-6196, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34189923

RESUMO

The hydration effect on the folding behavior of oligopeptides is of vital importance both in the structure basis of biomolecules and in the rational design of peptide-based materials, which however has rarely been addressed. Here we present the hydration impact on the spontaneous folding of dipeptides conjugated by the ferrocene spacer. In organic phase, the ferrocene-glycine-phenylalanine dipeptide formed a parallel ß-sheet structure and Herrick's conformation, which underwent conformational transformation encountering aqueous media, by significantly switching dipeptide arm angles around the ferrocene axis up to 72°. The conformational transformation behavior aroused inversion of the chiroptical activity. Solid X-ray structures, proton nuclear magnetic resonance, chiroptical spectroscopy, and the density functional theory calculation were employed to unveil the hydration effect in the secondary structure transition, in which the rearrangement of hydrogen bonds played the vital role. This work deepens the understanding of water functioning in the structure modulation of biomolecules and also provides an alternative protocol in designing novel chiroptical switches and adaptive peptide-based biomaterials.


Assuntos
Dipeptídeos/química , Compostos Ferrosos/química , Metalocenos/química , Fenômenos Ópticos , Água/química , Modelos Moleculares , Conformação Proteica , Dobramento de Proteína , Estereoisomerismo
8.
Adv Sci (Weinh) ; 8(15): e2100606, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34047074

RESUMO

Mitochondrial antiviral signaling (MAVS) protein is the core signaling adaptor in the RNA signaling pathway. Thus, appropriate regulation of MAVS expression is essential for antiviral immunity against RNA virus infection. However, the regulation of MAVS expression at the mRNA level especially at the post transcriptional level is not well-defined. Here, it is reported that the MAVS mRNA undergoes N6 -methyladenosine (m6 A) modification through methyltransferase-like protein 14 (METTL14), which leads to a fast turnover of MAVS mRNA. Knockdown or deficiency of METTL14 increases MAVS mRNA stability, and downstream phosphorylation of TBK1/IRF3 and interferon-ß production in response to RNA viruses. Compared to wild-type mice, heterozygotes Mettl14+/- mice better tolerate RNA virus infection. The authors' findings unveil a novel mechanism to regulate the stability of MAVS transcripts post-transcriptionally through m6 A modification.

9.
Cell Death Differ ; 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34017102

RESUMO

Protein ubiquitination plays an important role in the regulation of TGF-ß-activated kinase 1 (TAK1)-mediated NF-κB activation. It is well established that TAK1 activation is tightly regulated with its binding partners, TAK1-binding proteins (TAB1-3). However, the tight regulation of TAK1 activation remains elusive. Here, using Trim26-knockout mice and Trim26-transgenic mice, we found that TRIM26 acts as a positive regulator of TAK1 activation by ubiquitinating its binding partner TAB1. Knockout of Trim26 inhibited TAK1 activation and downstream kinases activation, thus decreasing the induction of proinflammatory cytokines following LPS, TNF-α, and IL-1ß stimulation. Mechanistically, TRIM26 catalyzes the K11-linked polyubiquitination of TAB1 at Lys294, Lys319, and Lys335 to enhance the activation of TAK1 and subsequent NF-κB and MAPK signaling. Consequently, Trim26 deficiency protects mice from LPS-induced septic shock in vivo. Moreover, Trim26 deficiency attenuates the severity of dextran sodium sulfate (DSS)-induced colitis. Thus, these finding provides a novel insight into how TAK1 activation is regulated through TRIM26-mediated ubiquitination of TAB1 and reveals the new function of TRIM26 in the regulation of the inflammatory innate immune response.

10.
Nat Commun ; 12(1): 2970, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34016972

RESUMO

Activation of MAVS, an adaptor molecule in Rig-I-like receptor (RLR) signaling, is indispensable for antiviral immunity, yet the molecular mechanisms modulating MAVS activation are not completely understood. Ubiquitination has a central function in regulating the activity of MAVS. Here, we demonstrate that a mitochondria-localized deubiquitinase USP18 specifically interacts with MAVS, promotes K63-linked polyubiquitination and subsequent aggregation of MAVS. USP18 upregulates the expression and production of type I interferon following infection with Sendai virus (SeV) or Encephalomyocarditis virus (EMCV). Mice with a deficiency of USP18 are more susceptible to RNA virus infection. USP18 functions as a scaffold protein to facilitate the re-localization of TRIM31 and enhances the interaction between TRIM31 and MAVS in mitochondria. Our results indicate that USP18 functions as a post-translational modulator of MAVS-mediated antiviral signaling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Infecções por Cardiovirus/imunologia , Infecções por Respirovirus/imunologia , Ubiquitina Tiolesterase/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/isolamento & purificação , Animais , Infecções por Cardiovirus/virologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Vírus da Encefalomiocardite/imunologia , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Imunidade Inata , Interferon Tipo I/metabolismo , Lisina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Processamento de Proteína Pós-Traducional/imunologia , Células RAW 264.7 , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Infecções por Respirovirus/virologia , Vírus Sendai/imunologia , Transdução de Sinais/imunologia , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/isolamento & purificação , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/imunologia
11.
J Immunol ; 206(8): 1832-1843, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33789983

RESUMO

CARD9 is an essential adaptor protein in antifungal innate immunity mediated by C-type lectin receptors. The activity of CARD9 is critically regulated by ubiquitination; however, the deubiquitinases involved in CARD9 regulation remain incompletely understood. In this study, we identified ovarian tumor deubiquitinase 1 (OTUD1) as an essential regulator of CARD9. OTUD1 directly interacted with CARD9 and cleaved polyubiquitin chains from CARD9, leading to the activation of the canonical NF-κB and MAPK pathway. OTUD1 deficiency impaired CARD9-mediated signaling and inhibited the proinflammatory cytokine production following fungal stimulation. Importantly, Otud1 -/- mice were more susceptible to fungal infection than wild-type mice in vivo. Collectively, our results identify OTUD1 as an essential regulatory component for the CARD9 signaling pathway and antifungal innate immunity through deubiquitinating CARD9.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Candida albicans/fisiologia , Candidíase/imunologia , Enzimas Desubiquitinantes/metabolismo , Neutrófilos/imunologia , Animais , Células Cultivadas , Citotoxicidade Imunológica , Enzimas Desubiquitinantes/genética , Modelos Animais de Doenças , Humanos , Imunidade Inata , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Células RAW 264.7 , Transdução de Sinais , Ubiquitinação
12.
Elife ; 102021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33827753

RESUMO

Self-motion signals, distributed ubiquitously across parietal-temporal lobes, propagate to limbic hippocampal system for vector-based navigation via hubs including posterior cingulate cortex (PCC) and retrosplenial cortex (RSC). Although numerous studies have indicated posterior cingulate areas are involved in spatial tasks, it is unclear how their neurons represent self-motion signals. Providing translation and rotation stimuli to macaques on a 6-degree-of-freedom motion platform, we discovered robust vestibular responses in PCC. A combined three-dimensional spatiotemporal model captured data well and revealed multiple temporal components including velocity, acceleration, jerk, and position. Compared to PCC, RSC contained moderate vestibular temporal modulations and lacked significant spatial tuning. Visual self-motion signals were much weaker in both regions compared to the vestibular signals. We conclude that macaque posterior cingulate region carries vestibular-dominant self-motion signals with plentiful temporal components that could be useful for path integration.


Assuntos
Giro do Cíngulo/fisiologia , Percepção de Movimento , Propriocepção , Animais , Movimentos da Cabeça , Macaca mulatta , Masculino , Movimento (Física) , Neurônios/metabolismo , Estimulação Luminosa/métodos , Lobo Temporal/fisiologia , Vestíbulo do Labirinto/fisiologia , Realidade Virtual , Córtex Visual/fisiologia , Análise de Ondaletas
13.
Mar Pollut Bull ; 163: 111990, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33461075

RESUMO

The hydromedusa Blackfordia virginica is an invasive species that has disrupted coastal marine food webs throughout the world. Here, we report the response of plankton community to B. virginica blooms in a subtropical lagoon in China. Chlorophyll-a concentrations increased after the peak of B. virginica abundance, which was coincident with high concentrations of ammonium. An increase of the biomass and composition of pico- and nano-phytoplankton during the bloom resulted from bottom-up effects due to the nutrients excreted by B. virginica. The average size and grazing rates of microzooplankton concurrently decreased. The negative correlation between the abundances of B. virginica and microzooplankton was accurately simulated by a generalized linear model and redundancy analysis. This study provided empirical evidence of the impacts of the B. virginica bloom on the food web and the mechanisms responsible for those effects. These impacts may lead to serious ecological and environmental consequences for the lagoonal ecosystem.


Assuntos
Ecossistema , Plâncton , Biomassa , China , Cadeia Alimentar , Fitoplâncton
14.
Angew Chem Int Ed Engl ; 60(12): 6639-6645, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33314510

RESUMO

Self-resistance genes are employed by many microbial producers of bioactive natural products to avoid self-harm. Herein, we describe a unique strategy for self-resistance toward a macrolide antibiotic, A26771B (1), identified by elucidating its biosynthetic pathway in the fungus Penicillium egyptiacum. A highly reducing polyketide synthase and a trans-acting thioesterase generate the macrolide backbone, and a cytochrome P450 and an acyltransferase, respectively catalyze hydroxylation and succinylation to form the prodrug berkeleylactone E (2). Then, extracellular oxidative activation by a secreted flavin-dependent oxidase forms 1, while intracellular reductive inactivation by a short-chain reductase reforms 2, forming a redox cycle. Our work illustrates a unique redox-mediated resistance mechanism for fungal antibiotics and contributes to the understanding of antibiotic biosynthesis and resistance.


Assuntos
Antibacterianos/biossíntese , Penicillium/química , Antibacterianos/química , Lactonas/química , Lactonas/metabolismo , Conformação Molecular , Oxirredução , Penicillium/metabolismo
15.
J Nat Prod ; 83(11): 3262-3269, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33064488

RESUMO

Seven new ß-caryophyllene derivatives, pestalotiphains A-G (1-7), along with six known analogues (8-13), were isolated from the plant-associated Pestalotiopsis hainanensis. Compound 1 represents the first example of a caryophyllene-adenine hybrid, and 2 contains a novel oxatricyclo[4.3.1.0] system. Their structures and absolute configurations were assigned by interpretation of a combination of spectroscopic data and electronic circular dichroism calculations. Compound 8 exhibited moderate inhibition of HL-60 and THP-1 cell lines (IC50, 6.2 and 2.0 µM, respectively). A candidate biosynthetic gene cluster responsible for these compounds was uncovered by bioinformatics analyses and confirmed by a biochemical approach.

16.
Cell Mol Immunol ; 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879469

RESUMO

Stimulator of interferon genes (STING) is an adaptor protein that is critical for effective innate antiviral and antitumor immunity. The activity of STING is heavily regulated by protein ubiquitination, which is fine-tuned by both E3 ubiquitin ligases and deubiquitinases. Here, we report that the deubiquitinase OTUD5 interacts with STING, cleaves its K48-linked polyubiquitin chains, and promotes its stability. Consistently, knockout of OTUD5 resulted in faster turnover of STING and subsequently impaired type I IFN signaling following cytosolic DNA stimulation. More importantly, Lyz2-Cre Otud5fl/Y mice and CD11-Cre Otud5fl/Y mice showed more susceptibility to herpes simplex virus type 1 (HSV-1) infection and faster development of melanomas than their corresponding control littermates, indicating that OTUD5 is indispensable for STING-mediated antiviral and antitumor immunity. Our data suggest that OTUD5 is a novel checkpoint in the cGAS-STING cytosolic DNA sensing pathway.

17.
Exp Ther Med ; 20(2): 802-809, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32765650

RESUMO

Temozolomide (TMZ) resistance is a complication of treatment of glioma, and new strategies are urgently required to overcome chemoresistance in glioma cells. In the present study, it was demonstrated that tripartite motif-containing 31 (TRIM31) was abnormally upregulated in glioma tissues and cell lines compared with normal samples. Furthermore, the role of TRIM31 was assessed by overexpressing and knocking down its expression. Overexpression of TRIM31 increased cell viability, increased TMZ IC50 values and inhibited apoptosis in A172 and U251 cells; whereas overexpression of TRIM31 decreased the expression of the apoptosis-associated protein p53. Knockdown of TRIM31 increased apoptosis in cells treated with TMZ. Additionally, the mechanisms by which TRIM31 affected glioma cells treated with TMZ were determined. Overexpression of TRIM31 increased phosphorylation of AKT and inhibiting the PI3K/AKT signaling pathway abolished the increase in cell viability and decreased phospho-Akt protein expression in TRIM31 overexpressing A172 cells treated with TMZ. Together, the findings suggest that TRIM31 may be a potentially novel target for glioma chemotherapy.

18.
J Immunol ; 204(2): 418-427, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31826938

RESUMO

Stringent regulation of the transcription factor NF-κB signaling is essential for the activation of host immune responses and maintaining homeostasis, yet the molecular mechanisms involved in its tight regulation are not completely understood. In this study, we report that IKK-interacting protein (IKIP) negatively regulates NF-κB activation. IKIP interacted with IKKα/ß to block its association with NEMO, thereby inhibiting the phosphorylation of IKKα/ß and the activation of NF-κB. Upon LPS, TNF-α, and IL-1ß stimulation, IKIP-deficient macrophages exhibited more and prolonged IKKα/ß phosphorylation, IκB, and p65 phosphorylation and production of NF-κB-responsive genes. Moreover, IKIP-deficient mice were more susceptible to LPS-induced septic shock and dextran sodium sulfate-induced colitis. Our study identifies a previously unrecognized role for IKIP in the negative regulation of NF-κB activation by inhibition of IKKα/ß phosphorylation through the disruption of IKK complex formation.


Assuntos
Colite/metabolismo , Quinase I-kappa B/metabolismo , Inflamação/imunologia , Animais , Colite/imunologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Células HEK293 , Humanos , Quinase I-kappa B/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , NF-kappa B/genética , NF-kappa B/metabolismo , Fragmentos de Peptídeos/metabolismo , Fosforilação , Ligação Proteica , Dodecilsulfato de Sódio , Fator de Necrose Tumoral alfa/metabolismo
19.
Braz. J. Pharm. Sci. (Online) ; 56: e00222, 2020. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1089183

RESUMO

A series of 2,3-dioxoindolin-N-phenylacetamide derivatives was evaluated for inhibitory activity against CDC25B and PTP1B enzymes. Most of the derivatives showed inhibitory activity against CDC25B (IC50 = 3.2-23.2 µg/mL) and PTP1B (IC50 = 2.9-21.4 µg/mL). Compound 2h showed the most inhibitory activity in vitro with IC50 values of 3.2 and 2.9 µg/mL against CDC25B and PTP1B, respectively, compared with the reference drugs Na3VO4 (IC50 = 2.7 µg/mL) and oleanolic acid (IC50 = 2.3 µg/mL). The results of selectivity experiments showed that the 2,3-dioxoindolin-N-phenylacetamide derivatives were selective inhibitors against CDC25B and PTP1B. Enzyme kinetic experiments demonstrated that compound 2h was a specific inhibitor with the typical characteristics of a mixed inhibitor. In cytotoxic activity assays compound 2h had potent activity against A549, HeLa, and HCT116 cell lines. In addition, compound 2h showed potent tumor inhibitory activity in a colo205 xenograft model in vivo.

20.
Braz. J. Pharm. Sci. (Online) ; 56: e17721, 2020. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1089201

RESUMO

In the present study, a series of novel 5,7-diisoprenyloxyflavone derivatives were designed, synthesized, and evaluated for their antibacterial activity. Most of these compounds displayed significant antibacterial effects against Gram-positive bacteria, especially against strains of multidrug-resistant clinical isolates. Compounds 4c, 4g, 4i, 4j, 4k, 4l, 4n, 4q and 4t showed high levels of antimicrobial activity against Staphylococcus aureus RN4220 with minimum inhibitory concentrations of 4.0-20 µM. Compound 4k showed the most potent activity among these compounds against all multidrug-resistant clinical isolates tested. Unfortunately, none of the compounds were active against Gram-negative bacteria at the doses of 24-164 µM.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...