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We investigate the mechanism of action of astragalin (AST) in the treatment of Alzheimer's disease (AD). Network pharmacology was conducted to analyze the relationships among AST, AD, and neuroinflammation, The APP/PS1 transgenic mice with AD were used in the experiments; to be specific, the influence of AST on the behavior of mice was analyzed by Morris water maze and eight-arm radial maze tests, the tissue inflammatory factor levels were detected by ELISA, and pathological changes were analyzed by H&E and immunohistochemical staining. Analysis results of network pharmacology suggested that AST exerted the multi-target effect on neuroinflammation in AD. Through molecular docking and dynamics analyses, COX2 might be the target of AST. Moreover, animal experimental results demonstrated that AST improved the behavior of AD mice, and enhanced the motor and memory abilities, meanwhile, it suppressed the expression of inflammatory factors in tissues and the activation of microglial cells. this study discovers that AST can suppress microglial cell activation via COX2 to improve neuroinflammation in AD.
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Enfermedad de Alzheimer , Quempferoles , Ratones Transgénicos , Simulación del Acoplamiento Molecular , Farmacología en Red , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Ratones , Quempferoles/farmacología , Quempferoles/uso terapéutico , Aprendizaje por Laberinto/efectos de los fármacos , Masculino , Ciclooxigenasa 2/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismoRESUMEN
The increasing resistance of agricultural pests to existing acaricides presents a significant challenge to sustainable agriculture. Therefore, this study introduced FM-1088, a novel isoindolinone-based phenyl trifluoroethyl thioether derivative generated through an innovative design strategy combining bioisosterism and novel cyclization methods. We synthesized several compounds and evaluated their acaricidal efficacy against Tetranychus cinnabarinus in greenhouses and Panonychus citri in field settings. FM-1088 emerged as a standout candidate, demonstrating a lower median lethal concentration (LC50) of 0.722 mg/L compared to the commercial acaricide, cyetpyrafen. Notably, 30 days after application, FM-1088 showed a field control efficacy of 96.4% against P. citri, highlighting its potential for broader applications. The results underscore the utility of the isoindolinone scaffold in pesticide development, offering a promising solution to combat pest resistance with implications for enhanced crop protection and agricultural productivity. Future studies should explore the detailed mode of action of FM-1088 and its potential applicability across diverse agricultural settings, further confirming its role as a sustainable solution for pest management.
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Acaricidas , Acaricidas/química , Acaricidas/farmacología , Animales , Tetranychidae/efectos de los fármacos , Tetranychidae/crecimiento & desarrollo , Estructura MolecularRESUMEN
We isolated a polypeptide PNP2 from Corn Cervi Pantotrichum and investigated its effect and mechanism on cognitive impairment in Alzheimer's disease (AD) mice. Morris water maze was used to assess the degree of cognitive impairment in mice. Histopathological changes were detected by H&E staining; the expressions of inflammatory cytokines were assayed by ELISA. Western blotting was employed to detect the protein expressions. PNP2 could improve cognitive impairment, central inflammatory response, and NLRP3 signaling in AD mice. In vitro experiments revealed that PNP2 could suppress the inflammatory response of microglial cells and reduce the activation of NLRP3 in microglial cells, while MCC950 could antagonize the effects of PNP2. Polypeptide component PNP2 in Corn Cervi Pantotrichum can ameliorate central nervous inflammation and cognitive impairment in AD mice by suppressing NLRP3 signaling.
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Using nicofluprole as the lead compound, we designed and synthesized a series of new phenylpyrazole analogues through substituting the methyl group on the nitrogen atom of the amide with an acyl group. Bioassay results showed that compounds A12-A17 with a 1-cyanocyclopropimide group exhibited outstanding insecticidal activity. The LC50 values for compounds A12-A17 against Tetranychus cinnabarinus ranged from 0.58 to 0.91 mg/L. Compound A15 showed an LC50 value of 0.29 and 3.10 mg/L against Plutella xylostella and Myzus persicae, respectively. Molecular docking indicated the potential binding interactions of compound A15 with a gamma-aminobutyric acid receptor. Additionally, density functional theory calculations implied that the 1-cyanocyclopropimide structure might be essential for its biological activity. Phenylpyrazole derivatives, containing a 1-cyanocyclopropimide fragment, have the potential for further development as potential insecticides.
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Acaricidas , Diseño de Fármacos , Insecticidas , Simulación del Acoplamiento Molecular , Pirazoles , Animales , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Acaricidas/química , Acaricidas/farmacología , Acaricidas/síntesis química , Insecticidas/química , Insecticidas/farmacología , Insecticidas/síntesis química , Relación Estructura-Actividad , Imidas/química , Imidas/farmacología , Imidas/síntesis química , Áfidos/efectos de los fármacos , Mariposas Nocturnas/efectos de los fármacos , Tetranychidae/efectos de los fármacos , Estructura MolecularRESUMEN
AIM: We reveal the mechanism of action whereby ambient PM2.5 promotes kidney injury. METHODS: Using C57BL/6 mice, the effects of PM2.5 exposure on the acute kidney injury (AKI) were investigated, including renal function changes, expression of inflammatory cytokines, histopathological changes, as well as activation of nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3ï¼NLRP3ï¼. The effects of PM2.5 on renal injury after NLRP3 inhibition were explored using NLRP3 inhibitor (MCC950) and NLRP3 knockout mice. The effects of PM2.5 on the inflammatory response of renal macrophages were investigated at the cellular level. RESULTS: PM2.5 exposure could promote kidney injury, NLRP3 activation and inflammatory response in mice. After using MCC950 and NLRP3 knockout mice, the effects of PM2.5 and the kidney injury could be inhibited. The cellular-level results also suggested that MCC950 could inhibit the effects of PM2.5. CONCLUSION: PM2.5 can promote the progression of AKI and aggravate tissue inflammation through NLRP3, which is an important environmental toxicological mechanism of PM2.5.
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Lesión Renal Aguda , Inflamación , Macrófagos , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR , Material Particulado , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Material Particulado/toxicidad , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Ratones , Macrófagos/efectos de los fármacos , Inflamación/inducido químicamente , Masculino , Sulfonamidas/toxicidad , Sulfonamidas/farmacología , Indenos/toxicidad , Contaminantes Atmosféricos/toxicidad , Furanos/toxicidad , Sulfonas/toxicidadRESUMEN
Coumarin was detected as one of the most abundant compounds by nontargeted analysis of natural product components in actual water samples prior to disinfection. More importantly, prechlorination of humic acid generated 3-hydroxycoumarin and monohydroxy-monomethyl-substituted coumarin with a total yield of ≤10.1%, which suggested the humic substance in raw water is an important source of coumarins. 7-Hydroxycoumarin, 6-hydroxy-4-methylcoumarin, 6,7-dihydroxycoumarin, and 7-methoxy-4-methylcoumarin were identified in raw water by high-performance liquid chromatography-tandem high-resolution mass spectrometry because only some coumarin standards were commercially available. Their chlorination generated monochlorinated and polychlorinated coumarins, and their structures were confirmed by the synthesized standards. These products could form at various dosages of chlorine and pH levels, and some with a concentration of 600 ng/L can be stable in tap water for days. 3,6,8-Trichloro-7-hydroxycoumarin, 3-chloro-7-methoxy-4-methylcoumarin, and 3,6-dichloro-7-methoxy-4-methylcoumarin were first identified in finished water with concentrations of 0.0670, 78.1, and 14.7 ng/L, respectively, but not in source water, suggesting that they are new DBPs formed during disinfection. The cytotoxicity of 3-chloro-7-methoxy-4-methylcoumarin in CHO-K1 cells was comparable to those of 2,6-dibromo-1,4-benzoquinone and 2,6-dichloro-1,4-benzoquinone in TIC-Tox analyses, suggesting that further investigation of their occurrence and control in drinking water systems is warranted.
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Cumarinas , Cricetulus , Agua Potable , Halogenación , Contaminantes Químicos del Agua , Cumarinas/química , Agua Potable/química , Animales , Células CHO , Cricetinae , Cromatografía Líquida de Alta Presión , Purificación del AguaRESUMEN
AIM: This work aimed to investigate the role of M1 intestinal macrophages-derived exosomes (M1-Exo) in colitis and its mechanism. METHODS: M1 polarization of intestinal macrophages was induced in vitro, and their exosomes were extracted and identified. Thereafter, the DSS-induced colitis mouse model was built. Each mouse was given intraperitoneal injection of exosomes, and then mouse weight and DAI were dynamically monitored. In addition, the levels of cytokines were detected by ELISA. After treatment with the TLR4 inhibitor Resatorvid, the effects of M1 macrophages-derived exosomes were observed. Besides, the mouse intestinal epithelial cells were cultured in vitro for observing function of M1-Exo. RESULTS: M1-exo aggravated the colitis and tissue inflammation in mice, activated the TLR4 signal, and destroyed the mucosal barrier. But M0 macrophages-derived exosomes (M0-Exo) did not have the above effects. Resatorvid treatment antagonized the roles of M1-exo. Moreover, as confirmed by cellular experiments in vitro, M1-exo destroyed mucosal barrier. CONCLUSION: M1-exo serve as the pro-inflammatory mediator, which can promote mouse colitis progression by activating TLR4 signal.
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Colitis , Exosomas , Sulfonamidas , Animales , Ratones , Receptor Toll-Like 4 , Colitis/inducido químicamente , MacrófagosRESUMEN
Deer sinew as a by-product has high collagen and nutritional value. This study focuses on its hydrolysate being used as a calcium carrier to develop functional foods. The chelation mechanism was analyzed by SEM, EDS, UV-vis, FTIR, and fluorescence spectroscopy and zeta potential analysis after using peptide-sequenced deer sinew peptides for chelation with calcium ions. The results showed that the chelation of deer sinew peptides with calcium ions occurs mainly at the O and N atoms of carboxyl, amino and amide bonds. In vitro and in vivo studies revealed that deer sinew peptide-calcium chelate (DSPs-Ca) promoted the proliferation of MC3T3-E1 cells without toxic side effects and increased the alkaline phosphatase activity. The DSPs-Ca group improved the bone microstructure induced by low calcium, as well as up-regulated the expression of genes responsible for calcium uptake in the kidneys, as evidenced by serum markers, bone sections, bone parameters, and gene expression analyses in low-calcium-fed mice. From the above, it can be concluded that DSPs-Ca is expected to be a calcium supplement food for promoting bone health.
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Calcio , Ciervos , Ratones , Animales , Calcio/metabolismo , Ciervos/metabolismo , Proliferación Celular , Calcio de la Dieta/metabolismo , Péptidos/farmacología , Péptidos/metabolismo , Iones/metabolismo , Iones/farmacología , OsteoblastosRESUMEN
This study aimed to investigate the role of protein kinase HIPK2 in depression and its associated mechanism. The chronic unpredictable mild stress (CUSM) model was constructed to simulate mice with depression to detect the mouse behaviors. Moreover, by using mouse microglial cells BV2 as the model. After conditional knockdown of HIPK2, the depressive behavior disorder of mice was improved, meanwhile, neuroinflammation was alleviated, and the M1 cell proportion was reduced. Similar results were obtained after applying the HIPK2 inhibitor tBID or ASO-HIPK2 treatment. HIPK2 was overexpressed in BV2 cells, which promoted M1 polarization of cells, while tBID suppressed the effect of HIPK2 and reduced the M1 polarized level in BV2 cells. Pull-down assay results indicated that HIPK2 bound to STAT3 and promoted STAT3 phosphorylation. We found that HIPK2 can bind to STAT3 to promote its phosphorylation, which accelerates M1 polarization of microglial cells, aggravates the depressive neuroinflammation, and leads to abnormal behaviors. HIPK2 is promising as the new therapeutic target of depression.
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Depresión , Microglía , Enfermedades Neuroinflamatorias , Proteínas Serina-Treonina Quinasas , Factor de Transcripción STAT3 , Animales , Ratones , Depresión/genética , Depresión/metabolismo , Microglía/metabolismo , Enfermedades Neuroinflamatorias/metabolismo , Fosforilación , Transducción de Señal , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Polaridad CelularRESUMEN
To investigate the key molecular mechanisms of palmatine for the treatment of neuroinflammation through modulation of a pathway using molecular docking, molecular dynamics (MD) simulation combined with network pharmacology, and animal experiments. Five alkaloid components were obtained from the traditional Chinese medicine Huangteng through literature mining. Molecular docking and MD simulation with acetylcholinesterase were used to screen palmatine. At the animal level, mice were injected with LPS intracerebrally to cause a neuroinflammatory model, and the Morris water maze experiment was performed to examine the learning memory of mice. Anxiety levels were tested using the autonomous activity behavior experiment with the open field and elevated behavior experiments. HE staining and Niss staining were performed on brain tissue sections to observe morphological lesions and apoptosis; serum was examined for inflammatory factors TNF-α, IL-6, and IL-1ß; Western blot was performed to detect the protein expression. The expression of PI3K/AKT/NFkB signaling pathway-related proteins was examined by Western blot. The results of network pharmacology showed that the screening of palmatine activation containing the PI3K/Akt/NFkB signaling pathway exerts antineuroinflammatory effects. Results from behavioral experiments showed that Pal enhanced learning memory in model mice, improved anxiety behavior, and significantly improved brain damage caused by neuroinflammation. The results of HE staining and Niss staining of brain tissue sections showed that palmatine could alleviate morphological lesions and nucleus damage in brain tissue. Palmatine improved the levels of serum inflammatory factors TNF-α, IL-6, and IL-1ß. SOD, MDA, CAT, ACH, and ACHE in the hippocampus were improved. Western blot results showed that palmatine administration ameliorated LPS-induced neuroinflammation through the PI3K/Akt/NFkB pathway.
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Alcaloides de Berberina , FN-kappa B , Proteínas Proto-Oncogénicas c-akt , Ratones , Animales , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Lipopolisacáridos/toxicidad , Factor de Necrosis Tumoral alfa/metabolismo , Enfermedades Neuroinflamatorias , Interleucina-6 , Acetilcolinesterasa , Simulación del Acoplamiento MolecularRESUMEN
To explore the antidepressant effects and targets of atractylenolide I (ATR) through a network pharmacological approach. Relevant targets of ATR and depression analyzed by network pharmacology were scored (identifying 5-HT2A targets). Through elevated plus maze, open field, tail suspension, and forced swimming tests, the behavioral changes of mice with depression (chronic unpredictable mild stress [CUMS]) were examined, and the levels of neurotransmitters including serotonin, dopamine, and norepinephrine (5-HT, DA, and NE) were determined. The binding of ATR to 5-HT2A was verified by small molecular-protein docking. ATR improved the behaviors of CUMS mice, elevated their levels of neurotransmitters 5-HT, DA, and NE, and exerted a protective effect on their nerve cell injury. After 5-HT2A knockout, ATR failed to further improve the CUMS behaviors. According to the results of small molecular-protein docking and network pharmacological analysis, ATR acted as an inhibitor by binding to 5-HT2A. ATR can improve the behaviors and modulate the neurotransmitters of CUMS mice by targeting 5-HT2A.
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Depresión , Lactonas , Serotonina , Sesquiterpenos , Ratones , Animales , Depresión/tratamiento farmacológico , Depresión/metabolismo , Serotonina/metabolismo , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Neurotransmisores/metabolismo , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Modelos Animales de Enfermedad , Hipocampo , Conducta AnimalRESUMEN
OBJECTIVE: To investigate the long-term effects of polystyrene (PS) exposure on acute liver injury. METHODS: The carbon tetrachloride-induced acute injury mouse model was subjected to long-term PS exposure. Pyroptosis was inhibited by knocking out Gsdmd in mice or treating with the Gsdmd inhibitor necrosulfonamide (NSA) to evaluate the effect of PS on liver injury. Kupffer cells were used as a cellular model to examine the effects of PS on cell pyroptosis, lactate dehydrogenase release rate, structural integrity (propidium iodide staining), and inflammatory factor levels. RESULTS: In mice, PS exposure exacerbated acute liver injury, which was mitigated upon Gsdmd knockout (KO) or NSA treatment along with the downregulation of tissue inflammatory response. In vitro studies demonstrated that PS promoted Kupffer cell pyroptosis, which was suppressed upon Gsdmd KO or NSA treatment along with the alleviation of inflammation. CONCLUSION: These results suggest that long-term PS exposure exacerbates acute liver injury by promoting Kupffer cell pyroptosis, which is one of the hepatotoxic mechanisms of PS.
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Macrófagos del Hígado , Poliestirenos , Ratones , Animales , Poliestirenos/farmacología , Microplásticos/farmacología , Plásticos/farmacología , Piroptosis , Péptidos y Proteínas de Señalización Intracelular/genética , HígadoRESUMEN
AIM: We investigated the effects and target of gastrodin (GAS) for treating depression through network pharmacology combined with experimentation. METHODS: The therapeutic target and signal of GAS for depression were analyzed by network pharmacology. Depression in mice was mimicked with a chronic unpredictable mouse stress (CUMS) model. Through open field, elevated plus maze, forced swimming, and tail suspension tests, the effects of GAS on the CUMS mice behaviors were examined, and the levels of neurotransmitters were detected. The histopathological changes were assayed by H&E and IHC staining, and the protein expressions were detected by Western blotting. Small molecule-protein docking and molecular dynamics experiments were conducted to simulate the binding mode between GAS and Caspase-3. RESULTS: Network pharmacological analysis revealed that Caspase-3 was the action target of GAS. GAS could improve depression-like behaviors in CUMS mice, elevate their neurotransmitter levels, ameliorate their nerve cell injury, and inhibit their Caspase-3 expression. After knocking out Caspase-3, the effects of GAS were inhibited. Molecular dynamics simulation and small molecule-protein docking found that GAS bound to Caspase-3 at SER25, inhibiting the maturation and activation of Caspase-3. CONCLUSION: We find that GAS can act as a Caspase-3 inhibitor, which improves depression-like behaviors and nerve cell injury in CUMS mice by inhibiting Caspase-3-mediated apoptosis.
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Alcoholes Bencílicos , Depresión , Glucósidos , Neuronas , Ratones , Animales , Depresión/tratamiento farmacológico , Depresión/metabolismo , Caspasa 3/metabolismo , Neuronas/metabolismo , Apoptosis , Estrés Psicológico/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismoRESUMEN
Chlorpyrifos (CPF) plays a vital role in the control of various pests in agriculture and household life, even though some studies have indicated that CPF residues pose a significant risk to human health. Baicalin (BA) is a flavonoid drug with an obvious effect on the prevention and treatment of liver diseases. In this study, the protective effect of BA in vitro and in vivo was investigated by establishing a CPF-induced AML12 cell damage model and a CPF-induced Kunming female mouse liver injury model. The AML12 cell damage model indicated that BA had a good positive regulatory effect on various inflammatory factors, redox indexes, and abnormal apoptosis factors induced by CPF. The liver injury model of female mice in Kunming showed that BA significantly improved the liver function indexes, inflammatory response, and fibrosis of mice. In addition, BA alleviated CPF-induced AML12 cell damage and Kunming female mouse liver injury by enhancing autophagy and regulating apoptosis pathways through Western blotting. Collectively, these data suggest that the potential mechanism of BA is a multi-target and multi-channel treatment for chlorpyrifos-induced liver injury.
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Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Cloropirifos , Insecticidas , Femenino , Ratones , Humanos , Animales , Cloropirifos/toxicidad , Cloropirifos/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Estrés Oxidativo , Flavonoides/farmacología , Flavonoides/metabolismo , Hígado , Insecticidas/farmacologíaRESUMEN
Alzheimer's disease is a common degenerative disease which has a great impact on people's daily lives, but there is still a certain market gap in the drug research about it. Palmatine, one of the main components of Huangteng, the rattan stem of Fibraurea recisa Pierre (Menispermaceae), has potential in the treatment of Alzheimer's disease. The aim of this study was to evaluate the neuroprotective effect of palmatine on amyloid beta protein 25-35-induced rat pheochromocytoma cells and AD mice and to investigate its mechanism of action. CCK8 assays, ELISA, the Morris water maze assay, fluorescent probes, calcein/PI staining, immunofluorescent staining and Western blot analysis were used. The experimental results show that palmatine can increase the survival rate of Aß25-35-induced PC12 cells and mouse hippocampal neurons, reduce apoptosis, reduce the content of TNF-α, IL-1ß, IL-6, GSH, SOD, MDA and ROS, improve the learning and memory ability of AD mice, inhibit the expression of Keap-1 and Bax, and promote the expression of Nrf2, HO-1 and Bcl-2. We conclude that palmatine can ameliorate oxidative stress and neuroinflammation produced by Aß25-35-induced PC12 cells and mice by modulating the Nrf2/HO-1 pathway. In conclusion, our results suggest that palmatine may have a potential therapeutic effect on AD and could be further investigated as a promising therapeutic agent for AD. It provides a theoretical basis for the development of related drugs.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Humanos , Ratas , Ratones , Animales , Péptidos beta-Amiloides/toxicidad , Péptidos beta-Amiloides/metabolismo , Células PC12 , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Enfermedades Neuroinflamatorias , Estrés OxidativoRESUMEN
In recent years, the phenomenon of acute poisoning and organ damage caused by organophosphorus pesticides (OPs) has been a frequent occurrence. Chlorpyrifos (CPF) is one of the most widely used organophosphorus pesticides. The main active components of ginseng stems and leaves are total ginseng stem-and-leaf saponins (GSLSs), which have various biological effects, including anti-inflammatory, antioxidant and anti-tumor activities. We speculate that these could have great potential in the treatment of severe diseases and the relief of organophosphorus-pesticide-induced side effects; however, their mechanism of action is still unknown. At present, our work aims to evaluate the effects of GSLSs on the antioxidation of CPF in vivo and in vitro and their potential pharmacological mechanisms. Mice treated with CPF (5 mg/kg) showed severe intestinal mucosal injury, an elevated diamine oxidase (DAO) index, the decreased expression of occlusive protein-1 (ZO-1) and occlusive protein, an impaired intestinal mucosal oxidation system and intestinal villi relaxation. In addition, chlorpyrifos exposure significantly increased the contents of the inflammatory factor TNF-α and the oxidative-stress-related indicators superoxide dismutase (SOD), catalase (CAT), glutathione SH (GSH), glutathione peroxidase (GSH-PX), reactive oxygen species (ROS) and total antioxidant capacity (T-AOC); elevated the level of lipid peroxide malondialdehyde (MDA); reversed the expression of Bax and caspase; and activated NF-κB-related proteins. Interestingly, GSLS supplementation at doses of 100 and 200 mg/kg significantly reversed these changes after treatment. Similar results were observed in cultured RAW264.7 cells. Using flow cytometry, Hoechst staining showed that GSLSs (30 µg/mL, 60 µg/mL) could improve the cell injury and apoptosis caused by CPF and reduce the accumulation of ROS in cells. In conclusion, GSLSs play a protective role against CPF-induced enterotoxicity by inhibiting NF-κB-mediated apoptosis and alleviating oxidative stress and inflammation.
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Cloropirifos , Panax , Plaguicidas , Saponinas , Ratones , Animales , Cloropirifos/toxicidad , Antioxidantes/farmacología , Antioxidantes/metabolismo , Especies Reactivas de Oxígeno/metabolismo , FN-kappa B/metabolismo , Panax/metabolismo , Saponinas/farmacología , Compuestos Organofosforados/farmacología , Plaguicidas/farmacología , Estrés Oxidativo , Glutatión/metabolismo , Apoptosis , Hojas de la Planta/metabolismoRESUMEN
AIM: We investigated the effect and mechanism of Icariin (ICA) on improving neurobehavioral ability of mice with Alzheimer's disease (AD). METHODS: We selected 10-month-old APP/PS1 mice (AD) and wild-type C57BL/6J mice (Normal). After intragastric administration of ICA, Morris water maze was employed to detect neurobehavioral improvements, and to assay key ferroptosis indicators and oxidative stress levels. The common target of ICA for resisting ferroptosis and AD was predicted by network pharmacology. RESULTS: ICA could improve the neurobehavioral, memory and motor abilities of AD mice. It could lower the ferroptosis level and enhance the resistance to oxidative stress. After inhibition of MDM2, ICA could no longer improve the cognitive ability of AD mice, nor could it further inhibit ferroptosis. Network pharmacological analysis revealed that MDM2 might be the target of ICA action. CONCLUSIONS: We found that ICA can inhibit ferroptosis of nerve cells, thereby ameliorating neural damage in mice with AD.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Ferroptosis , Ratones , Animales , Precursor de Proteína beta-Amiloide/metabolismo , Ratones Transgénicos , Hipocampo/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Enfermedad de Alzheimer/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Neuronas/metabolismoRESUMEN
Aflatoxin B1 (AFB1) is a toxic food/feed contaminant and the liver is its main target organ, thus it poses a great danger to organisms. Dihydromyricetin (DHM), a natural flavonoid compound, can be used as a food additive with high safety and has been shown to have strong hepatoprotective effects. In this experiment, PPI network and KEGG pathway analysis were constructed by network pharmacological analysis technique using software and platforms such as Swiss, String, and David and Cytoscape. We screened AFB1 and DHM cross-targets and pathways of action, followed by molecular docking based on the strength of binding affinity of genes to DHM. In addition, we exposed AFB1 (200 µg/kg) to mice to establish a liver injury model. Histological observation, biochemical assay, oxidative stress indicator assay, TUNEL staining and Western blot were used to evaluate the liver injury. Network pharmacological results were screened to obtain 25 cross-targets of action and 20 pathways of action. It was found that DHM may exert anti-hepatic injury effects by inhibiting the overexpression of Caspase-3 protein and increasing the expression of Bcl-2 protein. DHM (200 mg/kg) was found to reduce AFB1-induced liver indices such as alanine aminotransferase (ALT) and aspartate acyltransferase (AST), and attenuate hepatic histopathological damage through animal models. Importantly, DHM inhibited malondialdehyde (MDA) formation in liver tissue and attenuated AFB1-induced oxidative stress injury by increasing glutathione-S-transferase (GST) glutathione (GPX) catalase (CAT) and superoxide dismutase (SOD). Meanwhile, DHM also restored the expression of anti-apoptotic protein Bcl-2 and antioxidant proteins, Nrf2, Keap1 and its downstream HO-1, and down-regulated the expression of pro-apoptotic proteins Bax and Caspase-3 in AFB1-induced liver tissues. The results confirmed that liver injury caused by AFB1 exposure could be alleviated by DHM, providing valuable guidance for in-depth study of DHM in the treatment of liver-related diseases, and laying the foundation for in-depth development and utilization of DHM.
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To study the effect of co-administration of Jujuboside A and B (Ju A+B) on sleep, healthy KM mice were given different doses of Ju A+B with a behavioral evaluation of sleep state. Serum levels of key neurotransmitters (5HT, DA, and NE) were measured. The hypothalamus of KM mice was analyzed for differential protein expression using TMT quantitative proteomics, and differential expression protein (DEP) bioinformatics analysis was used to explore potential mechanisms. The result shows that Ju A+B affects sleep by expressing the protein in the hypothalamus. Compared with the control group, the test group showed 10 up-regulated and 139 down-regulated DEPs. The key DEPs were found at the tight junction. Western blot showed reliable alteration of the key DEPs in proteomics. The result of interaction network analysis attributed the potential of Jujuboside to the changes in blood-brain barrier, which provided basic and theoretical data for the efficacy evaluation and mechanism of Jujuboside.