RESUMEN
SCOPE: This study investigates the potential of glutamine to mitigate intestinal mucositis and dysbiosis caused by the chemotherapeutic agent 5-fluorouracil (5-FU). METHODS AND RESULTS: Over twelve days, Institute of Cancer Research (ICR) mice are given low (0.5 mg kg-1) or high (2 mg kg-1) doses of L-Glutamine daily, with 5-FU (50 mg kg-1) administered between days six and nine. Mice receiving only 5-FU exhibited weight loss, diarrhea, abnormal cell growth, and colonic inflammation, correlated with decreased mucin proteins, increased endotoxins, reduced fecal short-chain fatty acids, and altered gut microbiota. Glutamine supplementation counteracted these effects by inhibiting the Toll-like receptor 4/nuclear factor kappa B (TLR4/NF-κB) pathway, modulating nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) oxidative stress proteins, and increasing mammalian target of rapamycin (mTOR) levels, thereby enhancing microbial diversity and protecting intestinal mucosa. CONCLUSIONS: These findings underscore glutamine's potential in preventing 5-FU-induced mucositis by modulating gut microbiota and inflammation pathways.
Asunto(s)
Fluorouracilo , Microbioma Gastrointestinal , Glutamina , Mucosa Intestinal , Mucositis , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Fluorouracilo/efectos adversos , Glutamina/farmacología , Mucositis/inducido químicamente , Mucositis/tratamiento farmacológico , Mucositis/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Ratones Endogámicos ICR , Masculino , Receptor Toll-Like 4/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Disbiosis/inducido químicamente , Disbiosis/tratamiento farmacológico , Ratones , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Antimetabolitos Antineoplásicos/efectos adversos , Hemo-Oxigenasa 1/metabolismoRESUMEN
HemoHIM is a standardized medicinal herbal preparation consisting of extracts of Angelica gigas Nakai, Cnidium officinale Makino, and Paeonia lactiflora Pallas that possesses immune regulatory activities. This study aimed to research the potential antioxidant effects of HemoHIM and its capacity for reducing fatigue in aged mice subjected to forced exercise. After administering HemoHIM 125 (500 mg/kg orally) for 4 weeks in 8-month-old female C57BL/6 mice (4 groups of 10 mice), various parameters were evaluated. The analyses revealed that HemoHIM enhanced swimming time and grip strength. In addition, it significantly reduced serum lactate levels and increased liver glutathione peroxidase (GPx) levels after exercise challenge. The expression levels of antioxidant enzymes and factors, including nuclear factor erythroid 2-related factor-2 (Nrf-2), heme oxygenase 1, superoxide dismutase, GPx, and glutathione reductase, were significantly higher in liver and muscle tissues of mice treated with HemoHIM. These results indicate that HemoHIM might function as an anti-fatigue and antioxidant agent by modulating the Nrf-2 signaling pathway.
Asunto(s)
Angelica , Antioxidantes , Fatiga , Glutatión Peroxidasa , Hígado , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2 , Extractos Vegetales , Superóxido Dismutasa , Animales , Antioxidantes/farmacología , Fatiga/tratamiento farmacológico , Femenino , Angelica/química , Ratones , Glutatión Peroxidasa/metabolismo , Superóxido Dismutasa/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificación , Factor 2 Relacionado con NF-E2/metabolismo , Cnidium/química , Paeonia/química , Condicionamiento Físico Animal , Glutatión Reductasa/metabolismo , Humanos , Envejecimiento/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Estrés Oxidativo/efectos de los fármacosRESUMEN
Osteoarthritis (OA) is a complicated joint disorder characterized by inflammation that causes joint destruction. Cucurbitacin B (CuB) is a naturally occurring triterpenoid compound derived from plants in the Cucurbitaceae family. The aim of this study is to investigate the potential role and mechanisms of CuB in a mouse model of OA. This study identified the key targets and potential pathways of CuB through network pharmacology analysis. In vivo and in vitro studies confirmed the potential mechanisms of CuB in OA. Through network pharmacology, 54 potential targets for CuB in treating OA were identified. The therapeutic potential of CuB is associated with the nod-like receptor pyrin domain 3 (NLRP3) inflammasome and pyroptosis. Molecular docking results indicate a strong binding affinity of CuB to nuclear factor erythroid 2-related factor 2 (Nrf2) and p65. In vitro experiments demonstrate that CuB effectively inhibits the expression of pro-inflammatory factors induced by interleukin-1ß (IL-1ß), including cyclooxygenase-2, inducible nitric oxide synthase, IL-1ß, and IL-18. CuB inhibits the degradation of type II collagen and aggrecan in the extracellular matrix (ECM), as well as the expression of matrix metalloproteinase-13 and a disintegrin and metalloproteinase with thrombospondin motifs-5. CuB protects cells by activating the Nrf2/hemeoxygenase-1 (HO-1) pathway and inhibiting nuclear factor-κB (NF-κB)/NLRP3 inflammasome-mediated pyroptosis. Moreover, in vivo experiments show that CuB can slow down cartilage degradation in an OA mouse model. CuB effectively prevents the progression of OA by inhibiting inflammation in chondrocytes and ECM degradation. This action is further mediated through the activation of the Nrf2/HO-1 pathway to inhibit NF-κB/NLRP3 inflammasome activation. Thus, CuB is a potential therapeutic agent for OA.
Asunto(s)
Hemo-Oxigenasa 1 , Inflamasomas , Factor 2 Relacionado con NF-E2 , Proteína con Dominio Pirina 3 de la Familia NLR , Osteoartritis , Piroptosis , Triterpenos , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Osteoartritis/tratamiento farmacológico , Ratones , Triterpenos/farmacología , Triterpenos/química , Piroptosis/efectos de los fármacos , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Masculino , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Transducción de Señal/efectos de los fármacos , Simulación del Acoplamiento Molecular , Proteínas de la Membrana/metabolismoRESUMEN
This study aims to clarify the specific anti-fatigue components of Schizophyllum commune (S.commune) and analyze its potential anti-fatigue mechanism. The main anti-fatigue active ingredient of S.commune was locked in n-butanol extract (SPE-n) by activity evaluation. Twelve compounds were identified by high performance liquid chromatography-electrospray tandem mass spectrometry (LC-ESI-MS/MS). The anti-fatigue effect of morusin is the most predominant among these 12 ingredients. The determination of biochemical indices showed that morusin could increase liver glycogen reserves, improve the activity of antioxidant enzymes in liver, and reduce reactive oxygen species (ROS) content in muscle tissue, thereby reducing myocyte damage. Further studies revealed that morusin could reduce the level of oxidative stress by activating Nrf2/HO-1 pathway, thus alleviating the fatigue of mice caused by exhaustive exercise. The current findings provide a theoretical basis for the development of natural anti-fatigue functional food.
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Fatiga , Schizophyllum , Animales , Ratones , Fatiga/tratamiento farmacológico , Masculino , Estrés Oxidativo/efectos de los fármacos , Hígado/efectos de los fármacos , Estructura Molecular , Especies Reactivas de Oxígeno/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Antioxidantes/farmacología , Antioxidantes/aislamiento & purificación , Hemo-Oxigenasa 1/metabolismo , Músculo Esquelético , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Espectrometría de Masas en Tándem , Proteínas de la Membrana , Animales no ConsanguíneosRESUMEN
Three undescribed sesquiterpenes, designed as pichinenoid A-C (1-3), along with nine known ones (4-12) were isolated from the stems and leaves of Picrasma chinensis. The new isolates including their absolute configurations were elucidated based on extensive spectroscopic methods, single crystal X-ray diffraction, and electronic circular dichroism (ECD) experiments, as well as comparison with literature data. Structurally, compounds 1 and 2 are descending sesquiterpenes, while pichinenoid C (3) is a rare sesquiterpene bearing a 2-methylenebut-3-enoic acid moiety at the C-6 side chain. All the isolated compounds were tested for their neuroprotective effects against the H2O2-induced damage on human neuroblastoma SH-SY5Y cells, and most of them showed moderate neuroprotective activity. Especially, compounds 1, 3-5, and 7 showed a potent neuroprotective effect at 25 or 50 µM. Moreover, the neuroprotective effects of compounds 1 and 4 were tested on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model. Results of western blot and immunofluorescence indicated that compound 4 significantly counteract the toxicity of MPTP, and reversed the expression of tyrosine hydroxylase (TH) in substantia nigra (SN) and striatum (ST) of the mouse brain. Interestingly, western blot data suggested compound 4 also enhanced B-cell lymphoma-2 (Bcl-2) and heme oxygenase 1 (HO-1) expressions in the brain tissues from MPTP damaged mouse.
Asunto(s)
Fármacos Neuroprotectores , Picrasma , Hojas de la Planta , Tallos de la Planta , Sesquiterpenos , Animales , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/aislamiento & purificación , Sesquiterpenos/farmacología , Sesquiterpenos/aislamiento & purificación , Ratones , Humanos , Línea Celular Tumoral , Estructura Molecular , Picrasma/química , Tallos de la Planta/química , Hojas de la Planta/química , Masculino , Hemo-Oxigenasa 1/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , China , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Multiple myeloma (MM) is an incurable hematological malignancy with limited therapeutic efficacy. Eclipta prostrata is a traditional Chinese medicinal plant reported to possess antitumor properties. However, the effects of E. prostrata in MM have not been explored. PURPOSE: The aim of this study was to define the mechanism of the ethanol extract of E. prostrata (EEEP) in treating MM and identify its major components. METHODS: The pro-ferroptotic effects of EEEP on cell death, cell proliferation, iron accumulation, lipid peroxidation, and mitochondrial morphology were determined in RPMI-8226 and U266 cells. The expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), kelch-like ECH-associated protein 1 (Keap1), heme oxygenase-1 (HO-1), glutathione peroxidase 4 (GPX4), and 4-hydroxynonenal (4HNE) were detected using western blotting during EEEP-mediated ferroptosis regulation. The RPMI-8226 and U266 xenograft mouse models were used to explore the in vivo anticancer effects of EEEP. Finally, high performance liquid chromatography (HPLC) and ultra-high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry system (UPLC-Q/TOF-MS) were used to identify the major constituents of EEEP. RESULTS: EEEP inhibited MM cell growth and induced cell death in vitro and in vivo. By promoting malondialdehyde and Fe2+ accumulation, lipid peroxidation, and GSH suppression, EEEP triggers ferroptosis in MM. Mechanistically, EEEP regulates the Keap1/Nrf2/HO-1 axis and stimulates ferroptosis. EEEP-induced lipid peroxidation and malondialdehyde accumulation were blocked by the Nrf2 activator NK-252. In addition, HPLC and UPLC-Q/TOF-MS analysis elucidated the main components of EEEP, including demethylwedelolactone, wedelolactone, chlorogenic acid and apigenin, which may play important roles in the anti-tumor function of EEEP. CONCLUSION: In summary, EEEP exerts its anti-MM function by inducing MM cell death and inhibiting tumor growth in mice. We also showed that EEEP can induce lipid peroxidation and accumulation of ferrous irons in MM cells both in vivo and in vitro, leading to ferroptosis. In addition, this anti-tumor function may be achieved by the EEEP activation of Keap1/Nrf2/HO-1 axis. This is the first study to reveal that EEEP exerts anti-MM activity through the Keap1/Nrf2/HO-1-dependent ferroptosis regulatory axis, making it a promising candidate for MM treatment.
Asunto(s)
Eclipta , Ferroptosis , Hemo-Oxigenasa 1 , Proteína 1 Asociada A ECH Tipo Kelch , Mieloma Múltiple , Factor 2 Relacionado con NF-E2 , Extractos Vegetales , Ferroptosis/efectos de los fármacos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Humanos , Extractos Vegetales/farmacología , Línea Celular Tumoral , Hemo-Oxigenasa 1/metabolismo , Ratones , Eclipta/química , Peroxidación de Lípido/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Proliferación Celular/efectos de los fármacos , Ratones Desnudos , Ratones Endogámicos BALB C , Masculino , Antineoplásicos Fitogénicos/farmacología , EtanolRESUMEN
Inflammatory bowel disease, a disease featured by intestinal epithelial barrier destruction and dysfunction, has been a constant threat to animal health. The primary objective of this research was to assess the impact of the extract derived from lotus leaves (LLE) on lipopolysaccharide (LPS) induced damage to the intestines in mice, as well as to investigate the fundamental mechanism involved. The LLE was prepared using ultrasonic extraction in this experiment, and the LLE total flavonoid content was 117.02 ± 10.73 mg/g. The LLE had strong antioxidant activity in vitro, as assessed by 2, 2-diphenyl-1-picrylhydrazyl, ferric reducing antioxidant power, and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) methods. In the vivo experiment, different doses of LLE (50, 100, and 200 mg/kg) were administered for 2 weeks before LPS treatment in mice. The results revealed that LLE alleviates intestinal tissue damage in LPS-induced mice. In the jejunum tissue, LLE significantly upregulated mRNA and protein expression levels of tight junction proteins, such as ZO-1, occludin, and claudin-1, and decreased the contents of the inflammatory cytokines, interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α. Furthermore, the malondialdehyde and lactate dehydrogenase contents increased by LPS in the liver were significantly reduced after administration of LLE, and the total antioxidant capacity, superoxide dismutase, and reduced glutathione decreased by LPS were remarkably increased by LLE. It was found that LLE could relieve LPS-induced oxidative stress by upregulating mRNA and protein expression of Nrf2 and HO-1 in jejunum tissue. In conclusion, LLE alleviates LPS-induced intestinal damage through regulation of the Nrf2/HO-1 signal pathway to alleviate oxidative stress, reducing inflammatory factors and increasing the expression of tight junction proteins in mice.
Asunto(s)
Lipopolisacáridos , Lotus , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Extractos Vegetales , Hojas de la Planta , Animales , Estrés Oxidativo/efectos de los fármacos , Lipopolisacáridos/efectos adversos , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificación , Ratones , Hojas de la Planta/química , Lotus/química , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Antioxidantes/farmacología , Inflamación/tratamiento farmacológico , Inflamación/inducido químicamente , Inflamación/metabolismo , Humanos , Intestinos/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Hemo-Oxigenasa 1/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/metabolismoRESUMEN
BACKGROUND: The heme oxygenase (HO) system plays a significant role in neuroprotection and reduction of neuroinflammation and neurodegeneration. The system, via isoforms HO-1 and HO-2, regulates cellular redox balance. HO-1, an antioxidant defense enzyme, is highlighted due to its association with depression, characterized by heightened neuroinflammation and impaired oxidative stress responses. METHODOLOGY: We observed the pathophysiology of HO-1 and phytochemicals as its modulator. We explored Science Direct, Scopus, and PubMed for a comprehensive literature review. Bibliometric and temporal trend analysis were done using VOSviewer. RESULTS: Several phytochemicals can potentially alleviate neuroinflammation and oxidative stress-induced depressive symptoms. These effects result from inhibiting the MAPK and NK-κB pathways - both implicated in the overproduction of pro-inflammatory factors - and from the upregulation of HO-1 expression mediated by Nrf2. Bibliometric and temporal trend analysis further validates these associations. CONCLUSION: In summary, our findings suggest that antidepressant agents can mitigate neuroinflammation and depressive disorder pathogenesis via the upregulation of HO-1 expression. These agents suppress pro-inflammatory mediators and depressive-like symptoms, demonstrating that HO-1 plays a significant role in the neuroinflammatory process and the development of depression.
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Hemo-Oxigenasa 1 , Enfermedades Neuroinflamatorias , Humanos , Hemo-Oxigenasa 1/metabolismo , Depresión/tratamiento farmacológico , Hemo Oxigenasa (Desciclizante)/metabolismo , Antioxidantes/farmacología , Estrés Oxidativo , Factor 2 Relacionado con NF-E2/metabolismoRESUMEN
BACKGROUND & AIMS: The effect fraction of Bletilla striata (Thunb.) Reichb.f. (EFBS), a phenolic-rich extract, has significant protective effects on lipopolysaccharide (LPS)-induced acute lung injury (ALI), but its composition and molecular mechanisms are unclear. This study elucidated its chemical composition and possible protective mechanisms against LPS-induced ALI from an antioxidant perspective. METHODS: EFBS was prepared by ethanol extraction, enriched by polyamide column chromatography, and characterized using ultra-performance liquid chromatography/time-of-flight mass spectrometry. The LPS-induced ALI model and the RAW264.7 model were used to evaluate the regulatory effects of EFBS on oxidative stress, and transcriptome analysis was performed to explore its possible molecular mechanism. Then, the pathway by which EFBS regulates oxidative stress was validated through inhibitor intervention, flow cytometry, quantitative PCR, western blotting, and immunofluorescence techniques. RESULTS: A total of 22 compounds in EFBS were identified. The transcriptome analyses of RAW264.7 cells indicated that EFBS might reduce reactive oxygen species (ROS) production by inhibiting the p47phox/NADPH oxidase 2 (NOX2) pathway and upregulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. Both in vitro and in vivo data confirmed that EFBS significantly inhibited the expression and phosphorylation of p47phox protein, thereby weakening the p47phox/NOX2 pathway and reducing ROS production. EFBS significantly increased the expression of Nrf2 in primary peritoneal macrophages and lung tissue and promoted its nuclear translocation, dose-dependent increase in HO-1 levels, and enhancement of antioxidant activity. In vitro, both Nrf2 and HO-1 inhibitors significantly reduced the scavenging effects of EFBS on ROS, further confirming that EFBS exerts antioxidant effects at least partially by upregulating the Nrf2/HO-1 pathway. CONCLUSIONS: EFBS contains abundant phenanthrenes and dibenzyl polyphenols, which can reduce ROS production by inhibiting the p47phox/NOX2 pathway and enhance ROS clearance activity by upregulating the Nrf2/HO-1 pathway, thereby exerting regulatory effects on oxidative stress and improving LPS-induced ALI.
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Lesión Pulmonar Aguda , Lipopolisacáridos , Humanos , Lipopolisacáridos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , NADPH Oxidasa 2/metabolismo , Hemo-Oxigenasa 1/metabolismo , Transducción de Señal , Estrés Oxidativo , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Antioxidantes/farmacología , Antioxidantes/metabolismoRESUMEN
Oligoasthenoteratozoospermia (OAT) decreases male fertility, seriously affecting the production of offspring. This study clarified the preventive impact of different moxibustion frequencies on OAT and selected the optimal frequency to elucidate the underlying mechanism. An OAT rat model was constructed by gavage of tripterygium glycosides (TGS) suspension. Daily moxibustion (DM) or alternate-day moxibustion (ADM) was administered on the day of TGS suspension administration. Finally, we selected DM for further study based on sperm quality and DNA fragmentation index, testicular and epididymal morphology, and reproductive hormone level results. Subsequently, the oxidative stress (OS) status was evaluated by observing the OS indices levels; malondialdehyde (MDA), 8-hydroxy-deoxyguanosine (8-OHdG), total antioxidant capacity (T-AOC), and total superoxide dismutase (T-SOD) in testicular tissue using colorimetry and enzyme-linked immunosorbent assay. Furthermore, heme oxygenase 1 (HO-1) and nuclear factor erythropoietin-2-related factor 2 (Nrf2) were evaluated using Western blotting. Immunohistochemistry was employed to locate and assess the expression of HO-1 and Nrf2 protein, while quantitative real-time polymerase chain reaction was utilized to detect their mRNA expression. MDA and 8-OHdG levels decreased following DM treatment, while T-SOD and T-AOC increased, suggesting that DM may prevent TGS-induced OAT in rats by decreasing OS in the testis. Furthermore, protein and mRNA expression of Nrf2 and HO-1 in the testis were elevated, indicating that DM may reduce OS by activating the signaling pathway of Nrf2/HO-1. Therefore, DM could prevent OAT in rats via the Nrf2/HO-1 pathway, thereby presenting a promising therapeutic approach against OAT.
Asunto(s)
Astenozoospermia , Infertilidad Masculina , Moxibustión , Oligospermia , Ratas , Masculino , Animales , Humanos , Hemo-Oxigenasa 1/metabolismo , Ratas Sprague-Dawley , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Tripterygium/genética , Tripterygium/metabolismo , Oligospermia/inducido químicamente , Glicósidos/farmacología , Astenozoospermia/inducido químicamente , Astenozoospermia/terapia , Infertilidad Masculina/inducido químicamente , Infertilidad Masculina/prevención & control , Semillas , Estrés Oxidativo , Antioxidantes/farmacología , Antioxidantes/metabolismo , Transducción de Señal , Superóxido Dismutasa/metabolismo , ARN Mensajero/metabolismoRESUMEN
Capsicum annuum var. abbreviatum (CAAE), which is in the genus Capsicum L. (Solanaceae), was found to be richer in polyphenols and flavonoids than other prevalent peppers of Capsicum annuum var. angulosum and Capsicum annuum. L. Yet, it is still unclear how CAAE reduces inflammation. In this study, we used the lipopolysaccharide-stimulated RAW264.7 macrophage cell line and bone marrow-derived macrophages to assess its anti-inflammatory activities. Initially, we discovered that CAAE decreased the levels of nitric oxide and inducible nitric oxide synthase. In addition, CAAE decreased the intracellular reactive oxygen species levels and increased the nuclear factor-erythroid 2-related factor 2 and heme oxygenase-1 compared with the phenotype of M2 macrophages. CAAE inhibited the activation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases, c-Jun N-terminal kinases, and p38 MAPKs. CAAE also inhibited the translocation of nuclear factor kappa B into nuclear, hence preventing the production of proinflammatory cytokines. Therefore, we suggest that CAAE might have potential as a candidate therapeutic agent for inflammatory diseases.
Asunto(s)
Capsicum , Lipopolisacáridos/farmacología , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Macrófagos/metabolismo , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , FN-kappa B/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fenotipo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico/metabolismoRESUMEN
Osteoporosis is an aging disease characterized by an imbalance between bone formation and resorption. However, drugs that inhibit bone resorption have various adverse effects. Ginseng (Panax ginseng), a prominent herbal medicine in East Asia for >2000 years, is renowned for its manifold beneficial properties, including antioxidant, anti-cancer, anti-diabetic, and anti-adipogenic activities. Despite its long history of use, the pharmacological functions of ginseng leaves are not yet fully comprehended. In this study, we evaluated the potential effects of ginseng leaf extract (GLE) on receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in RAW264.7 macrophage cells. Tartrate-resistant acid phosphatase (TRAP) staining revealed that GLE had significant anti-osteoclastogenic activity. GLE significantly reduced mRNA levels of osteoclast differentiation markers including TRAP, nuclear factor of activated T cell cytoplasmic 1, and cathepsin K. It also suppressed the production of reactive oxygen species (ROS) and secretion of high mobility group box-1 (HMGB1) in RANKL-treated RAW264.7 cells. In addition, GLE upregulated dose- and time-dependently the expression of heme oxygenase-1 (HO-1), eventually suppressing ROS production and HMGB1 secretion. This effects of GLE were significantly reversed by Tin Protoporphyrin IX dichloride, an inhibitor of HO-1, and HO-1 shRNA, indicating that HO-1 potently inhibits RANKL-induced osteoclast differentiation by inhibiting ROS production and HMGB1 secretion. Taken together, these observations suggest that GLE could have therapeutic potential as a natural product-derived medicine for the treatment of bone disorders.
Asunto(s)
Resorción Ósea , Proteína HMGB1 , Panax , Osteoclastos , Proteína HMGB1/metabolismo , Proteína HMGB1/farmacología , Diferenciación Celular , Especies Reactivas de Oxígeno/metabolismo , Hemo-Oxigenasa 1/metabolismo , Estructura Molecular , Extractos Vegetales/farmacología , Extractos Vegetales/metabolismo , Ligando RANKRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Fatsia japonica is a traditional medicine used to treat various diseases, including inflammation-related disorders. However, its antineuroinflammatory and neuroprotective effects remain unclear. AIM OF THE STUDY: We aimed to evaluate the anti-neuroinflammatory and neuroprotective effects of F. japonica extract to identify the underlying mechanisms. MATERIALS AND METHODS: The components of F. japonica extract were profiled using ultra-high-performance liquid chromatography-mass spectrometry. The effects of F. japonica extract were investigated in BV2 microglia and HT22 hippocampal cells. Furthermore, in vivo effects of F. japonica extract were assessed using zebrafish models treated with H2O2 and LPS to evaluate the effects of in vivo. RESULTS: We identified 27 compounds in the F. japonica extract. F. japonica extract demonstrated anti-inflammatory properties by suppressing LPS-induced inflammatory responses in both BV2 cells and zebrafish, along with inhibiting the activation of the nuclear factor (NF)-κB (p65) pathway. The protective effects of this extract were also observed on glutamate-treated HT22 cells and in H2O2-induced zebrafish. Furthermore, F. japonica extract upregulated nuclear factor E2-related (Nrf) 2/heme oxygenase (HO)-1 expression in BV2 and HT22 cells. CONCLUSIONS: F. japonica extract exerted anti-neuroinflammatory and neuroprotective effects through Nrf2/HO-1 and the NF-κB pathway.
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Fármacos Neuroprotectores , Animales , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/metabolismo , Pez Cebra , Antioxidantes/farmacología , Antioxidantes/metabolismo , Lipopolisacáridos/farmacología , Peróxido de Hidrógeno/metabolismo , Línea Celular , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Microglía , Hemo-Oxigenasa 1/metabolismoRESUMEN
BACKGROUND: Acute liver damage is a type of liver disease that has a significant global occurrence and a lack of successful treatment and prevention approaches. Sodium humate (HNa), a natural organic substance, has extensive applications in traditional Chinese medicine due to its antibacterial, anti-diarrheal, and anti-inflammatory characteristics. The purpose of this research was to examine the mitigating impacts of HNa on liver damage induced by lipopolysaccharide (LPS) in mice. METHODS AND RESULTS: A total of 30 female mice were randomly assigned into Con, Mod, L-HNa, M-HNa, and H-HNa groups. Mice in the Con and Mod groups were gavaged with PBS, whereas L-HNa, M-HNa, and H-HNa groups mice were gavaged with 0.1%, 0.3%, and 0.5% HNa, daily. On day 21, Mod, L-HNa, M-HNa, and H-HNa groups mice were challenged with LPS (10 mg/kg). We discovered that pretreatment with HNa improved liver pathological damage and inflammation by inhibiting the toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling pathway, enhancing the polarization of liver M2 macrophages, and reducing the levels of inflammatory cytokines. Our further study found that pretreatment with HNa enhanced the liver ability to combat oxidative stress and reduced hepatocyte apoptosis by activating the nuclear factor erythroid-2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) signaling pathway and enhancing the activities of antioxidant enzymes. CONCLUSIONS: In conclusion, HNa could alleviate LPS-induced liver damage through inhibiting TLR4/NF-κB and activating NRF2/HO-1 signaling pathways. This study is the first to discover the therapeutic effects of HNa on liver damage induced by LPS.
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Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , FN-kappa B , Femenino , Animales , Ratones , Lipopolisacáridos , Receptor Toll-Like 4 , Factor 2 Relacionado con NF-E2 , Hemo-Oxigenasa 1 , Transducción de SeñalRESUMEN
This study aims to explore the anti-inflammatory mechanisms of sargachromenol in both RAW 264.7 cells and lipopolysaccharide (LPS)-treated mice, as previous reports have suggested that sargachromenol possesses anti-aging, anti-inflammatory, antioxidant, and neuroprotective properties. Although the precise mechanism behind its anti-inflammatory activity remains unclear, pretreatment with sargachromenol effectively reduced the production of nitric oxide, prostaglandin E2, and interleukin (IL)-1ß in LPS-stimulated RAW 264.7 cells by inhibiting cyclooxygenase-2. Moreover, sargachromenol inhibited the activation of nuclear factor-κB (NF-κB) by preventing the degradation of the inhibitor of κB-α (IκB-α) and inhibiting protein kinase B (Akt) phosphorylation in LPS-stimulated cells. We also found that sargachromenol induced the production of heme oxygenase-1 (HO-1) by activating the nuclear transcription factor erythroid-2-related factor 2 (Nrf2). In LPS-treated mice, oral administration of sargachromenol effectively reduced the levels of IL-1ß, IL-6, and tumor necrosis factor-α (TNF-α) in the serum, suggesting its ability to suppress the production of inflammatory mediators by inhibiting the Akt/NF-κB pathway and upregulating the Nrf2/HO-1 pathway.
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Lipopolisacáridos , FN-kappa B , Animales , Ratones , FN-kappa B/metabolismo , Células RAW 264.7 , Lipopolisacáridos/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Antiinflamatorios/farmacología , Hemo-Oxigenasa 1/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ciclooxigenasa 2/metabolismoRESUMEN
Cardiac dysfunction and arrhythmia are severe complications of sepsis-induced cardiomyopathy and are associated with an increased risk of morbidity and mortality. Currently, the precise mechanism for sepsis-induced myocardial damage remains unclear. Astilbin, a flavonoid, is reported to have anti-inflammatory, antioxidative, and antiapoptotic properties. However, the effects of astilbin on sepsis-induced cardiomyopathy have not been studied so far. This study aims to investigate the effect of astilbin in sepsis-induced myocardial injury and elucidate the underlying mechanism. In vivo and in vitro sepsis models were created using lipopolysaccharide (LPS) as an inducer in H9C2 cardiomyocytes and C57BL/6 mice, respectively. Our results demonstrated that astilbin reduced myocardial injury and improved cardiac function. Moreover, astilbin prolonged the QT and corrected QT intervals, attenuated myocardial electrical remodeling, and promoted gap junction protein (Cx43) and ion channels expression, thereby reducing the susceptibility of ventricular fibrillation. In addition, astilbin alleviated LPS-induced inflammation, oxidative stress, and apoptosis. Astilbin suppressed the toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway in vivo and in vitro models. Astilbin remarkedly upregulated the nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase 1 (HO-1) expression. The in vitro treatment with an NRF2 inhibitor reversed the inhibition of the TLR4/NF-κB pathway and antioxidant properties of astilbin. Astilbin attenuated LPS-induced myocardial injury, cardiac dysfunction, susceptibility to VF, inflammation, oxidative stress, and apoptosis by activating the NRF2/HO-1 pathway and inhibiting TLR4/ NF-κB pathway. These results suggest that astilbin could be an effective and promising therapeutics target for the treatment of sepsis-induced cardiomyopathy.
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Cardiomiopatías , Flavonoles , Cardiopatías , Sepsis , Ratones , Animales , FN-kappa B/metabolismo , Receptor Toll-Like 4/metabolismo , Transducción de Señal , Factor 2 Relacionado con NF-E2/metabolismo , Hemo-Oxigenasa 1/metabolismo , Lipopolisacáridos/farmacología , Ratones Endogámicos C57BL , Inflamación , Estrés Oxidativo , Antioxidantes/farmacología , Antioxidantes/metabolismo , Cardiomiopatías/tratamiento farmacológico , Sepsis/complicaciones , Sepsis/tratamiento farmacológicoRESUMEN
Polycystic ovarian syndrome (PCOS) is an endocrine disorder in women's reproductive age. Currently, the pathophysiology of PCOS is unclear, and the limited treatment options are unsatisfactory. Virgin coconut oil (VCO) is functional food oil associated with pharmacological effects in reproductive disorders. Therefore, we aimed to evaluate whether VCO could enhance clomiphene (CLO) therapy against PCOS in female rats. Rats were randomly divided: (1) Control, (2) PCOS model, (3) PCOS + CLO, (4) PCOS + VCO, and (5) PCOS + CLO + VCO. The PCOS was induced via daily letrozole (1 mg/kg, orally) administration for 21 days. After the PCOS induction, CLO, VCO, and CLO + VCO were administered from days 22 to 36. Serum levels of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, estrogen, progesterone, and prolactin were estimated. Polymerase chain reaction gene expression for nuclear factor-erythroid-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), catalase (CAT), glutathione reductase (GSR), LH receptor (LHr), androgen receptor (AR), tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and caspase-3 were analyzed. The letrozole-induced PCOS caused considerable increases in GnRH, LH, prolactin, estrogen, and testosterone, whereas FSH decreased significantly compared to the control. The gene expression of Nrf2, HO-1, CAT, and GSR were markedly diminished, while IL-1ß, TNF-α, caspase-3, AR, and LHr prominently increased compared to control. Interestingly, the CLO and VCO separately exerted anti-inflammatory and endocrine balance effects. However, VCO-enhanced CLO effect in LH, prolactin and testosterone, Nrf2, HO-1, CAT, GSR, and AR. VCO may synergize with CLO to depress hyperandrogenism and oxidative inflammation in PCOS.
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Síndrome del Ovario Poliquístico , Animales , Femenino , Humanos , Ratas , Caspasa 3 , Clomifeno/toxicidad , Aceite de Coco/toxicidad , Estrógenos , Hormona Folículo Estimulante , Hormona Liberadora de Gonadotropina/farmacología , Hemo-Oxigenasa 1 , Letrozol/toxicidad , Hormona Luteinizante , Factor 2 Relacionado con NF-E2/genética , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Prolactina/efectos adversos , Testosterona , Factor de Necrosis Tumoral alfaRESUMEN
Heme oxygenase-1 (HO-1), which could be highly induced under the stimulation of oxidative stress, functions in reducing the damage caused by oxidative stress, and sulforaphane (SFN) is an antioxidant. This study aims to investigate whether HO-1 is involved in the repair of oxidative damage induced by oxidized fish oil (OFO) in Litopenaeus vannamei by sulforaphane (SFN). The oxidative stress model of L. vannamei was established by feeding OFO feed (OFO accounts for 6%), and they were divided into the following four groups: control group (injected with dsRNA-EGFP and fed with common feed), dsRNA-HO-1 group (dsRNA-HO-1, common feed), dsRNA-HO-1 + SFN group (dsRNA-HO-1, supplement 50 mg kg-1 SFN feed), and SFN group (dsRNA-EGFP, supplement 50 mg kg-1 SFN feed). The results showed that the expression level of HO-1 in the dsRNA-HO-1 + SFN group was significantly increased compared with the dsRNA-HO-1 group (p < 0.05). The activities of SOD in muscle and GPX in hepatopancreas and serum of the dsRNA-HO-1 group were significantly lower than those of the control group, and MDA content in the dsRNA-HO-1 group was the highest among the four groups. However, SFN treatment increased the activities of GPX and SOD in hepatopancreas, muscle, and serum and significantly reduced the content of MDA (p < 0.05). SFN activated HO-1, upregulated the expression of antioxidant-related genes (CAT, SOD, GST, GPX, Trx, HIF-1α, Nrf2, prx 2, Hsp 70), and autophagy genes (ATG 3, ATG 5), and stabilized the expression of apoptosis genes (caspase 2, caspase 3) in the hepatopancreas (p < 0.05). In addition, knocking down HO-1 aggravated the vacuolation of hepatopancreas and increased the apoptosis of hepatopancreas, while the supplement of SFN could repair the vacuolation of hepatopancreas and reduce the apoptosis signal. In summary, HO-1 is involved in the repair of the oxidative damage induced by OFO in L. vannamei by SFN.
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Antioxidantes , Hemo-Oxigenasa 1 , Antioxidantes/farmacología , Antioxidantes/metabolismo , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Aceites de Pescado/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Sulfóxidos , Superóxido Dismutasa/metabolismoRESUMEN
Notopterol, an active component isolated from the traditional Chinese medicine Notopterygium incisum Ting ex H.T. Chang, exerts anti-inflammatory activity in rheumatoid arthritis. However, its roles in suppression of inflammatory insults and halting progression of tissue destruction in periodontitis remain elusive. In this study, we reveal that notopterol can inhibit osteoclastogenesis, thereby limiting alveolar bone loss in vivo. In vitro results demonstrated that notopterol administration inhibited synthesis of inflammatory mediators such as IL-1ß, IL-32, and IL-8 in LPS-stimulated human gingival fibroblasts. Mechanistically, notopterol inhibits activation of the NF-κB signaling pathway, which is considered a prototypical proinflammatory signaling pathway. RNA sequencing data revealed that notopterol activates the PI3K/protein kinase B (Akt)/NF-E2-related factor 2 (Nrf2) signaling pathway in LPS-stimulated human gingival fibroblasts, a phenomenon validated via Western blot assay. Additionally, notopterol treatment suppressed reactive oxygen species levels by upregulating the expression of antioxidant genes, including heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), catalase (CAT), and glutathione reductase (GSR), indicating that notopterol confers protection against oxidative stress. Notably, inhibition of Akt activity by the potent inhibitor, MK-2206, partially attenuated both anti-inflammatory and antioxidant effects of notopterol. Collectively, these results raise the possibility that notopterol relieves periodontal inflammation by suppressing and activating the NF-κB and PI3K/AKT/Nrf2 signaling pathways in periodontal tissue, respectively, suggesting its potential as an efficacious treatment therapy for periodontitis.
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FN-kappa B , Periodontitis , Humanos , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Lipopolisacáridos/farmacología , Antiinflamatorios/farmacología , Antioxidantes , Hemo-Oxigenasa 1/metabolismoRESUMEN
BACKGROUND: This research aimed to evaluate the protective effects of Artemisia Absinthium L. (Abs) against liver damage induced by aluminium oxide nanoparticles (Al2O3 NPs) in rats, including both structural and functional changes associated with hepatotoxicity. METHODS: Thirty-six rats were randomly divided into six groups (n = 6). The first group received no treatment. The second group was orally administered Abs at a dose of 200 mg/kg/b.w. The third and fifth groups were injected intraperitoneally with γ-Al2O3 NPs and α-Al2O3 NPs, respectively, at a dose of 30 mg/kg/b.w. The fourth and sixth groups were pre-treated with oral Abs at a dose of 200 mg/kg/b.w. along with intraperitoneal injection of γ-Al2O3 NPs and α-Al2O3 NPs, respectively, at a dose of 30 mg/kg/b.w. RESULTS: Treatment with γ-Al2O3 NPs resulted in a significant decrease (P < 0.05) in total body weight gain, relative liver weight to body weight, and liver weight in rats. However, co-administration of γ-Al2O3 NPs with Abs significantly increased body weight gain (P < 0.05). Rats treated with Al2O3 NPs (γ and α) exhibited elevated levels of malondialdehyde (MDA), inducible nitric oxide synthase (iNOS), alanine transaminase (ALT), and aspartate aminotransferase (AST). Conversely, treatment significantly reduced glutathione peroxidase (GPx), catalase (CAT), total superoxide dismutase (T-SOD), and total antioxidant capacity (TAC) levels compared to the control group. Furthermore, the expression of heme oxygenase-1 (HO-1) and metallothionein-1 (MT-1) mRNAs, cytochrome P450 (CYP P450) protein, and histopathological changes were significantly up-regulated in rats injected with Al2O3 NPs. Pre-treatment with Abs significantly reduced MDA, AST, HO-1, and CYP P450 levels in the liver, while increasing GPx and T-SOD levels compared to rats treated with Al2O3 NPs. CONCLUSION: The results indicate that Abs has potential protective effects against oxidative stress, up-regulation of oxidative-related genes and proteins, and histopathological alterations induced by Al2O3 NPs. Notably, γ-Al2O3 NPs exhibited greater hepatotoxicity than α-Al2O3 NPs.