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1.
Sci Rep ; 14(1): 12786, 2024 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-38834626

RESUMO

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease marked by inflammatory cell infiltration and joint damage. The Chinese government has approved the prescription medication sinomenine (SIN), an effective anti-inflammation drug, for treating RA. This study evaluated the possible anti-inflammatory actions of SIN in RA based on bioinformatics analysis and experiments. Six microarray datasets were acquired from the gene expression omnibus (GEO) database. We used R software to identify differentially expressed genes (DEGs) and perform function evaluations. The CIBERSORT was used to calculate the abundance of 22 infiltrating immune cells. The weighted gene co-expression network analysis (WGCNA) was used to discover genes associated with M1 macrophages. Four public datasets were used to predict the genes of SIN. Following that, function enrichment analysis for hub genes was performed. The cytoHubba and least absolute shrinkage and selection operator (LASSO) were employed to select hub genes, and their diagnostic effectiveness was predicted using the receiver operator characteristic (ROC) curve. Molecular docking was undertaken to confirm the affinity between the SIN and hub gene. Furthermore, the therapeutic efficacy of SIN was validated in LPS-induced RAW264.7 cells line using Western blot and Enzyme-linked immunosorbent assay (ELISA). The matrix metalloproteinase 9 (MMP9) was identified as the hub M1 macrophages-related biomarker in RA using bioinformatic analysis and molecular docking. Our study indicated that MMP9 took part in IL-17 and TNF signaling pathways. Furthermore, we found that SIN suppresses the MMP9 protein overexpression and pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the LPS-induced RAW264.7 cell line. In conclusion, our work sheds new light on the pathophysiology of RA and identifies MMP9 as a possible RA key gene. In conclusion, the above findings demonstrate that SIN, from an emerging research perspective, might be a potential cost-effective anti-inflammatory medication for treating RA.


Assuntos
Artrite Reumatoide , Biologia Computacional , Citocinas , Metaloproteinase 9 da Matriz , Morfinanos , Morfinanos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Camundongos , Animais , Células RAW 264.7 , Biologia Computacional/métodos , Citocinas/metabolismo , Humanos , Simulação de Acoplamento Molecular , Regulação da Expressão Gênica/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Anti-Inflamatórios/farmacologia
2.
Phytomedicine ; 121: 155114, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37816287

RESUMO

BACKGROUND: Sinomenine (SIN) is the main pharmacologically active component of Sinomenii Caulis and protects against rheumatoid arthritis (RA). In recent years, many studies have been conducted to elucidate the pharmacological mechanisms of SIN in the treatment of RA. However, the molecular mechanism of SIN in RA has not been fully elucidated. PURPOSE: To summarize the pharmacological effects and molecular mechanisms of SIN in RA and clarify the most valuable regulatory mechanisms of SIN to provide clues and a basis for basic research and clinical applications. METHODS: We systematically searched SciFinder, Web of Science, PubMed, China National Knowledge Internet (CNKI), the Wanfang Databases, and the Chinese Scientific Journal Database (VIP). We organized our work based on the PRISMA statement and selected studies for review based on predefined selection criteria. OUTCOME: After screening, we identified 201 relevant studies, including 88 clinical trials and 113 in vivo and in vitro studies on molecular mechanisms. Among these studies, we selected key results for reporting and analysis. CONCLUSIONS: We found that most of the known pharmacological mechanisms of SIN are indirect effects on certain signaling pathways or proteins. SIN was manifested to reduce the release of inflammatory cytokines such as Tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), and IL-1ß, thereby reducing the inflammatory response, and apparently blocking the destruction of bone and cartilage. The regulatory effects on inflammation and bone destruction make SIN a promising drug to treat RA. More notably, we believe that the modulation of α7nAChR and the regulation of methylation levels at specific GCG sites in the mPGES-1 promoter by SIN, and its mechanism of directly targeting GBP5, certainly enriches the possibilities and the underlying rationale for SIN in the treatment of inflammatory immune-related diseases.


Assuntos
Artrite Reumatoide , Morfinanos , Humanos , Artrite Reumatoide/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Morfinanos/farmacologia , Morfinanos/uso terapêutico , Transdução de Sinais
3.
Molecules ; 28(15)2023 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-37570700

RESUMO

The roots of Astilbe grandis, known as "Ma sang gou bang", are used as a Miao traditional medicine with anti-inflammatory and analgesic properties. However, the active components and mechanism of action of this plant remain mostly uncharacterized. The aim of this study was to identify its active components and verify their pharmacological activity. The extract of A. grandis root was separated using various chromatographic methods. As a result, we obtained one novel triterpenoid, named astigranlactone (1), which has an unusual lactone moiety formed between C-7 and C-27. Additionally, a known coumarin compound, 11-O-galloyl bergenin (2) was isolated from this plant. The structures of these two compounds were elucidated by extensive NMR experiments in conjunction with HR-ESI-MS data. To the best of our knowledge, both compounds were isolated from this species for the first time. Moreover, we tested the anti-inflammation effect of the two compounds by establishing a cellular inflammation model induced by LPS in RAW264.7 cells. The effect of different concentrations of these compounds on the activity of RAW264.7 cells was assessed using a CCK8 assay. The levels of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) in the supernatant of each group were evaluated using the Griess method and an enzyme-linked immunosorbent assay (ELISA). Western blot and quantitative real-time PCR (qRT-RCR) were used to measure the levels of cyclooxygenase 2 (COX-2) and nitric oxide synthase (iNOS) gene expression. Our findings revealed that these two compounds inhibited the high levels of NO, TNF-α, IL-6, IL-1ß, COX-2, and iNOS (induced by LPS). Mechanistic studies demonstrated that these two compounds reduced the activation of the nuclear transcription factor-B (NF-κB) signaling pathway by inhibiting the phosphorylation of p65. Therefore, our study indicates that compounds 1 and 2 can exert a definite anti-inflammatory effect by inhibiting the NF-κB signaling pathway.


Assuntos
Lipopolissacarídeos , NF-kappa B , Animais , Camundongos , NF-kappa B/metabolismo , Lipopolissacarídeos/farmacologia , Interleucina-6/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Macrófagos , Células RAW 264.7 , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/metabolismo , Cumarínicos/farmacologia , Cumarínicos/metabolismo , Óxido Nítrico/metabolismo
4.
Molecules ; 27(19)2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36234773

RESUMO

Akebia saponin D (ASD) is derived from the Dipsacus asper Wall. ex Henry, which is a traditional Chinese medicine commonly used to treat rheumatic arthritis (RA). However, the in-depth mechanism of the anti-inflammatory effect of ASD is still unclear. This study aimed to preliminarily explore the anti-inflammatory effect of ASD and the underlying mechanisms from the perspective of DNA methylation and inflammation-related pathways. We found that ASD significantly reduced the production of multiple inflammatory mediators, including nitric oxide (NO) and prostaglandin E2 (PGE2), in LPS-induced RAW264.7 cells. The expression of DNA methyltransferase (DNMT) 3b and inducible nitric oxide synthase (iNOS) was also obviously inhibited by the ASD treatment. The protein and mRNA levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were also significantly inhibited by ASD. ASD inhibited the macrophage M1 phenotype, inhibited the high level of DNMT3b, and downregulated the signal transducer and activator of the transcription 3 (STAT3) pathway to exert its anti-inflammatory activity. Furthermore, DNMT3b siRNA and Nrf2 siRNA significantly promoted the anti-inflammatory effect of ASD. Our study demonstrates for the first time that ASD inhibits the IL-6-STAT3-DNMT3b axis and activates the nuclear factor-E2-related factor 2 (Nrf2) signaling pathway to achieve its inhibitory effect on inflammatory reactions.


Assuntos
Interleucina-6 , Fator 2 Relacionado a NF-E2 , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , DNA/uso terapêutico , Dinoprostona/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Metiltransferases/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , RNA Mensageiro , RNA Interferente Pequeno/uso terapêutico , Fator de Transcrição STAT3 , Saponinas , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
5.
Front Pharmacol ; 13: 934720, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35800436

RESUMO

The purpose of this study was to investigate the effects of Huangqi Liuyi decoction extract (HQD) on diabetic nephropathy (DN), and the tissue distribution difference of six main active ingredients of HQD between normal and DN mouse models. DN mice were administered HQD for 12 weeks to investigate its efficacy in the treatment of DN. Liquid chromatography-tandem mass-spectrometry (HPLC-MS/MS) was used to analyze the tissue distribution of the six active ingredients of HQD in normal and DN mice, including astragaloside IV, calycosin-7-O-ß-D-glucoside, calycosin glucuronide, ononin, formononetin, and glycyrrhizic acid. DN mice treated with HQD showed significantly decreased fasting blood glucose (FBG), 24-h urinary protein (24 h U-Alb), blood urea nitrogen (BUN), serum creatinine (Scr), and triglyceride levels (TG) (p < 0.05). Moreover, there were no significant differences in pharmacodynamics between HQD and Huangqi Liuyi decoction. Treated mice also had decreased expression of collagen I, ɑ-smooth muscle actin (ɑ-SMA), and vimentin; and upregulated expression of E-cadherin in their kidneys. Compared to normal mice, distributions of the six ingredients in the liver, heart, spleen, lungs, kidneys, stomach, small intestine, brain, and muscle of DN mice were different. The results indicated that the HQD could be used for the treatment of DN and to improve renal function. The pathological state of diabetic nephropathy may affect tissue distribution of HQD active ingredients in mice.

6.
Biochim Biophys Acta Gene Regul Mech ; 1865(3): 194813, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35417776

RESUMO

Prostaglandin E2 (PGE2) in cancer and inflammatory diseases is a key mediator of disease progression. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to inhibit the expression of PGE2 by depressing cyclooxygenase (COX) in inflammatory treatments. However, the inhibition to COXs may cause serious side effects. Thus, it is urgent to develop new anti-inflammatory drugs aiming new targets to inhibit PGE2 production. Microsomal prostaglandin E synthase 1 (mPGES-1) catalyzes the final step of PGE2 biosynthesis. Therefore, the selective inhibition of mPGES-1 has become a promising strategy in the treatments of cancer and inflammatory diseases. Our previous studies confirmed that sinomenine (SIN) is a specific mPGES-1 inhibitor. However, the exact mechanism by which SIN inhibits mPGES-1 remains unknown. This study aimed to explain the regulation effect of SIN to mPGES-1 gene expression by its DNA methylation induction effect. We found that the demethylating agent 5-azacytidine (5-AzaC) reversed the inhibitory effect of SIN to mPGES-1. Besides, SIN selectively increased the methylation level of the promoter region in the mPGES-1 gene while the pretreatment of 5-AzaC suppressed this effect. The results also shows that pretreatment with SIN increased the methylation level of specific GCG sites in the promoter region of mPGES-1. This specific methylation site may become a new biomarker for predicting and diagnosing RA and cancer with high expression of mPGES-1. Also, our research provides new ideas and solutions for clinical diagnosis and treatment of diseases related to mPGES-1 and for targeted methylation strategy in drug development.


Assuntos
Anti-Inflamatórios , Dinoprostona , Dinoprostona/metabolismo , Metilação , Morfinanos , Regiões Promotoras Genéticas , Prostaglandina-E Sintases/genética , Prostaglandina-E Sintases/metabolismo
7.
Phytomedicine ; 100: 154050, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35397284

RESUMO

BACKGROUND: Sinomenine (SIN) is an anti-inflammatory drug that has been used for decades in China to treat arthritis. In a previous study, SIN acted on α7 nicotinic acetylcholine receptor (α7nAChR) to inhibit inflammatory responses in macrophages, which indicates a new anti-inflammatory mechanism of SIN. However, the level of α7nAChR was increased in the inflammatory responses and was downregulated by SIN in vitro, so the underlying mechanisms of SIN acting on α7nAChR remain unclear. PURPOSE: To analyze the role of α7nAChR in inflammation and the effect and mechanism of SIN regulation of α7nAChR. METHODS: The effects of SIN on α7nAChR in endotoxemic mice and LPS-stimulated macrophages were observed. Nicotine (Nic) was used as a positive control, and berberine (Ber) was used as a negative control targeting α7nAChR. The antagonists of α7nAChR, α-bungarotoxin (BTX) and mecamylamine (Me), were used to block α7nAChR. In RAW264.7 macrophage cells in vitro, α7nAChR short hairpin RNA (shRNA) was used to knock down α7nAChR. Macrophage polarization was analyzed by the detection of TNF-α, IL-6, iNOS, IL-10, Arg-1, and Fizz1. U0126 was used to block ERK phosphorylation. The cytokines α7nAChR, ERK1/2, p-ERK1/2 and Egr-1 were detected. RESULTS: SIN decreased the levels of TNF-α, IL-6 and the expression of α7nAChR increased by LPS in endotoxemic mice. The above effects of SIN were attenuated by BTX. In the α7nAChR shRNA transfected RAW264.7 cells, compared with the control, α7nAChR was knocked down, and M1 phenotype markers (including TNF-α, IL-6, and iNOS) were significantly downregulated, whereas M2 phenotype markers (including IL-10, Arg-1, and Fizz1) were significantly upregulated when stimulated by LPS. SIN inhibited the expression of p-ERK1/2 and the transcription factor Egr-1 induced by LPS in RAW264.7 cells, and the above effects of SIN were attenuated by BTX. The expression of α7nAChR was suppressed by U0126, which lessened the expression of p-ERK1/2 and Egr-1. CONCLUSIONS: SIN acts on α7nAChR to inhibit inflammatory responses and downregulates high expression of α7nAChR in vivo and in vitro. The increase of α7nAChR expression is correlated with inflammatory responses and participates in macrophage M1 polarization. SIN downregulates α7nAChR via a feedback pathway of α7nAChR/ERK/Egr-1, which contributes to inhibiting macrophage M1 polarization and inflammatory responses.


Assuntos
Interleucina-10 , Receptor Nicotínico de Acetilcolina alfa7 , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Retroalimentação , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos , Camundongos , Morfinanos , RNA Interferente Pequeno/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
8.
Pharmacol Res ; 175: 105977, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34798265

RESUMO

Inflammation is closely linked to the abnormal phospholipid metabolism chain of cyclooxygenase-2/microsomal prostaglandin E2 synthase-1/prostaglandin E2 (COX-2/mPGES-1/PGE2). In clinical practice, non-steroidal anti-inflammatory drugs (NSAIDs) as upstream COX-2 enzyme activity inhibitors are widely used to block COX-2 cascade to relieve inflammatory response. However, NSAIDs could also cause cardiovascular and gastrointestinal side effects due to its inhibition on other prostaglandins generation. To avoid this, targeting downstream mPGES-1 instead of upstream COX is preferable to selectively block overexpressed PGE2 in inflammatory diseases. Some mPGES-1 inhibitor candidates including synthetic compounds, natural products and existing anti-inflammatory drugs have been proved to be effective in in vitro experiments. After 20 years of in-depth research on mPGES-1 and its inhibitors, ISC 27864 have completed phase II clinical trial. In this review, we intend to summarize mPGES-1 inhibitors focused on their inhibitory specificity with perspectives for future drug development.


Assuntos
Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Prostaglandina-E Sintases/antagonistas & inibidores , Prostaglandina-E Sintases/metabolismo , Animais , Humanos
9.
Artigo em Inglês | MEDLINE | ID: mdl-33163082

RESUMO

AIM: To screen active sites from roots, stems, and leaves of Caesalpinia minax and study its antitumor effect. METHODS: Human liver cancer HuH-7 cells were used to screen the active sites of C. minax by MTT assay, and the polar extracts were analyzed by high-performance liquid chromatography (HPLC). The medicated serum prepared from rats was used to investigate the effect on the proliferation of Hepa 1-6 mouse hepatoma cells. The H22 hepatoma-bearing mice model was established and treated with the petroleum ether extract of stems and leaves (HY②) by intraperitoneal injection (20, 60 mg·kg-1) and intragastric (100, 300 mg·kg-1) for 12 days. RESULTS: The petroleum ether extracts were the effective active site. The IC50 value of the petroleum ether extract of stems and leaves (HY②) was 58.9 µg·ml-1, and that of the roots (HG②) was 46.79 µg·ml-1. The grey relational analysis cleared that the 11 common peaks of the active extracts had a close correlation with the antitumor activity. The medicated serum prepared by ip. administration had a significant inhibitory effect on the Hepa1-6 cells, but it had no inhibitory effect by intragastric administration. High-dose administration significantly reduced tumor size in H22 hepatoma-bearing mice, and the tumor inhibition rates were 64.47% and 53.41%. Necrosis of tumor cells, infiltration of inflammatory cells, and fibrous tissue proliferation were promoted, and the expression of the proliferating cell nuclear antigen (PCNA) and vascular endothelial growth factor (VEGF) was reduced compared with the control group. CONCLUSION: The petroleum ether extract of C. minax had a significant antitumor activity. An immunohistochemical study showed that, through inhibiting the expression of the VEGF and growth of the tumor blood vessel, the proliferation of tumor cell and expression of PCNA can be inhibited.

10.
Biochem Pharmacol ; 173: 113639, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31536727

RESUMO

The side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in the cardiovascular system mainly result from its inhibitory effect on cyclooxygenase-2 (COX-2). Since NSAIDs are one of the most commonly used anti-inflammatory drugs in the clinic, it is necessary to identify new anti-inflammatory drugs that are safer than NSAIDs. Nardosinanone N (NAN), a compound isolated from the roots and rhizomes of Nardostachys chinensis, was evaluated for its anti-inflammatory effects using the lipopolysaccharide (LPS)-stimulated RAW264.7 cell line and rat peritoneal macrophage models. First, we found that NAN down regulated the levels of nitric oxide (NO), inducible nitric oxide synthase (iNOS) and prostaglandin E2 (PGE2), but not cyclooxygenase-2 (COX-2). Additionally, NAN reduced the M1 macrophage phenotype and increased the M2 macrophage phenotype. Furthermore, mechanistic studies showed that NAN activated the nuclear factor-erythroid 2 -related factor 2 (Nrf2) signaling pathway, which, in turn, increased the expression of antioxidant protein heme oxygenase-1 (HO-1) to achieve its anti-inflammatory effect. Finally, Nrf2 siRNA and the HO-1 inhibitor significantly attenuated the anti-inflammatory effect of NAN. More interestingly, we found that NAN did not affect COX-2 expression and activity but reduced the PGE2 concentration by selective inhibition of microsomal prostaglandin E synthase-1 (mPGES-1). In conclusion, NAN may be a new anti-inflammatory drug that has fewer side effects than NSAIDs and can be a new potential Nrf2 activator and mPGES-1 inhibitor.


Assuntos
Compostos de Epóxi/farmacologia , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Nardostachys/química , Preparações de Plantas/farmacologia , Prostaglandina-E Sintases/metabolismo , Terpenos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Células Cultivadas , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Compostos de Epóxi/química , Expressão Gênica/efeitos dos fármacos , Macrófagos/classificação , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Microssomos/efeitos dos fármacos , Microssomos/enzimologia , Estrutura Molecular , Fator 2 Relacionado a NF-E2/genética , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Preparações de Plantas/química , Prostaglandina-E Sintases/genética , Células RAW 264.7 , Ratos , Transdução de Sinais/efeitos dos fármacos , Terpenos/química , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
11.
Molecules ; 24(13)2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31284554

RESUMO

Nardochinoid B (NAB) is a new compound isolated from Nardostachys chinensis. Although our previous study reported that the NAB suppressed the production of nitric oxide (NO) in lipopolysaccharide (LPS)-activated RAW264.7 cells, the specific mechanisms of anti-inflammatory action of NAB remains unknown. Thus, we examined the effects of NAB against LPS-induced inflammation. In this study, we found that NAB suppressed the LPS-induced inflammatory responses by restraining the expression of inducible nitric oxide synthase (iNOS) proteins and mRNA instead of cyclooxygenase-2 (COX-2) protein and mRNA in RAW264.7 cells, implying that NAB may have lower side effects compared with nonsteroidal anti-inflammatory drugs (NSAIDs). Besides, NAB upregulated the protein and mRNA expressions of heme oxygenase (HO)-1 when it exerted its anti-inflammatory effects. Also, NAB restrained the production of NO by increasing HO-1 expression in LPS-stimulated RAW264.7 cells. Thus, it is considered that the anti-inflammatory effect of NAB is associated with an induction of antioxidant protein HO-1, and thus NAB may be a potential HO-1 inducer for treating inflammatory diseases. Moreover, our study found that the inhibitory effect of NAB on NO is similar to that of the positive drug dexamethasone, suggesting that NAB has great potential for developing new drugs in treating inflammatory diseases.


Assuntos
Heme Oxigenase-1/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/metabolismo , Citocinas/biossíntese , Mediadores da Inflamação , Magnoliopsida/química , Camundongos , Modelos Biológicos , Estrutura Molecular , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Extratos Vegetais/química , Células RAW 264.7
12.
Immunopharmacol Immunotoxicol ; 41(1): 172-177, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30896303

RESUMO

Objective: To investigate the cellular mechanism that sinomenine (SIN) inhibits inflammation in macrophages induced by LPS through α7 nicotinic acetylcholine receptor (α7nAChR). Materials and methods: RAW264.7 cells were stimulated with LPS and treated by SIN or nicotine (Nic). A selective antagonist of α7nAChR, α-bungarotoxin (BTX) was used to block α7nAChR. AG490 was used to inhibit JAK2 activation. ELISA was performed to detect the levels of TNF-α and MCP-1. Western blotting was used to analyze the expression of MIF, MMP-9, CD14, TLR4, STAT3 and p-STAT3. Intracellular-free calcium level was measured by Fluorescent probe fluo-3/AM Results: SIN inhibited the production of TNF-α, MCP-1, MIF, and MMP-9, decreased the expression of CD14 and TLR4, and inhibited the release of intracellular-free calcium from intracellular stores in RAW 264.7 cells stimulated by LPS. JAK-specific inhibitor AG490 attenuated the inhibitory effect of SIN on TNF-α. SIN increased the phosphorylation of STAT3. And the above effects of SIN were attenuated by antagonist of α7nAChR. Conclusions: SIN can decrease the expression of CD14/TLR4 and intracellular free calcium level, activate JAK2/STAT3 pathway to inhibit inflammatory response through α7nAChR in macrophages.


Assuntos
Anti-Inflamatórios/farmacologia , Cálcio/metabolismo , Janus Quinase 2/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Morfinanos/farmacologia , Fator de Transcrição STAT3/metabolismo , Receptor 4 Toll-Like/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Células RAW 264.7 , Transdução de Sinais
13.
Front Pharmacol ; 9: 911, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30233360

RESUMO

The roots and rhizomes of Nardostachys chinensis have neuroprotection and cardiovascular protection effects. However, the specific mechanism of N. chinensis is not yet clear. Nardochinoid C (DC) is a new compound with new skeleton isolated from N. chinensis and this study for the first time explored the anti-inflammatory and anti-oxidant effect of DC. The results showed that DC significantly reduced the release of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-activated RAW264.7 cells. The expression of pro-inflammatory proteins including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were also obviously inhibited by DC in LPS-activated RAW264.7 cells. Besides, the production of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were also remarkably inhibited by DC in LPS-activated RAW264.7 cells. DC also suppressed inflammation indicators including COX-2, PGE2, TNF-α, and IL-6 in LPS-stimulated THP-1 macrophages. Furthermore, DC inhibited the macrophage M1 phenotype and the production of reactive oxygen species (ROS) in LPS-activated RAW264.7 cells. Mechanism studies showed that DC mainly activated nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, increased the level of anti-oxidant protein heme oxygenase-1 (HO-1) and thus produced the anti-inflammatory and anti-oxidant effects, which were abolished by Nrf2 siRNA and HO-1 inhibitor. These findings suggested that DC could be a new Nrf2 activator for the treatment and prevention of diseases related to inflammation and oxidative stress.

14.
Org Lett ; 20(18): 5813-5816, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30156853

RESUMO

Three unusual sesquiterpenoid dimers, nardochinoids A-C (1-3), were isolated from Nardostachys chinensis Batal. Compound 1 features a rare fused 3,8-dioxatricyclo[7.2.1.01,6]dodecane-11-one ring system, compound 2 is the first nitrogen-containing nornardosinane-aristolane sesquiterpene conjugate, and compound 3 represents the first example of the dimer of a nornardosinane and a nardosinane sesquiterpene. Their structures were characterized by NMR spectroscopic methods and X-ray single-crystal diffraction analysis. Compound 3 showed significant anti-inflammatory activities.

15.
Biochem Pharmacol ; 142: 133-144, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28711625

RESUMO

Recently, microsomal prostaglandin E synthase 1 (mPGES-1) has attracted much attention from pharmacologists as a promising strategy and an attractive target for treating various types of diseases including rheumatoid arthritis (RA), which could preserve the anti-inflammatory effect while reducing the adverse effects often occur during administration of non-steroidal anti-inflammatory drugs (NSAIDs). Here, we report that sinomenine (SIN) decreased prostaglandin (PG)E2 levels without affecting prostacyclin (PG)I2 and thromboxane (TX)A2 synthesis via selective inhibiting mPGES-1 expression, a possible reason of low risk of cardiovascular event compared with NSAIDs. In addition, mPGES-1 protein expression was down-regulated by SIN treatment in the inflamed paw tissues both in carrageenan-induced edema model in rats and the collagen-II induced arthritis (CIA) model in DBA mice. More interestingly, SIN suppressed the last step of mPGES-1 gene expression by decreasing the DNA binding ability of NF-κB, paving a new way for drug discovery.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/tratamento farmacológico , Edema/tratamento farmacológico , Expressão Gênica/efeitos dos fármacos , Morfinanos/uso terapêutico , Prostaglandina-E Sintases/genética , Células A549 , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/imunologia , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Edema/imunologia , Feminino , Macrófagos Peritoneais/efeitos dos fármacos , Masculino , Camundongos Endogâmicos DBA , Morfinanos/efeitos adversos , Morfinanos/isolamento & purificação , Morfinanos/farmacologia , Ratos Sprague-Dawley , Transfecção
16.
Fitoterapia ; 119: 75-82, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28390974

RESUMO

Six new sesquiterpenoids, namely nardosinanones J-N and nardoaristolone C, were isolated from the rhizomes and roots of Nardostachys chinensis Batal. Their structures were determined by interpretation of spectroscopic data (HR-ESI-MS, 1D and 2D NMR). A combination of X-ray crystal diffraction, ECD calculation, and Mosher ester methods was employed to determine the absolute configuration of the isolated compounds. Compounds 1-2, 4-6 were evaluated anti-inflammatory activities in LPS-stimulated RAW264.7 macrophages. The results showed that compound 5 obviously inhibited LPS-induced iNOS and COX-2 protein expression compared to single LPS stimulation, which indicated the potential effect to medicate anti-inflammatory.


Assuntos
Anti-Inflamatórios/química , Nardostachys/química , Sesquiterpenos/química , Animais , Anti-Inflamatórios/isolamento & purificação , Ciclo-Oxigenase 2/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Óxido Nítrico Sintase Tipo II/metabolismo , Raízes de Plantas/química , Células RAW 264.7 , Rizoma/química , Sesquiterpenos/isolamento & purificação
17.
Oncotarget ; 8(14): 22563-22580, 2017 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-28186966

RESUMO

Prostate cancer (PCa) is one of the most common malignant tumors in men. The etiology and pathogenesis of PCa remain unclear. P21-activated kinase 1 (PAK1) is a member of a family of serine/threonine kinases and regulates cell growth and contributes to tumor invasion and metastasis. However, the association of PAK1 with PCa tumorigenesis and in particular with cell autophagy remains unknown. We found that the positive expression of PAK1 was significantly increased in PCa patients compared with BPH patients (P < 0.05). The expression of PAK1, p-PAK1 and LC3B1 in DU145 was increased by the activator of mTOR MYH1485. The expression of PAK1, p-PAK1, mTOR and Beclin1 decreased in PAK1-shRNA expressing DU145 cell. Knocking down of PAK1 inhibited DU145 cell growth, invasion and migration in vitro, and inhibited tumor growth in vivo. Our study demonstrated that PAK1 is upregulated in PCa and regulated by the mTOR signaling pathway and contributes to tumor autophagy. Thus, PAK1 may be a potential tumor marker and therapeutic target of PCa.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Próstata/imunologia , Quinases Ativadas por p21/metabolismo , Autofagia , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Biomarcadores Tumorais/genética , Carcinogênese , Proliferação de Células/genética , Células Cultivadas , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Neoplasias da Próstata/diagnóstico , RNA Interferente Pequeno/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Transcriptoma , Quinases Ativadas por p21/genética
18.
PLoS One ; 12(1): e0170964, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28129392

RESUMO

BACKGROUND AND AIM: Many studies have reported that genetic variants correlate with higher risk for coronary artery disease (CAD) or in-stent restenosis (ISR) after bare metal stent (BMS) implantation. However, there is limited data assessing the impact of these variants on ISR in patients treated with drug-eluting stent (DES). The purpose of this study was to investigate the effects of genetic risk factors on ISR in Chinese Han patients treated with DES. METHODS: A total of 425 patients with a diagnosis of CAD who underwent successful revascularization in native coronary arteries with DES were included in this retrospective study. Genotyping was performed on six single nucleotide polymorphisms (SNPs) in the endothelial nitric oxide synthase gene (eNOS), the angiotensin converting enzyme gene (ACE), the angiotensin II type 1 receptor gene (AT1R), the transforming growth factor beta gene (TGF-ß), and the vascular endothelial growth factor gene (VEGF). Quantitative coronary angiography (QCA) was performed during the follow-up period to detect ISR. Logistic regression models were used to test for association. RESULTS: Fifty-four patients (12.7%) developed ISR during the follow-up period. Of the six analyzed SNPs, the frequency of the C allele of T786C polymorphism in eNOS was significantly higher in the ISR group (22.2%) compared to the non-ISR group (12.7%) (p<0.01). In the ISR group, the frequency of the TT, TC, and CC genotypes was 61.1%, 33.3%, and 5.6%, respectively, and in the non-ISR group, the frequencies were 76.8%, 21.0%, and 2.2%, respectively. The multivariable analysis adjusted for potential confounders and revealed that the T786C polymorphism increased the risk of ISR in both additive and dominant models with odds ratios of 1.870 (95% confidence interval [CI]: 1.079-3.240, p = 0.03) and 2.045 (95% CI: 1.056-3.958, p = 0.03), respectively. CONCLUSION: The eNOS T786C polymorphism was associated with ISR in Chinese Han patients treated with DES. Genotyping may be helpful to identify patients with higher risks of ISR after DES implantation.


Assuntos
Doença da Artéria Coronariana/genética , Reestenose Coronária/genética , Stents Farmacológicos/efeitos adversos , Óxido Nítrico Sintase/genética , Adulto , Idoso , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/cirurgia , Reestenose Coronária/patologia , Reestenose Coronária/cirurgia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Stents/efeitos adversos
19.
Shock ; 44(2): 188-95, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25895149

RESUMO

Sinomenine (SIN), an alkaloid derived from the plant Sinomenium acutum, has anti-inflammatory and analgesic effects and has been used for rheumatoid arthritis treatment in China. This study aims to verify the hypothesis that SIN acts on α7 nicotinic acetylcholine receptor (α7nAChR) to inhibit the activation of macrophages stimulated by lipopolysaccharide. The prototypical α7nAChR antagonist α-bungarotoxin and mecamylamine attenuated the effect of SIN on tumor necrosis factor-α and interleukin-6 in RAW264.7 murine macrophage-like cells and primary peritoneal macrophages of mouse induced by lipopolysaccharide. With the knockdown of α7nAChR expression in RAW264.7 cells by small interfering RNA, the inhibitory effect of SIN on tumor necrosis factor-α and interleukin-6 was reversed. Sinomenine decreased p65 expression in nuclear and increased IκBα expression in cytoplasm, and these effects were reversed by the α7nAChR small interfering RNA as well. These results indicate that the anti-inflammatory effects of SIN on macrophages in vitro depend on α7nAChR.


Assuntos
Anti-Inflamatórios/química , Lipopolissacarídeos/química , Macrófagos Peritoneais/efeitos dos fármacos , Morfinanos/química , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Bungarotoxinas/química , Citoplasma/metabolismo , Proteínas I-kappa B/metabolismo , Interleucina-6/metabolismo , Macrófagos Peritoneais/metabolismo , Masculino , Mecamilamina/química , Camundongos , Camundongos Endogâmicos BALB C , Inibidor de NF-kappaB alfa , Células RAW 264.7 , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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