RÉSUMÉ
Retinal injury may be exacerbated by iron overload. Astragaloside IV (AS-IV) has potential applications in the food and healthcare industry to promote eye health. We sought to determine the mechanisms responsible for the protective effects of AS-IV on photoreceptor and retinal pigment epithelium cell death induced by iron overload. We conducted in vitro and in vivo experiments involving AS-IV pretreatment. We tested AS-IV for its ability to protect iron-overload mice from retinal injury. In particular, we analyzed the effects of AS-IV on iron overload-induced ferroptosis in 661W and ARPE-19 cells. AS-IV not only attenuated iron deposition and retinal injury in iron-overload mice but also effectively reduced iron overload-induced ferroptotic cell death in 661W and ARPE-19 cells. AS-IV effectively prevented ferroptosis by inhibiting iron accumulation and lipid peroxidation. In addition, inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2) eliminated the protective effect of AS-IV against ferroptosis. The results suggest that ferroptosis might be a significant cause of retinal cell death associated with iron overload. AS-IV provides protection from iron overload-induced ferroptosis, partly by activating the Nrf2 signaling pathway.
Sujet(s)
Ferroptose , Surcharge en fer , Souris de lignée C57BL , Épithélium pigmentaire de la rétine , Saponines , Triterpènes , Ferroptose/effets des médicaments et des substances chimiques , Animaux , Triterpènes/pharmacologie , Triterpènes/usage thérapeutique , Saponines/pharmacologie , Surcharge en fer/métabolisme , Surcharge en fer/traitement médicamenteux , Souris , Épithélium pigmentaire de la rétine/effets des médicaments et des substances chimiques , Épithélium pigmentaire de la rétine/métabolisme , Épithélium pigmentaire de la rétine/anatomopathologie , Modèles animaux de maladie humaine , Peroxydation lipidique/effets des médicaments et des substances chimiques , Humains , Rétinopathies/prévention et contrôle , Rétinopathies/métabolisme , Rétinopathies/anatomopathologie , Rétinopathies/traitement médicamenteux , Facteur-2 apparenté à NF-E2/métabolisme , Technique de Western , Mâle , Fer/métabolismeRÉSUMÉ
Betulinic acid (BA) is a natural triterpenoid extracted from Bacopa monnieri. BA has been reported to be used as a neuroprotective agent, but their molecular mechanisms are still unknown. Therefore, in this study, we attempted to investigate the precise mechanism of BA for its protective effect against Titanium dioxide nanoparticles (TiO2NP) induced neurotoxicity in zebrafish. Hence, our study observation showed that 10 µg/ml dose of TiO2NP caused a rigorous behavioral deficit in zebrafish. Further, biochemical analysis revealed TiO2NP significantly decreased GSH, and SOD, and increased MDA, AChE, TNF-α, IL-1ß, and IL-6 levels, suggesting it triggers oxidative stress and neuroinflammation. However, BA at doses of 2.5,5,10 mg/kg improved behavioral as well as biochemical changes in zebrafish brain. Moreover, BA also significantly raised the levels of DA, NE, 5-HT, and GABA and decreased glutamate levels in TiO2NP-treated zebrafish brain. Our histopathological analysis proved that TiO2NP causes morphological changes in the brain. These changes were expressed by increasing pyknotic neurons, which were dose-dependently reduced by Betulinic acid. Likewise, BA upregulated the levels of NRF-2 and HO-1, which can reduce oxidative stress and neuroinflammation. Thus, our study provides evidence for the molecular mechanism behind the neuroprotective effect of Betulinic acid. Rendering to the findings, we can consider BA as a suitable applicant for the treatment of AD-like symptoms.
Sujet(s)
Acide bétulinique , Encéphale , Neuroprotecteurs , Stress oxydatif , Triterpènes pentacycliques , Titane , Danio zébré , Animaux , Neuroprotecteurs/pharmacologie , Neuroprotecteurs/usage thérapeutique , Triterpènes pentacycliques/pharmacologie , Titane/toxicité , Stress oxydatif/effets des médicaments et des substances chimiques , Encéphale/effets des médicaments et des substances chimiques , Encéphale/anatomopathologie , Encéphale/métabolisme , Syndromes neurotoxiques/traitement médicamenteux , Triterpènes/pharmacologie , Triterpènes/usage thérapeutique , Protéines de poisson-zèbre/métabolisme , Protéines de poisson-zèbre/génétique , Cytokines/métabolisme , Nanoparticules , Comportement animal/effets des médicaments et des substances chimiques , Nanoparticules métalliques/toxicité , Mâle , Neurones/effets des médicaments et des substances chimiques , Neurones/anatomopathologieRÉSUMÉ
The glomerular podocyte, a terminally differentiated cell, is crucial for the integrity of the glomerular filtration barrier. The re-entry of podocytes into the mitotic phase results in injuries or death, known as mitotic catastrophe (MC), which significantly contributes to the progression of diabetic nephropathy (DN). Furthermore, P62-mediated autophagic flux has been shown to regulate DN-induced podocyte injury. Although previous studies, including ours, have demonstrated that ursolic acid (UA) mitigates podocyte injury by enhancing autophagy under high glucose conditions, the protective functions and potential regulatory mechanisms of UA against DN have not been fully elucidated. For aiming to investigate the regulatory mechanism of podocyte injuries in DN progression, and the protective function of UA treatment against DN progression, we utilized db/db mice and high glucose (HG)-induced podocyte models in vivo and in vitro, with or without UA administration. Our findings indicate that UA treatment reduced DN progression by improving biochemical indices. P62 accumulation led to Murine Double Minute gene 2 (MDM2)-regulated MC in podocytes during DN, which was ameliorated by UA through enhanced P62-mediated autophagy. Additionally, the overexpression of NF-κB p65 or TNF-α abolished the protective effects of UA both in vivo and in vitro. Overall, our results provide strong evidence that UA could be a potential therapeutic agent for DN, regulated by inhibiting podocyte MC through the NF-κB/MDM2/Notch1 pathway by targeting autophagic-P62 accumulation.
Sujet(s)
Autophagie , Néphropathies diabétiques , Podocytes , Triterpènes , , Podocytes/effets des médicaments et des substances chimiques , Podocytes/métabolisme , Animaux , Triterpènes/pharmacologie , Triterpènes/usage thérapeutique , Néphropathies diabétiques/métabolisme , Néphropathies diabétiques/traitement médicamenteux , Souris , Autophagie/effets des médicaments et des substances chimiques , Mitose/effets des médicaments et des substances chimiques , Mâle , Souris de lignée C57BLRÉSUMÉ
Background: Oligospermia is one of the most common reasons for male infertility which is troubling numerous couples of child-bearing age. This investigation scrutinizes the implications and mechanistic underpinnings of ursolic acid's effect on busulfan-induced oligospermia in mouse models. Methods: A singular intraperitoneal injection of busulfan at a dosage of 30 mg/kg induced oligospermia. Two weeks subsequent to this induction, mice were subjected to various dosages of ursolic acid (10, 30, and 50 mg/kg body weight, respectively) on a daily basis for four consecutive weeks. Following this treatment period, a meticulous analysis of epididymal sperm parameters, encompassing concentration and motility, was conducted using a computer-assisted sperm analysis system. The histopathology of the mice testes was performed utilizing hematoxylin and eosin staining, and the cytoskeleton regeneration of the testicular tissues was analyzed via immunofluorescent staining. Serum hormone levels, including testosterone, luteinizing hormone, and follicle-stimulating hormone, as well as reactive oxygen species levels (inclusive of reactive oxygen species and malondialdehyde), were gauged employing specific enzyme-linked immunosorbent assay kits. Differentially expressed genes of testicular mRNA between the oligospermia-induced group and the various ursolic acid treatment groups were identified through RNA sequencing analysis. Results: The results revealed that a dosage of 50 mg/kg ursolic acid treatment could increase the concentration of epididymal sperm in oligospermia mice, promote the recovery of testicular morphology, regulate hormone levels and ameliorate oxidative damage. The mechanism research results indicated that ursolic acid increased the expression level of genes related to motor proteins in oligospermia mice.
Sujet(s)
Busulfan , Oligospermie , Testicule , Triterpènes , , Animaux , Mâle , Triterpènes/pharmacologie , Triterpènes/usage thérapeutique , Oligospermie/induit chimiquement , Oligospermie/traitement médicamenteux , Souris , Testicule/effets des médicaments et des substances chimiques , Testicule/anatomopathologie , Testicule/métabolisme , Modèles animaux de maladie humaine , Mobilité des spermatozoïdes/effets des médicaments et des substances chimiques , Spermatozoïdes/effets des médicaments et des substances chimiques , Spermatozoïdes/anatomopathologie , Spermatozoïdes/métabolisme , Espèces réactives de l'oxygène/métabolisme , Testostérone/sang , Hormone folliculostimulante/sang , Hormone lutéinisante/sang , Hormone lutéinisante/métabolisme , Épididyme/effets des médicaments et des substances chimiques , Épididyme/anatomopathologie , Épididyme/métabolismeRÉSUMÉ
Platycodin D (PLD), a major bioactive component of triterpene saponins found in Platycodon grandiflora, is renowned for its anti-inflammatory and antioxidant properties. This study aims to explore the protective effects and regulatory mechanisms of PLD in an LPS-induced inflammation injury model of BEAS-2B cells. Initially, PLD was identified from Platycodon grandiflora extracts utilizing UPLC-Q-TOF-MS/MS technology. The effects of PLD on the viability, morphology, ROS levels, and inflammatory factors of LPS-induced BEAS-2B cells were then investigated. The results showed that PLD significantly alleviated LPS-induced oxidative stress and inflammatory injury. Further analysis revealed that PLD positively influenced apoptosis levels, mitochondrial morphology, and related gene expression, indicating its potential to mitigate LPS-induced apoptosis and alleviate mitochondrial dysfunction. Using molecular docking technology, we predicted the binding sites of PLD with mitochondrial autophagy protein. Gene expression levels of autophagy-related proteins were measured to determine the impact of PLD on mitochondrial autophagy. Additionally, the study examined whether the mitochondrial autophagy agonists rapamycin (RAPA) could modulate the upregulation of inflammasome-related factors NLRP3 and Caspase-1 in LPS-induced BEAS-2B cells. This was done to evaluate the regulator mechanisms of PLD in pulmonary inflammatory injury. Our findings suggest that PLD's mechanism of action involves the regulation of mitochondrial autophagy, which in turn modulates inflammatory responses.
Sujet(s)
Anti-inflammatoires , Apoptose , Autophagie , Lipopolysaccharides , Platycodon , Saponines , Triterpènes , Humains , Saponines/pharmacologie , Saponines/usage thérapeutique , Triterpènes/pharmacologie , Triterpènes/usage thérapeutique , Platycodon/composition chimique , Anti-inflammatoires/pharmacologie , Anti-inflammatoires/usage thérapeutique , Lignée cellulaire , Apoptose/effets des médicaments et des substances chimiques , Autophagie/effets des médicaments et des substances chimiques , Stress oxydatif/effets des médicaments et des substances chimiques , Mitochondries/effets des médicaments et des substances chimiques , Mitochondries/métabolisme , Simulation de docking moléculaire , Protéine-3 de la famille des NLR contenant un domaine pyrine/métabolisme , Inflammation/traitement médicamenteux , Inflammation/induit chimiquement , Espèces réactives de l'oxygène/métabolismeRÉSUMÉ
The pathogenesis of membranous nephropathy (MN) involves podocyte injury that is attributed to inflammatory responses induced by local immune deposits. Astragaloside IV (AS-IV) is known for its robust anti-inflammatory properties. Here, we investigated the effects of AS-IV on passive Heymann nephritis (PHN) rats and TNF-α-induced podocytes to determine the underlying molecular mechanisms of MN. Serum biochemical parameters, 24-h urine protein excretion and renal histopathology were evaluated in PHN and control rats. The expression of tumor necrosis factor receptor associated factor 6 (TRAF6), the phosphorylation of nuclear factor kappa B (p-NF-κB), the expression of associated proinflammatory cytokines (TNF-α, IL-6 and IL-1ß) and the ubiquitination of TRAF6 were measured in PHN rats and TNF-α-induced podocytes. We detected a marked increase in mRNA expression of TNF-α, IL-6 and IL-1ß and in the protein abundance of p-NF-κB and TRAF6 within the renal tissues of PHN rats and TNF-α-induced podocytes. Conversely, there was a reduction in the K48-linked ubiquitination of TRAF6. Additionally, AS-IV was effective in ameliorating serum creatinine, proteinuria, and renal histopathology in PHN rats. This effect was concomitant with the suppression of NF-κB pathway activation and decreased expression of TNF-α, IL-6, IL-1ß and TRAF6. AS-IV decreased TRAF6 levels by promoting K48-linked ubiquitin conjugation to TRAF6, which triggered ubiquitin-mediated degradation. In summary, AS-IV averted renal impairment in PHN rats and TNF-α-induced podocytes, likely by modulating the inflammatory response through the TRAF6/NF-κB axis. Targeting TRAF6 holds therapeutic promise for managing MN.
Sujet(s)
Glomérulonéphrite extra-membraneuse , Facteur de transcription NF-kappa B , Podocytes , Saponines , Facteur-6 associé aux récepteurs de TNF , Triterpènes , Animaux , Podocytes/effets des médicaments et des substances chimiques , Podocytes/anatomopathologie , Podocytes/métabolisme , Rats , Triterpènes/pharmacologie , Triterpènes/usage thérapeutique , Facteur-6 associé aux récepteurs de TNF/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Saponines/pharmacologie , Saponines/usage thérapeutique , Mâle , Glomérulonéphrite extra-membraneuse/traitement médicamenteux , Glomérulonéphrite extra-membraneuse/anatomopathologie , Glomérulonéphrite extra-membraneuse/métabolisme , Rat Sprague-Dawley , Transduction du signal/effets des médicaments et des substances chimiques , Facteur de nécrose tumorale alpha/métabolisme , Modèles animaux de maladie humaine , Ubiquitination/effets des médicaments et des substances chimiques , Rein/anatomopathologie , Rein/effets des médicaments et des substances chimiques , Rein/métabolisme , Cytokines/métabolisme , Anti-inflammatoires/pharmacologieRÉSUMÉ
ETHNOPHARMACOLOGICAL RELEVANCE: Astragaloside IV (AS), a key active ingredient obtained from Chinese herb Astragalus mongholicus Bunge, exerts potent neuroprotective and anti-inflammatory effects for treating neurodegenerative diseases. However, mechanisms of AS on improvement of ischemic brain tissue repair remain unclear. AIM OF THE STUDY: This research aims at using magnetic resonance imaging (MRI) to noninvasively determine whether AS facilitates brain tissue repair, and investigating whether AS exerts brain remodeling through adenosine monophosphate-activated protein kinase (AMPK) metabolic signaling regulating key glycolytic enzymes and energy transporters, thereby impacting microglia polarization. MATERIALS AND METHODS: Ischemic stroke model in male Sprague-Dawley rats were induced through permanent occlusion of the middle cerebral artery (MCAO). Infarct volume, the alterations of brain microstructure and nerve fibers reorganization were examined by multi-parametric MRI. The pathological damages of myelinated axons and microglia polarization surrounding infarct tissue were detected using pathological techniques. Furthermore, M1/M2 microglia polarization associated protein, glycolytic rate-limiting enzymes, energy transporters and AMPK/mammalian target of rapamycin (mTOR)/hypoxia inducible factor-1α (HIF-1α) signal were examined both in ischemic stroke rats and BV2 microglia treated with lipopolysaccharide (LPS) + interferon-γ (IFN-γ) by western blotting. RESULTS: MRI revealed that AS obviously decreased infarct volume, relieved brain microstructure damage and improved nerve fibers reorganization in ischemic stroke rats. Histological tests supported MRI findings. Notably, AS promoted microglia M2 and reduced M1 polarization, induced the AMPK activation accompanied with decreased levels of phosphorylated mTOR and HIF-1α. Moreover, AS suppressed the expression of glycolytic rate-limiting enzymes and energy transporters in ischemic stroke rats and BV2 microglia. In contrast, these beneficial effects were greatly blocked by AMPK inhibitor compound C. CONCLUSION: Overall, these results collectively suggested that AS facilitated tissue remodeling that may be partially through modulating polarization of microglia in AMPK- dependent metabolic pathways after ischemic stroke.
Sujet(s)
AMP-Activated Protein Kinases , Microglie , Rat Sprague-Dawley , Saponines , Triterpènes , Animaux , Triterpènes/pharmacologie , Triterpènes/usage thérapeutique , Mâle , Saponines/pharmacologie , Saponines/usage thérapeutique , Microglie/effets des médicaments et des substances chimiques , AMP-Activated Protein Kinases/métabolisme , Rats , Neuroprotecteurs/pharmacologie , Accident vasculaire cérébral ischémique/traitement médicamenteux , Infarctus du territoire de l'artère cérébrale moyenne/traitement médicamenteux , Sérine-thréonine kinases TOR/métabolisme , Encéphale/effets des médicaments et des substances chimiques , Encéphale/anatomopathologie , Transduction du signal/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaine , Lignée cellulaireRÉSUMÉ
Neurodegenerative diseases represent a cluster of conditions characterized by the progressive degeneration of the structure and function of the nervous system. Despite significant advancements in understanding these diseases, therapeutic options remain limited. The medicinal mushroom Ganoderma lucidum has been recognized for its comprehensive array of bioactive compounds with anti-inflammatory and antioxidative effects, which possess potential neuroprotective properties. This literature review collates and examines the existing research on the bioactivity of active compounds and extracts from Ganoderma lucidum in modulating the pathological hallmarks of neurodegenerative diseases. The structural information and preparation processes of specific components, such as individual ganoderic acids and unique fractions of polysaccharides, are presented in detail to facilitate structure-activity relationship research and scale up the investigation of in vivo pharmacology. The mechanisms of these components against neurodegenerative diseases are discussed on multiple levels and elaborately categorized in different patterns. It is clearly presented from the patterns that most polysaccharides of Ganoderma lucidum possess neurotrophic effects, while ganoderic acids preferentially target specific pathogenic proteins as well as regulating autophagy. Further clinical trials are necessary to assess the translational potential of these components in the development of novel multi-target drugs for neurodegenerative diseases.
Sujet(s)
Maladies neurodégénératives , Neuroprotecteurs , Reishi , Maladies neurodégénératives/traitement médicamenteux , Humains , Reishi/composition chimique , Neuroprotecteurs/pharmacologie , Neuroprotecteurs/composition chimique , Neuroprotecteurs/usage thérapeutique , Animaux , Triterpènes/pharmacologie , Triterpènes/composition chimique , Triterpènes/usage thérapeutique , Anti-inflammatoires/pharmacologie , Anti-inflammatoires/composition chimique , Anti-inflammatoires/usage thérapeutique , Antioxydants/pharmacologie , Antioxydants/composition chimique , Antioxydants/usage thérapeutique , Polyosides/composition chimique , Polyosides/pharmacologie , Polyosides/usage thérapeutiqueRÉSUMÉ
OBJECTIVE: To unveil the pathological changes associated with demyelination in schizophrenia (SZ) and its consequential impact on interstitial fluid (ISF) drainage, and to investigate the therapeutic efficacy of ursolic acid (UA) in treating demyelination and the ensuing abnormalities in ISF drainage in SZ. METHODS: Female C57BL/6J mice, aged 6-8 weeks and weighing (20±2) g, were randomly divided into three groups: control, SZ model, and UA treatment. The control group received intraperitoneal injection (ip) of physiological saline and intragastric administration (ig) of 1% carboxymethylcellulose sodium (CMC-Na). The SZ model group was subjected to ip injection of 2 mg/kg dizocilpine maleate (MK-801) and ig administration of 1% CMC-Na. The UA treatment group underwent ig administration of 25 mg/kg UA and ip injection of 2 mg/kg MK-801. The treatment group received UA pretreatment via ig administration for one week, followed by a two-week drug intervention for all the three groups. Behavioral assessments, including the open field test and prepulse inhibition experiment, were conducted post-modeling. Subsequently, changes in the ISF partition drainage were investigated through fluorescent tracer injection into specific brain regions. Immunofluorescence analysis was employed to examine alterations in aquaporin 4 (AQP4) polarity distribution in the brain and changes in protein expression. Myelin reflex imaging using Laser Scanning Confocal Microscopy (LSCM) was utilized to study modifications in myelin within the mouse brain. Quantitative data underwent one-way ANOVA, followed by TukeyHSD for post hoc pairwise comparisons between the groups. RESULTS: The open field test revealed a significantly longer total distance [(7 949.39±1 140.55) cm vs. (2 831.01±1 212.72) cm, P < 0.001] and increased central area duration [(88.43±22.06) s vs. (56.85±18.58) s, P=0.011] for the SZ model group compared with the controls. The UA treatment group exhibited signifi-cantly reduced total distance [(2 415.80±646.95) cm vs. (7 949.39±1 140.55) cm, P < 0.001] and increased central area duration [(54.78±11.66) s vs. (88.43±22.06) s, P=0.007] compared with the model group. Prepulse inhibition test results demonstrated a markedly lower inhibition rate of the startle reflex in the model group relative to the controls (P < 0.001 for both), with the treatment group displaying significant improvement (P < 0.001 for both). Myelin sheath analysis indicated significant demyelination in the model group, while UA treatment reversed this effect. Fluorescence tracing exhibited a significantly larger tracer diffusion area towards the rostral cortex and reflux area towards the caudal thalamus in the model group relative to the controls [(13.93±3.35) mm2 vs. (2.79±0.94) mm2, P < 0.001 for diffusion area; (2.48±0.38) mm2 vs. (0.05±0.12) mm2, P < 0.001 for reflux area], with significant impairment of drainage in brain regions. The treatment group demonstrated significantly reduced tracer diffusion and reflux areas [(7.93±2.48) mm2 vs. (13.93±3.35) mm2, P < 0.001 for diffusion area; (0.50±0.30) mm2 vs. (2.48±0.38) mm2, P < 0.001 for reflux area]. Immunofluorescence staining revealed disrupted AQP4 polarity distribution and reduced AQP4 protein expression in the model group compared with the controls [(3 663.88±733.77) µm2 vs. (13 354.92±4 054.05) µm2, P < 0.001]. The treatment group exhibited restored AQP4 polarity distribution and elevated AQP4 protein expression [(11 104.68±3 200.04) µm2 vs. (3 663.88±733.77) µm2, P < 0.001]. CONCLUSION: UA intervention ameliorates behavioral performance in SZ mice, Thus alleviating hyperactivity and anxiety symptoms and restoring sensorimotor gating function. The underlying mechanism may involve the improvement of demyelination and ISF drainage dysregulation in SZ mice.
Sujet(s)
Maladies démyélinisantes , Modèles animaux de maladie humaine , Liquide extracellulaire , Souris de lignée C57BL , Schizophrénie , Triterpènes , , Animaux , Souris , Triterpènes/usage thérapeutique , Triterpènes/pharmacologie , Schizophrénie/traitement médicamenteux , Femelle , Maladies démyélinisantes/traitement médicamenteux , Liquide extracellulaire/effets des médicaments et des substances chimiques , Liquide extracellulaire/métabolisme , Maléate de dizocilpine , Aquaporine-4/métabolismeRÉSUMÉ
Acute liver failure is mainly caused by the overdose of acetaminophen (APAP) globally. The traditional Chinese medicinal (TCM) herb, Taraxacum, contains Taraxasterol (TAX) as one of the active components. It is a pentacyclic-triterpene compound isolated from this herb. Present work aimed to investigate the in vitro and in vivo protection effect of TAX in APAP-induced acute liver injury, and determine the potential regulatory mechamisms. The liver injury caused by APAP is attenuated by TAX, as shown by the alleviated pathological changes of mice liver and the reduced serological indexes. TAX evidently controlled the oxidative stress and liver inflammation in mice liver. In vitro studies found that TAX reversed the decrease in LO2 cell viability induced by APAP, and protected LO2 cells from APAP-induced injury. In addition, TAX reduced the secretion of inflammatory factors in RAW264.7 macrophages as induced via APAP. Besides, TAX inhibited oxidative stress in LO2 cells induced by APAP in vitro. Noteworthy, TAX enhanced protein and mRNA expressions of Nrf2 in vivo, and knockdown of Nrf2 by using adeno-associated virus (AAV)-Nrf2-KO attenuated inhibitory impact of TAX in acute liver injury induced by APAP. Also, AAV-NRF2-KO weakened the inhibitory impact of TAX against APAP-triggered liver inflammation and oxidative stress of mice liver. Moreover, TAX activated the Nrf2 signaling in APAP-induced LO2 cells, as shown by the increased nuclear Nrf2 expression together with downstream HO-1 expression in vitro. Inhibition of Nrf2 by using ML-385, anNrf2inhibitor, weakened the inhibitory effect of TAX against APAP-induced oxidative stress and cell injury in LO2 cells. Moreover, inhibition of Nrf2 attenuated anti-inflammatory effect of TAX for APAP-induced RAW264.7 cells. Collectively, TAX could protect against APAP-triggered hepatotoxicitythrough suppression of liver oxidative stress and inflammatory response in mice.
Sujet(s)
Acétaminophène , Lésions hépatiques dues aux substances , Facteur-2 apparenté à NF-E2 , Stress oxydatif , Animaux , Stress oxydatif/effets des médicaments et des substances chimiques , Souris , Lésions hépatiques dues aux substances/traitement médicamenteux , Lésions hépatiques dues aux substances/anatomopathologie , Lésions hépatiques dues aux substances/immunologie , Lésions hépatiques dues aux substances/prévention et contrôle , Lésions hépatiques dues aux substances/métabolisme , Facteur-2 apparenté à NF-E2/métabolisme , Mâle , Foie/effets des médicaments et des substances chimiques , Foie/anatomopathologie , Foie/métabolisme , Foie/immunologie , Triterpènes/pharmacologie , Triterpènes/usage thérapeutique , Cellules RAW 264.7 , Souris de lignée C57BL , Humains , Anti-inflammatoires/pharmacologie , Anti-inflammatoires/usage thérapeutique , Lignée cellulaire , StérolsRÉSUMÉ
Aim: Ursolic acid (UA) has an important biological role in the fight against fat accumulation, insulin resistance, obesity and inflammation. Therefore, in the current review and meta-analysis work, we investigate the effects of UA (dosage range is 50.94 to 450 mg/day) on cardiometabolic risk factors. Materials & methods: After searching the studies up to February 2023, six articles were included in the study. Results: The pooled effect size showed that UA supplementation didn't significantly change body weight, body mass index, waist circumference, body fat percentage, lean body mass, systolic blood pressure, diastolic blood pressure, fasting blood glucose, insulin, triglyceride and high-density lipoprotein compared with control groups. Conclusion: UA supplementation had no significant effect on the cardiometabolic risk factors in adults.
Cardiovascular disease (CVD) is a significant reason for morbidity and mortality. Ursolic acid (UA) has been shown to play important biological roles in the fight against fat accumulation, oxidative stress, insulin resistance via insulin-like growth factor 1, cancer, muscle atrophy, obesity and inflammation responsible for CVD. A systematic review and meta-analysis were conducted up to February 2023; six articles were included in the study and eleven cardiometabolic risk factors were identified. The pooled effect size showed that UA supplementation (dosage range is 50.94 to 450 mg/day) didn't significantly change body weight, body mass index, waist circumference, body fat percentage, lean body mass, systolic blood pressure, diastolic blood pressure, fasting blood glucose, insulin, triglyceride, and high-density lipoprotein compared with control groups.
Sujet(s)
Facteurs de risque cardiométabolique , Triterpènes , , Humains , Indice de masse corporelle , Maladies cardiovasculaires/prévention et contrôle , Maladies cardiovasculaires/étiologie , Compléments alimentaires , Triterpènes/pharmacologie , Triterpènes/usage thérapeutiqueRÉSUMÉ
BACKGROUND: Astragaloside IV (AS-IV) is the most active monomer in the traditional Chinese herbal medicine Radix Astragali, which has a wide range of antiviral, anti-inflammatory, and antifibrosis pharmacological effects, and shows protective effects in acute lung injury. METHODS: This study utilized the immunofluorescence, flow cytometry, enzyme-linked immunosorbent assay, quantitative reverse transcription-polymerase chain reaction, western blot, and hematoxylin and eosin staining methods to investigate the mechanism of AS-IV in reducing viral pneumonia caused by influenza A virus in A549 cells and BALB/c mice. RESULTS: The results showed that AS-IV suppressed reactive oxygen species production in influenza virus-infected A549 cells in a dose-dependent manner, and subsequently inhibited the activation of nucleotide-binding oligomerization domain-like receptor thermal protein domain associated protein 3 inflammasome and Caspase-1, decreased interleukin (IL) -1ß and IL-18 secretion. In BALB/c mice infected with Poly (I:C), oral administration of AS-IV can significantly reduce Poly (I:C)-induced acute pneumonia and lung pathological injury. CONCLUSIONS: AS-IV alleviates the inflammatory response induced by influenza virus in vitro and lung flammation and structural damage caused by poly (I:C) in vivo.
Sujet(s)
Caspase-1 , Souris de lignée BALB C , Protéine-3 de la famille des NLR contenant un domaine pyrine , Infections à Orthomyxoviridae , Espèces réactives de l'oxygène , Saponines , Transduction du signal , Triterpènes , Animaux , Saponines/pharmacologie , Triterpènes/pharmacologie , Triterpènes/usage thérapeutique , Souris , Transduction du signal/effets des médicaments et des substances chimiques , Humains , Espèces réactives de l'oxygène/métabolisme , Cellules A549 , Caspase-1/métabolisme , Infections à Orthomyxoviridae/traitement médicamenteux , Infections à Orthomyxoviridae/immunologie , Infections à Orthomyxoviridae/virologie , Protéine-3 de la famille des NLR contenant un domaine pyrine/métabolisme , Inflammation/traitement médicamenteux , Virus de la grippe A/effets des médicaments et des substances chimiques , Anti-inflammatoires/pharmacologie , Anti-inflammatoires/usage thérapeutiqueRÉSUMÉ
This study aims to explore the protective machinery of pegylated polymeric micelles of boswellic acid-selenium (PMBS) against secondary neuronal damage triggered by mild repetitive traumatic brain injury (RTBI). After PMBS characterization in terms of particle size, size distribution, zeta potential, and transmission electronic microscopy, the selected formula was used to investigate its potency against experimental RTBI. Five groups of rats were used; group 1 (control) and the other four groups were subjected to RTBI. Groups 2 was RTBI positive control, while 3, 4, and 5 received boswellic acid (BSA), selenium (SEL), and PMBS, respectively. The open-field behavioral test was used for behavioral assessment. Subsequently, brain tissues were utilized for hematoxylin and eosin staining, Nissl staining, Western blotting, and ELISA in addition to evaluating microRNA expression (miR-155 and miR-146a). The behavioral changes, oxidative stress, and neuroinflammation triggered by RTBI were all improved by PMBS. Moreover, PMBS mitigated excessive glutamate-induced excitotoxicity and the dysregulation in miR-155 and miR-146a expression. Besides, connexin43 (Cx43) expression as well as klotho and brain-derived neurotrophic factor (BDNF) were upregulated with diminished neuronal cell death and apoptosis because of reduced Forkhead Box class O3a(Foxo3a) expression in the PMBS-treated group. The current study has provided evidence of the benefits produced by incorporating BSA and SEL in PEGylated polymeric micelles formula. PMBS is a promising therapy for RTBI. Its beneficial effects are attributed to the manipulation of many pathways, including the regulation of miR-155 and miR-146a expression, as well as the BDNF /Klotho/Foxo3a signaling pathway.
Sujet(s)
Facteur neurotrophique dérivé du cerveau , Protéine O3 à motif en tête de fourche , Protéines Klotho , Micelles , microARN , Polyéthylène glycols , Sélénium , Triterpènes , Animaux , microARN/génétique , microARN/métabolisme , Facteur neurotrophique dérivé du cerveau/métabolisme , Facteur neurotrophique dérivé du cerveau/génétique , Protéine O3 à motif en tête de fourche/métabolisme , Protéine O3 à motif en tête de fourche/génétique , Mâle , Rats , Sélénium/composition chimique , Triterpènes/pharmacologie , Triterpènes/usage thérapeutique , Transduction du signal/effets des médicaments et des substances chimiques , Rat Sprague-Dawley , Neuroprotecteurs/pharmacologie , Neuroprotecteurs/usage thérapeutique , Modèles animaux de maladie humaine , Stress oxydatif/effets des médicaments et des substances chimiques , Lésions traumatiques de l'encéphale/traitement médicamenteux , Lésions traumatiques de l'encéphale/métabolisme , Encéphale/effets des médicaments et des substances chimiques , Encéphale/métabolisme , Encéphale/anatomopathologie , Polymères/composition chimiqueRÉSUMÉ
The administration of nonsteroidal anti-inflammatory drugs (NSAIDs) may cause significant intestinal alteration and inflammation and lead to the occurrence of inflammatory diseases resembling duodenal ulcers. Astragaloside IV (AS-IV) is a glycoside of cycloartane-type triterpene isolated from the dried root of Astragalus membranaceus (Fisch.) Bge. (family Fabaceae), and has been used for ameliorating the NSAID-induced inflammation in the small intestine. The present study aimed to investigate the effects of AS-IV on indomethacin (IND)-induced inflammation in the small intestine of rats and its underlying mechanisms. Hematoxylin-eosin (H&E) staining, transmission and scanning electron microscopy were carried out to observe the surface morphology and ultrastructure of the small intestinal mucosa. Immunofluorescence and ELISA tests were employed to detect the expressions of NLRP3, ASC, caspase-1, and NF-κB proteins, as well as inflammatory factors IL-1ß and IL-18, to uncover potential molecular mechanisms responsible for mitigating small intestinal inflammation. The results demonstrated that AS-IV significantly decreased the ulcer index, improved the surface morphology and microstructure of the small intestinal mucosa, and increased mucosal blood flow. Molecular docking revealed a strong and stable binding capacity of AS-IV to NLRP3, ASC, caspase-1, and NF-κB proteins. Further experimental validation exhibited that AS-IV markedly decreased levels of IL-1ß and IL-18, and inhibited the protein expression of NLRP3, ASC, caspase-1, and NF-κB. Our data demonstrate that AS-IV ameliorates IND-induced intestinal inflammation in rats by inhibiting the activation of NLRP3 inflammasome and reducing the release of IL-1ß and IL-18, thereby representing a promising therapy for IND-induced intestinal inflammation.
Sujet(s)
Indométacine , Inflammasomes , Protéine-3 de la famille des NLR contenant un domaine pyrine , Rat Sprague-Dawley , Saponines , Triterpènes , Animaux , Saponines/pharmacologie , Saponines/usage thérapeutique , Protéine-3 de la famille des NLR contenant un domaine pyrine/métabolisme , Triterpènes/pharmacologie , Triterpènes/usage thérapeutique , Inflammasomes/métabolisme , Inflammasomes/effets des médicaments et des substances chimiques , Mâle , Rats , Anti-inflammatoires non stéroïdiens/pharmacologie , Intestin grêle/effets des médicaments et des substances chimiques , Intestin grêle/anatomopathologie , Intestin grêle/métabolisme , Intestin grêle/immunologie , Muqueuse intestinale/effets des médicaments et des substances chimiques , Muqueuse intestinale/anatomopathologie , Muqueuse intestinale/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Interleukine-1 bêta/métabolisme , Simulation de docking moléculaire , Caspase-1/métabolisme , Inflammation/traitement médicamenteux , Inflammation/induit chimiquementRÉSUMÉ
The neuronal and renal deteriorations observed in patients exposed to methotrexate (MTX) therapy highlight the need for medical interventions to counteract these complications. Boswellic acid (BA) and apigenin (APG) are natural phytochemicals with prominent neuronal and renal protective impacts in various ailments. However, their impacts on MTX-provoked renal and hippocampal toxicity have not been reported. Thus, the present work is tailored to clarify the ability of BA and APG to counteract MTX-provoked hippocampal and renal toxicity. BA (250 mg/kg) or APG (20 mg/kg) were administered orally in rats once a day for 10 days, while MTX (20 mg/kg, i.p.) was administered once on the sixth day of the study. At the histopathological level, BA and APG attenuated MTX-provoked renal and hippocampal aberrations. They also inhibited astrocyte activation, as proven by the inhibition of glial fibrillary acidic protein (GFAP). These impacts were partially mediated via the activation of autophagy flux, as proven by the increased expression of beclin1, LC3-II, and the curbing of p62 protein, alongside the regulation of the p-AMPK/mTOR nexus. In addition, BA and APG displayed anti-inflammatory features as verified by the damping of NOD-2 and p-NF-κB p65 to reduce TNF-α, IL-6, and NLRP3/IL-1ß cue. These promising effects were accompanied with a notable reduction in one of the gap junction proteins, connexin-43 (Conx-43). These positive impacts endorse BA and APG as adjuvant modulators to control MTX-driven hippocampal and nephrotoxicity.
Sujet(s)
Apigénine , Autophagie , Connexine 43 , Hippocampe , Rein , Méthotrexate , Facteur de transcription NF-kappa B , Protéine-3 de la famille des NLR contenant un domaine pyrine , Triterpènes , Animaux , Hippocampe/effets des médicaments et des substances chimiques , Hippocampe/métabolisme , Hippocampe/anatomopathologie , Méthotrexate/effets indésirables , Protéine-3 de la famille des NLR contenant un domaine pyrine/métabolisme , Apigénine/pharmacologie , Apigénine/usage thérapeutique , Triterpènes/pharmacologie , Triterpènes/usage thérapeutique , Facteur de transcription NF-kappa B/métabolisme , Mâle , Rats , Connexine 43/métabolisme , Autophagie/effets des médicaments et des substances chimiques , Rein/effets des médicaments et des substances chimiques , Rein/anatomopathologie , Rein/métabolisme , Rat Wistar , Transduction du signal/effets des médicaments et des substances chimiquesRÉSUMÉ
Mogroside, the main component of Siraitia grosvenorii (Swingle) C. Jeffrey (Cucurbitaceae) is a natural product with hypoglycemic and intestinal microbiota regulating properties. However, whether the alteration of intestinal microbiota is associated with the antidiabetic effect of mogroside remains poorly understood. This study investigated the mechanism underlying the hypoglycemic effect of mogroside in regulating intestinal flora and attenuating metabolic endotoxemia. Kunming mice with type 2 diabetes mellitus (T2DM) induced by high-fat diet and intraperitoneal injection of streptozotocin were randomly divided into model, pioglitazone (2.57 mg/kg) and mogroside (200, 100, and 50 mg/kg) groups. After 28 d of administration, molecular changes related to glucose metabolism and metabolic endotoxemia in mice were evaluated. The levels of insulin receptor substrate-1 (IRS-1), cluster of differentiation 14 (CD14) and toll-like receptor 4 (TLR4) mRNAs were measured, and the composition of intestinal microflora was determined by 16s ribosomal DNA (rDNA) sequencing. The results showed that mogroside treatment significantly improved hepatic glucose metabolism in T2DM mice. More importantly, mogroside treatment considerably reduced plasma endotoxin (inhibition rate 65.93%, high-dose group) and inflammatory factor levels, with a concomitant decrease in CD14 and TLR4 mRNA levels. Moreover, mogroside treatment reduced the relative abundance of Firmicutes and Proteobacteria (the inhibition rate of Proteobacteria was 85.17% in the low-dose group) and increased the relative abundance of Bacteroidetes (growth rate up to 40.57%, high-dose group) in the intestines of diabetic mice. This study reveals that mogroside can relieve T2DM, regulating intestinal flora and improving intestinal mucosal barrier, indicating that mogroside can be a potential therapeutic agent or intestinal microbiota regulator in the treatment of T2DM.
Sujet(s)
Diabète expérimental , Diabète de type 2 , Microbiome gastro-intestinal , Hypoglycémiants , Animaux , Microbiome gastro-intestinal/effets des médicaments et des substances chimiques , Mâle , Diabète de type 2/traitement médicamenteux , Diabète de type 2/métabolisme , Diabète de type 2/microbiologie , Diabète expérimental/traitement médicamenteux , Diabète expérimental/métabolisme , Diabète expérimental/sang , Souris , Hypoglycémiants/pharmacologie , Hypoglycémiants/usage thérapeutique , Alimentation riche en graisse/effets indésirables , Glycémie/effets des médicaments et des substances chimiques , Triterpènes/pharmacologie , Triterpènes/usage thérapeutique , Récepteur de type Toll-4/métabolisme , Endotoxémie/traitement médicamenteux , Foie/effets des médicaments et des substances chimiques , Foie/métabolismeRÉSUMÉ
BACKGROUND: Our previous study has revealed that asiaticoside (AC) promotes endoplasmic reticulum stress and antagonizes proliferation and migration of gastric cancer (GC) via miR-635/HMGA1 axis. However, the effect and mechanism of AC on other progressions of GC, such as ferroptosis and immune escape, are still unknown. METHODS: AGS and HGC27 cells were incubated with 1, 2 and 4 µM of AC for 24 h. Mice xenografted with AGS cells were intragastrically injected with AC. The effect and mechanism of AC on GC were determined by the measurement of the ferrous iron level, the ROS level and the glutathione peroxidase (GSH) content, flow cytometry, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry and western blotting assays. RESULTS: AC increased the Fe2+ level and the ROS level, but decreased the expression of GPX4 and SLC7A11 and the GSH level. Besides, AC enhanced the percent of CD8+ T cells and the IFN-γ concentration, but reduced the PD-L1 expression and the IL-10 level. Mechanically, AC downregulated the relative levels of ß-catenin, active-ß-catenin, p-GSK3ß/GSK3ß, cyclin D1 and c-Myc in GC cells, which were rescued with the application of LiCl (an activator of Wnt/ß-catenin pathway) in AGS cells. Moreover, activation of Wnt/ß-catenin pathway by LiCl or the ß-catenin overexpression inverted the effect of AC on ferroptosis and immune escape in GC cells. In vivo, AC treatment declined the tumor size and weight, the level of GPX4, SLC7A11, PD-L1 and IFN-γ, and the expression of Wnt/ß-catenin pathway. CONCLUSION: AC enhanced ferroptosis and repressed immune escape by downregulating the Wnt/ß-catenin signaling in GC.
Sujet(s)
Régulation négative , Ferroptose , Tumeurs de l'estomac , Triterpènes , Échappement de la tumeur à la surveillance immunitaire , Voie de signalisation Wnt , Ferroptose/effets des médicaments et des substances chimiques , Tumeurs de l'estomac/traitement médicamenteux , Tumeurs de l'estomac/immunologie , Tumeurs de l'estomac/anatomopathologie , Animaux , Humains , Voie de signalisation Wnt/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Triterpènes/pharmacologie , Triterpènes/usage thérapeutique , Échappement de la tumeur à la surveillance immunitaire/effets des médicaments et des substances chimiques , Souris , Régulation négative/effets des médicaments et des substances chimiques , Souris de lignée BALB C , bêta-Caténine/métabolisme , Tests d'activité antitumorale sur modèle de xénogreffe , Souris nude , Phospholipid hydroperoxide glutathione peroxidase/métabolisme , Phospholipid hydroperoxide glutathione peroxidase/génétique , Mâle , Espèces réactives de l'oxygène/métabolisme , Système y+ de transport d'acides aminés/métabolisme , Système y+ de transport d'acides aminés/génétique , Lymphocytes T CD8+/immunologie , Lymphocytes T CD8+/effets des médicaments et des substances chimiquesRÉSUMÉ
Ulcerative colitis (UC) is an idiopathic, chronic inflammatory condition of the colon, characterized by repeated attacks, a lack of effective treatment options, and significant physical and mental health complications for patients. The endoplasmic reticulum (ER) is a vital intracellular organelle in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is induced when the body is exposed to adverse external stimuli. Numerous studies have shown that ERS-induced apoptosis plays a vital role in the pathogenesis of UC. Mogroside V (MV), an active ingredient of Monk fruit, has demonstrated excellent anti-inflammatory and antioxidant effects. In this study, we investigated the therapeutic effects of MV on dextran sulfate sodium (DSS)-induced UC and its potential mechanisms based on ERS. The results showed that MV exerted a protective effect against DSS-induced UC in mice as reflected by reduced DAI scores, increased colon length, reduced histological scores of the colon, and levels of pro-inflammatory cytokines, as well as decreased intestinal permeability. In addition, the expression of ERS pathway including BIP, PERK, eIF2α, ATF4, CHOP, as well as the apoptosis-related protein including Caspase-12, Bcl-2 and Bax, was found to be elevated in UC. However, MV treatment significantly inhibited the UC and reversed the expression of inflammation signaling pathway including ERS and ERS-induced apoptosis. Additionally, the addition of tunicamycin (Tm), an ERS activator, significantly weakened the therapeutic effect of MV on UC in mice. These findings suggest that MV may be a therapeutic agent for the treatment of DSS-induced UC by inhibiting the activation of the ERS-apoptosis pathway, and may provide a novel avenue for the treatment of UC.
Sujet(s)
Apoptose , Rectocolite hémorragique , Sulfate dextran , Stress du réticulum endoplasmique , Animaux , Stress du réticulum endoplasmique/effets des médicaments et des substances chimiques , Rectocolite hémorragique/traitement médicamenteux , Rectocolite hémorragique/anatomopathologie , Rectocolite hémorragique/induit chimiquement , Rectocolite hémorragique/métabolisme , Apoptose/effets des médicaments et des substances chimiques , Mâle , Souris de lignée C57BL , Côlon/anatomopathologie , Côlon/effets des médicaments et des substances chimiques , Triterpènes/pharmacologie , Triterpènes/usage thérapeutique , Souris , Cytokines/métabolisme , Perméabilité/effets des médicaments et des substances chimiques , Transduction du signal/effets des médicaments et des substances chimiquesRÉSUMÉ
BACKGROUND: Atherosclerosis (AS) is a chronic inflammatory vascular disease with a complex pathogenesis. Astragaloside IV (AST IV), the primary active component of Astragalus, possesses anti-inflammatory, antioxidant, and immunomodulatory properties. This research aims to investigate the outcome of AST IV on AS and its potential molecular mechanism. METHODS: A high-fat diet (21% fat, 50% carbohydrate, 20% protein, 0.15% cholesterol, and 34% sucrose) was utilized to feed Apolipoprotein E deficient (ApoE-/-) SD rats for 8 weeks, followed by continuous intragastric administration of AST IV for 8 weeks. Biochemical detection was conducted for serum lipid levels and changes in vasoactive substances. After Masson staining, aortic root oil red O staining, and Hematoxylin Eosin (HE) staining, the efficacy of AST IV was verified using quantitative reverse transcription polymerase chain reaction (qRT-PCR). The mRNA expression levels of inflammatory factors and endothelial dysfunction-related biomarkers in rat aortic root tissues were appraised. The changes in the composition of intestinal flora in rats after AST IV treatment were appraised using Image J (Multi-point Tool). Western blot was used to evaluate phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway-related protein levels in rat aortic root tissues. RESULTS: AST IV administration alleviated the pathological symptoms of AS rats. AST IV administration reduced serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), endothelin-1 (ET-1) and angiotensin (Ang)-II (Ang-II) levels, and augmented serum high-density lipoprotein cholesterol (HDL-C) and nitric oxide (NO) levels. At the same time, AST IV administration inhibited the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1ß, vascular cell adhesion molecule-1 (VCAM-1), matrix metalloproteinase-2 (MMP-2), macrophage inflammatory protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) in the aortic root tissue of AS rats. In addition, the intestinal flora changed significantly after AST IV administration. The number of Bifidobacterium, Lactobacillus, and Bacteroides augmented significantly, and Enterobacter, Enterococcus, Fusobacterium, and Clostridium significantly decreased. Mechanistically, AST IV administration inhibited the phosphorylation of PI3K, Akt, and mTOR in AS rats. When combined with Dactolisib (BEZ235) (a PI3K/Akt/mTOR pathway inhibitor), AST IV could further inhibit phosphorylation and reduce inflammation. CONCLUSION: AST IV has a potential anti-AS effect, which can improve the pathological changes of the aorta in ApoE-/- rats fed with a high-fat diet, reduce the level of inflammatory factors, and modulate the composition of intestinal flora via the PI3K/Akt/mTOR pathway.
Sujet(s)
Apolipoprotéines E , Athérosclérose , Modèles animaux de maladie humaine , Microbiome gastro-intestinal , Phosphatidylinositol 3-kinases , Protéines proto-oncogènes c-akt , Rat Sprague-Dawley , Saponines , Transduction du signal , Sérine-thréonine kinases TOR , Triterpènes , Animaux , Saponines/pharmacologie , Saponines/usage thérapeutique , Saponines/administration et posologie , Sérine-thréonine kinases TOR/métabolisme , Rats , Triterpènes/pharmacologie , Triterpènes/usage thérapeutique , Triterpènes/administration et posologie , Athérosclérose/traitement médicamenteux , Athérosclérose/anatomopathologie , Protéines proto-oncogènes c-akt/métabolisme , Microbiome gastro-intestinal/effets des médicaments et des substances chimiques , Mâle , Phosphatidylinositol 3-kinases/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Apolipoprotéines E/génétique , Alimentation riche en graisse/effets indésirablesRÉSUMÉ
BACKGROUND/AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) has become an increasingly important health challenge, with a substantial rise linked to changing lifestyles and global obesity. Ursolic acid, a natural pentacyclic triterpenoid, has been explored for its potential therapeutic effects. Given its multifunctional bioactive properties, this research further revealed the pharmacological mechanisms of ursolic acid on MASLD. METHODS: Drug target chips and bioinformatics analysis were combined in this study to explore the potential therapeutic effects of ursolic acid on MASLD. Molecular docking simulations, surface plasmon resonance analyses, pull-down experiments, and co-immunoprecipitation assays were used to verify the direct interactions. Gene knockdown mice were generated, and high-fat diets were used to validate drug efficacy. Furthermore, initial CD4+ T cells were isolated and stimulated to demonstrate our findings. RESULTS: In this study, the multifunctional extracellular matrix phosphorylated glycoprotein secreted phosphoprotein 1 (SPP1) was investigated, highlighting its capability to induce Th17 cell differentiation, amplifying inflammatory cascades, and subsequently promoting the evolution of MASLD. In addition, this study revealed that in addition to the canonical TGF-ß/IL-6 cytokine pathway, SPP1 can directly interact with ITGB1 and CD44, orchestrating Th17 cell differentiation via their joint downstream ERK signaling pathway. Remarkably, ursolic acid intervention notably suppressed the protein activity of SPP1, suggesting a promising avenue for ameliorating the immunoinflammatory trajectory in MASLD progression. CONCLUSION: Ursolic acid could improve immune inflammation in MASLD by modulating SPP1-mediated Th17 cell differentiation via the ERK signaling pathway, which is orchestrated jointly by ITGB1 and CD44, emerging as a linchpin in this molecular cascade.