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1.
J Mol Model ; 27(1): 14, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33403456

RESUMO

Rheumatoid arthritis (RA) is a systemic autoimmune disorder that commonly affects multiple joints of the body. Currently, there is no permanent cure to the disease, but it can be managed with several potent drugs that cause serious side effects on prolonged use. Traditional remedies are considered promising for the treatment of several diseases, particularly chronic conditions, because they have lower side effects compared to synthetic drugs. In folklore, the rhizome of Alpinia calcarata Roscoe (Zingiberaceae) is used as a major ingredient of herbal formulations to treat RA. Phytoconstituents reported in A. calcarata rhizomes are diterpenoids, sesquiterpenoid, flavonoids, phytosterol, and volatile oils. The present study is intended to understand the molecular-level interaction of phytoconstituents present in A. calcarata rhizomes with RA molecular targets using computational approaches. A total of 30 phytoconstituents reported from the plant were used to carry out docking with 36 known targets of RA. Based on the docking results, 4 flavonoids were found to be strongly interacting with the RA targets. Further, molecular dynamics simulation confirmed stable interaction of quercetin with 6 targets (JAK3, SYK, MMP2, TLR8, IRAK1, and JAK1), galangin with 2 targets (IRAK1 and JAK1), and kaempferol (IRAK1) with one target of RA. Moreover, the presence of these three flavonoids was confirmed in the A. calcarata rhizome extract using LC-MS analysis. The computational study suggests that flavonoids present in A. calcarata rhizome may be responsible for RA modulatory activity. Particularly, quercetin and galangin could be potential development candidates for the treatment of RA. Investigation of Alpinia calcarata constituent interactions with molecular targets of rheumatoid arthritis: docking, molecular dynamics, and network approach.


Assuntos
Alpinia/química , Artrite Reumatoide/tratamento farmacológico , Biologia Computacional , Flavonoides/farmacologia , Compostos Fitoquímicos/farmacologia , Artrite Reumatoide/metabolismo , Cromatografia Líquida , Flavonoides/análise , Flavonoides/química , Humanos , Quinases Associadas a Receptores de Interleucina-1/química , Quinases Associadas a Receptores de Interleucina-1/efeitos dos fármacos , Janus Quinase 1/química , Janus Quinase 1/efeitos dos fármacos , Janus Quinase 3/química , Janus Quinase 3/efeitos dos fármacos , Quempferóis/química , Quempferóis/farmacologia , Espectrometria de Massas , Metaloproteinase 2 da Matriz/química , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/química , Extratos Vegetais/química , Quercetina/química , Quercetina/farmacologia , Rizoma/química , Quinase Syk/química , Quinase Syk/efeitos dos fármacos , Receptor 8 Toll-Like/química , Receptor 8 Toll-Like/efeitos dos fármacos
2.
Acta Neuropathol Commun ; 8(1): 166, 2020 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-33076989

RESUMO

Repeated exposure to mild TBI (mTBI) has been linked to an increased risk of Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE) and other neurodegenerative diseases. Some pathological features typically observed in AD have been found in postmortem brains of TBI and CTE, hence treatments tested for AD have a potential to be effective against r-mTBI outcomes. Neuroinflammation may present a possible answer due to its central role both in acute brain injury and in chronic degenerative-like disorders. Our previous studies have shown that drug nilvadipine, acting as an inhibitor of spleen tyrosine kinase (SYK), is effective at reducing inflammation, tau hyperphosphorylation and amyloid production in AD mouse models. To demonstrate the effect of nilvadipine in the absence of age-related variables, we introduced the same treatment to young r-mTBI mice. We further investigate therapeutic mechanisms of nilvadipine using its racemic properties. Both enantiomers, (+)-nilvadipine and (-)-nilvadipine, can lower SYK activity, whereas (+)-nilvadipine is also a potent L-type calcium channel blocker (CCB) and shown to be anti-hypertensive. All r-mTBI mice exhibited increased neuroinflammation and impaired cognitive performance and motor functions. Treatment with racemic nilvadipine mitigated the TBI-induced inflammatory response and significantly improved spatial memory, whereas (-)-enantiomer decreased microgliosis and improved spatial memory but failed to reduce the astroglial response to as much as the racemate. These results suggest the therapeutic potential of SYK inhibition that is enhanced when combined with the CCB effect, which indicate a therapeutic advantage of multi-action drugs for r-mTBI.


Assuntos
Concussão Encefálica/fisiopatologia , Bloqueadores dos Canais de Cálcio/farmacologia , Nifedipino/análogos & derivados , Aprendizagem Espacial/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Quinase Syk/antagonistas & inibidores , Animais , Antígenos CD/efeitos dos fármacos , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/efeitos dos fármacos , Antígenos de Diferenciação Mielomonocítica/metabolismo , Concussão Encefálica/metabolismo , Concussão Encefálica/psicologia , Proteínas de Ligação ao Cálcio/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Proteína Glial Fibrilar Ácida/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Inflamação/metabolismo , Camundongos , Proteínas dos Microfilamentos/efeitos dos fármacos , Proteínas dos Microfilamentos/metabolismo , Nifedipino/farmacologia , Fosforilação , Teste de Desempenho do Rota-Rod , Aprendizagem Espacial/fisiologia , Memória Espacial/fisiologia , Quinase Syk/efeitos dos fármacos , Quinase Syk/metabolismo
3.
Cell Signal ; 57: 102-109, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30707930

RESUMO

Persistent exposure to ambient fine particulate matter (PM2.5) can exacerbate allergic diseases in humans. Mast cells play an important role in allergic inflammation in peripheral tissues, such as skin, mucosa, and lung. Engagement of the high-affinity Fc receptor leads to mast cell degranulation, releasing a variety of highly active mediators including histamine, leukotrienes, and inflammatory cytokines. How PM2.5 exposure affects mast cell activation and function remains largely unknown. To characterize the effect of PM2.5 on mast cells, we used bone marrow-derived mast cells (BMMCs) to examine whether PM2.5 affected FcεRI-mediated signaling, cytokine production, and degranulation. Exposure to high doses of PM2.5 caused pronounced apoptosis and death of BMMCs. In contrast, exposure to low doses of PM2.5 enhanced mast cell degranulation and FcεRI-mediated cytokine production. Further analysis showed that PM2.5 treatment increased Syk activation and subsequently phosphorylation of its substrates including LAT, PLC-γ1, and SLP-76. Moreover, PM2.5 treatment led to activation of the PI3K and MAPK pathways. Intriguingly, water-soluble fraction of PM2.5 were found responsible for the enhancement of FcεRI-mediated signaling, mast cell degranulation, and cytokine production. Our data suggest that PM2.5, mainly water-soluble fraction of PM2.5, could affect mast cell activation through enhancing FcεRI-mediated signaling.


Assuntos
Mastócitos/efeitos dos fármacos , Material Particulado/farmacologia , Receptores de IgE/imunologia , Quinase Syk/efeitos dos fármacos , Animais , Citocinas/imunologia , Mastócitos/metabolismo , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Proteínas Tirosina Quinases/efeitos dos fármacos , Proteínas Tirosina Quinases/metabolismo
4.
Toxicol Appl Pharmacol ; 355: 93-102, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-29960001

RESUMO

NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome is a component of innate immunity, and is responsible for producing mature IL-1ß and -18. Several flavonoids were found to affect inflammasome pathway, but the mechanism of action is still obscure. To elucidate the effects on NLRP3 inflammasome pathway and to determine the structure-activity relationships, NLRP3 inflammasome in differentiated THP-1 cells was activated via treatment with monosodium urate (MSU) crystals. Levels of mature IL-1ß, NLRP3 inflammasome components and apoptosis-associated speck-like protein containing a CARD (caspase recruitment domain) (ASC) oligomerization were investigated and the mechanisms of action were also elucidated. Among the 56 flavonoids initially tested, only flavone, 2',4'-dihhydroxyflavone, 3',4'-dichloroflavone, 4',5,7-trihydroxyflavone (apigenin), 3,4',5,7-tetrahydroxyflavone (kaempferol) and 3,3',4',5,7-pentahydroxyflavone (quercetin) significantly inhibited IL-1ß production at 10 µM. Apigenin, kaempferol and 3',4'-dichloroflavone inhibited ASC oligomerization without affecting the ASC level in cell lysates. Apigenin also inhibited absent in melanoma 2 (AIM2) inflammasome-related pathway, but not NLR family CARD domain-containing protein 4 (NLRC4) inflammasome activation. The action of apigenin on NLRP3 inflammasome activation is mediated partly via inhibition of phosphorylation of spleen tyrosine kinase/protein tyrosine kinase 2 (Syk/Pyk2) pathway. Furthermore, orally administered apigenin (100 mg/kg) strongly reduced the number of neutrophils and monocytes in MSU-induced peritonitis in mice. The present study, for the first time, demonstrated the structure-activity profiles of flavonoids in NLRP3 inflammasome activation and mechanisms of cellular action. Certain flavonoids including apigenin are expected to ameliorate the inflammatory symptoms in autoinflammatory diseases associated with NLRP3 inflammasome activation.


Assuntos
Flavonoides/farmacologia , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Animais , Caspase 1/efeitos dos fármacos , Linhagem Celular , Quinase 2 de Adesão Focal/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Monócitos/efeitos dos fármacos , Peritonite/induzido quimicamente , Peritonite/prevenção & controle , Relação Estrutura-Atividade , Quinase Syk/efeitos dos fármacos , Ácido Úrico
5.
J Infect ; 77(2): 137-144, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29746940

RESUMO

OBJECTIVES: To investigate the involvement of NLRP3 in the effector functions of human dendritic cells (DCs) in response to Paracoccidioides brasiliensis yeast cells (Pb) and to evaluate its role in the modulation of the adaptive immune response. METHODS: DCs were differentiated from purified peripheral blood monocytes and analyzed in relation to the participation of TLR-2, dectin-1, and Syk in Pb recognition, as well as, the indirect mechanisms (Reactive Oxygen Species production, endosome acidification, or K+ efflux) involved in NLRP3 inflammasome activation after the stimulus with Pb. Additionally, we analyzed the role of NLRP3 in the activation of T cells. RESULTS: Our results demonstrated that the NLRP3 inflammasome activation and cytokines production by DCs are dependent on ROS generation, endosome acidification, and K+ efflux and involve the Pb recognition by dectin-1 and Syk phosphorylation. Our data also demonstrate that the NLRP3 inflammasome is essential for the activation/expansion of Th1/Th17 cells and its inhibition leads to an increased frequency of Th2 and Treg cells. CONCLUSION: Altogether our data indicated that activation of NLRP3 presents an important role in both the induction of the initial inflammatory response and in the development of the acquired immune response associated with resistance to infection.


Assuntos
Células Dendríticas/fisiologia , Inflamassomos/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Paracoccidioides/imunologia , Células Th17/fisiologia , Anticorpos , Diferenciação Celular , Citocinas/genética , Citocinas/metabolismo , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/imunologia , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Fosforilação , Quinase Syk/efeitos dos fármacos , Quinase Syk/genética , Quinase Syk/metabolismo
6.
Oncogene ; 36(32): 4653-4661, 2017 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-28368423

RESUMO

Dysregulation of the oncogenic transcription factor MYC induces B-cell transformation and is a driver for B-cell non-Hodgkin lymphoma (B-NHL). MYC overexpression in B-NHL is associated with more aggressive phenotypes and poor prognosis. Although genomic studies suggest a link between MYC overexpression and B-cell receptor (BCR) signaling molecules in B-NHL, signaling pathways essential to Myc-mediated B-cell transformation have not been fully elucidated. We utilized intracellular phospho-flow cytometry to investigate the relationship between Myc and BCR signaling in pre-malignant B cells. Utilizing the Eµ-myc mouse model, where Myc is overexpressed specifically in B cells, both basal and stimulated BCR signaling were increased in precancerous B lymphocytes from Eµ-myc mice compared with wild-type littermates. B cells overexpressing Myc displayed constitutively higher levels of activated CD79α, Btk, Plcγ2 and Erk1/2. Notably, Myc-overexpressing B cells maintained elevated BCR signaling despite treatment with ibrutinib, a Bruton's tyrosine kinase inhibitor. Furthermore, PI3K/Akt pathway signaling was also increased in Eµ-myc B cells, and this increase was partially suppressed with ibrutinib. In addition, experiments with Btk-null B cells revealed off-target effects of ibrutinib on BCR signaling. Our data show that in pre-malignant B cells, Myc overexpression is sufficient to activate BCR and PI3K/Akt signaling pathways and further enhances signaling following BCR ligation. Therefore, our results indicate that precancerous B cells have already acquired enhanced survival and growth capabilities before transformation, and that elevated MYC levels confer resistance to pharmacologic inhibitors of BCR signaling, which has significant implications for B-NHL treatment.


Assuntos
Linfócitos B/metabolismo , Linfoma não Hodgkin/metabolismo , Lesões Pré-Cancerosas/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/metabolismo , Neoplasias Esplênicas/metabolismo , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Animais , Linfócitos B/patologia , Antígenos CD79/metabolismo , Proliferação de Células , Citometria de Fluxo , Humanos , Linfoma não Hodgkin/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfolipase C gama/metabolismo , Fosforilação/efeitos dos fármacos , Piperidinas , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptores de Antígenos de Linfócitos B/metabolismo , Neoplasias Esplênicas/patologia , Quinase Syk/efeitos dos fármacos , Quinase Syk/metabolismo
7.
Brain Behav Immun ; 60: 346-360, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27845194

RESUMO

Subarachnoid hemorrhage (SAH) is a devastating subtype of stroke. Microglial macrophage-inducible C-type lectin (Mincle) receptor launches microglial innate immunity after SAH, and thereby achieves a key step of early cerebral injury in SAH. We previously revealed albumin could improve long-term neurological outcomes after SAH. In this study, we examined the role of microglia-mediated innate immunity in the salutary effects of albumin. SAH was induced by endovascular perforation in rats. We found that albumin can significantly mitigate early neurovascular dysfunction of SAH rats. Albumin administration resulted in reduced Iba-1 and CD68 staining in cortex. Markers of microglia M1 polarization (iNOS, IL-1ß, CD16, and CD32) were remarkably suppressed. Neutrophil invasion was inhibited as chemokines (MCP-1, CINC-1, and CXCL-2) mRNA levels, myeloperoxidase (MPO) and intracellular adhesion molecule-1 (ICAM-1) expressions were decreased. Mechanistically, albumin bound with microglial Mincle receptor, and retarded Mincle/Syk/IL-1ß signaling in ipsilateral hemisphere subjected to SAH. In the cultured BV-2 microglial cells, we found Mincle and its ligand SAP130 mediate the cross-talk between neuronal necroptosis and microglial immunity response following SAH-related injury. Albumin could attenuate SAP130-induced Mincle upregulation and subsequent microglial inflammatory responses. The anti-inflammation effect of albumin was similar to the effect of genetic knockdown of Mincle. This effect may be attributed to a direct association between albumin and Mincle. The interaction also yielded a depression in the initiation of Mincle/Syk/IL-1ß pathway. In conclusion, our results indicate that albumin can ameliorate innate immune responses after SAH. This anti-inflammatory action may be through direct restraining microglial Mincle receptor.


Assuntos
Imunidade Inata/efeitos dos fármacos , Microglia/efeitos dos fármacos , Albumina Sérica Humana/farmacologia , Hemorragia Subaracnóidea/tratamento farmacológico , Animais , Edema Encefálico/tratamento farmacológico , Masculino , Microglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos Sprague-Dawley , Quinase Syk/efeitos dos fármacos
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