Showing papers in "Planta Medica in 2013"

Pharmacological properties of shikonin - a review of literature since 2002

Abstract: The naphthoquinone shikonin is the main active principle of Zicao, a traditional Chinese herbal medicine made from the dried root of Lithospermum erythrorhizon. Studies carried out over the past 30 years have provided a scientific basis for the use of Zicao which has been long employed in folk medicine to treat a variety of inflammatory and infectious diseases. In particular, shikonin has been shown to possess many diverse properties, including antioxidant, anti-inflammatory, antithrombotic, antimicrobial, and wound healing effects. The fact that shikonin shows so many beneficial properties has increased the interest in this molecule dramatically, especially in the past few years. The aim of this review is to provide an update of the new data published on shikonin, whose wide spectrum of pharmacological effects as well as pharmacokinetic properties and toxicity make it a highly interesting target molecule.

Topical application of St. John's wort (Hypericum perforatum).

Abstract: St. Johnʼs wort (Hypericum perforatum) has been intensively investigated for its antidepressive activity, but dermatological applications also have a long tradition. Topical St. Johnʼs wort preparations such as oils or tinctures are used for the treatment of minor wounds and burns, sunburns, abrasions, bruises, contusions, ulcers, myalgia, and many others. Pharmacological research supports the use in these fields. Of the constituents, naphthodianthrones (e.g., hypericin) and phloroglucinols (e.g., hyperforin) have interesting pharmacological profiles, including antioxidant, anti-inflammatory, anticancer, and antimicrobial activities. In addition, hyperforin stimulates growth and differentiation of keratinocytes, and hypericin is a photosensitizer which can be used for selective treatment of nonmelanoma skin cancer. However, clinical research in this field is still scarce. Recently, sporadic trials have been conducted in wound healing, atopic dermatitis, psoriasis, and herpes simplex infections, partly with purified single constituents and modern dermatological formulations. St. Johnʼs wort also has a potential for use in medical skin care. Composition and stability of pharmaceutical formulations vary greatly depending on origin of the plant material, production method, lipophilicity of solvents, and storage conditions, and this must be regarded with respect to practical as well as scientific purposes.

The effects of berberine on blood lipids: a systemic review and meta-analysis of randomized controlled trials.

Abstract: Clinical trials have reported lipid-lowering effects of berberine intake, but the findings have been inconsistent. The aim of this meta-analysis was to assess the safety of berberine and its effects on blood lipid profiles. A systemic review was designed, undertaken and reported in accordance with the PRISMA statement. Randomized controlled trials of the effects of berberine on blood lipids in adults were included. Study population characteristics and the main results, including changes in the levels of total cholesterol, triglycerides, low-density and high-density lipoprotein cholesterol, were extracted. Weighted mean differences were calculated for net changes in blood lipid concentrations using fixed-effect or random-effects models. After filtering, eleven randomized controlled trials (including a total of 874 participants) were included in this study. The methodological quality of these studies was generally low. The final analysis showed that administration of berberine produced a significant reduction in total cholesterol (mean difference − 0.61 mmol/L; 95 % confidence interval − 0.83 to − 0.39), triglycerides (mean difference − 0.50 mmol/L; 95 % confidence interval − 0.69 to − 0.31), and low-density lipoprotein cholesterol (mean difference − 0.65 mmol/L; 95 % confidence interval − 0.76 to − 0.54) levels, with a remarkable increase in high-density lipoprotein (mean difference 0.05 mmol/L; 95 % confidence interval 0.02 to 0.09). No serious adverse effects of berberine have been reported. In conclusion, berberine may have beneficial effects in the control of blood lipid levels. However, the efficacy of berberine in treating hyperlipidemia should be further evaluated by more randomized controlled trials in a larger population of patients.

From olive drupes to olive oil. An HPLC-orbitrap-based qualitative and quantitative exploration of olive key metabolites.

Abstract: The aim of the current study was the qualitative exploration and quantitative monitoring of key olive secondary metabolites in different production steps (drupes, paste, first and final oil) throughout a virgin olive oil production line. The Greek variety Koroneiki was selected as one of the most representative olives, which is rich in biological active compounds. For the first time, an HPLC-Orbitrap platform was employed for both qualitative and quantitative purposes. Fifty-two components belonging to phenyl alcohols, secoiridoids, flavonoids, triterpenes, and lactones were identified based on HRMS and HRMS/MS data. Nine biologically and chemically significant metabolites were quantitatively determined throughout the four production steps. Drupes and paste were found to be rich in several components, which are not present in the final oil. The current study discloses the chemical nature of different olive materials in a successive and integrated way and reveals new sources of high added value constituents of olives.

Curcumin: therapeutical potential in ophthalmology.

Abstract: Curcumin (diferuloylmethane) is the main curcuminoid of the popular Indian spice turmeric (Curcuma longa). In the last 50 years, in vitro and in vivo experiments supported the main role of polyphenols and curcumin for the prevention and treatment of many different inflammatory diseases and tumors. The anti-inflammatory, antioxidant, and antitumor properties of curcumin are due to different cellular mechanisms: this compound, in fact, produces different responses in different cell types. Unfortunately, because of its low solubility and oral bioavailability, the biomedical potential of curcumin is not easy to exploit; for this reason more attention has been given to nanoparticles and liposomes, which are able to improve curcuminʼs bioavailability. Pharmacologically, curcumin does not show any dose-limiting toxicity when it is administered at doses of up to 8 g/day for three months. It has been demonstrated that curcumin has beneficial effects on several ocular diseases, such as chronic anterior uveitis, diabetic retinopathy, glaucoma, age-related macular degeneration, and dry eye syndrome. The purpose of this review is to report what has so far been elucidated about curcumin properties and its potential use in ophthalmology.

Plants: A Source for New Antimycobacterial Drugs

Abstract: Tuberculosis, also called TB, is currently a major health hazard due to multidrug-resistant forms of bacilli. Global efforts are underway to eradicate TB using new drugs with new modes of action, higher activity, and fewer side effects in combination with vaccines. For this reason, unexplored new sources and previously explored sources were examined and around 353 antimycobacterial compounds (Nat Prod Rep 2007; 24: 278–297) 7 have been previously reported. To develop drugs from these new sources, additional work is required for preclinical and clinical results. Since ancient times, different plant part extracts have been used as traditional medicines against diseases including tuberculosis. This knowledge may be useful in developing future powerful drugs. Plant natural products are again becoming important in this regard. In this review, we report 127 antimycobacterial compounds and their antimycobacterial activities. Of these, 27 compounds had a minimum inhibitory concentration of < 10 µg/mL. In some cases, the mechanism of activity has been determined. We hope that some of these compounds may eventually develop into effective new drugs against tuberculosis.

Daphniphyllum Alkaloids: Recent Findings on Chemistry and Pharmacology

Abstract: The unique polycyclic fused ring systems of Daphniphyllum alkaloids, along with their extensive bioactivities, make this family of alkaloids especially attractive targets for total synthesis and biogenetic studies. Successive discoveries of new alkaloids with unprecedented skeletons have made a great contribution to structural diversities of alkaloids elaborated by plants of the genus Daphniphyllum. By the end of 2008, more than 200 alkaloids belonging to 14 different skeletal types have been isolated from different parts of plants of thirteen Daphniphyllum species. These alkaloids show cytotoxic, antioxidant, vasorelaxant, and antiplatelet activating factor effects. The plausible biosynthetic pathways for Daphniphyllum alkaloids have been proposed and biomimetic total syntheses of some alkaloids completed. To provide an update of the previous reviews published in 2009, new structures, synthesis, and bioactivity of Daphniphyllum alkaloids reported in recent years are presented in this article. In the meantime, an additional 54 novel alkaloids have been isolated and identified. Among them, some possess unprecedented frameworks. Several inspired organic syntheses were completed.

Structure-activity relationship study of biflavonoids on the Dengue virus polymerase DENV-NS5 RdRp.

Abstract: Dengue virus is the worldʼs most prevalent human pathogenic arbovirus. There is currently no treatment or vaccine, and solutions are urgently needed. We previously demonstrated that biflavonoids from Dacrydium balansae, an endemic gymnosperm from New Caledonia, are potent inhibitors of the Dengue virus NS5 RNA-dependent RNA polymerase. Herein we describe the structure-activity relationship study of 23 compounds: biflavonoids from D. balansae (1–4) and from D. araucarioides (5–10), hexamethyl-amentoflavone (11), cupressuflavone (12), and apigenin derivatives (13–23). We conclude that 1) over the four different biflavonoid skeletons tested, amentoflavone (1) and robustaflavone (5) are the most promising ones for antidengue drug development, 2) the number and position of methyl groups on the biflavonoid moiety modulate their inhibition of Dengue virus NS5 RNA-dependent RNA polymerase, and 3) the degree of oxygenation of flavonoid monomers influences their antidengue potential. Sotetsuflavone (8), with an IC50 = 0.16 µM, is the most active compound of this series and is the strongest inhibitor of the Dengue virus NS5 RNA-dependent RNA polymerase described in the literature.

Screening of natural compounds as activators of the keap1-nrf2 pathway.

Abstract: Nuclear factor erythroid 2-related factor 2 is a master regulator that promotes transcription of cytoprotective genes in response to oxidative/electrophilic stress. A large number of natural dietary compounds are thought to protect against oxidative stress, and a few have been reported to induce genes involved in antioxidant defense through activating nuclear factor erythroid 2-related factor 2. Therefore, a library of 54 natural compounds were collected to determine whether they are nuclear factor erythroid 2-related factor 2 activators and to compare their efficacy and potency to activate nuclear factor erythroid 2-related factor 2. The assay utilized AREc32 cells that contain a luciferase gene under the control of antioxidant response element promoters. Each natural compound was tested at 13 concentrations between 0.02 and 30 µM. Known nuclear factor erythroid 2-related factor 2 activators tert -butylhydroquinone and 2-cyano-3,12-dioxooleana-1,9-diene-28-imidazolide were used as positive controls in parallel with the natural compounds. Among the 54 tested natural compounds, andrographolide had the highest efficacy, followed by trans -chalcone, sulforaphane, curcumin, flavone, kahweol, and carnosol, all of which had better efficacy than tert -butylhydroquinone. Among the compounds tested, 2-cyano-3,12-dioxooleana-1,9-diene-28-imidazolide was the most potent, having an EC 50 of 0.41 µM. Seven of the natural compounds, namely andrographolide, trans -chalcone, sulforaphane, curcumin, flavone, kahweol, and cafestol had lower EC 50 values than tert -butylhydroquinone but higher than 2-cyano-3,12-dioxooleana-1,9-diene-28-imidazolide. The present study provides insights into which natural compounds activate the Keap1-nuclear factor erythroid 2-related factor 2 pathway and thus might be useful for detoxifying oxidative/electrophilic stress.

New Concepts, Experimental Approaches, and Dereplication Strategies for the Discovery of Novel Phytoestrogens from Natural Sources

Abstract: Phytoestrogens constitute an attractive research topic due to their estrogenic profile and their biological involvement in womanʼs health. Therefore, numerous studies are currently performed in natural products chemistry area aiming at the discovery of novel phytoestrogens. The main classes of phytoestrogens are flavonoids (flavonols, flavanones), isoflavonoids (isoflavones, coumestans), lignans, stilbenoids as well as miscellaneous chemical groups abundant in several edible and/or medicinal plants, belonging mostly to the Leguminosae family. As for other bioactives, the detection of new structures and more potent plant-derived phytoestrogens typically follows the general approaches currently available in the natural product discovery process. Plant-based approaches selected from traditional medicine knowledge and bioguided concepts are routinely employed. However, these approaches are associated with serious disadvantages such as time-consuming, repeated, and labor intensive processes as well as lack of specificity and reproducibility. In recent years, the natural products chemistry became more technology-driven, and several different strategies have been developed. Structure-oriented procedures and miniaturized approaches employing advanced hyphenated analytical platforms have recently emerged. They facilitate significantly not only the discovery of novel phytoestrogens but also the dereplication procedure leading to the anticipation of major drawbacks in natural products discovery. In this review, apart from the traditional concepts followed in phytochemistry for the discovery of novel biologically active compounds, recent applications in the field of extraction, analysis, fractionation, and identification of phytoestrogens will be discussed. Moreover, specific methodologies combining identification of actives and biological evaluation in parallel, such as liquid chromatography-biochemical detection, frontal affinity chromatography-mass spectrometry and pulsed ultrafiltration-MS will also be presented. Finally, miniaturized methods (microchip and biosensor) will be also discussed. With the current review, we attempt to give a wide and holistic overview of the different approaches which could be employed in the discovery of new phytoestrogens. On the other hand, we anticipate to attract more scientists to the area of phytoestrogens and to indicate the need of multidisciplinary concepts.

Effect of topical application of chlorogenic acid on excision wound healing in rats.

Abstract: This study was undertaken to evaluate the therapeutic effects of topical chlorogenic acid on excision wounds in Wistar rats. A 1 % (w/w) chlorogenic acid or silver sulfadiazine ointment was applied topically once a day for 15 days on full-thickness excision wounds created on rats. The 1 % (w/w) chlorogenic acid ointment had potent wound healing capacity as evident from the wound contraction on the 15th post-surgery day, which was similar to that produced by 1 % (w/w) silver sulfadiazine ointment. Increased rates of epithelialization were observed in the treated rats. It also improved cellular proliferation, increased tumor necrosis factor-α levels during the inflammatory phase (12 h, 24 h, 48 h, and 72 h post-wounding) of wound healing, upregulated transforming growth factor-β1 and elevated collagen IV synthesis in the chlorogenic acid-treated group. The results also indicated that chlorogenic acid possesses potent antioxidant activity by increasing superoxide dismutase, catalase, and glutathione, and decreasing lipid peroxidation. In conclusion, these results demonstrate that topical application of chlorogenic acid can accelerate the process of excision wound healing by its ability to increase collagen synthesis through upregulation of key players such as tumor necrosis factor-α and transforming growth factor-β1 in different phases of wound healing as well as by its antioxidant potential.

Antitumor activity of PEGylated nanoliposomes containing crocin in mice bearing C26 colon carcinoma.

Abstract: Crocin is a pharmacologically active component of Crocus sativus. It is an unusual water-soluble carotenoid responsible for the red color of saffron. In various studies, the anticancer effect of saffron and its constituents has been established. Polyethylene glycolated nanoliposomes with a size range up to 200 nm are suitable for encapsulation of cytotoxic drugs and can target tumors passively through the enhanced permeation and retention effect. The aim of this study was to develop a nanoliposomal formulation containing crocin with a higher therapeutic index for the treatment of cancer. Four formulations of polyethylene glycolated nanoliposomes containing 25 mg/ml crocin were prepared with hydrogenated soy phosphatidylcholine, cholesterol, and methoxy-polyethylene glycol (MW 2000)-distearoylphosphatidylcholine at different molar ratios by a solvent evaporation method plus extrusion. Then the liposomes were characterized for their size, zeta potential, crocin encapsulation, release properties, and in vitro cytotoxicity against C26 colon carcinoma cells. Based on in vitro results, the best formulation was selected for an in vivo study, and its antitumor activity was evaluated in BALB/c mice bearing C26 colon carcinoma. The IC50 of crocin itself against C26 colon carcinoma was 0.73 mM. The characterization of the best formulation was as follow: Z-average size: 127.6 ± 1.5 nm; polydispersity index: 0.087 ± 0.018; zeta potential: − 21.7 mV ± 6.7; % encapsulation: 84.62 ± 0.59; % release after 168 hours in RPMI 1640 containing 30 % FBS: 16.26 ± 0.01 %. Liposomal crocin at doses of 50 and 100 mg/kg significantly decreased tumor size and increased survival rate compared with PBS and crocin in buffer (100 mg/kg) groups. The results of this study indicated that liposomal encapsulation of crocin could increase its antitumorigenic activity. Thus, to obtain an optimal dose for use in humans, the formulation merits further investigation.

Cardiotonic steroids-mediated Na+/K+-ATPase targeting could circumvent various chemoresistance pathways.

Abstract: Many cancer patients fail to respond to chemotherapy because of the intrinsic resistance of their cancer to pro-apoptotic stimuli or the acquisition of the multidrug resistant phenotype during chronic treatment. Previous data from our groups and from others point to the sodium/potassium pump (the Na+/K+-ATPase, i.e., NaK) with its highly specific ligands (i.e., cardiotonic steroids) as a new target for combating cancers associated with dismal prognoses, including gliomas, melanomas, non-small cell lung cancers, renal cell carcinomas, and colon cancers. Cardiotonic steroid-mediated Na+/K+-ATPase targeting could circumvent various resistance pathways. The most probable pathways include the involvement of Na+/K+-ATPase β subunits in invasion features and Na+/K+-ATPase α subunits in chemosensitisation by specific cardiotonic steroid-mediated apoptosis and anoikis-sensitisation; the regulation of the expression of multidrug resistant-related genes; post-translational regulation, including glycosylation and ubiquitinylation of multidrug resistant-related proteins; c-Myc downregulation; hypoxia-inducible factor downregulation; NF-κB downregulation and deactivation; the inhibition of the glycolytic pathway with a reduction of intra-cellular ATP levels and an induction of non-apoptotic cell death. The aims of this review are to examine the various molecular pathways by which the NaK targeting can be more deleterious to biologically aggressive cancer cells than to normal cells.

Botanical modulation of menopausal symptoms: Mechanisms of action?

Abstract: Menopausal women suffer from a variety of symptoms, including hot flashes and night sweats, which can affect quality of life. Although it has been the treatment of choice for relieving these symptoms, hormone therapy has been associated with increased breast cancer risk leading many women to search for natural, efficacious, and safe alternatives such as botanical supplements. Data from clinical trials suggesting that botanicals have efficacy for menopausal symptom relief have been controversial, and several mechanisms of action have been proposed including estrogenic, progestogenic, and serotonergic pathways. Plant extracts with potential estrogenic activities include soy, red clover, kudzu, hops, licorice, rhubarb, yam, and chasteberry. Botanicals with reported progestogenic activities are red clover, hops, yam, and chasteberry. Serotonergic mechanisms have also been proposed since women taking antidepressants often report a reduction in hot flashes and night sweats. Black cohosh, kudzu, kava, licorice, and dong quai all either have reported 5-hydroxytryptamine receptor 7 ligands or inhibit serotonin reuptake, therefore have potential serotonergic activities. Understanding the mechanisms of action of these natural remedies used for women's health could lead to more efficacious formulations and to the isolation of active components which have the potential of becoming effective medications in the future.

2-(2-phenylethyl)chromone derivatives in Chinese agarwood "Qi-Nan" from Aquilaria sinensis.

Abstract: Five new 2-(2-phenylethyl)chromone derivatives, qinanones A−E (1–5), together with eight known 2-(2-phenylethyl)chromone derivatives (6–13), were isolated from the Et2O extract of high-quality Chinese agarwood “Qi-Nan” originating from Aquilaria sinensis. The structures of the new 2-(2-phenylethyl)chromones were elucidated by spectroscopic techniques (UV, IR, 1D and 2D NMR) and MS analyses. In the bioassay for acetylcholinesterase inhibitors, compounds 1–6, 10, and 12 exhibited weak inhibitory activities (inhibition percentage ranged from 10 % to 24 % at the concentration of 50 µg/mL). Compared with other agarwoods, “Qi-Nan” was different in containing 2-(2-phenylethyl)chromones with unsubstituted chromone rings.

Antioxidative and anti-inflammatory activities of paeoniflorin and oxypaeoniflora on AGEs-induced mesangial cell damage.

Abstract: Paeonia suffruticosa, an important traditional herbal medicine, has been reported to prevent the pathogenesis of diabetic nephropathy through modulating advanced glycation end products-induced inflammatory and oxidative stress responses. However, little was known about the protective effect of the two major compounds in P. suffruticosa, paeoniflorin and oxypaeoniflora, on advanced glycation end products-induced mesangial cell damage. In the present study, we investigated the protective activities of paeoniflorin and oxypaeoniflora on advanced glycation end product-induced oxidative stress and inflammation in mesangial cells HBZY-1. The IC50 values of paeoniflorin and oxypaeoniflora for inhibiting 2,2′-azinobis-(3-thylbenzothiazoline-6-sulfonic acid) formation were 4.197 × 10−4 M and 1.002 × 10−4 M, respectively. The pretreatment with paeoniflorin and oxypaeoniflora (10−8–10−4 M) significantly increased advanced glycation end product-induced glutathione peroxidase and catalase activities. In the coculture system of HBZY-1 and macrophages, paeoniflorin and oxypaeoniflora could inhibit remarkably the migration of macrophages. Furthermore, paeniflorin and oxypaeniflora attenuated markedly advanced glycation end products-induced inflammation cytokines interleukin-6 and monocyte chemoattractant protein-1 levels in ELISA and western blot analysis in a dose-dependent manner. Taken together, our data provided the reliable evidence that paeniflorin and oxypaeniflora were able to attenuate advanced glycation end products-induced oxidative damage and inflammation in mesangial cells. Paeniflorin and oxypaeniflora might therefore have a beneficial effect in the treatment of diabetic nephropathy.

Abietane diterpenoids from Salvia sahendica--antiprotozoal activity and determination of their absolute configurations.

Abstract: In a screening of Iranian plants for antiprotozoal activity, an n-hexane extract of the roots of Salvia sahendica potently inhibited the growth of Plasmodium falciparum K1 strain. Subsequent HPLC-based activity profiling led to the identification of seven known and one new abietane-type diterpenoid. Structure elucidation was achieved by analysis of spectroscopic data including 1D and 2D NMR. The absolute configuration of sahandol (7) and sahandone (8) were assigned by comparison of experimental ECD spectra with calculated ECD data, using time-dependent density functional theory and methanol as the solvent. In vitro biological activity against P. falciparum and Trypanosoma brucei rhodesiense STIB 900 strain and cytotoxicity in rat myoblast (L6) cells were determined. The IC50 values of the compounds ranged from 0.8 µM to over 8.8 µM against P. falciparum, and from 1.8 µM to over 32.3 µM against T. brucei rhodesiense. The cytotoxic IC50 values ranged from 0.5-15.5 µM. Selectivity indices for P. falciparum were 0.1 to 18.2, and 0.1 to 1.2 for T. brucei rhodesiense.

Hop extracts and hop substances in treatment of menopausal complaints.

Abstract: Hop extract is a long used medicinal product and, regarding hormonal activities, in 1999 a number of prenylflavanones have been identified as its major constituents with 8-prenylnaringenin (8- PN) being the main active estrogenic compound. There have been several in vivo studies performed that demonstrate the potential of hop extract and the single compound 8-PN to alleviate climacteric symptoms like osteoporosis, vasomotoric com- plaints, and sexual motivation. On the other hand, onlya fewclinical studies have been performed so far, and these mainly focused on menopausal dis- comforts, especially hot flushes, yielding rather inconclusive results. Despite preferentially acti- vating estrogen receptor α, 8-PN is only slightly uterotrophic, but it also elucidates estrogenic ef- fects on the mammary gland. In conclusion, although hop extract and especially 8-PN are promising candidates as a relief for climacteric symptoms, data on the safety and efficacy is still scarce. " Humulus lupulus L. l " Cannabaceae l " menopause

Chemical Constituents and Anticancer Effects of the Essential Oil from Leaves of Xylopia laevigata

Abstract: Xylopia laevigata, popularly known as “meiu” and “pindaiba”, is a medicinal plant used in the folk medicine of the Brazilian Northeast for several purposes. The chemical constituents of the essential oil from leaves of X. laevigata, collected from wild plants growing at three different sites of the remaining Atlantic forest in Sergipe State (Brazilian Northeast), were analyzed by GC/FID and GC/MS. The effect of the essential oil samples was assessed on tumor cells in culture, as well on tumor growth in vivo. All samples of the essential oil were dominated by sesquiterpene constituents. A total of 44 compounds were identified and quantified. Although some small differences were observed in the chemical composition, the presence of γ-muurolene (0.60–17.99 %), δ-cadinene (1.15–13.45 %), germacrene B (3.22–7.31 %), α-copaene (3.33–5.98 %), germacrene D (9.09–60.44 %), bicyclogermacrene (7.00–14.63 %), and (E)-caryophyllene (5.43–7.98 %) were verified as major constituents in all samples of the essential oil. In the in vitro cytotoxic study, the essential oil displayed cytotoxicity to all tumor cell lines tested, with the different samples displaying a similar profile; however, they were not hemolytic or genotoxic. In the in vivo antitumor study, tumor growth inhibition rates were 37.3–42.5 %. The treatment with the essential oil did not significantly affect body weight, macroscopy of the organs, or blood leukocyte counts. In conclusion, the essential oil from the leaves of X. laevigata is chemically characterized by the presence of γ-muurolene, δ-cadinene, germacrene B, α-copaene, germacrene D, bicyclogermacrene, and (E)-caryophyllene as major constituents and possesses significant in vitro and in vivo anticancer potential.

Cytotoxic dihydrothiophene-condensed chromones from the marine-derived fungus Penicillium oxalicum.

Abstract: Two new dihydrothiophene-condensed chromones and a new natural chromone, namely oxalicumones A-C (1-3), respectively, were isolated from a culture broth of a marine-derived fungus Penicillium oxalicum SCSGAF 0023, Meripilaceae family. The structures of 1-3 and acetylated derivatives of 1 (4-7) were elucidated on the basis of spectroscopic methods and chemical reactions. The absolute configuration of 1 was established by using the modified Mosher ester method and circular dichroism data of in situ formed [Rh-2(OCOCF3)(4)] and [Mo-2(OAc)(4)] complexes. (R)-MTPA ester of 1 showed cytotoxicity against A375, SW-620, and HeLa carcinoma cell lines with IC50 values of 8.9, 7.8, and 18.4 mu M, respectively. Compound 1 displayed cytotoxicity against A375 and SW-620 cell lines with IC50 values of 11.7 and 22.6 mu M, respectively. The structure-biological activity relationship of 1 is discussed.

Anthelmintic Activity of the Natural Compound (+)-Limonene Epoxide against Schistosoma mansoni

Abstract: Blood fluke of the genus Schistosoma are the etiological agents of human schistosomiasis, an important neglected tropical disease that afflicts over 200 million people worldwide. The treatment for this disease relies heavily on a single drug, praziquantel. Recent reports of praziquantel resistance raise concerns about future control of the disease and show the importance of developing new antischistosomal drugs. Currently, natural products have been a good source for drug development. (+)-Limonene epoxide is a mixture of cis and trans isomers found in many plants. Here, we report the in vitro effect of this natural compound on the survival time of Schistosoma mansoni adult worms. In addition, we examined alterations on the tegumental surface of adult schistosomes by means of confocal laser scanning microscopy. The effects of (+)-limonene epoxide at 25 µg/mL on S. mansoni adult worms were similar to those of the positive control (praziquantel), with reduction in motility and death of all worms after 120 h. Confocal laser scanning microscopy revealed that (+)-limonene epoxide-mediated worm killing was associated with tegumental destruction. Our results, along with the low toxicity of the (+)-limonene epoxide, suggest that this natural compound might be promising for the development of new schistosomicidal agents.

Alterations in sulfur amino acid metabolism in mice treated with silymarin: a novel mechanism of its action involved in enhancement of the antioxidant defense in liver.

Abstract: It has been known that silymarin exhibits protective activity against oxidative liver injury induced by various hepatotoxicants, but the underlying mechanism of its beneficial action remains unclear. We determined the alterations in sulfur-containing amino acid metabolism induced by silymarin in association with its effects on the antioxidant capacity of liver. Male mice were treated with silymarin (100 or 200 mg/kg, p. o.) every 12 h for a total of 3 doses, and sacrificed 6 h after the final dosing. The hepatic methionine level was increased, but the activity and protein expression of methionine adenosyltransferase were decreased by silymarin in a dose-dependent manner. S-Adenosylmethionine or homocysteine concentration was not changed, whereas the sulfur-containing metabolites generated from homocysteine in the transsulfuration pathway including cystathionine, cysteine, and glutathione were increased significantly. Cystathionine β-synthase was induced, but cysteine dioxygenase was downregulated, both of which would contribute to the elevation of cysteine and its product, glutathione, in liver. Oxygen radical scavenging capacity of liver cytosol against peroxyl radical and peroxynitrite was increased, and also hepatic lipid peroxidation was diminished in the silymarin-treated mice. Taken together, the results demonstrate that silymarin enhances hepatic glutathione generation by elevating cysteine availability via an increment in cysteine synthesis and an inhibition of its catabolism to taurine, which may subsequently contribute to the antioxidant defense of liver.

Application of plant metabonomics in quality assessment for large-scale production of traditional Chinese medicine.

Abstract: The curative effects of traditional Chinese medicines are principally based on the synergic effect of their multi-targeting, multi-ingredient preparations, in contrast to modern pharmacology and drug development that often focus on a single chemical entity. Therefore, the method employing a few markers or pharmacologically active constituents to assess the quality and authenticity of the complex preparations has a number of severe challenges. Metabonomics can provide an effective platform for complex sample analysis. It is also reported to be applied to the quality analysis of the traditional Chinese medicine. Metabonomics enables comprehensive assessment of complex traditional Chinese medicines or herbal remedies and sample classification of diverse biological statuses, origins, or qualities in samples, by means of chemometrics. Identification, processing, and pharmaceutical preparation are the main procedures in the large-scale production of Chinese medicinal preparations. Through complete scans, plants metabonomics addresses some of the shortfalls of single analyses and presents a considerable potential to become a sharp tool for traditional Chinese medicine quality assessment.

In vitro BACE1 inhibitory activity of geraniin and corilagin from Geranium thunbergii.

Abstract: Generation of amyloid β peptide through the proteolytic process of amyloid precursor protein by β-secretase and γ-secretase is a main casual factor of Alzheimer's disease, since amyloid β peptide is a major and crucial component of senile plaques in Alzheimer's disease brains In the process of searching for β-secretase inhibitors from natural resources, the EtOAc soluble fraction of Geranium thunbergii exhibited significant β-secretase inhibitory activity Two compounds, geraniin and corilagin, isolated from the most active EtOAc fraction of G thunbergii, exhibited predominant inhibition against β-secretase with IC₅₀ values of 40 × 10⁻⁶ M and 34 × 10⁻⁵ M, respectively Dixon plot of geraniin and corilagin demonstrated that the β-secretase inhibition was noncompetitive with the substrate, thus clearly suggesting that these compounds might bind either to the β-secretase subsites or to another regulatory domain with Ki values of 28 × 10⁻⁶ M and 79 × 10⁻⁵ M, respectively Both compounds exhibited no significant inhibition against α-secretase and other serine proteases including trypsin and chymotrypsin, showing that they were relatively specific and selective inhibitors of β-secretase These novel findings suggest that geraniin and corilagin from G thunbergii may be effective therapeutic agents for further drug development in Alzheimer's disease

Alfa-glucosidase inhibiting activity of five Mexican plants used in the treatment of type 2 diabetes

Abstract: Type 2 diabetes is an endocrine disease, which accounts for 9% of deaths worldwide. The aim of oral therapy is to reach normoglycemia to prevent later complications. Among glucose-lowering medications, alpha-glucosidase inhibitors delay the absorption of ingested carbohydrates, reducing the postprandial glucose and insulin peaks. In the present study, we tested the butanolic extracts of four Mexican plants with respect to their alpha-glucosidase inhibition activity, without excluding other possible mechanisms of action. The plants Cecropia obtusifolia Bertol., Equisetum myriochaetum Schlecht & Cham, Acosmium panamense (Benth.) Yacolev and Malmea depressa (Baill) R.E. Fries are used in traditional medicine to treat type 2 diabetes. In previous studies, we have demonstrated these plants' hypoglycemic activity and determined the phytochemical composition of their extracts. Our results in n-STZ diabetic rats loaded with maltose showed that Malmea and Acosmium extracts decreased plasma glucose significantly from 30 min on resembling the effect of acarbose. Cecropia extract produced the highest reduction of plasma glucose, and at 90 min, the glucose level was lower than the fasting level, which suggests another mechanism of action. Equisetum did not exert any effect. In vitro assays of alpha-glucosidase activity showed an IC(50) of 14 microg/ml for Cecropia, 21 microg/ml for Malmea, and 109 microg/ml for Acosmium, which were lower than that of acarbose (128 microg/ml). Equisetum did not show any significant effect on this assay, either. These results contribute to understand the mechanism of action of these plants on glucose metabolism.

Two New Flavonol Glycosides and a Metabolite Profile of Bryophyllum pinnatum, a Phytotherapeutic Used in Obstetrics and Gynaecology

Abstract: Bryophyllum pinnatum is a succulent perennial plant native to Madagascar which is used in anthroposophical medicine to treat psychiatric disorders and as a tocolytic agent to prevent premature labour. We performed a metabolite profiling study in order to obtain a comprehensive picture of the constituents in B. pinnatum leaves and to identify chromatographic markers for quality control and safety assessment of medicinal preparations. Preliminary HPLC-PDA-ESIMS analyses revealed that flavonoid glycosides were the main UV-absorbing constituents in the MeOH extract of B. pinnatum. Two phenolic glucosides, syringic acid β-D-glucopyranosyl ester (1) and 4'-O-β-D-glucopyranosyl-cis-p-coumaric acid (2), as well as nine flavonoids (3-11) including kaempferol, quercetin, myricetin, acacetin, and diosmetin glycosides were unambiguously identified by 1H and 2D NMR analysis after isolation from a MeOH extract. The flavonol glycosides quercetin 3-O-α-L-arabinopyranosyl-(1 → 2)-α-L-rhamnopyranoside 7-O-β-D-glucopyranoside (3) and myricetin 3-O-α-L-arabinopyranosyl-(1 → 2)-α-L-rhamnopyranoside (4) were new natural products. With the aid of HPLC-PDA-APCIMS and authentic references isolated from the related species B. daigremontianum, the presence of four bufadienolides, bersaldegenin-1-acetate (12), bryophyllin A (13), bersaldegenin-3-acetate (14), and bersaldegenin-1,3,5-orthoacetate (15) was detected in B. pinnatum.

[6]-Gingerol: A Novel AT1 Antagonist for the Treatment of Cardiovascular Disease

Abstract: Considering the prevalence of cardiovascular disease in public health and the limited validated therapeutic options, this study aimed to find novel compounds targeting the angiotensin II type 1 receptor, accepted as a therapeutic target in cardiovascular disease. A small library consisting of 89 compounds from 39 Chinese herbs was profiled using a cell-based calcium mobilization assay which was developed and characterized for high-throughput screening. [6]-Gingerol derived from Zingiber officinale Roscoe (ginger) was identified as a novel angiotensin II type 1 receptor antagonist, with an IC50 value of 8.173 µM. The hit was further tested by a specificity assay indicating that it had no antagonistic effects on other evaluated GPCRs, such as endothelin receptors. The major ingredient of ginger, [6]-gingerol, could inhibit angiotensin II type 1 receptor activation, which partially clarified the mechanism of ginger regulating blood pressure and strengthening heart in the cardiovascular system.

Antidiabetic attributes of desert and steppic plants: a review.

Abstract: The rapidly increasing incidence of diabetes mellitus is becoming a serious threat to mankindʼs health in all parts of the world. In fact, known cases reflect only part of the problem, as many diabetics, especially with type 2 diabetes, are unaware of their disease, which initially shows no definitive symptoms. Despite the great efforts invested in diabetes research, its prevalence continues to grow, while current medications do not cover all of the symptoms and complications of the disease. The present review highlights a plethora of studies focusing on the antidiabetic properties of desert and semidesert (steppic) plants, many of them being used for centuries in traditional medicine by Bedouins living in the arid zones of the Middle East and also by ethnic groups in other arid and semiarid parts of the world. The review concludes in summarizing the work done on the subject and also in pointing to the yet existing gaps in diabetes research of desert and steppic plants, and suggests directions for future exploration.

Phenolic compounds with in vitro activity against respiratory syncytial virus from the Nigerian lichen Ramalina farinacea.

Abstract: The extract of the Nigerian lichen Ramalina farinacea showed inhibitory activity against the respiratory syncytial virus in a preliminary assay. A follow-up chemical investigation of this lichen led to the isolation of thirteen phenolic compounds (1-13), including one new hydroquinone depside, designated 5-hydroxysekikaic acid (1), and one new orsellinic acid derivative, 2,3-dihydroxy-4-methoxy-6-pentylbenzoic acid (8). Their structures were unambiguously determined by analysis of 1D and 2D NMR and mass spectroscopic data, as well as by comparison with literature data. Compound 1 was found to partially convert to a 1,4-benzoquinone derivative (1a) during storage. The antiviral activities of the isolated compounds were evaluated against the respiratory syncytial virus. Among them, sekikaic acid (2) showed potent inhibition towards a recombinant strain rg respiratory syncytial virus (IC50 5.69 µg/mL) and respiratory syncytial virus A2 strain (IC50 7.73 µg/mL). The effect of sekikaic acid on the cell viability of HEp2 and Vero cell lines was investigated, and the time of addition assay revealed that sekikaic acid clearly interferes with viral replication at a viral post-entry step, which is over 1.3-fold more active than the control ribavirin at 4 hours postinfection addition. Furthermore, sekikaic acid did not display virucidal activity at concentrations below the TC50, whereas the parental extract did.

Natural product libraries: assembly, maintenance, and screening.

Abstract: This review discusses successful strategies and potential pitfalls to assembling a natural product-based library suitable for high-throughput screening. Specific extraction methods for plants, microorganisms, and marine invertebrates are detailed, along with methods for generating a fractionated sub-library. The best methods to store, maintain and prepare the library for screening are addressed, as well as recommendations on how to develop a robust high-throughput assay. Finally, the logistics of moving from an assay hit to pure bioactive compound are discussed.