RESUMEN
PURPOSE: To investigate the impact of the Chinese medicine compound Ento-PB on oxazolone (OXZ)-induced ulcerative colitis (UC) in rats. METHODS: UC rats induced by OXZ were treated with Ento-PB. The damage to the colon was assessed using several measures, including the disease activity index (DAI), colon length, colon weight/length ratio, colonic mucosal damage index, and histological score. The levels of interleukin-4 (IL-4), interleukin-10 (IL-10), interleukin-13 (IL-13), epidermal growth factor (EGF), inducible nitric oxide synthase, and total nitric oxide synthase (tNOS) in rat serum, as well as the levels of tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO) in rat colon tissue, were determined using enzyme-linked immunosorbent assay and conventional kits. RESULTS: After being treated with Ento-PB, the DAI score and macroscopic lesion score of OXZ-induced UC rats were significantly reduced. Ento-PB prevented the shortening of rat colons, reduced the ratio of colon weight to length, and improved colon tissue lesions. Meanwhile, Ento-PB could significantly inhibit the activities of proinflammatory cytokines TNF-α, IL-13, and MPO, as well as tNOS and iNOS, while upregulating the expression of anti-inflammatory cytokines IL-4 and IL-10. Moreover, a significant increase in the expression level of EGF was observed in UC rats treated with Ento-PB, indicating that Ento-PB could enhance the repair of damaged intestinal epithelial tissue. CONCLUSIONS: Ento-PB demonstrates significant anti-UC activities in OXZ-induced UC rats by regulating the expression levels of inflammatory factors and promoting the repair of colon tissue. This study provides scientific evidence to support the further development of Ento-PB.
Asunto(s)
Colitis Ulcerosa , Colon , Oxazolona , Peroxidasa , Animales , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Masculino , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Peroxidasa/análisis , Peroxidasa/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Modelos Animales de Enfermedad , Factor de Necrosis Tumoral alfa/análisis , Factor de Necrosis Tumoral alfa/metabolismo , Ratas Sprague-Dawley , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Ratas , Ensayo de Inmunoadsorción Enzimática , Factor de Crecimiento Epidérmico/análisis , Citocinas/metabolismo , Interleucina-13/análisis , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo II/análisis , Reproducibilidad de los Resultados , Resultado del TratamientoRESUMEN
Airborne particulate matter (PM) contains polycyclic aromatic hydrocarbons (PAHs) as primary toxic components, causing oxidative damage and being associated with various inflammatory skin pathologies such as premature aging, atopic dermatitis, and psoriasis. Coffee cherry pulp (CCS) extract, rich in chlorogenic acid, caffeine, and theophylline, has demonstrated strong antioxidant properties. However, its specific anti-inflammatory effects and ability to protect macrophages against PAH-induced inflammation remain unexplored. Thus, this study aimed to evaluate the anti-inflammatory properties of CCS extract on RAW 264.7 macrophage cells exposed to atmospheric PAHs, compared to chlorogenic acid (CGA), caffeine (CAF), and theophylline (THP) standards. The CCS extract was assessed for its impact on the production of nitric oxide (NO) and expression of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Results showed that CCS extract exhibited significant antioxidant activities and effectively inhibited protease and lipoxygenase (LOX) activities. The PAH induced the increase in intracellular reactive oxygen species, NO, TNF-α, IL-6, iNOS, and COX-2, which were markedly suppressed by CCS extract in a dose-dependent manner, comparable to the effects of chlorogenic acid, caffeine, and theophylline. In conclusion, CCS extract inhibits PAH-induced inflammation by reducing pro-inflammatory cytokines and reactive oxygen species (ROS) production in RAW 264.7 cells. This effect is likely due to the synergistic effects of its bioactive compounds. Chlorogenic acid showed strong antioxidant and anti-inflammatory activities, while caffeine and theophylline enhanced anti-inflammatory activity. CCS extract did not irritate the hen's egg chorioallantoic membrane. Therefore, CCS extract shows its potential as a promising cosmeceutical ingredient for safely alleviating inflammatory skin diseases caused by air pollution.
Asunto(s)
Antiinflamatorios , Estrés Oxidativo , Extractos Vegetales , Hidrocarburos Policíclicos Aromáticos , Animales , Ratones , Células RAW 264.7 , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Hidrocarburos Policíclicos Aromáticos/toxicidad , Antiinflamatorios/farmacología , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , Inflamación/metabolismo , Antioxidantes/farmacología , Especies Reactivas de Oxígeno/metabolismo , Óxido Nítrico/metabolismo , Contaminación del Aire/efectos adversos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ácido Clorogénico/farmacología , Administración Tópica , Factor de Necrosis Tumoral alfa/metabolismo , Coffea/química , Cafeína/farmacología , Material Particulado/toxicidadRESUMEN
we aimed to monitor liver injury in rat model during heat stress and heatstroke in dry-heat environment and investigate the effects of curcumin on heatstroke-induced liver injury and the underlying mechanisms. Sprague-Dawley (SD) rats were randomly divided into four groups: normal saline (NS), and 50 (50-cur), 100 (100-cur), and 200 mg/kg curcumin (200-cur) groups. They were administered the indicated doses of curcumin by gavage once daily for 7 days. On day 8, the rats were transferred to a simulated climate cabin, At 0, 50, 100, and 150 min, the core temperature (Tc) was measured respectively. After sacrificing the rats, tissue samples were collected, measure histology indices, serum enzymes, lipopolysaccharides (LPSs), cytokines, nuclear factor-kappa B (NF-κB), inducible nitric oxide synthase (iNOS), and intercellular adhesion molecule-1 (ICAM-1). The Tc increased with time in all groups. Curcumin alleviation of symptoms and improvement in pathological scores. The level of enzymes, LPS, and cytokines increased during heatstroke in the NS group, but curcumin decreased the levels of these indicators. The differences of the indicators between NS and 200-cur groups at 150 min were significant (P < 0.05). The expression of NF-κB p65, iNOS, and ICAM-1 was upregulated in the NS group at 150 min, but their expression was relatively lower in the curcumin groups (P < 0.05). Thus, our findings indicate acute liver injury during heat stress and heatstroke. The mechanism involves cascade-amplification inflammatory response induced by the gut endotoxin. Furthermore, curcumin alleviated heatstroke-induced liver injury in a dose-dependent manner by downregulating NF-κB, iNOS, and ICAM-1.
Asunto(s)
Curcumina , Golpe de Calor , Molécula 1 de Adhesión Intercelular , Hígado , FN-kappa B , Óxido Nítrico Sintasa de Tipo II , Ratas Sprague-Dawley , Animales , Curcumina/farmacología , Curcumina/uso terapéutico , Golpe de Calor/complicaciones , Golpe de Calor/tratamiento farmacológico , Óxido Nítrico Sintasa de Tipo II/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Intercelular/genética , FN-kappa B/metabolismo , Ratas , Masculino , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Lipopolisacáridos , Hepatopatías/etiología , Hepatopatías/tratamiento farmacológico , Hepatopatías/metabolismo , Hepatopatías/patologíaRESUMEN
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
Despite the immune system's role in the detection and eradication of abnormal cells, cancer cells often evade elimination by exploitation of various immune escape mechanisms. Among these mechanisms is the ability of cancer cells to upregulate amino acid-metabolizing enzymes, or to induce these enzymes in tumor-infiltrating immunosuppressive cells. Amino acids are fundamental cellular nutrients required for a variety of physiological processes, and their inadequacy can severely impact immune cell function. Amino acid-derived metabolites can additionally dampen the anti-tumor immune response by means of their immunosuppressive activities, whilst some can also promote tumor growth directly. Based on their evident role in tumor immune escape, the amino acid-metabolizing enzymes glutaminase 1 (GLS1), arginase 1 (ARG1), inducible nitric oxide synthase (iNOS), indoleamine 2,3-dioxygenase 1 (IDO1), tryptophan 2,3-dioxygenase (TDO) and interleukin 4 induced 1 (IL4I1) each serve as a promising target for immunotherapeutic intervention. This review summarizes and discusses the involvement of these enzymes in cancer, their effect on the anti-tumor immune response and the recent progress made in the preclinical and clinical evaluation of inhibitors targeting these enzymes.
Asunto(s)
Aminoácidos , Arginasa , Inmunoterapia , Indolamina-Pirrol 2,3,-Dioxigenasa , Neoplasias , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Inmunoterapia/métodos , Animales , Aminoácidos/metabolismo , Arginasa/metabolismo , Glutaminasa/metabolismo , Glutaminasa/antagonistas & inhibidores , Escape del Tumor , Óxido Nítrico Sintasa de Tipo II/metabolismo , Triptófano Oxigenasa/metabolismo , Triptófano Oxigenasa/antagonistas & inhibidores , Terapia Molecular Dirigida , Microambiente Tumoral/inmunología , L-Aminoácido OxidasaRESUMEN
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.
Asunto(s)
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
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.
Asunto(s)
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
Macrophage metabolic plasticity is central to inflammatory programming, yet mechanisms of coordinating metabolic and inflammatory programs during infection are poorly defined. Here, we show that type I interferon (IFN) temporally guides metabolic control of inflammation during methicillin-resistant Staphylococcus aureus (MRSA) infection. We find that staggered Toll-like receptor and type I IFN signaling in macrophages permit a transient energetic state of combined oxidative phosphorylation (OXPHOS) and aerobic glycolysis followed by inducible nitric oxide synthase (iNOS)-mediated OXPHOS disruption. This disruption promotes type I IFN, suppressing other pro-inflammatory cytokines, notably interleukin-1ß. Upon infection, iNOS expression peaks at 24 h, followed by lactate-driven Nos2 repression via histone lactylation. Type I IFN pre-conditioning prolongs infection-induced iNOS expression, amplifying type I IFN. Cutaneous MRSA infection in mice constitutively expressing epidermal type I IFN results in elevated iNOS levels, impaired wound healing, vasculopathy, and lung infection. Thus, kinetically regulated type I IFN signaling coordinates immunometabolic checkpoints that control infection-induced inflammation.
Asunto(s)
Inflamación , Interferón Tipo I , Macrófagos , Staphylococcus aureus Resistente a Meticilina , Óxido Nítrico Sintasa de Tipo II , Transducción de Señal , Infecciones Estafilocócicas , Animales , Interferón Tipo I/metabolismo , Inflamación/patología , Inflamación/metabolismo , Ratones , Óxido Nítrico Sintasa de Tipo II/metabolismo , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/metabolismo , Infecciones Estafilocócicas/patología , Staphylococcus aureus Resistente a Meticilina/patogenicidad , Macrófagos/metabolismo , Macrófagos/inmunología , Macrófagos/microbiología , Ratones Endogámicos C57BL , Fosforilación Oxidativa , Glucólisis , Interleucina-1beta/metabolismoRESUMEN
A bioassay-guided isolation from Atractylodes lancea (Thunb.) DC. obtained 22 compounds, including eight previously undescribed sesquiterpenoids and polyacetylenes (1, 3 and 12-17), as well as fourteen known analogues, and their structures were confirmed by extensive spectroscopic methods. This study evaluated their antibacterial activity against methicillin resistant Staphylococcus aureus (MRSA) for the first time, as well as anti-inflammatory activity. Most of them, including new compounds, showed varying degrees of antibacterial activity against S. aureus and MRSA. Notably, compound 21 exhibited significant antibacterial activity against four different bacteria (MIC 6.25-20.00 µg/mL). This suggested that 21 may have the potential to be developed into a broad-spectrum antibacterial agent. Moreover, except for 9 and 11, most compounds exhibited great anti-inflammatory activity (IC50 1.92-37.91 µM), and iNOS might be a potential target of these compounds according to the molecular docking analysis.
Asunto(s)
Antibacterianos , Antiinflamatorios , Atractylodes , Staphylococcus aureus Resistente a Meticilina , Pruebas de Sensibilidad Microbiana , Atractylodes/química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Estructura Molecular , Simulación del Acoplamiento Molecular , Animales , Relación Estructura-Actividad , Ratones , 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 , Bioensayo , Células RAW 264.7 , Staphylococcus aureus/efectos de los fármacosRESUMEN
This study investigates the efficacy of nebivolol (NBV) in experimental models of toxoplasmosis, focusing on parasite burden reduction and neuronal protection. In the acute model of experimental toxoplasmosis, Swiss mice infected with RH strain tachyzoites received oral NBV chlorhydrate doses of 2 mg/kg/day and 4 mg/kg/day for 8 days. Treatment with NBV significantly reduced parasite burden compared to vehicle and standard drug (PYR) groups. In the chronic model of experimental toxoplasmosis, C57/BL6 mice infected with the ME49 strain received NBV chlorhydrate 41 days post-infection and were evaluated after 10 days of treatment. NBV chlorhydrate effectively reduced cyst number and area, as well as bradyzoite burden compared to controls. Histological analysis demonstrated that NBV chlorhydrate preserved neuronal count, with the 4 mg/kg/day dose yielding counts similar to non-infected mice. Statistical analysis confirmed significant differences compared to control groups. Furthermore, immunohistochemical analysis revealed a significant reduction in iNOS labeling in the brains of mice treated with NBV chlorhydrate, indicating a decrease in nitric oxide production compared to control groups. These findings suggest NBV's potential as a promising candidate for toxoplasmosis treatment, highlighting its ability to reduce parasite burden and protect neuronal integrity. Further research is warranted to elucidate NBV's mechanisms of action and its clinical application in managing toxoplasmosis.
Asunto(s)
Encéfalo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Nebivolol , Carga de Parásitos , Toxoplasmosis Animal , Animales , Nebivolol/farmacología , Nebivolol/uso terapéutico , Ratones , Toxoplasmosis Animal/tratamiento farmacológico , Toxoplasmosis Animal/parasitología , Encéfalo/parasitología , Encéfalo/patología , Encéfalo/efectos de los fármacos , Femenino , Neuronas/efectos de los fármacos , Neuronas/parasitología , Etanolaminas/farmacología , Etanolaminas/uso terapéutico , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Antiprotozoarios/administración & dosificación , Benzopiranos/farmacología , Benzopiranos/uso terapéutico , Resultado del Tratamiento , Óxido Nítrico/metabolismo , Toxoplasma/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/metabolismoRESUMEN
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.
Asunto(s)
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
The Warburg effect occurs both in cancer cells and in inflammatory macrophages. The aim of our work was to demonstrate the role of PI3K-Akt-mTOR axis in the Warburg effect in HL-60 derived, rat peritoneal and human blood macrophages and to investigate the potential of selected inhibitors of this pathway to antagonize it. M1 polarization in HL-60-derived and human blood monocyte-derived macrophages was supported by the increased expression of NOS2 and inflammatory cytokines. All M1 polarized and inflammatory macrophages investigated expressed higher levels of HIF-1α and NOS2, which were reduced by selected kinase inhibitors, supporting the role of PI3K-Akt-mTOR axis. Using Seahorse XF plates, we found that in HL-60-derived and human blood-derived macrophages, glucose loading reduced oxygen consumption (OCR) and increased glycolysis (ECAR) in M1 polarization, which was antagonized by selected kinase inhibitors and by dichloroacetate. In rat peritoneal macrophages, the changes in oxidative and glycolytic metabolism were less marked and the NOS2 inhibitor decreased OCR and increased ECAR. Non-mitochondrial oxygen consumption and ROS production were likely due to NADPH oxidase, expressed in each macrophage type, independently of PI3K-Akt-mTOR axis. Our results suggest that inflammation changed the metabolism in each macrophage model, but a clear relationship between polarization and Warburg effect was confirmed only after glucose loading in HL-60 and human blood derived macrophages. The effect of kinase inhibitors on Warburg effect was variable in different cell types, whereas dichloroacetate caused a shift toward oxidative metabolism. Our findings suggest that these originally anti-cancer inhibitors may also be candidates for anti-inflammatory therapy.
Asunto(s)
Macrófagos , Fosfatidilinositol 3-Quinasas , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Humanos , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Fosfatidilinositol 3-Quinasas/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/inmunología , Transducción de Señal/efectos de los fármacos , Células HL-60 , Masculino , Glucólisis/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Células Cultivadas , Ratas Wistar , Óxido Nítrico Sintasa de Tipo II/metabolismo , Citocinas/metabolismo , Efecto Warburg en Oncología/efectos de los fármacos , Glucosa/metabolismoRESUMEN
This study evaluated the probiotic properties, safety profile, and antioxidative and immune system-enhancing effects of Enterococcus faecium strains isolated from human infant feces. E. faecium KU22001, E. faecium KU22002, and E. faecium KU22005 exhibited potential probiotic properties; however, to eliminate concerns about toxin production and antibiotic resistance, the E. faecium strains were heat-treated prior to experimental usage. E. faecium KU22001 showed the highest antioxidant activity and lowest reactive oxygen species production among the three strains. The immune system-enhancing effects of heat-killed E. faecium strains were evaluated using a nitric oxide assay. E. faecium KU22001 induced an increase in the mRNA expression of inducible nitric oxide synthase, cyclooxygenase-2, and proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1ß, and interleukin-6 in RAW 264.7 cells. Furthermore, E. faecium KU22001 activated the mitogen-activated protein kinase pathway, which was a key regulator of the immune system. These results demonstrate the potential use of E. faecium KU22001 as a multifunctional food material.
Asunto(s)
Antioxidantes , Citocinas , Enterococcus faecium , Heces , Probióticos , Probióticos/farmacología , Ratones , Animales , Células RAW 264.7 , Humanos , Antioxidantes/metabolismo , Citocinas/metabolismo , Heces/microbiología , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Ciclooxigenasa 2/metabolismo , Ciclooxigenasa 2/genética , Calor , Interleucina-6/metabolismo , Interleucina-6/genética , Factores Inmunológicos/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Interleucina-1beta/metabolismo , Interleucina-1beta/genéticaRESUMEN
Cerebral ischemia disrupts calcium homeostasis in the brain causing excitotoxicity, oxidative stress, inflammation, and neuronal cell apoptosis. During ischemic conditions, T-type calcium channel channels contribute to increase in intracellular calcium ions in both neurons and glial cells therefore, the current study hypothesizes the antagonism of these channels using ML218, a novel specific T-Type inhibitor in experimental model of cerebral ischemia-reperfusion (CI/R) brain injury. CI/R injury was induced in Swiss Albino mice by occlusion of common carotid arteries followed by reperfusion. Animals were assessed for learning and memory (MWM), motor coordination (Rota rod), neurological function (neurological deficit score), cerebral infarction, edema, and histopathological alterations. Biochemical assessments were made for calcium binding proteins (Calmodulin- CaM, calcium/calmodulin-dependent protein kinase II-CaMKII, S100B), oxidative stress (4-hydroxy 2-nonenal-4-HNE, glutathione-GSH, inflammation (nuclear factor kappa-light-chain-enhancer of activated B-p65-NF-kB, tumor necrosis factor-TNF-α, interleukin-IL-10) inducible nitric oxide synthase (iNOS) levels, and acetylcholinesterase activity (AChE) in brain supernatants. Furthermore, serum levels of NF-kB, iNOS, and S100B were also assessed. CI/R animals showed impairment in learning, memory, motor coordination, and neurological function along with increase in cerebral infarction, edema, and histopathological alterations. Furthermore, increase in brain calcium binding proteins, oxidative stress, inflammation, and AChE activity along with serum NF-kB, iNOS, and S100B levels were recorded in CI/R animals. Administration of ML218 (5 mg/kg and 10 mg/kg; i.p.) was observed to recuperate CI/R induced impairments in behavioral, biochemical, and histopathological analysis. Hence, it may be concluded that ML218 mediates neuroprotection during CI/R via decreasing brain and serum calcium binding proteins, inflammation, iNOS, and oxidative stress markers.
Asunto(s)
Proteínas de Unión al Calcio , Estrés Oxidativo , Daño por Reperfusión , Animales , Estrés Oxidativo/efectos de los fármacos , Ratones , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Daño por Reperfusión/complicaciones , Masculino , Proteínas de Unión al Calcio/metabolismo , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Inflamación/patología , Inflamación/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Encéfalo/patología , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Modelos Animales de EnfermedadRESUMEN
There has been significant global interest in respiratory health driven by the coronavirus disease (COVID-19) and severe environmental pollution. This study explored the potential of schisantherin A (SchA), a compound derived from Schisandra chinensis, to protect against acute pneumoconiosis. We assessed the effects of SchA on phorbol 12-myristate 13-acetate (PMA)-stimulated A549 alveolar epithelial cells and SiO2/TiO2-induced pulmonary injury in mice. In A549 cells, SchA significantly decreased pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and interleukin (IL)-8 levels. SchA-mediated reduction in inflammatory mediators was associated with the downregulation of PMA-stimulated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling activation. In SiO2/TiO2-induced lung-injured mice, SchA administration significantly reduced MUC5AC production in lung tissue. SchA administration significantly downregulated the overexpression of NK-κB and the subsequent production of COX-2, iNOS, and NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasomes. It significantly suppressed expected increases in total cell numbers and pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and IL-1ß in the bronchoalveolar lavage fluid (BALF) in SiO2/TiO2-stimulated mice. In contrast, the SiO2/TiO2-mediated decrease in IL-10 levels was significantly improved by SchA treatment. These fundamental results can be used to develop potential treatments involving SchA for acute pneumoconiosis.
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Lesión Pulmonar Aguda , Ciclooctanos , Nanopartículas , Dióxido de Silicio , Titanio , Animales , Dióxido de Silicio/toxicidad , Titanio/toxicidad , Humanos , Ciclooctanos/farmacología , Ciclooctanos/uso terapéutico , Ratones , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/metabolismo , Células A549 , Masculino , Nanopartículas/química , Lignanos/farmacología , Lignanos/uso terapéutico , Mucina 5AC/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Silicosis/patología , Silicosis/tratamiento farmacológico , Silicosis/metabolismo , Ciclooxigenasa 2/metabolismoRESUMEN
Rheumatoid arthritis is an inflammatory condition primarily affecting the joints. Nuciferine (NCF), a key bioactive aporphine alkaloid biosynthesized in lotus leaves, exhibits promising anti-inflammatory and antioxidant properties. In this study, we investigated whether NCF could alleviate inflammatory arthritis conditions in a complete Freund's adjuvant (CFA)-mediated arthritis model in rats. The arthritis model was established through intradermal injection of CFA (100 µL) in the sub-plantar region of the right hind paw. The arthritic animals were treated orally with NCF at 5 and 10 mg/kg and indomethacin (Indo) at 5 mg/kg body weight as reference control. NCF treatment remarkably alleviated inflammatory joint swelling and arthritic index. The radiological and histological analysis revealed evidence of the beneficial effects of NCF. NCF treatment decreased the content of pro-inflammatory cytokines (TNF-α and IL-1ß) and myeloperoxidase (MPO) activity and restored the anti-inflammatory cytokine (IL-10) in the paw joints. The serum levels of pro-inflammatory cytokines were also markedly reduced in the NCF (10 mg/kg) treatment group. Moreover, the arthritis-induced inflammatory mediators, including cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) and the toll-like receptor (TLR)-4, mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) signaling proteins were substantially decreased in the NCF treatment groups. NCF treatment also restored the antioxidant defense enzymes and abrogated lipid peroxidation in the paw tissue. Our findings strongly suggest that NCF is a promising therapeutic molecule for rheumatoid arthritis, inspiring further research, and development in this area.
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Aporfinas , Artritis Experimental , FN-kappa B , Receptor Toll-Like 4 , Animales , FN-kappa B/metabolismo , Receptor Toll-Like 4/metabolismo , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Artritis Experimental/metabolismo , Ratas , Aporfinas/farmacología , Aporfinas/uso terapéutico , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Transducción de Señal/efectos de los fármacos , Ratas Sprague-Dawley , Citocinas/metabolismo , Citocinas/sangre , Ciclooxigenasa 2/metabolismo , Adyuvante de FreundRESUMEN
Hyponatremia is the most common clinical electrolyte disorder. Chronic hyponatremia has been recently reported to be associated with falls, fracture, osteoporosis, neurocognitive impairment, and mental manifestations. In the treatment of chronic hyponatremia, overly rapid correction of hyponatremia can cause osmotic demyelination syndrome (ODS), a central demyelinating disease that is also associated with neurological morbidity and mortality. Using a rat model, we have previously shown that microglia play a critical role in the pathogenesis of ODS. However, the direct effect of rapid correction of hyponatremia on microglia is unknown. Furthermore, the effect of chronic hyponatremia on microglia remains elusive. Using microglial cell lines BV-2 and 6-3, we show here that low extracellular sodium concentrations (36 mmol/L decrease; LS) suppress Nos2 mRNA expression and nitric oxide (NO) production of microglia. On rapid correction of low sodium concentrations, NO production was significantly increased in both cells, suggesting that acute correction of hyponatremia partly directly contributes to increased Nos2 mRNA expression and NO release in ODS pathophysiology. LS also suppressed expression and nuclear translocation of nuclear factor of activated T cells-5 (NFAT5), a transcription factor that regulates the expression of genes involved in osmotic stress. Furthermore, overexpression of NFAT5 significantly increased Nos2 mRNA expression and NO production in BV-2 cells. Expressions of Nos2 and Nfat5 mRNA were also modulated in microglia isolated from cerebral cortex in chronic hyponatremia model mice. These data indicate that LS modulates microglial NO production dependent on NFAT5 and suggest that microglia contribute to hyponatremia-induced neuronal dysfunctions.
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Hiponatremia , Microglía , Óxido Nítrico Sintasa de Tipo II , Óxido Nítrico , Factores de Transcripción , Microglía/metabolismo , Microglía/patología , Animales , Óxido Nítrico/metabolismo , Hiponatremia/metabolismo , Hiponatremia/patología , Hiponatremia/genética , Ratones , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Sodio/metabolismo , Línea Celular , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/genética , Ratas , Regulación de la Expresión GénicaRESUMEN
Nitric oxide synthases (NOSs), a family of flavo-hemoproteins with relatively rigid domains linked by flexible regions, require optimal FMN domain docking to the heme domain for efficient interdomain electron transfer (IET). To probe the FMN-heme interdomain docking, the magnetic dipole interactions between the FMN semiquinone radical (FMNHâ¢) and the low-spin ferric heme centers in oxygenase/FMN (oxyFMN) constructs of neuronal and inducible NOS (nNOS and iNOS, respectively) were measured using the relaxation-induced dipolar modulation enhancement (RIDME) technique. The FMNH⢠RIDME data were analyzed using the mesoscale Monte Carlo calculations of conformational distributions of NOS, which were improved to account for the native degrees of freedom of the amino acid residues constituting the flexible interdomain tethers. This combined computational and experimental analysis allowed for the estimation of the stabilization energies and populations of the docking complexes of calmodulin (CaM) and the FMN domain with the heme domain. Moreover, combining the five-pulse and scaled four-pulse RIDME data into a single trace has significantly reduced the uncertainty in the estimated docking probabilities. The obtained FMN-heme domain docking energies for nNOS and iNOS were similar (-3.8 kcal/mol), in agreement with the high degree of conservation of the FMN-heme domain docking interface between the NOS isoforms. In spite of the similar energetics, the FMN-heme domain docking probabilities in nNOS and iNOS oxyFMN were noticeably different (~ 0.19 and 0.23, respectively), likely due to differences in the lengths of the FMN-heme interdomain tethers and the docking interface topographies. The analysis based on the IET theory and RIDME experiments indicates that the variations in conformational dynamics may account for half of the difference in the FMN-heme IET rates between the two NOS isoforms.
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Mononucleótido de Flavina , Hemo , Óxido Nítrico Sintasa de Tipo II , Animales , Ratas , Espectroscopía de Resonancia por Spin del Electrón , Mononucleótido de Flavina/metabolismo , Mononucleótido de Flavina/química , Hemo/química , Hemo/metabolismo , Modelos Moleculares , Simulación del Acoplamiento Molecular , Óxido Nítrico Sintasa de Tipo II/química , Óxido Nítrico Sintasa de Tipo II/metabolismo , Conformación Proteica , Dominios Proteicos , HumanosRESUMEN
Sepsis is a severe condition induced by microbial infection. It elicits a systemic inflammatory response, leading to multi-organ failure, and the liver, as a scavenger, plays a significant role in this process. Controlling hepatic inflammation and maintaining liver function is crucial in managing sepsis. CD44-ICD, as a CD44 signal transductor, is involved in multiple inflammatory responses. However, the role of CD44-ICD in lipopolysaccharide (LPS)-induced hepatic inflammation has not been investigated. Therefore, we aimed to examine whether CD44-ICD initiates hepatic inflammation in septic mice. We induced hepatic inflammation in mice by administering LPS. DAPT, a CD44-ICD inhibitor, was given to mice or Chang cells 30 min or 1 h before LPS administration (10 mg/kg, i.p., or 100 ng/mL, respectively). Inhibition of CD44-ICD decreased the level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), hepatic necrosis, inflammatory cell infiltration, interleukin (IL)-1ß, inducible NO synthase (iNOS), nitric oxide (NO) production, nuclear factor (NF)κB signaling pathway proteins, and CD44 expression in mice. CD44-ICD inhibition also decreased IL-1ß and CD44 expression levels in Chang cells. CD44-ICD may be a primary regulatory function in CD44-associated LPS-induced initiation of hepatic inflammation in mice.
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Receptores de Hialuranos , Lipopolisacáridos , Sepsis , Animales , Ratones , Receptores de Hialuranos/metabolismo , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Sepsis/inducido químicamente , Masculino , Transducción de Señal/efectos de los fármacos , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Humanos , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Ratones Endogámicos C57BL , Interleucina-1beta/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Modelos Animales de EnfermedadRESUMEN
Respiratory failure occurs more frequently after thoracic surgery than abdominal surgery. Although the etiology for this complication is frequently attributed to underlying lung disease present in patients undergoing thoracic surgery, this notion is often unfounded because many patients with normal preoperative pulmonary function often require prolonged oxygen supplementation even after minimal resection of lung tissue. Using a murine model of pulmonary resection and peripheral blood samples from patients undergoing resection of the lung or abdominal organs, we demonstrated that lung surgery initiates a proinflammatory loop that results in damage to the remaining lung tissue, noncardiogenic pulmonary edema, hypoxia, and even death. Specifically, we demonstrated that resection of murine lung tissue increased concentrations of the homeostatic cytokine interleukin-7, which led to local and systemic activation of type 2 innate lymphoid cells. This process activated lung-resident eosinophils and facilitated stress-induced eosinophil maturation in the bone marrow in a granulocyte-macrophage colony-stimulating factor-dependent manner, resulting in systemic eosinophilia in both mice and humans. Up-regulation of inducible nitric oxide synthase in lung-resident eosinophils led to tissue nitrosylation, pulmonary edema, hypoxia, and, at times, death. Disrupting this activation cascade at any stage ameliorated deleterious outcomes and improved survival after lung resection in the mouse model. Our data suggest that repurposing US Food and Drug Administration-approved eosinophil-targeting strategies may potentially offer a therapeutic intervention to improve outcomes for patients who require lung resection for benign or malignant etiology.