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1.
BMJ Open Ophthalmol ; 9(1)2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38702178

RESUMO

BACKGROUND: Dry eye disease is the most commonplace multifractional ocular complication, which has already affected millions of people in the world. It is identified by the excessive buildup of reactive oxygen species, leading to substantial corneal epithelial cell demise and ocular surface inflammation attributed to TLR4. In this study, we aimed to identify potential compounds to treat of dry eye syndrome by exploring in silico methods. METHODS: In this research, molecular docking and dynamics simulation tests were used to examine the effects of selected compounds on TLR4 receptor. Compounds were extracted from different databases and were prepared and docked against TLR4 receptor via Autodock Vina. Celastrol, lumacaftor and nilotinib were selected for further molecular dynamics studies for a deeper understanding of molecular systems consisting of protein and ligands by using the Desmond module of the Schrodinger Suite. RESULTS: The docking results revealed that the compounds are having binding affinity in the range of -5.1 to -8.78 based on the binding affinity and three-dimensional interactions celastrol, lumacaftor and nilotinib were further studied for their activity by molecular dynamics. Among the three compounds, celastrol was the most stable based on molecular dynamics trajectory analysis from 100 ns in the catalytic pockets of 2Z63.pdb.pdb. Root mean square deviation of celastrol/2Z63 was in the range of 1.8-4.8 Å. CONCLUSION: In particular, Glu376 of TLR4 receptor is crucial for the identification and binding of lipopolysaccharides (LPS), which are part of Gram-negative bacteria's outer membrane. In our investigation, celastrol binds to Glu376, suggesting that celastrol may prevent the dry eye syndrome by inhibiting LPS's binding to TLR4.


Assuntos
Síndromes do Olho Seco , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Triterpenos Pentacíclicos , Pirimidinas , Receptor 4 Toll-Like , Síndromes do Olho Seco/tratamento farmacológico , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/química , Humanos , Triterpenos Pentacíclicos/farmacologia , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/uso terapêutico , Triterpenos/farmacologia , Triterpenos/química , Simulação por Computador , Ligantes , Aminopiridinas/farmacologia , Aminopiridinas/química , Aminopiridinas/uso terapêutico
2.
Nat Prod Res ; 38(11): 1956-1960, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38739565

RESUMO

Magonia pubescens is a natural species from the Brazilian cerrado biome. Its fruits and seeds are used in the treatment of seborrheic dermatitis, a common inflammatory skin disease. In this work, the known compounds lapachol, stigmasterol, maniladiol and scopoletin were isolated from hexane and dichloromethane extracts of M. pubescens branches. The aqueous extract of this material was fractioned through a liquid-liquid partition and the obtained fractions were analyzed by UHPLC-MS/MS. The results obtained were compared with data from three databases, leading to the putative identification of 51 compounds from different classes, including flavonoids, saponins and triterpenes. The cytotoxicity of aqueous fractions was assayed against breast cancer (MDA-MB-231) and leukemia (THP-1 and K562) cells. The best activity was observed for fraction AE3 against MDA-MB-231 cells (IC50 30.72 µg.mL-1).


Assuntos
Antineoplásicos Fitogênicos , Neoplasias da Mama , Compostos Fitoquímicos , Extratos Vegetais , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Neoplasias da Mama/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Feminino , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Triterpenos/farmacologia , Triterpenos/química , Brasil , Leucemia/tratamento farmacológico , Flavonoides/farmacologia , Flavonoides/química , Células K562 , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas em Tandem , Saponinas/farmacologia , Saponinas/química , Células THP-1 , Estrutura Molecular
3.
Spectrochim Acta A Mol Biomol Spectrosc ; 316: 124384, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38701576

RESUMO

The bioactive compounds Acetyl-11-keto-ß-boswellic acid (AKBA) and 11-keto-ß-boswellic acid (KBA), found in the resin of the Boswellia tree, exhibit anti-inflammatory properties, rendering Boswellia resin an intriguing natural medicinal products. However, the content of boswellic acids varies across different Boswellia species and proper knowledge of its species-dependent nature, as well as alternatives to the resource- and time-intensive HPLC analysis, are lacking. Here we present a comprehensive investigation into the boswellic acid content of seven Boswellia species from ten countries and introduce a novel and non-destructive Near-Infrared spectroscopy method for predicting boswellic acid concentrations in solid resin samples. The HPLC-UV reference analysis revealed AKBA concentrations of up to 7.27 % (w/w) with KBA concentrations reaching up to 1.28 % (w/w). Principal Component Analysis of the HPLC and NIR spectroscopy data unveiled species-specific variations, facilitating differentiation based on boswellic acid content, characteristic chromatograms and NIR spectra. Using the HPLC-UV quantification as reference, we developed a Partial Least Squares regression model based on NIR spectra of the resin samples. This model demonstrated highly satisfactory predictive capabilities for AKBA content, achieving a root mean square error of prediction of 0.74 % (w/w) and an R2val of 0.79 in independent test set validation. Although the model was less effective for predicting KBA content, it still offered valuable estimates. The spectroscopic method introduced in this study provides a cost-effective and solvent-free approach for predicting boswellic acid content, demonstrating the potential for application in non-laboratory settings through the use of miniaturized NIR spectrometers. Consequently, this method aligns well with the principles of green chemistry and addresses the growing demand for alternative analytical techniques.


Assuntos
Boswellia , Análise de Componente Principal , Resinas Vegetais , Espectroscopia de Luz Próxima ao Infravermelho , Triterpenos , Boswellia/química , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Triterpenos/análise , Cromatografia Líquida de Alta Pressão/métodos , Resinas Vegetais/química , Resinas Vegetais/análise , Análise Multivariada , Especificidade da Espécie
4.
CNS Neurosci Ther ; 30(4): e14725, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38615367

RESUMO

OBJECTIVES: Astragaloside IV (AST IV) and ligustrazine (Lig), the main ingredients of Astragali Radix and Chuanxiong Rhizoma respectively, have demonstrated significant benefits in treatment of cerebral ischemia -reperfusion injury (CIRI); however, the mechanisms underlying its benificial effects remain unclear. SUMO-1ylation and deSUMO-2/3ylation of dynamin-related protein 1 (Drp1) results in mitochondrial homeostasis imbalance following CIRI, which subsequently aggravates cell damage. This study investigates the mechanisms by which AST IV combined with Lig protects against CIRI, focusing on the involvement of SUMOylation in mitochondrial dynamics. METHODS: Rats were administrated AST IV and Lig for 7 days, and middle cerebral artery occlusion was established to mimic CIRI. Neural function, cerebral infarction volume, cerebral blood flow, cognitive function, cortical pathological lesions, and mitochondrial morphology were measured. SH-SY5Y cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury. Mitochondrial membrane potential and lactic dehydrogenase (LDH), reactive oxygen species (ROS), and adenosine triphosphate (ATP) levels were assessed with commercial kits. Moreover, co-immunoprecipitation (Co-IP) was used to detect the binding of SUMO1 and SUMO2/3 to Drp1. The protein expressions of Drp1, Fis1, MFF, OPA1, Mfn1, Mfn2, SUMO1, SUMO2/3, SENP1, SENP2, SENP3, SENP5, and SENP6 were measured using western blot. RESULTS: In rats with CIRI, AST IV and Lig improved neurological and cognitive functions, restored CBF, reduced brain infarct volume, and alleviated cortical neuron and mitochondrial damage. Moreover, in SH-SY5Y cells, the combination of AST IV and Lig enhanced cellular viability, decreased release of LDH and ROS, increased ATP content, and improved mitochondrial membrane potential. Furthermore, AST IV combined with Lig reduced the binding of Drp1 with SUMO1, increased the binding of Drp1 with SUMO2/3, suppressed the expressions of Drp1, Fis1, MFF, and SENP3, and increased the expressions of OPA1, Mfn1, Mfn2, SENP1, SENP2, and SENP5. SUMO1 overexpression promoted mitochondrial fission and inhibited mitochondrial fusion, whereas SUMO2/3 overexpression suppressed mitochondrial fission. AST IV combined with Lig could reverse the effects of SUMO1 overexpression while enhancing those of SUMO2/3 overexpression. CONCLUSIONS: This study posits that the combination of AST IV and Lig has the potential to reduce the SUMO-1ylation of Drp1, augment the SUMO-2/3ylation of Drp1, and thereby exert a protective effect against CIRI.


Assuntos
Dinâmica Mitocondrial , Neuroblastoma , Pirazinas , Saponinas , Triterpenos , Humanos , Animais , Ratos , Espécies Reativas de Oxigênio , Trifosfato de Adenosina , Dinaminas , Cisteína Endopeptidases
5.
Eur J Pharmacol ; 973: 176562, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38588767

RESUMO

In recent years, immunosuppressants have shown significant success in the treatment of autoimmune diseases. Therefore, there is an urgent need to develop additional immunosuppressants that offer more options for patients. Toosendanin has been shown to have immunosuppressive activity in vitro as well as effects on autoimmune hepatitis (AIH) in vivo. Toosendanin did not induce apoptosis in activated T-cells and affect the survival rate of naive T-cells. Toosendanin did not affect the expression of CD25 or secretion of IL-2 by activated T-cells, and not affect the expression of IL-4 and INF-γ. Toosendanin did not affect the phosphorylation of STAT5, ERK, AKT, P70S6K. However, toosendanin inhibited proliferation of anti-CD3/anti-CD28 mAbs-activated T-cells with IC50 of (10 ± 2.02) nM. Toosendanin arrested the cell cycle in the G0/G1 phase, significantly inhibited IL-6 and IL-17A secretion, promoted IL-10 expression, and inhibited the P38 MAPK pathway. Finally, toosendanin significantly alleviated ConA-induced AIH in mice. In Summary, toosendanin exhibited immunosuppressive activity in vivo and in vitro. Toosendanin inhibits the proliferation of activated T-cells through the P38 MAPK signalling pathway, significantly suppresses the expression of inflammatory factors, enhances the expression of anti-inflammatory factors, and effectively alleviates ConA-induced AIH in mice, suggesting that toosendanin may be a lead compound for the development of novel immunomodulatory agents with improved efficacy and reduced toxicity.


Assuntos
Proliferação de Células , Medicamentos de Ervas Chinesas , Linfócitos T , Triterpenos , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Proliferação de Células/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Camundongos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Medicamentos de Ervas Chinesas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/imunologia , Hepatite Autoimune/patologia , Citocinas/metabolismo , Imunossupressores/farmacologia , Camundongos Endogâmicos BALB C , Feminino
6.
Eur J Pharmacol ; 973: 176564, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38614383

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease that is characterized by vascular remodeling of the pulmonary artery. Pulmonary vascular remodeling is primarily caused by the excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), which are facilitated by perivascular inflammatory cells including macrophages. Corosolic acid (CRA) is a natural pentacyclic triterpenoid that exerts anti-inflammatory effects. In the present study, the effects of CRA on the viability of macrophages were examined using monocrotaline (MCT)-induced PAH rats and human monocyte-derived macrophages. Although we previously reported that CRA inhibited signal transducer and activator of transcription 3 (STAT3) signaling and ameliorated pulmonary vascular remodeling in PAH, the inhibitory mechanism remains unclear. Therefore, the underlying mechanisms were investigated using PASMCs from idiopathic PAH (IPAH) patients. In MCT-PAH rats, CRA inhibited the accumulation of macrophages around remodeled pulmonary arteries. CRA reduced the viability of human monocyte-derived macrophages. In IPAH-PASMCs, CRA attenuated cell proliferation and migration facilitated by platelet-derived growth factor (PDGF)-BB released from macrophages and PASMCs. CRA also downregulated the expression of PDGF receptor ß and its signaling pathways, STAT3 and nuclear factor-κB (NF-κB). In addition, CRA attenuated the phosphorylation of PDGF receptor ß and STAT3 following the PDGF-BB simulation. The expression and phosphorylation levels of PDGF receptor ß after the PDGF-BB stimulation were reduced by the small interfering RNA knockdown of NF-κB, but not STAT3, in IPAH-PASMCs. In conclusion, CRA attenuated the PDGF-PDGF receptor ß-STAT3 and PDGF-PDGF receptor ß-NF-κB signaling axis in macrophages and PASMCs, and thus, ameliorated pulmonary vascular remodeling in PAH.


Assuntos
Movimento Celular , Proliferação de Células , Macrófagos , Miócitos de Músculo Liso , Fator de Transcrição STAT3 , Transdução de Sinais , Triterpenos , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Animais , Transdução de Sinais/efeitos dos fármacos , Humanos , Fator de Transcrição STAT3/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Ratos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ratos Sprague-Dawley , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Artéria Pulmonar/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Monocrotalina , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/patologia , Becaplermina/farmacologia , Remodelação Vascular/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia
7.
Medicine (Baltimore) ; 103(16): e37846, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38640324

RESUMO

The current study aimed to investigate the potential role of astragaloside IV (AS-IV) in improving cellular lipid deposition and its underlying mechanism. A fatty liver cell model was established by treating hepatoma cells with palmitic acid. AS-IV and SC79 were used for treatment. Oil Red O staining was applied to detect intracellular lipid deposition, and transmission electron microscopy was utilized to assess autophagosome formation. Immunofluorescence double staining was applied to determine microtubule-associated proteins 1A/1B light chain 3 (LC3) expression. Western blot analysis was performed to detect the expression of LC3, prostacyclin, Beclin-1, V-akt murine thymoma viral oncogene homolog (Akt), phosphorylated Akt, mTOR, and phosphorylated mTOR. Oil Red O staining revealed that AS-IV reduced intracellular lipid accumulation. Further, it increased autophagosome synthesis and the expression of autophagy proteins LC3 and Beclin-1 in the cells. It also reduced the phosphorylation levels of Akt and mTOR and the levels of prostacyclin. However, the effects of AS-IV decreased with SC79 treatment. In addition, LC3B + BODIPY493/503 fluorescence double staining showed that AS-IV reduced intracellular lipid deposition levels by enhancing autophagy. AS-IV can reduce lipid aggregation in fatty liver cells, which can be related to enhanced hepatocyte autophagy by inhibiting the Akt/mTOR signaling pathway.


Assuntos
Autofagia , Fígado Gorduroso , Metabolismo dos Lipídeos , Saponinas , Triterpenos , Animais , Humanos , Camundongos , Autofagia/efeitos dos fármacos , Compostos Azo , Proteína Beclina-1/metabolismo , Fígado Gorduroso/tratamento farmacológico , Lipídeos , Prostaglandinas I , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Saponinas/farmacologia , Serina-Treonina Quinases TOR/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Triterpenos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos
8.
Eur J Pharmacol ; 972: 176560, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38604543

RESUMO

Obese asthma is a unique asthma phenotype that decreases sensitivity to inhaled corticosteroids, and currently lacks efficient therapeutic medication. Celastrol, a powerful bioactive substance obtained naturally from the roots of Tripterygium wilfordii, has been reported to possess the potential effect of weight loss in obese individuals. However, its role in the treatment of obese asthma is not fully elucidated. In the present study, diet-induced obesity (DIO) mice were used with or without ovalbumin (OVA) sensitization, the therapeutic effects of celastrol on airway hyperresponsiveness (AHR) and airway inflammation were examined. We found celastrol significantly decreased methacholine-induced AHR in obese asthma, as well as reducing the infiltration of inflammatory cells and goblet cell hyperplasia in the airways. This effect was likely due to the inhibition of M1-type alveolar macrophages (AMs) polarization and the promotion of M2-type macrophage polarization. In vitro, celastrol yielded equivalent outcomes in Lipopolysaccharide (LPS)-treated RAW264.7 macrophage cells, featuring a reduction in the expression of M1 macrophage makers (iNOS, IL-1ß, TNF-α) and heightened M2 macrophage makers (Arg-1, IL-10). Mechanistically, the PI3K/AKT signaling pathway has been implicated in these processes. In conclusion, we demonstrated that celastrol assisted in mitigating various parameters of obese asthma by regulating the balance of M1/M2 AMs polarization.


Assuntos
Asma , Macrófagos Alveolares , Obesidade , Triterpenos Pentacíclicos , Triterpenos , Animais , Asma/tratamento farmacológico , Triterpenos Pentacíclicos/farmacologia , Obesidade/tratamento farmacológico , Obesidade/complicações , Camundongos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Células RAW 264.7 , Inflamação/tratamento farmacológico , Inflamação/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Hipersensibilidade Respiratória/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Camundongos Endogâmicos C57BL , Ovalbumina , Polaridade Celular/efeitos dos fármacos
9.
Neuropharmacology ; 252: 109939, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38570065

RESUMO

To investigate the efficacy of Ursolic acid in alleviating neuropathic pain in rats with spinal nerve ligation (SNL), the SNL rat model was surgically induced. Different concentrations of Ursolic acid and manipulated target mitogen-activated protein kinase 1 (MAPK1) were administered to the SNL rats. Fecal samples were collected from each group of rats for 16S rDNA analysis to examine the impact of gut microbiota. Molecular docking experiments were conducted to assess the binding energy between Ursolic acid and MAPK1. In vivo studies were carried out to evaluate the expression of inflammatory factors and signaling pathways in spinal cord and colon tissues. Ursolic acid was found to have a beneficial effect on pain reduction in rats by increasing plantar withdrawal latency (PWL) and paw withdrawal threshold (PWT). Comparing the Ursolic acid group with the control group revealed notable differences in the distribution of Staphylococcus, Allobaculum, Clostridium, Blautia, Bifidobacterium, and Prevotella species. Network pharmacology analysis identified MAPK1 and intercellular adhesion molecule-1 (ICAM1) as common targets for Ursolic acid, SNL, and neuropathic pain. Binding sites between Ursolic acid and these targets were identified. Additionally, immunofluorescent staining showed a decrease in GFAP and IBA1 intensity in the spinal cord along with an increase in NeuN following Ursolic acid treatment. Overexpression of MAPK1 in SNL rats led to an increase in inflammatory factors and a decrease in PWL and PWT. Furthermore, MAPK1 counteracted the pain-relieving effects of Ursolic acid in SNL rats. Ursolic acid was found to alleviate neuropathic pain in SNL rats by targeting MAPK1 and influencing gut microbiota homeostasis.


Assuntos
Antígenos Nucleares , Microbioma Gastrointestinal , Proteína Quinase 1 Ativada por Mitógeno , Proteínas do Tecido Nervoso , Neuralgia , Ratos Sprague-Dawley , Triterpenos , Ácido Ursólico , Animais , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Triterpenos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Simulação de Acoplamento Molecular , Modelos Animais de Doenças , Nervos Espinhais/efeitos dos fármacos , Analgésicos/farmacologia , Colo/efeitos dos fármacos , Colo/microbiologia , Colo/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo
10.
Molecules ; 29(7)2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38611920

RESUMO

Six new 2α-hydroxy ursane triterpenoids, 3α-cis-p-coumaroyloxy-2α,19α-dihydroxy-12-ursen-28-oic acid (1), 3α-trans-p-coumaroyloxy-2α,19α-dihydroxy-12-ursen-28-oic acid (2), 3α-trans-p-coumaroyloxy-2α-hydroxy-12-ursen-28-oic acid (3), 3ß-trans-p-coumaroyloxy-2α-hydroxy-12,20(30)-ursadien-28-oic acid (4), 3ß-trans-feruloyloxy-2α-hydroxy-12,20(30)-ursadien-28-oic acid (5), and 3α-trans-feruloyloxy-2α-hydroxy-12,20(30)-ursadien-28-oic acid (6), along with eleven known triterpenoids (7-17), were isolated from the leaves of Diospyros digyna. Their chemical structures were elucidated by comprehensive analysis of UV, IR, HRESIMS, and NMR spectra. All the isolated compounds were evaluated for their PTP1B inhibitory activity. 3ß-O-trans-feruloyl-2α-hydroxy-urs-12-en-28-oic acid (13) showed the best inhibition activity with an IC50 value of 10.32 ± 1.21 µM. The molecular docking study found that the binding affinity of compound 13 for PTP1B was comparable to that of oleanolic acid (positive control).


Assuntos
Diospyros , Triterpenos , Simulação de Acoplamento Molecular , Folhas de Planta , Hidroxiácidos , Triterpenos/farmacologia
11.
Int J Mol Sci ; 25(7)2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38612831

RESUMO

Many people around the world suffer from neurodegenerative diseases associated with cognitive impairment. As life expectancy increases, this number is steadily rising. Therefore, it is extremely important to search for new treatment strategies and to discover new substances with potential neuroprotective and/or cognition-enhancing effects. This study focuses on investigating the potential of astragaloside IV (AIV), a triterpenoid saponin with proven acetylcholinesterase (AChE)-inhibiting activity naturally occurring in the root of Astragalus mongholicus, to attenuate memory impairment. Scopolamine (SCOP), an antagonist of muscarinic cholinergic receptors, and lipopolysaccharide (LPS), a trigger of neuroinflammation, were used to impair memory processes in the passive avoidance (PA) test in mice. This memory impairment in SCOP-treated mice was attenuated by prior intraperitoneal (ip) administration of AIV at a dose of 25 mg/kg. The attenuation of memory impairment by LPS was not observed. It can therefore be assumed that AIV does not reverse memory impairment by anti-inflammatory mechanisms, although this needs to be further verified. All doses of AIV tested did not affect baseline locomotor activity in mice. In the post mortem analysis by mass spectrometry of the body tissue of the mice, the highest content of AIV was found in the kidneys, then in the spleen and liver, and the lowest in the brain.


Assuntos
Saponinas , Triterpenos , Humanos , Animais , Camundongos , Acetilcolinesterase , Saponinas/farmacologia , Triterpenos/farmacologia , Transtornos da Memória/tratamento farmacológico , Lipopolissacarídeos/toxicidade
12.
J Nat Prod ; 87(4): 935-947, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38575516

RESUMO

We report on the use of nitric oxide-mediated transcriptional activation (NOMETA) as an innovative means to detect and access new classes of microbial natural products encoded within silent biosynthetic gene clusters. A small library of termite nest- and mangrove-derived fungi and actinomyces was subjected to cultivation profiling using a miniaturized 24-well format approach (MATRIX) in the presence and absence of nitric oxide, with the resulting metabolomes subjected to comparative chemical analysis using UPLC-DAD and GNPS molecular networking. This strategy prompted study of Talaromyces sp. CMB-TN6F and Coccidiodes sp. CMB-TN39F, leading to discovery of the triterpene glycoside pullenvalenes A-D (1-4), featuring an unprecedented triterpene carbon skeleton and rare 6-O-methyl-N-acetyl-d-glucosaminyl glycoside residues. Structure elucidation of 1-4 was achieved by a combination of detailed spectroscopic analysis, chemical degradation, derivatization and synthesis, and biosynthetic considerations.


Assuntos
Aminoglicosídeos , Isópteros , Óxido Nítrico , Triterpenos , Animais , Triterpenos/farmacologia , Triterpenos/química , Triterpenos/metabolismo , Óxido Nítrico/biossíntese , Óxido Nítrico/metabolismo , Estrutura Molecular , Isópteros/microbiologia , Aminoglicosídeos/farmacologia , Austrália , Ativação Transcricional/efeitos dos fármacos , Fungos/metabolismo , Talaromyces/química , Talaromyces/metabolismo , Actinomyces/metabolismo , Actinomyces/efeitos dos fármacos
13.
J Nat Prod ; 87(4): 1036-1043, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38600636

RESUMO

Triterpenoids are a type of specialized metabolites that exhibit a wide range of biological activities. However, the availability of some minor triterpenoids in nature is limited, which has hindered our understanding of their pharmacological potential. To overcome this limitation, heterologous biosynthesis of triterpenoids in yeast has emerged as a promising and time-efficient production platform for obtaining these minor compounds. In this study, we analyzed the transcriptomic data of Enkianthus chinensis to identify one oxidosqualene cyclase (EcOSC) gene and four CYP716s. Through heterologous expression of these genes in yeast, nine natural pentacyclic triterpenoids, including three skeleton products (1-3) produced by one multifunctional OSC and six minor oxidation products (4-9) catalyzed by CYP716s, were obtained. Of note, we discovered that CYP716E60 could oxidize ursane-type and oleanane-type triterpenoids to produce 6ß-OH derivatives, marking the first confirmed C-6ß hydroxylation in an ursuane-type triterpenoid. Compound 9 showed moderate inhibitory activity against NO production and dose-dependently reduced IL-1ß and IL-6 production at the transcriptional and protein levels. Compounds 1, 2, 8, and 9 exhibited moderate hepatoprotective activity with the survival rates of HepG2 cells from 61% to 68% at 10 µM.


Assuntos
Anti-Inflamatórios , Sistema Enzimático do Citocromo P-450 , Transferases Intramoleculares , Triterpenos , Triterpenos/farmacologia , Triterpenos/química , Humanos , Sistema Enzimático do Citocromo P-450/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Estrutura Molecular , Saccharomyces cerevisiae , Hidroxilação , Células Hep G2 , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Substâncias Protetoras/farmacologia , Substâncias Protetoras/química
14.
Behav Brain Res ; 466: 114976, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38599249

RESUMO

Although there are various treatments available for depression, some patients may experience resistance to treatment or encounter adverse effects. Centella asiatica (C. asiatica) is an ancient medicinal herb used in Ayurvedic medicine for its rejuvenating, neuroprotective and psychoactive properties. This study aims to explore the antidepressant-like effects of the major constituents found in C. asiatica, i.e., asiatic acid, asiaticoside, madecassic acid, and madecassoside at three doses (1.25, 2.5, and 5 mg/kg, i.p), on the behavioural and cortisol level of unpredictable chronic stress (UCS) zebrafish model. Based on the findings from the behavioural study, the cortisol levels in the zebrafish body after treatment with the two most effective compounds were measured using enzyme-linked immunosorbent assay (ELISA). Furthermore, a molecular docking study was conducted to predict the inhibitory impact of the triterpenoid compounds on serotonin reuptake. The in vivo results indicate that madecassoside (1.25, 2.5, and 5 mg/kg), asiaticoside and asiatic acid (5 mg/kg) activated locomotor behaviour. Madecassoside at all tested doses and asiaticoside at 2.5 and 5 mg/kg significantly decreased cortisol levels compared to the stressed group, indicating the potential regulation effect of madecassoside and asiaticoside on the hypothalamic-pituitary-adrenal axis overactivity. This study highlights the potential benefits of madecassoside and asiaticoside in alleviating depressive symptoms through their positive effects on behaviour and the hypothalamic-pituitary-adrenal (HPA)- axis in a chronic unpredictable stress zebrafish model. Furthermore, the in silico study provided additional evidence to support these findings. These promising results suggest that C. asiatica may be a valuable and cost-effective therapeutic option for depression, and further research should be conducted to explore its potential benefits.


Assuntos
Antidepressivos , Centella , Simulação de Acoplamento Molecular , Triterpenos Pentacíclicos , Triterpenos , Peixe-Zebra , Animais , Triterpenos/farmacologia , Centella/química , Antidepressivos/farmacologia , Triterpenos Pentacíclicos/farmacologia , Hidrocortisona/metabolismo , Modelos Animais de Doenças , Extratos Vegetais/farmacologia , Extratos Vegetais/administração & dosagem , Depressão/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Biomarcadores/metabolismo , Masculino
15.
BMC Cancer ; 24(1): 472, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38622523

RESUMO

BACKGROUND: Prostate cancer (PCa) is becoming the most common malignancy in men worldwide. We investigated the effect of astragaloside IV combined with PESV on the gut microbiota and metabolite of PCa mice and the process of treating PCa. METHODS: Nude mice were genetically modified to develop tumors characteristic of PCa. The treatment of PCa mice involved the administration of a combination of astragaloside IV and peptides derived from scorpion venom (PESV). Feces were collected for both 16 S rDNA and metabolic analysis. Fecal supernatant was extracted and used for fecal transplantation in PCa mice. Tumor development was observed in both PCa mice and nude mice. Tumor histopathology was examined, and the expression of inflammatory factors and the AGE-RAGE axis in PCa tissues were analyzed. RESULTS: PCa mice treated with Astragaloside IV in combination with PESV showed a significant reduction in tumor volume and weight, and stabilization of gut microbiota and metabolites. At the Genus level, significant differences were observed in Porphyromonas, Corynebacterium, Arthromitus and Blautia, and the differential metabolites were PA16_016_0, Astragaloside+, Vitamin A acid, Nardosinone, a-Nortestoster, D-Pantethine, Hypoxanthine, Pregnenolone, cinnamic acid, Pyridoxa, Cirtruline and Xanthurenate. There was a correlation between gut microbiota and metabolites. After the fecal transplantation, tumor growth was effectively suppressed in the PCa mice. Notably, both the mRNA and protein levels of the receptor for advanced glycation end products (RAGE) were significantly decreased. Furthermore, the expression of inflammatory factors, namely NF-κB, TNF-α, and IL-6, in the tumor tissues was significantly attenuated. Conversely, upregulation of RAGE led to increased inflammation and reversed tumor growth in the mice. CONCLUSION: Astragaloside IV combined with PESV could treat PCa by intervening in gut microbiota composition and metabolite by targeting RAGE.


Assuntos
Microbioma Gastrointestinal , Neoplasias Hepáticas , Neoplasias da Próstata , Saponinas , Triterpenos , Masculino , Humanos , Animais , Camundongos , Camundongos Nus , Receptor para Produtos Finais de Glicação Avançada , Neoplasias da Próstata/tratamento farmacológico , Homeostase
16.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(3): 523-532, 2024 Mar 20.
Artigo em Chinês | MEDLINE | ID: mdl-38597444

RESUMO

OBJECTIVE: To investigate the effect of asiaticoside on blood pressure and relaxation of thoracic aorta in rats and explore the underlying mechanism. METHODS: SD rats treated with 50 and 100 mg/kg asiaticoside by daily gavage for 2 weeks were monitored for systolic blood pressure changes, and histological changes of the thoracic aorta were evaluated using HE staining. In isolated rat endothelium-intact and endothelium-denuded thoracic aorta rings, the effects of asiaticoside on relaxation of the aortic rings were tested at baseline and following norepinephrine (NE)- and KCl-induced constriction. The vascular relaxation effect of asiaticoside was further observed in NE-stimulated endothelium-intact rat aortic rings pretreated with L-nitroarginine methyl ester, indomethacin, zinc protoporphyrin Ⅸ, tetraethyl ammonium chloride, glibenclamide, barium chloride, Iberiotoxin, 4-aminopyridine, or TASK-1-IN-1. The aortic rings were treated with KCl and NE followed by increasing concentrations of CaCl2 to investigate the effect of asiaticoside on vasoconstriction induced by external calcium influx and internal calcium release. RESULTS: Asiaticoside at 50 and 100 mg/kg significantly lowered systolic blood pressure in rats without affecting the thoracic aorta histomorphology. While not obviously affecting resting aortic rings with intact endothelium, asiaticoside at 100 mg/kg induced significant relaxation of the rings constricted by KCl and NE, but its effects differed between endothelium-intact and endothelium-denuded rings. In endothelium-intact aortic rings pretreated with indomethacin, ZnPP Ⅸ, barium chloride, glyburide, TASK-1-IN-1 and 4-aminopyridine, asiaticoside did not produce significant effect on NE-induced vasoconstriction, and tetraethylammonium, Iberiotoxin and L-nitroarginine methyl ester all inhibited the relaxation effect of asiaticoside. In KCland NE-treated rings, asiaticoside obviously inhibited CaCl2-induced vascular contraction. CONCLUSION: Asiaticoside induces thoracic aorta relaxation by mediating high-conductance calcium-activated potassium channel opening, promoting nitric oxide release from endothelial cells and regulating Ca2+ influx and outflow, thereby reducing systolic blood pressure in rats.


Assuntos
Aorta Torácica , Compostos de Bário , Cloretos , Triterpenos , Vasodilatação , Ratos , Animais , Pressão Sanguínea , Células Endoteliais , Cálcio , Cloreto de Cálcio/farmacologia , Nitroarginina/farmacologia , Ratos Sprague-Dawley , 4-Aminopiridina/farmacologia , Indometacina/farmacologia , Ésteres/farmacologia , Endotélio Vascular , Relação Dose-Resposta a Droga
17.
Org Lett ; 26(15): 3054-3059, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38557107

RESUMO

While pentacyclic triterpenoids have a rich history in chemistry and biology, the challenges associated with their asymmetric synthesis contribute to the current reality that medicinal exploration in the area is largely constrained to natural product derivatization. To address this deficiency, a function-oriented synthesis of pentacyclic triterpenoids was pursued. Overall, we report a divergent synthesis of 26-norgermanicol and 26-norlupeol and we have identified a new class of androgen receptor antagonist that is ∼6× more potent than lupeol.


Assuntos
Produtos Biológicos , Triterpenos , Triterpenos Pentacíclicos , Triterpenos/farmacologia , Antagonistas de Receptores de Andrógenos/farmacologia , Produtos Biológicos/farmacologia
18.
Food Chem Toxicol ; 187: 114631, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38570025

RESUMO

Toosendanin (TSN) is the main active compound derived from Melia toosendan Sieb et Zucc with various bioactivities. However, liver injury was observed in TSN limiting its clinical application. Lipid metabolism plays a crucial role in maintaining cellular homeostasis, and its disruption is also essential in TSN-induced hepatotoxicity. This study explored the hepatotoxicity caused by TSN in vitro and in vivo. The lipid droplets were significantly decreased, accompanied by a decrease in fatty acid transporter CD36 and crucial enzymes in the lipogenesis including ACC and FAS after the treatment of TSN. It was suggested that TSN caused lipid metabolism disorder in hepatocytes. TOFA, an allosteric inhibitor of ACC, could partially restore cell survival via blocking malonyl-CoA accumulation. Notably, TSN downregulated the LXRα/Lipin1/SREBP1 signaling pathway. LXRα activation improved cell survival and intracellular neutral lipid levels, while SREBP1 inhibition aggravated the cell damage and caused a further decline in lipid levels. Male Balb/c mice were treated with TSN (5, 10, 20 mg/kg/d) for 7 days. TSN exposure led to serum lipid levels aberrantly decreased. Moreover, the western blotting results showed that LXRα/Lipin1/SREBP1 inhibition contributed to TSN-induced liver injury. In conclusion, TSN caused lipid metabolism disorder in liver via inhibiting LXRα/Lipin1/SREBP1 signaling pathway.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Medicamentos de Ervas Chinesas , Transtornos do Metabolismo dos Lipídeos , Triterpenos , Camundongos , Animais , Masculino , Metabolismo dos Lipídeos , Medicamentos de Ervas Chinesas/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Lipídeos
19.
Org Lett ; 26(15): 3119-3123, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38588021

RESUMO

Six oxidosqualene cyclases (NiOSC1-NiOSC6) from Neoalsomitra integrifoliola were characterized for the biosynthesis of diverse triterpene scaffolds, including tetracyclic and pentacyclic triterpenes from the 2,3-oxidosqualene (1) and oxacyclic triterpenes from the 2,3:22,23-dioxidosqualene (2). NiOSC1 showed high efficiency in the production of naturally rare (20R)-epimers of oxacyclic triterpenes. Mutagenesis results revealed that the NiOSC1-F731G mutant significantly increased the yields of (20R)-epimers compared to the wild type. Homology modeling and molecular docking elucidated the origin of the (20R)-configuration in the epoxide addition step.


Assuntos
Transferases Intramoleculares , Esqualeno/análogos & derivados , Triterpenos , Simulação de Acoplamento Molecular , Triterpenos Pentacíclicos , Transferases Intramoleculares/genética
20.
Carbohydr Polym ; 335: 122079, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38616076

RESUMO

The polysaccharides and triterpenes are important functional components of Ganoderma lucidum, but traditional preparation process of G. lucidum functional components can only realize the preparation of single functional component, which has poor targeting and low efficiency. In this study, the existence state of the functional components of G. lucidum was revealed. Then, the single step extraction process for functional components was established, and the precise structure evaluation of polysaccharide and triterpenes was conducted based on the process. The results showed that preparation time required for this strategy is only one-sixth of the traditional one, and 50 % of raw materials can be saved. Structural analysis of the functional components revealed that triterpenes were mainly Ganoderic acid and Lucidenic acid, and the polysaccharide structure was mainly 1,3-glucan and 1,3,6-glucan. The establishment of single step extraction strategy and the evaluation of the fine structure of functional components improved the efficiency of preparation and result determination, and provided an important basis for the development and utilization of green and low-carbon G. lucidum and even edible fungi resources and human nutritional dietary improvement strategies.


Assuntos
Reishi , Triterpenos , Humanos , Polissacarídeos , Glucanos , China
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