Planta medica [journal]
- Rutin Prevents High Glucose-Induced Renal Glomerular Endothelial Hyperpermeability by Inhibiting the ROS/Rhoa/ROCK Signaling Pathway. [JOURNAL ARTICLE]
- Planta Med 2016 Aug 23.
Diabetic nephropathy is a progressive kidney disease caused by damage to the capillaries in the glomeruli. Endothelial dysfunction is an early sign of diabetic cardiovascular disease and may contribute to progressive diabetic nephropathy. Hyperglycemia-induced endothelial hyperpermeability is crucial to diabetic nephropathy. Rutin has beneficial effects on diabetic nephropathy, but the exact mechanisms of its protective effect remain elusive. The aim of this study was to assess the role of pretreatment with rutin in an in vitro model of hyperglycemia-induced barrier dysfunction in human renal glomerular endothelial cells. Human renal glomerular endothelial cells were exposed to rutin and/or hyperglycemia for 24 h. Hyperglycemia increased permeability and decreased the junction protein occludin in the cell-cell junction area and the total expression in human renal glomerular endothelial cells, whereas rutin treatment significantly corrected these abnormalities. Furthermore, hyperglycemia-induced activation of RhoA/ROCK was reversed by treatment with rutin or the knockdown of ROCK2. Interestingly, rutin prevented hyperglycemia-induced hyperpermeability, and dysfunction of the tight junction, a high level of reactive oxygen species, and activation of RhoA/ROCK were significantly abolished with the knockdown of Nrf2. In conclusion, rutin significantly prevented hyperglycemia-disrupted renal endothelial barrier function by inhibiting the RhoA/ROCK signaling pathway through decreasing reactive oxygen species, which was mediated by the activation of Nrf2. Our results may explain, at least in part, some beneficial effects of rutin that may be applicable to the treatment of vascular disorders in diabetic nephropathy.
- Glycyrrhizic Acid Decreases Gentamicin-Resistance in Vancomycin-Resistant Enterococci. [JOURNAL ARTICLE]
- Planta Med 2016 Aug 23.
The resistance of commensal bacteria against first and second line antibiotics has reached an alarming level in many parts of the world and endangers the effective treatment of infectious diseases. Particularly vancomycin-resistant Enterococcus faecium represents an increasing clinical problem in the treatment of infectious diseases and hinders adequate antibiotic stewardship. In consideration of the lack of novel antibiotic compounds, the development of resistance-modifying agents, however, can mitigate the spread of bacterial drug resistance and might possibly extend the useful application indices of an existing licensed antibiotic. Given that saponins modify the local chemical environment at cell membranes and might modify the uptake or mode of action of antibiotics in bacteria, we investigated the influence of the triterpenoid saponin glycyrrhizic acid of Glycyrrhiza glabra on the susceptibility of vancomycin-resistant enterococci against the aminoglycoside antibiotic gentamicin in 47 clinical isolates by applying the checkerboard method. The fractional inhibitory concentration indices values were determined between 0.016 and ≤ 0.5 (synergy is accepted with values ≤ 0.5). Glycyrrhizic acid at the subinhibitory concentration of 2.4 mM was found to reduce the minimal inhibitory concentration of gentamicin in intrinsically resistant E. faecium strains down to 6.25 % of the minimal inhibitory concentration of gentamicin alone, whereas relatively low concentrations of glycyrrhizic acid (18 µM) resulted in increased susceptibilities for some E. faecium isolates to gentamicin. In conclusion, our study points towards a therapeutic potential of glycyrrhizic acid in co-application with gentamicin for defined local bacterial infections caused by vancomycin resistant Enterococcus strains.
- Naturally Occurring Diterpenoid Dimers: Source, Biosynthesis, Chemistry and Bioactivities. [JOURNAL ARTICLE]
- Planta Med 2016 Aug 19.
Diterpenoid dimers are rare in nature and mainly found in higher plants including the families Acanthaceae, Annonaceae, Asteraceae, Calceolariaceae, Chrysobalanaceae, Cupressaceae, Euphorbiaceae, Fabaceae, Lamiaceae, Liliaceae, Meliaceae, Rhizophoraceae, Taxaceae, Velloziaceae, and Zingiberaceae. In addition, a few diterpenoid dimers have been also reported from fungi (Psathyrellaceae), liverworts (Scapaniaceae), and a gorgonian (Gorgoniidae). They feature a wide variety of structures due to different core skeletons, linkage patterns, substituents, and configurations. Accordingly, diterpenoid dimers exhibit a broad range of bioactivities, including cytotoxic, anti-inflammatory, antimicrobial, antimalarial, and antifouling properties, which have attracted more and more research interests in the past decades. This review with 176 metabolites from 109 references provides a comprehensive and up-to-date overview of the source, biosynthesis, structure, synthesis, and bioactivities of diterpenoid dimers.
- Narciclasine - an Amaryllidaceae Alkaloid with Potent Antitumor and Anti-Inflammatory Properties. [JOURNAL ARTICLE]
- Planta Med 2016 Aug 19.
The isocarbostyril alkaloid narciclasine, also known as lycoricidinol, was discovered in Narcissus species (Amaryllidaceae) in 1967. A few years later, the 60S subunit of ribosomes, and thus protein biosynthesis, were shown to be directly targeted by narciclasine. Due to its selective and highly potent cytotoxic action on cancer cells, narciclasine was intensively investigated as an antitumor compound both in vitro and in vivo. However, narciclasine did not show a strong pharmacological activity in animal tumor models. During the last decade, new fascinating actions, mechanisms, and targets of narciclasine have emerged. This review intends to present a brief but comprehensive overview of these novel insights. Beneficial therapeutical actions have been reported particularly in brain tumor models. The translation elongation factor eEF1A, which does not only participate in protein biosynthesis but also in the regulation of the actin cytoskeleton, was discovered as new direct target. Moreover, narciclasine was found to trigger actin stress fiber formation via the activation of the small GTPase RhoA. Progress has also been made regarding the pharmacokinetic characterization of the alkaloid. The synthesis of a great number of narciclasine derivatives led to a substantial understanding of its pharmacophore and of the structure-activity relationships. However, an optimized compound did not result from these efforts. Most importantly, a new field of indication has emerged: Narciclasine was proven to exert profound anti-inflammatory actions in vivo. Taken together, there has been a strong advance in the preclinical knowledge about the alkaloid. Nevertheless, narciclasine has not been tested in human clinical trials up to now.
- Acronychiabaueri Analogue Derivative-Loaded Ultradeformable Vesicles: Physicochemical Characterization and Potential Applications. [JOURNAL ARTICLE]
- Planta Med 2016 Aug 19.
Elastic and ultradeformable liposomes were synthesized and physicochemically characterized to make suitable topical formulations for delivering the anti-inflammatory and anticancer compound 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic acid. The average sizes of elastic and ultradeformable liposomes are below 300 nm, while the size distribution and Z-potential are below 0.3 and - 25 mV, respectively. The presence of 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic acid does not affect the physicochemical parameters of nanovesicles. Elastic and ultradeformable liposomes show a zero order release kinetic and are stable at room temperature for a long time with or without 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic acid. The ultradeformable liposomes are more deformable than elastic liposomes. These differences may depend on sodium cholate derivatives making nanoformulations. The 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic acid-loaded elastic and ultradeformable liposomes can provide innovative nanotherapeutics-based natural compounds for the potential treatment of cutanous inflammation.
- Butyrolactones and Diketopiperazines from Marine Microbes: Inhibition Effects on Dengue Virus Type 2 Replication. [JOURNAL ARTICLE]
- Planta Med 2016 Aug 19.
Two new compounds, 4S,10R-dihydroxy-11-methyl-dodec-2-en-1,4-olide (1) (butyrolactone-type) and cyclo-(4-trans-6-dihydroxy-proline-D-leucine) (2) (diketopiperazine-type), as well as one known 4S,10-dihydroxy-10-methyl-dodec-2-en-1,4-olide (3) and three known diketopiperazines, cyclo-(L-proline-L-leucine) (4), cyclo-(4-trans-hydroxy-L-proline-L-leucine) (5), and cyclo-(4-trans-hydroxy-L-proline-L-phenylalanine) (6), were isolated from the ethyl acetate extracts of Streptomyces gougerotii GT and Microbulbifer variabilis C-03. Compounds 3, 4, 5, and 6 exhibited a significant reduction effect on dengue virus type 2 replication with EC50 values of 21.2, 16.5, 12.3, and 11.2 µM, respectively.
- Protective Effect of Silybum marianum and Silibinin on Endothelial Cells Submitted to High Glucose Concentration. [JOURNAL ARTICLE]
- Planta Med 2016 Aug 15.
Silybum marianum Gaertn. (Milk thistle) has been used since ancient times for the relief of liver diseases characterized by intense oxidative stress such as inflammatory liver disease and cirrhosis. As oxidative stress by hyperglycemia is involved in micro- and macrovascular complications of type 2 diabetes, our aim was to assess the protective effect of milk thistle seed extract against oxidative stress induced by a high glucose concentration on endothelial cells (EA.hy926 cells). High-performance liquid chromatographic analysis shows flavonolignans silychristin and silibinin A and B as major components. No cell toxicity was observed for concentrations up to 100 µg/mL of milk thistle extract for 24 h. Concentrations of 5-25 µg/mL of the extract were used to assess the protective effect on EA.hy926 cells treated with 30 mM glucose for 24 h. Oxidative damage by 30 mM glucose was shown as a significant decrease in reduced glutathione and a significant increase in protein carbonyls and antioxidant enzyme activities. S. marianum extract recovered reduced glutathione and balanced the elevated carbonyls and enzyme activity. Silibinin alone also recovered reduced glutathione and antioxidant enzymes. S. marianum protects endothelial cell against oxidative damage by modulating antioxidant enzyme activity, reduced glutathione, and protein carbonyl levels.
- 6-Gingerol Suppresses Adipocyte-Derived Mediators of Inflammation In Vitro and in High-Fat Diet-Induced Obese Zebra Fish. [JOURNAL ARTICLE]
- Planta Med 2016 Aug 15.
The present study was performed to investigate the molecular mechanism of 6-gingerol on adipocyte-mediated systemic inflammation in vitro and in high-fat diet-induced obese zebra fish. 6-Gingerol decreased adipogenesis due to the suppression of adipocyte differentiation markers, including peroxisome proliferator-activated receptor gamma, CCAATT enhancer binding protein α, and adipocyte protein 2, and triglyceride synthesis enzymes, including sterol regulatory element-binding protein-1, fatty acid synthase, lysophosphatidic acid acyltransferase, and acyl-coA : diacylglycerol acyltransferase 1, in 3T3-L1. A coculture insert system using 3T3-L1 with RAW 264.7 (coculture insert system using fully differentiated 3T3-L1 cells with RAW 264.7 macrophages) revealed that 6-gingerol increased anti-inflammatory cytokine interleukin-10. The expression of TNFα, monocyte chemotactic protein-1, interleukin-1β, and interleukin-6 were decreased in the coculture insert system using fully differentiated 3T3-L1 cells with RAW 264.7 macrophages treated with 6-gingerol. Moreover, the coculture insert system using fully differentiated 3T3-L1 cells with RAW 264.7 macrophages treated with 6-gingerol inhibited the protein expression of TNFα and monocyte chemotactic protein-1 in RAW 264.7. 6-Gingerol decreased c-JUN N-terminal kinase and I kappa B kinase beta and its downstream target AP-1 expression in the coculture insert system using fully differentiated 3T3-L1 cells with RAW 264.7 macrophages. Furthermore, 6-gingerol decreased the expression of inducible nitric oxide synthase stimulated by the coculture insert system using fully differentiated 3T3-L1 cells with RAW 264.7 macrophages in RAW 264.7 and attenuated nitric oxide production in diet-induced obese zebra fish. Our results suggest that 6-gingerol suppresses inflammation through the regulation of the c-JUN N-terminal kinase-I kappa B kinase beta and its downstream targets.
- Amyrins from Protium heptaphyllum Reduce High-Fat Diet-Induced Obesity in Mice via Modulation of Enzymatic, Hormonal And Inflammatory Responses. [JOURNAL ARTICLE]
- Planta Med 2016 Aug 15.
Obesity remains a global problem. In search of phytochemicals that have antiobesity potential, this study evaluated α,β-amyrin, a triterpenoid mixture from Protium heptaphyllum, on high-fat diet-induced obesity in mice. Groups of mice (n = 8) were fed a normal diet or a high-fat diet, and were orally treated or not treated with either α,β-amyrin (10 or 20 mg/kg) or sibutramine (10 mg/kg) for 15 weeks. Variables measured at termination were body weight, visceral fat accumulation, adipocyte surface area, peroxisome proliferator-activated receptor gamma, and lipoprotein lipase expressions in adipose tissue, the levels of plasma glucose and insulin, the satiety hormones ghrelin and leptin, the digestive enzymes amylase and lipase, and the inflammatory mediators TNF-α, interleukin-6, and MCP-1. Results showed that α,β-amyrin treatment resulted in lower high-fat diet-induced increases in body weight, visceral fat content, adipocyte surface area, peroxisome proliferator-activated receptor gamma, and lipoprotein lipase expressions, and blood glucose and insulin levels. Additionally, the markedly elevated leptin and decreased ghrelin levels seen in the high-fat diet-fed control mice were significantly modulated by α,β-amyrin treatment. Furthermore, α,β-amyrin decreased serum TNF-α and MCP-1. These results suggest that α,β-amyrin could be beneficial in reducing high-fat diet-induced obesity and associated disorders via modulation of enzymatic, hormonal, and inflammatory responses.
- In Vitro Metabolism Evaluation of the Ergot Alkaloid Dihydroergotamine: Application of Microsomal and Biomimetic Oxidative Model. [JOURNAL ARTICLE]
- Planta Med 2016 Aug 2.
Dihydroergotamine is a semisynthetic natural product derived from ergotamine, an ergot alkaloid. It is used to treat migraines, a neurological disease characterized by recurrent moderate to severe headaches. In this work, the in vitro metabolism of dihydroergotamine was evaluated in a biomimetic phase I reaction, aiming to verify all possible formed metabolites. Dihydroergotamine was submitted to an in vitro metabolism assay using rat liver microsomes, and the metabolites were analyzed by HPLC-MS/MS. The biomimetic reactions were performed with Jacobsen catalyst for scaling up production of oxidized metabolites. Two hydroxylated metabolites were isolated and characterized by MS/MS and (1)H NMR analysis.