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1.
Chem Pharm Bull (Tokyo) ; 71(2): 183-187, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36724981

RESUMO

A formerly unpublicized briarane diterpenoid, briastecholide M (1), and its established analogue, brianodin B (2), were purified from Briareum stechei, an octocoral collected from Okinawan waters. Using spectroscopic methods, the structure of 1 was established. Functional study showed that 1 can reducing the release of inducible nitric oxide synthase (iNOS) but enhancing cyclooxygenase-2 (COX-2) protein expression.


Assuntos
Antozoários , Diterpenos , Animais , Antozoários/química , Antozoários/metabolismo , Diterpenos/farmacologia , Diterpenos/química , Óxido Nítrico Sintase Tipo II/metabolismo , Ciclo-Oxigenase 2/metabolismo
2.
J Adv Res ; 44: 201-212, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36725190

RESUMO

INTRODUCTION: Lipopolysaccharide (LPS) causes lesions of the epithelial barrier, which allows translocation of pathogens from the intestinal lumen to the host's circulation. Hydrogen sulfide (H2S) regulates multiple physiological and pathological processes in colonic epithelial tissue, and CBS-H2S axis involved in multiple gastrointestinal disorder. However, the mechanism underlying the effect of the CBS-H2S axis on the intestinal and systemic inflammation in colitis remains to be illustrated. OBJECTIVES: To investigate the effect of CBS-H2S axis on the intestinal and systematic inflammation related injuries in LPS induced colitis and the underlying mechanisms. METHODS: Wild type and CBS-/+ mice were used to evaluate the effect of endogenous and exogenous H2S on LPS-induced colitis in vivo. Cytokine quantitative antibody array, western blot and real-time PCR were applied to detect the key cytokines in the mechanism of action. Biotin switch of S-sulfhydration, CRISPR/Cas9 mediated knockout, immunofluorescence and ActD chase assay were used in the in vitro experiment to further clarify the molecular mechanisms. RESULTS: H2S significantly alleviated the symptoms of LPS-induced colitis in vivo and attenuated the increase of COX-2 expression. The sulfhydrated HuR increased when CBS express normally or GYY4137 was administered. While after knocking kown CBS, the expression of COX-2 in mice colon increased significantly, and the sulfhydration level of HuR decreased. The results in vitro illustrated that HuR can increase the stability of COX-2 mRNA, and the decrease of COX-2 were due to increased sulfhydration of HuR rather than the reduction of total HuR levels. CONCLUSION: These results indicated that CBS-H2S axis played an important role in protecting intestinal barrier function in colitis. CBS-H2S axis increases the sulfhydration level of HuR, by which reduces the binding of HuR with COX-2 mRNA and inhibited the expression of COX-2.


Assuntos
Colite , Sulfeto de Hidrogênio , Humanos , Camundongos , Animais , Ciclo-Oxigenase 2 , Lipopolissacarídeos , Sulfeto de Hidrogênio/metabolismo , Sulfeto de Hidrogênio/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Inflamação
3.
J Enzyme Inhib Med Chem ; 38(1): 2162511, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36633257

RESUMO

A novel series of 12 antipyrine derivatives containing 1,3,4-oxadiazoles (4a-d), 1,3,4-thiadiazoles (6a-d), and pyrimidines (8a-d), was preparedand assessed for its potential in vitro COX-2 inhibitors. Compared to Celecoxib, compounds 4b-d and 8d were the most potent derivatives c with a half-maximal inhibitory concentration range of 53-69 nM. Considering COX-2 selectivity index, compounds 4 b and 4c were chosen among these most potent derivatives for further investigation. The in vivo ability of compounds 4 b and 4c to counteract carrageenan-induced paw edoema has been assessed and their potential underlying mechanisms have been elucidated and the results have been further validated using molecular docking simulations.


Assuntos
Anti-Inflamatórios , Antipirina , Humanos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antipirina/farmacologia , Celecoxib/farmacologia , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Edema/tratamento farmacológico , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
4.
Mediators Inflamm ; 2023: 5156320, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36687217

RESUMO

Background: Breast and ovarian cancers are two common malignancies in women and a leading cause of death globally. The aim of the present study was to explore the effects of a novel chalcone derivative 1-(4-(methylsulfonyl)phenyl)-3-(phenylthio)-3-(p-tolyl)propane-1-one (MPP) individually or combined with curcumin, a well-known herbal medicine with anticancer properties, as a new combination therapy on inflammatory pathways in breast and ovarian cancer cell lines. Methods: LPS-induced NF-κB DNA-binding activity and the levels of proinflammatory cytokines were measured in the MPP- and MPP-curcumin combination-treated MDA-MB-231 and SKOV3 cells by ELISA-based methods. The expression of COX2, INOS, and MMP9 genes and nitrite levels was also evaluated by real-time qRT-PCR and Griess method, respectively. IκB levels were evaluated by Western blotting. Results: MPP significantly inhibited the DNA-binding activity of NF-κB in each cell line and subsequently suppressed the expression of downstream genes including COX2, MMP9, and INOS. The levels of proinflammatory cytokines, as well as NO, were also decreased in response to MPP. All the effects of MPP were enhanced by the addition of curcumin. MPP, especially when combined with curcumin, caused a remarkable increase in the concentration of IκB. Conclusion: MPP and its coadministration with curcumin effectively reduced the activity of the NF-κB signaling pathway, leading to a reduced inflammatory response in the environment of cancer cells. Thus, MPP, either alone or combined with curcumin, might be considered an effective remedy for the suppression of inflammatory processes in breast and ovarian cancer cells.


Assuntos
Chalconas , Curcumina , Neoplasias Ovarianas , Feminino , Humanos , NF-kappa B/metabolismo , Metaloproteinase 9 da Matriz , Ciclo-Oxigenase 2 , Citocinas/metabolismo , Proteínas I-kappa B , Neoplasias Ovarianas/tratamento farmacológico
5.
J Neuroendocrinol ; 35(1): e13228, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36690381

RESUMO

Hippocampal neuropathology is a recognized feature of the spontaneously hypertensive rat (SHR). The hippocampal alterations associate with cognitive impairment. We have shown that hippocampal abnormalities are reversed by 17ß-estradiol, a steroid binding to intracellular receptors (estrogen receptor α and ß subtypes) or the membrane-located G-protein coupled estradiol receptor. Genistein (GEN) is a neuroprotective phytoestrogen which binds to estrogen receptor ß and G-protein coupled estradiol receptor. Here, we investigated whether GEN neuroprotection extends to SHR. For this purpose, we treated 5-month-old SHR for 2 weeks with 10 mg kg-1 daily s.c injections of GEN. We analyzed the expression of doublecortin+ neuronal progenitors, glial fibrillary acidic protein+ astrocytes and ionized calcium-binding adapter molecule 1+ microglia in the CA1 region and dentate gyrus of the hippocampus using immunocytochemistry, whereas a quantitative real-time polymerase chain reaction was used to measure the expression of pro- and anti-inflammatory factors tumor necrosis factor α, cyclooxygenase-2 and transforming growth factor ß. We also evaluated hippocampal dependent memory using the novel object recognition test. The results showed a decreased number of doublecortin+ neural progenitors in the dentate gyrus of SHR that was reversed with GEN. The number of glial fibrillary acidic protein+ astrocytes in the dentate gyrus and CA1 was increased in SHR but significantly decreased by GEN treatment. Additionally, GEN shifted microglial morphology from the predominantly activated phenotype present in SHR, to the more surveillance phenotype found in normotensive rats. Furthermore, treatment with GEN decreased the mRNA of the pro-inflammatory factors tumor necrosis factor α and cyclooxygenase-2 and increased the mRNA of the anti-inflammatory factor transforming growth factor ß. Discrimination index in the novel object recognition test was decreased in SHR and treatment with GEN increased this parameter. Our results indicate important neuroprotective effects of GEN at the neurochemical and behavioral level in SHR. Our data open an interesting possibility for proposing this phytoestrogen as an alternative therapy in hypertensive encephalopathy.


Assuntos
Genisteína , Fitoestrógenos , Ratos , Animais , Ratos Endogâmicos SHR , Genisteína/farmacologia , Fitoestrógenos/farmacologia , Fitoestrógenos/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Receptores de Estradiol/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ciclo-Oxigenase 2/metabolismo , Ratos Endogâmicos WKY , Hipocampo/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteínas do Domínio Duplacortina , RNA Mensageiro/metabolismo
6.
Int J Immunopathol Pharmacol ; 37: 3946320221150720, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36600460

RESUMO

INTRODUCTION: Ulcerative colitis (UC) is a chronic non-specific inflammatory bowel disease, and until now therapeutic agents for UC still cannot exert satisfied effects. Therefore, this study aimed to investigate the ameliorative effect of boswellic acid coated zinc nanoparticles (BAs-ZnNPs) on dextran sodium sulphate (DSS) induced-UC in rats. METHODS: Rats were divided into five groups; control, BAs-ZnNPs, DSS, DSS+BAs, and DSS + BAs-ZnNPs. The activity of alkaline phosphatase (ALP) was determined colorimetrically, while the concentration of IgM, IgG, TNF-α, IL-1ß, and IL-8 were measured by ELISA. Levels of gene expression of NF-κB and COX-2 genes were evaluated by RT-qPCR, while the expression of protein levels of PI3K and STAT-3 were done by western blotting. Finally, histopathological examination of colon tissues of different groups of rats was done. RESULTS: The depicted ball-like structure of the BAs-ZnNPs in the TEM images ranging in size from 50 to 100 nm in diameter while their formation was confirmed by UV-visible spectroscopy with a sharp peak of maximum absorbance at 266 nm. Our results revealed that BAs-ZnNPs exerted an anti-inflammatory effect in the experimental model of colitis, demonstrated histologically and biochemically as shown by the improvement of ALP, IgM, IgG, and the gene expression levels of NF-κB and COX-2. Also, this beneficial effect was associated with the reduction in the expression of TNF-α, IL-1ß, IL-8, PI3K, and STAT-3. Thus, this effect improves the altered immune response associated with the colonic inflammation. CONCLUSION: BAs-ZnNPs can be proposed as a therapeutic candidate to attenuate UC. The potential underlying mechanism includes suppression of ALP, IgM, IgG, IL-1ß, and IL-8 levels via regulation of NF-κB and COX-2 gene expression and STAT-3 and PI3K protein expression in a UC rat model.


Assuntos
Colite Ulcerativa , Nanopartículas Metálicas , Zinco , Animais , Ratos , Doença Crônica , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Imunoglobulina G , Imunoglobulina M , Inflamação , Interleucina-8 , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases , Fator de Necrose Tumoral alfa/metabolismo , Zinco/uso terapêutico
7.
Biochem Biophys Res Commun ; 644: 40-48, 2023 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-36623397

RESUMO

Prostate cancer highly metastasizes to bone, and such cancer is associated with severe bone resorption and bone formation at the site of metastasis. Prostaglandin E2 (PGE2) promotes bone resorption in inflammatory diseases; however, the roles in prostate cancer-induced bone formation are still unclear. In the present study, we investigated the effects of membrane-bound TGF-α on prostate cancer-induced bone formation through autocrine PGE2 signaling in osteoblasts. In the prostate cancer explant experiment into tibiae, injected prostate cancer cells induced bone formation with the increased expression of osteogenic genes, such as Runx2 and Wnt5a, and prostaglandin synthase Ptgs2. In osteoblasts, PGE2 increased the number of calcified bone nodules with enhanced expression of Runx2 and Wnt5a. We also screened the factors involved in cancer progression, and 11 EGF family members were found to be expressed in the human prostate cancer cell line PC3. PC3 highly expressed amphiregulin, HB-EGF, and especially TGF-α. Treatment with recombinant TGF-α increased the Ptgs2 expression and PGE2 production in osteoblasts, which promoted the formation of calcified bone nodules, suggesting that the interaction between PC3 and osteoblasts promoted PGE2 production. In co-culture of osteoblasts and fixed PC3 cells, the phosphorylation of EGFR and ERK and subsequent Ptgs2 expression and PGE2 production were increased, an effect that was attenuated by treatment with inhibitors of EGFR and ERK. These results indicate that membrane-bound TGF-α enhances ERK signaling while also inducing PGE2-mediated bone formation in osteoblasts, thus suggesting that prostate cancer regulates both PGE2-mediated bone resorption and bone formation at the site of bone metastasis of prostate cancer.


Assuntos
Reabsorção Óssea , Neoplasias da Próstata , Masculino , Humanos , Osteogênese , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Ciclo-Oxigenase 2/metabolismo , Fator de Crescimento Transformador alfa/metabolismo , Osteoblastos/metabolismo , Neoplasias da Próstata/patologia , Reabsorção Óssea/metabolismo , Receptores ErbB/metabolismo , Prostaglandinas/metabolismo
8.
Int J Mol Sci ; 24(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36614313

RESUMO

An active form of cathelicidin antimicrobial peptide, LL-37, has immunomodulatory and stimulatory effects, though the specific pathways are not clear. The purpose of this study was to identify the cellular pathways by which LL-37 amplifies the inflammation induced by damage-associated molecular patterns (DAMPs). We performed DNA microarray, reverse transcription polymerase chain reaction, immunoblotting, and proximity ligation assays using cultured keratinocytes treated with LL-37 and/or the DAMP poly(I:C), a synthetic double-stranded RNA. In contrast to the combination of LL-37 and poly(I:C), LL-37 alone induced genes related to biological metabolic processes such as VEGFA and PTGS2 (COX-2). Inhibition of FPR2, a known receptor for cathelicidin, partially suppressed the induction of VEGFA and PTGS2. Importantly, VEGFA and PTGS2 induced by LL-37 alone were diminished by the knockdown of scavenger receptors including SCARB1 (SR-B1), OLR1 (SR-E1), and AGER (SR-J1). Moreover, LL-37 alone, as well as the combination of LL-37 and poly(I:C), showed proximity to the scavenger receptors, indicating that LL-37 acts via scavenger receptors and intermediates between them and poly(I:C). These results showed that the broad function of cathelicidin is generally dependent on scavenger receptors. Therefore, inhibitors of scavenger receptors or non-functional mock cathelicidin peptides may serve as new anti-inflammatory and immunosuppressive agents.


Assuntos
Peptídeos Catiônicos Antimicrobianos , Catelicidinas , Catelicidinas/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Antimicrobianos , Ciclo-Oxigenase 2/genética , Receptores Depuradores , Poli I-C/farmacologia
9.
Lasers Med Sci ; 38(1): 36, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36626000

RESUMO

Epidermal growth factor (EGF) and light-emitting diode (LED) are currently deployed as promissory treatments for skin repair; however, the mechanisms of their association are not yet evidenced. Thus, the present study aimed to evaluate the effects of combined treatment with EGF and red LED on the wound healing processes in rats. Adult Wistar rats were randomized in control group (CG) wounds without treatment; wounds submitted to EGF treatment (EGF); wounds submitted to LED treatment (LED); wounds submitted to EGF associated with LED treatments (EGF/LED). Treatments were performed immediately after the surgical procedure and each 24 h, totaling 8 sessions. Moreover, LED was applied before EGF treatment at a single point in the center of the wound. Morphological characteristics and the immunoexpression of COX-2, VEGF, and TGF-ß were measured. The results demonstrated that EGF/LED group presented a higher wound healing index. Additionally, all experimental groups presented similar findings in the histological evaluation, the degree of inflammation, and the area of dermis-like tissue. However, for EGF-treated animals (with or without LED), neoepithelial length was higher. Furthermore, all the treated groups decreased COX-2 and increased VEGF immunoexpression, and only EGF/LED group enhanced the TGF-ß protein expression when compared to the untreated group. This research shows that EGF and LED modulate inflammatory process and increase the vascularity. In addition, treatment of EGF associated with LED promoted a more evident positive effect for increasing TGF-ß expression and may be promising resources in the clinical treatment of cutaneous wounds.


Assuntos
Fator de Crescimento Epidérmico , Fator A de Crescimento do Endotélio Vascular , Ratos , Animais , Fator de Crescimento Epidérmico/metabolismo , Ciclo-Oxigenase 2 , Ratos Wistar , Cicatrização , Fototerapia
10.
PLoS One ; 18(1): e0280548, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36689408

RESUMO

OBJECTIVES: Diabetic retinopathy (DR) is a retinal microvascular disease associated with diabetes. Ferroptosis is a new type of programmed cell death that may participate in the occurrence and development of DR. Therefore, this study aimed to identify the DR ferroptosis-related genes by bioinformatics methods. METHODS: The RNAseq data of DR and healthy control retinas were downloaded from the gene expression synthesis (GEO) database and analyzed using the R package DESeq2. The key modules were obtained using the WGCNA algorithm, and their genes were intersected with ferroptosis-related genes in the FerrDb database to obtain differentially expressed ferroptosis-related genes (DE-FRGs). Enrichment analysis was conducted to understand the function and enrichment pathways of ferroptosis genes in DR, and hub genes were identified by protein-protein interaction (PPI) analysis. The diagnostic accuracy of hub genes for DR was evaluated according to the area under the ROC curve. The TRRUST database was then used to predict the regulatory relationship between transcription factors and target genes, with the mirDIP, ENCORI, RNAnter, RNA22, miRWalk and miRDB databases used to predict the regulatory relationship between miRNAs and target genes. Finally, another data set was used to verify the hub genes. RESULTS: In total, 52 ferroptosis-related DEGs (43 up-regulated and 9 down-regulated) were identified using 15 DR samples and 3 control samples and were shown to be significantly enriched in the intrinsic apoptotic signaling pathway, autophagosome, iron ion binding and p53 signaling pathway. Seven hub genes of DR ferroptosis were identified through PPI network analysis, but only HMOX1 and PTGS2 were differentially expressed in another data set. The miRNAs prediction showed that hsa-miR-873-5p was the key miRNA regulating HMOX1, while hsa-miR-624-5p and hsa-miR-542-3p were the key miRNAs regulating PTGS2. Furthermore, HMOX1 and PTGS2 were regulated by 13 and 20 transcription factors, respectively. CONCLUSION: The hub genes HMOX1 and PTGS2, and their associated transcription factors and miRNAs, may be involved in ferroptosis in diabetic retinopathy. Therefore, the specific mechanism is worthy of further investigation.


Assuntos
Diabetes Mellitus , Retinopatia Diabética , Ferroptose , MicroRNAs , Doenças Retinianas , Humanos , Ciclo-Oxigenase 2 , Biologia Computacional
11.
Sci Rep ; 13(1): 1253, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36690661

RESUMO

Nephrosclerosis patients are at an exceptionally high cardiovascular (CV) risk. We aimed to determine whether genetic variability represented by 38 tag-SNPs in genes of the cyclooxygenase pathway (PTGS1, PTGS2, PTGES, PTGES2 and PTGES3) leading to prostaglandin E2 (PGE2) synthesis, modified CV traits and events in 493 nephrosclerosis patients. Additionally, we genotyped 716 controls to identify nephrosclerosis risk associations. The addition of three variants, namely PTGS2 rs4648268, PTGES3 rs2958155 and PTGES3 rs11300958, to a predictive model for CV events containing classic risk factors in nephrosclerosis patients, significantly enhanced its statistical power (AUC value increased from 78.6 to 87.4%, p = 0.0003). Such increase remained significant after correcting for multiple testing. In addition, two tag-SNPs (rs11790782 and rs2241270) in PTGES were linked to higher systolic and diastolic pressure [carriers vs. non-carriers = 5.23 (1.87-9.93), p = 0.03 and 5.9 (1.87-9.93), p = 0.004]. PTGS1(COX1) rs10306194 was associated with higher common carotid intima media thickness (ccIMT) progression [OR 1.90 (1.07-3.36), p = 0.029], presence of carotid plaque [OR 1.79 (1.06-3.01), p = 0.026] and atherosclerosis severity (p = 0.041). These associations, however, did not survive Bonferroni correction of the data. Our findings highlight the importance of the route leading to PGE2 synthesis in the CV risk experienced by nephrosclerosis patients and add to the growing body of evidence pointing out the PGE2 synthesis/activity axis as a promising therapeutic target in this field.


Assuntos
Dinoprostona , Nefroesclerose , Humanos , Dinoprostona/metabolismo , Ciclo-Oxigenase 2/metabolismo , Espessura Intima-Media Carotídea , Prostaglandina-E Sintases , Fatores de Risco
12.
Nutr Neurosci ; 26(2): 127-137, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36692990

RESUMO

ABSTRACTMicroglia are key regulators of inflammation and oxidative stress (OS) in the CNS. Microglia activation can lead to chronic inflammation, OS, and neurodegeneration. Blueberries (BB) reduce inflammation and OS when administered to microglia before stressors such as lipopolysaccharide (LPS), but the therapeutic value of BBs administered after activation by stressors has not been examined. Therefore, this study investigated the differential effects of pre-, post-, and pre-/post-BB on inflammation and OS in LPS-activated microglia. Rat microglia were pretreated with BB (0.5 mg/mL) or control media (C) for 24 hours, incubated overnight with LPS (0 or 200 ng/mL), and post-treated with BB or C for 24 hours. Biomarkers of inflammation (e.g. nitrite [NO2-], tumor necrosis factor-ɑ [TNFɑ], inducible nitric oxide synthase [iNOS], cyclooxygenase-2 [COX-2], phosphorylated IκB-α [pIκB-ɑ]) and OS (e.g. NADPH oxidase [NOX2]) were assessed. LPS increased NO2-, TNFɑ, COX-2, iNOS, pIκB-ɑ, and NOX2 compared to non-stressed conditions (P < 0.05), however BB before and/or after LPS significantly reduced these markers compared to no BB (P < 0.05). Pre-BB was more effective than post-BB at reducing LPS-induced NO2-, TNFɑ, and COX-2 (P < 0.05). Pre-BB was also more effective than pre-/post-BB at attenuating LPS-induced NO2- and TNFɑ (P < 0.05). All BB treatments were equally effective in reducing LPS-induced iNOS, pIκB-ɑ, and NOX2. Results suggest that BBs can target the downstream events of LPS-induced microglial activation and prevent stressor-induced neuroinflammation and OS. Furthermore, BBs may not need to be present prior to microglial activation for beneficial effects, suggesting that dietary interventions may be effective even after initiation of disease processes.Graphical Abstract. Cascade of inflammatory and OS-inducing events associated with self-propelling microglial activation by LPS and the effects of blueberry (0.5 mg/mL) administered before and/or after LPS on these processes (blue arrows). BB, blueberry; COX2, cyclooxygenase-2; IκB-ɑ, inhibitor kappa-B-ɑ; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; NF-κB, nuclear factor kappa-B; NO, nitric oxide; NOX2, NADPH oxidase; OS, oxidative stress; ROS, reactive oxygen species; TNFɑ, tumor necrosis factor-ɑ.


Assuntos
Mirtilos Azuis (Planta) , Microglia , Ratos , Animais , Transdução de Sinais , Lipopolissacarídeos/farmacologia , Inibidor de NF-kappaB alfa/farmacologia , Inibidor de NF-kappaB alfa/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ciclo-Oxigenase 2/efeitos adversos , Ciclo-Oxigenase 2/metabolismo , Dióxido de Nitrogênio/efeitos adversos , NF-kappa B/metabolismo , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Inflamação/tratamento farmacológico , NADPH Oxidases/metabolismo , NADPH Oxidases/farmacologia , NADPH Oxidases/uso terapêutico , Estresse Oxidativo , Óxido Nítrico/metabolismo
13.
Pharm Biol ; 61(1): 228-240, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36655330

RESUMO

CONTEXT: Da-Yuan-Yin is a Chinese traditional prescription. OBJECTIVE: This study explores the therapeutic effects of the Da-Yuan-Yin decoction polyphenol fraction (DYY-4) on acute lung injury (ALI) in mice induced by lipopolysaccharide (LPS). MATERIALS AND METHODS: The mice (n = 10) were orally administrated with DYY-4 (15, 30, and 60 mg/kg) or DXM (5 mg/kg), half an hour after LPS (2 mg/kg) instilled intratracheally. The protein content and the levels of inflammatory factors, the levels of complements, the mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), the level of myeloperoxidase (MPO) and superoxide dismutase (SOD), the expression of the IkB kinase (IKK) and nuclear factor-kappa B (NF-κB), the lung wet-to-dry weight (W/D) ratio and lung tissue were evaluated, 24 h after LPS challenge. Network pharmacology predicted potential targets. RESULTS: DYY-4 (30, 60 mg/kg, p < 0.01, p < 0.01) decreased the lung W/D ratio, total protein concentration, the levels of C3, C3c and C5a, the levels of TNF-α, IL-6, and IL-1ß, while increased the levels of IL-4 and IL-10. DYY-4 (60 mg/kg) decreased the levels of C5aR1, C5b-9 and COX-2 mRNA (p < 0.05), the levels of MPO and iNOS mRNA, the activation of the IKK/NF-κB pathway (p < 0.01), and increased the levels of IL-13 and SOD (p < 0.01). DYY-4 (60 mg/kg) relieved the lung tissue pathological changes and reduced the C3c deposition. DISCUSSION AND CONCLUSIONS: Network pharmacology combined with animal experiments revealed the targets of DYY-4 alleviating ALI.


Assuntos
Lesão Pulmonar Aguda , NF-kappa B , Camundongos , Animais , NF-kappa B/metabolismo , Lipopolissacarídeos/toxicidade , Polifenóis/efeitos adversos , Ciclo-Oxigenase 2/genética , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/prevenção & controle , Pulmão , Superóxido Dismutase , RNA Mensageiro
14.
J Ethnopharmacol ; 305: 116111, 2023 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-36592822

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Curcumae Rhizoma-Sparganii Rhizoma (CR-SR) is a classic herbal pair to promote blood circulation and remove blood stasis in ancient China. However, the molecular mechanism is still unclear. AIM OF STUDY: To screen out the anti-liver fibrosis active ingredients in CR-SR. Moreover, preliminary exploration the molecular mechanism of CR-SR to ameliorates liver fibrosis. MATERIALS AND METHODS: In this research, plant taxonomy has been confirmed in the "The Plant List" database (www.theplantlist.org). The chemical components of CR-SR were analysed by ultra-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-Q/TOF-MS). "Component-Target-Pathway-Disease" network of CR-SR components were built by network pharmacology. Then, the interaction between primary components and predicted protein targets based on network pharmacology were validated by molecular docking. The pharmacological actions of CR-SR were verified by blood biochemical indexes, histopathologic examination of CCL4 induced rats' model. The core protein targets were verified by Western blot. The effects of screened active components by molecular autodocking were verified by HSC-T6 cell experiment. RESULTS: The result shows that 57 chemical constituents in CR-SR herbal pair were identified by UPLC-Q/TOF-MS, in which, 27 compounds were closely connected with liver fibrosis related protein targets. 55 protein targets screened out by "component-target-pathway-disease network" maybe the underlying targets for CR-SR to cure liver fibrosis. Moreover, the 55 protein targets are mainly related to RNA transcription, apoptosis, and signal transduction. The molecular autodocking predicted that ten components can bond well with PTGS2 and RELA protein targets. The blood biochemical indexes, histopathologic examination of CCL4 induced rats experiment showed that CR-SR has well intervention effect of liver fibrosis. The Western blot analysis indicated that CR-SR could significantly inhibit RELA, PTGS2, IL-6, SRC, and AKT1 protein expression to exert the anti-fibrosis effect. The HSC-T6 cell experiment indicated that both formononetin (FNT) and curdione could significantly inhibit the activation of HSC and reduce the expression of PTGS2, and p-AKT1 which was accordance with the molecular autodocking results. CONCLUSION: This study proved the molecular mechanism of CR-SR multi-component and multi-target anti-liver fibrosis effect through mass spectrometry, network pharmacology, and western blotting technology. The research provides a theoretical evidence for the development and utilization of CR-SR herbal pair.


Assuntos
Medicamentos de Ervas Chinesas , Ratos , Animais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/análise , Simulação de Acoplamento Molecular , Farmacologia em Rede , Ciclo-Oxigenase 2 , Rizoma/química
15.
Immun Inflamm Dis ; 11(1): e709, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36705401

RESUMO

MP-AzeFlu (intranasal fluticasone and azelastine) has been widely studied and has demonstrated efficacy in Allergic rhinitis with a superior effect compared to these drugs administered individually; however, the mechanism by which MP-AzeFlu produces this improved clinical effect has not yet been fully explained. In this study, we investigated the effect of MP-AzeFlu and fluticasone propionate (FP) on arachidonic acid metabolism as measured by changes in regulation of cyclooxygenase (COX) isoforms, prostaglandin (PG) D2 , PGE2 , PGE2 receptor (EP) 2, and EP3. Expression of these key inflammation markers was assessed through an in vitro model of upper airway inflammation using fibroblasts derived from both healthy and inflamed upper airway mucosa. Both MP-AzeFlu and FP inhibited interleukin-1ß-induced COX-2 messenger RNA (mRNA) and protein expression and PGE2 secretion in vitro. MP-AzeFlu and FP both upregulated EP2 mRNA expression, though neither upregulated EP2 protein expression. This downregulation of COX-2 and PGE2 coupled with upregulation of EP2 receptor expression reinforces the anti-inflammatory effect of MP-AzeFlu in upper airway inflammation.


Assuntos
Dinoprostona , Membrana Mucosa , Humanos , Ciclo-Oxigenase 2/genética , Fluticasona/uso terapêutico , RNA Mensageiro , Inflamação/tratamento farmacológico
16.
Life Sci ; 315: 121364, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36610639

RESUMO

BACKGROUND: Oxaliplatin is one of the first-line drugs in solid tumors treatment. However, neuropathy is a devastating side effect leading to poor compliance and treatment cessation. AIM: The current study explored pterostilbene plausible neuroprotective effects aiming to ascertain the potential mechanisms involved in relieving oxaliplatin-induced peripheral neuropathy (OIPN) and investigating whether pterostilbene and celecoxib combination could show better relief. MAIN METHODS: Rats were divided into six groups; control, pterostilbene (40 mg/kg/day, p.o. for 5 weeks), oxaliplatin (4 mg/kg, i.p. twice per week for 4.5 weeks), celecoxib (30 mg/kg/day, p.o. for 5 weeks) and combination of pterostilbene and celecoxib. Behavioral tests and histopathological analysis of sciatic nerves were done. MAPKs, cytokines, COX-2, and PGE2 gene and protein expressions were estimated using qRT-PCR, western, and ELISA techniques. Malondialdehyde (MDA) and total antioxidant capacity (TAC) were assessed by colorimetric assay while apoptotic markers by immunohistochemical analysis and qRT-PCR. KEY FINDINGS: The study revealed that pterostilbene and celecoxib averted oxaliplatin-induced behavioral and motor impairments along with restoration of histopathological changes. Moreover, pterostilbene and celecoxib have significantly attenuated sciatic nerve: p38 MAPK, JNK, ERK1/2, NF-κB, COX-2, PGE2, TNF-α, and interleukins levels. Pterostilbene and celecoxib have reduced caspase-3, Bax, and MDA while increasing Bcl-2 level and TAC. SIGNIFICANCE: Altogether, Pterostilbene mitigates OIPN by interrupting the vicious cycle of inflammation, oxidation, and apoptosis. Furthermore, pterostilbene and celecoxib show comparable attenuation on MAPKs cascades, inflammatory cytokines, oxidative and apoptotic markers. Likewise, co-administration of pterostilbene and celecoxib shows further relief of neuropathic pain.


Assuntos
Neuralgia , Fármacos Neuroprotetores , Animais , Ratos , Anti-Inflamatórios/uso terapêutico , Antioxidantes/metabolismo , Celecoxib/uso terapêutico , Ciclo-Oxigenase 2 , Citocinas/uso terapêutico , Neuralgia/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Oxaliplatina/uso terapêutico
17.
Anal Bioanal Chem ; 415(5): 913-933, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36683060

RESUMO

Oxylipins derived from the cyclooxygenase (COX) and lipoxygenase (LOX) pathways of the arachidonic acid (ARA) cascade are essential for the regulation of the inflammatory response and many other physiological functions. Comprehensive analytical methods comprised of oxylipin and protein abundance analysis are required to fully understand mechanisms leading to changes within these pathways. Here, we describe the development of a quantitative multi-omics approach combining liquid chromatography tandem mass spectrometry-based targeted oxylipin metabolomics and proteomics. As the first targeted proteomics method to cover these pathways, it enables the quantitative analysis of all human COX (COX-1 and COX-2) and relevant LOX pathway enzymes (5-LOX, 12-LOX, 15-LOX, 15-LOX-2, and FLAP) in parallel to the analysis of 239 oxylipins with our targeted oxylipin metabolomics method from a single sample. The detailed comparison between MRM3 and classical MRM-based detection in proteomics showed increased selectivity for MRM3, while MRM performed better in terms of sensitivity (LLOQ, 16-122 pM vs. 75-840 pM for the same peptides), linear range (up to 1.5-7.4 µM vs. 4-368 nM), and multiplexing capacities. Thus, the MRM mode was more favorable for this pathway analysis. With this sensitive multi-omics approach, we comprehensively characterized oxylipin and protein patterns in the human monocytic cell line THP-1 and differently polarized primary macrophages. Finally, the quantification of changes in protein and oxylipin levels induced by lipopolysaccharide stimulation and pharmaceutical treatment demonstrates its usefulness to study molecular modes of action involved in the modulation of the ARA cascade.


Assuntos
Lipoxigenases , Oxilipinas , Humanos , Oxilipinas/análise , Ácido Araquidônico , Proteômica , Ciclo-Oxigenase 2
18.
Biochem Pharmacol ; 208: 115403, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36592708

RESUMO

Severe acne vulgaris is a common chronic inflammatory skin disease worldwide. 5-Aminolaevulinic acid photodynamic therapy (ALA-PDT) is effective and safe for severe acne. However, the mechanism is not fully understood. Intense acute inflammatory response at 24 h after ALA-PDT is reported positively correlated to the effectiveness. Inflammation regulation influence the progression or outcome of diseases. ALA-PDT may exert its therapeutic effect by augmenting intense inflammation and break the chronic inflammation. This study was set out to explore the mechanism of ALA-PDT augmenting intense acute inflammation in the treatment of acne. As a result, transcriptome microarrays analysis of severe acne patients showed that ALA-PDT significantly up-regulated expression of various inflammation-related genes, especially TREM1 and PTGS2, which were further confirmed by a C.acnes induced acne-like mouse ear model. The subsequent experiments demonstrated that ALA-PDT could trigger pro-inflammatory M1 polarization of macrophages in vitro and in vivo. Additionally, the crosstalk between keratinocytes and macrophages studied by a transwell co-culture system indicated that PGE2 secreted by ALA-PDT treated HaCaT cells could promote THP-1 macrophages M1 polarization by COX2/PGE2/TLR4/TREM1 axis to augment inflammation. Our study provides a novel insight that ALA-PDT could amplify inflammation by COX2/TREM1 mediated macrophages M1 polarization for the treatment of acne. It is hoped that this research will decipher the mechanism of ALA-PDT for the treatment of acne and provide a theoretical basis for optimizing the clinical ALA-PDT management.


Assuntos
Acne Vulgar , Fotoquimioterapia , Animais , Camundongos , Fármacos Fotossensibilizantes , Ciclo-Oxigenase 2/genética , Dinoprostona , Receptor Gatilho 1 Expresso em Células Mieloides , Ácido Aminolevulínico/farmacologia , Ácido Aminolevulínico/uso terapêutico , Acne Vulgar/tratamento farmacológico , Inflamação/tratamento farmacológico , Macrófagos , Resultado do Tratamento
19.
ACS Appl Mater Interfaces ; 15(3): 3812-3825, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36646643

RESUMO

The deposition of monosodium urate (MSU) crystals induces the overexpression of reactive oxygen species (ROS) and proinflammatory cytokines in residential macrophages, further promoting the infiltration of inflammatory leukocytes in the joints of gouty arthritis. Herein, a peroxidase-mimicking nanoscavenger was developed by forming manganese dioxide over albumin nanoparticles loaded with an anti-inflammatory drug, indomethacin (BIM), to block the secretion of ROS and COX2-induced proinflammatory cytokines in the MSU-induced gouty arthritis model. In the MSU-induced arthritis mouse model, the BIM nanoparticles alleviated joint swelling, which is attributed to the abrogation of ROS and inflammatory cytokine secretions from proinflammatory macrophages that induces neutrophil infiltration and fluid building up in the inflammation site. Further, the BIM nanoparticle treatment reduced the influx of macrophages and neutrophils in the injured region by blocking migration and inducing reverse migration in the zebrafish larva tail amputation model as well as in MSU-induced peritonitis and air pouch mouse models. Overall, the current strategy of employing biomineralized nanoscavengers for arthritis demonstrates clinical significance in dual blocking of peroxides and COX2 to prevent influx of inflammatory cells into the sites of inflammation.


Assuntos
Artrite Gotosa , Animais , Camundongos , Artrite Gotosa/induzido quimicamente , Artrite Gotosa/tratamento farmacológico , Neutrófilos , Espécies Reativas de Oxigênio/efeitos adversos , Peixe-Zebra , Ciclo-Oxigenase 2 , Ácido Úrico , Inflamação/tratamento farmacológico , Inflamação/induzido quimicamente , Citocinas , Macrófagos , Modelos Animais de Doenças
20.
Int J Mol Sci ; 24(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36675101

RESUMO

Sepsis leads to multi-organ failure due to aggressive systemic inflammation, which is one of the main causes of death clinically. This study aimed to evaluate whether ginseng sprout extracts (GSE) can rescue sepsis and explore its underlying mechanisms. C57BL/6J male mice (n = 15/group) were pre-administered with GSE (25, 50, and 100 mg/kg, p.o) for 5 days, and a single injection of lipopolysaccharide (LPS, 30 mg/kg, i.p) was administered to construct a sepsis model. Additionally, RAW264.7 cells were treated with LPS with/without GSE/its main components (Rd and Re) to explain the mechanisms corresponding to the animal-derived effects. LPS injection led to the death of all mice within 38 h, while GSE pretreatment delayed the time to death. GSE pretreatment also notably ameliorated LPS-induced systemic inflammation such as histological destruction in both the lung and liver, along with reductions in inflammatory cytokines, such as TNF-α, IL-6, and IL-1ß, in both tissues and serum. Additionally, GSE markedly diminished the drastic secretion of nitric oxide (NO) by suppressing the expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2) in both tissues. Similar changes in TNF-α, IL-1ß, NO, iNOS, and COX2 were observed in LPS-stimulated RAW264.7 cells, and protein expression data and nuclear translocation assays suggested GSE could modulate LPS-binding protein (LBP), Toll-like receptor 4 (TLR4), and NF-κB. Ginsenoside Rd could be a major active component in GSE that produces the anti-sepsis effects. Our data support that ginseng sprouts could be used as an herbal resource to reduce the risk of sepsis. The corresponding mechanisms may involve TLR4/NF-κB signaling and a potentially active component.


Assuntos
NF-kappa B , Panax , Extratos Vegetais , Sepse , Animais , Masculino , Camundongos , Ciclo-Oxigenase 2/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Lipopolissacarídeos/efeitos adversos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Panax/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Sepse/tratamento farmacológico , Sepse/genética , Sepse/metabolismo , Extratos Vegetais/uso terapêutico , Fitoterapia , Plântula
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