RESUMEN
Allergic asthma is a major health burden on society as a chronic respiratory disease characterized by inflammation and muscle tightening around the airways in response to inhaled allergens. Daphne kiusiana Miquel is a medicinal plant that can suppress allergic airway inflammation; however, its specific molecular mechanisms of action are unclear. In this study, we aimed to elucidate the mechanisms by which D. kiusiana inhibits allergic airway inflammation. We evaluated the anti-inflammatory effects of the ethyl acetate (EA) fraction of D. kiusiana and its major compound, daphnetin, on murine T lymphocyte EL4 cells stimulated with phorbol 12-myristate 13-acetate and ionomycin in vitro and on asthmatic mice stimulated with ovalbumin in vivo. The EA fraction and daphnetin inhibited T-helper type 2 (Th2) cytokine secretion, serum immunoglobulin E production, mucus secretion, and inflammatory cell recruitment in vivo. In vitro, daphnetin suppressed intracellular Ca2+ mobilization (a critical regulator of nuclear factor of activated T cells) and functions of the activator protein 1 transcription factor to reduce interleukin (IL)-4 and IL-13 expression. Daphnetin effectively suppressed the IL-4/-13-induced activation of Janus kinase (JAK)/signal transducer and activator of transcription 6 (STAT6) signaling in vitro and in vivo, thereby inhibiting the expression of GATA3 and PDEF, two STAT6-target genes responsible for producing Th2 cytokines and mucins. These findings indicate that daphnetin suppresses allergic airway inflammation by stabilizing intracellular Ca2+ levels and subsequently inactivating the JAK/STAT6/GATA3/PDEF pathway, suggesting that daphnetin is a promising alternative to existing asthma treatments.
Asunto(s)
Asma , Quinasas Janus , Factor de Transcripción STAT6 , Transducción de Señal , Umbeliferonas , Animales , Umbeliferonas/farmacología , Umbeliferonas/uso terapéutico , Factor de Transcripción STAT6/metabolismo , Transducción de Señal/efectos de los fármacos , Ratones , Asma/tratamiento farmacológico , Asma/inmunología , Asma/metabolismo , Quinasas Janus/metabolismo , Activación de Linfocitos/efectos de los fármacos , Ratones Endogámicos BALB C , Femenino , Citocinas/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Células Th2/efectos de los fármacos , Células Th2/inmunología , Línea Celular , Daphne/química , Factor de Transcripción GATA3/metabolismo , Factor de Transcripción GATA3/genética , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Calcio/metabolismoRESUMEN
The development and progression of hyperglycemia (HG) and HG-associated atherosclerosis are exacerbated by mitochondrial dysfunction due to dysregulated mitochondria-derived ROS generation. We recently synthesized a novel mitochondria-targeted esculetin (Mito-Esc) and tested its dose-response therapeutic efficacy in mitigating HG-induced atherosclerosis in db/db mice. In comparison to simvastatin and pioglitazone, Mito-Esc administration resulted in a considerable reduction in body weights and improved glucose homeostasis, possibly by reducing hepatic gluconeogenesis, as indicated by a reduction in glycogen content, non-esterified free fatty acids (NEFA) levels, and fructose 1,6-bisphosphatase (FBPase) activity. Interestingly, Mito-Esc treatment, by regulating phospho-IRS and phospho-AKT levels, greatly improved palmitate-induced insulin resistance, resulting in enhanced glucose uptake in adipocytes and HepG2 cells. Also, and importantly, Mito-Esc administration prevented HG-induced atheromatous plaque formation and lipid accumulation in the descending aorta. In addition, Mito-Esc administration inhibited the HG-mediated increase in VACM, ICAM, and MAC3 levels in the aortic tissue, as well as reduced the serum pro-inflammatory cytokines and markers of senescence. In line with this, Mito-Esc significantly inhibited monocyte adherence to human aortic endothelial cells (HAECs) treated with high glucose and reduced high glucose-induced premature senescence in HAECs by activating the AMPK-SIRT1 pathway. In contrast, Mito-Esc failed to regulate high glucose-induced endothelial cell senescence under AMPK/SIRT1-depleted conditions. Together, the therapeutic efficacy of Mito-Esc in the mitigation of hyperglycemia-induced insulin resistance and the associated atherosclerosis is in part mediated by potentiating the AMPK-SIRT1 axis. KEY MESSAGES: Mito-Esc administration significantly mitigates diabetes-induced atherosclerosis. Mito-Esc improves hyperglycemia (HG)-associated insulin resistance. Mito-Esc inhibits HG-induced vascular senescence and inflammation in the aorta. Mito-Esc-mediated activation of the AMPK-SIRT1 axis regulates HG-induced endothelial cell senescence.
Asunto(s)
Aterosclerosis , Hiperglucemia , Resistencia a la Insulina , Mitocondrias , Umbeliferonas , Animales , Hiperglucemia/tratamiento farmacológico , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Aterosclerosis/etiología , Umbeliferonas/farmacología , Umbeliferonas/uso terapéutico , Humanos , Ratones , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Masculino , Células Hep G2 , Sirtuina 1/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Glucosa/metabolismoRESUMEN
Silicosis is a hazardous occupational disease caused by inhalation of silica, characterized by persistent lung inflammation that leads to fibrosis and subsequent lung dysfunction. Moreover, the complex pathophysiology of silicosis, the challenges associated with early detection, and the unfavorable prognosis contribute to the limited availability of treatment options. Daphnetin (DAP), a natural lactone, has demonstrated various pharmacological properties, including anti-inflammatory, anti-fibrotic, and pulmonary protective effects. However, the effects of DAP on silicosis and its molecular mechanisms remain uncover. This study aimed to evaluate the therapeutic effects of DAP against pulmonary inflammation and fibrosis using a silica-induced silicosis mouse model, and investigate the potential mechanisms and targets through network pharmacology, proteomics, molecular docking, and cellular thermal shift assay (CETSA). Here, we found that DAP significantly alleviated silica-induced lung injury in mice with silicosis. The results of H&E staining, Masson staining, and Sirius red staining indicated that DAP effectively reduced the inflammatory response and collagen deposition over a 28-day period following lung exposure to silica. Furthermore, DAP reduced the number of TUNEL-positive cells, increased the expression levels of Bcl-2, and decreased the expression of Bax and cleaved caspase-3 in the mice with silicosis. More importantly, DAP suppressed the expression levels of NLRP3 signaling pathway-related proteins, including NLRP3, ASC, and cleaved caspase-1, thereby inhibiting silica-induced lung inflammation. Further studies demonstrated that DAP possesses the ability to inhibit the epithelial mesenchymal transition (EMT) induced by silica through the inhibition of the TGF-ß1/Smad2/3 signaling pathway. The experimental results of proteomic analysis found that the PI3K/AKT1 signaling pathway was the key targets of DAP to alleviate lung injury induced by silica. DAP significantly inhibited the activation of the PI3K/AKT1 signaling pathway induced by silica in lung tissues. The conclusion was also verified by the results of molecular and CETSA. To further verify this conclusion, the activity of PI3K/AKT1 signaling pathway was inhibited in A549 cells using LY294002. When the A549 cells were pretreated with LY294002, the protective effect of DAP on silica-induced injury was lost. In conclusion, the results of this study suggest that DAP alleviates pulmonary inflammation and fibrosis induced by silica by modulating the PI3K/AKT1 signaling pathway, and holds promise as a potentially effective treatment for silicosis.
Asunto(s)
Ratones Endogámicos C57BL , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Fibrosis Pulmonar , Transducción de Señal , Dióxido de Silicio , Silicosis , Umbeliferonas , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Umbeliferonas/farmacología , Umbeliferonas/uso terapéutico , Silicosis/tratamiento farmacológico , Silicosis/metabolismo , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/inducido químicamente , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones , Humanos , Neumonía/tratamiento farmacológico , Neumonía/inducido químicamente , Neumonía/patología , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Masculino , Pulmón/patología , Pulmón/efectos de los fármacos , Modelos Animales de Enfermedad , Simulación del Acoplamiento MolecularRESUMEN
The aim of this work was to compare the anti-inflammatory and antioxidant effects of three natural coumarins: 1,2-benzopyrone, umbelliferone and esculetin. The antioxidant capacity of coumarins was evaluated using both chemical and biological in vitro assays. Chemical assays included DPPH and ABTSâ+ radical scavenging as well as ferric ion reducing ability power (FRAP) assay. Inhibition of mitochondrial ROS generation and lipid peroxidation in brain homogenates were used as biological in vitro assays. The experimental method of carrageenan-induced pleurisy in rats was used for the in vivo investigation of the anti-inflammatory activity. In silico molecular docking analysis was undertaken to predict the affinity of COX-2 to the coumarins. Considering the antioxidant capacity, esculetin was the most efficient one as revealed by all employed assays. Particularly, the mitochondrial ROS generation was totally abolished by the compound at low concentrations (IC50 = 0.57 µM). As for the anti-inflammatory effects, the COX-2 enzyme presented good affinities to the three coumarins, as revealed by the molecular docking analyses. However, considering the in vivo anti-inflammatory effects, 1,2-benzopyrone was the most efficient one in counteracting pleural inflammation and it potentiated the anti-inflammatory actions of dexamethasone. Umbelliferone and esculetin treatments failed to reduce the volume of pleural exudate. Overall, therefore, our results support the notion that this class of plant secondary metabolites displays promising effects in the prevention and/or treatment of inflammation and other diseases associated with oxidative stress, although the singularities regarding the type of the inflammatory process and pharmacokinetics must be taken into account.
Asunto(s)
Antioxidantes , Cumarinas , Ratas , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Cumarinas/farmacología , Cumarinas/uso terapéutico , Especies Reactivas de Oxígeno , Ciclooxigenasa 2/metabolismo , Simulación del Acoplamiento Molecular , Umbeliferonas/farmacología , Umbeliferonas/uso terapéutico , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Extractos Vegetales/farmacologíaRESUMEN
Ulcerative colitis (UC) is a chronic inflammatory bowel disease of the colonic mucosa. Esculetin is a type of natural coumarin that has many pharmacological activities such as antioxidant, anticancer, anti-inflammatory, etc. A previous study showed that esculetin improved intestinal inflammation and reduced serum proinflammatory cytokines in UC. The present study aimed to utilize network pharmacology and molecular docking to explore the potential mechanism of esculetin against UC. The potential gene targets of esculetin were predicted through SwissTargetPrediction and Super-PRED web servers. UC-related genes were obtained from DisGeNet, OMIM, and GeneCards databases. The overlap between gene targets of esculetin and UC-related genes were identified as the potential targets of esculetin against UC. The interaction between these overlapping genes was analyzed by the STRING database and the core genes were identified by Cytoscape platform. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of the core genes were then performed. And the results of these analyses were further confirmed through molecular docking. A total of 50 overlapping genes were identified as the potential action targets of esculetin against UC. Among them, 10 genes (AKT1, STAT1, CCND1, SRC, PTGS2, EGFR, NFKB1, ESR1, MMP9, SERPINE1) were finally identified as the core genes. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis results showed that the top signaling pathway associated with the core genes of esculetin against UC was the prolactin (PRL) signaling pathway. Molecular docking results showed that esculetin has a strong binding affinity to the core genes, as well as PRL and prolactin receptor. This study suggests that esculetin may have a crucial impact on UC through the PRL signaling pathway and provides insights into the potential mechanism of esculetin in the treatment of UC, which may shed light on the mechanism and treatment of UC.
Asunto(s)
Colitis Ulcerosa , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/genética , Simulación del Acoplamiento Molecular , Farmacología en Red , Umbeliferonas/farmacología , Umbeliferonas/uso terapéuticoRESUMEN
In this study, we investigated the nephroprotective effects of Umbelliferone (UMB) against cisplatin-induced acute kidney injury (AKI). C57BL/6J mice were treated with cisplatin via a single intraperitoneal injection (25 mg/kg) with or without UMB (40 mg/kg/day) by gavage. Renal function, apoptosis, oxidative stress, inflammation, and mitochondrial function were analyzed to evaluate kidney injury. In vitro, human proximal tubule epithelial cells were treated with cisplatin, with or without UMB, for 24 h. Western blotting and immunohistochemistry were performed to explore the mechanisms underlying the nephroprotective effects of UMB. Cisplatin-induced renal dysfunction, including increases in blood urea nitrogen, serum creatinine, and renal tubular injury indices (NGAL and KIM-1), were significantly attenuated by UMB treatment, along with renal phenotypic changes and renal tubular injury, as evidenced by improved renal histology. Moreover, NRF2 was activated by UMB pretreatment, along with the inhibition of oxidative stress and inflammatory response, as evidenced by decreased levels of antioxidant genes and inflammatory cytokines in cisplatin-induced AKI. Our results demonstrate that UMB can protect against cisplatin-induced nephrotoxicity, which is mediated by the NRF2 signaling pathway via antioxidant and anti-inflammatory activities, suggesting the clinical potential of UMB for the treatment of AKI.
Asunto(s)
Lesión Renal Aguda , Cisplatino , Ratones , Animales , Humanos , Cisplatino/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antioxidantes/metabolismo , Ratones Endogámicos C57BL , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & control , Riñón/metabolismo , Estrés Oxidativo , Inflamación/metabolismo , Apoptosis , Umbeliferonas/farmacología , Umbeliferonas/uso terapéutico , Umbeliferonas/metabolismoRESUMEN
Esculin and esculetin are 2 widely studied coumarin components of Cortex Fraxini, which is a well-known herbal medicine with a 2000-year history. In vivo and in vitro studies have demonstrated that both have a variety of pharmacological activities, including antioxidant, anti-tumor, anti-inflammatory, antibacterial, antidiabetic, immunomodulatory, anti-atherosclerotic, and so on. Their underlying mechanisms of action and biological activities include scavenging free radicals, modulating the nuclear factor erythroid 2-related factor 2 pathway, regulating the cell cycle, inhibiting tumor cell proliferation and migration, promoting mitochondrial pathway apoptosis, inhibiting the NF-κB and MAPK signaling pathways, regulating CD4+ T cells differentiation and associated cytokine release, inhibiting vascular smooth muscle cells, etc. This review aims to provide comprehensive information on pharmacological studies of esculin and esculetin, which is of noteworthy importance in exploring the therapeutic potential of both coumarin compounds.
Asunto(s)
Esculina , Umbeliferonas , Humanos , Esculina/farmacología , Esculina/uso terapéutico , Umbeliferonas/farmacología , Umbeliferonas/uso terapéutico , Cumarinas/farmacología , Cumarinas/uso terapéutico , ApoptosisRESUMEN
In this study, the anticancer activity of umbelliferone (7-hydroxycoumarin-UMB) was investigated in MKN-45 human gastric cancer and MIA PaCa-2 human pancreatic cancer cells. The cytotoxic effect of UMB on MKN-45 and MIA PaCa-2 cells was determined by WST-8 cell viability assay; the effect on colony formation and migration potential by colony forming assay and wound healing/cell migration assay. Apoptotic effect of UMB was determined by measuring the change in mitochondrial membrane potentials, reactive oxygen species levels, and Caspase-3 activities in cells. Anticancer drugs cisplatin and gemcitabine were used as positive controls in experiments, and NIH/Swiss 3 T3 mouse embryonic fibroblast cells were used as a healthy cell group. The results of this study showed that umbelliferone had a significant cytotoxic effect in MKN-45 and MIA PaCa-2 cells, especially after 72 h treatment, while its cytotoxic effect in NIH/3 T3 cells was low. Furthermore, UMB reduces significantly the potential of cells to colonize and migrate; it has been determined that it causes apoptosis by decreasing the mitochondrial membrane potential, increasing intracellular ROS levels and Caspase-3 activity. UMB was found to have more anticancer effect on MIA PaCa-2 cells compared to MKN-45 cells. This showed that UMB has a cell-selective effect.
Asunto(s)
Antineoplásicos , Neoplasias Pancreáticas , Animales , Humanos , Ratones , Línea Celular Tumoral , Caspasa 3 , Fibroblastos , Gemcitabina , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Apoptosis , Umbeliferonas/farmacología , Umbeliferonas/uso terapéuticoRESUMEN
AIMS: Cisplatin is a widely-used drug in the clinical treatment of tumors, but kidney nephrotoxicity is one of the reasons that limits its widespread use. We previously found that 7-hydroxycoumarin-ß-D-glucuronide (7-HCG) was one of metabolites of skimmin and highly enriched in the kidneys and maintained a high blood concentration in skimmin-treated rats. Therefore, we investigated whether 7-HCG has a protective effect on cisplatin-induced acute kidney injury. MATERIALS AND METHODS: Male C57BL/6 mice were continuously administered 7-HCG for five days, and on the third day, an intraperitoneal injection of cisplatin was given to induce acute kidney injury. After 72 h, the mice were sacrificed for analysis. Serum and renal tissue were collected for renal function evaluation. RNA sequencing was used to explore mechanism, and further validated by western blot and immunohistochemistry. In addition, pharmacokinetic study of oral 7-HCG administration was performed to examine how much 7-hydroxycoumarin (7-HC) was metabolized and 7-HC possible effect on renal protection. KEY FINDINGS: 7-HCG significantly reduced serum BUN and SCR levels, and alleviated pathological damage in renal tissue, and reduced the renal index. RNA sequencing revealed that 7-HCG could reverse p38 MAPK regulation and apoptosis. By western blotting, it was found that 7-HCG could reduce renal injury by reducing p-p38, p-ERK, p-JNK, cleaved-caspase3 and Bax. The immunohistochemical results of cleaved-caspase3 were consistent with western blotting. 7-HCG also significantly reduced the production of ROS in kidney tissue. Pharmacokinetic experiments have shown that 7-HCG in the blood increased rapidly and was eliminated slowly, with an average t1/2ß of 18.3 h. And the concentration of 7-HCG in the target organ kidney was about 4 times higher than that in blood. SIGNIFICANCE: Our findings indicate that 7-HCG could exert its protective effect against cisplatin-induced acute kidney injury by inhibiting apoptosis via p38 MAPK regulation and elucidates its pharmacokinetics.
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Lesión Renal Aguda , Cisplatino , Ratones , Masculino , Ratas , Animales , Cisplatino/toxicidad , Glucurónidos/efectos adversos , Glucurónidos/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Ratones Endogámicos C57BL , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & control , Riñón/metabolismo , Apoptosis , Umbeliferonas/farmacología , Umbeliferonas/uso terapéuticoRESUMEN
Coumarin, a plant secondary metabolite, has various pharmacological activities, including antioxidant stress and anti-inflammatory effects. Umbelliferone, a common coumarin compound found in almost all higher plants, has been extensively studied for its pharmacological effects in different disease models and doses with complex action mechanisms. This review aims to summarize these studies and provide useful information to relevant scholars. The pharmacological studies demonstrate that umbelliferone has diverse effects such as anti-diabetes, anti-cancer, anti-infection, anti-rheumatoid arthritis, neuroprotection, and improvement of liver, kidney, and myocardial tissue damage. The action mechanisms of umbelliferone include inhibition of oxidative stress, inflammation, and apoptosis, improvement of insulin resistance, myocardial hypertrophy, and tissue fibrosis, in addition to regulation of blood glucose and lipid metabolism. Among the action mechanisms, the inhibition of oxidative stress and inflammation is the most critical. In short, these pharmacological studies disclose that umbelliferone is expected to treat many diseases, and more research should be conducted.
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Antioxidantes , Hígado , Humanos , Antioxidantes/farmacología , Estrés Oxidativo , Inflamación/tratamiento farmacológico , Umbeliferonas/farmacología , Umbeliferonas/uso terapéuticoRESUMEN
Intestinal injury is a common adverse effect of methotrexate (MTX) therapy, limiting its clinical use. Despite oxidative stress and inflammation being the most embedded mechanism of injury, pharmacological agents that exhibit antioxidant and anti-inflammatory impacts could prevent such toxicities. This study aimed to assess the enteroprotective effect of lactobacillus acidophilus (LB) and/or umbelliferone (UMB) against MTX-induced intestinal injury. Histologically, pretreatment with LB, UMB, or their combinations preserve the intestinal histological structure and mucin content with superior effect in combination therapy. In addition, oral pretreatment with UMB, LB, or their combinations significantly restored oxidant/antioxidant status, as evidenced by the upregulation of Nrf2, SOD3, HO-1, GSH, and GST levels concurrent with a decline in MDA contents. Besides, they suppressed the inflammatory burden by inhibiting STAT3, MPO, TLR4, NF-κB, TNF-α, and IL-6 levels. Moreover, LB, UMB, or their combinations significantly upregulated Wnt and ß-catenin expression. Notably, pretreatment with the combination therapy is superior to monotherapy in protecting rats' small intestines from MTX-induced enteritis. In conclusion, combined pretreatment with LB and UMB could be a novel therapeutic regimen for conditions of intestinal injury induced by MTX via restoring oxidant/antioxidant balance and suppressing inflammatory burden.
Asunto(s)
Antioxidantes , Metotrexato , Ratas , Animales , Antioxidantes/farmacología , Antioxidantes/metabolismo , Metotrexato/toxicidad , Transducción de Señal , Lactobacillus acidophilus/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo , Umbeliferonas/farmacología , Umbeliferonas/uso terapéutico , Oxidantes/farmacología , Factor 2 Relacionado con NF-E2/metabolismoRESUMEN
Effective therapeutic treatments for ischemic stroke are limited. Previous studies suggest selective activation of mitophagy alleviates cerebral ischemic injury while excessive autophagy is detrimental. However, few compounds are available to selectively activate mitophagy without affecting autophagy flux. Here, we found that acute administration of Umbelliferone (UMB) upon reperfusion exerted neuroprotective effects against ischemic injury in mice subjected to transient middle cerebral artery occlusion (tMCAO) and suppressed oxygen-glucose deprivation reperfusion (OGD-R)-induced apoptosis in SH-SY5Y cells. Interestingly, UMB promoted the translocation of mitophagy adaptor SQSTM1 to mitochondria and further reduced the mitochondrial content as well as the expression of SQSTM1 in SHSY5Y cells after OGD-R. Importantly, both the mitochondrial loss and reduction of SQSTM1 expression after UMB incubation can be reversed by autophagy inhibitor chloroquine and wortmannin, proving the mitophagy activation by UMB. Nevertheless, UMB failed to further affect neither LC3 lipidation nor the number of autophagosomes after cerebral ischemia in vivo and in vitro. Furthermore, UMB facilitated OGD-R-induced mitophagy in a Parkin-dependent manner. Inhibition of autophagy/mitophagy either pharmaceutically or genetically abolished the neuroprotective effects of UMB. Taken all, these results suggest that UMB protects against cerebral ischemic injury, both in vivo and in vitro, via promoting mitophagy without increasing the autophagic flux. UMB might serve as a potential leading compound for selectively activating mitophagy and the treatment of ischemic stroke.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Neuroblastoma , Fármacos Neuroprotectores , Daño por Reperfusión , Ratones , Humanos , Animales , Fármacos Neuroprotectores/uso terapéutico , Proteína Sequestosoma-1 , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Daño por Reperfusión/metabolismo , Neuroblastoma/metabolismo , Autofagia/fisiología , Mitocondrias/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/prevención & control , Isquemia Encefálica/metabolismo , Oxígeno/metabolismo , Umbeliferonas/metabolismo , Umbeliferonas/farmacología , Umbeliferonas/uso terapéutico , Accidente Cerebrovascular Isquémico/metabolismoRESUMEN
Umbelliferone (UMB), 7-hydroxycoumarin, is a naturally occurring coumarin derivative that has a plethora of biological and therapeutic activities. The focus of this research was to elucidate the curative effects of two different doses of UMB on diabetic cardiomyopathy (DCM) in a type 2 diabetic rat model induced by 50 mg/kg body weight of streptozotocin (STZ). Diabetic rats orally received 10 or 30 mg/kg of UMB daily for 8 weeks. Compared to the nontreated diabetic group, both UMB treatment doses significantly decreased glucose levels, glycated hemoglobin (HbA1c), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), creatine kinase MB (CK-MB), cardiovascular risk indices, and oxidative stress by reducing malondialdehyde (MDA) and increasing the activity of the antioxidant enzymes. The hypercholesterolemia and hypertriglyceridemia also dramatically decreased in diabetic groups with UMB treatments accompanied by an improvement in insulin, and insulin sensitivity indices (HOMA-IR and QUICKI). Furthermore, the cardiac gene expressions and protein levels of Janus kinase2 (JAK2), signal transducer and activator of transcription3 (STAT3), and transforming growth factor beta1 (TGF-ß1) were also markedly downregulated in a dose-dependent manner by UMB treatments. Finally, the biochemical results were assured by the reduction of histological alterations in cardiac tissues. In conclusion, UMB is a propitious substance for the treatment of DCM by virtuousness of its antihyperglycemic, antihyperlipidemic, antioxidant, and anti-inflammatory properties through modulating the JAK/STAT signaling pathway that may be the underlying mechanism in UMB action.
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Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Ratas , Animales , Cardiomiopatías Diabéticas/tratamiento farmacológico , Antioxidantes/metabolismo , Transducción de Señal , Diabetes Mellitus Experimental/metabolismo , Estrés Oxidativo , Inflamación/tratamiento farmacológico , Umbeliferonas/farmacología , Umbeliferonas/uso terapéuticoRESUMEN
Daphne koreana Nakai is a cherished medicinal plant in the Changbai Mountain region of China. It can be incorporated into medicinal meals and used for various skin diseases by infiltrating liquor. Daphnetin (7,8-dihydroxycoumarin, Dap.) is a main constituent of D. koreana Nakai, which has been used to treat inflammatory conditions and immune disorders due to its numerous pharmacological activities, including anti-oxidant, anti-inflammatory, analgesic, etc. Atopic dermatitis (AD) and allergic asthma are typical diseases of type 2-immune responses. In the present study, the therapeutic potential of Dap. against AD and allergic asthma was investigated using animal and cell experiments. AD-like lesions were induced by repeated application of 1-chloro-2,4-dinitrobenzene (DNCB) to the shaved dorsal skin of BALB/c mice. Ovalbumin (OVA) induction was utilized to establish a mouse asthma model. A passive cutaneous anaphylaxis (PCA) mouse ear model and immunoglobulin E (IgE)/bovine serum albumin (BSA)-stimulated RBL-2H3 cells were used for in vitro assays. The skin lesions and serum and tissue homogenates of the mice were analyzed using histological analysis, immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA), respectively, in order to investigate the anti-AD effects of Dap. Histological analysis was performed on the allergic asthma model to observe inflammatory cell infiltration in the lung tissues. Total IgE and OVA-specific IgE in the serum were measured by ELISA. The levels of inflammatory cytokines in BALF were detected by ELISA. In addition, ELISA and western blotting were performed for the in vitro analysis of RBL-2H3 cells. The results showed that Dap. inhibited the development of DNCB-induced AD-like lesions in the BALB/c mice by reducing the severity of the lesions, epidermal thickness and mast cell infiltration; this was accompanied by reduced levels of IgE and inflammatory cytokines [interleukin (IL)-4, IL-5, IL-9, IL-13, IL-33 and thymic stromal lymphopoietin (TSLP)]. In the allergic asthma model, Dap. reduced the number of infiltrated inflammatory cells in the lung tissues. Moreover, the levels of total serum IgE and OVA-specific IgE were reduced in the high daphnetin dose groups (Dap., -100 mg kg-1). Dap. administered at a dose of -100 mg kg-1 decreased the levels of inflammatory cytokines (IL-4, IL-5, IL-9, IL-13, IL-33 and TSLP in BALF). Furthermore, Dap. administered to IgE-sensitized mice effectively attenuated the IgE-triggered PCA reaction. In vitro, Dap. decreased the expression levels of histamine, IL-4, IL-6, IL-13, MIP-1α and INF-α, and reduced the protein expression levels of phosphorylated MAPKs, P-Lyn and P-syk in the RBL-2H3 cells. Therefore, Dap. can be represented as a potential therapeutic strategy for the treatment of allergic inflammatory conditions via immunoregulation.
Asunto(s)
Antiinflamatorios , Asma , Dermatitis Atópica , Umbeliferonas , Animales , Ratones , Alérgenos/efectos adversos , Antiinflamatorios/uso terapéutico , Asma/inducido químicamente , Asma/tratamiento farmacológico , Citocinas/metabolismo , Dermatitis Atópica/tratamiento farmacológico , Dinitroclorobenceno/efectos adversos , Modelos Animales de Enfermedad , Inmunidad , Inmunoglobulina E , Interleucina-13 , Interleucina-33 , Interleucina-4 , Interleucina-5 , Interleucina-9 , Ratones Endogámicos BALB C , Umbeliferonas/uso terapéuticoRESUMEN
Esculetin is a coumarin compound, which belongs to the class of benzopyrone enriched in various plants such as Sonchus grandifolius, Aesculus turbinata, etc. Free radicals lead to the development of oxidative stress causing inflammation, arthritis, cancer, diabetes, fatty liver disease, etc. These further reduce the efficacy of anticancer drugs, activate inflammatory signaling pathways, degrade joints and cartilage, and disrupt the glycemic index and normal function of liver enzymes. For instance, the current treatment modalities used in arthritis such as non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatoid drugs, and lipoxygenase inhibitors present limited efficacy and adverse effects. Thus, there is a constant need to find newer and safer alternatives. Esculetin has an immense antioxidative potential thereby alleviating arthritis, diabetes, malignancies, and hepatic disorders. Structurally, esculetin contains two hydroxyl groups, which enhance its ability to function as an antioxidant by inhibiting oxidative stress in pathological conditions. Leukotriene B4 synthesis, NF-κB and MPAK pathway activation, and inflammatory cytokine production are the main causes of bone and joint deterioration in arthritis, whereas esculetin treatment reverses these factors and relieves the disease condition. In contrast, lipid peroxidation caused by upregulation of TGF-ß-mediated expression and dysfunction of antioxidant enzymes is inhibited by esculetin therapy, thus reducing liver fibrosis by acting on the PI3K/FoxO1 pathway. Therefore, targeting NF-κB, pro-inflammatory cytokines, TGF-ß and oxidative stress may be a therapeutic strategy to alleviate arthritis and liver fibrosis.
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Antineoplásicos , Artritis , Humanos , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , FN-kappa B/metabolismo , Inhibidores de la Lipooxigenasa , Leucotrieno B4 , Umbeliferonas/farmacología , Umbeliferonas/uso terapéutico , Cirrosis Hepática , Citocinas , Antiinflamatorios , Fosfatidilinositol 3-Quinasas , Factor de Crecimiento Transformador betaRESUMEN
The kidneys are vulnerable to toxicity and acute kidney injury (AKI) is the main adverse effect associated with the clinical use of the chemotherapeutic agent cisplatin (CIS). Oxidative stress and inflammation are implicated in CIS nephrotoxicity. In this study, the effect of the antioxidant 7-hydroxycoumarin (7-HC) against CIS-induced renal intoxication was evaluated. Rats received 7-HC (25, 50, and 100 mg/kg) orally for 14 days and CIS (7 mg/kg) at day 15, and samples were collected 3 days after CIS administration. CIS increased serum urea, creatinine and kidney injury molecule (Kim)-1, caused multiple histopathological changes and increased renal reactive oxygen species (ROS), malondialdehyde (MDA), nitric oxide (NO), NF-κB p65, iNOS, and pro-inflammatory cytokines. 7-HC dose-dependently prevented kidney dysfunction and tissue injury and suppressed ROS and inflammatory mediators. 7-HC boosted renal antioxidants and Bcl-2 while decreased Bax and caspase-3 expression in CIS-administered rats. In addition, 7-HC downregulated Keap-1 and microRNA-34a and upregulated Nrf2, NQO-1, HO-1, and SIRT1. Molecular docking revealed the binding affinity of 7-HC towards NF-κB, Keap-1, and SIRT1. In Conclusion, 7-HC prevented CIS nephrotoxicity by attenuating tissue injury, oxidative stress, inflammation, and apoptotic cell death. The protective efficacy of 7-HC was associated with inhibiting NF-κB and Keap-1, and modulating Nrf2/HO-1 and microRNA34a/Sirt1 signaling.
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MicroARNs , Factor 2 Relacionado con NF-E2 , Animales , Ratas , Antioxidantes/metabolismo , Cisplatino/farmacología , Inflamación/metabolismo , Riñón/metabolismo , MicroARNs/metabolismo , Simulación del Acoplamiento Molecular , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Sirtuina 1/metabolismo , Umbeliferonas/farmacología , Umbeliferonas/uso terapéuticoRESUMEN
Over the years, great attention has been paid to coumarin derivatives, a set of versatile molecules that exhibit a wide variety of biological activities and have few toxic side effects. In this study, we investigated the antidiabetic potential of 6-formyl umbelliferone (6-FU), a novel furanocoumarin isolated from Angelica decursiva. Numerous pharmacological activities of 6-FU have been previously reported; however, the mechanism of its antidiabetic activity is unknown. Therefore, we examined the action of 6-FU on a few candidate-signaling molecules that may underlie its antidiabetic activity, including its inhibition of protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, human recombinant aldose reductase (HRAR), and advanced glycation end-product (AGE) formation (IC50 = 1.13 ± 0.12, 58.36 ± 1.02, 5.11 ± 0.21, and 2.15 ± 0.13 µM, respectively). A kinetic study showed that 6-FU exhibited mixed-type inhibition against α-glucosidase and HRAR and competitive inhibition of PTP1B. Docking simulations of 6-FU demonstrated negative binding energies and close proximity to residues in the binding pockets of those enzymes. We also investigated the molecular mechanisms underlying 6-FU's antidiabetic effects. 6-FU significantly increased glucose uptake and decreased PTP1B expression in insulin-resistant C2C12 skeletal muscle cells. Moreover, 6-FU (0.8-100 µM) remarkably inhibited the formation of fluorescent AGEs in glucose-fructose-induced human serum albumin glycation over the course of 4 weeks. The findings clearly indicate that 6-FU will be useful in the development of multiple target-oriented therapeutic modalities for the treatment of diabetes and diabetes-related complications.
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Angelica , Diabetes Mellitus , Furocumarinas , Angelica/química , Diabetes Mellitus/tratamiento farmacológico , Humanos , Hipoglucemiantes/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Umbeliferonas/farmacología , Umbeliferonas/uso terapéutico , alfa-Glucosidasas/metabolismoRESUMEN
Obesity is a chronic metabolic disease caused by an imbalance between energy intake and expenditure during a long period and is characterized by adipose tissue disfunction and hepatic steatosis. The aim of this study was to investigate the effect of 4-methylesculetin (4-ME), a coumarin derivative, upon adipose microenvironment and hepatic steatosis in mice induced by a high-fat diet (HFD), and to explore potential mechanisms of its beneficial effect on metabolic disorders. HFD-fed mice displayed visceral obesity, insulin resistance, and hepatic lipid accumulation, which was remarkably ameliorated by 4-ME treatment. Meanwhile, 4-ME ameliorated adipocyte hypertrophy, macrophage infiltration, hypoxia, and fibrosis in epididymal adipose tissue, thus improving the adipose tissue microenvironment. Furthermore, 4-ME reversed the increase in CD36, PPAR-γ, SREBP-1, and FASN, and the decrease in CPT-1A, PPAR-α, and Nrf2 translocation into the nucleus in livers of HFD mice and in FFA-incubated hepatocytes. Moreover, the beneficial effects of 4-ME upon lipid deposition and the expression of proteins related to lipid metabolism in FFA-induced LO2 cells were abolished by ML385, a specific Nrf2 inhibitor, indicating that Nrf2 is necessary for 4-ME to reduce hepatic lipid deposition. These findings suggested that 4-ME might be a potential lead compound candidate for preventing obesity and MAFLD.
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Hígado Graso , Resistencia a la Insulina , Síndrome Metabólico , Animales , Dieta Alta en Grasa/efectos adversos , Hígado Graso/metabolismo , Lípidos/farmacología , Hígado/metabolismo , Síndrome Metabólico/metabolismo , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Obesidad/metabolismo , PPAR alfa/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Umbeliferonas/metabolismo , Umbeliferonas/farmacología , Umbeliferonas/uso terapéuticoRESUMEN
Umbelliferone (UMB), a natural coumarin compound, has been reported to possess anti-rheumatic effects on rheumatoid arthritis (RA) experimental models, but its potential role of UMB in regulating migration, invasion and inflammation of RA fibroblast-like synoviocytes (FLS) remain unclear. Herein, MTT assay was performed to confirm the non-cytotoxic concentrations (10, 20, and 40[Formula: see text][Formula: see text]M) and the treatment time (24[Formula: see text]h) of UMB on TNF-[Formula: see text]-stimulated RA FLS (MH7A cells) in vitro. Results of wound-healing, transwell and phalloidin staining assays revealed that UMB inhibited TNF-[Formula: see text]-induced migration, invasion and F-actin cytoskeletal reorganization in MH7A. Results of ELISA, western blot and gelatin zymography indicated that UMB decreased the productions of pro-inflammatory factors, including IL-1[Formula: see text], IL-6, IL-8, MMP-2 and MMP-9, and inhibited MMP-2 activity in TNF-[Formula: see text]-stimulated MH7A cells. In vivo, UMB (25[Formula: see text]mg/kg and 50[Formula: see text]mg/kg) relieved the joint damage and synovial inflammation in rats with adjuvant-induced arthritis (AIA). Mechanistically, UMB could suppress Wnt/[Formula: see text]-catenin signaling both in TNF-[Formula: see text]-induced MH7A cells and in AIA rat synovium, evidenced by decreasing Wnt1 protein level, activating GSK-3[Formula: see text] kinase by blocking GSK-3[Formula: see text] (Ser9) phosphorylation, and reducing the protein level and nuclear translocation of [Formula: see text]-catenin. Importantly, combined use of lithium chloride (a Wnt/[Formula: see text]-catenin signaling agonist) eliminated the inhibitory effects of UMB on migration, invasion and inflammation in vitro and the anti-arthritic effects of UMB in vivo. We concluded that UMB inhibited TNF-[Formula: see text]-induced migration, invasion and inflammation of RA FLS and attenuated the severity of rat AIA through its ability to block Wnt/[Formula: see text]-catenin signaling pathway.
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Artritis Experimental , Artritis Reumatoide , Sinoviocitos , Ratas , Animales , Sinoviocitos/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Vía de Señalización Wnt , Glucógeno Sintasa Quinasa 3/metabolismo , Movimiento Celular , Células Cultivadas , Artritis Reumatoide/tratamiento farmacológico , Artritis Experimental/tratamiento farmacológico , Membrana Sinovial/metabolismo , Fibroblastos/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Umbeliferonas/farmacología , Umbeliferonas/uso terapéutico , Cateninas/metabolismo , Cateninas/farmacología , Proliferación CelularRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Aesculetin (6,7-dihydroxy-2H-1-benzopyran-2-one) has been reported to exhibit potent anti-inflammatory property both in vitro and in vivo. AIMS OF THIS STUDY: In this study, we evaluated the anti-inflammatory effect and investigated underlying molecular mechanisms of aesculetin in LPS-induced RAW264.7 macrophages and DSS-induced colitis. MATERIALS AND METHODS: In this study, the production of NO, TNF-α, and IL-6 were measured to identify the aesculetin with potent anti-inflammatory effect. Then, the underlying anti-inflammatory mechanisms were explored by western blotting in LPS-induced cells. Next, we verify the anti-inflammatory potential of aesculetin in DSS-induced colitis in vivo. The clinical symptoms of colitis, including weight loss, DAI, colon length and MPO activity, and the secretion of TNF-α and IL-6 were evaluated. Finally, Western blot analysis was applied to further investigate underlying mechanism in DSS-induced colitis model. RESULTS: Our studies showed that aesculetin exhibited anti-inflammatory potential by inhibiting NO, TNF-α, and IL-6 production and reducing iNOS and NLRP3 expression in LPS-induced RAW264.7 cells. Mechanically, we found that aesculetin significantly inhibited LPS-induced activation of NF-κB and MAPKs signaling pathways. In DSS-induced mouse model, the colitis-related symptoms were relieved by treatment with aesculetin. Besides, aesculetin also inhibited the secretion of TNF-α and IL-6, and the activation of NF-κB and MAPKs signaling pathways in DSS-induced colitis. CONCLUSIONS: The anti-inflammatory effect of aesculetin was connected with its inhibition on the activation of NF-κB and MAPKs signaling pathways both in vitro and in vivo. Therefore, aesculetin was expected to be developed as an anti-inflammatory drug.