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1.
Mol Med Rep ; 30(1)2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38785143

RESUMO

Astragaloside IV (AS­IV) has various pharmacological effects, including antioxidant and immunoregulatory properties, which can improve myasthenia gravis (MG) symptoms. However, the potential mechanism underlying the effects of AS­IV on MG remains to be elucidated. The present study aimed to investigate whether AS­IV has a therapeutic effect on MG and its potential mechanism of action. By subcutaneously immunizing rats with R97­116 peptide, an experimental autoimmune (EA) MG rat model was established. AS­IV (40 or 80 mg/kg/day) treatment was then applied for 28 days after modeling. The results demonstrated that AS­IV significantly ameliorated the weight loss, Lennon score and pathological changes in the gastrocnemius muscle of EAMG rats compared with the model group. Additionally, the levels of acetylcholine receptor antibody (AChR­Ab) were significantly decreased, whereas mitochondrial function [ATPase and cytochrome c (Cyt­C) oxidase activities] and ultrastructure were improved in the AS­IV treated rats. Moreover, the mRNA and protein expression levels of phosphatase and tensin homolog­induced putative kinase 1, Parkin, LC3II and Bcl­2, key signaling molecules for mitophagy and apoptosis, were upregulated, whereas the mRNA and protein expression levels of p62, Cyt­C, Bax, caspase 3 and caspase 9 were downregulated following AS­IV intervention. In conclusion, AS­IV may protect against EAMG in a rat model by modulating mitophagy and apoptosis. These findings indicated the potential mechanism underlying the effects of AS­IV on MG and provided novel insights into treatment strategies for MG.


Assuntos
Apoptose , Mitofagia , Miastenia Gravis Autoimune Experimental , Saponinas , Triterpenos , Animais , Saponinas/farmacologia , Apoptose/efeitos dos fármacos , Triterpenos/farmacologia , Mitofagia/efeitos dos fármacos , Ratos , Miastenia Gravis Autoimune Experimental/tratamento farmacológico , Feminino , Modelos Animais de Doenças , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Receptores Colinérgicos/metabolismo , Ratos Sprague-Dawley , Substâncias Protetoras/farmacologia
2.
J Obstet Gynaecol ; 44(1): 2350761, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38785148

RESUMO

BACKGROUND: Asiaticoside (AS) has been reported to improve the changes induced by high glucose stimulation, and it may have potential therapeutic effects on gestational diabetes mellitus (GDM). This study aims to explore the effect of AS on the cell model of GDM and the action mechanism of the PI3K/AKT pathway. METHODS: The GDM model was established in HTR-8/Svneo cells with a high glucose (HG) medium. After the cytotoxicity assay of AS, cells were divided into the control group, HG group and HG + AS group to conduct control experiment in cells. The cell proliferation and migration were detected by CCK-8 assay and scratch test, respectively. The mRNA levels of PI3K, AKT2, mTORC1, and GLUT4 in PI3K/AKT signalling pathway were measured by RT-PCR, and the protein expressions of these signalling molecules were monitored by western blot. RESULTS: AS showed a promotion effect on the cell proliferation rate of HTR-8/Svneo cells, and 80 µmol/L AS with a treatment time of 48 h had no cytotoxicity. The cell proliferation rate, migration rate, mRNA levels and protein expressions of PI3K, AKT2, mTORC1, and GLUT4 in the HG group were significantly lower than those in the control group, which were significantly increased in the HG + AS group (p < 0.05). CONCLUSIONS: AS can facilitate the cell proliferation and migration in the cell model of GDM, and might play a role in GDM treatment via PI3K/AKT pathway.


Asiaticoside possesses various pharmacological effects and has been reported to show a beneficial effect on the treatment of diabetes mellitus. This research firstly investigated the effect and mechanism of asiaticoside on gestational diabetes mellitus, and found that asiaticoside could facilitate the cell proliferation and migration of HTR-8/Svneo cells treated with high glucose, and affect the signalling molecules of PI3K/AKT pathway. Therefore, asiaticoside may be a novel useful therapeutic drug in the treatment of gestational diabetes mellitus.


Assuntos
Movimento Celular , Proliferação de Células , Diabetes Gestacional , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Triterpenos , Humanos , Diabetes Gestacional/metabolismo , Feminino , Gravidez , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proliferação de Células/efeitos dos fármacos , Triterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Movimento Celular/efeitos dos fármacos , Linhagem Celular , Trofoblastos/efeitos dos fármacos , Trofoblastos/metabolismo , Glucose/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo
3.
Bioorg Med Chem ; 106: 117737, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38718553

RESUMO

Ursolic acid and uvaol are naturally occurring triterpenoids that exhibit a broad spectrum of pharmacological activities, including cytotoxicity. However, a primary challenge in the development of ursane-type pentacyclic triterpenoids for pharmacological use is their poor aqueous solubility, which can impede their effectiveness as therapeutics agents. In this study, we present the facile synthesis of ursolic acid monodesmosides and uvaol bidesmosides, incorporating naturally occurring and water-soluble pentoses and deoxyhexose sugar moieties of opposite d- and l-configurations at the C3 or C3/C28 positions of the ursane core. The twenty synthetic saponins were evaluated in vitro for their cytotoxicity against lung carcinoma (A549) and colorectal adenocarcinoma (DLD-1) cell lines. Notably, all the bidesmosidic uvaol saponins were shown to be cytotoxic as compared to their non-cytotoxic parent triterpenoid. For each series of ursane-type saponins, the most active compounds were 3-O-α-l-arabinopyranosyl ursolic acid (3h) and 3,28-di-O-α-l-rhamnopyranosyl uvaol (4f), showing IC50 values in the low micromolar range against A549 and DLD-1 cancer lines.


Assuntos
Ensaios de Seleção de Medicamentos Antitumorais , Saponinas , Triterpenos , Humanos , Saponinas/farmacologia , Saponinas/síntese química , Saponinas/química , Triterpenos/química , Triterpenos/farmacologia , Triterpenos/síntese química , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Triterpenos Pentacíclicos
4.
Drug Des Devel Ther ; 18: 1673-1694, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38779590

RESUMO

Pristimerin, a natural triterpenoid isolated from the plants of southern snake vine and Maidenwood in the family Weseraceae, is anti-inflammatory, insecticidal, antibacterial, and antiviral substance and has been used for its cardioprotective and antitumor effects and in osteoporosis treatment. These qualities explain Pristimerin's therapeutic effects on different types of tumors and other diseases. More and more studies have shown that pristimerin acts in a wide range of biological activities and has shown great potential in various fields of modern and Chinese medicine. While Pristimerin's wide range of pharmacological effects have been widely studied by others, our comprehensive review suggests that its mechanism of action may be through affecting fundamental cellular events, including blocking the cell cycle, inducing apoptosis and autophagy, and inhibiting cell migration and invasion, or through activating or inhibiting certain key molecules in several cell signaling pathways, including nuclear factor κB (NF-κB), phosphatidylinositol 3-kinase/protein kinase B/mammalian-targeted macromycin (PI3K/Akt/mTOR), mitogen-activated protein kinases (MAPKs), extracellular signal-regulated protein kinase 1/2 (ERK1/2), Jun amino-terminal kinase (JNK1/2/3), reactive oxygen species (ROS), wingless/integrin1 (Wnt)/ß-catenin, and other signaling pathways. This paper reviews the research progress of Pristimerin's pharmacological mechanism of action in recent years to provide a theoretical basis for the molecular targeting therapy and further development and utilization of Pristimerin. It also provides insights into improved treatments and therapies for clinical patients and the need to explore pristimerin as a potential facet of treatment.


Assuntos
Triterpenos Pentacíclicos , Transdução de Sinais , Animais , Humanos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Triterpenos Pentacíclicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Triterpenos/química , Triterpenos/isolamento & purificação
5.
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
6.
Respir Res ; 25(1): 215, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38764025

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung cancer patients with mutated EGFR. However, the efficacy of EGFR-TKIs in wild-type EGFR tumors has been shown to be marginal. Methods that can sensitize EGFR-TKIs to EGFR wild-type NSCLC remain rare. Hence, we determined whether combination treatment can maximize the therapeutic efficacy of EGFR-TKIs. METHODS: We established a focused drug screening system to investigate candidates for overcoming the intrinsic resistance of wild-type EGFR NSCLC to EGFR-TKIs. Molecular docking assays and western blotting were used to identify the binding mode and blocking effect of the candidate compounds. Proliferation assays, analyses of drug interactions, colony formation assays, flow cytometry and nude mice xenograft models were used to determine the effects and investigate the molecular mechanism of the combination treatment. RESULTS: Betulinic acid (BA) is effective at targeting EGFR and synergizes with EGFR-TKIs (gefitinib and osimertinib) preferentially against wild-type EGFR. BA showed inhibitory activity due to its interaction with the ATP-binding pocket of EGFR and dramatically enhanced the suppressive effects of EGFR-TKIs by blocking EGFR and modulating the EGFR-ATK-mTOR axis. Mechanistic studies revealed that the combination strategy activated EGFR-induced autophagic cell death and that the EGFR-AKT-mTOR signaling pathway was essential for completing autophagy and cell cycle arrest. Activation of the mTOR pathway or blockade of autophagy by specific chemical agents markedly attenuated the effect of cell cycle arrest. In vivo administration of the combination treatment caused marked tumor regression in the A549 xenografts. CONCLUSIONS: BA is a potential wild-type EGFR inhibitor that plays a critical role in sensitizing EGFR-TKI activity. BA combined with an EGFR-TKI effectively suppressed the proliferation and survival of intrinsically resistant lung cancer cells via the inhibition of EGFR as well as the induction of autophagy-related cell death, indicating that BA combined with an EGFR-TKI may be a potential therapeutic strategy for overcoming the primary resistance of wild-type EGFR-positive lung cancers.


Assuntos
Autofagia , Ácido Betulínico , Carcinoma Pulmonar de Células não Pequenas , Sinergismo Farmacológico , Receptores ErbB , Neoplasias Pulmonares , Camundongos Nus , Triterpenos Pentacíclicos , Inibidores de Proteínas Quinases , Transdução de Sinais , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inibidores , Humanos , Animais , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Camundongos , Autofagia/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Triterpenos/farmacologia , Gefitinibe/farmacologia , Células A549 , Compostos de Anilina/farmacologia , Acrilamidas/farmacologia , Simulação de Acoplamento Molecular , Antineoplásicos/farmacologia , Indóis , Pirimidinas
7.
Carbohydr Polym ; 338: 122196, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38763723

RESUMO

Triple negative breast cancer (TNBC) represents the most aggressive and heterogenous disease, and combination therapy holds promising potential. Here, an enzyme-responsive polymeric prodrug with self-assembly properties was synthesized for targeted co-delivery of paclitaxel (PTX) and ursolic acid (UA). Hyaluronic acid (HA) was conjugated with UA, yielding an amphiphilic prodrug with 13.85 mol% UA and a CMC of 32.3 µg/mL. The HA-UA conjugate exhibited ∼14 % and 47 % hydrolysis at pH 7.4 and in tumor cell lysate. HA-UA/PTX NPs exhibited a spherical structure with 173 nm particle size, and 0.15 PDI. The nanoparticles showed high drug loading (11.58 %) and entrapment efficiency (76.87 %) of PTX. Release experiments revealed accelerated drug release (∼78 %) in the presence of hyaluronidase enzyme. Cellular uptake in MDA-MB-231 cells showed enhanced uptake of HA-UA/PTX NPs through CD44 receptor-mediated endocytosis. In vitro, HA-UA/PTX NPs exhibited higher cytotoxicity, apoptosis, and mitochondrial depolarization compared to PTX alone. In vivo, HA-UA/PTX NPs demonstrated improved pharmacokinetic properties, with 2.18, 2.40, and 2.35-fold higher AUC, t1/2, and MRT compared to free PTX. Notably, HA-UA/PTX NPs exhibited superior antitumor efficacy with a 90 % tumor inhibition rate in 4T1 tumor model and low systemic toxicity, showcasing their significant potential as carriers for TNBC combination therapy.


Assuntos
Ácido Hialurônico , Nanopartículas , Paclitaxel , Neoplasias de Mama Triplo Negativas , Triterpenos , Ácido Ursólico , Triterpenos/química , Triterpenos/farmacologia , Ácido Hialurônico/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Humanos , Nanopartículas/química , Animais , Feminino , Paclitaxel/farmacologia , Paclitaxel/química , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Apoptose/efeitos dos fármacos , Camundongos , Portadores de Fármacos/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Camundongos Endogâmicos BALB C , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/química
8.
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
9.
Vet Res ; 55(1): 67, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38783392

RESUMO

Porcine reproductive and respiratory syndrome (PRRS), caused by the PRRS virus (PRRSV), has caused substantial economic losses to the global swine industry due to the lack of effective commercial vaccines and drugs. There is an urgent need to develop alternative strategies for PRRS prevention and control, such as antiviral drugs. In this study, we identified ursonic acid (UNA), a natural pentacyclic triterpenoid from medicinal herbs, as a novel drug with anti-PRRSV activity in vitro. Mechanistically, a time-of-addition assay revealed that UNA inhibited PRRSV replication when it was added before, at the same time as, and after PRRSV infection was induced. Compound target prediction and molecular docking analysis suggested that UNA interacts with the active pocket of PTPN1, which was further confirmed by a target protein interference assay and phosphatase activity assay. Furthermore, UNA inhibited PRRSV replication by targeting PTPN1, which inhibited IFN-ß production. In addition, UNA displayed antiviral activity against porcine epidemic diarrhoea virus (PEDV) and Seneca virus A (SVA) replication in vitro. These findings will be helpful for developing novel prophylactic and therapeutic agents against PRRS and other swine virus infections.


Assuntos
Antivirais , Imunidade Inata , Vírus da Síndrome Respiratória e Reprodutiva Suína , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Triterpenos , Replicação Viral , Animais , Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Antivirais/farmacologia , Suínos , Triterpenos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Plantas Medicinais/química , Síndrome Respiratória e Reprodutiva Suína/imunologia , Síndrome Respiratória e Reprodutiva Suína/virologia
10.
J Transl Med ; 22(1): 488, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773576

RESUMO

Ulcerative colitis (UC) is an idiopathic, chronic inflammatory condition of the colon, characterized by repeated attacks, a lack of effective treatment options, and significant physical and mental health complications for patients. The endoplasmic reticulum (ER) is a vital intracellular organelle in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is induced when the body is exposed to adverse external stimuli. Numerous studies have shown that ERS-induced apoptosis plays a vital role in the pathogenesis of UC. Mogroside V (MV), an active ingredient of Monk fruit, has demonstrated excellent anti-inflammatory and antioxidant effects. In this study, we investigated the therapeutic effects of MV on dextran sulfate sodium (DSS)-induced UC and its potential mechanisms based on ERS. The results showed that MV exerted a protective effect against DSS-induced UC in mice as reflected by reduced DAI scores, increased colon length, reduced histological scores of the colon, and levels of pro-inflammatory cytokines, as well as decreased intestinal permeability. In addition, the expression of ERS pathway including BIP, PERK, eIF2α, ATF4, CHOP, as well as the apoptosis-related protein including Caspase-12, Bcl-2 and Bax, was found to be elevated in UC. However, MV treatment significantly inhibited the UC and reversed the expression of inflammation signaling pathway including ERS and ERS-induced apoptosis. Additionally, the addition of tunicamycin (Tm), an ERS activator, significantly weakened the therapeutic effect of MV on UC in mice. These findings suggest that MV may be a therapeutic agent for the treatment of DSS-induced UC by inhibiting the activation of the ERS-apoptosis pathway, and may provide a novel avenue for the treatment of UC.


Assuntos
Apoptose , Colite Ulcerativa , Sulfato de Dextrana , Estresse do Retículo Endoplasmático , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Apoptose/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Colo/patologia , Colo/efeitos dos fármacos , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Camundongos , Citocinas/metabolismo , Permeabilidade/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
11.
Int J Biol Macromol ; 268(Pt 1): 131644, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38642691

RESUMO

Diabetes is a chronic metabolic disorder. Diabetes complications can affect many organs and systems in the body. Ganoderma lucidum (G. lucidum) contains various compounds that have been studied for their potential antidiabetic effects, including polysaccharides, triterpenoids (ganoderic acids, ganoderol B), proteoglycans, and G. lucidum extracts. G. lucidum polysaccharides (GLPs) and triterpenoids have been shown to act through distinct mechanisms, such as improving glucose metabolism, modulating the mitogen-activated protein kinase (MAPK) system, inhibiting the nuclear factor-kappa B (NF-κB) pathway, and protecting the pancreatic beta cells. While GLPs exhibit a significant role in controlling diabetic nephropathy and other associated complications. This review states the G. lucidum antidiabetic mechanisms of action and potential biologically active compounds that contribute to diabetes management and associated complications. To make G. lucidum an appropriate replacement for the treatment of diabetes with fewer side effects, more study is required to completely comprehend the number of physiologically active compounds present in it as well as the underlying cellular mechanisms that influence their effects on diabetes.


Assuntos
Diabetes Mellitus , Hipoglicemiantes , Polissacarídeos , Reishi , Triterpenos , Triterpenos/farmacologia , Triterpenos/química , Triterpenos/uso terapêutico , Humanos , Reishi/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/química , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Animais , Polissacarídeos/farmacologia , Polissacarídeos/química , Polissacarídeos/uso terapêutico , Polissacarídeos Fúngicos/farmacologia , Polissacarídeos Fúngicos/química , Polissacarídeos Fúngicos/uso terapêutico
12.
Bioorg Chem ; 147: 107385, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38663255

RESUMO

Chronic liver diseases caused by hepatitis B virus (HBV) are the accepted main cause leading to liver cirrhosis, hepatic fibrosis, and hepatic carcinoma. Sodium taurocholate cotransporting polypeptide (NTCP), a specific membrane receptor of hepatocytes for triggering HBV infection, is a promising target against HBV entry. In this study, pentacyclic triterpenoids (PTs) including glycyrrhetinic acid (GA), oleanolic acid (OA), ursolic acid (UA) and betulinic acid (BA) were modified via molecular hybridization with podophyllotoxin respectively, and resulted in thirty-two novel conjugates. The anti-HBV activities of conjugates were evaluated in HepG2.2.15 cells. The results showed that 66% of the conjugates exhibited lower toxicity to the host cells and had significant inhibitory effects on the two HBV antigens, especially HBsAg. Notably, the compounds BA-PPT1, BA-PPT3, BA-PPT4, and UA-PPT3 not only inhibited the secretion of HBsAg but also suppressed HBV DNA replication. A significant difference in the binding of active conjugates to NTCP compared to the HBV PreS1 antigen was observed by SPR assays. The mechanism of action was found to be the competitive binding of these compounds to the NTCP 157-165 epitopes, blocking HBV entry into host cells. Molecular docking results indicated that BA-PPT3 interacted with the amino acid residues of the target protein mainly through π-cation, hydrogen bond and hydrophobic interaction, suggesting its potential as a promising HBV entry inhibitor targeting the NTCP receptor.


Assuntos
Antivirais , Vírus da Hepatite B , Transportadores de Ânions Orgânicos Dependentes de Sódio , Triterpenos Pentacíclicos , Simportadores , Internalização do Vírus , Humanos , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismo , Simportadores/antagonistas & inibidores , Antivirais/farmacologia , Antivirais/síntese química , Antivirais/química , Internalização do Vírus/efeitos dos fármacos , Células Hep G2 , Triterpenos Pentacíclicos/farmacologia , Triterpenos Pentacíclicos/síntese química , Triterpenos Pentacíclicos/química , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Simulação de Acoplamento Molecular , Triterpenos/farmacologia , Triterpenos/química , Triterpenos/síntese química , Antígenos de Superfície da Hepatite B/metabolismo
13.
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
14.
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
15.
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
16.
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
17.
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
18.
Ecotoxicol Environ Saf ; 276: 116316, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38615640

RESUMO

Aflatoxins B1 (AFB1) a dangerous type of aflatoxin, poses a serious threat to human health. Meanwhile, Taraxasterol, a bioactive compound in dandelion, exhibits strong anti-inflammatory and antioxidant activity. Therefore, the aim of this study was to investigate the impact of AFB1 on the intrinsic and extrinsic pathways of apoptosis, as well as evaluate the protective role of taraxasterol in the TM3 Leydig cell line. Cell viability was evaluated using an MTT assay, measuring the effects of 3.6 µM AFB1 and varying concentrations of taraxasterol. Expression levels of Caspase 3,8, and 9 were analyzed with RT-qPCR, and flow cytometry was used to assess cell cycle progression and apoptotic alterations. The findings of this study demonstrated that exposure to 3.6 µM of AFB1 resulted in an upregulation of Caspase 3 and Caspase 9 expression, indicating an activation of apoptotic pathways in TM3 cells. Additionally, the analysis of apoptosis revealed a significant increase in cellular apoptosis at this AFB1 concentration. However, when TM3 cells were exposed to 5 µM of taraxasterol, a downregulation of Caspase 3 and Caspase 9 expression was observed, suggesting a protective effect against apoptosis. Moreover, the apoptotic rate in TM3 cells was reduced in the presence of 5 µM of taraxasterol. Consequently, this study highlights the potential of taraxasterol as a protective agent against AFB1-induced apoptosis and suggest its potential application in regulating cell survival and apoptosis-related processes. Further investigations are necessary to elucidate the underlying mechanisms and evaluate the clinical implications of taraxasterol in the context of fertility disorders and other conditions associated with AFB1 exposure.


Assuntos
Aflatoxina B1 , Apoptose , Sobrevivência Celular , Células Intersticiais do Testículo , Triterpenos , Aflatoxina B1/toxicidade , Apoptose/efeitos dos fármacos , Células Intersticiais do Testículo/efeitos dos fármacos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Masculino , Triterpenos/farmacologia , Esteróis/farmacologia , Caspase 3/metabolismo , Substâncias Protetoras/farmacologia , Caspase 9/metabolismo
19.
J Ethnopharmacol ; 330: 118225, 2024 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-38670408

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Neuroinflammation is involved in the pathogenesis of depression disorder by activating microglia cells, increasing proinflammatory cytokines, effecting serotonin synthesis and metabolism, and neuronal apoptosis and neurogenesis. Arjunolic acid (ARG) is a triterpenoid derived from the fruits of Akebia trifoliata for treating psychiatric disorders in TCM clinic, which exhibits anti-inflammatory and neuroprotective effects. However, its anti-depressive effect and underlying mechanism are unknown. AIM OF THE STUDY: The aim of this study is to explore the effect of arjunolic acid on depression and its possible mechanisms. METHODS: Intraperitoneal injection of LPS in mice and LPS stimulated-BV2 microglia were utilized to set up in vivo and in vitro models. Behavioral tests, H&E staining and ELISA were employed to evaluate the effect of arjunolic acid on depression. RT-qPCR, immunofluorescence, molecular docking and Western blot were performed to elucidate the molecular mechanisms. RESULTS: Arjunolic acid dramatically ameliorated depressive behavior in LPS-induced mice. The levels of BDNF and 5-HT in the hippocampus of the mice were increased, while the number of iNOS + IBA1+ cells in the brain were decreased and Arg1+IBA1+ positive cells were increased after arjunolic acid treatment. In addition, arjunolic acid promoted the polarization of BV2 microglia from M1 to M2 type. Notably, drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and molecular docking technologies identified SIRT1 as the target of arjunolic acid. Moreover, after SIRT1 inhibition by using EX-527, the effects of arjunolic acid on ameliorating LPS-induced depressive behavior in mice and promoting M2 Microglia polarization were blocked. In addition, arjunolic acid activated AMPK and decreased Notch1 expression, however, inhibition of AMPK, the effect of arjunolic acid on the downregulation of Notch1 expression were weaken. CONCLUSIONS: This study elucidates that arjunolic acid suppressed neuroinflammation through modulating the SIRT1/AMPK/Notch1 signaling pathway. Our study demonstrates that arjunolic acid might serve as a potiential anti-depressant.


Assuntos
Depressão , Lipopolissacarídeos , Microglia , Receptor Notch1 , Transdução de Sinais , Sirtuína 1 , Triterpenos , Animais , Microglia/efeitos dos fármacos , Microglia/metabolismo , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Lipopolissacarídeos/toxicidade , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Camundongos , Masculino , Depressão/tratamento farmacológico , Depressão/induzido quimicamente , Depressão/metabolismo , Receptor Notch1/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Comportamento Animal/efeitos dos fármacos , Linhagem Celular , Simulação de Acoplamento Molecular
20.
Molecules ; 29(8)2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38675611

RESUMO

Obacunone, a natural triterpenoid, is an active component of the herbs Dictamnus dasycarpus Turcz. and Phellodendron amurense Rupr, and an indicator of the herbs' quality. Owing to its multiple health benefits, several studies have investigated the multi-targeting potential action mechanisms of obacunone. To summarize recent developments on the pharmacological actions of obacunone and focus on the underlying molecular mechanisms and signaling networks, we searched PubMed, Europe PMC, Wiley Online Library, Web of Science, Google Scholar, Wanfang Medical Network, and China National Knowledge Infrastructure for articles published prior to March 2024. Existing research indicates obacunone has great potential to become a promising therapeutic option against tumors, fibrotic diseases, bone and cholesterol metabolism diseases, and infections of pathogenic microorganisms, among others. The paper contributes to providing up-to-date references for further research and clinical applications of obacunone.


Assuntos
Compostos Fitoquímicos , Triterpenos , Humanos , Triterpenos/farmacologia , Triterpenos/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Animais , Transdução de Sinais/efeitos dos fármacos , Neoplasias/tratamento farmacológico
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