RESUMO
Protein aggregation and the abnormal accumulation of aggregates are considered as common mechanisms of neurodegeneration such as Parkinson's disease (PD). Ursolic acid (UA), a natural pentacyclic triterpenoid compound, has shown a protective activity in several experimental models of brain dysfunction through inhibiting oxidative stress and inflammatory responses and suppressing apoptotic signaling in the brain. In this study, we investigated whether UA promoted autophagic clearance of protein aggregates and attenuated the pathology and characteristic symptoms in PD mouse model. Mice were injected with rotenone (1 mg · kg-1 · d-1, i.p.) five times per week for 1 or 2 weeks. We showed that rotenone injection induced significant motor deficit and prodromal non-motor symptoms accompanied by a significant dopaminergic neuronal loss and the deposition of aggregated proteins such as p62 and ubiquitin in the substantia nigra and striatum. Co-injection of UA (10 mg · kg-1 · d-1, i.p.) ameliorated all the rotenone-induced pathological alterations. In differentiated human neuroblastoma SH-SY5Y cells, two-step treatment with a proteasome inhibitor MG132 (0.25, 2.5 µM) induced marked accumulation of ubiquitin and p62 with clear and larger aggresome formation, while UA (5 µM) significantly attenuated the MG132-induced protein accumulation. Furthermore, we demonstrated that UA (5 µM) significantly increased autophagic clearance by promoting autophagic flux in primary neuronal cells and SH-SY5Y cells; UA affected autophagy regulation by increasing the phosphorylation of JNK, which triggered the dissociation of Bcl-2 from Beclin 1. These results suggest that UA could be a promising therapeutic candidate for reducing PD progression from the prodromal stage by regulating abnormal protein accumulation in the brain.
Assuntos
Neuroblastoma , Doença de Parkinson , Humanos , Camundongos , Animais , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Rotenona , Autofagia/fisiologia , Ubiquitinas/uso terapêutico , Ácido UrsólicoRESUMO
Tacrolimus (FK506), a calcineurin inhibitor, is an effective immunosuppressive agent mainly used to lower the risk of organ rejection after allogeneic organ transplant. However, FK506-associated adverse effects, such as nephrotoxicity, may limit its therapeutic use. In this study, we confirmed that epigallocatechin-3-gallate (EGCG), sanguiin H-6, and gallic acid increased cell survival following FK506-induced cytotoxicity in renal epithelial LLC-PK1. Among these compounds, gallic acid exerted the strongest protective effect, further confirmed in the FK506-induced nephrotoxicity rat model. Additionally, we identified supporting evidence for the nephroprotective function of gallic acid using molecular docking and bioavailability investigations.
Assuntos
Ácido Gálico/farmacologia , Rim/efeitos dos fármacos , Células LLC-PK1/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Syzygium/química , Tacrolimo/antagonistas & inibidores , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ácido Gálico/química , Masculino , Estrutura Molecular , Substâncias Protetoras/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Suínos , Tacrolimo/farmacologiaRESUMO
Ionic liquids (ILs) have sparked much interest as alternative solvents for plant materials as they provide distinctive properties. Therefore, in this study, the capacity of ILs to extract oxypeucedanin hydrate and byakangelicin from the roots of Angelica dahurica (A. dahurica) was investigated. The back-extraction method was examined to recover target components from the IL solution as well. Herein, [Bmim]Tf2N demonstrated outstanding performance for extracting oxypeucedanin hydrate and byakangelicin. Moreover, factors including solvent/solid ratio, extraction temperature and time were investigated and optimized using a statistical approach. Under optimum extraction conditions (solvent/solid ratio 8:1, temperature 60 °C and time 180 min), the yields of oxypeucedanin hydrate and byakangelicin were 98.06% and 99.52%, respectively. In addition, 0.01 N HCl showed the most significant ability to back-extract target components from the [Bmim]Tf2N solution. The total content of both oxypeucedanin hydrate (36.99%) and byakangelicin (45.12%) in the final product exceeded 80%. Based on the data, the proposed approach demonstrated satisfactory extraction ability, recovery and enrichment of target compounds in record time. Therefore, the developed approach is assumed essential to considerably reduce drawbacks encountered during the separation of oxypeucedanin hydrate and byakangelicin from the roots of A. dahurica.
Assuntos
Angelica/química , Fracionamento Químico/métodos , Furocumarinas/isolamento & purificação , Líquidos Iônicos/química , Furocumarinas/química , Solventes/química , Fatores de TempoRESUMO
Ionic liquids (ILs) have attracted significant interest because of their desirable properties. These characteristics have improved their application to overcome the shortcomings of conventional separation techniques for phytochemicals. In this study, several ILs were investigated for their capacity to extract isoimperatorin, a bioactive furanocoumarin, from the roots of Ostericum koreanum. Herein, 1-Butyl-3-methylimidazolium tetrafluoroborate ([Bmim][BF4]) was selected as a promising IL for separating isoimperatorin. A central composite design was applied to optimize the extraction conditions. Under the optimal conditions, the yield of isoimperatorin reached 97.17 ± 1.84%. Additionally, the recovery of isoimperatorin from the [Bmim][BF4] solution was successfully achieved (87.73 ± 2.37%) by crystallization using water as an antisolvent. The purity of the isoimperatorin was greatly enhanced, from 0.26 ± 0.28% in the raw material to 26.94 ± 1.26% in the product, in a one-step crystallization process. Namely, an enhancement of approximately 103-folds was reached. The developed approach overcomes the shortcomings of conventional separation methods applied for gaining isoimperatorin by significantly reducing the laboriousness of the process and the consumption of volatile organic solvents. Moreover, the simplicity and effectiveness of the method are assumed to be valuable for producing isoimperatorin-enriched products and for promoting its purification. This work also confirms the efficiency of ILs as a promising material for the separation of phytochemicals.
Assuntos
Apiaceae/química , Furocumarinas/isolamento & purificação , Líquidos Iônicos/química , Furocumarinas/química , Estrutura Molecular , Raízes de Plantas/químicaRESUMO
Ionic liquids (ILs) have gained much attention as alternative solvents to volatile organic solvents due to their attractive properties. This study aimed to develop an efficient method for the selective separation of decursin (D) and decursinol angelate (DA) from Angelica gigas Nakai (A. gigas) using ILs and crystallization. The IL 1-butyl-3-methylimidazolium tetrafluoroborate ((BMIm)BF4) was the most efficient at extracting D and DA. Parameters including solid-to-liquid ratio, time, and temperature were optimized by response surface methodology (RSM). Under optimal extraction conditions (1 g/6.5 mL solid-to-liquid ratio, 60 °C temperature, and 120 min time), the extraction yields of D and DA were 43.32 mg/g (97.06%) and 17.87 mg/g (97.12%), respectively. Moreover, drowning out crystallization using deionized water (DW) as an anti-solvent offered an excellent ability to recover D and DA from the A. gigas-(BMIm)BF4 extraction solution. The rates of recovery and the total purity of D and DA were found to be greater than 97%. Therefore, a rapid and efficient method of combining ILs with crystallization was effectively achieved for the selective separation of D and DA. This approach is assumed to be beneficial in the pharmaceutical industry for the effective obtention of D- and DA-enriched products.
Assuntos
Angelica/química , Benzopiranos/isolamento & purificação , Imidazóis/química , Benzopiranos/química , Butiratos , Cristalização , Líquidos Iônicos/química , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificaçãoRESUMO
Alpha (α)-mangostin, a yellow crystalline powder with a xanthone core structure, is isolated from mangosteen (Garcinia mangostana), which is a tropical fruit of great nutritional value. The aim of the present study was to investigate the anti-diabetic effects of α-mangostin and to elucidate the molecular mechanisms underlying its effect on pancreatic beta (ß)-cell dysfunction. To assess the effects of α-mangostin on insulin production, rat pancreatic INS-1 cells were treated with non-toxic doses of α-mangostin (1â»10 µM) and its impact on insulin signaling was examined by Western blotting. In addition, the protective effect of α-mangostin against pancreatic ß-cell apoptosis was verified by using the ß-cell toxin streptozotocin (STZ). Our results showed that α-mangostin stimulated insulin secretion in INS-1 cells by activating insulin receptor (IR) and pancreatic and duodenal homeobox 1 (Pdx1) followed by phosphorylation of phospho-phosphatidylinositol-3 kinase (PI3K), Akt, and extracellular signal regulated kinase (ERK) signaling cascades, whereas it inhibited the phosphorylation of insulin receptor substrate (IRS-1) (Ser1101). Moreover, α-mangostin was found to restore the STZ-induced decrease in INS-1 cell viability in a dose-dependent manner. In addition, treatment of INS-1 cells with 50 µM STZ resulted in an increase in intracellular reactive oxygen species (ROS) levels, which was represented by the fluorescence intensity of 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA). This oxidative stress was decreased by co-treatment with 5 µM α-mangostin. Similarly, marked increases in the phosphorylation of P38, c-Jun N-terminal kinase (JNK), and cleavage of caspase-3 by STZ were decreased significantly by co-treatment with 5 µM α-mangostin. These results suggest that α-mangostin is capable of improving insulin secretion in pancreatic ß-cells and protecting cells from apoptotic damage.
Assuntos
Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Xantonas/farmacologia , Animais , Cálcio/metabolismo , Caspases/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Glucose/metabolismo , Resistência à Insulina , Secreção de Insulina , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais , Estreptozocina/efeitos adversos , Xantonas/químicaRESUMO
In this study, we investigated the anti-inflammatory effects and mechanisms of cirsimaritin isolated from an ethanol extract of the aerial parts of Cirsium japonicum var. maackii Maxim. using RAW264.7 cells. The extract and its flavonoid cirsimaritin inhibited nitric oxide (NO) production and inducible nitric oxide synthase expression in RAW264.7 cells. Cirsimaritin inhibited interleukin-6, tumor necrosis factor-α, and NO production in a concentration-dependent manner in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. From a western blot study, pretreatment with cirsimaritin inhibited phosphorylation/degradation of IκBα and phosphorylation of Akt in LPS-stimulated RAW264.7 cells. Moreover, cirsimaritin suppressed activation of LPS-induced transcription factors, such as c-fos and signal transducer and activator of transcription 3 (STAT3), in RAW264.7 cells. Collectively, these results show that cirsimaritin possesses anti-inflammatory activity, which is regulated by inhibition of c-fos and STAT3 phosphorylation in RAW264.7 cells.
Assuntos
Anti-Inflamatórios/química , Cirsium/química , Flavonas/química , Extratos Vegetais/química , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Cirsium/metabolismo , Flavonas/isolamento & purificação , Flavonas/farmacologia , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Inibidor de NF-kappaB alfa/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação/efeitos dos fármacos , Componentes Aéreos da Planta/química , Componentes Aéreos da Planta/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Células RAW 264.7 , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Pleurotus cornucopiae (Pleurotaceae) is an edible and medicinal mushroom widely distributed in Korea, China, and Japan. The MeOH extract of the fruiting bodies of P. cornucopiae showed renoprotective effects against cisplatin-induced kidney cell damage. Chemical investigation of the MeOH extract led to the isolation and identification of 12 compounds including noransine (1), uridine (2), uracil (3), (3ß, 5α, 6ß, 22E, 24S) -ergosta-7, 22-diene-3, 5, 6, 9-tetrol (4), (22E,24S)-ergosta-7,22-diene-3ß,5α,6ß-triol (5), (22E,24R)-ergosta-8(14),22-diene-3ß,5α,6ß,7α-tetrol (6), cerebroside B (7), (2R) -N- [(1S, 2R, 3E, 7E) -1- [(ß-d-glucopyranosyloxy) methyl] -2-hydroxy-8-methyl-3, 7-heptadecadien-1-yl] -2-hydroxy-heptadecanamide (8), cerebroside D (9), nicotinamide (10), 1,2-bis(hydroxymethyl)-4,5-dimethoxybenzene (11), and benzoic acid (12). Among them, compounds 1 and 11 were isolated as naturally occurring products for the first time, though they were reported as synthetic products in previous papers. All of the compounds (except 8 and 11) abrogated cisplatin-induced LLC-PK1 cell damage in a dose-dependent manner. Of special note, compounds 2, 5, 6, and 12 ameliorated cisplatin-induced nephrotoxicity to 80% of the control value at 10µM. The protective effects of compounds 2, 5, 6, and 12 were mediated via the deactivation of JNK-caspase 3 apoptotic cascade. This study is the first to demonstrate that the chemical constituents of P. cornucopiae display renoprotective effects against anticancer drug-induced damage in kidney cells.
Assuntos
Antineoplásicos/efeitos adversos , Produtos Biológicos/farmacologia , Cisplatino/efeitos adversos , Carpóforos/química , Rim/efeitos dos fármacos , Pleurotus/química , Substâncias Protetoras/farmacologia , Animais , Apoptose/efeitos dos fármacos , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Linhagem Celular , Rim/patologia , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação , SuínosRESUMO
Emodin is a component in a Chinese herb, Rheum officinale Baill, traditionally used for diabetes and anticancer. Its poor solubility is one of the major challenges to pharmaceutical scientists. We previously reported on thermoreversible gel formulations based on poloxamer for the topical delivery of emodin. The present study was to understand the effect of poloxamer type on emodin solubility and its application in cellular activity screening. Various gel formulations composed of poloxamer 407 (P407), poloxamer 188 (P188) and PEG400 were prepared and evaluated. Major evaluation parameters were the gelation temperature (Tgel) and solubility of emodin. The emodin solubility increased with increasing poloxamer concentration and the Tgel was modulated by the proper combination of P407. In particular, this study showed that the amount of P407 in thermoreversible poloxamer gel (PG) was the dominant factor in enhancing solubility and P188 was effective at fixing gelation temperature in the desired range. A thermoreversible emodin PG was selected as the proper composition with the liquid state at room temperature and gel state at body temperature. The gel showed the solubility enhancement of emodin at least 100-fold compared to 10% ethanol or water. The thermoreversible formulation was applied for in vitro cellular activity screening in the human dermal fibroblast cell line and DLD-1 colon cancer cell line after dilution with cell culture media. The thermoreversible gel formulation remained as a clear solution in the microplate, which allowed reliable cellular activity screening. In contrast, emodin solution in ethanol or DMSO showed precipitation at the corresponding emodin concentration, complicating data interpretation. In conclusion, the gel formulation is proposed as a useful prototype topical formulation for testing emodin in vivo as well as in vitro.
Assuntos
Emodina/química , Poloxâmero/química , Administração Tópica , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , Química Farmacêutica , Avaliação Pré-Clínica de Medicamentos , Emodina/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Géis , Humanos , Solubilidade , Solventes/químicaRESUMO
Tenofovir disoproxil (TD), an anti-virus drug, is currently marketed under its most stable form, Form-I of Tenofovir disoproxil fumarate (TDF). However, studies regarding the properties of TD free base crystal as a promising drug as well as its crystal structure have not yet been reported. This assumption was made because TD free base is not directly produced in a solid form during the manufacturing process. TD free base is first obtained in an oil form, and is then synthesized into TDF crystal. In this regard, the present study was conducted to investigate both the potentiality of TD free base to be an active pharmaceutical ingredient (API) and its crystal structure. Here, TD free base solid was produced by means of drowning-out crystallization. Next, single crystal X-ray diffraction (SXD) was employed to determine the crystal structure. Powder X-ray diffraction (PXRD) and a differential scanning calorimetry (DSC) analysis were performed to evaluate the crystal's properties. Furthermore, experiments were carried out at 15%, 35%, 55%, 75%, and 95% relative humidity (RH) for 12 h using a hygroscopic tester to determine and to compare the hygroscopicity and stability of TD free base with TDF crystal. Additionally, experiments were conducted under accelerated (40 °C, RH 75%) and stress storage (60 °C, RH 75%) conditions for 30 days to investigate the changes in purity and the formation of dimer. In this work, we report that TD free base possesses lower hygroscopicity, and thus does not generate dimer impurity from hydrolysis. Primarily, this is attributed to the fact that TD free base is not an easily ionized salt but comprises neutral hydrophobic molecules. According to the structural properties, the improved hygroscopic property of the TD free base crystal was due to the decrease of crystal polarity owing to the intermolecular H-bonds present in TD free base rings. In addition, the solubility investigation study carried out in aqueous solution and at gastrointestinal pH revealed a similarity in TDF and TD free base solubility under the mentioned conditions. Accordingly, we could confirm the potentiality of TD free base as an active pharmaceutical ingredient.
Assuntos
Antivirais/química , Cristalografia por Raios X/métodos , Composição de Medicamentos/métodos , Tenofovir/química , Varredura Diferencial de Calorimetria/métodos , Cristalização/métodos , Estabilidade de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Solubilidade , MolhabilidadeRESUMO
This study was performed to investigate the renoprotective effect and mechanism of Momordicae Semen, gac seeds, against the cisplatin-induced damage in LLC-PK1 kidney cells. In order to identify the active components, three major saponins were isolated from extract of the gac seed, gypsogenin 3-O-ß-d-galactopyranosyl(1â2)-[α-L-rhamnopyranosyl(1â3)]-ß-d-glucuronopyranoside (1), quillaic acid 3-O-ß-D-galactopyranosyl(1â2)-[α-L-rhamnopyranosyl(1â3)]-ß-D-glucuronopyranoside (2), and momordica saponin I (3). Compounds 1 and 2 ameliorated cisplatin-induced nephrotoxicity up to 80% of the control value at both 5 and 25µM. Phosphorylation of MAPKs was decreased along cisplatin treatment after treatment with compounds 1 and 2. These results show that blocking the MAPKs signaling cascade plays a critical role in mediating the renoprotective effect of Momordicae Semen extract and compounds 1 and 2.
Assuntos
Apoptose/efeitos dos fármacos , Cisplatino/antagonistas & inibidores , Rim/efeitos dos fármacos , Rim/patologia , Momordica/química , Saponinas/farmacologia , Sementes/química , Animais , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Células LLC-PK1 , Estrutura Molecular , Saponinas/química , Saponinas/isolamento & purificação , Relação Estrutura-Atividade , SuínosRESUMO
Radiographic contrast media facilitate the visibility of internal body structures, but its use to patients with lowered renal function needs to be careful because of severe side effect in kidney. The present study aims to evaluate potential protective effect and mechanism of Alpha mangostin (α-mangostin) against contrast-induced apoptotic damage in LLC-PK1 cells. As a result, α-mangostin in non-toxic concentrations improved the viability of the iodixanol-treated cells up to 90.42% against contrast-induced damage in LLC-PK1 cells. Iodixanol treatment increased the phosphorylation of p38, ERK and cleavage of caspase-3 in LLC-PK1 cells, which were significantly decreased by co-treatment with α-mangostin (2.5 and 5µM). The protective effect of α-mangostin on contrast-induced apoptotic damage was mediated by the inhibition of MAPKs and caspase activation.
Assuntos
Apoptose/efeitos dos fármacos , Ácidos Tri-Iodobenzoicos/antagonistas & inibidores , Xantonas/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células LLC-PK1 , Estrutura Molecular , Relação Estrutura-Atividade , Suínos , Ácidos Tri-Iodobenzoicos/farmacologia , Xantonas/síntese química , Xantonas/químicaRESUMO
The present study reports a renoprotective effect and the mechanism of action of lupane triterpenes isolated from Cornus walteri in cisplatin-induced renal toxicity. A phytochemical investigation of the MeOH extract of the stems and stem bark of C. walteri resulted in the isolation and identification of twelve lupane triterpenes. Among these, betulinic acid, 29-oxobetulinic acid, betulin 3-acetate, and lupeol ameliorated cisplatin-induced nephrotoxicity to 80% of the control value at 125 µM. Upregulated phosphorylation of JNK, ERK, and p38 following cisplatin treatment were markedly decreased after co-treatment with betulinic acid, 29-oxobetulinic acid, betulin 3-acetate, and lupeol. In addition, the protein expression level of cleaved caspase-3 and the percentage of apoptotic cells were also significantly reduced after co-treatment with betulinic acid, 29-oxobetulinic acid, betulin 3-acetate, and lupeol. These results show that blocking the MAPK signaling cascade plays a critical role in mediating the renoprotective effect of betulinic acid, 29-oxobetulinic acid, betulin 3-acetate, and lupeol isolated from C. walteri extract.
Assuntos
Cisplatino , Cornus/química , Triterpenos/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/toxicidade , Humanos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Padrões de Referência , Triterpenos/farmacologiaRESUMO
A new cerebroside, cerebroside E (1) was isolated from the fruiting bodies of Hericium erinaceus (Hericiaceae). The structure of 1 was elucidated by a combination of extensive spectroscopic analyses, including extensive 2D NMR, HR-MS, and chemical reactions. Compound 1 was evaluated for its applicability to medicinal use in several human diseases using cell-based assays. As a result, compound 1 attenuated cisplatin-induced nephrotoxicity in LLC-PK1 cells and exhibited a significant inhibitory effect on angiogenesis in HUVECs. These results collectively reflect the beneficial effects of compound 1 in cancer treatment.
Assuntos
Basidiomycota/química , Cerebrosídeos/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Basidiomycota/metabolismo , Cerebrosídeos/isolamento & purificação , Cerebrosídeos/farmacologia , Carpóforos/química , Carpóforos/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Células LLC-PK1 , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Conformação Molecular , Neovascularização Fisiológica/efeitos dos fármacos , SuínosRESUMO
Two triterpenoidal saponins were isolated from the seeds of Momordica cochinchinensis Sprenger (Cucurbitaceae). Identification of chemical structures has been performed by (1)H- and (13)C-NMR spectroscopy and gas chromatography (GC). One of the saponins is a new gypsogenin glycoside, named as gypsogenin 3-O-ß-D-galactopyranosyl(1â2)-[α-L-rhamnopyranosyl(1â3)]-ß-D-glucuronopyranoside (compound 1), which is reported for the first time from natural resources. The other saponin is a quillaic acid glycoside (compound 2), which showed anti-inflammatory activities in RAW 264.7 cells. The mechanistic understanding of anti-inflammatory activities demonstrates that compound 2 inhibits lipopolysaccharide-induced expression of nitric oxide and IL-6 via NF-κB pathway.
Assuntos
Anti-Inflamatórios/farmacologia , Glicosídeos/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Momordica/química , Terpenos/farmacologia , Triterpenos/farmacologia , Animais , Anti-Inflamatórios/química , Linhagem Celular , Cromatografia Gasosa/métodos , Glicosídeos/química , Interleucina-6/imunologia , Interleucina-6/metabolismo , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Camundongos , NF-kappa B/imunologia , NF-kappa B/metabolismo , Óxido Nítrico/imunologia , Óxido Nítrico/metabolismo , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Saponinas/química , Saponinas/farmacologia , Sementes/química , Terpenos/química , Triterpenos/químicaRESUMO
Momordicae Semen, Momordica cochinchinensis Springer (Cucurbitaceae), has long been known to effectively relieve boils, rheumatic pain, and hemorrhoids. In this study, we investigated whether Momordicae Semen extract (MSE) has anti-gastritis effects in various rodent models and also explored possible mechanisms for the gastroprotective effects of MSE. MSE provided remarkable protective effects, comparable to those of rebamipide, in ethanol- and diclofenac-induced acute gastritis. In addition, it has demonstrated protective effect in a Helicobacter pylori-insulted chronic gastritis model. MSE also showed wound healing effect on cutaneous injury of mice and stimulated calcitonin gene-related peptide and somatostatin receptors, which may be related to its anti-gastritis effects. In a single oral dose toxicity study, the approximate lethal dose of MSE was determined at >2000 mg/kg/day. The NOAEL was set to be 2000 mg/kg/day from the repeated oral dose toxicity study. Moreover, momordica saponin I, a major ingredient of MSE, treatment decreased gastric mucosa damage indices in the ethanol- and diclofenac-induced acute gastritis models. The results suggest that MSE could be a promising gastroprotective herbal medicine and momordica saponin I might be used as an active marker compound for MSE.
Assuntos
Antiulcerosos/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Gastrite/tratamento farmacológico , Momordica/química , Extratos Vegetais/farmacologia , Cicatrização/efeitos dos fármacos , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Antiulcerosos/química , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Mucosa Gástrica/metabolismo , Gastrite/induzido quimicamente , Gastrite/metabolismo , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/metabolismo , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/metabolismo , Masculino , Camundongos , Extratos Vegetais/química , Quinolonas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Somatostatina/metabolismo , Saponinas/química , Saponinas/farmacologia , Sementes/química , Pele/efeitos dos fármacos , Pele/metabolismoRESUMO
Mirabegron (MBR) is a ß3-adrenoceptor agonist used for treating overactive bladder syndrome. Due to its poor solubility and low bioavailability (F), the development of novel MBR formulations has garnered increasing attention. Recently, co-amorphous dispersions of MBR, such as MBR-1,2-ethanedisulfonic acid (MBR-EFA), MBR-1,5-naphthalenedisulfonic acid (MBR-NDA), and MBR-L-pyroglutamic acid (MBR-PG), have been developed, showing improved solubility and thermodynamic stability. Nevertheless, the pharmacokinetic feasibility of these co-amorphous dispersions has not been evaluated. Therefore, this study aimed to characterize the pharmacokinetic profiles of MBR-EFA, MBR-NDA, and MBR-PG in rats and mice. Our results exhibited that relative F24h and AUC0-24h values of MBR in MBR-EFA, MBR-NDA, and MBR-PG rats were increased by 143-195% compared with the MBR rats. The absolute F24h, relative F24h, and AUC0-24h values of MBR in MBR-EFA and MBR-NDA mice were enhanced by 178-234% compared with the MBR mice. In tissue distribution, MBR was extensively distributed in the gastrointestinal tract, liver, kidneys, lung, and heart of mice. Notably, MBR distribution in the liver, kidneys, and lung was considerably high in MBR-EFA, MBR-NDA, or MBR-PG mice compared with MBR mice. These findings highlight the potential of these co-amorphous dispersions to enhance oral F of MBR.
RESUMO
Febuxostat (FBX), a selective xanthine oxidase inhibitor, belongs to BCS class II, showing low solubility and high permeability with a moderate F value (<49%). Recently, FBX/L-pyroglutamic acid cocrystal (FBX-PG) was developed with an improving 4-fold increase of FBX solubility. Nevertheless, the in vivo pharmacokinetic properties of FBX-PG have not been evaluated yet. Therefore, the pharmacokinetic feasibility of FBX in FBX- and FBX-PG-treated rats and mice was compared in this study. The results showed that the bioavailability (F) values of FBX were 210% and 159% in FBX-PG-treated rats and mice, respectively. The 2.10-fold greater total area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) of FBX was due to the increased absorption [i.e., 2.60-fold higher the first peak plasma concentration (Cmax,1) at 15 min] and entero-hepatic circulation of FBX [i.e., 1.68-fold higher the second peak plasma concentration (Cmax,2) at 600 min] in FBX-PG-treated rats compared to the FBX-treated rats. The 1.59-fold greater AUC0-inf of FBX was due to a 1.65-fold higher Cmax,1 at 5 min, and a 1.15-fold higher Cmax,2 at 720 min of FBX in FBX-PG-treated mice compared to those in FBX-treated mice. FBX was highly distributed in the liver, stomach, small intestine, and lungs in both groups of mice, and the FBX distributions to the liver and lungs were increased in FBX-PG-treated mice compared to FBX-treated mice. The results suggest the FBX-PG has a suitable pharmacokinetic profile of FBX for improving its oral F value.
RESUMO
Tenofovir (TEV) is a nucleotide reverse transcriptase inhibitor used against human immunodeficiency virus (HIV) reverse transcriptase. To improve the poor bioavailability of TEV, TEV disoproxil (TD), an ester prodrug of TEV, was developed, and TD fumarate (TDF; Viread®) has been marketed due to the hydrolysis of TD in moisture. Recently, a stability-enhanced solid-state TD free base crystal (SESS-TD crystal) was developed with improved solubility (192% of TEV) under gastrointestinal pH condition and stability under accelerated conditions (40 °C, RH 75%) for 30 days. However, its pharmacokinetic property has not been evaluated yet. Therefore, this study aimed to evaluate the pharmacokinetic feasibility of SESS-TD crystal and to determine whether the pharmacokinetic profile of TEV remained unchanged when administering SESS-TD crystal stored for 12 months. In our results, the F and systemic exposure (i.e., AUC and Cmax) of TEV in the SESS-TD crystal and TDF groups were increased compared to those in the TEV group. The pharmacokinetic profiles of TEV between the SESS-TD and TDF groups were comparable. Moreover, the pharmacokinetic profiles of TEV remained unchanged even after the administration of the SESS-TD crystal and TDF stored for 12 months. Based on the improved F after the SESS-TD crystal administration and the stable condition of the SESS-TD crystal after 12 months, SESS-TD crystal may have enough pharmacokinetic feasibility to replace TDF.
RESUMO
The suppressive effects of flavonoids on macrophage-associated adipocyte inflammation in a differentiated murine preadipocyte cell line (3T3-L1) co-cultured with a murine macrophage cell line (RAW264.7) were evaluated. Extracellular lipid accumulation was investigated via Oil Red O staining. The expression levels of adipogenesis- and inflammation-associated proteins, including CCAAT/enhancer-binding protein (C/EBP)-α, inducible nitric oxide synthase (iNOS), C/EBPß, peroxisome proliferator-activated receptor γ (PPARγ), and cyclooxygenase-2 (COX-2), were determined via Western blotting. Proinflammatory cytokines, including monocyte chemoattractant protein 1 (MCP-1) and interleukin-6 (IL-6), were assessed using enzyme-linked immunosorbent assay kits. We found that silybin, formononetin, and diosmetin inhibited lipid accumulation and production of proinflammatory cytokines in the co-cultures of 3T3-L1 and RAW264.7 cells. Moreover, they inhibited the protein expression of PPARγ, C/EBPα, COX-2, C/EBPß, and iNOS in the co-cultures of 3T3-L1 and RAW264.7 cells. These data support that silybin, formononetin, and diosmetin inhibit macrophage-associated adipocyte inflammation and lipid accumulation.