RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Leonurus japonicus Houtt. (Labiatae), commonly known as Chinese motherwort, is a herbaceous flowering plant that is native to Asia. It is widely acknowledged in traditional medicine for its diuretic, hypoglycemic, antiepileptic properties and neuroprotection. Currently, Leonurus japonicus (Leo) is included in the Pharmacopoeia of the People's Republic of China. Traditional Chinese Medicine (TCM) recognizes Leo for its myriad pharmacological attributes, but its efficacy against ICH-induced neuronal apoptosis is unclear. AIMS OF THE STUDY: This study aimed to identify the potential targets and regulatory mechanisms of Leo in alleviating neuronal apoptosis after ICH. MATERIALS AND METHODS: The study employed network pharmacology, UPLC-Q-TOF-MS technique, molecular docking, pharmacodynamic studies, western blotting, and immunofluorescence techniques to explore its potential mechanisms. RESULTS: Leo was found to assist hematoma absorption, thus improving the neurological outlook in an ICH mouse model. Importantly, molecular docking highlighted JAK as Leo's potential therapeutic target in ICH scenarios. Further experimental evidence demonstrated that Leo adjusts JAK1 and STAT1 phosphorylation, curbing Bax while augmenting Bcl-2 expression. CONCLUSION: Leo showcases potential in mitigating neuronal apoptosis post-ICH, predominantly via the JAK/STAT mechanism.
Assuntos
Apoptose , Hemorragia Cerebral , Leonurus , Simulação de Acoplamento Molecular , Farmacologia em Rede , Neurônios , Animais , Apoptose/efeitos dos fármacos , Leonurus/química , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Camundongos , Masculino , Hemorragia Cerebral/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Janus Quinase 1/metabolismo , Fator de Transcrição STAT1/metabolismo , Modelos Animais de DoençasRESUMO
Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. As one of the major degradation pathways, autophagy plays a pivotal role in maintaining the effective turnover of proteins and damaged organelles in cells. Lewy bodies composed of α-synuclein (α-syn) abnormally aggregated in the substantia nigra are important pathological features of PD, and autophagy dysfunction is considered to be an important factor leading to abnormal aggregation of α-syn. Phenylpropionamides (PHS) in the seed of Cannabis sativa L. have a protective effect on neuroinflammation and antioxidant activity. However, the therapeutic role of PHS in PD is unclear. In this study, the seeds of Cannabis sativa L. were extracted under reflux with 60% EtOH-H2O, and the 60% EtOH-H2O elution fraction was identified as PHS with the UPLC-QTOF-MS. The 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)-induced PD model in C57BL/6 J mice was used for behavioral and pharmacodynamic experiments. Behavioral symptoms were improved, Nissl-stained and TH-positive neurons in the substantia nigra were significantly increased in PHS-treated MPTP-induced PD model mice. Compared with the model group, PHS treatment reduced the expression level of α-syn, and the expression of TH increased significantly by western blotting, compared with the model group, the PHS group suppressed Caspase 3 and Bax expression and promoted Bcl-2 expression and levels of p62 decreased significantly, the ratio of LC3-II/I and p-mTOR/mTOR in the PHS group had a downward trend, suggesting that the therapeutic effect of PHS on MPTP-induced PD model mice may be triggered by the regulation of autophagy.
Assuntos
Autofagia , Cannabis , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores , Sementes , Animais , Autofagia/efeitos dos fármacos , Camundongos , Sementes/química , Cannabis/química , Masculino , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/isolamento & purificação , Doença de Parkinson/tratamento farmacológico , Substância Negra/efeitos dos fármacos , Modelos Animais de Doenças , Serina-Treonina Quinases TOR/metabolismoRESUMO
Three undescribed sesquiterpenes, designed as pichinenoid A-C (1-3), along with nine known ones (4-12) were isolated from the stems and leaves of Picrasma chinensis. The new isolates including their absolute configurations were elucidated based on extensive spectroscopic methods, single crystal X-ray diffraction, and electronic circular dichroism (ECD) experiments, as well as comparison with literature data. Structurally, compounds 1 and 2 are descending sesquiterpenes, while pichinenoid C (3) is a rare sesquiterpene bearing a 2-methylenebut-3-enoic acid moiety at the C-6 side chain. All the isolated compounds were tested for their neuroprotective effects against the H2O2-induced damage on human neuroblastoma SH-SY5Y cells, and most of them showed moderate neuroprotective activity. Especially, compounds 1, 3-5, and 7 showed a potent neuroprotective effect at 25 or 50 µM. Moreover, the neuroprotective effects of compounds 1 and 4 were tested on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model. Results of western blot and immunofluorescence indicated that compound 4 significantly counteract the toxicity of MPTP, and reversed the expression of tyrosine hydroxylase (TH) in substantia nigra (SN) and striatum (ST) of the mouse brain. Interestingly, western blot data suggested compound 4 also enhanced B-cell lymphoma-2 (Bcl-2) and heme oxygenase 1 (HO-1) expressions in the brain tissues from MPTP damaged mouse.
Assuntos
Fármacos Neuroprotetores , Picrasma , Folhas de Planta , Caules de Planta , Sesquiterpenos , Animais , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/isolamento & purificação , Sesquiterpenos/farmacologia , Sesquiterpenos/isolamento & purificação , Camundongos , Humanos , Linhagem Celular Tumoral , Estrutura Molecular , Picrasma/química , Caules de Planta/química , Folhas de Planta/química , Masculino , Heme Oxigenase-1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , China , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Camundongos Endogâmicos C57BLRESUMO
Two new quinoline alkaloids with an α, ß-unsaturated amide side chain, xylarinines A and B (1 and 2), were isolated from the ethyl acetate extracts of Xylaria longipes solid fermentation. The structures of these were primarily determined though NMR and HRESIMS data analysis. The absolute configuration of compound 1 was assigned using experimental and calculated ECD data. The neuroprotective effects of compounds 1 and 2 against glutamate-induced damage in PC12 cells were evaluated in vitro bioassay. The results demonstrated that both compounds significantly improved cell viability, inhibited apoptosis, decreased malondialdehyde (MDA) levels, increased superoxide dismutase (SOD) and glutathione (GSH) levels, and reduced intracellular reactive oxygen species (ROS) accumulation. These findings suggested that these mechanisms contribute to the neuroprotective effects of the compounds.
Assuntos
Alcaloides , Apoptose , Fármacos Neuroprotetores , Quinolinas , Espécies Reativas de Oxigênio , Xylariales , Células PC12 , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/isolamento & purificação , Animais , Ratos , Quinolinas/farmacologia , Quinolinas/isolamento & purificação , Estrutura Molecular , Alcaloides/farmacologia , Alcaloides/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo , Xylariales/química , Apoptose/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Malondialdeído/metabolismo , Glutationa/metabolismo , Sobrevivência Celular/efeitos dos fármacos , China , Ácido GlutâmicoRESUMO
The popular perennial creeping plant known as Bacopa monnieri (also known as Brahmi) is being utilized in the Indian Ayurvedic medicine practice. It has a variety of bioactive phytoconstituents that have been used therapeutically to treat a number of serious illnesses. Ancient Vedic scholars used this herb because of its pharmacological effects, particularly as a nerve booster and nootropic supporter. However, it is vital to comprehend the active phytochemical components of Bacopa monnieri extract (BME) and their molecular mechanisms in order to better grasp the effect of BME on neurological illnesses and diseases. Understanding its active phytochemical constituents and their molecular processes is essential. Numerous clinical investigations indicated that BME may have neuroprotective benefits, so it is worthwhile to re-evaluate this wellknown plant. Here, we focused on neurological problems as we examined the pharmacological and phytochemical characteristics of BME. For their effective usage in neuroprotection and cognition, many clinical concerns and the synergistic potential of Bacopa extract have been investigated. Alzheimer's disease is a neurological condition caused by the production of reactive oxygen species, which also causes amyloid-beta (Aß) and tau protein aggregation and increases neuro-inflammation and neurotoxicity. Our review offers a more indepth molecular understanding of the neuroprotective functions of BME, which can also be connected to its therapeutic management of neurological illnesses and cognitive-improving effects.
Assuntos
Bacopa , Doenças do Sistema Nervoso , Extratos Vegetais , Bacopa/química , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Doenças do Sistema Nervoso/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Animais , AyurvedaRESUMO
Aggregation of amyloid ß42 (Aß42) is one of the hallmarks of Alzheimer's disease (AD). Inhibition of Aß42 aggregation is thus a promising approach for AD therapy. Kampo medicine has been widely used to combat dementias such as AD. Crude drug known as Shoyaku is an ingredient of Kampo that could have potential as a natural source of novel drugs. However, given that a mixture of compounds, rather than singular compounds, could contribute to the biological functions of crude drug, there are very limited studies on the structure and mechanism of each constituent in crude drug which may have anti-Aß42 aggregation properties. Herein we provide an efficient method, using LC-MS combined with principal component analysis (PCA), to search for activity-dependent compounds that inhibit Aß42 aggregation from 46 crude drug extracts originating from 18 plants. Only 5 extracts (Kakou, Kayou, Gusetsu, Rensu, and Renbou) from lotus demonstrated differentially inhibitory activities depending on the part of the plant from which they are derived (e.g. petiole, leaf, root node, stamen, and receptacle, respectively). To compare the anti-aggregative properties of compounds of active crude drug with those of inactive crude drug, these extracts were subjected to LC-MS measurement, followed by PCA. From 12 candidate compounds identified from the analysis, glucuronized and glucosidized quercetin, as well as 6 flavonoids (datiscetin, kaempferol, morin, robinetin, quercetin, and myricitrin), including catechol or flatness moiety suppressed Aß42 aggregation, whereas curcumol, a sesquiterpene, did not. In conclusion, this study offers a new activity-differential methodology to identify bioactive natural products in crude drugs that inhibit Aß42 aggregation and that could be applied to future AD therapies.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Medicamentos de Ervas Chinesas/farmacologia , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Análise de Componente Principal , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Cromatografia Líquida , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Humanos , Espectrometria de Massas , Medicina Kampo , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Plantas Medicinais/química , Agregados Proteicos/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Silybum marianum is a traditional Chinese medicine that has been used for treating liver disease. Silybin consisting of silybin A and silybin B, is a member of Silybum marianum, and exerts a therapeutic effect on many diseases. However, the protective effect of silybin on cisplatin-induced neurotoxicity and the stereoisomer contributing to the effect remain unknown. AIM OF THE STUDY: The present study aimed to study the effect of silybin on cisplatin-induced neuronal injury, compare the difference of protective effect between silybin A and silybin B, and the potential mechanism. MATERIALS AND METHODS: High performance liquid chromatography (HPLC) was used to separate silybin A and silybin B. X-ray crystallographic analysis in combination with experimental and calculated ECD were performed to identify the structure of silybin A and silybin B. The toxicity of the silybin or cisplatin against murine hippocampal neuronal HT22 cells was determined through MTT assay. The cell cycle and cell apoptosis were measured by PI staining and Annexin V-FITC/PI staining, respectively, and then subjected to flow cytometry. Western blot analysis was conducted to quantify the expression of proteins related to apoptosis and DNA damage. Immunofluorescence was used to evaluate the expression of DNA damage marker. In vivo experiment, the behavioral analysis was determined through pole test, swimming test and Morris water maze test. The index of superoxide dismutase (SOD), reduced glutathione (GSH), total antioxidant capacity (T-AOC) and lipid peroxidation (LPO) were examined to evaluate the antioxidant capacity in mice brain. Nissl staining and Tunel assay were used to detect the neuronal viability and apoptosis in hippocampus. RESULTS: We successfully separated and identified silybin A and silybin B. We found both silybin A and silybin B alleviated cisplatin-induced apoptosis and cell cycle arrest in HT22 cells, and silybin B was more effective. We chose silybin B for further mechanism investigation, and found silybin B alleviated DNA damage by enhancing phosphorylation of ATR and decreasing expression of γ-H2AX. In the in vivo experiment, we observed that silybin B markedly improved the behavioral abnormalities in cisplatin-treated mice, reduced LPO level while increased SOD, GSH and T-AOC in mice brain tissue. Nissl staining and Tunel assay showed that silybin B alleviated cisplatin-induced hippocampal damage. CONCLUSIONS: These results suggest that silybin B might serve as a promising drug candidate in mitigating cisplatin-induced neural injury in the brain and thereby improving the chemotherapeutic outcomes.
Assuntos
Cisplatino/toxicidade , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Silibina/farmacologia , Animais , Antineoplásicos/toxicidade , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Dano ao DNA/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Silybum marianum/química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Síndromes Neurotóxicas/etiologia , Silibina/química , Silibina/isolamento & purificaçãoRESUMO
CONTEXT: Fruits of Forsythia suspensa Vahl (Oleaceae) and seeds of Cassia obtusifolia Linne (Caesalpinaceae) have been used to treat inflammation in Asia. OBJECTIVE: We examined the alleviation of memory function in Alzheimer's disease (AD) rats fed Forsythiae Fructus (FF) and Cassiae Semen water extracts (CS) and investigated the mechanisms responsible for the effects. MATERIALS AND METHODS: Thirty Sprague-Dawley male rats had hippocampal infusions of amyloid-ß(25-35) (AD rats; memory deficit), and ten rats were infused with amyloid-ß(35-25) (non-AD rats; no memory deficit). For eight weeks, all rats freely consumed high-fat diets (43% lard) incorporated with 200 mg/kg body weight assigned aqueous herbal extracts: AD-FF, AD-CS, or without extracts AD-CON (control), non-AD (normal-control). RESULTS: Memory impairment was prevented in the AD-FF (0.54 ± 0.06-fold) and the AD-CS rats (0.33 ± 0.04-fold) compared to the AD-CON by inhibiting amyloid-ß deposition to the levels less than one-fourth of the AD-CON group. The hippocampal pAktâpGSK-3ßâpFOXO1 pathway was attenuated by approximately 3.25-fold in the AD-CON, while AD-FF prevented the attenuation better than AD-CS. The relative intensity of hippocampal tau protein based on ß-actin was suppressed with AD-FF (0.68 ± 0.09) and AD-CS (0.96 ± 0.81), compared to AD-CON (1.19 ± 0.13). AD decreased the abundance of Bacteroidales by 34.2% and Lactobacillales by 23.8% and increased Clostridiales by 181% while the AD-FF, but not the AD-CS, normalised the gut microbiota changes to be similar to the non-AD. DISCUSSION AND CONCLUSIONS: FF improved memory deficits better than CS in an AD-induced rat model. The potential neuroprotective benefits of FF against AD may be applicable to human AD therapy with additional clinical research.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Cassia/química , Forsythia/química , Extratos Vegetais/farmacologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Frutas , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , SementesRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Rehmannioside A is derived from Rehmannia glutinosa Libosch, which is widely used as an important ingredient in diverse traditional Chinese medicines to treat diseases caused by "kidney deficiency" such as cerebral arteriosclerosis, aging-related stroke and dementia in China. Recent studies have proved that Rehmannia glutinosa Libosch and Rehmannioside A can improve memory capability and recover nerve damage. AIM OF THE STUDY: To investigate the effect of Rehmannioside A on cognitive impairment after ischemia in rats and SH-SY5Y cells, and further evaluate the anti-oxidative and anti-ferroptosis mechanisms. MATERIALS AND METHODS: Differentially expressed proteins (DEPs) in patients after cerebral ischemic stroke were revealed by a RayBio protein array. Cognitive impairment model was established by middle cerebral artery occlusion and reperfusion (MCAO) 14 days in rats. Rehmannioside A was administered intraperitoneally injection at dose of 80 mg/kg. The SH-SY5Y cells were exposed to H2O2 for 24 h and treated with Rehmannioside A (80 µM) for 24 h. The neuroprotecion of Rehmannioside A were evaluated by infarct volume (TTC), neurological defects (Garcia score) and learning memory (Morris water maze test) in vivo, and cell viability (CCK-8 or LDH) in vitro. Superoxide dismutase (SOD), malondialdehyde (MDA) and myeloperoxidase (MPO) activity of rats, glutathione (GSH), oxidized glutathione (GSSG) and nicotinamide adenine dinucleotide phosphate (NADPH) of cells were detected by biochemical assay. Intracellular reactive oxygen species (ROS) were measured by DCFH-DA assay. Myeloperoxidase (MPO), PI3 kinase (PI3K), p-PI3K, Akt, p-Akt, heme oxygenase-1 (HO-1), nuclear factor-E2-related factor 2 (Nrf2), SLC7A11, glutathione peroxidase 4 (GPX4) of the cerebral cortex in rats or SH-SY5Y cells were examined by western blotting. RESULTS: Compared with model group, the cognitive impairment and neurological deficits of Rehmannioside A group were significantly improved, and the cerebral infarction was reduced in MCAO rats. Moreover, the cell viability obviously increased and the H2O2-induced toxicity was reduced in Rehmannioside A group. Further research indicated that the expression of p-PI3K, p-Akt, nuclear Nrf2, HO-1 and SLC7A11 in Rehmannioside A group was significantly higher than model group. CONCLUSION: Rehmannioside A has neuroprotection effect and improves cognitive impairment after cerebral ischemia by inhibiting ferroptosis and activating PI3K/AKT/Nrf2 and SLC7A11/GPX4 signaling pathway. These findings provide valuable insight into the pathogenesis and therapeutic target of ischemic stroke.
Assuntos
Isquemia Encefálica , Disfunção Cognitiva , Medicamentos de Ervas Chinesas , Fármacos Neuroprotetores , Rehmannia , Animais , Humanos , Masculino , Ratos , Isquemia Encefálica/tratamento farmacológico , Estudos de Casos e Controles , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Infarto da Artéria Cerebral Média , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Rehmannia/química , Transdução de Sinais/efeitos dos fármacos , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologiaRESUMO
Two new seco-prezizaane-type sesquiterpenes, 2ß-hydroxy-6-deoxyneoanisatin (1) and 3,4-anhydro-2-oxo-1α-hydroxy-6-deoxyneoanisatin (2), and two new prenylated C6 -C3 compounds, illilanceofunones A (3) and B (4), were obtained from the fruits of Illicium lanceolatum, along with four known prenylated C6 -C3 compounds (5-8). Their structures were proposed through HR-ESI-MS, 1 H, 13 C, and 2D NMR data interpretation. Moreover, the absolute configuration of 1 and 2 were further assigned by single-crystal X-ray diffraction analysis and electronic circular dichroism (ECD) calculations, respectively. Illihenryipyranol A (6) exhibited neuroprotective activity against MPP+ -induced PC12â cell damage in a dose-dependent manner.
Assuntos
Illicium/química , Fármacos Neuroprotetores/química , Sesquiterpenos/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Frutas/química , Frutas/metabolismo , Illicium/metabolismo , Espectroscopia de Ressonância Magnética , Conformação Molecular , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Células PC12 , Extratos Vegetais/química , Prenilação , Ratos , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The use of Panax ginseng C.A.Mey. in traditional Chinese medicine dates back to about 5000 years ago thanks to its several beneficial and healing properties. Panaxadiol is a triterpenoid sapogenin monomer found in the roots of Panax ginseng C.A.Mey. and has been proven to have various bio-activities such as anti-inflammatory, anti-tumour and neuroprotective effects. AIM OF THE STUDY: The present study focuses on investigating the inflammation inhibitory effect and mechanism of panaxadiol by regulating zinc finger protein 91-regulated activation of non-canonical caspase-8 inflammasome and MAPKs in macrophages. MATERIALS AND METHODS: In vitro, the underlying mechanisms by which panaxadiol inhibits ZFP91-regulated IL-1ß expression were investigated using molecular docking, western blotting, RT-PCR, ELISA, immunofluorescence, and immunoprecipitation assays. In vivo, colitis was induced by oral administration of DSS in drinking water, and peritonitis was induced by an intraperitoneal injection of alum. Recombinant adeno-associated virus (AAV serotype 9) vector was used to establish ZFP91 knockdown mouse. RESULTS: We confirmed that panaxadiol inhibited IL-1ß secretion by suppressing ZFP91 in macrophages. Further analysis revealed that panaxadiol inhibited IL-1ß secretion by suppressing ZFP91-regulated activation of non-canonical caspase-8 inflammasome. Meanwhile, panaxadiol inhibited IL-1ß secretion by suppressing ZFP91-regulated activation of MAPKs. In vivo, prominent anti-inflammatory effects of panaxadiol were demonstrated in a DSS induced acute colitis mouse model and in an alum-induced peritonitis model by suppressing ZFP91-regulated secretion of inflammatory mediators, consistent with the results of the AAV-ZFP91 knockdown in mice. CONCLUSIONS: We report for the first time that panaxadiol inhibited IL-1ß secretion by suppressing ZFP91-regulated activation of non-canonical caspase-8 inflammasome and MAPKs, providing evidence for anti-inflammation mechanism of panaxadiol treatment for inflammatory diseases.
Assuntos
Anti-Inflamatórios/farmacologia , Ginsenosídeos/farmacologia , Fármacos Neuroprotetores/farmacologia , Panax/química , Animais , Anti-Inflamatórios/isolamento & purificação , Caspase 8/metabolismo , Colite/tratamento farmacológico , Técnicas de Silenciamento de Genes , Ginsenosídeos/isolamento & purificação , Células HEK293 , Humanos , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Interleucina-1beta/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/isolamento & purificação , Células THP-1 , Ubiquitina-Proteína Ligases/genéticaRESUMO
Dried flowers of Inula britannica commercially serve as pharmaceutical/nutraceutical herbs in the manufacture of medicinal products and functional tea that has been reported to possess extensive biological property. However, the neuroprotective constituents in I. britannica flowers are not known. In the current study, phytochemicals of sesquiterpenoid-enriched I. britannica flowers extract and their potential multifunctional neuroprotective effects were investigated. Nineteen structurally diverse sesquiterpenoids, including two new sesquiterpenoid dimers, namely, inubritanolides A and B (1, 2), and four new sesquiterpenoid monomers (3-6), namely, 1-O-acetyl-6-O-chloracetylbritannilactone (3), 6-methoxybritannilactone (4), 1-hydroxy-10ß-methoxy-4αH-1,10-secoeudesma-5(6),11(13)-dien-12,8ß-olide (5) and 1-hydroxy-4αH-1,10-secoeudesma-5(6),10(14),11(13)-trien-12,8ß-olide (6), as well as 13 known congeners (7-19) were isolated from this source. The structures of compounds 1-6 were elucidated by 1D- and 2D- NMR and HR-ESI-MS data, and their absolute configurations were discerned by electronic circular dichroism (ECD) data analysis and single crystal X-ray diffraction. Interestingly, inubritannolide A (1) is a new type [4 + 2] Diels-Alder dimer featuring a hepta-membered cycloether skeleton. Most of the compounds showed potential multifunctional neuroprotective effects, including antioxidative, anti-neuroinflammatory, and microglial polarization properties. Specifically, 1 and 6 displayed slight strong neuroprotective potency against different types of neuronal cells mediated by various inducers including H2O2, 6-hydroxydopamine (6-OHDA), and lipopolysaccharide (LPS). Overall, this is the first report on multifunctional neuroprotective effects of sesquiterpenoid-enriched I. britannica flowers extract, which supports its potential pharmaceutical/nutraceutical application in neurodegenerative diseases.
Assuntos
Antioxidantes/farmacologia , Flores/química , Inula/química , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Sesquiterpenos/farmacologia , Antioxidantes/química , Antioxidantes/isolamento & purificação , Relação Dose-Resposta a Droga , Humanos , Inflamação/tratamento farmacológico , Estrutura Molecular , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
Withania somnifera (L.) Dunal (Solanaceae) has been used as a traditional Rasayana herb for a long time. Traditional uses of this plant indicate its ameliorative properties against a plethora of human medical conditions, viz. hypertension, stress, diabetes, asthma, cancer etc. This review presents a comprehensive summary of the geographical distribution, traditional use, phytochemistry, and pharmacological activities of W. somnifera and its active constituents. In addition, it presents a detailed account of its presence as an active constituent in many commercial preparations with curative properties and health benefits. Clinical studies and toxicological considerations of its extracts and constituents are also elucidated. Comparative analysis of relevant in-vitro, in-vivo, and clinical investigations indicated potent bioactivity of W. somnifera extracts and phytochemicals as anti-cancer, anti-inflammatory, apoptotic, immunomodulatory, antimicrobial, anti-diabetic, hepatoprotective, hypoglycaemic, hypolipidemic, cardio-protective and spermatogenic agents. W. somnifera was found to be especially active against many neurological and psychological conditions like Parkinson's disease, Alzheimer's disease, Huntington's disease, ischemic stroke, sleep deprivation, amyotrophic lateral sclerosis, attention deficit hyperactivity disorder, bipolar disorder, anxiety, depression, schizophrenia and obsessive-compulsive disorder. The probable mechanism of action that imparts the pharmacological potential has also been explored. However, in-depth studies are needed on the clinical use of W. somnifera against human diseases. Besides, detailed toxicological analysis is also to be performed for its safe and efficacious use in preclinical and clinical studies and as a health-promoting herb.
Assuntos
Etnofarmacologia , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Withania , Animais , Antivirais/isolamento & purificação , Antivirais/farmacologia , COVID-19/virologia , Humanos , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/toxicidade , Segurança do Paciente , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/toxicidade , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Raízes de Plantas , Psicotrópicos/isolamento & purificação , Psicotrópicos/farmacologia , Psicotrópicos/toxicidade , Medição de Risco , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Withania/química , Tratamento Farmacológico da COVID-19RESUMO
Vitis vinifera (grape) contains various compounds with acknowledged phytochemical and pharmacological properties. Among the different parts of the plant, pomace is of particular interest as a winemaking industry by-product. A characterization of the water extract from grape pomace from Montepulciano d'Abruzzo variety (Villamagna doc) was conducted, and the bioactive phenolic compounds were quantified through HPLC-DAD-MS analysis. HypoE22, a hypothalamic cell line, was challenged with an oxidative stimulus and exposed to different concentrations (1 µg/mL-1 mg/mL) of the pomace extract for 24, 48, and 72 h. In the same conditions, cells were exposed to the sole catechin, in a concentration range (5-500 ng/mL) consistent with the catechin level in the extract. Cell proliferation was investigated by MTT assay, dopamine release through HPLC-EC method, PGE2 amount by an ELISA kit, and expressions of neurotrophin brain-derived neurotrophic factor (BDNF) and of cyclooxygenase-2 (COX-2) by RT-PCR. The extract reverted the cytotoxicity exerted by the oxidative stimulus at all the experimental times in a dose-dependent manner, whereas the catechin was able to revert the oxidative stress-induced depletion of dopamine 48 h and 72 h after the stimulus. The extract and the catechin were also effective in preventing the downregulation of BDNF and the concomitant upregulation of COX-2 gene expression. In accordance, PGE2 release was augmented by the oxidative stress conditions and reverted by the administration of the water extract from grace pomace and catechin, which were equally effective. These results suggest that the neuroprotection induced by the extract could be ascribed, albeit partially, to its catechin content.
Assuntos
Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Fenóis/farmacologia , Vitis/química , Animais , Artemia/efeitos dos fármacos , Linhagem Celular , Daphnia/efeitos dos fármacos , Humanos , Hipotálamo/citologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Neuroproteção/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fenóis/química , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , RatosRESUMO
Three undescribed hydroxycinnamic acid amide dimers 1-3 were isolated and identified from an extract of Goji berry. Their molecular structures were elucidated based on NMR, MS, and IR spectra analysis. Compounds 1-3 were hydroxycinnamic acid amide dimers, which possess a cyclic butane moiety formed by head-to-head connection. These compounds at 25â µM showed the disaggregation potency on the copper-mediated Aß1-42 aggregation ranging from 27.3±3.2 to 31.0±2.9 %. This study provides new information on the antiaging traditional usage of goji berry.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Amidas/farmacologia , Ácidos Cumáricos/farmacologia , Lycium/química , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Doença de Alzheimer/metabolismo , Amidas/química , Amidas/isolamento & purificação , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ácidos Cumáricos/química , Ácidos Cumáricos/isolamento & purificação , Relação Dose-Resposta a Droga , Humanos , Conformação Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Agregados Proteicos/efeitos dos fármacosRESUMO
Senecio graciliflorus DC root extract was studied for secondary metabolite composition following the bioactivity-guided isolation technique. The ethyl acetate extract of Senecio graciliflorus root yielded nine chemical constituents: 3,4-di-tert-butyl toluene, stigmasterol, ß-sitosterol, 2ß-(angeloyloxy)furanoeremophilane, gallic acid, 2ß-{[(Z)-2-hydroxymethylbut-2-enoyl]oxy}furanoeremophilane, 1-hydroxypentan-2-yl-4-methylbenzoate, sarcinic acid, and sitosterol 3-O-ß-D-glucopyranoside. The structures of the chemical constituents were elucidated on the basis of spectral data analysis in the light of literature. All the compounds are being reported for the first time from this plant. The isolated constituents were screened for neuroprotective effects against corticosterone-induced impairment in neuroblastoma cell lines (SH-SY5S cells). The viability of SH-SY5S cells was determined using MTT assay. Among various isolated compounds, three natural products (sarcinic acid, gallic acid, and ß-sitosterol) displayed robust neurotropic activity. The compounds increased neuronal cell survival in differentiated neuroblastoma cells (SH-SY5Y) from high-dose corticosterone (400 µM)-induced cell death. All the three constituents showed maximum AKT/ERK pathway activation at 20 µM concentration. The studies are aimed to explore small molecules for treating neurodegeneration underlying various neurological disorders to restore neuronal cell plasticity.
Assuntos
Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Senécio/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Corticosterona , Humanos , Neuroblastoma/patologia , Fármacos Neuroprotetores/isolamento & purificação , Raízes de Plantas , Metabolismo Secundário , Senécio/metabolismoRESUMO
Ergosta-7,9(11),22-trien-3ß-ol (EK100) was isolated from the Taiwan-specific medicinal fungus Antrodia camphorata, which is known for its health-promotion and anti-aging effects in folk medicine. Alzheimer's disease (AD) is a major aging-associated disease. We investigated the efficacy and potential mechanism of ergosta-7,9(11),22-trien-3ß-ol for AD symptoms. Drosophila with the pan-neuronal overexpression of human amyloid-ß (Aß) was used as the AD model. We compared the life span, motor function, learning, memory, oxidative stress, and biomarkers of microglia activation and inflammation of the ergosta-7,9(11),22-trien-3ß-ol-treated group to those of the untreated control. Ergosta-7,9(11),22-trien-3ß-ol treatment effectively improved the life span, motor function, learning, and memory of the AD model compared to the untreated control. Biomarkers of microglia activation and inflammation were reduced, while the ubiquitous lipid peroxidation, catalase activity, and superoxide dismutase activity remained unchanged. In conclusion, ergosta-7,9(11),22-trien-3ß-ol rescues AD deficits by modulating microglia activation but not oxidative stress.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Drosophila , Humanos , Microglia/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Polyporales/químicaRESUMO
The mold Monascus has been used as a natural food coloring agent and food additive for more than 1000 years in Asian countries. In Chinese herbology, it was also used for easing digestion and antiseptic effects. Through a thorough investigation of a citrinin-free strain: M. purpureus BCRC 38110, four azaphilones, three benzenoids, one benzofuranone, one 5',6'-dihydrospiro[isochromane-1,2'-pyran]-4'(3'H)-one derivative, two steroids, and six tetralones have been successfully identified. Among them, monapyridine A (1), monatetralones A-E (2-6), and monabenzofuranone (7) were first reported. Their structures were characterized by 1D and 2D NMR, UV, IR, and HRESIMS analyses. With a series of bioactivity screening, monascuspirolide B (14) and ergosterol peroxide (16) exhibited concentration-dependent attenuation of the paclitaxel-induced neurite damage of mouse dorsal root ganglion neurons. The interleukin (IL)-1ß-induced release of inflammatory cytokines IL-8 and tumor necrosis factor (TNF)-α in human chondrosarcoma cells was inhibited by monapurpureusone (8) and monascuspirolide B (14). Altogether, M. purpureus BCRC 38110 possessed potentials as natural therapeutics against inflammatory osteoarthritis and paclitaxel-induced neurotoxicity.
Assuntos
Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Monascus/química , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Animais , Anti-Inflamatórios/química , Linhagem Celular Tumoral , Células Cultivadas , Gânglios Espinais/efeitos dos fármacos , Humanos , Interleucina-1beta/imunologia , Interleucina-8/metabolismo , Camundongos , Estrutura Molecular , Monascus/metabolismo , Crescimento Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/química , Osteoartrite/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Parkinson's disease (PD), the typical neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN). However, no therapeutic agent used currently could slow down neuronal cell loss so as to decelerate or halt the progression of PD. Traditional Chinese medicine (TCM) has been utilized to treat the dysfunction of the autonomic nervous system. Wen-Shen-Yang-Gan decoction (WSYGD) has a good effect on the clinical treatment of PD with constipation. However, it is not clear which ingredients and what mechanism are responsible for the therapeutic effect. In this study, the pharmacodynamic study of WSYGD in PD mice was applied. Concurrently, a novel method for the identification of metabolic profiles of WSYGD has been developed. Finally, we found that WSYGD could protect the PD mice induced by rotenone. The underlying mechanism of the protective effect may be related to the reduction of the DA neurons apoptosis via reducing inflammatory reaction. By virtue of UPLC-MS and chemoinformatics method, 35 prototype compounds and 27 metabolites were filtered out and tentatively characterized. In conclusion, this study provides an insight into the metabolism of WSYGD in vivo to enable understanding of the metabolic process and therapeutic mechanism of PD.
Assuntos
Antiparkinsonianos/farmacologia , Metabolômica , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Extratos Vegetais/farmacologia , Administração Oral , Animais , Antiparkinsonianos/isolamento & purificação , Quimioinformática/métodos , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise Multivariada , Fármacos Neuroprotetores/isolamento & purificação , Doença de Parkinson/patologia , Extratos Vegetais/isolamento & purificação , Rotenona , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Espectrometria de Massas em TandemRESUMO
CONTEXT: Panax japonicus is the dried rhizome of Panax japonicus C.A. Mey. (Araliaceae). Saponins from Panax japonicus (SPJ) exhibit anti-inflammatory and antioxidative effects. OBJECTIVE: To explore the neuroprotective effect of SPJ on natural ageing of rat. MATERIALS AND METHODS: Sprague-Dawley (SD) rats 18-month-old were divided into ageing control, ageing treated with SPJ 10 or 30 mg/kg (n = 8). Five-month-old rats were taken as the adult control (n = 8). Rats were fed regular feed or feed containing SPJ for 4 months. Cognitive level was evaluated by Morris water maze (MWM) test. The mechanisms of SPJ's neuroprotection were evaluated by transmission electron microscope, western blot analysis, and immunofluorescence in vivo and in vitro. RESULTS: SPJ attenuated ageing-induced cognitive impairment as indicated by elevated number of times crossing the target platform (from 1.63 to 3.5) and longer time spent in the target platform quadrant (from 1.33 to 1.98). Meanwhile, SPJ improved the morphology of microglia and synapse, and activated M2 microglia polarisation including increased hippocampus levels of CD206 (from 0.98 to 1.47) and YM-1 (from 0.67 to 1.1), and enhanced autophagy-related proteins LC3B (from 0.48 to 0.82), Beclin1 (from 0.32 to 0.51), Atg5 (from 0.22 to 0.89) whereas decreased p62 level (from 0.71 to 0.45) of ageing rats. In vitro study also showed that SPJ regulated the microglial polarisation and autophagy. DISCUSSION AND CONCLUSIONS: SPJ improved cognitive deficits of ageing rats through attenuating microglial inflammation and enhancing microglial autophagy, which could be used to treat neurodegenerative disorders.