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1.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361744

RESUMO

Korean red pine (Pinus densiflora) belongs to the Genus Pinus, and its bark contains a great amount of naturally occurring phenolic compounds. Until now, few studies have been conducted to assess the neuroprotective effects of Pinus densiflora bark extract against brain ischemic injury. The aim of this study was to investigate the neuroprotective effects of pre-treatment with the extract in the hippocampus following 5-min transient forebrain ischemia in gerbils. Furthermore, this study examined the anti-inflammatory effect as a neuroprotective mechanism of the extract. Pinus densiflora bark was extracted by pure water (100 °C), and this extract was quantitatively analyzed and contained abundant polyphenols, flavonoids, and proanthocyanidins. The extract (25, 50, and 100 mg/kg) was orally administered once a day for seven days before the ischemia. In the gerbil hippocampus, death of the pyramidal neurons was found in the subfield cornu ammonis 1 (CA1) five days after the ischemia. This death was significantly attenuated by pre-treatment with 100 mg/kg, not 25 or 50 mg/kg, of the extract. The treatment with 100 mg/kg of the extract markedly inhibited the activation of microglia (microgliosis) and significantly decreased the expression of pro-inflammatory cytokines (interleukin 1ß and tumor necrosis factor α). In addition, the treatment significantly increased anti-inflammatory cytokines (interleukin 4 and interleukin 13). Taken together, this study clearly indicates that pre-treatment with 100 mg/kg of Pinus densiflora bark extract in gerbils can exert neuroprotection against brain ischemic injury by the attenuation of neuroinflammatory responses.


Assuntos
Anti-Inflamatórios/farmacologia , Isquemia Encefálica/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pinus/química , Prosencéfalo/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Flavonoides/química , Flavonoides/farmacologia , Expressão Gênica/efeitos dos fármacos , Gerbillinae , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação , Interleucina-13/agonistas , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-4/agonistas , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Fármacos Neuroprotetores/química , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Proantocianidinas/química , Proantocianidinas/farmacologia , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
2.
Cancer Sci ; 112(10): 4151-4165, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34293235

RESUMO

Submucosal invasion and lymph node metastasis are important issues affecting treatment options for early colorectal cancer (CRC). In this study, we aimed to unravel the molecular mechanism underlying the invasiveness of early CRCs. We performed RNA-sequencing (RNA-seq) with poorly differentiated components (PORs) and their normal counterparts isolated from T1 CRC tissues and detected significant upregulation of serum amyloid A1 (SAA1) in PORs. Immunohistochemical analysis revealed that SAA1 was specifically expressed in PORs at the invasive front of T1b CRCs. Upregulation of SAA1 in CRC cells promoted cell migration and invasion. Coculture experiments using CRC cell lines and THP-1 cells suggested that interleukin 1ß (IL-1ß) produced by macrophages induces SAA1 expression in CRC cells. Induction of SAA1 and promotion of CRC cell migration and invasion by macrophages were inhibited by blocking IL-1ß. These findings were supported by immunohistochemical analysis of primary T1 CRCs showing accumulation of M1-like/M2-like macrophages at SAA1-positive invasive front regions. Moreover, SAA1 produced by CRC cells stimulated upregulation of matrix metalloproteinase-9 in macrophages. Our data suggest that tumor-associated macrophages at the invasive front of early CRCs promote cancer cell migration and invasion through induction of SAA1 and that SAA1 may be a predictive biomarker and a useful therapeutic target.


Assuntos
Neoplasias Colorretais/patologia , Interleucina-1beta/metabolismo , Proteína Amiloide A Sérica/metabolismo , Macrófagos Associados a Tumor/fisiologia , Idoso , Sequência de Bases , Movimento Celular , Técnicas de Cocultura , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Interleucina-1beta/antagonistas & inibidores , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , Células THP-1 , Macrófagos Associados a Tumor/metabolismo , Regulação para Cima
3.
JAMA ; 326(3): 230-239, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34283183

RESUMO

Importance: Effective treatments for patients with severe COVID-19 are needed. Objective: To evaluate the efficacy of canakinumab, an anti-interleukin-1ß antibody, in patients hospitalized with severe COVID-19. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled phase 3 trial was conducted at 39 hospitals in Europe and the United States. A total of 454 hospitalized patients with COVID-19 pneumonia, hypoxia (not requiring invasive mechanical ventilation [IMV]), and systemic hyperinflammation defined by increased blood concentrations of C-reactive protein or ferritin were enrolled between April 30 and August 17, 2020, with the last assessment of the primary end point on September 22, 2020. Intervention: Patients were randomly assigned 1:1 to receive a single intravenous infusion of canakinumab (450 mg for body weight of 40-<60 kg, 600 mg for 60-80 kg, and 750 mg for >80 kg; n = 227) or placebo (n = 227). Main Outcomes and Measures: The primary outcome was survival without IMV from day 3 to day 29. Secondary outcomes were COVID-19-related mortality, measurements of biomarkers of systemic hyperinflammation, and safety evaluations. Results: Among 454 patients who were randomized (median age, 59 years; 187 women [41.2%]), 417 (91.9%) completed day 29 of the trial. Between days 3 and 29, 198 of 223 patients (88.8%) survived without requiring IMV in the canakinumab group and 191 of 223 (85.7%) in the placebo group, with a rate difference of 3.1% (95% CI, -3.1% to 9.3%) and an odds ratio of 1.39 (95% CI, 0.76 to 2.54; P = .29). COVID-19-related mortality occurred in 11 of 223 patients (4.9%) in the canakinumab group vs 16 of 222 (7.2%) in the placebo group, with a rate difference of -2.3% (95% CI, -6.7% to 2.2%) and an odds ratio of 0.67 (95% CI, 0.30 to 1.50). Serious adverse events were observed in 36 of 225 patients (16%) treated with canakinumab vs 46 of 223 (20.6%) who received placebo. Conclusions and Relevance: Among patients hospitalized with severe COVID-19, treatment with canakinumab, compared with placebo, did not significantly increase the likelihood of survival without IMV at day 29. Trial Registration: ClinicalTrials.gov Identifier: NCT04362813.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/tratamento farmacológico , Interleucina-1beta/antagonistas & inibidores , Respiração Artificial/estatística & dados numéricos , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Proteína C-Reativa/análise , COVID-19/mortalidade , COVID-19/terapia , Terapia Combinada , Método Duplo-Cego , Feminino , Ferritinas/sangue , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Hospitalização , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Resultado do Tratamento
4.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201546

RESUMO

Tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) are two cytokines involved in the perpetuation of the chronic inflammation state characterizing rheumatoid arthritis (RA). Significant advances in the treatment of this pathology have been made over the past ten years, partially through the development of anti-TNF and anti-IL-1 therapies. However, major side effects still persist and new alternative therapies should be considered. The formulation of the micro-immunotherapy medicine (MIM) 2LARTH® uses ultra-low doses (ULD) of TNF-α, IL-1ß, and IL-2, in association with other immune factors, to gently restore the body's homeostasis. The first part of this review aims at delineating the pivotal roles played by IL-1ß and TNF-α in RA physiopathology, leading to the development of anti-TNF and anti-IL-1 therapeutic agents. In a second part, an emphasis will be made on explaining the rationale of using multiple therapeutic targets, including both IL-1ß and TNF-α in 2LARTH® medicine. Particular attention will be paid to the ULD of those two main pro-inflammatory factors in order to counteract their overexpression through the lens of their molecular implication in RA pathogenesis.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Citocinas/administração & dosagem , Imunoterapia/métodos , Interleucina-1beta/administração & dosagem , Fator de Necrose Tumoral alfa/administração & dosagem , Administração Oral , Animais , Artrite Reumatoide/fisiopatologia , Relação Dose-Resposta a Droga , Humanos , Interleucina-1beta/efeitos adversos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/fisiologia , Interleucina-2/administração & dosagem , Interleucina-2/efeitos adversos , Terapia de Alvo Molecular/métodos , Medicina de Precisão , Fator de Necrose Tumoral alfa/efeitos adversos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/fisiologia
5.
Eur J Med Chem ; 223: 113620, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34186234

RESUMO

Interleukin-1ß is a central mediator of innate immune responses and inflammation. It plays a key role in a wide variety of pathologies, ranging from autoinflammatory diseases to metabolic syndrome and malignant tumors. It is well established that its inhibition results in a rapid and sustained reduction in disease severity, underlining the importance of having a repertoire of drugs of this class. At present, there are only three interleukin-1ß blockers approved in the clinic. All of them are biologics, requiring parenteral administration and resulting in expensive treatments. In an exercise to identify small molecule allosteric inhibitors of MAP kinases, we discovered a series of compounds that block IL-1ß release produced as a consequence of a stimulus involved in triggering an inflammatory response. The present study reports the hit-to-lead optimization process that permitted the identification of the compound 13b (AIK3-305) an orally available, potent and selective inhibitor of IL-1ß. Furthermore, the study also reports the results of an in vivo efficacy study of 13b in a LPS endotoxic shock model in male BALB/c mice, where IL-1ß inhibition is monitored in different tissues.


Assuntos
Interleucina-1beta/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Piridinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Feminino , Humanos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Piridinas/síntese química , Piridinas/metabolismo , Piridinas/farmacocinética , Ratos Wistar
6.
Front Immunol ; 12: 623610, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093519

RESUMO

Severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) strongly hampered the broad clinical applicability of chimeric antigen receptor T cell (CAR-T) therapy. Vascular endothelial activation has been suggested to contribute to the development of CRS and ICANS after CAR-T therapy. However, therapeutic strategies targeting endothelial dysfunction during CAR-T therapy have not been well studied yet. Here, we found that tumor necrosis factor α (TNFα) produced by CAR-T cells upon tumor recognition and interleukin 1ß (IL1ß) secreted by activated myeloid cells were the main cytokines in inducing endothelial activation. Therefore, we investigated the potential effectiveness of TNFα and IL1ß signaling blockade on endothelial activation in CAR-T therapy. The blockade of TNFα and IL1ß with adalimumab and anti-IL1ß antibody respectively, as well as the application of focal adhesion kinase (FAK) inhibitor, effectively ameliorated endothelial activation induced by CAR-T, tumor cells, and myeloid cells. Moreover, adalimumab and anti-IL1ß antibody exerted synergistic effect on the prevention of endothelial activation induced by CAR-T, tumor cells, and myeloid cells. Our results indicate that TNFα and IL1ß blockade might have therapeutic potential for the treatment of CAR-T therapy-associated CRS and neurotoxicity.


Assuntos
Adalimumab/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Imunoterapia Adotiva , Interleucina-1beta/antagonistas & inibidores , Células Mieloides/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/efeitos dos fármacos , Inibidores do Fator de Necrose Tumoral/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Antígenos CD19/genética , Antígenos CD19/imunologia , Antígenos CD19/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/metabolismo , Síndrome da Liberação de Citocina/prevenção & controle , Células HEK293 , Células Endoteliais da Veia Umbilical Humana/imunologia , Humanos , Imunoterapia Adotiva/efeitos adversos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Células Mieloides/imunologia , Células Mieloides/metabolismo , Síndromes Neurotóxicas/imunologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
7.
Int J Mol Sci ; 22(9)2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064436

RESUMO

2-Arachidonyl-lysophosphatidylethanolamine, shortly 2-ARA-LPE, is a polyunsaturated lysophosphatidylethanolamine. 2-ARA-LPE has a very long chain arachidonic acid, formed by an ester bond at the sn-2 position. It has been reported that 2-ARA-LPE has anti-inflammatory effects in a zymosan-induced peritonitis model. However, it's action mechanisms are poorly investigated. Recently, resolution of inflammation is considered to be an active process driven by M2 polarized macrophages. Therefore, we have investigated whether 2-ARA-LPE acts on macrophages for anti-inflammation, whether 2-ARA-LPE modulates macrophage phenotypes to reduce inflammation, and whether 2-ARA-LPE is anti-inflammatory in a carrageenan-induced paw edema model. In mouse peritoneal macrophages, 2-ARA-LPE was found to inhibit lipopolysaccharide (LPS)-induced M1 macrophage polarization, but not induce M2 polarization. 2-ARA-LPE inhibited the inductions of inducible nitric oxide synthase and cyclooxygenase-2 in mouse peritoneal macrophages at the mRNA and protein levels. Furthermore, products of the two genes, nitric oxide and prostaglandin E2, were also inhibited by 2-ARA-LPE. However, 1-oleoyl-LPE did not show any activity on the macrophage polarization and inflammatory responses. The anti-inflammatory activity of 2-ARA-LPE was also verified in vivo in a carrageenan-induced paw edema model. 2-ARA-LPE inhibits LPS-induced M1 polarization, which contributes to anti-inflammation and suppresses the carrageenan-induced paw edema in vivo.


Assuntos
Anti-Inflamatórios/farmacologia , Ácidos Araquidônicos/farmacologia , Edema/tratamento farmacológico , Lisofosfolipídeos/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Ácidos Araquidônicos/química , Carragenina/administração & dosagem , Ciclo-Oxigenase 2/imunologia , Dinoprostona/antagonistas & inibidores , Dinoprostona/biossíntese , Edema/induzido quimicamente , Edema/imunologia , Edema/patologia , Membro Posterior/efeitos dos fármacos , Membro Posterior/imunologia , Membro Posterior/metabolismo , Subunidade p35 da Interleucina-12/antagonistas & inibidores , Subunidade p35 da Interleucina-12/imunologia , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/imunologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Lisofosfolipídeos/química , Macrófagos Peritoneais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/imunologia , Cultura Primária de Células , Resultado do Tratamento
8.
Biochem Pharmacol ; 188: 114580, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33930349

RESUMO

Statins are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that lower atherogenic LDL-cholesterol levels. Statins exert clinically relevant anti-inflammatory effects; however, the underlying molecular mechanism remains unclear. Studies have shown that endogenous and exogenous pathogenic crystals, such as cholesterol and monosodium urate (MSU), and needle-like nanomaterials, such as multi-wall carbon nanotubes (MWCNT), induce the production of IL-1ß and play a critical role in the development of crystal-associated sterile inflammatory pathologies. In this study, we evaluated the effect of statins on crystal-induced IL-1ß production in macrophages. We found that various statins, including pitavastatin, atorvastatin, fluvastatin, and lovastatin, but not squalene synthase inhibitor, repressed IL-1ß release upon MWCNT stimulation. In addition, IL-1ß production induced by cholesterol crystals and MSU crystals, but not by ATP or nigericin, was diminished. MWCNT-stimulated IL-1ß release was dependent on the expression of NLRP3, but not AIM2, NLRC4, or MEFV. Statin-induced repression was accompanied by reduced levels of mature caspase-1 and decreased uptake of MWCNT into cells. Supplementation of mevalonate, geranylgeranyl pyrophosphate, or farnesyl pyrophosphate prevented the reduction in IL-1ß release, suggesting a crucial role of protein prenylation, but not cholesterol synthesis. The statin-induced repression of MWCNT-elicited IL-1ß release was observed in THP-1-derived and mouse peritoneal macrophages, but not in bone marrow-derived macrophages where statins act in synergy with lipopolysaccharide to enhance the expression of IL-1ß precursor protein. In summary, we describe a novel anti-inflammatory mechanism through which statins repress mature IL-1ß release induced by pathogenic crystals and nanoneedles by inhibiting the internalization of crystals by macrophages.


Assuntos
Colesterol/toxicidade , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Interleucina-1beta/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Nanotubos de Carbono/toxicidade , Animais , Cristalização/métodos , Feminino , Humanos , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Células THP-1
9.
Chem Biodivers ; 18(3): e2000989, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33528898

RESUMO

Artemisia lavandulaefolia, a traditional herbal medicine, has been utilized as anti-inflammatory and analgesia agent in clinic. Bioassay-guided fractionation resulted in a fraction (ALDF) with anti-inflammatory effect obtained from A. lavandulaefolia. Its main constituents were analyzed and identified by UPLC-ESI-Q-TOF-MS technology. ALDF showed the strong inhibitory activity on the nitrogen oxide (NO) production in LPS-induced RAW 264.7 macrophages with an IC50 value of 1.64±0.41 µg/mL. Further results displayed that ALDF also significantly suppressed the secretion of key pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2 ) and interleukin-1ß (IL-1ß), and the increase of the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression induced by LPS stimulation. Mechanism study indicated that ALDF was able to block NF-κB signaling pathway through inhibiting IκB and p65 phosphorylation, as well as NF-κB p65 nuclear translocation. Furthermore, in vivo results in mice revealed that treatments with ALDF evoked significant inhibition on ear edema induced by xylene and on the writhing responses induced by acetic acid. These results suggest that ALDF holds great potential in the prevention and treatment of inflammatory disorders.


Assuntos
Anti-Inflamatórios/farmacologia , Artemisia/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Ácido Acético , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ciclo-Oxigenase 2/biossíntese , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/tratamento farmacológico , Feminino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/biossíntese , Dor/induzido quimicamente , Dor/tratamento farmacológico , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Células RAW 264.7 , Estereoisomerismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo , Xilenos
10.
J Neurochem ; 157(3): 611-623, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33453127

RESUMO

Artemisinin and its derivatives have been the frontline drugs for treating malaria. In addition to the antiparasitic effect, accumulating evidence shows that artemisinins can alleviate neuroinflammatory responses in the central nervous system (CNS). However, the precise mechanisms underlying their anti-neuroinflammatory effects are unclear. Herein we attempted to delineate the molecule target of artemisinin in microglia. In vitro protein intrinsic fluorescence titrations and saturation transfer difference (STD)-NMR showed the direct binding of artemisinin to Toll-like receptor TLR4 co-receptor MD2. Cellular thermal shift assay (CETSA) showed that artemisinin binding increased MD2 stability, which implies that artemisinin directly binds to MD2 in the cellular context. Artemisinin bound MD2 showed much less collapse during the molecular dynamic simulations, which supports the increased stability of MD2 upon artemisinin binding. Flow cytometry analysis showed artemisinin inhibited LPS-induced TLR4 dimerization and endocytosis in microglial BV-2 cells. Therefore, artemisinin was found to inhibit the TLR4-JNK signaling axis and block LPS-induced pro-inflammatory factors nitric oxide, IL-1ß and TNF-α in BV-2 cells. Furthermore, artemisinin restored LPS-induced decrease of junction proteins ZO-1, Occludin and Claudin-5 in primary brain microvessel endothelial cells, and attenuated LPS-induced blood-brain barrier disruption in mice as assessed by Evans blue. In all, this study unambiguously adds MD2 as a direct binding target of artemisinin in its anti-neuroinflammatory function. The results also suggest that artemisinin could be repurposed as a potential therapeutic intervention for inflammatory CNS diseases.


Assuntos
Artemisininas/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Antígeno 96 de Linfócito/efeitos dos fármacos , Microglia/efeitos dos fármacos , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Linhagem Celular , Vazamento de Líquido Cefalorraquidiano , Endocitose/efeitos dos fármacos , Interleucina-1beta/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Óxido Nítrico/metabolismo , Proteínas de Junções Íntimas/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores
11.
Immun Inflamm Dis ; 9(2): 399-405, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33465283

RESUMO

BACKGROUND: Clinicians all around the world are currently experiencing a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several therapeutic strategies have been used until now but, to date, there is no specific therapy to treat SARS-CoV-2 infection. In this study, we used canakinumab, a human monoclonal antibody targeting interleukin-1 beta to improve respiratory function and laboratory parameters compared with standard therapy (hydroxycloroquine plus lopinavir/ritonavir). METHODS: We enrolled 34 patients with mild or severe non intensive care unit (ICU) coronavirus disease 2019 (COVID-19): 17 patients treated with standard therapy and 17 patients treated with a subcutaneous single dose of canakinumab 300 mg. We collected data about oxygen supports and laboratory parameters such as inflammation indices and hemogasanalysis. We compared the data collected before the administration of canakinumab (T0), 3 days after T0 (T1) and 7 days after T0 (T2) with the same data from patients taking the standard therapy. RESULTS: We observed a reduction in inflammation indices and a significant and rapid increase in P/F ratio in canakinumab group, with improvement of 60.3% after the administration. We reported a significant reduction in oxygen flow in patients treated with canakinumab (-28.6% at T1 vs. T0 and -40.0% at T2 vs. T1). Conversely, the standard group increased the supply of high oxygen at T1 versus T0 (+66.7%), but reduced oxygen flows at T2 versus T1 (-40.0%). CONCLUSION: In hospitalized adult patients with mild or severe non ICU COVID-19, canakinumab could be a valid therapeutic option. Canakinumab therapy causes rapid and long-lasting improvement in oxygenation levels in the absence of any severe adverse events.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/tratamento farmacológico , Interleucina-1beta/antagonistas & inibidores , Terapia de Alvo Molecular , Pandemias , SARS-CoV-2 , Idoso , Antivirais/uso terapêutico , COVID-19/sangue , COVID-19/terapia , Terapia Combinada , Quimioterapia Combinada , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Lopinavir/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxigenoterapia , Ritonavir/uso terapêutico , Resultado do Tratamento
12.
Carbohydr Polym ; 255: 117392, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33436221

RESUMO

Fructooligosaccharide was isolated from Polygonatum Cyrtonema Hua (PFOS) for the first time. Structure characterized using FT-IR, MALDI-TOF-MS, NMR, AFM, and TEM, indicated that PFOS was graminan-type fructan with a degree of polymerization ranging from 5 to 10. A murine model of lipopolysaccharide (LPS)-induced peritonitis was used to evaluate the in vivo anti-inflammatory and lung protective efficacy of PFOS. The result shown that pretreatment with PFOS (1.0 mg/mL) in peritonitis-induced mice could significantly inhibit the level of pro-inflammatory cytokines (TNF-α, IL-1ß) in serum (P < 0.001), increase mice survival rate from 12.5 % to 54 % (P < 0.05), and alleviated lung injury through ameliorating the damage of the pulmonary cellular architecture and reducing inflammatory monocyte accumulation in lung tissue. This effect of oligosaccharides could explain the traditional usage of P. cyrtonema as a tonic medicine for respiratory problems and it could be used as a potential natural ingredient with anti-inflammatory activity.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Anti-Inflamatórios/farmacologia , Pulmão/efeitos dos fármacos , Oligossacarídeos/farmacologia , Peritonite/tratamento farmacológico , Polygonatum/química , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/mortalidade , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Expressão Gênica , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Lipopolissacarídeos/administração & dosagem , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/patologia , Oligossacarídeos/química , Oligossacarídeos/isolamento & purificação , Peritonite/induzido quimicamente , Peritonite/imunologia , Peritonite/mortalidade , Análise de Sobrevida , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
14.
Biochem Biophys Res Commun ; 534: 212-218, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33272570

RESUMO

Infection and/or drug-mediated acute liver injury, the leading cause of lethal liver failure, is a critical health problem worldwide and lacks effective treatment. Here, we used Lipopolysaccharides (LPS)/D-galactosamine (D-gal)-treated primary hepatocytes to screen a natural library that contains 1130 chemicals. Baicalein in the library showed highest inhibitory effects against LPS/D-Gal-induced liver injury. In-vivo study similarly validated the protection of baicalein against dampened liver function and increased lethality after a challenge of LPS/D-Gal. Using a cytometric bead array, we found that IL-1α and IL-1ß, the downstream of NLRP3, had highest reduction among the plasma inflammatory cytokines in LPS/D-Gal-challenged mice after a treatment of baicalein. To determine the target of baicalein and the underlying mechanism, Nlrp3-/-, Gsdmd-/- or WT mice were treated with or without baicalein, IL-1R antibody or recombinant mouse IL-1ß (rmIL-1ß) prior to a challenge of LPS/D-Gal. Deficiency of Nlrp3 or Gsdmd significantly restored LPS/D-Gal-induced acute liver injury and lethality, and further administration of baicalein did not have additive effects. In addition, the inhibition of the downstream by IL-1R antibody phenocopied the knockout of Nlrp3 or Gsdmd. Moreover, a challenge of rmIL-1ß reversed the improvement in Nlrp3-/- mice or the mice treated with baicalein. Taken together, NLRP3 functions as a pivotal promoter in acute liver injury and baicalein attenuates acute liver injury by inhibiting NLRP3 inflammasome.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Flavanonas/uso terapêutico , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Animais , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Galactosamina , Interleucina-1beta/antagonistas & inibidores , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Transdução de Sinais/efeitos dos fármacos
15.
Toxicol Appl Pharmacol ; 410: 115341, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33242555

RESUMO

Andrographolide (AND) is the major diterpenoid in A. paniculata with wide clinical application and has been shown to be a potent anti-inflammatory agent. Gout is the leading inflammatory disease of the joints, and the deposition of urate in the articular cavity attracts immune cells that release inflammatory cytokines. Monosodium urate (MSU) is known to be one of the activators of the NLRP3 (NLR family pyrin domain containing 3) inflammasome. After activation, the NLRP3 inflammasome releases interleukin-1ß (IL-1ß), which causes the development of many inflammatory diseases. The aim of the present study was to investigate whether AND attenuates the release of IL-1ß mediated by the NLRP3 inflammasome. The effects of AND were studied in bone marrow-derived macrophages (BMDMs) treated with lipopolysaccharide (LPS) and MSU and in mice with MSU-induced joint inflammation. AND suppressed MSU phagocytosis dose-dependently and markedly inhibited LPS- and MSU-induced IL-1ß release in BMDMs. Moreover, AND pretreatment inhibited the LPS-induced NLRP3 inflammasome priming stage by inhibiting the IKK/NFκB signaling pathway, which resulted in decreased protein expression of NLRP3 and proIL-1ß. AND induced HO-1 protein expression in a dose-dependent manner and attenuated MSU-induced ROS generation. Silencing HO-1 mitigated AND inhibition of LPS/MSU-induced IL-1ß release in J774A.1 cells. In addition, AND decreased MSU-mediated ASC binding to NLRP3. Oral administration of AND attenuated MSU-induced monocyte infiltration in mouse knee joints. These results suggest that the working mechanisms by which AND down-regulates MSU-induced joint inflammation might be via HO-1 induction and attenuation of ROS-mediated NLRP3 inflammasome assembly and subsequent IL-1ß release.


Assuntos
Diterpenos/farmacologia , Interleucina-1beta/antagonistas & inibidores , Articulação do Joelho/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Ácido Úrico/toxicidade , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/toxicidade , Linhagem Celular , Células Cultivadas , Humanos , Interleucina-1beta/metabolismo , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo
16.
J Surg Res ; 257: 468-476, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32896815

RESUMO

BACKGROUND: Donation after circulatory death donors (DCD) can expand the donor pool for heart transplantation, which primarily depends on brain death donors. Ischemia and reperfusion injury are inherent to the DCD process. We hypothesize that pharmacologic inhibition of interleukin-1 (IL-1) and/or IL-18 is protective to DCD hearts. MATERIALS AND METHODS: Following clinical protocol, in-situ ischemia time in control beating-heart donor (CBD) and DCD groups was less than 5 and 40 min, respectively. Wild type (WT) C57Bl6/j, IL-1 receptor type I knockout (IL-1RI-KO), and IL-18 KO mice were used. Hearts were reanimated for 90 min on a Langendorff system with Krebs-Henseleit buffer at 37°C, to assess physiologic parameters. Recombinant IL-1 receptor antagonist (IL-1Ra) and/or IL-18 binding protein (IL-18BP) were added to the Krebs-Henseleit buffer to inhibit IL-1 and/or the IL-18 signaling, respectively. RESULTS: Developed pressure and ± dP/dt were significantly impaired in the DCD-WT group compared to CBD-WT (P ≤ 0.05). Troponin release was higher in DCD-WT groups. Functional parameters were preserved, and troponin release was significantly less in the DCD knockout groups. Heart function was improved in DCD groups treated with IL-1Ra or IL-18BP compared to the DCD-WT group. CONCLUSIONS: Heart function was significantly impaired in the DCD-WT group compared to CBD-WT. Genetic deletion or pharmacologic blockade of IL-1 or IL-18 was protective to DCD hearts.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Obtenção de Tecidos e Órgãos , Animais , Morte , Avaliação Pré-Clínica de Medicamentos , Coração/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-18/antagonistas & inibidores , Interleucina-18/genética , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Masculino , Camundongos Knockout , Traumatismo por Reperfusão Miocárdica/metabolismo , Distribuição Aleatória
17.
J Med Chem ; 64(1): 101-122, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33351619

RESUMO

Inhibiting the NLRP3 inflammasome mediates inflammation in an extensive number of preclinical models. As excitement in this field has grown, several companies have recently initiated testing of direct NLRP3 inhibitors in the clinic. At the same time, the NLRP3 inflammasome is part of a larger pro-inflammatory pathway, whose modulation is also being explored. Multiple targets in this pathway are already impinged upon by molecules that have been through clinical trials. These data, informed by the growing mechanistic understanding of the NLRP3 inflammasome in the preclinical space, provide a rich backdrop to assess the current state of the field. Here we explore attempts to inhibit the NLRP3 inflammasome in light of clinical and preclinical data around efficacy and safety.


Assuntos
Sistemas de Liberação de Medicamentos , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Caspase 1/efeitos dos fármacos , Ensaios Clínicos como Assunto , Humanos , Inflamação/tratamento farmacológico , Interleucina-1beta/antagonistas & inibidores , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Ligação Proteica , Receptores de Interleucina-1/antagonistas & inibidores , Transdução de Sinais
18.
Mediators Inflamm ; 2020: 3412763, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33380899

RESUMO

Cryptococcus neoformans is an encapsulated yeast that causes disease mainly in immunosuppressed hosts. It is considered a facultative intracellular pathogen because of its capacity to survive and replicate inside phagocytes, especially macrophages. This ability is heavily dependent on various virulence factors, particularly the glucuronoxylomannan (GXM) component of the polysaccharide capsule. Inflammasome activation in phagocytes is usually protective against fungal infections, including cryptococcosis. Nevertheless, recognition of C. neoformans by inflammasome receptors requires specific changes in morphology or the opsonization of the yeast, impairing proper inflammasome function. In this context, we analyzed the impact of molecules secreted by C. neoformans B3501 strain and its acapsular mutant Δcap67 in inflammasome activation in an in vitro model. Our results showed that conditioned media derived from B3501 was capable of inhibiting inflammasome-dependent events (i.e., IL-1ß secretion and LDH release via pyroptosis) more strongly than conditioned media from Δcap67, regardless of GXM presence. We also demonstrated that macrophages treated with conditioned media were less responsive against infection with the virulent strain H99, exhibiting lower rates of phagocytosis, increased fungal burdens, and enhanced vomocytosis. Moreover, we showed that the aromatic metabolite DL-Indole-3-lactic acid (ILA) and DL-p-Hydroxyphenyllactic acid (HPLA) were present in B3501's conditioned media and that ILA alone or with HPLA is involved in the regulation of inflammasome activation by C. neoformans. These results were confirmed by in vivo experiments, where exposure to conditioned media led to higher fungal burdens in Acanthamoeba castellanii culture as well as in higher fungal loads in the lungs of infected mice. Overall, the results presented show that conditioned media from a wild-type strain can inhibit a vital recognition pathway and subsequent fungicidal functions of macrophages, contributing to fungal survival in vitro and in vivo and suggesting that secretion of aromatic metabolites, such as ILA, during cryptococcal infections fundamentally impacts pathogenesis.


Assuntos
Cryptococcus neoformans/metabolismo , Inflamassomos/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Polissacarídeos/química , Animais , Caspase 1/metabolismo , Criptococose , Meios de Cultivo Condicionados , Células Dendríticas/metabolismo , Imunofluorescência , Ácido Láctico/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose , Polissacarídeos/metabolismo , Fatores de Virulência/metabolismo
19.
Front Immunol ; 11: 589654, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33362770

RESUMO

The role of inflammation in atherosclerosis has been recognized several decades ago and existing treatments provide benefits in part through non-specific anti-inflammatory actions. Compared with other cytokines, interleukin-1ß (IL-1ß) is associated with acute and chronic inflammation. Anti-inflammatory therapy with canakinumab targeting the IL-1ß innate immunity pathway could significantly reduce the rate of recurrent cardiovascular events than placebo. The results of CANTOS suggested an important role of IL-1ß in atherosclerosis. However, there are numerous mechanisms that are to be clarified. We herein discussed the important immunomodulatory effect IL-1ß exerts on atherosclerosis and the potential mechanisms underlying it. We also reviewed bench-to-bedside clinical translation of IL-1ß neutralizing strategies associated with the use of IL-1ß blockade in patients with atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Interleucina-1beta/antagonistas & inibidores , Animais , Aterosclerose/imunologia , Humanos , Interleucina-1alfa/imunologia , Interleucina-1beta/imunologia
20.
Sci Rep ; 10(1): 21775, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33311551

RESUMO

There is the urgent need to study the effects of immunomodulating agents as therapy for Covid-19. An observational, cohort, prospective study with 30 days of observation was carried out to assess clinical outcomes in 88 patients hospitalized for Covid-19 pneumonia and treated with canakinumab (300 mg sc). Median time from diagnosis of Covid-19 by viral swab to administration of canakinumab was 7.5 days (range 0-30, IQR 4-11). Median PaO2/FiO2 increased from 160 (range 53-409, IQR 122-210) at baseline to 237 (range 72-533, IQR 158-331) at day 7 after treatment with canakinumab (p < 0.0001). Improvement of oxygen support category was observed in 61.4% of cases. Median duration of hospitalization following administration of canakinumab was 6 days (range 0-30, IQR 4-11). At 7 days, 58% of patients had been discharged and 12 (13.6%) had died. Significant differences between baseline and 7 days were observed for absolute lymphocyte counts (mean 0.60 vs 1.11 × 109/L, respectively, p < 0.0001) and C-reactive protein (mean 31.5 vs 5.8 mg/L, respectively, p < 0.0001).Overall survival at 1 month was 79.5% (95% CI 68.7-90.3). Oxygen-support requirements improved and overall mortality was 13.6%. Confirmation of the efficacy of canakinumab for Covid-19 warrants further study in randomized controlled trials.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , COVID-19 , Hospitalização , Interleucina-1beta/antagonistas & inibidores , SARS-CoV-2 , Idoso , COVID-19/tratamento farmacológico , COVID-19/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxigênio/administração & dosagem , Estudos Prospectivos , Taxa de Sobrevida
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