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1.
Int J Mol Sci ; 23(13)2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35806130

RESUMO

Lindera erythrocarpa contains various constituents such as cyclopentenedione-, flavonoid-, and chalcone-type components. In this study, a novel bi-linderone derivative and 17 known compounds were isolated from the leaves of L. erythrocarpa by using various chromatographic methods. The structures of the components were determined from nuclear magnetic resonance and mass spectrometry data. All isolated compounds were tested for anti-inflammatory and anti-neuroinflammatory activities in lipopolysaccharide (LPS)-induced BV2 and RAW264.7 cells. Some of these compounds showed anti-inflammatory effects by inhibiting the nitric oxide (NO) produced by LPS. In particular, linderaspirone A (16), bi-linderone (17) and novel compound demethoxy-bi-linderone (18) showed significant inhibitory effects on the production of prostaglandin E2 (PGE2), tumor necrosis factor-α, and interleukin-6. The three compounds also inhibited the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), which are pro-inflammatory proteins, and the activation of nuclear factor κB (NF-κB). Therefore, linderaspirone A (16), bi-linderone (17), and demethoxy-bi-linderone (18) isolated from the leaves of L. erythrocarpa have therapeutic potential in neuroinflammatory diseases.


Assuntos
Lindera , Microglia , Anti-Inflamatórios/química , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Lindera/química , Lindera/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Microglia/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo
2.
Sci Rep ; 12(1): 11749, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35817806

RESUMO

This study aimed to explore the mechanisms of action of a sulindac acetohydrazide derivative, N'-(4-dimethylaminobenzylidene)-2-1-(4-(methylsulfinyl) benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl) acetohydrazide, against anticancer drug cisplatin induced organ damage. Using a rodent model, various markers of organ function and signaling pathways were examined and validated by molecular docking studies. The study involves five groups of animals: control, DMSO, CDDP, CDDP + DMFM, and DMFM. Biochemical enzyme activity, histopathology, tissue antioxidant, and oxidative stress markers were examined. RT-PCR and western blot analyses were conducted for the expression of inducible cyclooxygenase enzyme (COX-2), nuclear factor kappa beta (NF-κB), p65, IL-1, TNF-α, and inducible nitric oxide synthase (iNOS). Flow cytometry analysis of CD4 + TNF-α, CD4 + COX-2, and CD4 + STAT-3 cells in whole blood was performed. Structural and dynamic behavior of DMFM upon binding with receptor molecule molecular docking and dynamic simulations were performed using bioinformatics tools and software. Treatment with DMFM reversed cisplatin-induced malondialdehyde (MDA) and nitric oxide (NO) induction, whereas the activity of glutathione peroxidase (GPx), and superoxide dismutase (SOD) in the kidney, heart, liver, and brain tissues were increased. DMFM administration normalized plasma levels of biochemical enzymes. We observed a marked decline in CD4 + STAT3, TNF-α, and COX2 cell populations in whole blood after treatment with DMFM. DMFM downregulated the expression factors related to inflammation at the mRNA and protein levels, i.e., IL-1, TNF-α, iNOS, NF-κB, STAT-3, and COX-2. Dynamic simulations and in silico docking data supports the experimental findings. Our experimental and in silico results illustrated that DMFM may affect protective action against cisplatin-induced brain, heart, liver, and kidney damage via reduction of inflammation and ROS.


Assuntos
Antioxidantes , Cisplatino , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Cisplatino/efeitos adversos , Cisplatino/metabolismo , Ciclo-Oxigenase 2/metabolismo , Humanos , Hidrazinas , Inflamação/metabolismo , Interleucina-1/metabolismo , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo , Transdução de Sinais , Sulindaco , Fator de Necrose Tumoral alfa/metabolismo
3.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 53(4): 637-641, 2022 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-35871734

RESUMO

Objective: To explore the effect of changes in the expression level of necorsis factor (NF)-κB/inducible nitric oxide synthase (iNOS) signaling pathway on hearing loss in a mouse model of sensorineural hearing loss (SNHL) induced by 3-nitropropionic acid (3-NP). Methods: The animal model was established by tympanic injection. C57BL/6 male mice were divided into three groups, 3-NP group receiving tympanic injection of 3-NP solution, 3-NP+EVP4593 group receiving tympanic injection of 3-NP solution and intraperitoneal injection of EVP4593 solution, and a control group receiving tympanic injection of phosphate buffered saline (PBS). Auditory brainstem response (ABR) was tested before and after injection. After 4 weeks, the cochlea was harvested and immunohistochemistry and qRT-PCR of NF-κB p65, RelB, iNOS, and Caspase-3 were conducted accordingly. Results: The hearing thresholds of the 3-NP group were higher than those of the control group and the 3-NP+EVP4593 group ( P<0.05), and the hearing thresholds of the 3-NP+EVP4593 group were also higher than those of the control group ( P<0.05). Immunofluorescence staining and qRT-PCR results showed that 3-NP exposure caused an increase in the expressions of NF-κB p65, RelB, and iNOS in the spiral ganglion in comparison with those of the control group ( P<0.05), and their expressions decreased with the administration of EVP4593 ( P<0.05). The expression of Caspase-3 in the spiral ganglion cells in the 3-NP group was higher than that in the control group, while in the 3-NP+EVP4593 group, it was lower than that in the 3-NP group ( P<0.05). Conclusion: This study found that, by activating the NF-κB/iNOS signaling pathway, 3-NP may cause inflammation in the spiral ganglion of the cochlear in the SNHL model mice, which may play an important role in the pathogenesis of SNHL.


Assuntos
Perda Auditiva Neurossensorial , Gânglio Espiral da Cóclea , Animais , Caspase 3 , Modelos Animais de Doenças , Perda Auditiva Neurossensorial/induzido quimicamente , Perda Auditiva Neurossensorial/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B , Óxido Nítrico Sintase Tipo II , Transdução de Sinais , Gânglio Espiral da Cóclea/patologia , Gânglio Espiral da Cóclea/fisiologia
4.
J Agric Food Chem ; 70(28): 8788-8798, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35816492

RESUMO

Flavones benefit human health through their anti-inflammatory activity; however, their structure-activity relationship is unclear. Herein, we selected 15 flavones with the same backbone but different substituents and systematically assessed their anti-inflammatory activities in RAW 264.7 regarding cellular-Src kinase (c-Src) affinity, suppression of IκBα phosphorylation, inhibition of nitric oxide (NO) and inducible nitric oxidase (iNOS) production, and downregulation of genes of proinflammatory cytokines interleukin 6 (IL-6), interleukin 1ß (IL-1ß), and tumor necrosis factor α (TNF-α). Overall, our results showed that the double bond between C2-C3 and C3'- and C4'-OH promoted anti-inflammatory activity, while C8- and C5'-OH and the methoxy group on C4' attenuated the overall anti-inflammatory and antioxidant activities. The hydroxyl groups at other positions exhibited more complicated functions. The two most effective flavones are 3',4'-dihydroxyflavone and luteolin with inhibitory concentration (IC50) values for inhibiting the LPS-induced nitric oxide level are 9.61 ± 1.36 and 16.90 ± 0.74 µM, respectively. Furthermore, they suppressed the production of iNOS by approximately 90% and inhibited IL-1ß and IL-6 by more than 95%. Taken together, our results established a relationship between the flavone structure and anti-inflammatory activity in vitro.


Assuntos
Anti-Inflamatórios , Flavonas , Macrófagos , NF-kappa B , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Proteína Tirosina Quinase CSK , Flavonas/química , Flavonas/farmacologia , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade
5.
Inflammopharmacology ; 30(4): 1369-1382, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35831735

RESUMO

Plant-derived medicinal compounds are increasingly being used to treat acute and chronic inflammatory diseases, which are generally caused by aberrant inflammatory responses. Stephania pierrei Diels, also known as Sabu-lueat in Thai, is a traditional medicinal plant that is used as a remedy for several inflammatory disorders. Since aporphine alkaloids isolated from S. pierrei tubers exhibit diverse pharmacological characteristics, we aimed to determine the anti-inflammatory effects of crude extracts and alkaloids isolated from S. pierrei tubers against lipopolysaccharide (LPS)-activated RAW264.7 macrophages. Notably, the n-hexane extract strongly suppressed nitric oxide (NO) while exhibiting reduced cytotoxicity. Among the five alkaloids isolated from the n-hexane extract, the aporphine alkaloid oxocrebanine exerted considerable anti-inflammatory effects by inhibiting NO secretion. Oxocrebanine also significantly suppressed prostaglandin E2, tumour necrosis factor-α, interleukin (IL)-1ß, IL-6, inducible nitric oxide synthase, and cyclooxygenase (COX)-2 protein expression by inactivating the nuclear factor κB, c-Jun NH2-terminal kinase, extracellular signal-regulated kinase 1/2, and phosphatidylinositol 3-kinase/Akt inflammatory signalling pathways. Molecular docking analysis further revealed that oxocrebanine has a higher affinity for toll-like receptor 4/myeloid differentiation primary response 88 signalling targets and the COX-2 protein than native ligands. Thus, our findings highlight the potential anti-inflammatory effects of oxocrebanine and suggest that certain alkaloids of S. pierrei could be used to treat inflammatory diseases.


Assuntos
Aporfinas , Stephania , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Aporfinas/metabolismo , Aporfinas/farmacologia , Ciclo-Oxigenase 2/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Stephania/metabolismo
6.
Int J Mol Sci ; 23(14)2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35887036

RESUMO

Mulberry (Morus alba L.) is a flowering tree traditionally used in Chinese herbal medicine. Mulberry leaf flavonoids (MLFs) have been reported to exert important anti-inflammatory and antioxidant properties. The purpose of this study was to select the MLF with the best anti-inflammatory and antioxidative activities from MLFs eluted by different ethanol concentrations (30%, 50%, and 75%) and explore its pharmacological properties. Three types of MLFs inhibited the production of nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and inflammatory cytokines in lipopolysaccharide (LPS)-induced RAW 264.7 cells. All MLFs boosted the antioxidative capacity by decreasing the reactive oxygen species (ROS) production and the scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals and improving the metal ion chelating activity and reducing power. The results revealed that the MLFs eluted by 30% ethanol exhibited the best anti-inflammatory and antioxidative activities. A nontargeted metabolomic analysis was used to analyze 24 types of differential flavonoids between the MLFs. Quercetin, kaempferol, and their derivatives in 30%MLF were more abundant than the other two MLFs. Furthermore, we evaluated the pharmacological activities of 30%MLF in dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) mice. The 30%MLF could alleviate the clinical symptoms, reduce the secretion of inflammatory cytokines, and inhibit the activation of the inflammatory pathway in DSS-induced colitis mice. This study will provide valuable information for the development of MLFs eluted by 30% ethanol as a functional food.


Assuntos
Morus , Animais , Anti-Inflamatórios/análise , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/análise , Antioxidantes/farmacologia , Citocinas/metabolismo , Sulfato de Dextrana , Etanol/química , Flavonoides/análise , Flavonoides/farmacologia , Camundongos , Morus/química , Óxido Nítrico Sintase Tipo II/metabolismo , Extratos Vegetais/química , Folhas de Planta/metabolismo
7.
Biomed Res Int ; 2022: 2717196, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35872858

RESUMO

Lichens are a life form in which algae and fungi have a symbiotic relationship and have various biological activities, including anti-inflammatory and antiproliferative activities. This is the first study to investigate the anti-inflammatory activity of a Phlebia sp. fungal extract (PSE) isolated from Peltigera neopolydactyla in lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophage. PSE reduced the production of the proinflammatory cytokine (tumor necrosis factor-α, interleukin-6, and interleukin-1ß), chemokine (granulocyte-macrophage colony-stimulating factor), nitric oxide, and prostaglandin E2 in the LPS-stimulated RAW264.7 macrophages. Especially, PSE inhibits the phosphorylation of activator protein-1 (AP-1) signaling (c-Fos and c-Jun) and their upstream mitogen-activated protein kinase kinases/mitogen-activated protein kinases (MKK/MAPKs: MKK4, MKK7, and JNK) and finally reduced the production of the inflammatory cytokines. The inhibitory effects mainly act via suppressing JNK-mediated AP-1 rather than the NF-κB pathway. Furthermore, PSE inhibited the production of final inflammatory effector molecules involved in AP-1 signaling, including nitric oxide (NO) and prostaglandin E2 (PGE2). Here, we report that PSE has the potential to be developed as an anti-inflammatory agent.


Assuntos
Anti-Inflamatórios , Produtos Biológicos , Polyporales , Fator de Transcrição AP-1 , Animais , Anti-Inflamatórios/farmacologia , Produtos Biológicos/farmacologia , Citocinas/metabolismo , Dinoprostona/metabolismo , Lipopolissacarídeos , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Polyporales/química , Células RAW 264.7 , Fator de Transcrição AP-1/metabolismo
8.
Org Lett ; 24(27): 4998-5002, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35792521

RESUMO

Two new peptides named uniformides A and B (1 and 2, respectively) were isolated from the cultured extracts of Nocardia uniformis IFM0856T in the presence of mouse macrophage-like cell line J774.1, in modified Czapek-Dox medium. These compounds were not produced in a culture containing only N. uniformis but in one that also included J774.1. Compounds 1 and 2 showed high cytotoxicity against J774.1 and suppressed the production of nitric oxide, IL-6, and IL-1ß by inhibiting the NF-κB pathway.


Assuntos
Nocardia , Animais , Linhagem Celular , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico , Óxido Nítrico Sintase Tipo II/metabolismo , Nocardia/metabolismo
9.
Ann Parasitol ; 68(2): 331-338, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35810365

RESUMO

Leishmaniosis is a parasitic infection spreads to humans by sand flies. Over 20 different species of Leishmania are responsible for the disease, which infect over 14 million people around the world. Chemotherapy is one of the most effective treatments for leishmaniosis, however it is restricted by the high cost and/or toxicity. In this study, the possible effect of artemisinin (ART) was detected on intracellular amastigotes of Iraqi strain of Leishmania donovani in ex vivo condition in U937 macrophage cell line. Gene expression of inducible nitric oxide synthase (iNOS) in U937 macrophage was investigated, before and after treatment with artemisinin. Kinetic result by real-time PCR demonstrated that the iNOS expression folding reached the maximum at concentration of 500 µM after 24 hours, at 750 µM after 48 hours and at 1000 µM after 72 hours, which was 56, 11, and 6, respectively. The copy number of iNOS gene expression was also significantly higher in treated infected U937 cells compared to both non-treated-infected cells and intact macrophages, under different concentration of ART along the three times of follow-up. Moreover, stained macrophages with fluorescent DAPI proved that the percentage of intracellular infective amastigotes was decreased to the minimum in treated U937 cells, in comparison to non-treated cells. The minimal amastigote-invasion percentage was recorded at 1000 µM, which was 26%, 27%, 21% compared to 61%, 87%, 75% in untreated cells after 24, 48, 72 hours respectively. These findings demonstrated ART positive efficacy against iNOS expression and this compound can be further studied as novel therapeutic rather than toxic available chemotherapies.


Assuntos
Artemisininas , Leishmania donovani , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Expressão Gênica , Humanos , Leishmania donovani/genética , Macrófagos , Óxido Nítrico/farmacologia , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/farmacologia , Células U937
10.
Pharmacol Res ; 182: 106310, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35714824

RESUMO

Non-steroidal anti-inflammatory drugs (NSAIDs) relieve inflammation by suppressing prostaglandin E2/cyclooxygenase 2 (PGE2/COX-2) with cardiovascular and gastrointestinal bleeding risk. Theoretically, suppressing PGE2 through inhibiting the terminal synthase microsomal prostaglandin E2 synthase-1 (mPGES-1) instead of upstream COX-2 is ideal for inflammation. Here, (9S,13R)-12-oxo-phytodienoic acid (AA-24) extracted from Artemisia anomala was first screened as an anti-inflammatory candidate and decreased inducible nitric oxide synthase (iNOS), nitric oxide (NO), mPGES-1, and PGE2 without affecting COX-1/2, thromboxane A2 (TXA2) and prostaglandin I2 (PGI2). Besides, AA-24 suppressed the differentiation of M0 macrophages to M1 phenotype but enhanced it to M2 phenotype, blocked the activation of NF-κB pathway, and increased the activation of Nrf2 and heme oxygenase-1 (HO-1). Moreover, AA-24 selectively inhibited mPGES-1 and reduced inflamed paw edema in carrageenan-induced mice. In conclusion, AA-24 attenuates inflammation by inhibiting mPGES-1 and modulating macrophage polarization via the NF-κB and Nrf2/HO-1 pathways and could be a promising candidate for developing anti-inflammatory drugs.


Assuntos
Heme Oxigenase-1 , NF-kappa B , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Ácidos Graxos Insaturados , Heme Oxigenase-1/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo
11.
Biosci Rep ; 42(7)2022 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-35722824

RESUMO

Sepsis is one of the leading causes of acute kidney injury (AKI), and several mechanisms including microcirculatory alterations, oxidative stress, and endothelial cell dysfunction are involved. Nitric oxide (NO) is one of the common elements to all these mechanisms. Although all three nitric oxide synthase (NOS) isoforms are constitutively expressed within the kidneys, they contribute in different ways to nitrergic signaling. While the endothelial (eNOS) and neuronal (nNOS) isoforms are likely to be the main sources of NO under basal conditions and participate in the regulation of renal hemodynamics, the inducible isoform (iNOS) is dramatically increased in conditions such as sepsis. The overexpression of iNOS in the renal cortex causes a shunting of blood to this region, with consequent medullary ischemia in sepsis. Differences in the vascular reactivity among different vascular beds may also help to explain renal failure in this condition. While most of the vessels present vasoplegia and do not respond to vasoconstrictors, renal microcirculation behaves differently from nonrenal vascular beds, displaying similar constrictor responses in control and septic conditions. The selective inhibition of iNOS, without affecting other isoforms, has been described as the ideal scenario. However, iNOS is also constitutively expressed in the kidneys and the NO produced by this isoform is important for immune defense. In this sense, instead of a direct iNOS inhibition, targeting the NO effectors such as guanylate cyclase, potassium channels, peroxynitrite, and S-nitrosothiols, may be a more interesting approach in sepsis-AKI and further investigation is warranted.


Assuntos
Injúria Renal Aguda , Sepse , Injúria Renal Aguda/etiologia , Humanos , Rim/metabolismo , Microcirculação , Óxido Nítrico , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Isoformas de Proteínas , Sepse/complicações
12.
Sci Rep ; 12(1): 9465, 2022 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-35676302

RESUMO

Evidence suggests that exposure to UV-A radiation can liberate nitric oxide from skin cells eliciting vasodilation in-vivo. However, the duration of nitric oxide release in skin cells after UV exposure is not well studied, with emphasis on UV-B mediated iNOS upregulation. The current study demonstrated persistence of nitric oxide release in a dark reaction after moderate UV-A exposure, peaking around 48 h post exposure; this effect was shown in keratinocytes, fibroblasts and endothelial cells from neonatal donors and keratinocytes from aged donors and confirmed the hypothesis that UV-A exposure appeared to upregulate cNOS alongside iNOS. Release of nitric oxide in the skin cells induced by a moderate exposure to UV-A in sunlight may be especially beneficial for some demographic groups such as the elderly, hypertensive patients or those with impaired nitric oxide function, not only during exposure but many hours and days after that.


Assuntos
Óxido Nítrico Sintase , Óxido Nítrico , Idoso , Células Endoteliais/metabolismo , Humanos , Recém-Nascido , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Pele/metabolismo , Raios Ultravioleta , Regulação para Cima
13.
Eur Rev Med Pharmacol Sci ; 26(10): 3695-3702, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35647851

RESUMO

OBJECTIVE: Coronary artery disease (CAD) is a well-known cause of morbidity and mortality in type 2 diabetes mellitus (T2DM). The role of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) in T2DM patients in relation to CAD is not well understood. We examined serum inducible and endothelial nitric oxide synthase activities in patients with T2DM in relation to the presence of coronary artery disease. PATIENTS AND METHODS: The present study was conducted in the Department of Physiology, King Saud University, Riyadh, Saudi Arabia. Subjects were grouped into control (Group A, n=87), T2DM without CAD (Group B, n=70), and T2DM patients with CAD (Group C, n=49). The selection of T2DM subjects was according to the American Diabetes Association (ADA). Serum iNOS, eNOS, hsCRP, nitrates and nitrites along with lipid profile were compared between different groups. Spearman's correlation and ROC analysis were also performed. RESULTS: Serum eNOS levels were significantly high in the control group (112.38±47.16 U/ml) than in DM without CAD (81.43±49.91 U/ml) and DM with CAD (84.80±43.32 U/ml, p<.001). Serum iNOS levels were significantly higher in DM with CAD (42.87±28.83 U/ml) compared to both control (22.08±11.77 U/ml) and DM without CAD (16.24±12.30 U/ml, p<.001). Additionally, the differences in nitrite and NO were not significant between the three groups (34.06±24.75, 33.02±21.50, 38.83±24.34 uM, p = .384), and (56.51±36.78, 49.89±28.83 vs. 55.77±30.34 uM, p=.416) respectively. ROC curve analysis revealed a sensitivity and specificity of 73.5% and 68.6% of iNOS level at a cutoff point of 21.1 U/ml to predict CAD in T2DM patients. The ROC analysis for iNOS, eNOS, and hs-CRP were .782 (p<.001), .574 (p=.170), and .726 (p<.001), respectively. CONCLUSIONS: Patients with T2DM have significantly higher levels of serum iNOS and lower levels of eNOS. However, iNOS levels were significantly higher in T2DM patients with concomitant CAD. Moreover, iNOS activity positively correlated with glycemic control and hsCRP. Therefore, iNOS could be an emerging future marker for CAD in T2DM patients and its antagonists could be useful in the management of these patients.


Assuntos
Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Óxido Nítrico Sintase Tipo III , Óxido Nítrico Sintase Tipo II , Proteína C-Reativa/metabolismo , Doença da Artéria Coronariana/complicações , Diabetes Mellitus Tipo 2/complicações , Humanos , Óxido Nítrico Sintase Tipo II/sangue , Óxido Nítrico Sintase Tipo III/sangue
14.
Carbohydr Polym ; 291: 119569, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35698336

RESUMO

The immunomodulatory effects and signalling pathways of five water-soluble yeast ß-glucan fractions (WYG1-5) with different molecular weights (Mw) and chain conformations were investigated in RAW264.7 macrophages. All five WYG fractions were shown to increase nitric oxide (NO) production, phagocytosis activity and cytokine secretion compared with the normal group. The incubation of cells with WYG for 2 h and then with lipopolysaccharide (LPS) for 24 h showed an inhibition of NO production, phagocytosis activity, cytokine secretion, and the expression of inducible nitric oxide synthase (iNOS) and cytokine mRNA compared with the LPS group. The results showed a two-way immunomodulatory effect of WYG on inflammatory factors, with the best effect for WYG-2 having a Mw of 2830 × 103 g/mol and spherical conformation. Furthermore, both mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) signalling pathways were triggered in the two-way immunomodulation. This study reveals the structure-activity relationship and provides a pharmacological basis for controlling inflammatory disorders with WYG.


Assuntos
Lipopolissacarídeos , beta-Glucanas , Citocinas/metabolismo , Imunomodulação , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Saccharomyces cerevisiae/metabolismo , Água/metabolismo , beta-Glucanas/metabolismo , beta-Glucanas/farmacologia
15.
Int J Mol Sci ; 23(11)2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35682568

RESUMO

Lipoteichoic acid (LTA) is a key cell wall component and virulence factor of Gram-positive bacteria. LTA contributes a major role in infection and it mediates inflammatory responses in the host. Rutaecarpine, an indolopyridoquinazolinone alkaloid isolated from Evodia rutaecarpa, has shown a variety of fascinating biological properties such as anti-thrombotic, anticancer, anti-obesity and thermoregulatory, vasorelaxing activity. It has also potent effects on the cardiovascular and endocrine systems. Herein, we investigated rutaecarpine's (Rut) anti-inflammatory effects in LTA-stimulated RAW macrophage cells. The Western blot and spectrophotometric results revealed that Rut inhibited the production of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and interleukin (IL)-1ß in the LTA-induced macrophage cells. Successively, our mechanistic studies publicized that Rut inhibited LTA-induced phosphorylation of mitogen-activated protein kinase (MAPK) including the extracellular signal-regulated kinase (ERK), and p38, but not c-Jun NH2-terminal kinase (JNK). In addition, the respective Western blot and confocal image analyses exhibited that Rut reserved nuclear transcription factor kappa-B (NF-κB) by hindering inhibitor of nuclear factor κB-α (IκBα) and NF-κB p65 phosphorylation and p65 nuclear translocation. These results indicate that Rut exhibits its anti-inflammatory effects mainly through attenuating NF-κB and ERK/p38 signaling pathways. Overall, this result suggests that Rut could be a potential therapeutic agent for the treatment of Gram-positive bacteria induced inflammatory diseases.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular , NF-kappa B , Animais , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Alcaloides Indólicos/farmacologia , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Quinazolinas , Células RAW 264.7 , Ácidos Teicoicos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Molecules ; 27(11)2022 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-35684465

RESUMO

Neuroinflammation is the cornerstone of most neuronal disorders, particularly neurodegenerative diseases. During the inflammatory process, various pro-inflammatory cytokines, chemokines, and enzymes-such as interleukin 1-ß (IL1-ß), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), inducible nitric oxide synthases (iNOS), inhibitory kappa kinase (IKK), and inducible nitric oxide (NO)-are over-expressed in response to every stimulus. Methods: In the present study, we focused on the anti-neuroinflammatory efficacy of (2E,4E)-N,5-bis(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienamide, encoded D5. We investigated the efficacy of D5 on the upstream and downstream products of inflammatory pathways in CHME3 and SVG cell lines corresponding to human microglia and astrocytes, respectively, using various in silico, in vitro, and in situ techniques. Results: The results showed that D5 significantly reduced the level of pro-inflammatory cytokines by up-regulating PPAR-γ expression and suppressing IKK-ß, iNOS, NO production, and NF-κB activation in inflamed astrocytes (SVG) and microglia (CHME3) after 24 h of incubation. The data demonstrated remarkably higher efficacy of D5 compared to ASA (Aspirin) in reducing NF-κB-dependent neuroinflammation. Conclusions: We observed that the functional-group alteration had an extreme influence on the levels of druggability and the immunomodulatory properties of two analogs of piperamide, D5, and D4 ((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-(4-(hydroxymethyl)phenyl)penta-2,4-dienamide)). The present study suggested D5 as a potential anti-neuroinflammatory agent for further in vitro, in vivo, and clinical investigations.


Assuntos
NF-kappa B , Óxido Nítrico , Aspirina/farmacologia , Citocinas/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , NF-kappa B/metabolismo , Neuroglia/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
17.
Sci Rep ; 12(1): 11009, 2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-35773404

RESUMO

We have previously reported that amodiaquine, a compound that binds to the ligand-binding domain of a nuclear receptor Nurr1, attenuates inflammatory responses and neurological deficits after intracerebral hemorrhage (ICH) in mice. 1,1-Bis(3'-indolyl)-1-(p-chlorophenyl)methane (C-DIM12) is another Nurr1 ligand that recognizes a domain of Nurr1 different from the ligand-binding domain. In the present study, mice were treated daily with C-DIM12 (50 or 100 mg/kg, p.o.) or amodiaquine (40 mg/kg, i.p.), or twice daily with 1400 W (20 mg/kg, i.p.), an inducible nitric oxide synthase (iNOS) inhibitor, from 3 h after ICH induction by microinjection of collagenase into the striatum. C-DIM12 improved the recovery of neurological function and prevented neuron loss in the hematoma, while suppressed activation of microglia/macrophages and expression of inflammatory mediators interleukin-6 and CC chemokine ligand 2. In addition, C-DIM12 as well as amodiaquine preserved axonal structures in the internal capsule and axonal transport function. We also found that C-DIM12 and amodiaquine suppressed the increases of iNOS mRNA expression after ICH. Moreover, 1400 W improved neurological function and prevented neuron loss, activation of microglia/macrophages and axonal transport dysfunction. These results suggest that suppression of iNOS induction contributes to several features of the therapeutic effects of Nurr1 ligands.


Assuntos
Amodiaquina , Hemorragia Cerebral , Encefalite , Indóis , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares , Animais , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Encefalite/tratamento farmacológico , Encefalite/metabolismo , Indóis/farmacologia , Ligantes , Camundongos , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo
18.
Molecules ; 27(12)2022 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-35744907

RESUMO

Inflammation is a severe topic in the immune system and play a role as pro-inflammatory mediators. In response to such inflammatory substances, immune cells release cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). Lipopolysaccharide (LPS) is known as an endotoxin in the outer membrane of Gram-negative bacteria, and it catalyzes inflammation by stimulating the secretion of inflammatory-mediated cytokines such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) by stimulated immune cells. Among the pathways involved in inflammation, nuclear factor kappa (NF-кB) and mitogen-activated protein kinases (MAPKs) are important. NF-kB is a diploid composed of p65 and IkBα and stimulates the pro- gene. MAPKs is a family consisting of the extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38, JNK and p38 play a role as proinflammatory mediators. Thus, we aim to determine the scutellarein (SCU) effect on LPS stimulated RAW264.7 cells. Furthermore, since scutellarein has been shown to inhibit the SARS coronavirus helicase and has been used in Chinese medicine to treat inflammatory disorders like COVID-19, it would be required to examine scutellarein's anti-inflammatory mechanism. We identified inflammation-inducing substances using western blot with RAW264.7 cells and SCU. And we discovered that was reduced by treatment with SCU in p-p65 and p-IκBα. Also, we found that p-JNK and p-ERK were also decreased but there was no effect in p-p38. In addition, we have confirmed that the iNOS was also decreased after treatment but there is no change in the expression of COX-2. Therefore, this study shows that SCU can be used as a compound to treat inflammation.


Assuntos
COVID-19 , NF-kappa B , Animais , Apigenina , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/efeitos adversos , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Transdução de Sinais
19.
Molecules ; 27(12)2022 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-35744910

RESUMO

Crocodile oil (CO) is generated from the fatty tissues of crocodiles as a by-product of commercial aquaculture. CO is extensively applied in the treatment of illnesses including asthma, emphysema, skin ulcers, and cancer, as well as wound healing. Whether CO has anti-inflammatory properties and encourages an immune response remains uncertain. The impact of CO on inflammatory conditions in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and the mechanisms behind it were examined in this work. Cells were treated with 0.125-2% CO dissolved in 0.5% propylene glycol with or without LPS. The production and expression of inflammatory cytokines and mediators were also examined in this research. CO reduced the synthesis and gene expression of interleukin-6 (IL-6). Consistently, CO inhibited the expression and synthesis of inflammatory markers including cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), nitric oxide (NO), and nuclear factor kappa B (NF-κB). Furthermore, CO reduced the effects of DNA damage. CO also increased the cell-cycle regulators, cyclins D2 and E2, which improved the immunological response. CO might thus be produced as a nutraceutical supplement to help avoid inflammatory diseases.


Assuntos
Jacarés e Crocodilos , Lipopolissacarídeos , Animais , Ciclo-Oxigenase 2/metabolismo , Imunidade , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óleos , Células RAW 264.7
20.
Molecules ; 27(12)2022 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-35745046

RESUMO

Oxyresveratrol (OXY) has been reported for its anti-inflammatory activity; however, the pharmaceutical applications of this compound are limited by its physicochemical properties and poor pharmacokinetic profiles. The use of an ester prodrug is a promising strategy to overcome these obstacles. In previous researches, several carboxylate esters of OXY were synthesized and oxyresveratrol tetraacetate (OXY-TAc) was reported to possess anti-melanogenic and anti-skin-aging properties. In this study, in addition to OXY-TAc, two novel ester prodrugs of OXY, oxyresveratrol tetrapropionate (OXY-TPr), and oxyresveratrol tetrabutyrate (OXY-TBu), were synthesized. Results from the Caco-2-permeation assay suggested that synthesized ester prodrugs can improve the membrane-permeation ability of OXY. The OXY-TAc exhibited the most significant profile, then this prodrug was chosen to observe anti-inflammatory activities with lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Our results showed that OXY-Tac significantly alleviated secretion of several pro-inflammatory mediators (nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)), mitigated expression of enzyme-regulated inflammation (inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)), and suppressed the MAPK cascades. Interestingly, the observed anti-inflammatory activities of OXY-TAc were more remarkable than those of its parent compound OXY. Taken together, we demonstrated that OXY-TAc improved physicochemical and pharmacokinetic profiles and enhanced the pharmacological effects of OXY. Hence, the results in the present study would strongly support the clinical utilities of OXY-TAc for the treatment of inflammation-related disorders.


Assuntos
Lipopolissacarídeos , Pró-Fármacos , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Células CACO-2 , Ciclo-Oxigenase 2/metabolismo , Ésteres/metabolismo , Ésteres/farmacologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Extratos Vegetais , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Células RAW 264.7 , Estilbenos
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