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1.
Molecules ; 26(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203815

RESUMO

In continuation of our search for leads from medicinal plants against protozoal pathogens, we detected antileishmanial activity in polar fractions of a dichloromethane extract from Boswellia serrata resin. 11-keto-ß-boswellic acid (KBA) could be isolated from these fractions and was tested in vitro against Leishmania donovani axenic amastigotes along with five further boswellic acid derivatives. 3-O-acetyl-11-keto-ß-boswellic acid (AKBA) showed the strongest activity with an IC50 value of 0.88 µM against axenic amastigotes but was inactive against intracellular amastigotes in murine macrophages.


Assuntos
Leishmania donovani/efeitos dos fármacos , Triterpenos/química , Triterpenos/farmacologia , Animais , Linhagem Celular , Humanos , Concentração Inibidora 50 , Leishmania donovani/metabolismo , Macrófagos , Camundongos , Extratos Vegetais/química , Ratos , Resinas Vegetais/química , Triterpenos/análise , Triterpenos/metabolismo
2.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206308

RESUMO

Horse chestnut (Aesculus hippocastanum L.)-derived drugs have shown their potential in biomedical applications. The seed of A. hippocastanum contains various kinds of chemical compounds including phenolics, flavonoids, coumarins, and triterpene saponins. Here, we investigated the chemical components in A. hippocastanum L. grown in Uzbekistan, which has not yet been studied in detail. We identified 30 kinds of triterpene saponins in an extract of A. hippocastanum L. Classifying extracted saponins into eight fractions, we next studied the hypoglycemic and the anti-inflammatory activities of escin and its derivatives through in vivo experiments. We came by data indicating the highest (SF-1 and SF-2) and the lowest (SF-5 and SF-8) antidiabetic and anti-inflammatory effects of those eight fractions. These results imply the prospective use of A. hippocastanum L. grown in Uzbekistan in the production of pharmaceutical drugs to treat diabetes and inflammation.


Assuntos
Aesculus/química , Anti-Inflamatórios , Glicosídeos , Hipoglicemiantes , Triterpenos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Feminino , Glicosídeos/química , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Masculino , Ratos , Ratos Wistar , Triterpenos/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Uzbequistão
3.
Molecules ; 26(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203232

RESUMO

Colorectal cancer is one of the life-threatening ailments causing high mortality and morbidity worldwide. Despite the innovation in medical genetics, the prognosis for metastatic colorectal cancer in patients remains unsatisfactory. Recently, lichens have attracted the attention of researchers in the search for targets to fight against cancer. Lichens are considered mines of thousands of metabolites. Researchers have reported that lichen-derived metabolites demonstrated biological effects, such as anticancer, antiviral, anti-inflammatory, antibacterial, analgesic, antipyretic, antiproliferative, and cytotoxic, on various cell lines. However, the exploration of the biological activities of lichens' metabolites is limited. Thus, the main objective of our study was to evaluate the anticancer effect of secondary metabolites isolated from lichen (Usnea barbata 2017-KL-10) on the human colorectal cancer cell line HCT116. In this study, 2OCAA exhibited concentration-dependent anticancer activities by suppressing antiapoptotic genes, such as MCL-1, and inducing apoptotic genes, such as BAX, TP53, and CDKN1A(p21). Moreover, 2OCAA inhibited the migration and invasion of colorectal cancer cells in a concentration-dependent manner. Taken together, these data suggest that 2OCAA is a better therapeutic candidate for colorectal cancer.


Assuntos
Antineoplásicos , Apoptose/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Triterpenos , Usnea/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias Colorretais/metabolismo , Células HCT116 , Humanos , Triterpenos/química , Triterpenos/farmacologia
4.
An Acad Bras Cienc ; 93(3): e20201850, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34287462

RESUMO

This study evaluated the cellular uptake and cytotoxicity of low permeable Ursolic acid (UA) on cancer cells using niosomes composed of span 60 and cholesterol. The results showed that the addition of chitosan increased particle sizes and ζ-potentials. The UA niosomes with chitosan layers had higher cytotoxicity in HeLa cells than without chitosan, however, there was no improvement observed for Huh7it cells. Moreover, chitosan layers improved the cellular uptake, which clathrin-mediated endocytosis may determine the cellular transport of UA niosomes. In conclusion, the addition of chitosan improved cellular uptake and cytotoxicity of UA niosomes in the HeLa cells.


Assuntos
Quitosana , Triterpenos , Quitosana/toxicidade , Células HeLa , Humanos , Lipossomos , Triterpenos/farmacologia
5.
Molecules ; 26(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198892

RESUMO

This study investigated the antioxidant activity DPPH, ABTS, and Folin-Ciocalteu methods of betulin (compound 1) and its derivatives (compounds 2-11). Skin permeability and accumulation associated with compounds 1 and 8 were also examined. Identification of the obtained products (compound 2-11) and betulin isolated from plant material was based on the analysis of 1H- NMR and 13C-NMR spectra. The partition coefficient was calculated to determine the lipophilicity of all compounds. In the next stage, the penetration through pig skin and its accumulation in the skin were evaluated of ethanol vehicles containing compound 8 (at a concentration of 0.226 mmol/dm3), which was characterized by the highest antioxidant activity. For comparison, penetration studies of betulin itself were also carried out. Poor solubility and the bioavailability of pure compounds are major constraints in combination therapy. However, we observed that the ethanol vehicle was an enhancer of skin permeation for both the initial betulin and compound 8. The betulin 8 derivative showed increased permeability through biological membranes compared to the parent betulin. The paper presents the transformation of polycyclic compounds to produce novel derivatives with marked antioxidant activities and as valuable intermediates for the pharmaceutical industry. Moreover, the compounds contained in the vehicles, due to their mechanism of action, can have a beneficial effect on the balance between oxidants and antioxidants in the body, minimizing the effects of oxidative stress. The results of this work may contribute to knowledge regarding vehicles with antioxidant potential. The use of vehicles for this type of research is therefore justified.


Assuntos
Antioxidantes/farmacologia , Pele/química , Triterpenos/farmacologia , Animais , Antioxidantes/química , Antioxidantes/farmacocinética , Disponibilidade Biológica , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Absorção Cutânea , Solubilidade , Suínos , Triterpenos/química , Triterpenos/farmacocinética
6.
Molecules ; 26(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206087

RESUMO

Polyphenolic and Terpenoids are potent natural antiparasitic compounds. This study aimed to identify new drug against Leishmania parasites, leishmaniasis's causal agent. A new in silico analysis was accomplished using molecular docking, with the Autodock vina program, to find the binding affinity of two important phytochemical compounds, Masticadienonic acid and the 3-Methoxycarpachromene, towards the trypanothione reductase as target drugs, responsible for the defense mechanism against oxidative stress and virulence of these parasites. There were exciting and new positive results: the molecular docking results show as elective binding profile for ligands inside the active site of this crucial enzyme. The ADMET study suggests that the 3-Methoxycarpachromene has the highest probability of human intestinal absorption. Through this work, 3-Methoxycarpachromene and Masticadienonic acid are shown to be potentially significant in drug discovery, especially in treating leishmaniasis. Hence, drug development should be completed with promising results.


Assuntos
Leishmania infantum/enzimologia , NADH NADPH Oxirredutases/antagonistas & inibidores , Compostos Fitoquímicos/farmacologia , Triterpenos/farmacologia , Domínio Catalítico/efeitos dos fármacos , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Humanos , Absorção Intestinal , Leishmania infantum/efeitos dos fármacos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacocinética , Proteínas de Protozoários/antagonistas & inibidores , Relação Estrutura-Atividade , Triterpenos/química , Triterpenos/farmacocinética
7.
Folia Biol (Praha) ; 67(1): 37-47, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34273265

RESUMO

Platycodin D is an active component isolated from Chinese herb Platycodonis radix with various pharmacological activities, such as antitussive, expectorant, anti-inflammatory, and analgesic effects. Interestingly, platycodin D also exerts anticancer effects against several types of cancer. However, few studies on the anti-tumour effects of platycodin against urinary bladder cancer have been reported. In this study, we explored the anti-tumour effect of platycodin D against human bladder cancer and its mechanisms in vitro and in vivo. We found that platycodin D had significant anti-proliferative effects on four types of cancer cells, especially the 5637 bladder cancer cell line, and exerted these effects by preventing cell cycle progression from G0/G1 to S phase, down-regulating Ki-67 and cyclin D1 protein expression and up-regulating P21 protein expression. Furthermore, platycodin D inhibited 5637 cell migration by decreasing twist-related protein 1 (Twist1) and matrix metallopeptidase 2 (MMP2) expression and exerted significant tumour-suppressive effects in tumour-bearing nude mice. Platycodin D also increased caspase-9, caspase-8, caspase-3, and p53 expression and decreased Bcl-2 expression in tumour tissues. Taken together, our results provide a theoretical basis for application of platycodin D in treating urinary bladder cancer.


Assuntos
Carcinoma de Células de Transição , Triterpenos , Animais , Apoptose , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Nus , Saponinas , Triterpenos/farmacologia
8.
Phytomedicine ; 88: 153598, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34111615

RESUMO

INTRODUCTION: Depression is one of the leading causes of death worldwide. Lower antioxidant concentrations and increased oxidative stress levels contribute to the development of depression. Effective and tolerable medications are urgently needed. Nrf2 and PRDX2 are promising targets in the treatment of oxidative stress and, therefore, promising for the development of novel antidepressants. Ursolic acid (UA), a natural triterpenoid found in various plants is known to exert neuroprotective and antioxidant effects. Skn-1 (which corresponds to human Nrf2) and prdx2 deficient mutants of the nematode Caenorhabditis elegans are suitable models to study the effect of UA on these targets. Additionally, stress assays are used to mimic stress or depressed state. METHODS: We examined the antioxidant activity of UA in Caenorhabditis elegans wildtype and skn-1- and prdx2-deficient strains by H2DCF-DA and juglone assays as well as osmotic and heat stress assays. Additionally, we analyzed the binding of UA to human PRDX2 and Skn-1 proteins by molecular docking and microscale thermophoresis. RESULTS: UA exerted strong antioxidant activities. Additionally, induction of stress resistance towards osmotic and heat stress was observed. qRT-PCR revealed that UA upregulated the gene expression of skn-1 and prdx2. Molecular docking studies supported these findings. CONCLUSION: Our findings implicate that the strong antioxidant activity of UA may exert anti-depressive effects by its interaction with the Skn-1 transcription factor, which is part of a detoxification network, and the antioxidant PRDX2 protein, which protects the organism from the detrimental effects of radical oxygen species.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Depressão/genética , Estresse Fisiológico/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Antidepressivos/farmacologia , Antioxidantes/farmacologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Simulação de Acoplamento Molecular , Mutação , Estresse Oxidativo/efeitos dos fármacos , Peroxirredoxinas/genética , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/genética , Triterpenos/química
9.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070938

RESUMO

The excessive accumulation of lipids in hepatocytes induces a type of cytotoxicity called hepatic lipotoxicity, which is a fundamental contributor to liver metabolic diseases (such as NAFLD). Magnesium isoglycyrrhizinate (MGIG), a magnesium salt of the stereoisomer of natural glycyrrhizic acid, is widely used as a safe and effective liver protectant. However, the mechanism by which MGIG protects against NAFLD remains unknown. Based on the significant correlation between NAFLD and the reprogramming of liver metabolism, we aimed to explore the beneficial effects of MGIG from a metabolic viewpoint in this paper. We treated HepaRG cells with palmitic acid (PA, a saturated fatty acid of C16:0) to induce lipotoxicity and then evaluated the antagonistic effect of MGIG on lipotoxicity by investigating the cell survival rate, DNA proliferation rate, organelle damage, and endoplasmic reticulum stress (ERS). Metabolomics, lipidomics, and isotope tracing were used to investigate changes in the metabolite profile, lipid profile, and lipid flux in HepaRG cells under different intervention conditions. The results showed that MGIG can indeed protect hepatocytes against PA-induced cytotoxicity and ERS. In response to the metabolic abnormality of lipotoxicity, MGIG curtailed the metabolic activation of lipids induced by PA. The content of total lipids and saturated lipids containing C16:0 chains increased significantly after PA stimulation and then decreased significantly or even returned to normal levels after MGIG intervention. Lipidomic data show that glycerides and glycerophospholipids were the two most affected lipids. For excessive lipid accumulation in hepatocytes, MGIG can downregulate the expression of the metabolic enzymes (GPATs and DAGTs) involved in triglyceride biosynthesis. In conclusion, MGIG has a positive regulatory effect on the metabolic disorders that occur in hepatocytes under lipotoxicity, and the main mechanisms of this effect are in lipid metabolism, including reducing the total lipid content, reducing lipid saturation, inhibiting glyceride and glycerophospholipid metabolism, and downregulating the expression of metabolic enzymes in lipid synthesis.


Assuntos
Hepatócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Ácido Palmítico/antagonistas & inibidores , Substâncias Protetoras/farmacologia , Saponinas/farmacologia , Triterpenos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Regulação da Expressão Gênica , Glicerídeos/classificação , Glicerídeos/metabolismo , Glicerol-3-Fosfato O-Aciltransferase/antagonistas & inibidores , Glicerol-3-Fosfato O-Aciltransferase/genética , Glicerol-3-Fosfato O-Aciltransferase/metabolismo , Glicerofosfolipídeos/classificação , Glicerofosfolipídeos/metabolismo , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Metabolismo dos Lipídeos/genética , Lipidômica , Ácido Palmítico/toxicidade
10.
Molecules ; 26(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068164

RESUMO

Astragaloside IV (AS-IV) is one of the major bio-active ingredients of huang qi which is the dried root of Astragalus membranaceus (a traditional Chinese medicinal plant). The pharmacological effects of AS-IV, including anti-oxidative, anti-cancer, and anti-diabetic effects have been actively studied, however, the effects of AS-IV on liver regeneration have not yet been fully described. Thus, the aim of this study was to explore the effects of AS-IV on regenerating liver after 70% partial hepatectomy (PHx) in rats. Differentially expressed mRNAs, proliferative marker and growth factors were analyzed. AS-IV (10 mg/kg) was administrated orally 2 h before surgery. We found 20 core genes showed effects of AS-IV, many of which were involved with functions related to DNA replication during cell division. AS-IV down-regulates MAPK signaling, PI3/Akt signaling, and cell cycle pathway. Hepatocyte growth factor (HGF) and cyclin D1 expression were also decreased by AS-IV administration. Transforming growth factor ß1 (TGFß1, growth regulation signal) was slightly increased. In short, AS-IV down-regulated proliferative signals and genes related to DNA replication. In conclusion, AS-IV showed anti-proliferative activity in regenerating liver tissue after 70% PHx.


Assuntos
Ciclo Celular , Replicação do DNA , Regulação para Baixo , Hepatectomia , Regeneração Hepática/efeitos dos fármacos , Fígado/citologia , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclina D1/metabolismo , Replicação do DNA/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Fator de Crescimento de Hepatócito/metabolismo , Fígado/efeitos dos fármacos , Fígado/cirurgia , Masculino , Anotação de Sequência Molecular , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Saponinas/química , Análise de Sequência de RNA , Fator de Crescimento Transformador beta1/metabolismo , Triterpenos/química
11.
Molecules ; 26(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062829

RESUMO

Betulinic acid (BA) is a major constituent of Zizyphus seeds that have been long used as therapeutic agents for sleep-related issues in Asia. BA is a pentacyclic triterpenoid. It also possesses various anti-cancer and anti-inflammatory effects. Current commercially available sleep aids typically use GABAergic regulation, for which many studies are being actively conducted. However, few studies have focused on acetylcholine receptors that regulate wakefulness. In this study, we utilized BA as an antagonist of α3ß4 nicotinic acetylcholine receptors (α3ß4 nAChRs) known to regulate rapid-eye-movement (REM) sleep and wakefulness. Effects of BA on α3ß4 nAChRs were concentration-dependent, reversible, voltage-independent, and non-competitive. Site-directed mutagenesis and molecular-docking studies confirmed the binding of BA at the molecular level and showed that the α3 subunit L257 and the ß4 subunit I263 residues affected BA binding. These data demonstrate that BA can bind to a binding site different from the site for the receptor's ligand, acetylcholine (ACh). This suggests that BA may be an effective antagonist that is unaffected by large amounts of ACh released during wakefulness and REM sleep. Based on the above experimental results, BA is likely to be a therapeutically useful sleep aid and sedative.


Assuntos
Acetilcolina/metabolismo , Triterpenos Pentacíclicos/farmacologia , Receptores Nicotínicos/metabolismo , Animais , Sítios de Ligação , Bovinos , Eletrofisiologia , Ligantes , Simulação de Acoplamento Molecular , Mutagênese , Mutação , Oócitos/citologia , Oócitos/metabolismo , Ligação Proteica , Conformação Proteica , Subunidades Proteicas/química , Sementes , Sono , Distúrbios do Início e da Manutenção do Sono/metabolismo , Transcrição Genética , Triterpenos/farmacologia , Xenopus laevis , Ziziphus , Ácido gama-Aminobutírico/metabolismo
12.
Molecules ; 26(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062884

RESUMO

Osteoporosis is a systemic metabolic bone disorder that is caused by an imbalance in the functions of osteoclasts and osteoblasts and is characterized by excessive bone resorption by osteoclasts. Targeting osteoclast differentiation and bone resorption is considered a good fundamental solution for overcoming bone diseases. ß-boswellic acid (ßBA) is a natural compound found in Boswellia serrata, which is an active ingredient with anti-inflammatory, anti-rheumatic, and anti-cancer effects. Here, we explored the anti-resorptive effect of ßBA on osteoclastogenesis. ßBA significantly inhibited the formation of tartrate-resistant acid phosphatase-positive osteoclasts induced by receptor activator of nuclear factor-B ligand (RANKL) and suppressed bone resorption without any cytotoxicity. Interestingly, ßBA significantly inhibited the phosphorylation of IκB, Btk, and PLCγ2 and the degradation of IκB. Additionally, ßBA strongly inhibited the mRNA and protein expression of c-Fos and NFATc1 induced by RANKL and subsequently attenuated the expression of osteoclast marker genes, such as OC-STAMP, DC-STAMP, ß3-integrin, MMP9, ATP6v0d2, and CtsK. These results suggest that ßBA is a potential therapeutic candidate for the treatment of excessive osteoclast-induced bone diseases such as osteoporosis.


Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Reabsorção Óssea , Regulação da Expressão Gênica , Osteoclastos/metabolismo , Fosfolipase C gama/metabolismo , Ligante RANK , Triterpenos/farmacologia , Animais , Boswellia , Diferenciação Celular , Técnicas de Cocultura , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/metabolismo , Fosforilação , Transdução de Sinais
13.
Molecules ; 26(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063700

RESUMO

Momordica charantia is a popular vegetable associated with effective complementary and alternative diabetes management in some parts of the world. However, the molecular mechanism is less commonly investigated. In this study, we investigated the association between a major cucurbitane triterpenoid isolated from M. charantia, 3ß,7ß,25-trihydroxycucurbita-5,23(E)-dien-19-al (THCB) and peroxisome proliferator activated receptor gamma (PPARγ) activation and its related activities using cell culture and molecular biology techniques. In this study, we report on both M. charantia fruit crude extract and THCB in driving the luciferase activity of Peroxisome Proliferator Response Element, associated with PPARγ activation. Other than that, THCB also induced adipocyte differentiation at far less intensity as compared to the full agonist rosiglitazone. In conjunction, THCB treatment on adipocytes also resulted in upregulation of PPAR gamma target genes expression; AP2, adiponectin, LPL and CD34 at a lower magnitude compared to rosiglitazone's induction. THCB also induced glucose uptake into muscle cells and the mechanism is via Glut4 translocation to the cell membrane. In conclusion, THCB acts as one of the many components in M. charantia to induce hypoglycaemic effect by acting as PPARγ ligand and inducing glucose uptake activity in the muscles by means of Glut4 translocation.


Assuntos
Momordica/química , PPAR gama/metabolismo , Triterpenos/química , Células 3T3-L1 , Adipócitos/citologia , Animais , Diferenciação Celular , Membrana Celular/metabolismo , Glucose/metabolismo , Hepatócitos/citologia , Hipoglicemia/tratamento farmacológico , Insulina/química , Ligantes , Camundongos , Células Musculares/citologia , Domínios Proteicos , Rosiglitazona/farmacologia , Triterpenos/farmacologia
14.
Ecotoxicol Environ Saf ; 220: 112393, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34098426

RESUMO

Previous study found that pedunsaponin A (PA) influenced the cytoskeleton of Pomacea canaliculata hemocytes, leading to depolarization and haemocyte destruction and eventually to snail death. In this study, we analysed the changes in protein expression by iTRAQ-mediated proteomics and identified 51 downregulated proteins. Among these, we focused on proteins related to cytoskeletal function and identified neural Wiskott-Aldrich syndrome isoform X1 (PcnWAS). The full-length PcnWAS gene contains 9791 bp and includes an open reading frame of 1401 bp that encodes 735 amino acids with a predicted molecular mass of 49.83 kD. PcnWAS exhibited a relatively distant genetic relationship with known species; the closest homologue is Biomphalaria glabrata (57%). RNA interference (RNAi) was adopted to verify the function of PcnWAS after screening the siRNA sequence with an efficiency of 97%. Interference with the gene expression of PcnWAS did not lead to snail death, but the depolarization level increased, which demonstrated that PcnWAS is an important depolarization-related protein. The results of PA treatment of snails subjected to RNAi proved that interfering with PcnWAS gene expression decreased the molluscicidal activity of PA toward P. canaliculata; snail mortality after RNAi was significantly lower (40%) than that in PA-treated snails without RNAi (54%), while the survival rate and depolarization level in haemocytes were not significant, indicating that PcnWAS is only one of the important target proteins of PA in P. canaliculata. This study lays the foundation for further exploration of the molecular mechanism by which PA kills this harmful snail.


Assuntos
Citoesqueleto/efeitos dos fármacos , Gastrópodes/efeitos dos fármacos , Moluscocidas/farmacologia , Saponinas/farmacologia , Triterpenos/farmacologia , Proteína da Síndrome de Wiskott-Aldrich/metabolismo , Animais , Regulação para Baixo , Gastrópodes/genética , Gastrópodes/metabolismo , Hemócitos/efeitos dos fármacos , Proteômica , Interferência de RNA , Proteína da Síndrome de Wiskott-Aldrich/genética
15.
Molecules ; 26(9)2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34062737

RESUMO

SARS CoV-2 pandemic is still considered a global health disaster, and newly emerged variants keep growing. A number of promising vaccines have been recently developed as a protective measure; however, cost-effective treatments are also of great importance to support this critical situation. Previously, betulinic acid has shown promising antiviral activity against SARS CoV via targeting its main protease. Herein, we investigated the inhibitory potential of this compound together with three other triterpene congeners (i.e., ursolic acid, maslinic acid, and betulin) derived from olive leaves against the viral main protease (Mpro) of the currently widespread SARS CoV-2. Interestingly, betulinic, ursolic, and maslinic acids showed significant inhibitory activity (IC50 = 3.22-14.55 µM), while betulin was far less active (IC50 = 89.67 µM). A comprehensive in-silico analysis (i.e., ensemble docking, molecular dynamic simulation, and binding-free energy calculation) was then performed to describe the binding mode of these compounds with the enzyme catalytic active site and determine the main essential structural features required for their inhibitory activity. Results presented in this communication indicated that this class of compounds could be considered as a promising lead scaffold for developing cost-effective anti-SARS CoV-2 therapeutics.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Proteases/farmacologia , SARS-CoV-2/enzimologia , Triterpenos/farmacologia , Antivirais/química , COVID-19/virologia , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Olea/química , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/farmacologia , Inibidores de Proteases/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , Triterpenos/química
16.
J Org Chem ; 86(11): 7588-7593, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34014670

RESUMO

Compounds 1-3, the rare examples of 9,11-seco euphane or lanostane triterpenoids featuring an enol-hemiacetal functionality, were isolated from Euphorbia stracheyi. Their structures were elucidated by a combination of spectroscopic, computational, chemical, and single-crystal X-ray diffraction means, which enables the structure of previously published euphorol J to be revised as 1. 1-3 showed significant cytotoxicities on the breast cancer cell line MDA-MB-468 with IC50 values in the range of 2.9-3.9 µM.


Assuntos
Euphorbia , Triterpenos , Cristalografia por Raios X , Estrutura Molecular , Esteroides , Triterpenos/farmacologia
17.
Chem Biol Interact ; 344: 109535, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34051208

RESUMO

Imatinib, a specific Bcr-Abl tyrosine kinase inhibitor, is the most commonly used drug in the treatment of chronic myeloid leukemia. However, optimal response is not achieved in up to 33% of patients. Therefore, development of novel therapeutic strategies for chronic myeloid leukemia is critical. Betulinic (1) and ursolic (2) acids are natural pentacyclic triterpenes that exhibit antileukemic activities. In this study, we evaluated the effects of pharmacomodulations at the C-3 position of the triterpene moiety of betulinic and ursolic acids on their activity against K562 leukemia cells. Six new derivatives (1a-2c) were synthesized and evaluated for pro-apoptotic and anti-proliferative effects in mammalian and leukemic cells. 2c derivative containing an amine group at the C-3 position of ursolic acid was the most active against leukemia cells with an IC50 value of 5.2 µM after 48 h of treatment. 2c did not exhibit cytotoxic effects against VERO and HepG2 cells and human lymphocytes, showing a good selectivity index for cancer over normal cells. Induced cell death by apoptosis via caspases 3 and 8, and also caused cell cycle arrest as evidenced by accumulation of cells in the G1 phase and decreased cell population in the G2 phase. Furthermore, co-treatment of 2c with imatinib, the chemotherapy drug most commonly used to treat leukemia, resulted in a synergistic effect. Our findings provide a strong rationale for further investigation of combination therapy using the 2c derivative and imatinib in pre-clinical studies.


Assuntos
Antineoplásicos/farmacologia , Mesilato de Imatinib/farmacologia , Triterpenos/farmacologia , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Triterpenos/síntese química , Células Vero
18.
Nutr Metab Cardiovasc Dis ; 31(6): 1929-1938, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33992512

RESUMO

BACKGROUND AND AIMS: Atherosclerosis is characterized by lipid deposition, oxidative stress, and inflammation in the arterial intima. Ganoderma lucidum triterpenoids (GLTs) and polysaccharides (GLPs) are traditional Chinese medicines with potential cardiovascular benefits. We aimed to comprehensively evaluate the effect of GLTs and GLPs on atherosclerosis and the associated underlying mechanisms in vivo and in vitro. METHODS AND RESULTS: Japanese big-ear white rabbits were randomly divided into three groups of blank, model, and treatment, and the treatment group was fed with GLSO and GLSP (0.3 g/kg body-weight/day) for 4 months. Serum levels of triglyceride (TG), total (TC), and low density lipoprotein cholesterol (LDL-C) in GL treatment group were significantly lower than those in the model group. The area of aortic plaques was significantly reduced in the treatment group. Further, GL administration in oxidized low-density lipoprotein (ox-LDL) stimulated human umbilical vein endothelial cells (HUVECs) reduced the generation of reactive oxygen species (ROS) and malondialdehyde (MDA) by inhibiting the upregulation of the nuclear transcription factor (NF)-κB p65 and the relative receptor LOX-1. In THP-1 cells treated with phorbol myristate acetate, GL inhibited the inflammatory polarization of macrophages (as evidenced by reduced TNF-α levels) via regulation of Notch1 and DLL4 pathways. Ox-LDL-stimulated THP-1 cells treated with GL showed an increase in the apoptosis of foam cells. CONCLUSIONS: GLTs and GLPs attenuated the progression of atherosclerosis by alleviating endothelial dysfunction and inflammatory polarization of macrophages, thus promoting apoptosis of foam cells.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Células Espumosas/efeitos dos fármacos , Placa Aterosclerótica , Polissacarídeos/farmacologia , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Apoptose/efeitos dos fármacos , Aterosclerose/metabolismo , Aterosclerose/patologia , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Feminino , Células Espumosas/metabolismo , Células Espumosas/patologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Polissacarídeos/isolamento & purificação , Coelhos , Espécies Reativas de Oxigênio/metabolismo , Reishi/química , Células THP-1 , Triterpenos/isolamento & purificação
19.
Life Sci ; 278: 119658, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34048809

RESUMO

AIMS: Maslinic acid (MA) is a naturally occurring pentacyclic triterpene known to exert cardioprotective effects. This study aims to investigate the involvement of nuclear factor erythroid 2-related factor 2 (Nrf2) for MA-mediated anti-inflammatory effects in atheroma pathogenesis in vitro, including evaluation of tumor necrosis factor-alpha (TNF-α)-induced monocyte recruitment, oxidized low-density lipoprotein (oxLDL)-induced scavenger receptors expression, and nuclear factor-kappa B (NF-ĸB) activity in human umbilical vein endothelial cells (HUVECS) and human acute monocytic leukemia cell line (THP-1) macrophages. MATERIALS AND METHODS: An in vitro monocyte recruitment model utilizing THP-1 and HUVECs was developed to evaluate TNF-α-induced monocyte adhesion and trans-endothelial migration. To study the role of Nrf2 for MA-mediated anti-inflammatory effects, Nrf2 inhibitor ML385 was used as the pharmacological inhibitor. The expression of Nrf2, monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule 1 (VCAM-1), cluster of differentiation 36 (CD36), and scavenger receptor type A (SR-A) in HUVECs and THP-1 macrophages were investigated using RT-qPCR and Western blotting. The NF-κB activity was determined using NF-κB (p65) Transcription Factor Assay Kit. KEY FINDINGS: The results showed opposing effects of MA on Nrf2 expression in HUVECs and THP-1 macrophages. MA suppressed TNF-α-induced Nrf2 expression in HUVECs, but enhanced its expression in THP-1 macrophages. Combined effects of MA and ML385 suppressed MCP-1, VCAM-1, and SR-A expressions. Intriguingly, at the protein level, ML385 selectively inhibited SR-A but enhanced CD36 expression. Meanwhile, ML385 further enhanced MA-mediated inhibition of NF-κB activity in HUVECs. This effect, however, was not observed in THP-1 macrophages. SIGNIFICANCE: MA attenuated foam cell formation by suppressing VCAM-1, MCP-1, and SR-A expression, as well as NF-κB activity, possibly through Nrf2 inhibition. The involvement of Nrf2 for MA-mediated anti-inflammatory effects however differs between HUVECs and macrophages. Future investigations are warranted for a detailed evaluation of the contributing roles of Nrf2 in foam cells formation.


Assuntos
Anti-Inflamatórios/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Placa Aterosclerótica/metabolismo , Triterpenos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Monócitos/patologia , Fator 2 Relacionado a NF-E2/análise , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/patologia , Células THP-1 , Fator de Necrose Tumoral alfa/análise
20.
Int J Biol Macromol ; 183: 811-817, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-33957203

RESUMO

Inhibition of soluble epoxide hydrolase (sEH) is considered to be an effective treatment for inflammation-related diseases, and small molecules origin from natural products show promising activity against sEH. Two undescribed protostanes, 3ß-hydroxy-25-anhydro-alisol F (1) and 3ß-hydroxy-alisol G (2) were isolated from Alisma orientale and identified as new sEH inhibitors with IC50 values of 10.06 and 30.45 µM, respectively. Potential lead compound 1 was determined as an uncompetitive inhibitor against sEH, which had a Ki value of 5.13 µM. In-depth molecular docking and molecular dynamics simulations revealed that amino acid residue Ser374 plays an important role in the inhibition of 1, which also provides an idea for the development of sEH inhibitors based on protostane-type triterpenoids.


Assuntos
Alisma/química , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Triterpenos/farmacologia , Inibidores Enzimáticos/química , Epóxido Hidrolases/química , Concentração Inibidora 50 , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Farmacocinética , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Conformação Proteica , Triterpenos/química
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