RESUMO
Rheumatic diseases constitute a diversified group of diseases distinguished by arthritis and often involve other organs. The affected individual has low quality of life, productivity even life-threatening in some severe conditions. Moreover, they impose significant economic and social burdens. In recent years, the patient outcome has been improved significantly due to clearer comprehension of the pathology of rheumatic diseases and the effectiveness of "treat to target" therapies. However, the high cost and the adverse effects are the concerns and full remissions are not often observed. One of the main processes that contributes to the pathogenesis of rheumatic diseases is angiogenesis. Vascular endothelial growth factor (VEGF), a central mediator that regulates angiogenesis, has different isoforms and functions in various physiological processes. Increasing evidence suggests an association between the VEGF system and rheumatic diseases. Anti-VEGF and VEGF receptor (VEGFR) therapies have been used to treat several cancers and eye diseases. This review summarizes the current understanding of VEGF biology and its role in the context of rheumatic diseases, the contribution of VEGF bioavailability in the pathogenesis of rheumatic diseases, and the potential implications of therapeutic approaches targeting VEGF for these diseases.
Assuntos
Doenças Reumáticas/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Humanos , Neovascularização Patológica/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Panax vietnamensis, or Vietnamese ginseng (VG), an endemic Panax species in Vietnam, possesses a unique saponin profile and interesting biological activities. This plant is presently in danger of extinction due to over-exploitation, resulting in many preservation efforts towards the geographical acclimatization of VG. Yet, no information on the saponin content of the acclimatized VG, an important quality indicator, is available. Here, we analyzed the saponin content in the underground parts of two- to five-year-old VG plants acclimatized to Lam Dong province. Nine characteristic saponins, including notoginsenoside-R1, ginsenoside-Rg1, -Rb1, -Rd, majonoside-R1, -R2 vina-ginsenoside-R2, -R11, and pseudoginsenoside-RT4, were simultaneously determined by HPLC coupled with UV and with a charged aerosol detector (CAD). Analyzing the results illustrated that the detection of characteristic ocotillol-type saponins in VG by CAD presented a superior capacity compared with that of UV, thus implying a preferential choice of CAD for the analysis of VG. The quantitative results indicating the saponin content in the underground parts of VG showed an increasing tendency from two to five years old, with the root and the rhizome exhibiting different saponin accumulation patterns. This is the first study that reveals the preliminary success of VG acclimatization and thereby encourages the continuing efforts to develop this valuable saponin-rich plant.
Assuntos
Panax/química , Saponinas/análise , Cromatografia Líquida de Alta Pressão , Raios Ultravioleta , VietnãRESUMO
Cardiovascular disease (CVD) and its complications are the leading cause of morbidity and mortality in the world. Because of the side effects and incomplete recovery from current therapy, stem cell therapy emerges as a potential therapy for CVD treatment, and endothelial progenitor cell (EPC) is one of the key stem cells used for therapeutic applications. The effect of this therapy required the expansion of EPC function. To enhance the EPC activation, proliferation, and angiogenesis using dronedarone hydrochloride (DH) is the purpose of this study. DH received approval for atrial fibrillation treatment and its cardiovascular protective effects were already reported. In this study, DH significantly increased EPC proliferation, tube formation, migration, and maintained EPCs surface marker expression. In addition, DH treatment up-regulated the phosphorylation of AKT and reduced the reactive oxygen species production. In summary, the cell priming by DH considerably improved the functional activity of EPCs, and the use of which might be a novel strategy for CVD treatment.
RESUMO
The therapeutic potential of adiponectin regulation has received interest because of its association with diverse human disease conditions, such as diabetes, obesity, atherosclerosis, and cancer. Phenylethylchromone derivatives from Aquilaria malaccensis-derived agarwood promoted adiponectin secretion during adipogenesis in human bone marrow mesenchymal stem cells, and 5,6-dihydroxy-2-(2-phenylethyl)chromone (1) was identified as a new chromone derivative. A target identification study with the most potent adiponectin-secretion-promoting phenylethylchromones, 6-methoxy-2-(2-phenylethyl)chromone (3) and 7-methoxy-2-(2-phenylethyl)chromone (4), showed that they are PPARγ partial agonists. Therefore, the diverse therapeutic effects of agarwood are associated with a PPARγ-mediated adiponectin-secretion-promoting mechanism.
Assuntos
Adiponectina/metabolismo , Cromonas/isolamento & purificação , PPAR gama/agonistas , Thymelaeaceae/química , Madeira/química , Células Cultivadas , Cromonas/farmacologia , HumanosRESUMO
Cisplatin is a platinum-based anticancer agent used for treating a wide range of solid cancers. One of the side effects of this drug is its severe nephrotoxicity, limiting the safe dose of cisplatin. Therefore, many natural products have been studied and applied to attenuate the toxicity of this compound. In this study, we found that steamed Vietnamese ginseng (Panax vietnamensis) could significantly reduce the kidney damage of cisplatin in an in vitro model using porcine proximal tubular LLC-PK1 kidney cells. From processed ginseng under optimized conditions (120 °C, 12 h), we isolated seven compounds (20(R,S)-ginsenoside Rh2, 20(R,S)-ginsenoside Rg3, ginsenoside Rk1, ginsenoside-Rg5, and ocotillol genin) that showed kidney-protective potential against cisplatin toxicity. By comparing the 50% recovery concentration (RC50), the R form of ginsenoside, Rh2 and Rg3, had RC50 values of 6.67 ± 0.42 µM and 8.39 ± 0.3 µM, respectively, while the S forms of ginsenoside, Rh2 and Rg3, and Rk1, had weaker protective effects, with RC50 ranging from 46.15 to 88.4 µM. G-Rg5 and ocotillol, the typical saponin of Vietnamese ginseng, had the highest RC50 (180.83 ± 33.27; 226.19 ± 66.16, respectively). Our results suggest that processed Vietnamese gingseng (PVG), as well as those compounds, has the potential to improve kidney damage due to cisplatin toxicity.
Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Rim/efeitos dos fármacos , Panax/química , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Fracionamento Químico/métodos , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificaçãoRESUMO
Chemical and pharmacological studies of Panax vietnamensis (Vietnamese ginseng; VG) have been reported since its discovery in 1973. However, the content of each saponin in different parts of VG has not been reported. In this study, 17 ginsenosides in the different underground parts of P. vietnamensis were analyzed by HPLC/evaporative light scattering detector (ELSD). Their contents in the dried rhizome, radix, and fine roots were 195, 156, and 139 mg/g, respectively, which were extremely high compared to other Panax species. The content of protopanaxatriol (PPT)-type saponins were not much different among underground parts; however, the content of protopanaxadiol (PPD)- and ocotillol (OCT)-type saponins were greatly different. It is noteworthy that the ginsenoside pattern in the fine roots is different from other underground parts. In particular, despite the content of PPD-type saponins being the highest in the fine roots, which is similar to other Panax species, the total content of saponins was the lowest in the fine roots, which is different from other Panax species. The ratios of PPT : PPD : OCT-type saponins were 1 : 1.7 : 7.8, 1 : 1.6 : 5.5, and 1 : 4.8 : 3.3 for the rhizome, radix, and fine roots, respectively. OCT-type saponins accounted for 36-75% of total saponins and contributed mostly to the difference in the total saponin content of each part.
Assuntos
Panax/química , Raízes de Plantas/química , Saponinas/análise , Cromatografia Líquida de Alta Pressão , Ginsenosídeos/análise , Sapogeninas/análiseRESUMO
The extracts of Aquilaria crassna pericarp were investigated on the MDA-MB-468, a breast cancer cell line, at desired concentration (1-50 µg/mL). The results showed that the dichloromethane (DCM) extract exhibited the strongest toxicity and was carried out subsequently. A total of nine compounds were isolated from the DCM extract using column chromatography and recrystallization, of which their structures were determined. Intriguingly, in addition to the previously reported compounds, neocucurbitacin A, a cucurbitacin triterpenoid aglycone with a lactone in ring A, was reported for the first time in the Aquilaria genus. Among the isolated compounds, cucurbitacin E highly inhibited MDA-MB-468 cell growth in a dose-dependent manner. Owing to binding abilities with the SH2 domain in the molecular docking study, cucurbitacin E, neocucurbitan A, neocucurbitan B, and cucurbitacin E 2-O-ß-d-glucopyranoside act as STAT3 inhibitors and are suitable for further research. This study suggests thatAquilaria crassnafruits could serve as a promising source of natural compounds with potential anticancer effects, particularly against breast cancer.
RESUMO
Nine undescribed sesquiterpenes, which include five guaiane and four humulene-type, were isolated from the agarwood of Aquilaria malaccensis. The structures of these undescribed sesquiterpenes were elucidated by spectroscopic methods including UV, HRESI-MS, 1D and 2D-NMR, ECD, and X-ray diffraction (Cu Kα). The isolated compounds were tested for their inhibitory effect against LPS-induced NO production in RAW 264.7 cells. In particular, one sesquiterpene (1α,7α-dihydroxy-8oxo-4αH,5αH-guaia-9(10),11(13)-dien-12-oate) showed significant inhibition of NO production in LPS-stimulated macrophage RAW 264.7 cells with an IC50 value of 18.8 µM.
Assuntos
Sesquiterpenos , Thymelaeaceae , Animais , Anti-Inflamatórios/farmacologia , Camundongos , Estrutura Molecular , Células RAW 264.7 , Sesquiterpenos/farmacologiaRESUMO
BACKGROUND: Despite promising advances in stem cell-based therapy, the treatment of ischemic cardiovascular diseases remains a big challenge due to both the insufficient in vivo viability of transplanted cells and poor angiogenic potential of stem cells. The goal of this study was to develop therapeutic human cardiac progenitor cells (hCPCs) for ischemic cardiovascular diseases with a novel M13 peptide carrier. METHOD: In this study, an engineered M13 peptide carrier was successfully generated using a QuikChange Kit. The cellular function of M13 peptide carrier-treated hCPCs was assessed using a tube formation assay and scratch wound healing assay. The in vivo engraftment and cell survival bioactivities of transplanted cells were demonstrated by immunohistochemistry after hCPC transplantation into a myocardial infarction animal model. RESULTS: The engineered M13RGD+SDKP peptide carrier, which expressed RGD peptide on PIII site and SDKP peptide on PVIII site, did not affect morphologic change and proliferation ability in hCPCs. In contrast, hCPCs treated with M13RGD+SDKP showed enhanced angiogenic capacity, including tube formation and migration capacity. Moreover, transplanted hCPCs with M13RGD+SDKP were engrafted into the ischemic region and promoted in vivo cell survival. CONCLUSION: Our present data provides a promising protocol for CPC-based cell therapy via short-term cell priming of hCPCs with engineered M13RGD+SDKP before cell transplantation for treatment of cardiovascular disease.
Assuntos
Indutores da Angiogênese/farmacologia , Infarto do Miocárdio/terapia , Peptídeos/metabolismo , Transplante de Células-Tronco , Células-Tronco/efeitos dos fármacos , Animais , Bacteriófago M13/genética , Doenças Cardiovasculares , Sobrevivência Celular , Células Endoteliais , Engenharia Genética , Humanos , Masculino , Camundongos Endogâmicos BALB C , Miócitos Cardíacos/transplante , Peptídeos/farmacologia , CicatrizaçãoRESUMO
Cancer stem-like cells (CSCs) contribute to tumor recurrence and chemoresistance. Hence, strategies targeting CSCs are crucial for effective anticancer therapies. Here, we demonstrate the capacities of the non-saponin fraction of Panax ginseng and its active principle panaxynol to inhibit Hsp90 function and viability of both non-CSC and CSC populations of NSCLC in vitro and in vivo. Panaxynol inhibited the sphere forming ability of NSCLC CSCs at nanomolar concentrations, and micromolar concentrations of panaxynol suppressed the viability of NSCLC cells (non-CSCs) and their sublines carrying acquired chemoresistance with minimal effect on normal cells derived from various organs. Orally administered panaxynol significantly reduced lung tumorigenesis in KrasG12D/+ transgenic mice and mice carrying NSCLC xenografts without detectable toxicity. Mechanistically, panaxynol disrupted Hsp90 function by binding to the N-terminal and C-terminal ATP-binding pockets of Hsp90 without increasing Hsp70 expression. These data suggest the potential of panaxynol as a natural Hsp90 inhibitor targeting both the N-terminal and C-terminal of Hsp90 with limited toxicities.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Di-Inos/farmacologia , Álcoois Graxos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proteínas de Choque Térmico HSP90/fisiologia , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Agarwood, the resinous heartwood produced by some Aquilaria species such as Aquilaria crassna, Aquilaria malaccensis and Aquilaria sinensis, has been traditionally and widely used in medicine, incenses and especially perfumes. However, up to now, the authentication of agarwood has been largely based on morphological characteristics, a method which is prone to errors and lacks reproducibility. Hence, in this study, we applied metabolomics and a genetic approach to the authentication of two common agarwood chips, those produced by Aquilaria crassna and Aquilaria malaccensis. Primary metabolites, secondary metabolites and DNA markers of agarwood were authenticated by 1H NMR metabolomics, GC-MS metabolomics and DNA-based techniques, respectively. The results indicated that agarwood chips could be classified accurately by all the methods illustrated in this study. Additionally, the pros and cons of each method are also discussed. To the best of our knowledge, our research is the first study detailing all the differences in the primary and secondary metabolites, as well as the DNA markers between the agarwood produced by these two species.
Assuntos
Metabolômica , Cromatografia Gasosa-Espectrometria de Massas , Reprodutibilidade dos Testes , Resinas Vegetais , ThymelaeaceaeRESUMO
BACKGROUND: Steaming of ginseng is known to change its chemical composition and biological activity. This study was carried out to investigate the effect of different steaming time-scales on chemical constituents and antiproliferative activity of Vietnamese ginseng (VG). METHODS: VG was steamed at 105°C for 2-20 h. Its saponin constituents and antiproliferative activity were studied. The similarity of chemical compositions between steamed samples at 105°C and 120°C were compared. RESULTS: Most protopanaxadiol and protopanaxatriol ginsenosides lost the sugar moiety at the C-20 position with 10-14 h steaming at 105°C and changed to their less polar analogues. However, ocotillol (OCT) ginsenosides were reasonably stable to steaming process. Antiproliferative activity against A549 lung cancer cells was increased on steaming and reached its plateau after 12 h steaming. CONCLUSION: Steaming VG at 105°C showed a similar tendency of chemical degradation to the steaming VG at 120°C except the slower rate of reaction. Its rate was about one-third of the steaming at 120°C.
RESUMO
In a preliminary experiment, majonoside R2 (MR2), isolated from Vietnamese ginseng (Panax vietnamensis Ha et Grushv.), inhibited differentiation to Th17 cells and was metabolized to ocotillol via pseudoginsenoside RT4 (PRT4) by gut microbiota. Therefore, we examined the inhibitory effects of MR2 and its metabolites PRT4 and ocotillol against Th17 cell differentiation. These ginsenosides significantly suppressed interleukin (IL)-6/tumor growth factor beta-induced differentiation of splenic CD4(+) T cells into Th17 cells and expression of IL-17 in vitro. Among these ginsenosides, ocotillol showed the highest inhibitory effect. We also examined the anti-inflammatory effect of ocotillol in mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. Oral administration of ocotillol significantly suppressed TNBS-induced colon shortening, macroscopic score, myeloperoxidase activity, and production of nitric oxide and prostaglandin E2. Ocotillol treatment increased TNBS-suppressed expression of tight junction proteins ZO-1, occludin, and claudin-1 in the colon. Treatment with ocotillol inhibited TNBS-induced expression of tumor necrosis factor (TNF)-α and IL-1ß, as well as activation of NF-κB and MAPKs. Moreover, treatment with ocotillol inhibited TNBS- induced differentiation to Th17 cells in the lamina propria of colon, as well as expression of T-bet, RORγt, IL-17, and IL-23. Ocotillol treatment also increased Treg cell differentiation and Foxp3 and IL-10 expression. These findings suggest that orally administered MR2 may be metabolized to ocotillol in the intestine by gut microbiota and the transformed ocotillol may ameliorate inflammatory diseases such as colitis by restoring the balance of Th17/Treg cells.
Assuntos
Colite/tratamento farmacológico , Ginsenosídeos/administração & dosagem , Panax/química , Extratos Vegetais/administração & dosagem , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Colite/genética , Colite/imunologia , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Camundongos , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Ácido Trinitrobenzenossulfônico/efeitos adversos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: This study was carried out to investigate the effect of the steaming process on chemical constituents, free radical scavenging activity, and antiproliferative effect of Vietnamese ginseng. METHODS: Samples of powdered Vietnamese ginseng were steamed at 120°C for various times and their extracts were subjected to chemical and biological studies. RESULTS: Upon steaming, contents of polar ginsenosides, such as Rb1, Rc, Rd, Re, and Rg1, were rapidly decreased, whereas less polar ginsenosides such as Rg3, Rg5, Rk1, Rk3, and Rh4 were increased as reported previously. However, ocotillol type saponins, which have no glycosyl moiety at the C-20 position, were relatively stable on steaming. The radical scavenging activity was increased continuously up to 20 h of steaming. Similarly, the antiproliferative activity against A549 lung cancer cells was also increased. CONCLUSION: It seems that the antiproliferative activity is closely related to the contents of ginsenoside Rg3, Rg5, and Rk1.