RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The traditional use of plants for medicinal purposes, called phytomedicine, has been known to provide relief from pain. In Bangladesh, the Chakma indigenous community has been using Allophylus villosus and Mycetia sinensis to treat various types of pain and inflammation. AIM OF THE STUDY: The object of this research is to evaluate the effectiveness of these plants in relieving pain and their antioxidant properties using various approaches such as in vitro, in vivo, and computational techniques. Additionally, the investigation will also analyse the phytochemicals present in these plants. MATERIALS AND METHODS: We conducted in vivo analgesic experiment on Swiss albino mice and in-silico inhibitory activities on COX-2 & 15-LOX-2 enzymes. Assessment of DPPH, Anti Radical Activities (ARA), FRAP, H2O2 Free Radical Scavenging, Reducing the power of both plants performed significant % inhibition with tolerable IC50. Qualitative screening of functional groups of phytochemicals was précised by FTIR and GC-MS analysis demonstrated phytochemical investigations. RESULTS: The ethyl acetate (EtOAc) fractioned Mycetia sinensis extract as well as the ethanoic extract and all fractioned extracts of Allophylus villosus have reported a significant percentage (%) of writhing inhibition (p < 0.05) with the concentrated doses 250 mg as well as 500 mg among the Swiss albino mice for writhing observation of analgesic effect. In the silico observation, a molecular-docking investigation has performed according to GC-MS generated 43 phyto-compounds of both plants to screen their binding affinity by targeting COX-2 and 15-LOX-2 enzymes. Consequently, in order to assess and ascertain the effectiveness of the sorted phytocompounds, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) investigation, DFT (Density-functional theory) by QM (Quantum mechanics), and MDS (Molecular dynamics simulation) were carried out. As the outcome, compounds like 5-(2,4-ditert-butylphenoxy)-5-oxopentanoic acid; 2,4-ditert-butylphenyl 5-hydroxypentanoate; 3,3-diphenyl-5-methyl-3H-pyrazole; 2-O-(6-methylheptan-2-yl) 1-O-octyl benzene-1,2-dicarboxylate and dioctan-3-yl benzene-1,2-dicarboxylate derived from the ethnic plant A. villosus and another ethnic plant M. sinensis extracts enchants magnificent analgesic inhibitions and performed more significant drug like activities with the targeted enzymes. CONCLUSIONS: Phytocompounds from A. villosus & M. sinensis exhibited potential antagonist activity against human 15-lipoxygenase-2 and cyclooxygenase-2 proteins. The effective ester compounds from these plants performed more potential anti-nociceptive activity which could be used as a drug in future.
Asunto(s)
Analgésicos , Antioxidantes , Extractos Vegetales , Animales , Antioxidantes/farmacología , Antioxidantes/aislamiento & purificación , Analgésicos/farmacología , Analgésicos/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Ratones , Masculino , Dolor/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Fitoquímicos/farmacología , Fitoquímicos/análisis , Ciclooxigenasa 2/metabolismoRESUMEN
The use of direct injection ion mobility mass spectrometry (DI-IM-MS) to detect and identify betacyanin pigments in A. hortensis 'rubra' extracts was explored for the first time, with results compared to conventional LC-MS/MS analysis. The anti-inflammatory activities of leaf and seed extracts, alongside purified amaranthin and celosianin pigments, were investigated using a model of lipopolysaccharide (LPS)-activated murine macrophages. Extracts and purified pigments significantly inhibited the production of prostaglandin E2 and NO by up to 90% and 70%, respectively, and reduced the expression of Il6, Il1b, Nos2, and Cox2. Leaf and seed extracts also decreased secretion of Il6 and Il1b cytokines and reduced protein levels of Nos2 and Cox2. Furthermore, extracts and purified pigments demonstrated potent dose-dependent radical scavenging activity in a cellular antioxidant activity assay (CAA) without any cytotoxic effects. Our research highlights the promising biological potential of edible, climate-resilient A. hortensis 'rubra' as a valuable source of bioactive compounds.
Asunto(s)
Lipopolisacáridos , Macrófagos , Estrés Oxidativo , Extractos Vegetales , Ratones , Animales , Extractos Vegetales/farmacología , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Células RAW 264.7 , Estrés Oxidativo/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Lipopolisacáridos/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/inmunología , Ciclooxigenasa 2/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Espectrometría de Masas en TándemRESUMEN
Recently, the increasing incidence of malignant melanoma has become a major public health concern owing to its poor prognosis and impact on quality of life. Consuming foods with potent antitumor compounds can help prevent melanoma and maintain skin health. Fucoxanthin (FX), a naturally occurring carotenoid found in brown algae, possesses antitumor properties. However, its bioavailability, safety risks, and in vivo effects and mechanisms against melanoma remain unclear. This research focused on evaluating the safety and prospective antimelanoma impact of simulated gastrointestinal digestion products (FX-ID) on HaCaT and A375 cells.The results indicate that FX-ID exerts negative effects on mitochondria in A375 cells, increases Bax expression, releases Cytochrome C, and activates cleaved caspase-3, ultimately promoting apoptosis. Additionally, FX-ID influences the mitogen-activated protein kinase (MAPK) pathway by enhancing cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-κB) levels, consequently facilitating apoptosis and inflammation without significantly impacting HaCaT cells. These findings provide insight into inhibitory mechanism of FX-ID against melanoma, guiding the development of functional foods for prevention.
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Apoptosis , Queratinocitos , Melanoma , Xantófilas , Humanos , Melanoma/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Apoptosis/efectos de los fármacos , Xantófilas/farmacología , Xantófilas/química , Línea Celular Tumoral , FN-kappa B/metabolismo , FN-kappa B/genética , Digestión , Modelos Biológicos , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 2/genética , Antineoplásicos/farmacología , Antineoplásicos/química , Phaeophyceae/química , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Caspasa 3/metabolismo , Caspasa 3/genéticaRESUMEN
Monosodium glutamate (MSG) is commonly used as a flavor-enhancing agent in foods, and studies have demonstrated its toxic effects in animal models. Black garlic is known for its antioxidant and anti-inflammatory properties; however, there is a lack of studies on the potential hepatoprotective effect of black garlic ethanol extract (BGE) against MSG-induced hepatotoxicity in rats. The aim of this study was to investigate the hepatoprotective effects of ethanol extract of black garlic against MSG-induced liver damage in animal model. Twenty-five male Wistar rats were randomly assigned to five groups (n=5): negative control, MSG only, and MSG with three different doses of BGE. The MSG only and MSG with BGE groups were orally administered with 8 mg/kg MSG daily. After MSG treatment, the MSG with BGE groups received BGE orally at daily doses of 200, 400, or 600 mg/kg body weight for 16 consecutive days. Subsequently, the levels of serum liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), interferon-gamma (IFN-γ), and cyclooxygenase-2 (COX-2) were measured. Our data indicated that the group treated with 200 mg/kg BGE had significant lower levels of AST and ALT significantly compared to the MSG-only group. The MSG-treated group had higher levels of the inflammatory markers COX-2 and IFN-γ, which were lowered by administration of 200 mg/kg BGE. In contrast, higher doses of BGE led to greater levels of COX-2 and IFN-γ compared to those in the MSG-only group. This study suggested that BGE might have hepatoprotective effects at low dose, potentially mitigating MSG-induced liver damage. However, the higher dose of black garlic extract did not alleviate inflammation, as shown by the higher levels of COX-2 and IFN-γ.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Ajo , Extractos Vegetales , Ratas Wistar , Glutamato de Sodio , Animales , Ajo/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Ratas , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Masculino , Modelos Animales de Enfermedad , Alanina Transaminasa/sangre , Alanina Transaminasa/metabolismo , Aspartato Aminotransferasas/sangre , Aspartato Aminotransferasas/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Interferón gamma/metabolismo , Ciclooxigenasa 2/metabolismoRESUMEN
BACKGROUND: This study aimed to identify the roles of L-tryptophan (Trp) and its rate-limiting enzymes on the receptivity of bovine endometrial epithelial cells. Real-time PCR was conducted to analyze the differential expression of genes between different groups of bovine endometrial epithelial cells. Western blot was performed to detect Cyclooxygenase-2 (COX2) expression after treatment with Trp or kynurenine (the main metabolites of Trp). The kynurenine assay was used to examine if Trp or prostaglandin E2 (PGE2) can increase the production of kynurenine in the bovine endometrial epithelial cells. RESULTS: Trp significantly stimulates insulin growth factor binding protein 1 (IGFBP1) expression, a common endometrial marker of conceptus elongation and uterus receptivity for ruminants. When bovine endometrial epithelial cells are treated with Trp, tryptophan hydroxylase-1 remains unchanged, but tryptophan 2,3-dioxygenase 2 (TDO2) is significantly increased, suggesting tryptophan is mainly metabolized through the kynurenine pathway. Kynurenine significantly stimulates IGFBP1 expression. Furthermore, Trp and kynurenine significantly increase the expression of aryl hydrocarbon receptor (AHR). CH223191, an AHR inhibitor, abrogates the induction of Trp and kynurenine on IGFBP1. PGE2 significantly induces the expression of TDO2, AHR, and IGFBP1. CONCLUSIONS: The regulation between Trp / kynurenine and PGE2 may be crucial for the receptivity of the bovine uterus.
Asunto(s)
Endometrio , Células Epiteliales , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina , Quinurenina , Receptores de Hidrocarburo de Aril , Triptófano Oxigenasa , Triptófano , Animales , Bovinos , Femenino , Triptófano/farmacología , Triptófano/metabolismo , Endometrio/metabolismo , Endometrio/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/genética , Quinurenina/metabolismo , Quinurenina/farmacología , Triptófano Oxigenasa/metabolismo , Triptófano Oxigenasa/genética , Dinoprostona/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 2/genéticaRESUMEN
The objective of the study was to develop a novel topical gel by mixing Potentilla tormentilla ethanolic extract, thermosensitive poloxamer 407, and carbomer 940 and evaluating its stability and rheological behavior. The irritation potential of the gel was evaluated in accordance with the Organization for Economic Cooperation and Development Guidelines 404. The potential anti-inflammatory effects of the developed gel were evaluated in vivo in rats using the carrageenan-induced paw edema test. Moreover, the in silico binding affinity for chlorogenic and ellagic acid, as dominant components in the extract, against cyclooxygenase (COX) 1 and 2 was also determined. Our findings suggest that the gel containing Potentilla tormentilla extract remained stable throughout the observation period, exhibited pseudoplastic behavior, and caused no irritation in rats, thus being considered safe for topical treatment. Additionally, the developed gel showed the capability to reduce rat paw edema, which highlights significant anti-inflammatory potential. In silico analysis revealed that chlorogenic and ellagic acid exhibited a reduced binding affinity against COX-1 but had a similar inhibitory effect on COX-2 as flurbiprofen, which was confirmed by molecular dynamics results. The study proposes the possible application of Potentilla tormentilla ethanolic extract gel for the alleviation of localized inflammatory diseases; however, future clinical evaluation is required.
Asunto(s)
Antiinflamatorios , Ciclooxigenasa 1 , Edema , Extractos Vegetales , Potentilla , Animales , Potentilla/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ratas , Antiinflamatorios/farmacología , Antiinflamatorios/química , Edema/tratamiento farmacológico , Edema/inducido químicamente , Masculino , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 1/química , Geles/química , Ácido Elágico/farmacología , Ácido Elágico/química , Ciclooxigenasa 2/metabolismo , Carragenina , Ratas Wistar , Poloxámero/química , Resinas Acrílicas/química , Ácido Clorogénico/química , Ácido Clorogénico/farmacologíaRESUMEN
Osteoarthritis (OA) is a progressive joint disease characterized by extracellular matrix (ECM) degradation and inflammation, which is involved with pathological microenvironmental alterations induced by damaged chondrocytes. However, current therapies are not effective in alleviating the progression of OA. Isoquercetin is a natural flavonoid glycoside compound that has various pharmacological effects including anticancer, anti-diabetes and blood lipid regulation. Previous evidence suggests that isoquercetin has anti-inflammatory properties in various diseases, but its effect on OA has not been investigated yet. In this study, through western bolt, qRT-PCR and ELISA, it was found that isoquercetin could reduce the increase of ADAMTS5, MMP13, COX-2, iNOS and IL-6 induced by IL-1ß, suggesting that isoquercetin could inhibit the inflammation and ECM degradation of chondrocytes. Through nuclear-plasma separation technique, western blot and immunocytochemistry, it can be found that Nrf2 and NF-κB pathways are activated in this process, and isoquercetin may rely on this process to play its protective role. In vivo, the results of X-ray and SO staining show that intra-articular injection of isoquercetin reduces the degradation of cartilage in the mouse OA model. In conclusion, the present work suggests that isoquercetin may benefit chondrocytes by regulating the Nrf2/NF-κB signaling axis, which supports isoquercetin as a potential drug for the treatment of OA.
Asunto(s)
Condrocitos , Factor 2 Relacionado con NF-E2 , FN-kappa B , Osteoartritis , Quercetina , Transducción de Señal , Animales , Humanos , Masculino , Ratones , Proteína ADAMTS5/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Ciclooxigenasa 2/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Metaloproteinasa 13 de la Matriz/metabolismo , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/efectos de los fármacos , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Osteoartritis/patología , Quercetina/farmacología , Quercetina/análogos & derivados , Quercetina/química , Quercetina/uso terapéutico , Transducción de Señal/efectos de los fármacosRESUMEN
Lipophenols, phenolic compounds esterified with fatty alcohols or fatty acids, provide greater health benefits upon dietary ingestion of plant-based foods than unesterified (poly)phenols. Based on this premise, the present study aimed to demonstrate the role of gastrointestinal enzymes (pepsin, pancreatin, and pancreatic lipase) in releasing alkyl gallates and trans-caffeates from wine lees, providing bioactive compounds with enhanced capacities against oxidative stress (OS) and para-inflammation. The UHPLC-ESI-QqQ-MS/MS-based analysis revealed ethyl gallate and ethyl trans-caffeate as the most prominent compounds (1.675 and 0.872 µg/g dw, respectively), while the bioaccessibility of the derivatives of gallic and caffeic acids was dependent on the alkyl chain properties. The de novo formation of alkyl gallates during gastric and intestinal digestion resulted from intestinal enzyme activity. Moreover, the in vitro capacity of bioaccessible alkyl esters of gallic and trans-caffeic acids to reduce cyclooxygenase-2 concentration and modulate oxilipins related to OS (8-iso-PGF2α) and inflammation (PGF2α and PGE2) was demonstrated in a time-dependent manner. In conclusion, the presence of alkyl esters of gallic and trans-caffeic acids in wine lees and their subsequent formation during digestion of this byproduct emphasize their value as a source of antioxidant and anti-inflammatory compounds, encouraging the consideration of wine lees as a valuable ingredient for health-promoting coproducts.
Asunto(s)
Ciclooxigenasa 2 , Ésteres , Estrés Oxidativo , Fenoles , Vino , Estrés Oxidativo/efectos de los fármacos , Vino/análisis , Fenoles/química , Fenoles/metabolismo , Ésteres/química , Ésteres/metabolismo , Ciclooxigenasa 2/metabolismo , Humanos , Inflamación/metabolismo , Vitis/química , Ácidos Cafeicos/química , Ácidos Cafeicos/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Rheumatoid arthritis (RA) is a multifactorial, polygenic inflammatory disease. Mesua assamica (King & Prain) Kosterm. (MA) is an endangered medicinal plant indigenous to South Asia, primarily to Assam in India. The tree bark is claimed to possess anti-inflammatory, anti-diabetic, anti-cancer, and anti-malarial properties; nevertheless, its role in RA has not been elucidated. Hence, this study aims to investigate the in-vitro and in-vivo anti-arthritic effects of Mesua assamica bark ethanolic extract (MAE). AIM OF THE STUDY: This study aims to investigate the anti-rheumatic potential of MAE in-vitro on RAW 264.7 cells for its anti-oxidant and anti-inflammatory activities and in-vivo on the CFA-induced adjuvant arthritis in the rat model. MATERIALS AND METHODS: We investigated the possible therapeutic effects of MAE in-vitro using RAW 264.7 cells triggered by LPS. Meanwhile, adult Wistar rats were injected intradermally with 100 µl of CFA to induce arthritis, and they were given MAE orally at doses of 100 and 200 mg/kg for up to 28 days. Paw volume analysis, X-ray radiography, anti-oxidant levels analysis, gene and protein expression studies, and histological analysis were carried out to assess the effects of MAE in-vivo. RESULTS: MAE significantly mitigated the inflammation by reducing ROS levels and dropped the nitrite, PGE2, and COX-2 levels enhanced by LPS in-vitro. At the same time, MAE treatment reduced the paw and joint inflammation and increased the immune organ index in the CFA rats. Histopathology data revealed that MAE mitigated the CFA-induced lesions of the ankle joints and synovial tissues. Similarly, MAE significantly abated the secretion of pro-inflammatory cytokines, inhibited the protein expression of TLR4, NF-кB, COX-2, and iNOS, as well as improved the Nrf2 and HO-1 levels in-vitro and in-vivo. CONCLUSION: All the results highlighted the anti-rheumatic potential of MAE in RA in-vitro and in-vivo by inhibiting the TLR4/NF-кB/COX-2/iNOS and promoting the Nrf2/HO-1 signaling axis.
Asunto(s)
Artritis Experimental , Artritis Reumatoide , Ciclooxigenasa 2 , Etanol , Factor 2 Relacionado con NF-E2 , FN-kappa B , Corteza de la Planta , Extractos Vegetales , Receptor Toll-Like 4 , Animales , Extractos Vegetales/farmacología , Células RAW 264.7 , Ratones , Corteza de la Planta/química , Receptor Toll-Like 4/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Artritis Reumatoide/tratamiento farmacológico , FN-kappa B/metabolismo , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Etanol/química , Ciclooxigenasa 2/metabolismo , Masculino , Ratas , Ratas Wistar , Regulación hacia Abajo/efectos de los fármacos , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Antioxidantes/farmacología , Transducción de Señal/efectos de los fármacos , Hemo Oxigenasa (Desciclizante)/metabolismo , Antirreumáticos/farmacología , Antirreumáticos/aislamiento & purificación , Hemo-Oxigenasa 1/metabolismo , Proteínas de la MembranaRESUMEN
Total syntheses of two γ-butenolide natural products, asperjinone (1) and asperimide C (2) in both racemic and chiral forms have been accomplished utilizing Basavaiah's one-pot Friedel-Crafts/maleic anhydride formation protocol as a key strategy. Our syntheses verified the revised structure of 1 proposed by Williams et al. and the structure and absolute configuration of 2 reported by the Li group. This work also discloses the unprecedented anti-inflammatory activity of 1. Synthetic 1 exhibited significant anti-inflammatory activity in renal proximal tubular epithelial cells (RPTEC) by suppression of gene expression of pro-inflammatory cytokines TNF-α, IL-1ß and IL-6 under LPS-induced renal inflammation condition and was superior to (S)-1, rac-2, 2, and a positive drug control, indomethacin. Moreover, compound 1 inhibited downstream signaling of inflammation by significantly reducing iNOS and COX-2 gene expression and total NO production. The anti-inflammatory activity of asperjinone (1) renders it a potential and promising candidate for developing novel anti-inflammatory agents against inflammation worsening acute kidney injury.
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Antiinflamatorios , Animales , 4-Butirolactona/análogos & derivados , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/síntesis química , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/síntesis química , Ciclooxigenasa 2/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/farmacología , Estructura Molecular , Óxido Nítrico/biosíntesis , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Exogenous and endogenous advanced glycation end products (AGEs) contribute to the pathogenesis and progression of renal disease. This is a one-month controlled dietary counseling trial that restricts nutritional AGEs in patients with end-stage renal disease (ESRD) undergoing haemodialysis (n = 22 participants in the intervention and n = 20 participants in the control group). Haematological, biochemical markers, the soluble form of the receptor for AGEs (sRAGE), and carboxymethyl lysine (CML) were measured at baseline and at follow-up. Mononuclear cells were isolated and the protein expression of RAGE and the inflammatory marker COX-2 was measured using Western immunoblotting. The intervention group presented a lower increase in CML compared to the control group (12.39% median change in the intervention vs. 69.34% in the control group, p = 0.013), while RAGE (% mean change -56.54 in the intervention vs. 46.51 in the control group, p < 0.001) and COX-2 (% mean change -37.76 in the intervention vs. 0.27 in the control group, p < 0.001) were reduced compared to the control group. sRAGE was reduced in both groups. In addition, HbA1c (at two months), total cholesterol, and triglycerides were reduced in the intervention versus the control group. The adoption of healthy cooking methods deserves further research as a possible way of modulating inflammatory markers in patients with CKD.
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Productos Finales de Glicación Avanzada , Fallo Renal Crónico , Lisina , Receptor para Productos Finales de Glicación Avanzada , Diálisis Renal , Humanos , Productos Finales de Glicación Avanzada/metabolismo , Masculino , Femenino , Fallo Renal Crónico/terapia , Fallo Renal Crónico/metabolismo , Fallo Renal Crónico/dietoterapia , Persona de Mediana Edad , Lisina/análogos & derivados , Lisina/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Anciano , Inflamación/metabolismo , Biomarcadores , Adulto , Ciclooxigenasa 2/metabolismoRESUMEN
Inflammation plays a critical role in the development of numerous diseases. Cannabidiol (CBD), found in hemp, exhibits significant pharmacological activities. Accumulating evidence suggests that CBD has anti-inflammatory and cardiovascular protection effects, but the potential mechanisms require further exploration. In this study, we aimed to reveal the mechanisms of CBD against high-fat, high-cholesterol (HFC) diet-induced inflammation combining metabolomics with network pharmacology. First, plasma lipidomics results indicated that oxidized lipids could serve as potential biomarkers for HFC diet-induced inflammation, and CBD reversed the elevated levels of oxidized lipids. The HFC diet was also found to enhance intestinal permeability, facilitating the entry of lipopolysaccharides (LPSs) into the circulatory system and subsequently increasing systemic inflammation. Additionally, cell metabolomic results indicated that CBD could reverse 10 important differential metabolites in LPS-induced RAW 264.7 cells. Using network pharmacology, we identified 49 core targets, and enrichment analysis revealed that arachidonic acid was the most significantly affected by CBD, which was closely associated with inflammation. Further integrated analysis focused on three key targets, including PTGS2, ALOX5, and ALOX15. Molecular docking showed high affinities between key targets and CBD, and qPCR further demonstrated that CBD could reverse the mRNA expression of these key targets in RAW 264.7 cells. Collectively, this finding integrates lipidomics and metabolomics with network pharmacology to elucidate the anti-inflammatory effects of CBD and validates key therapeutic targets.
Asunto(s)
Antiinflamatorios , Cannabidiol , Dieta Alta en Grasa , Inflamación , Lipidómica , Metabolómica , Ratones Endogámicos C57BL , Farmacología en Red , Animales , Cannabidiol/farmacología , Ratones , Dieta Alta en Grasa/efectos adversos , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/química , Células RAW 264.7 , Humanos , Colesterol/metabolismo , Simulación del Acoplamiento Molecular , Araquidonato 5-Lipooxigenasa/metabolismo , Araquidonato 5-Lipooxigenasa/genética , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismoRESUMEN
Osteoarthritis (OA) is a degenerative joint disease characterised by inflammation and cartilage degeneration. Ellagic acid (EA) might have therapeutic potential in OA, but its molecular mechanisms of action remain unclear. In this study, we aimed to identify the docking protein of EA in M1 macrophage-related pro-inflammation in OA. Bioinformatics analysis was performed to identify ellagic acid's potential targets among OA-related dysregulated genes. THP-1 cells were induced into M0 and polarised into M1 macrophages for in vitro studies. Mice knee models of OA were generated for in vivo studies. Results showed that PTGS2 (also known as COX-2) is a potential target of ellagic acid among OA-related dysregulated genes. EA has multiple low-energy binding sites on PTGS2, including sites containing amino acid residues critical for the enzyme's catalytic activity. Surface plasmon resonance (SPR) assays confirmed the physical interaction between ellagic acid and recombinant PTGS2 protein, with a dissociation constant (KD) of 5.03 ± 0.84 µM. EA treatment suppressed PTGS2 expression and prostaglandin E2 (PGE2) production in M1 macrophages. Besides, ellagic acid can directly inhibit PTGS2 enzyme activity, with an IC50 around 50 µM. Importantly, in a mouse model of OA, ellagic acid administration alleviated disease severity, reduced collagen II degradation and MMP13 generation, and decreased serum PGE2 levels. Collectively, these results suggest that PTGS2 is a key target of ellagic acid's anti-inflammatory and chondroprotective effects in OA.
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Ciclooxigenasa 2 , Dinoprostona , Ácido Elágico , Macrófagos , Osteoartritis , Ácido Elágico/farmacología , Ciclooxigenasa 2/metabolismo , Animales , Ratones , Humanos , Dinoprostona/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Osteoartritis/patología , Células THP-1 , Masculino , Ratones Endogámicos C57BLRESUMEN
Osteoarthritis (OA) is a prevalent disease of the musculoskeletal system that causes functional deterioration and diminished quality of life. Myrislignan (MRL) has a wide range of pharmacological characteristics, including an anti-inflammatory ability. Although inflammation is a major cause of OA, the role of MRL in OA treatment is still not well-understood. In this study, we analyze the anti-inflammatory and anti-ECM degradation effects of MRL both in vivo and in vitro. Rat primary chondrocytes were treated with interleukin-1ß (IL-1ß) to simulate inflammatory environmental conditions and OA in vitro. The in vivo OA rat model was established by anterior cruciate ligament transection (ACLT) on rat. Our investigation discovered that MRL lowers the IL-1ß-activated tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX2) and inducible nitric-oxide synthase (iNOS) expression in chondrocytes. Moreover, MRL effectively alleviates IL-1ß-induced extracellular matrix (ECM) degradation and promotes ECM synthesis in chondrocytes by upregulating the mRNA level expression of collagen-II and aggrecan (ACAN), downregulating the expression of matrix metalloproteinases-3,-13 (MMP-3, MMP-13), and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5). Gene expression profiles of different groups identified DEGs that were mainly enriched in functions associated with NF-κB signaling pathway, and other highly enriched in functions related to TNF, IL-17, Rheumatoid arthritis and cytokine-cytokine receptor signaling pathways. Venn interaction of DEGs from the abovementioned five pathways showed that Nfkbia, Il1b, Il6, Nfkb1, Ccl2, Mmp3 were highly enriched DEGs. In addition, our research revealed that MRL suppresses NF-κB and modulates the Nrf2/HO-1/JNK signaling pathway activated by IL-1ß in chondrocytes. In vivo research shows that MRL slows the progression of OA in rats. Our findings imply that MRL might be a viable OA therapeutic choice.
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Condrocitos , Interleucina-1beta , Lignanos , Osteoartritis , Ratas Sprague-Dawley , Animales , Osteoartritis/tratamiento farmacológico , Osteoartritis/patología , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Células Cultivadas , Interleucina-1beta/metabolismo , Masculino , Ratas , Lignanos/farmacología , Lignanos/uso terapéutico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , FN-kappa B/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , Progresión de la Enfermedad , Factor de Necrosis Tumoral alfa/metabolismo , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 2/genética , Modelos Animales de Enfermedad , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Transducción de Señal/efectos de los fármacos , Proteína ADAMTS5/metabolismo , Proteína ADAMTS5/genética , HumanosRESUMEN
We investigate the mechanism of action of astragalin (AST) in the treatment of Alzheimer's disease (AD). Network pharmacology was conducted to analyze the relationships among AST, AD, and neuroinflammation, The APP/PS1 transgenic mice with AD were used in the experiments; to be specific, the influence of AST on the behavior of mice was analyzed by Morris water maze and eight-arm radial maze tests, the tissue inflammatory factor levels were detected by ELISA, and pathological changes were analyzed by H&E and immunohistochemical staining. Analysis results of network pharmacology suggested that AST exerted the multi-target effect on neuroinflammation in AD. Through molecular docking and dynamics analyses, COX2 might be the target of AST. Moreover, animal experimental results demonstrated that AST improved the behavior of AD mice, and enhanced the motor and memory abilities, meanwhile, it suppressed the expression of inflammatory factors in tissues and the activation of microglial cells. this study discovers that AST can suppress microglial cell activation via COX2 to improve neuroinflammation in AD.
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Enfermedad de Alzheimer , Quempferoles , Ratones Transgénicos , Simulación del Acoplamiento Molecular , Farmacología en Red , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Ratones , Quempferoles/farmacología , Quempferoles/uso terapéutico , Aprendizaje por Laberinto/efectos de los fármacos , Masculino , Ciclooxigenasa 2/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismoRESUMEN
Autism spectrum disorder (ASD) is associated with multiple physiological abnormalities. Current laboratory and clinical evidence most commonly report mitochondrial dysfunction, oxidative stress, and immunological imbalance in almost every cell type of the body. The present work aims to evaluate oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and inflammation-related molecules such as Cyclooxygenase-2 (COX-2), chitinase 3-like protein 1 (YKL-40), Interleukin-1 beta (IL-1ß), Interleukin-9 (IL-9) in ASD children with and without regression compared to healthy controls. Children with ASD (n = 56) and typically developing children (TDC, n = 12) aged 1.11 to 11 years were studied. Mitochondrial activity was examined in peripheral blood mononuclear cells (PBMCs) isolated from children with ASD and from the control group, using a metabolic analyzer. Gene and protein levels of IL-1ß, IL-9, COX-2, and YKL-40 were investigated in parallel. Our results showed that PBMCs of the ASD subgroup of regressed patients (ASD R(+), n = 21) had a specific pattern of mitochondrial activity with significantly increased maximal respiration, respiratory spare capacity, and proton leak compared to the non-regressed group (ASD R(-), n = 35) and TDC. Furthermore, we found an imbalance in the studied proinflammatory molecules and increased levels in ASD R(-) proving the involvement of inflammatory changes. The results of this study provide new evidence for specific bioenergetic profiles of immune cells and elevated inflammation-related molecules in ASD. For the first time, data on a unique metabolic profile in ASD R(+) and its comparison with a random group of children of similar age and sex are provided. Our data show that mitochondrial dysfunction is more significant in ASD R(+), while in ASD R(-) inflammation is more pronounced. Probably, in the group without regression, immune mechanisms (immune dysregulation, leading to inflammation) begin initially, and at a later stage mitochondrial activity is also affected under exogenous factors. On the other hand, in the regressed group, the initial damage is in the mitochondria, and perhaps at a later stage immune dysfunction is involved.
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Trastorno del Espectro Autista , Metabolismo Energético , Inflamación , Leucocitos Mononucleares , Mitocondrias , Humanos , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/sangre , Trastorno del Espectro Autista/patología , Niño , Masculino , Femenino , Preescolar , Mitocondrias/metabolismo , Mitocondrias/patología , Leucocitos Mononucleares/metabolismo , Inflamación/metabolismo , Inflamación/patología , Lactante , Consumo de Oxígeno , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 2/genética , Interleucina-1beta/metabolismo , Proteína 1 Similar a Quitinasa-3/metabolismo , Proteína 1 Similar a Quitinasa-3/sangreRESUMEN
Eighteen new oleanane-type triterpenoids were isolated from the stems of Sabia limoniacea, including sabialimon A (1), a triterpenoid with an unprecedented 6/6/6/7/7 pentacyclic skeleton and seventeen undescribed triterpenoids, sabialimons B-R (2 - 18), along with six previously described analogs (19 - 24). Their structures were fully elucidated via extensive spectroscopic analysis including 1D and 2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), experimental electronic circular dichroism measurements and X-ray crystallographic studies. Compound 1 is the first triterpenoid that possesses a rare ring system (6/6/6/7/7) with an oxygen-bearing bridge between C-17 and C-18 and a hemiketal form at C-17, which is generated a larger ring by the degradation of C-28 and D/E-ring expansion. Biological evaluation revealed that sabialimon I (9), sabialimon K (11), sabialimon P (16) and 11,13(18)-oleanadien-28-hydroxymethyl 3-one (20) exhibited significantly inhibitory activities against nitric oxide (NO) release with IC50 values of 29.65, 23.41, 18.12 and 26.64 µM, respectively, as compared with the positive control (dexamethasone, IC50 value: 40.35 µM). Furthermore, sabialimon P markedly decreased the secretion of TNF-α, iNOS, IL-6 and NF-κB and inhibited the expression of COX-2 and NF-κB/p65 in LPS-induced RAW264.7 cells in a dose-dependent manner.
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Ácido Oleanólico , Ratones , Animales , Células RAW 264.7 , Ácido Oleanólico/farmacología , Ácido Oleanólico/química , Ácido Oleanólico/aislamiento & purificación , Ácido Oleanólico/análogos & derivados , Estructura Molecular , Relación Estructura-Actividad , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Lipopolisacáridos/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ciclooxigenasa 2/metabolismoRESUMEN
Epidemiological studies have shown that coke oven emissions (COEs) affect the deterioration of asthma, but has not been proven by experimental results. In this study, we found for the first time that COEs exacerbate allergen house dust mite (HDM)-induced allergic asthma in the mouse model. The findings reveal that airway inflammation, airway remodeling and allergic reaction were aggravated in the COE + HDM combined exposure group compared with the individual exposure group. Mechanism studies indicated higher levels of iron and MDA in the COE + HDM combined exposure group, along with increased expression of Ptgs2 and reduced GPX4 expression. Iron chelator deferoxamine (DFO) effectively inhibited ferroptosis induced by COE synergistically with HDM in vitro. Further studies highlighted the role of ferritinophagy in the COE + HDM-induced ferroptosis. 3-methyladenine (3-MA) could inhibit ferroptosis in the COE + HDM exposure group. Interestingly, we injected DFO intraperitoneally into mice in the combined exposure group and found DFO could significantly inhibit the COE-exacerbated ferroptosis and allergic asthma. Our findings link ferroptosis with COE-exacerbated allergic asthma, implying that ferroptosis may have important therapeutic potential for asthma in patients with occupational exposure of COE.
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Asma , Células Epiteliales , Ferroptosis , Ratones Endogámicos BALB C , Animales , Ferroptosis/efectos de los fármacos , Asma/inducido químicamente , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Pyroglyphidae/inmunología , Ratones , Deferoxamina/farmacología , Femenino , Contaminantes Atmosféricos/toxicidad , Hierro/metabolismo , Ciclooxigenasa 2/metabolismoAsunto(s)
Ciclooxigenasa 2 , Células Madre Neoplásicas , Osteosarcoma , Osteosarcoma/genética , Osteosarcoma/patología , Animales , Perros , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Neoplasias Óseas/metabolismo , Regulación Neoplásica de la Expresión Génica , Enfermedades de los Perros/genética , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: Septic cardiomyopathy is a component of multiple organ dysfunction in sepsis. Mitochondrial dysfunction plays an important role in septic cardiomyopathy. Studies have shown that cyclooxygenase-2 (COX-2) had a protective effect on the heart, and prostaglandin E2 (PGE2), the downstream product of COX-2, was increasingly recognized to have a protective effect on mitochondrial function. OBJECTIVE: This study aims to demonstrate that COX-2/PGE2 can protect against septic cardiomyopathy by regulating mitochondrial function. METHODS: Cecal ligation and puncture (CLP) was used to establish a mouse model of sepsis and RAW264.7 macrophages and H9C2 cells were used to simulate sepsis in vitro. The NS-398 and celecoxib were used to inhibit the activity of COX-2. ZLN005 and SR18292 were used to activate or inhibit the PGC-1α activity. The mitochondrial biogenesis was examined through the Mitotracker Red probe, mtDNA copy number, and ATP content detection. RESULTS: The experimental data suggested that COX-2 inhibition attenuated PGC-1α expression thus decreasing mitochondrial biogenesis, whereas increased PGE2 could promote mitochondrial biogenesis by activating PGC-1α. The results also showed that the effect of COX-2/PGE2 on PGC-1α was mediated by the activation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB). Finally, the effect of COX-2/PGE2 on the heart was also verified in the septic mice. CONCLUSION: Collectively, these results suggested that COX-2/PGE2 pathway played a cardioprotective role in septic cardiomyopathy through improving mitochondrial biogenesis, which has changed the previous understanding that COX-2/PGE2 only acted as an inflammatory factor.