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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
Phytopolysaccharides are a class of natural macromolecules with a range of biological activities. Ginseng, red ginseng, American ginseng, and Panax notoginseng are all members of the Araliaceae family. They are known to contain a variety of medicinal properties and are typically rich in a wide range of medicinal values. Polysaccharides represent is one of the principal active ingredients in the aforementioned plants. However, there is a paucity of detailed reports on the separation methods, structural characteristics and comparison of various pharmacological effects of these polysaccharides. This paper presents a review of the latest research reports on ginseng, red ginseng, American ginseng and ginseng polysaccharides. The differences in extraction, separation, purification, structural characterization, and pharmacological activities of the four polysaccharides are compared and clarified. Upon examination of the current research literature, it becomes evident that the extraction and separation processes of the four polysaccharides are highly similar. Modern pharmacological studies have corroborated the multiple biological activities of these polysaccharides. These activities encompass a range of beneficial effects, including antioxidant stress injury, fatigue reduction, tumor inhibition, depression alleviation, regulation of intestinal flora, immunomodulation, diabetes management, central nervous system protection, anti-aging, and improvement of skin health. This paper presents a review of studies on the extraction, purification, characterization, and bioactivities of four natural plant ginseng polysaccharides. Furthermore, the review presents the most recent research findings on their pharmacological activities. The information provides a theoretical basis for the future application of natural plant polysaccharides and offers a new perspective for the in-depth development of the medicinal value of ginseng in the clinical practice of traditional Chinese medicine.
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Panax , Polisacáridos , Panax/química , Polisacáridos/farmacología , Polisacáridos/química , Polisacáridos/aislamiento & purificación , Humanos , Animales , Extractos Vegetales/química , Extractos Vegetales/farmacología , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/aislamiento & purificaciónRESUMEN
Depression is one of the most common psychological disorders nowadays. Studies have shown that 20(S)-protopanaxatriol (PPT) can effectively improve depressive symptoms in mice. However, its mechanism needs to be further explored. In this study, we used an integrated approach combining network pharmacology and transcriptomics to explore the potential mechanisms of PPT for depression. First, the potential targets and pathways of PPT treatment of depression were screened through network pharmacology. Secondly, the BMKCloud platform was used to obtain brain tissue transcription data of chronic unpredictable mild stress (CUMS) model mice and screen PPT-altered differential expression genes (DEGs). Gene ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed using network pharmacology and transcriptomics. Finally, the above results were verified by molecular docking, Western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR). In this study, we demonstrated that PPT improved depression-like behavior and brain histopathological changes in CUMS mice, downregulated nitric oxide (NO) and interleukin-6 (IL-6) levels, and elevated serum levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) after PPT treatment compared to the CUMS group. Eighty-seven potential targets and 350 DEGs were identified by network pharmacology and transcriptomics. Comprehensive analysis showed that transthyretin (TTR), klotho (KL), FOS, and the phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) signaling pathway were closely associated with the therapeutic effects of PPT. Molecular docking results showed that PPT had a high affinity for PI3K, AKT, TTR, KL, and FOS targets. Gene and protein level results showed that PPT could increase the expression of PI3K, phosphorylation of PI3K (p-PI3K), AKT, phosphorylation of AKT (p-AKT), TTR, and KL and inhibit the expression level of FOS in the brain tissue of depressed mice. Our data suggest that PPT may achieve the treatment of depression by inhibiting the expression of FOS, enhancing the expression of TTR and KL, and modulating the PI3K-AKT signaling pathway.
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Depresión , Farmacología en Red , Sapogeninas , Transcriptoma , Animales , Ratones , Depresión/tratamiento farmacológico , Depresión/metabolismo , Sapogeninas/farmacología , Transcriptoma/efectos de los fármacos , Masculino , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Simulación del Acoplamiento Molecular , Modelos Animales de Enfermedad , Transducción de Señal/efectos de los fármacos , Perfilación de la Expresión Génica , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacosRESUMEN
The dried rattan stem of the Fibraurea Recisa Pierre plant contains the active ingredient known as fibrauretine (FN). Although it greatly affects Alzheimer's disease (AD), the mechanism of their effects still remains unclear. Proteomics and transcriptomics analysis methods were used in this study to determine the mechanism of FN in the treatment of AD. AD model is used through bilateral hippocampal injection of Aß1-40. After successful modeling, FN was given for 30 days. The results showed that FN could improve the cognitive dysfunction of AD model rats, reduce the expression of Aß and P-Tau, increase the content of acetylcholine and reduce the activity of acetylcholinesterase. The Kyoto Encyclopedia of Genes and Genomes enriched differentially expressed genes and proteins are involved in signaling pathways including metabolic pathway, AD, pathway in cancer, PI3K-AKT signaling pathway, and cAMP signaling pathway. Transcriptomics and proteomics sequencing resulted in 19 differentially expressed genes and proteins. Finally, in contrast to the model group, after FN treatment, the protein expressions and genes associated with the PI3K-AKT pathway were significantly improved in RT-qPCR and Western blot and assays. This is consistent with the findings of transcriptomic and proteomic analyses. Our study found that, FN may improve some symptoms of AD model rats through PI3K-AKT signaling pathway.
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Depression ranks among the most common neuropsychiatric disorders globally. Current studies examining the roles of inflammation and mitochondrial autophagy in the antidepressant efficacy of paeoniflorin (PF) are sparse. This study aimed to elucidate PF's antidepressant mechanism by promoting autophagy and inhibiting NLRP3 inflammasome activation using chronic unpredictable mild stimulation (CUMS)-induced C57BL/6 mouse models in vivo and corticosterone (CORT)-induced HT22 cell models in vitro. Results demonstrated that PF enhanced the viability of HT22 cells following CORT exposure, restored mitochondrial membrane potential (MMP), reduced reactive oxygen species accumulation, increased LC3 fluorescence intensity, and suppressed inflammatory cytokine secretion and inflammation activation. Additionally, PF ameliorated depressive behaviors induced by CUMS and improved damage in hippocampal neurons. It also reduced the expression of NLRP3, ASC, Caspase-1, IL-1ß, and the assembly of the NLRP3 inflammasome. Moreover, PF upregulated the expression of autophagy-related proteins in the hippocampus, facilitating the clearance of damaged mitochondria and enhancing autophagy. The role of autophagy in PF's antidepressant effects was further confirmed through the use of the autophagy inhibitor 3-methyladenine (3-MA), which reduced the efficacy of PF. In conclusion, PF effectively improved depressive behaviors in CUMS-induced mice and reduced NLRP3-mediated inflammation both in vivo and in vitro, likely via the induction of autophagy.
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Autofagia , Depresión , Glucósidos , Inflamasomas , Ratones Endogámicos C57BL , Mitocondrias , Monoterpenos , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Glucósidos/farmacología , Autofagia/efectos de los fármacos , Monoterpenos/farmacología , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Masculino , Depresión/tratamiento farmacológico , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Modelos Animales de Enfermedad , Especies Reactivas de Oxígeno/metabolismoRESUMEN
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
Alzheimer's disease (AD) is a primary degenerative encephalopathy that first appeared as a decline in memory and learning skills. Over time, the condition's severity grew. Palmatine (Pal) alleviates Alzheimer's disease symptoms, which has neuroprotective benefits. Numerous investigations have demonstrated a close relationship among AD and gut structure changes. The aim of the research was investigating whether the improvement of Pal on AD is linked to regulating gut flora and autophagy. First, we used Aß1-40 to induce apoptosis in HT22 cells. After Pal treatment, apoptosis can be improved. Then, We used bilateral intracranial hippocampal injection of Aß1-40 for establishing the AD model, after treatment with Pal, the morris water maze experiment and eight-arm maze test demonstrated that Pal enhanced the AD rats' capacity for learning and memory, HE staining illustrated that Pal improved the morphological abnormalities of brain cells and gut tissue damage. Pal reduced the death of hippocampus neurons, as shown by Nissl staining. Pal substantially reduced Tau hyperphosphorylation and Aß accumulation in the brain, according to immunohistochemical labelling. Pal improved the expression of LC3, Beclin 1, AMPK, and suppressed the expression of mTOR and P62, as validated by RT-qPCR and immunofluorescence labelling. This suggests that Pal's treatment of AD may be associated with the control of the AMPK/mTOR autophagy signalling system. 16S rRNA sequencing and short-chain fatty acids (SCFAs) content detection analysis illustrated that Pal has the potential to enhance the content of SCFAs, reverse the alterations in gut microorganisms. It has been showed by the study that Pal could improve AD by activating autophagy signaling pathway and improving gut barrier changes.
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Enfermedad de Alzheimer , Autofagia , Alcaloides de Berberina , Disfunción Cognitiva , Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Hipocampo , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Autofagia/efectos de los fármacos , Alcaloides de Berberina/farmacología , Ratas , Masculino , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ratas Sprague-Dawley , Fármacos Neuroprotectores/farmacología , Péptidos beta-Amiloides/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Apoptosis/efectos de los fármacosRESUMEN
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
BACKGROUND: Depression is a common mental illness characterised by abnormal and depressed emotions. Total paeony glycoside (TPG) is a naturally active saponin extracted from the traditional Chinese medicine Radix Paeoniae rubra. However, the antidepressant and neuroinflammatory effects of TPG have not been thoroughly studied. PURPOSE: To study the therapeutic potential of TGP in depression caused by neuronal injury and neuroinflammation and to explore the mechanism of TGP and the relationship between the NLRP3 inflammasome, pyroptosis, and autophagy. STUDY DESIGN: A chronic unpredictable mild stress (CUMS)-induced depression model and a cell model of corticosterone (CORT)-induced hippocampal neuron injury were established to evaluate the therapeutic effects of TPG. METHODS: The composition of TPG was analysed using high-performance liquid chromatography and mass spectrometry. The effects of TPG and fluoxetine on depression-like behaviour, neuronal injury, neuroinflammation, pyroptosis, and mitochondrial autophagy in the mice models were evaluated. RESULTS: TGP alleviated depression-like behaviours in mice and inhibited hippocampal neuronal apoptosis. The secretion of inflammatory cytokines was significantly reduced in CORT-induced hippocampal neuron cells and in the serum of a mouse model of CUMS-induced depression. In addition, TGP treatment reduced the levels of NLRP3 family pyrin structural domains, including NLRP3, pro-caspase-1, caspase-1, and IL-1ß, and the pyroptosis related proteins such as GSDMD-N. Importantly, TPG attenuated mitochondrial dysfunction, promoted the clearance of damaged mitochondria, and the activation of mitochondrial autophagy, which reduced ROS accumulation and NLRP3 inflammasome activation. An in-depth study observed that the regulatory effect of TPG on autophagy was attenuated by the autophagy inhibitor 3-methyladenine (3-MA) in vitro and in vivo. However, administration of the caspase-1 inhibitor Belnacasan (VX-765) successfully inhibited pyroptosis and showed a synergistic therapeutic effect with TPG. CONCLUSION: These results indicate that TPG can repair neuronal damage by activating autophagy, restoring mitochondrial function, and reducing inflammation-mediated pyroptosis, thereby playing an important role in the alleviation of neuroinflammation and depression. This study suggests new potential drugs and treatment strategies for neuroinflammation-related diseases and depression.
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Antidepresivos , Autofagia , Depresión , Modelos Animales de Enfermedad , Glicósidos , Hipocampo , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Paeonia , Piroptosis , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Autofagia/efectos de los fármacos , Antidepresivos/farmacología , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Ratones , Masculino , Glicósidos/farmacología , Piroptosis/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Depresión/tratamiento farmacológico , Paeonia/química , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacologíaRESUMEN
BACKGROUND: Cartilage defects are some of the most common causes of arthritis. Cartilage lesions caused by inflammation, trauma or degenerative disease normally result in osteochondral defects. Previous studies have shown that decellularized extracellular matrix (ECM) derived from autologous, allogenic, or xenogeneic mesenchymal stromal cells (MSCs) can effectively restore osteochondral integrity. AIM: To determine whether the decellularized ECM of antler reserve mesenchymal cells (RMCs), a xenogeneic material from antler stem cells, is superior to the currently available treatments for osteochondral defects. METHODS: We isolated the RMCs from a 60-d-old sika deer antler and cultured them in vitro to 70% confluence; 50 mg/mL L-ascorbic acid was then added to the medium to stimulate ECM deposition. Decellularized sheets of adipocyte-derived MSCs (aMSCs) and antlerogenic periosteal cells (another type of antler stem cells) were used as the controls. Three weeks after ascorbic acid stimulation, the ECM sheets were harvested and applied to the osteochondral defects in rat knee joints. RESULTS: The defects were successfully repaired by applying the ECM-sheets. The highest quality of repair was achieved in the RMC-ECM group both in vitro (including cell attachment and proliferation), and in vivo (including the simultaneous regeneration of well-vascularized subchondral bone and avascular articular hyaline cartilage integrated with surrounding native tissues). Notably, the antler-stem-cell-derived ECM (xenogeneic) performed better than the aMSC-ECM (allogenic), while the ECM of the active antler stem cells was superior to that of the quiescent antler stem cells. CONCLUSION: Decellularized xenogeneic ECM derived from the antler stem cell, particularly the active form (RMC-ECM), can achieve high quality repair/reconstruction of osteochondral defects, suggesting that selection of decellularized ECM for such repair should be focused more on bioactivity rather than kinship.
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As a traditional Chinese herbal medicine, Cornu Cervi Degelatinatum (CCD) has the effect of warming the kidney to support yang, astringing, and stopping bleeding, and is used for spleen kidney yang deficient (SKYD). This experiment was to investigate the therapeutic effects of different processes of CCD on SKYD type ulcerative colitis (UC) rats and to explore its impact on the intestinal flora of rats. METHODS: ELISA was used to study the anti-inflammatory activity of Cornu Cervi Degelatinatum processed with water (WCCD) and Cornu Cervi Degelatinatum processed with vinegar (VCCD). 16SrRNA and transcriptome sequencing were used to detect the composition of rat intestinal flora and gene expression; RT-PCR and Western blot were used to verify the role of WCCD and VCCD in treating UC. RESULTS: WCCD and VCCD have therapeutic effects on UC, could reduce tissue damage. VCCD performed better in improving Bacteroidetes/Firmicutes ratios and species evenness and abundance; performed better in increasing the quantity of lactobacillus. VCCD simultaneously inhibit the intestinal inflammatory response through NCK2, PAK4, and JNK signaling pathways. CONCLUSIONS: WCCD and VCCD play a therapeutic role in UC by regulating the proportion of different flora in the intestinal flora. VCCD regulates the intestinal flora and inflammatory response by interfering with the NCK2, PAK4 and JNK signaling pathways.
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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
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
ETHNOPHARMACOLOGICAL RELEVANCE: Antler glue is a classic medicinal to enhance sexual function in traditional Chinese medicine (TCM), which was first recorded in Shen Nong Ben Cao Jing (Shennong's Classic of the Materia Medica). Vinegar-processing is a classic method of processing traditional Chinese medicine. The method of preparing antler glue by boiling antlers in vinegar and then concentrating them is recorded in Lei Gong Pao Zhi Lun (Master Lei's Discourse on Medicinal Processing). In modern times, the typical processing method of antler glue is water extraction and concentration. However, it is not clear whether there is a difference in the effect of these two processing methods on the chemical composition and pharmacological activity of antler glue. AIM OF THE STUDY: The Chinese Pharmacopoeia (2020) records that the processing method of antler glue is water extraction and concentration. But Lei Gong Pao Zhi Lun differs in Chinese Pharmacopoeia (2020), which records the processing method of vinegar extraction and concentration. The effect of the two processing methods on antler glue's chemical composition and pharmacological activity is unknown. So this study aimed to elucidate the difference between different processing methods on the chemical composition and the treatment effect on oligoasthenospermia of antler glue. MATERIALS AND METHODS: So the automatic amino acid analyzer is used to determine the amino acid content of two different processing methods of antler glue. Proteomics was performed to detect the protein components of two different processing methods of antler glue and analyze them. Cyclophosphamide-induced mice models of oligoasthenospermia were used to study the different pharmacological effects of antler glue in two different processing methods. An automatic sperm analyzer observed the quantity and quality of sperm in mice epididymis. Serum sex hormone testosterone (T), luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in mice were tested using the enzyme-linked immunosorbent assay (ELISA) kits. Hematoxylin-eosin (H&E) staining was used to analyze pathological alterations in mouse testicular tissue. The transcriptome has been used to reveal the potential mechanism of antler glue in treating oligoasthenospermia. Mitochondrial complex activity assay kits were used to assay the activity of mitochondrial respiratory chain complex I-V in mouse testicular tissue. Western blot was used to determine the expression of related proteins in mouse testicular tissue. RESULTS: Vinegar-processing can increase the alanine, proline, and glycine content in antler glue, reduce the length of protein peptides in antler glue, and produce a variety of unique proteins. Vinegar-processed antler glue (VAG) increased sperm density, sperm survival, sperm viability, and serum sex hormone levels in oligozoospermic mice. It reversed testicular damage caused by cyclophosphamide, and the effects were differently superior to those of water-processed antler glue (WAG). In addition, transcriptomics and related experiments have shown that VAG can increase the expression of Ndufa2, Uqcr11, Cox6b1, and Atp5i genes and proteins in mouse testis, thus promoting adenosine diphosphate (ATP) synthesis by increasing the activity of mitochondrial respiratory chain complexes I, III, IV and V. By promoting the oxidative phosphorylation process to produce more ATP, VAG can achieve the therapeutic effect of oligoasthenospermia. CONCLUSION: Vinegar-processing method can increase the content of active ingredients in antler glue. VAG increases ATP levels in the testes by promoting the process of oxidative phosphorylation to treat oligozoospermia.
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Cuernos de Venado , Oligospermia , Humanos , Ratones , Masculino , Animales , Cuernos de Venado/química , Ácido Acético , Semen/química , Proteínas , Hormonas Esteroides Gonadales , Aminoácidos , Ciclofosfamida , Adenosina TrifosfatoRESUMEN
ETHNOPHARMACOLOGY RELEVANCE: Sanghuangporus vaninii (S. vaninii), as a traditional large medicinal fungus, has a history of more than 2000 years in Chinese history and has been widely used to treat female diseases such as vaginal discharge, amenorrhea, and uterine bleeding, and recent pharmacological studies have also found that it has antioxidant, anti-inflammatory, and anti-tumor physiological activity, which has received more and more attention. AIM OF THE STUDY: The objective was to evaluate cytotoxicity and the acute, subacute toxicity, and in vitro antioxidant activity of S. vaninii crude polysaccharide (SVP). MATERIALS AND METHODS: The monosaccharide composition of SVP was determined by HPLC (high-performance liquid chromatography). The cytotoxicity of different concentrations of SVP on three types of cells (HT-22, Kupffer macrophages, HEK293) was assessed using CCk-8. The acute toxicity in vivo was evaluated for 14 days after the administration of SVP (2500,5000, or 10,000 mg/mL). For the evaluation of subacute toxicity, mice were daily treated for 28 days with SVP (2500,5000, or 10,000 mg/mL). In addition, DPPH, hydroxyl radical, and superoxide anion radical were used to evaluate the in vitro antioxidant activity of SVP. RESULTS: SVP was not toxic in all three cell lines tested. In vitro antioxidant tests on the extracts showed that SVP possessed a strong antioxidant capacity in vitro. In the acute study, the no-observed-adverse-effect level (NOAEL) in male and female rats was 10ï¼000 mg/kg body weight. There were also no deaths or severe toxicity associated with SVP in subacute studies. However, SVP treatment had a decreasing effect on body weight in mice of both sexes (2500, 5000, and 10000 mg/kg). At doses (5000 and 10,000 mg/kg), SVP had a reduced effect on food intake in both male and female mice. In addition, there were significant effects on organ coefficients of the liver, lung, and kidney. Hematological analysis showed significantly lower LYM (%) values in mice of both sexes, with significantly lower MCH (pg) values obtained in males (5000 mg/kg and 10000 mg/kg) and higher GRAN (%) values in females. In addition, the RDW-SD (fL) values were significantly lower in the male mice given the highest dose. Biochemical tests showed that there were no significant changes in ALT, AST, TP, and Cr levels after SVP treatment. In histopathological analysis, mild liver toxicity was observed in both female mice treated with 10,000 mg/kg SVP. CONCLUSION: The extract of SVP showed a predominance of polysaccharide compounds, with non-toxic action in vivo. Our approach revealed SVP on the chemical composition and suggests a high margin of safety in the popular use of medicinal fungi. In conclusion, our results suggest that SVP is safe, and can be used as health care products and food.
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Antioxidantes , Extractos Vegetales , Ratas , Ratones , Humanos , Masculino , Femenino , Animales , Antioxidantes/toxicidad , Extractos Vegetales/toxicidad , Células HEK293 , Pruebas de Toxicidad Aguda , Peso CorporalRESUMEN
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.