RESUMEN

Phytochemical investigation of the n-butanol extracts of the herbaceous stems of Epheda intermedia led to the isolation of eight flavonoids that included three new flavonoid glycosides (1-3) and five previously reported analogues (4-8). Their structures have been identified on the basis of various spectral data. Besides, all the flavonoids were tested in vitro for their ability to inhibit α-glucosidase under the positive control of acarbose, and the results indicated that none of them exhibited significant inhibitory effect on α-glucosidase at 100 µM.

RESUMEN

Psoriasis, an immune-mediated inflammatory skin disorder, seriously affects the quality of life of nearly four percent of the world population. Euphorbia helioscopia L. is the monarch constituent of Chinese ZeQi powder preparation for psoriasis, so it is necessary to illustrate its active ingredients. Thus, twenty-three diterpenoids, including seven new ones, were isolated from the whole herb of E. helioscopia L. Compounds 1 and 2, each featuring a 2,3-dicarboxylic functionality, are the first examples in the ent-2,3-sceo-atisane or the ent-2,3-sceo-abietane family. Extensive spectroscopic analysis (1D, 2D NMR, and HRMS data) and computational methods were used to confirm their structures and absolute configurations. According to the previous study and NMR data from the jatropha diterpenes obtained in this study, some efficient 1H NMR spectroscopic rules for assigning the relative configurations of 3α-benzyloxy-jatroph-11E-ene and 7,8-seco-3α-benzyloxy-jatropha-11E-ene were summarized. Moreover, the hyperproliferation of T cells and keratinocytes is considered a key pathophysiology of psoriasis. Anti-proliferative activities against induced T/B lymphocytes and HaCaT cells were tested, and IC50 values of some compounds ranged from 6.7 to 31.5 µM. Compounds 7 and 11 reduced the secretions of IFN-γ and IL-2 significantly. Further immunofluorescence experiments and a docking study with NF-κB P65 showed that compound 13 interfered with the proliferation of HaCaT cells by inhibiting the NF-κB P65 phosphorylation at the protein level.

Asunto(s)

Diterpenos , Euphorbia , Psoriasis , Euphorbia/química , Humanos , Psoriasis/tratamiento farmacológico , Psoriasis/patología , Diterpenos/farmacología , Diterpenos/química , Diterpenos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Extractos Vegetales/farmacología , Extractos Vegetales/química , Queratinocitos/efectos de los fármacos

RESUMEN

The study investigated the protective effect and mechanism of 2-phenylethyl-beta-glucopyranoside(Phe) from Huaizhong No.1 Rehmannia glutinosa on hypoxic pulmonary hypertension(PH), aiming to provide a theoretical basis for clinical treatment of PAH. Male C57BL/6N mice were randomly divided into normal group, model group, positive drug(bosentan, 100 mg·kg~(-1)) group, and low-and high-dose Phe groups(20 and 40 mg·kg~(-1)). Except for the normal group, all other groups were continuously subjected to model induction in a 10% hypoxic environment for 5 weeks, with oral administration for 14 days starting from the 3rd week. The cardiopulmonary function, right ventricular pressure, cough and asthma index, lung injury, cell apoptosis, oxidative stress-related indicators, immune cells, and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/hypoxic inducible factor 1α(HIF-1α) pathway-related proteins or mRNA levels were examined. Furthermore, hypoxia-induced pulmonary arterial smooth muscle cell(PASMC) were used to further explore the mechanism of Phe intervention in PH combined with PI3K ago-nist(740Y-P). The results showed that Phe significantly improved the cardiopulmonary function of mice with PH, decreased right ventricular pressure, cough and asthma index, and lung injury, reduced cell apoptosis, oxidative stress-related indicators, and nuclear levels of phosphorylated Akt(p-Akt) and phosphorylated mTOR(p-mTOR), inhibited the expression levels of HIF-1α and PI3K mRNA and proteins, and maintained the immune cell homeostasis in mice. Further mechanistic studies revealed that Phe significantly reduced the viability and migration ability of hypoxia-induced PASMC, decreased the expression of HIF-1α and PI3K proteins and nuc-lear levels of p-Akt and p-mTOR, and this effect was blocked by 740Y-P. Therefore, it is inferred that Phe may exert anti-PH effects by alleviating the imbalance of oxidative stress and apoptosis in lung tissues and regulating immune levels, and its mechanism may be related to the regulation of the PI3K/Akt/mTOR/HIF-1α pathway. This study is expected to provide drug references and research ideas for the treatment of PH.

Asunto(s)

Glucósidos , Hipertensión Pulmonar , Subunidad alfa del Factor 1 Inducible por Hipoxia , Hipoxia , Ratones Endogámicos C57BL , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Rehmannia , Serina-Treonina Quinasas TOR , Animales , Masculino , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Ratones , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Rehmannia/química , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Glucósidos/farmacología , Hipoxia/tratamiento farmacológico , Hipoxia/fisiopatología , Hipoxia/metabolismo , Transducción de Señal/efectos de los fármacos , Humanos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/química , Apoptosis/efectos de los fármacos

RESUMEN

One new canthinone glycoside (1), together with six known compounds (2-7) including three lignans (2-4), two coumarins (5-6) and one phenol (7) was isolated from the root barks of Ailanthus altissima. The structure of new compound 1 was established by the interpretation of UV, IR, MS and NMR data, while its absolute configuration was determined by acid hydrolysis and GIAO NMR calculations with DP4+ probability analysis. The inhibitory effects of all compounds on Nitric oxide (NO) production were investigated in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Results showed that compounds 2 and 5 displayed NO production inhibitory activity with IC50 values of 30.1 and 15.3 µM, respectively.

Asunto(s)

Ailanthus , Glicósidos , Lipopolisacáridos , Óxido Nítrico , Corteza de la Planta , Raíces de Plantas , Ailanthus/química , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Ratones , Estructura Molecular , Animales , Corteza de la Planta/química , Raíces de Plantas/química , Células RAW 264.7 , Glicósidos/farmacología , Glicósidos/química , Glicósidos/aislamiento & purificación , Lipopolisacáridos/farmacología , Lignanos/farmacología , Lignanos/química , Lignanos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/aislamiento & purificación , Cumarinas/farmacología , Cumarinas/química , Cumarinas/aislamiento & purificación , Resonancia Magnética Nuclear Biomolecular

RESUMEN

Urine metabolomics based on ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry(UHPLC-Q-TOF-MS) was utilized to investigate the metabolic regulation mechanism of Tingli Dazao Xiefei Decoction(TLDZ) in rats with allergic asthma. SD male rats were divided into a normal group, a model group, a dexamethasone group, and a TLDZ group. The allergic asthma model was established by intraperitoneal injection of ovalbumin(OVA) to induce allergy, combined with atomization excitation. Urine metabolites from all rats were collected by UHPLC-Q-TOF-MS. The metabolic profiles of rats in each group were built by principal component analysis(PCA). Besides, the differential metabolites between the model group and the TLDZ group were selected by orthogonal partial least squares discriminant analysis(OPLS-DA), t-test(P<0.05), and variable importance in the projection(VIP) values of more than 3. The differential metabolites were identified through HMDB, METLIN, and other online databa-ses. Heat maps and clustering analysis for relative quantitative information of biomarkers in each group were drawn by MeV 4.8.0 software. Finally, MetaboAnalyst, MBRole, and KEGG databases were used to enrich related metabolic pathways and construct metabolic networks. The result demonstrated that TLDZ could effectively regulate the disordered urine metabolic profiles of asthmatic rats. Combined with multivariate statistical analysis and online databases, a total of 45 differential metabolites with significant changes(P<0.05) between the model group and the TLDZ group were screened out. Metabolic pathways including histidine metabolism, tryptophan metabolism, and arginine and proline metabolism were enriched. TLDZ could improve asthma by regulating related metabolic pathways and interfering with pathological processes such as immune homeostasis airway inflammation. The study investigates the molecular mechanism of anti-asthma of TLDZ from the perspective of urine metabolomics, and combined with previous pharmacological studies, it provides a scientific basis for the clinical development and application of TLDZ in the treatment of asthma.

Asunto(s)

Asma , Medicamentos Herbarios Chinos , Metabolómica , Ratas Sprague-Dawley , Animales , Asma/tratamiento farmacológico , Asma/orina , Asma/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/administración & dosificación , Masculino , Ratas , Cromatografía Líquida de Alta Presión , Humanos , Orina/química , Espectrometría de Masas en Tándem

RESUMEN

Phytochemical investigation on the fruiting bodies of the medicinal fungus Ganoderma lingzhi led to the isolation of a new norsteroid, namely ganonorsterone A (1), together with one known steroid, cyathisterol (2). The structure and absolute configuration of compound 1 were assigned by extensive analysis of MS, NMR data, and quantum-chemical calculations including electronic circular dichroism (ECD) and calculated 13C NMR-DP4+ analysis. Bioassay results showed that compound 1 displayed moderate inhibition on NO production in RAW 264.7 macrophages.

Asunto(s)

Ganoderma , Óxido Nítrico , Ganoderma/química , Ratones , Células RAW 264.7 , Animales , Estructura Molecular , Óxido Nítrico/biosíntesis , Óxido Nítrico/antagonistas & inhibidores , Macrófagos/efectos de los fármacos , Cuerpos Fructíferos de los Hongos/química

RESUMEN

Nine undescribed compounds, along with eight known compounds, were isolated from the stipes of Lentinus edodes. Their structures were established by extensive spectroscopic and circular dichroism analyses. The protective effects against Aß25-35-induced N9 microglia cells injury of these compounds were tested by MTT method, and the levels of apoptosis and ROS were detected by flow cytometry. In addition, the binding sites and interactions of compound with amyloid precursor protein were revealed using molecular docking simulations. These findings further establish the structural diversity and bioactivity of stipes of L. edodes, and provide an experimental basis for targeting Alzheimer's disease as a potential strategy.

Asunto(s)

Péptidos beta-Amiloides , Apoptosis , Microglía , Simulación del Acoplamiento Molecular , Fragmentos de Péptidos , Microglía/efectos de los fármacos , Microglía/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Fragmentos de Péptidos/farmacología , Animales , Apoptosis/efectos de los fármacos , Ratones , Estructura Molecular , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/aislamiento & purificación , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , Lentinula/química , Línea Celular

RESUMEN

Five undescribed eremophilane-type sesquiterpenes, remophilanetriols E-I (1-5), along with seven known compounds (6-12) were isolated from the fresh roots of Rehmannia glutinosa. Their structures were characterized by extensive spectroscopic data analysis and their absolute configurations were determined by comparing their calculated electronic circular dichroism (ECD) spectra and experimental ECD spectra. The anti-pulmonary fibrosis activities of all compounds were evaluated in vitro by MTT methods, and compounds 2, 8, 10, and 12 exhibited excellent anti-pulmonary fibrosis activities. In addition, compound 2 can reduce the levels of ROS and apoptosis in TGF-ß1-induced BEAS-2B cells.

Asunto(s)

Fitoquímicos , Raíces de Plantas , Rehmannia , Raíces de Plantas/química , Estructura Molecular , Rehmannia/química , Humanos , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Sesquiterpenos/farmacología , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/química , Apoptosis/efectos de los fármacos , Línea Celular , Especies Reactivas de Oxígeno/metabolismo , China , Sesquiterpenos Policíclicos/farmacología , Sesquiterpenos Policíclicos/aislamiento & purificación , Sesquiterpenos Policíclicos/química

RESUMEN

The phytochemical investigation of the fruits of Cornus officinalis yielded a new phenolic acid derivative, neophenolic acid A (1), and a novel flavonoid glycoside, (2R)-naringenin-7-O-ß-(6''-galloyl-glucopyranoside) (2 a), along with six known flavonoid glycosides (2 b-7). Their structures were determined by 1D, 2D NMR and HRESIMS data. The absolute configuration of 1 was established by ECD analysis. Compounds 1- 7 were evaluated for their neuroprotective activities against corticosterone (CORT)-induced injury in PC-12 cells. Compounds 1, 2 a, 2 b, 5, and 6 exhibited neuroprotective activities against CORT-induced neurotoxicity in PC-12 cells. The underlying mechanism study suggested that compounds 1, 2 a, 2 b, 5, and 6 were able to attenuate CORT-induced apoptosis and damage, increase the levels of MMP and decrease Ca2+ inward flow in PC-12 cells.

Asunto(s)

Apoptosis , Cornus , Frutas , Fármacos Neuroprotectores , Cornus/química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/aislamiento & purificación , Animales , Frutas/química , Ratas , Células PC12 , Apoptosis/efectos de los fármacos , Corticosterona/farmacología , Supervivencia Celular/efectos de los fármacos , Estructura Molecular , Flavonoides/farmacología , Flavonoides/aislamiento & purificación , Flavonoides/química , Relación Estructura-Actividad , Calcio/metabolismo

RESUMEN

Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry(UPLC-Q/TOF-MS) was employed to examine the impact of Coptidis Rhizoma(CR) and its processed products on the metabolism in the rat model of oral ulcer due to excess heat and to compare the effectiveness of CR and its three products. Male SD rats were randomly allocated to the sham-operation(Sham), model(M, oral ulcer due to excess heat), CR, wine/Zingiberis Rhizoma Recens/Euodiae Fructus processed CR(wCR/zCR/eCR), and Huanglian Shangqing Tablets(HST) groups. Except the Sham group, the other groups were administrated with Codonopsis Radix-Astragali Radix decoction by gavage for two consecutive weeks. The anal temperature and water consumption of rats were monitored throughout the modeling period of excess heat. Following the completion of the modeling, oral ulcer was modeled with acetic acid. Hematoxylin-eosin(HE) staining was employed to observe the mucosal pathological changes in oral ulcer. A colorimetric assay was employed to determine the serum level of glutathione peroxidase(GSH-Px). Enzyme-linked immunosorbent assay(ELISA) was conducted to determine the levels of tumor necrosis factor-alpha(TNF-α), interleukin-6(IL-6), interleukin-1ß(IL-1ß), superoxide dismutase(SOD), and malondialdehyde(MDA) in the serum. The non-targeted metabolomics analysis based on UPLC-Q/TOF-MS was conducted on the serum samples. Metabolic profiles were then built, and the potential biomarkers were screened by principal component analysis(PCA) and orthogonal partial least squares discriminant analysis(OPLS-DA). The Mev software was used to establish a heat map and conduct cluster analysis on the quantitative results of the markers. The online databases including MBRole, KEGG, and MetaboAnalyst were used for pathway enrichment analysis and metabolic network building. The experimental results showed that the modeling led to pathological damage to the oral mucosa, elevated serum levels of TNF-α, IL-6, IL-1ß, and MDA, and lowered levels of SOD and GSH-Px in rats. The drug administration recovered all the indices to varying extents, and wCR exhibited the best performance. Non-targeted metabolomics identified 48 differential metabolites including 27 metabolites in the positive ion mode and 21 metabolites in the negative ion mode. Five enriched pathways were common, including glycerophospholipid metabolism, linoleic acid metabolism, and tyrosine metabolism. Conclusively, CR and its three processed products could alleviate the inflammation and oxidative stress injury in rats suffering from oral ulcers due to excess heat by regulating lipid and amino acid metabolism. Notably, wCR demonstrated the most significant therapeutic effect.

Asunto(s)

Medicamentos Herbarios Chinos , Úlceras Bucales , Ratas , Masculino , Animales , Medicamentos Herbarios Chinos/farmacología , Úlceras Bucales/tratamiento farmacológico , Interleucina-6 , Calor , Factor de Necrosis Tumoral alfa , Ratas Sprague-Dawley , Metabolómica/métodos , Cromatografía Líquida de Alta Presión , Superóxido Dismutasa , Biomarcadores

RESUMEN

Two previously undescribed chain diarylheptanoid derivatives (2-3), five previously undescribed dimeric diarylheptanoids (4-8), together with one known cyclic diarylheptanoid (1) were isolated from Zingiber officinale. Their structures were elucidated by extensive spectroscopic analyses (HR-ESI-MS, IR, UV, 1D and 2D NMR) and ECD calculations. Biological evaluation of compounds 1-8 revealed that compounds 2, 3 and 4 could inhibit nitrite oxide and IL-6 production in lipopolysaccharide induced RAW264.7 cells in a dose-dependent manner.

Asunto(s)

Zingiber officinale , Diarilheptanoides/farmacología , Diarilheptanoides/química , Espectroscopía de Resonancia Magnética , Antiinflamatorios/farmacología , Estructura Molecular

RESUMEN

Five new biflavonoids, diphybiflavonoids A - E (1-5), were isolated from the roots and rhizomes of Diphylleia sinensis. Their structures were elucidated by extensive spectroscopic data, including UV, IR, HR-ESI-MS and 2D NMR. Their absolute configurations were determined by ECD spectra. All isolated compounds were evaluated for acetylcholinesterase (AChE) inhibitory activity. Compounds 1-4 exhibited the potent AChE inhibitory activities with IC50 values of 1.62, 2.10, 2.08, and 5.15 µM, respectively. The preliminary structure-activity relationship study indicated that the connection mode (C2-O-C4'''/C3-O-C3''' or C2-O-C3'''/C3-O-C4''') of biflavonoid subunits, and 3-hydroxy group of flavonol subunit were important structural factors for AChE inhibitory activity. Biflavonoids, containing a C2-O-C4'''/C3-O-C3''' or C2-O-C3'''/C3-O-C4''' linkage, can be a potentially useful platform for development of cholinesterase inhibitors.

Asunto(s)

Berberidaceae , Biflavonoides , Biflavonoides/farmacología , Estructura Molecular , Acetilcolinesterasa/análisis , Acetilcolinesterasa/metabolismo , Relación Estructura-Actividad , Raíces de Plantas/química , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química

RESUMEN

This study aims to investigate the intervention effect of the aqueous extract of Epimedium sagittatum Maxim on the mouse model of bleomycin(BLM)-induced pulmonary fibrosis, so as to provide data support for the clinical treatment of pulmonary fibrosis. Ninety male C57BL/6N mice were randomized into normal(n=10), model(BLM, n=20), pirfenidone(PFD, 270 mg·kg~(-1), n=15), and low-, medium-, and high-dose E. sagittatum extract(1.67 g·kg~(-1), n=15; 3.33 g·kg~(-1), n=15; 6.67 g·kg~(-1), n=15) groups. The model of pulmonary fibrosis was established by intratracheal instillation of BLM(5 mg·kg~(-1)) in the other five groups except the normal group, which was treated with an equal amount of normal saline. On the day following the modeling, each group was treated with the corresponding drug by gavage for 21 days. During this period, the survival rate of the mice was counted. After gavage, the lung index was calculated, and the morphology and collagen deposition of the lung tissue were observed by hematoxylin-eosin(HE) and Masson staining, respectively. The levels of reactive oxygen species(ROS) in lung cell suspensions were measured by flow cytometry. The levels of glutathione peroxidase(GSH-Px), total superoxide dismutase(T-SOD), and malondialdehyde(MDA) the in lung tissue were measured. Terminal-deoxynucleoitidyl transferase-mediated nick-end labeling(TUNEL) was employed to examine the apoptosis of lung tissue cells. The content of interleukin-6(IL-6), chemokine C-C motif ligand 2(CCL-2), matrix metalloproteinase-8(MMP-8), transforming growth factor-beta 1(TGF-ß1), alpha-smooth muscle actin(α-SMA), E-cadherin, collagen Ⅰ, and fibronectin in the lung tissue was measured by enzyme-linked immunosorbent assay(ELISA). The expression levels of F4/80, Ly-6G, TGF-ß1, and collagen Ⅰ in the lung tissue were determined by immunohistochemistry. The mRNA levels of CCL-2, IL-6, and MMP-7 in the lung tissue were determined by qRT-PCR. The content of hydroxyproline(HYP) in the lung tissue was determined by alkaline hydrolysation. The expression of α-SMA and E-cadherin was detected by immunofluorescence, and the protein levels of α-SMA, vimentin, E-cadherin in the lung tissue were determined by Western blot. The results showed the aqueous extract of E. sagittatum increased the survival rate, decreased the lung index, alleviated the pathological injury, collagen deposition, and oxidative stress in the lung tissue, and reduced the apoptotic cells. Furthermore, the aqueous extract of E. sagittatum down-regulated the protein levels of F4/80 and Ly-6G and the mRNA levels of CCL-2, IL-6, and MMP-7 in the lung tissue, reduced the content of IL-6, CCL-2, and MMP-8 in the alveolar lavage fluid. In addition, it lowered the levels of HYP, TGF-ß1, α-SMA, collagen Ⅰ, fibronectin, and vimentin, and elevated the levels of E-cadherin in the lung tissue. The aqueous extract of E. sagittatum can inhibit collagen deposition, alleviate oxidative stress, and reduce inflammatory response by regulating the expression of the molecules associated with epithelial-mesenchymal transition, thus alleviating the symptoms of bleomycin-induced pulmonary fibrosis in mice.

Asunto(s)

Epimedium , Fibrosis Pulmonar , Ratones , Masculino , Animales , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Epimedium/metabolismo , Fibronectinas/metabolismo , Metaloproteinasa 7 de la Matriz/metabolismo , Metaloproteinasa 7 de la Matriz/farmacología , Metaloproteinasa 7 de la Matriz/uso terapéutico , Metaloproteinasa 8 de la Matriz/metabolismo , Metaloproteinasa 8 de la Matriz/farmacología , Metaloproteinasa 8 de la Matriz/uso terapéutico , Vimentina/metabolismo , Interleucina-6/metabolismo , Ratones Endogámicos C57BL , Pulmón , Colágeno/metabolismo , Bleomicina/toxicidad , ARN Mensajero/metabolismo , Cadherinas/metabolismo

RESUMEN

Alzheimer's disease (AD) is a progressive neurodegenerative disease for which there is a lack of effective therapeutic drugs. There is great potential for natural products to be used in the development of anti-AD drugs. P-coumaric acid (PCA), a small molecule phenolic acid widely distributed in the plant kingdom, has pharmacological effects such as neuroprotection, but its anti-AD mechanism has not been fully elucidated. In the current study, we investigated the mechanism of PCA intervention in the Aß25-35-induced AD model using gut microbiomics and serum metabolomics combined with in vitro and in vivo pharmacological experiments. PCA was found to ameliorate cognitive dysfunction and neuronal cell damage in Aß25-35-injected mice as measured by behavioral, pathological and biochemical indicators. 16S rDNA sequencing and serum metabolomics showed that PCA reduced the abundance of pro-inflammatory-associated microbiota (morganella, holdemanella, fusicatenibacter and serratia) in the gut, which were closely associated with metabolites of the glucose metabolism, arachidonic acid metabolism, tyrosine metabolism and phospholipid metabolism pathways in serum. Next, in vivo and in vitro pharmacological investigations revealed that PCA regulated Aß25-35-induced disruption of glucose metabolism through activation of PI3K/AKT/Glut1 signaling. Additionally, PCA ameliorated Aß25-35-induced neuroinflammation by inhibiting nuclear translocation of NF-κB and by modulating upstream MAPK signaling. In conclusion, PCA ameliorated cognitive deficits in Aß25-35-induced AD mice by regulating glucose metabolism and neuroinflammation, and the mechanism is related not only to restoring homeostasis of gut microbiota and serum metabolites, but also to PI3K/AKT/Glut1 and MAPK/NF-κB signaling.

Asunto(s)

Enfermedad de Alzheimer , Microbioma Gastrointestinal , Enfermedades Neurodegenerativas , Ratones , Animales , Péptidos beta-Amiloides/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Enfermedades Neuroinflamatorias , Enfermedades Neurodegenerativas/patología , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Glucosa/metabolismo , Encéfalo

RESUMEN

The purpose of this study was to investigate the effect of aqueous extract of Corni Fructus on ß-amyloid protein 25-35(Aß_(25-35))-induced brain injury and neuroinflammation in Alzheimer's disease(AD) mice to provide an experimental basis for the treatment of AD by aqueous extract of Corni Fructus. Sixty C57BL/6J male mice were randomly divided into a sham group, a model group, a positive control group(huperizine A, 0.2 mg·kg~(-1)), a low-dose aqueous extract of Corni Fructus group(1.3 g·kg~(-1)), a medium-dose aqueous extract of Corni Fructus group(2.6 g·kg~(-1)), and a high-dose aqueous extract of Corni Fructus group(5.2 g·kg~(-1)). The AD model was induced by lateral ventricular injection of Aß_(25-35) in mice except for those in the sham group, and AD model mice were treated with corresponding drugs by gavage for 24 days. The behavioral test was performed one week before animal dissection. Hematoxylin-eosin(HE) staining was performed to observe the morphology of neurons in the hippocampal region. Flow cytometry was used to detect the apoptosis level of primary hippocampal cells in mice. ELISA kits were used to detect the levels of ß-amyloid protein 1-42(Aß_(1-42)) and phosphorylated microtubule-associated protein Tau(p-Tau) in mouse brain tissues. Immunofluorescence and Western blot were used to detect the expression of related proteins in mouse brain tissues. MTT assay was used to detect the effect of compounds in aqueous extract of Corni Fructus on Aß_(25-35)-induced N9 cell injury. Molecular docking was employed to analyze the interactions of caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-ß-D-glucopyranoside, esculetin, and(+)-lyoniresinol with ß-amyloid precursor protein(APP), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α). Aqueous extract of Corni Fructus could improve the learning and memory abilities of Aß_(25-35)-induced mice by increasing the duration of the autonomous activity, the rate of autonomous alternation, the preference coefficient, and the discrimination coefficient, and reduce Aß_(25-35)-induced brain injury and neuroinflammation in mice by increasing the expression levels of interleukin-10(IL-10) and B-cell lymphoma-2(Bcl-2) in brain tissues, decreasing the expression levels of Aß_(1-42), p-Tau, IL-6, TNF-α, cysteine aspartate-specific protease 3(caspase-3), cysteine aspartate-specific protease 9(caspase-9), and Bcl-2-associated X protein(Bax), and decreasing the number of activated glial cells in brain tissues. The results of cell experiments showed that esculetin and(+)-lyoniresinol could improve Aß_(25-35)-induced N9 cell injury. Molecular docking results showed that caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-ß-D-glucopyranoside, esculetin, and(+)-lyoniresinol had good binding affinity with APP and weak binding affinity with IL-6 and TNF-α. Aqueous extract of Corni Fructus could ameliorate cognitive dysfunction and brain damage in Aß_(25-35)-induced mice by reducing the number of apoptotic cells and activated glial cells in the brain and decreasing the expression level of inflammatory factors. Caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-ß-D-glucopyranoside, esculetin, and(+)-lyoniresinol may be the material basis for the anti-AD effect of aqueous extract of Corni Fructus.

Asunto(s)

Enfermedad de Alzheimer , Lesiones Encefálicas , Cornus , Ratones , Masculino , Animales , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/toxicidad , Péptidos beta-Amiloides/metabolismo , Cornus/metabolismo , Enfermedades Neuroinflamatorias , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6 , Ácido Aspártico , Cisteína/uso terapéutico , Simulación del Acoplamiento Molecular , Ratones Endogámicos C57BL , Péptido Hidrolasas , Modelos Animales de Enfermedad , Ratones Transgénicos

RESUMEN

As a widely consumed spice and Traditional Chinese Medicine, Alpinae oxyphylla has been used to treat conditions such as diarrhea, ulcers, dementia, and enuresis. Fruits of A. oxyphylla were phytochemically studied and the bioactive constituents against renal fibrosis were identified. Eight previously undescribed acetylated flavonol glucuronides named oxyphyllvonides A-H (1-7 and 10), two known acetylated flavonol glucuronides (8 and 9), together with seven known flavone glycosides (11-17) were isolated from the fruits of A. oxyphylla. Among them, flavonol glucuronides were discovered in Zingiberaceae for the first time. The planar structures of 1-7 and 10 were determined using HRESIMS and extensive spectroscopic techniques (UV, IR, 1D-NMR, and 2D-NMR). The absolute configurations of the sugar moiety in these compounds were determined by using LC-MS analysis of acid-hydrolyzed derivatized monosaccharides. Biological evaluation showed that 7-10, 13, 14, 16 and 17 inhibit renal fibrosis in TGF-ß1-induced kidney proximal tubular cells. In addition, 7, 8 and 14 were superior to nootkatone in inhibiting Fibronectin expression. The finding has significant relevance to our ongoing research on the anti-renal fibrosis activity of A. oxyphylla.

Asunto(s)

Alpinia , Frutas , Alpinia/química , Glucurónidos , Flavonoles

RESUMEN

Three pairs of undescribed diarylpentanoid enantiomers (1-3) and five undescribed phenylpropanoids (4-8), along with seven known compounds, were isolated from the roots of Anthriscus sylvestris. The structures of compounds (1-8) were determined by analysis of their 1D and 2D NMR spectra, HRESIMS, and electronic circular dichroism. In addition, the inhibitory activities against hypoxia-stimulated pulmonary arterial smooth muscle cells abnormal proliferation were evaluated by MTT assay. The mRNA expression levels of Bcl-2, BAX, Caspase3, and IL-6 were detected by quantitative real-time PCR. The results showed that compounds (-)-1, (+)-1, (-)-2, (+)-3, 4, 8-10, 14, and 15 inhibited the abnormal proliferation of PASMCs by regulating the levels of apoptosis and inflammatory factors.

Asunto(s)

Apiaceae , Extractos Vegetales , Extractos Vegetales/química , Arteria Pulmonar , Proliferación Celular

RESUMEN

Fifteen undescribed diterpenoid quinones salviamilthone A-O (1-15), together with three known diterpenoid quinones (16-18), were isolated from the roots of Salvia miltiorrhiza Bunge. Their structures were elucidated using 1D and 2D NMR data, while the relative and absolute configurations were confirmed by NOESY correlations and comparison between experimental and calculated ECD spectra. In the evaluation of bioactivities, salviamilthone J (10), salviamone (18) (10 µM) significantly increased cell viability and decreased the expression of IL-1ß in lipopolysaccharide-induced BEAS-2B cells. These data provide the molecular justification for the usage of Salvia miltiorrhiza in treating acute lung injury.

Asunto(s)

Diterpenos , Salvia miltiorrhiza , Salvia , Salvia miltiorrhiza/química , Quinonas/farmacología , Raíces de Plantas/química , Salvia/química

RESUMEN

Rhizoma coptidis (CR) is traditionally used for treating gastrointestinal diseases. Wine-processed CR (wCR), zingiber-processed CR (zCR), and evodia-processed CR (eCR) are its major processed products. However, the related study of their specific mechanisms is very limited, and they need to be further clarified. The aim of this study is to compare the intervening mechanism of wCR/zCR/eCR on rats via faecal metabolomics and 16S rDNA gene sequencing analysis. First, faecal samples were collected from the control and CR/wCR/zCR/eCR groups. Then, a metabolomics analysis was performed using UHPLC-Q/TOF-MS to obtain the metabolic profile and significantly altered metabolites. The 16S rDNA gene sequencing analysis was carried out to analyze the composition of gut microbiota and screen out the significantly altered microbiota at the genus level. Finally, a pathway enrichment analysis of the significantly altered metabolites via the KEGG database and a functional prediction of relevant gut microbes based on PICRUSt2 software were performed in combination. Together with the correlation analysis between metabolites and gut microbiota, the potential intervening mechanism of wCR/zCR/eCR was explored. The results suggested that wCR played a good role in maintaining immune homeostasis, promoting glycolysis, and reducing cholesterol; zCR had a better effect on protecting the integrity of the intestinal mucus barrier, preventing gastric ulcers, and reducing body cholesterol; eCR was good at protecting the integrity of the intestinal mucus barrier and promoting glycolysis. This study scientifically elucidated the intervening mechanism of wCR/zCR/eCR from the perspective of faecal metabolites and gut microbiota, providing a new insight into the processing mechanism research of Chinese herbs.

Asunto(s)

Medicamentos Herbarios Chinos , Microbioma Gastrointestinal , Ratas , Animales , Coptis chinensis , Medicamentos Herbarios Chinos/farmacología , Metabolómica/métodos , Metaboloma

RESUMEN

A total of nine new phenolic amides (1-9), including four pairs of enantiomeric mixtures (3-5 and 8), along with ten known analogues (10-19) were identified from the fruits of Lycium barbarum using bioassay-guided chromatographic fractionation. Their structures were elucidated by comprehensive spectroscopic and spectrometric analyses, chiral HPLC analyses, and quantum NMR, and electronic circular dichroism calculations. Compounds 5-7 are the first example of feruloyl tyramine dimers fused through a cyclobutane ring. The activity results indicated that compounds 1, 11, and 13-17 exhibited remarkable inhibition against α-glucosidase with IC50 of 1.11-33.53 µM, 5-150 times stronger than acarbose (IC50 = 169.78 µM). Meanwhile, compounds 4a, 4b, 5a, 5b, 13, and 14 exerted moderate agonistic activities for peroxisome proliferator-activated receptor (PPAR-γ), with EC50 values of 10.09-44.26 µM. Especially,compound 14 also presented inhibitory activity on dipeptidyl peptidase-4 (DPPIV), with an IC50 value of 47.13 µM. Furthermore, the banding manner of compounds 14 and 17 with the active site of α-glucosidase, DPPIV, and PPAR-γ was explored by employing molecular docking analysis.

Asunto(s)

Lycium , alfa-Glucosidasas , alfa-Glucosidasas/análisis , Frutas/química , Lycium/química , Receptores Activados del Proliferador del Peroxisoma , Agonistas de PPAR-gamma , Amidas , Simulación del Acoplamiento Molecular , Fenoles/análisis , Espectroscopía de Resonancia Magnética , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/análisis , Estructura Molecular , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/química