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1.
Mol Carcinog ; 61(1): 111-121, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34727410

RESUMO

Ursolic acid (UA) is a triterpenoid phytochemical with a strong anticancer effect. The metabolic rewiring, epigenetic reprogramming, and chemopreventive effect of UA in prostate cancer (PCa) remain unknown. Herein, we investigated the efficacy of UA in PCa xenograft, and its biological effects on cellular metabolism, DNA methylation, and transcriptomic using multi-omics approaches. The metabolomics was quantified by liquid-chromatography-mass spectrometry (LC-MS) while epigenomic CpG methylation in parallel with transcriptomic gene expression was studied by next-generation sequencing technologies. UA administration attenuated the growth of transplanted human VCaP-Luc cells in immunodeficient mice. UA regulated several cellular metabolites and metabolism-related signaling pathways including S-adenosylmethionine (SAM), methionine, glucose 6-phosphate, CDP-choline, phosphatidylcholine biosynthesis, glycolysis, and nucleotide sugars metabolism. RNA-seq analyses revealed UA regulated several signaling pathways, including CXCR4 signaling, cancer metastasis signaling, and NRF2-mediated oxidative stress response. Epigenetic reprogramming study with DNA Methyl-seq uncovered a list of differentially methylated regions (DMRs) associated with UA treatment. Transcriptome-DNA methylome correlative analysis uncovered a list of genes, of which changes in gene expression correlated with the promoter CpG methylation status. Altogether, our results suggest that UA regulates metabolic rewiring of metabolism including SAM potentially driving epigenetic CpG methylation reprogramming, and transcriptomic signaling resulting in the overall anticancer chemopreventive effect.


Assuntos
Metilação de DNA/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Triterpenos/administração & dosagem , Animais , Linhagem Celular Tumoral , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Regiões Promotoras Genéticas/efeitos dos fármacos , Neoplasias da Próstata/genética , Análise de Sequência de RNA , Triterpenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Life Sci ; 289: 120232, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34919901

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a worldwide health issue primarily due to failure of pancreatic ß-cells to release sufficient insulin. PURPOSE: The present work aimed to assess the antidiabetic potential of arjunolic acid (AA) isolated from Terminalia arjuna in type 2 diabetic rats. STUDY DESIGN: After extraction, isolation and purification, AA was orally administered to type 2 diabetic Sprague Dawley rats to investigate antidiabetic effect of AA. METHOD: T2DM was induced via single intraperitoneal injection of streptozotocin-nicotinamide (STZ-NIC) in adult male rats. After 10 days, fasting and random blood glucose (FBG and RBG), body weight (BW), food and water intake, serum C-peptide, insulin and glycated hemoglobin (HbA1c) was measured to confirm T2DM development. Dose dependent effects of orally administered AA (25 and 50 mg/kg/day) for 4 weeks was investigated by measuring BW variation, fasting and postprandial hyperglycemia, oral glucose tolerance test (OGTT), and levels of serum HbA1c, serum total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), serum and pancreatic C-peptide, insulin, growth differentiation factor 15 (GDF-15), serum and pancreatic inflammatory cytokines. RESULTS: The oral administration of AA in preclinical model of T2DM significantly normalized FBG and RBG, restored BW, controlled polyphagia, polydipsia and glucose tolerance. In addition, AA notably reduced serum HbA1c, TC, TG, LDL with non-significant increase in HDL. On the other hand, significant increase in serum and pancreatic C-peptide and insulin was observed with AA treatment, while serum and pancreatic GDF-15 were non-significantly altered in AA treated diabetic rats. Moreover, AA showed dose dependent reduction in serum and pancreatic proinflammatory cytokines including TNF-α, IL-1ß and IL-6. CONCLUSION: For the first time our findings highlighted AA as a potential candidate in type 2 diabetic conditions.


Assuntos
Glicemia/metabolismo , Citocinas/sangue , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Regulação para Baixo/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inflamação/sangue , Inflamação/tratamento farmacológico , Masculino , Ratos , Ratos Sprague-Dawley , Terminalia/química , Triterpenos/química
3.
Food Chem ; 371: 131187, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34592625

RESUMO

Centella asiatica (Gotu Kola) is a green leafy vegetable rich in phytochemicals mainly including triterpenes and caffeoylquinic acids. Fresh leaves of this plant are consumed in salads and beverages in a variety of cuisines around the world. This is a well-known functional food for its neuroprotective and cognition enhancing properties in traditional societies. HPLC-DAD at lower wavelengths commonly used to identify and quantify major triterpenes of C. asiatica extracts, but associated with few drawbacks. This paper discusses a specific, sensitive and validated method developed based on UHPLC-ESI-MS-MS-MRM tandem mass spectroscopy for targeted quantification of C. asiatica bioactive compounds. The validated method enabled a precise estimation of major triterpenes and chlorogenic acid in C. asiatica in a shorter time. The findings of this study will contribute to the information on chemotype variation of C. asiatica plant grown under unique geographical, environmental and climatic conditions in New Zealand.


Assuntos
Centella , Triterpenos , Cromatografia Líquida de Alta Pressão , Folhas de Planta/química , Espectrometria de Massas em Tandem , Triterpenos/análise
4.
Food Chem ; 372: 131224, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-34624787

RESUMO

Triterpenoids are hypoglycemic substances and flavor components of Momordica charantia L., whether their bitterness correlated with hypoglycemic potential remain unknown. Thus, triterpenoids in M. charantia were isolated by phytochemical methods and identified by spectroscopic analysis. The bitterness levels and hypoglycaemic activity of isolated triterpenoids were evaluated by electronic tongue and hepatic gluconeogenesis assay. Eighteen triterpenoids including two new ones, Momordicoside Y and Z, were identified. Among the six identified bitter triterpenoids, karaviloside III, goyaglycoside C, and momordicoside F2 were bitterer than caffeine (P < 0.05), with caffeine equivalent (CE) values of 289.19, 4.32, and 41.24 mg CE/mg, respectively. Momordicoside Y, charantoside C, momordicoside F1, and momordicoside G could inhibit hepatic gluconeogenesis by 23.9%, 36.2%, 33.4%, 34.4% at 40 µM, respectively. These four compounds could interact with active site of phosphoenolpyruvate carboxykinase in molecular docking simulation. No correlation was observed between hepatic gluconeogenesis inhibitory activity and bitterness of triterpenoids.


Assuntos
Momordica charantia , Triterpenos , Frutas , Gluconeogênese , Glicosídeos , Simulação de Acoplamento Molecular , Extratos Vegetais/farmacologia , Triterpenos/farmacologia
5.
Phytochemistry ; 193: 112985, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34695707

RESUMO

Thirteen previously undescribed lanostane triterpenoids, as well as nine known lanostane triterpenoids, were isolated from the fruiting bodies of Fomitopsis pinicola (Sw.) P. Karst. Their structures and absolute configurations were characterized by extensive analysis of spectroscopic data and single-crystal X-ray diffraction. Nor-pinicolic acids A-F possess unusual C-25-C-27 nor-lanostane skeletons, which were first reported from F. pinicola. Anti-inflammatory assays indicated that pinicopsic acid F and 16α-hydroxy-3-oxolanosta-7,9(11),24-trien-21-oic acid showed moderate inhibitory activities against LPS-induced NO production in RAW 264.7 cells, with IC50 values of 24.5 and 25.7 µM, respectively.


Assuntos
Triterpenos , Anti-Inflamatórios/farmacologia , Coriolaceae , Carpóforos , Estrutura Molecular , Triterpenos/farmacologia
6.
Phytochemistry ; 193: 112988, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34717280

RESUMO

Four undescribed cucurbitacins, designated as petiolaticins A-D, and four known cucurbitacins were isolated from the bark and leaves of Elaeocarpus petiolatus (Jack) Wall. Their chemical structures were elucidated based on detailed analyses of the NMR and MS data. The absolute configuration of petiolaticin A was also determined by X-ray diffraction analysis. Petiolaticin A represents a cucurbitacin derivative incorporating a 3,4-epoxyfuranyl-bearing side chain, while petiolaticin B possesses a furopyranyl unit fused to the tetracyclic cucurbitane core structure. Petiolaticins A, B, and D were evaluated in vitro against a panel of human breast, pancreatic, and colorectal cancer cell lines. Petiolaticin A exhibited the greatest cytotoxicity against the MDA-MB-468, MDA-MB-231, MCF-7, and SW48 cell lines (IC50 7.4, 9.2, 9.3, and 4.6 µM, respectively). Additionally, petiolaticin D, 16α,23α-epoxy-3ß,20ß-dihydroxy-10αH,23ßH-cucurbit-5,24-dien-11-one, and 16α,23α-epoxy-3ß,20ß-dihydroxy-10αH,23ßH-cucurbit-5,24-dien-11-one 3-O-ß-D-glucopyranoside were tested for their ability to inhibit cell entry of a pseudotyped virus bearing the hemagglutinin envelope protein of a highly pathogenic avian influenza virus. Petiolaticin D showed the highest inhibition (44.3%), followed by 16α,23α-epoxy-3ß,20ß-dihydroxy-10αH,23ßH-cucurbit-5,24-dien-11-one (21.0%), and 16α,23α-epoxy-3ß,20ß-dihydroxy-10αH,23ßH-cucurbit-5,24-dien-11-one 3-O-ß-D-glucopyranoside showed limited inhibition (9.0%). These preliminary biological assays have demonstrated that petiolaticins A and D possess anticancer and antiviral properties, respectively, which warrant for further investigations.


Assuntos
Elaeocarpaceae , Triterpenos , Animais , Cucurbitacinas , Estrutura Molecular , Extratos Vegetais , Folhas de Planta , Triterpenos/farmacologia
7.
Phytomedicine ; 94: 153822, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34763313

RESUMO

BACKGROUND: Astragalus and Panax notoginseng are significant traditional Chinese medicines for treating ischemic stroke, with astragaloside IV (AST IV) and Panax notoginseng saponins (PNS) being the major effective compounds, respectively. These compounds can also be used in combination. We have previously shown that AST IV and PNS have an antagonistic effect on cerebral ischemia/reperfusion (I/R) injury, and the combination of these two drugs can elevate this effect; unfortunately, AST IV and PNS cannot easily enter the brain tissues through the blood brain barrier (BBB). Previous studies have confirmed that the combination of borneol with other agents could promote the penetration of the drug components through the BBB. However, it remains unclear whether borneol can promote entry of the active components of AST IV and PNS into the brain tissues and enhance their effect against cerebral ischemia. OBJECTIVE: This study aimed to investigate the effects of a combination of borneol with AST IV and PNS against I/R injury and explore the mechanisms of borneol-promoting penetration of drug components into the BBB based on the drug transport of brain tissues. METHODS: A rat model of focal cerebral I/R injury was established, and drugs, including borneol, AST IV, and PNS, as well as their combinations were intragastrically administered. Subsequently, drug efficacy was assessed, and the condition of AST IV and PNS active components (Rg1, Rb1, R1) delivered into the brain was analyzed. Moreover, BBB permeability was determined, and the expression of related drug transporters and their genes were evaluated. RESULTS: After treatment with borneol, AST IV, PNS, AST Ⅳ+PNS, and borneol+AST Ⅳ+PNS after cerebral I/R, the neurological function deficit scores, cerebral infarct rate, and brain water content markedly decreased. The effects of the three-drug-combination were better than those of the drugs used alone and those of AST Ⅳ+PNS. Moreover, after I/R in rats, AST IV and the components of PNS (Rg1, Rb1, R1) were mainly found in the cerebral cortex and in the cerebellum, respectively, when used alone. Borneol combined with AST IV and PNS increased the contents of AST IV, Rb1, Rg1, and R1 in the cerebral cortex and in the cerebellum, thus, promoting the enrichment of active components to the cerebral cortex, especially to the affected side. In addition, following I/R, diffuse distribution of lanthanum particles in the basement membrane, intercellular and intracellular locations of rat brain tissues indicated BBB destruction and increase in permeability, which were alleviated in each drug group. The effects of borneol combined with AST IV and PNS were stronger than those of the drug single-used and those of the AST IV+PNS group. Finally, the expression of effluent transporters (ET) and their genes, including P-glycoprotein (P-gp), multidrug resistance protein (MRP)-1, MRP-2, MRP-4, and MRP-5 in brain tissues, strikingly increased after I/R. Borneol remarkedly down-regulated the protein expression of P-gp, MRP-2, and MRP-4 in the brain, whereas PNS down-regulated MRP-4 and MRP-5 protein expression. AST IV, AST IV+PNS, and bornoel+AST IV+PNS effectively decreased the expression of P-gp, MRP-2, MRP-4, and MRP-5 proteins. The effects of the three-drug combination were significantly greater than those of the drug single-used and AST IV+PNS groups. The expression of each ET gene manifested corresponding results. Meanwhile, PNS, AST IV+PNS, and bornoel+AST IV+PNS significantly inhibited the down-regulation of the uptake transporter organic anion transporting polypeptide (OATP)-2 expression, and the effect of bornoel+AST IV+PNS was stronger than that of other groups. CONCLUSION: After I/R, the brain tissues were injured, BBB permeability increased, expression of critical ET and their genes were markedly up-regulated, and the main uptake transporters were down-regulated. We propose that the combination of borneol, AST IV and PNS could enhance the effect against cerebral I/R injury and protect BBB integrity. The potential mechanism might be the delivery of AST IV and active components of PNS to the brain tissues after treatment in combination with borneol, which could be effectively promoted by down-regulating the expression of ETs and up-regulating the expression of uptake transporters in the brain tissues. This study was the first to demonstrate that borneol combined with AST IV+PNS enhanced the effect against cerebral I/R injury through promoting the entry of AST and PNS active components to the brain tissues. Thus, this study proposes an instructive role in developing effective active ingredients combination of Chinese medicine with clear ingredients and synergistic effects in terms of the characteristic of borneol.


Assuntos
Isquemia Encefálica , Panax notoginseng , Traumatismo por Reperfusão , Saponinas , Animais , Encéfalo , Isquemia Encefálica/tratamento farmacológico , Canfanos , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Saponinas/farmacologia , Triterpenos
8.
J Pharm Biomed Anal ; 208: 114461, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-34775190

RESUMO

Liver toxicity induced by Triptolide (TP) has limited its clinical application on rheumatoid arthritis (RA). Saponins have been proved as an efficacious remedy to mitigate hepatotoxicity. However, the mechanism of reducing hepatotoxicity by saponins intervention remains incompletely characterized. Tryptophan (Trp) metabolites activate transcriptional regulators to mediate host detoxification responses. Our study aimed to investigate whether Clematichinenoside AR (C-AR) could attenuate TP-induced liver damage by regulating Trp metabolism. We used targeted metabolomics to quantify Trp metabolites in the serum and liver samples of collagen-induced arthritis rats treated by TP. Multiple comparison analyses helped the evaluation of promising biomarkers. The pronounced changed levels of Trp, indole acetic acid, and indole-3-carboxaldehyde in the serum and indole acetic acid, indole, and tryptamine in the liver are relevant to TP-induced liver injury. Intervention with C-AR could relieve TP-induced hepatotoxicity evidenced by ameliorative serum parameters and hepatic histology. In addition, C-AR regulated the levels of these indoles biomarker candidates to normal. Therapeutic modulation with natural compounds might be a useful clinical strategy to ameliorate toxicity induced by TP. Deciphering Trp metabolism will facilitate a better understanding of the pathogenesis of diseases and drug responding.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Diterpenos , Fenantrenos , Saponinas , Animais , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Diterpenos/toxicidade , Compostos de Epóxi/toxicidade , Fígado , Fenantrenos/toxicidade , Ratos , Triterpenos , Triptofano
9.
Phytomedicine ; 94: 153814, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34798522

RESUMO

BACKGROUND: Bryodulcosigenin (BDG) a cucurbitane-type triterpenoid has been isolated from the roots of Bryonia dioca and possesses marked anti-inflammatory effects, although its beneficial effect against intestinal disorders remains unclear. PURPOSE: To explore the underlying mechanism of BDG on the dysbiosis of chronic ulcerative colitis (UC) and its associated side-effects on lung tissues. METHODS: A chronic UC model was established using 2.5% dextran sulfate sodium (DSS) in mice treated for 64 days and diagnostic assessments, western blot analysis and quantitative real time-PCR were employed to determine the protective mechanism of BDG. RESULTS: Oral administration of BDG (10 mg/kg/day) significantly improved colon length, disease activity index, and alleviated colonic histopathological damage in the DSS-induced colitis  mice. BDG not only reversed the TNF-α-induced degradation of tight junction proteins (occludin and ZO-1) but also suppressed the elevated apoptosis seen in intestinal epithelial cells (NCM460). In addition, BDG significantly attenuated damage in alveolar epithelial cells (MLE-12) co-cultured with NCM460 cells under inflammatory conditions. Furthermore, BDG in vivo significantly prevented the symptoms of respiratory disorders and repressed alveolar inflammation by regulating DSS-induced chronic colitis in mice. CONCLUSION: BDG effectively inhibited the apoptosis of intestinal epithelial cells and suppressed the activation of the NLRP3 inflammasome which resulted in the restoration of the intestinal barrier. Therefore, the enhanced integrity of intestinal epithelial cells produced by BDG intervention contributed to its anti-colitis effects, indicating its great potential as an inhibitor of UC and lung injury. Therefore, restoring intestinal integrity may represent a promising strategy in the prevention of pulmonary disease.


Assuntos
Colite Ulcerativa , Colite , Triterpenos , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colo , Sulfato de Dextrana , Modelos Animais de Doenças , Glicosídeos , Mucosa Intestinal , Camundongos , Camundongos Endogâmicos C57BL , Triterpenos/farmacologia
10.
J Healthc Eng ; 2021: 3433615, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34900182

RESUMO

Effective drug intervention is the most important method to improve the prognosis, improve the quality of life, and prolong the life of patients with heart failure. This study aimed to explore the protective effect of astragaloside IV on myocardial cell injury induced by oxidized low-density lipoprotein (OxLDL) and its regulatory mechanism on the increase of brain natriuretic peptide (BNP) caused by myocardial cell injury. The model of myocardial cell injury, protection, and histone deacetylase (HDAC) inhibition in HL-1 mice was established by OxLDL treatment, astragaloside IV intervention, and UF010 coincubation. The effects of OxLDL and astragaloside IV on apoptosis were detected by flow cytometry. The expression level of BNP mRNA and protein in cells was investigated by real-time fluorescence quantification, western blot, and enzyme-linked immunosorbent assay. HDAC activity in nucleus was calibrated by fluorescence absorption intensity. Enzyme-linked immunosorbent assay (ELISA) was applied to test eNOS level in myocardial cells. OxLDL significantly promoted apoptosis, upregulated BNP mRNA, increased BNP protein level inside and outside cells, and decreased eNOS level. Compared with OxLDL treatment group, apoptosis decreased, BNP mRNA expression level decreased, BNP protein concentration decreased, and eNOS level increased significantly combined with low and high concentration astragaloside IV treatment group. HDAC activity significantly increased in OxLDL treatment group and significantly decreased after combined incubation with low and high concentrations of astragaloside IV. Inhibition of HDAC significantly increased eNOS level and decreased BNP protein level. In conclusion, astragaloside IV can reverse the low level of eNOS caused by OxLDL by regulating HDAC activity to protect myocardial cells from oxide damage, which is manifested by the decrease of BNP concentration.


Assuntos
Histona Desacetilases , Peptídeo Natriurético Encefálico , Animais , Lipoproteínas LDL , Camundongos , Qualidade de Vida , Saponinas , Triterpenos
11.
Zhongguo Zhong Yao Za Zhi ; 46(23): 6114-6129, 2021 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-34951239

RESUMO

At present, 141 compounds have been isolated from Picrorhiza scrophulariiflora and P. kurroa of the Scrophulariaceae plants, including 46 iridoid glycosides, 29 tetracyclic triterpenoids, 25 phenylpropanoids, and 11 phenylethanoid glycosides. Pharmacological studies have demonstrated that they have liver-, heart-, brain-, kidney-, and nerve cells-protecting effects as well as anti-tumor, anti-inflammatory, anti-bacterial, anti-asthma, anti-diabetic, immunomodulatory, and blood lipid-lowering activities. This article reviews the chemical components and pharmacological activities of P. scrophulariiflora and P. kurroa, aiming to provide a basis for the in-depth research, development, and utilization of the two plants.


Assuntos
Picrorhiza , Triterpenos , Glicosídeos Iridoides , Triterpenos/farmacologia
12.
PLoS One ; 16(12): e0260956, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34962953

RESUMO

Vulvovaginal candidiasis (VVC) is the second most common vaginal infection that affects women of reproductive age. Its increased occurrence and associated treatment cost coupled to the rise in resistance of the causative pathogen to current antifungal therapies has necessitated the need for the discovery and development of novel effective antifungal agents for the treatment of the disease. We report in this study the anti-Candida albicans activity of Solanum torvum 70% ethanol fruit extract (STF), fractions and some isolated compounds against four (4) fluconazole-resistant strains of C. albicans. We further report on the effect of the isolated compounds on the antifungal activity of fluconazole and voriconazole in the resistant isolates as well as their inhibitory effect on C. albicans biofilm formation. STF was fractionated using n-hexane, chloroform (CHCl3) and ethyl acetate (EtOAc) to obtain four respective major fractions, which were then evaluated for anti-C. albicans activity using the microbroth dilution method. The whole extract and fractions recorded MICs that ranged from 0.25 to 16.00 mg/mL. From the most active fraction, STF- CHCl3 (MIC = 0.25-1.00 mg/mL), four (4) known compounds were isolated as Betulinic acid, 3-oxo-friedelan-20α-oic acid, Sitosterol-3-ß-D-glucopyranoside and Oleanolic acid. The compounds demonstrated considerably higher antifungal activity (0.016 to 0.512 mg/mL) than the extract and fractions and caused a concentration-dependent anti-biofilm formation activity. They also increased the sensitivity of the C. albicans isolates to fluconazole. This is the first report of 3-oxo-friedelan-20α-oic acid in the plant as well as the first report of betulinic acid, sitosterol-3-ß-D-glucopyranoside and oleanolic acid from the fruits of S. torvum. The present study has demonstrated the anti-C. albicans activity of the constituents of S. torvum ethanol fruit extract and also shown that the constituents possess anti-biofilm formation and resistance modulatory activities against fluconazole-resistant clinical C. albicans isolates.


Assuntos
Antifúngicos/farmacologia , Biofilmes/crescimento & desenvolvimento , Candida albicans/fisiologia , Farmacorresistência Fúngica , Fluconazol/farmacologia , Frutas/química , Solanum/química , Triterpenos/farmacologia , Antifúngicos/química , Antifúngicos/isolamento & purificação , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Triterpenos/química , Triterpenos/isolamento & purificação
13.
Int J Nanomedicine ; 16: 7417-7432, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34764648

RESUMO

Background: The titrated extract of Centella asiatica (CA) has received much attention as a cosmeceutical ingredient owing to its anti-wrinkle effect. However, due to the low solubility and high molecular weight of pharmacologically active constituents, including asiatic acid (AA), madecassic acid (MA), and asiaticoside (AS), it is challenging to fabricate high-payload topical preparations of CA with satisfactory skin absorption profiles. Purpose: This study aimed to design a high-payload topical preparation of CA using nanocrystallization technique and to evaluate its skin absorption profile and local tolerability. Methods: High-payload nanocrystal suspensions (NSs) were prepared using lab-scale bead-milling technology, by adjusting the type and amount of suspending agent, CA content, type of vehicle, and milling speed. CA-loaded NSs were characterized in terms of morphology, particle size, crystallinity, and in vitro dissolution pattern. Skin absorption of CA nanocrystals was evaluated using a vertical Franz diffusion cell mounted with porcine skin. In vivo skin irritation following topical application of high-payload NS was assessed in normal rats. Results: The optimized NS system, composed of 10% (w/v) CA, 0.5% polyvinylpyrrolidone (PVP) K30 as steric stabilizer, and 89.5% of distilled water, was characterized as follows: spherical or elliptical in shape, 200 nm in size, with low crystallinity. The in vitro dissolution of AA or MA from NSs was markedly faster compared to raw material, under sink condition. Penetration of AA, MA, and AS in the porcine skin was markedly elevated using the high-payload NS formula, providing 5-, 4-, and 4.5-fold higher accumulation in skin layer, compared to that of the marketed cream formula (CA 1%, Madeca cream). Moreover, topical application of high-payload NS was tolerable, showing neither erythema nor oedema in normal rats. Conclusion: The novel NS system is expected to be a virtuous approach for offering a better skin absorption of CA, without using an excess quantity of solubilizers.


Assuntos
Centella , Triterpenos , Animais , Extratos Vegetais , Ratos , Pele , Absorção Cutânea , Suspensões
14.
J Nutr Sci Vitaminol (Tokyo) ; 67(5): 317-322, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34719617

RESUMO

Nutritional supplements are sometimes important for athletes to improve their sports performance and maintain their condition. Maslinic acid (MA) is a type of compound with a pentacyclic triterpene structure extracted from olives, and has a strong anti-inflammatory effect and improves metabolic function. This study aimed to investigate the effects of MA on muscle hypertrophy by functional overload using an animal model. Mice plantaris muscles were overloaded by synergist ablation surgery with/without MA and they were sampled at 4, 7, and 14 d after the operation. We demonstrated that MA significantly increased plantaris' cross-sectional area and activated the mechanistic target of rapamycin (mTOR) signaling compared with the non-supplemented group (main effect of MA, p<0.05). In addition, MA also significantly reduced catabolic proteins compared with the non-supplemented group. MA supplementation increased muscle fiber size and promoted muscle hypertrophy via mTOR signaling. Our results indicate that MA supplementation may be useful for promoting hypertrophy of skeletal muscle.


Assuntos
Triterpenos , Animais , Hipertrofia , Camundongos , Fibras Musculares Esqueléticas , Músculo Esquelético , Triterpenos/farmacologia
15.
Zhongguo Zhong Yao Za Zhi ; 46(19): 4959-4968, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34738390

RESUMO

Azadirachtin, as a botanical insecticide, is a highly oxidized limonoid triterpenoid existing in the seeds of Azadirachta indica. However, due to the low content in the seeds, the production of azadirachtin by seed extraction has low yield. Chemical synthesis of azadirachtin is characterized by complex process and low yield. Synthetic biology provides an alternative for the supply of azadirach-tin. In this study, two oxidosqualene cyclases AiOSC1 and MaOSC1 respectively derived from A. indica and Melia azedarach were identified in yeast. A yeast strain producing tirucalla-7,24-dien-3ß-ol was constructed by integration of AiOSC1, Arabidopsis thaliana-derived squalene synthase gene(AtAQS2), and Saccharomyces cerevisiae-derived truncated 3-hydroxy-3-methyl-glutaryl coenzyme A reductase gene(PgtHMGR) into the delta site of yeast. Then, the function of MaCYP71BQ5 was successfully verified in yeast after this gene was introduced into the constructed yeast strain. This study not only laid a foundation for the biosynthesis of tirucalla-7,24-dien-3ß-ol, but also provided a chassis cell for the functional identification of cytochrome oxidases(CYP450 s) in azadirachtin biosynthesis pathway.


Assuntos
Azadirachta , Limoninas , Triterpenos , Saccharomyces cerevisiae/genética
16.
Int J Mol Sci ; 22(19)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34639035

RESUMO

Cancer persists as a global challenge due to the extent to which conventional anticancer therapies pose high risks counterbalanced with their therapeutic benefit. Naturally occurring substances stand as an important safer alternative source for anticancer drug development. In the current study, a series of modified lupane and ursane derivatives was subjected to in vitro screening on the NCI-60 cancer cell line panel. Compounds 6 and 7 have been identified as highly active with GI50 values ranging from 0.03 µM to 5.9 µM (compound 6) and 0.18-1.53 µM (compound 7). Thus, these two compounds were further assessed in detail in order to identify a possible antiproliferative mechanism of action. DAPI (4',6-diamidino-2-phenylindole) staining revealed that both compounds induced nuclei condensation and overall cell morphological changes consistent with apoptotic cell death. rtPCR analysis showed that both compounds induced upregulation of proapoptotic Bak and Bad genes while downregulating Bcl-XL and Bcl-2 antiapoptotic genes. Molecular docking analysis revealed that both compounds exhibited high scores for Bcl-XL inhibition, while compound 7 showed higher in silico Bcl-XL inhibition potential as compared to the native inhibitor ATB-737, suggesting that compounds may induce apoptotic cell death through targeted antiapoptotic protein inhibition, as well.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Produtos Biológicos/farmacologia , Triterpenos/farmacologia , Inibidores da Angiogênese , Antineoplásicos/química , Sítios de Ligação , Produtos Biológicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Triterpenos/química
17.
Int J Mol Sci ; 22(19)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34639051

RESUMO

Defects in cardiac contractility and heart failure (HF) are common following doxorubicin (DOX) administration. Different miRs play a role in HF, and their targeting was suggested as a promising therapy. We aimed to target miR-24, a suppressor upstream of junctophilin-2 (JP-2), which is required to affix the sarcoplasmic reticulum to T-tubules, and hence the release of Ca2+ in excitation-contraction coupling using pachymic acid (PA) and/or losartan (LN). HF was induced with DOX (3.5 mg/kg, i.p., six doses, twice weekly) in 24 rats. PA and LN (10 mg/kg, daily) were administered orally for four weeks starting the next day of the last DOX dose. Echocardiography, left ventricle (LV) biochemical and histological assessment and electron microscopy were conducted. DOX increased serum BNP, HW/TL, HW/BW, mitochondrial number/size and LV expression of miR-24 but decreased EF, cardiomyocyte fiber diameter, LV content of JP-2 and ryanodine receptors-2 (RyR2). Treatment with either PA or LN reversed these changes. Combined PA + LN attained better results than monotherapies. In conclusion, HF progression following DOX administration can be prevented or even delayed by targeting miR-24 and its downstream JP-2. Our results, therefore, suggest the possibility of using PA alone or as an adjuvant therapy with LN to attain better management of HF patients, especially those who developed tolerance toward LN.


Assuntos
Doxorrubicina/efeitos adversos , Regulação da Expressão Gênica , Insuficiência Cardíaca/etiologia , Proteínas de Membrana/genética , MicroRNAs/genética , Triterpenos/farmacologia , Animais , Cardiomegalia/diagnóstico , Cardiomegalia/tratamento farmacológico , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Testes de Função Cardíaca , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/ultraestrutura , Ratos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Transdução de Sinais
18.
ScientificWorldJournal ; 2021: 8856147, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34594161

RESUMO

Candida albicans and Candida tropicalis are the leading causes of human fungal infections worldwide. There is an increase in resistance of Candida pathogens to existing antifungal drugs leading to a need to find new sources of antifungal agents. Tormentic acid has been isolated from different plants including Callistemon citrinus and has been found to possess antimicrobial properties, including antifungal activity. The study aimed to determine the effects of tormentic and extracts from C. citrinus on C. albicans and C. tropicalis and a possible mode of action. The extracts and tormentic acid were screened for antifungal activity using the broth microdilution method. The growth of both species was inhibited by the extracts, and C. albicans was more susceptible to the extract compared to C. tropicalis. The growth of C. albicans was inhibited by 80% at 100 µg/ml of both the DCM: methanol extract and the ethanol: water extract. Tormentic acid reduced the growth of C. albicans by 72% at 100 µg/ml. The effects of the extracts and tormentic acid on ergosterol content in C. albicans were determined using a UV/Vis scanning spectrophotometer. At concentrations of tormentic acid of 25 µg/ml, 50 µg/ml, 100 µg/ml, and 200 µg/ml, the content of ergosterol was decreased by 22%, 36%, 48%, and 78%, respectively. Similarly, the DCM: methanol extract at 100 µg/ml and 200 µg/ml decreased the content by 78% and 88%, respectively. A dose-dependent decrease in ergosterol content was observed in cells exposed to miconazole with a 25 µg/ml concentration causing a 100% decrease in ergosterol content. Therefore, tormentic acid inhibits the synthesis of ergosterol in C. albicans. Modifications of the structure of tormentic acid to increase its antifungal potency may be explored in further studies.


Assuntos
Candida albicans/efeitos dos fármacos , Candida tropicalis/efeitos dos fármacos , Ergosterol/biossíntese , Melaleuca/química , Extratos Vegetais/farmacologia , Triterpenos/farmacologia , Antifúngicos/farmacologia , Candida albicans/crescimento & desenvolvimento , Candida albicans/metabolismo , Candida tropicalis/crescimento & desenvolvimento , Candida tropicalis/metabolismo , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Folhas de Planta/química , Especificidade da Espécie , Espectrofotometria Ultravioleta
19.
Environ Toxicol Pharmacol ; 88: 103750, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34597787

RESUMO

Ulcerative colitis (UC) is an inflammatory bowel disease with limited therapeutic management approaches. The present study evaluated the potential therapeutic impact of betulin on acetic acid (AA)-induced UC in rats. UC was induced by intracolonic instillation of AA (3% v/v). Rats were treated with betulin (8 mg/kg, I.P., once daily) four days post AA instillation and for 14 consecutive days. Betulin attenuated AA-induced UC as evidenced by retracted macroscopic scores, serum CRP titre and LDH activity, attenuated histopathological hallmarks of UC including mucosal necrosis, haemorrhage, congestion and inflammatory cells infiltration. Moreover, betulin dampened UC-associated colonic inflammatory load with modulation of TLR4/NF-kB axis and reduction in colonic inflammatory cytokines; TNF-α, IL1ß and IL-6. Nevertheless, betulin suppressed colonic apoptosis with reduced colonic caspase-3 and caspase-8 expression. The current findings confirm a beneficial therapeutic impact of betulin against UC. The prospective underlying mechanisms include down-regulation of TLR4/NF-κB and the subsequent downstream signalling pathways.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Triterpenos/uso terapêutico , Ácido Acético , Animais , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Citocinas/metabolismo , Masculino , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Triterpenos/farmacologia
20.
Chem Biol Interact ; 349: 109678, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34600868

RESUMO

The present study describes the synthesis of pyridinium derivatives of betulin, including new 4-methyl- and 3,5-methyl-pyridinium analogs, their effect on artificial membrane systems (liposomes), cytotoxicity in models of prokaryotic (E. coli K-12 MG1655) and eukaryotic cells (rat thymocytes), as well as their effect on the functioning of membrane systems of rat liver mitochondria. We have shown that the presence of methyl groups in the pyridine ring of compounds determines the ability of the derivatives to effectively permeabilize the artificial membrane of lecithin liposomes for the fluorescent probe sulforhodamine B. The 4-methyl- and 3,5-methyl-pyridinium analogs inhibit the growth of E. coli K-12 MG1655 and, at the same time, did not have a cytotoxic effect on rat thymocytes. However, in the latter case, we noted a decrease in the mitochondrial potential of cells. The studied compounds reduced the functional activity of mitochondria, suppressing the activity of complexes of the respiratory chain and reducing the membrane potential. In addition, compounds containing methyl groups in the p- and m-positions of the pyridine ring were also able to permeabilize the inner membrane of mitochondria, causing them to swell. In this case, the most lipophilic compound containing two methyl substituents at the m-position of the pyridine fragment was most effective and had a protonophore effect on mitochondria. The paper discusses the dependence of the membranotropic and biological actions of the quaternized pyridine derivatives of betulin on their structure and lipophilicity.


Assuntos
Lipossomos , Mitocôndrias Hepáticas/metabolismo , Piridinas/química , Triterpenos/química , Análise Espectral/métodos , Triterpenos/síntese química
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