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Triterpenoids, as one of the largest classes of naturally occurring secondary metabolites in higher plants, are of interest due to their high structural diversity and wide range of biological activities. In addition to several promising pharmacological activities such as antimicrobial, antiviral, antioxidant, anti-inflammatory and hepatoprotective effects, a large number of triterpenoids have revealed high potential for cancer therapy through their strong cytotoxicity on cancer cell lines and, also, low toxicity in normal cells. So, this study was aimed at discovering novel and potentially bioactive triterpenoids from the Salvia urmiensis species. For this, an ethyl acetate fraction of the acetone extract of the aerial parts of the plant was chromatographed to yield five novel polyhydroxylated triterpenoids (1: -5: ). Their structure was elucidated by extensive spectroscopic methods including 1D ( 1 H, 13 C, DEPT-Q) and 2D NMR (COSY, HSQC, HMBC, NOESY) experiments, as well as HRESIMS analysis. Cytotoxic activity of the purified compounds was also investigated by MTT assay against the MCF-7 cancer cell line. Furthermore, a molecular docking analysis was applied to evaluate the inhibition potential of the ligands against the nuclear factor kappa B (NF- κ B) protein, which promotes tumor metastasis or affects gene expression in cancer disease. The 1 β ,11 β ,22 α -trihydroxy-olean-12-ene-3-one (compound 4: ) indicated the best activity in both in vitro and in silico assays, with an IC 50 value of 32 µM and a docking score value of - 3.976 kcal/mol, respectively., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Boswellia is a traditional medicine for bruises and injuries. Its main active ingredient, acetyl-11-keto-beta-boswellic acid, has antioxidant and antiapoptotic effects. In this experiment, we used Sprague-Dawley rats to make a sciatic nerve injury model to detect the transcription factor NF-E2-related factor 2/heme oxygenase 1 signaling pathway and apoptosis, combined with clinical indicators, for testing whether acetyl-11-keto-beta-boswellic acid can reduce oxidative stress and promote sciatic nerve repair. Our results showed that acetyl-11-keto-beta-boswellic acid administration promoted myelin regeneration and functional recovery in the rat sciatic nerve, reduced lipid peroxidation levels, upregulated the expression of various antioxidant enzymes and enhanced enzyme activity, decreased the expression levels of apoptosis-related proteins, and promoted nuclear translocation of the transcription factor NF-E2-related factor 2 protein. In vitro studies revealed that acetyl-11-keto-beta-boswellic acid reduced H 2 O 2 -induced reactive oxygen species production, restored mitochondrial membrane potential, upregulated the expression of various antioxidant enzymes, and downregulated apoptosis-related indicators in Schwann cells, and these therapeutic effects of acetyl-11-keto-beta-boswellic acid were reversed after ML385 treatment in Schwann cells. In summary, acetyl-11-keto-beta-boswellic acid alleviates oxidative stress and apoptosis caused by sciatic nerve injury in rats by activating the transcription factor NF-E2-related factor 2/heme oxygenase 1 signaling pathway, promotes the recovery of sciatic nerve function in rats, and is a promising therapeutic agent to promote sciatic nerve repair by alleviating excessive oxidative stress., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Lyonia doyonensis is a deciduous shrub native to high-altitude regions of Asia. So far, there is no report on any chemical and biological properties of L. doyonensis . An EtOH extract of L. doyonensis twigs and leaves showed inhibitory activities on protein tyrosine phosphatase 1B and lipopolysaccharide-induced inflammation in BV-2 microglial cells. A phytochemical investigation of this extract led to the isolation of a, so far only ambiguously described, 24-norursane-type triterpenoid, now named lyonensinol A (1: ), along with its two new derivatives, lyonensinols B and C (2: and 3: ), and six known triterpenoids (4 - 9: ). Their structures were elucidated by detailed analysis of spectroscopic data. A combination of chemical conversions, electronic circular dichroism, and Mo 2 (OAc) 4 -induced electronic circular dichroism was used to confirm their absolute configurations. Lyonensinols B (2: ) and C (3: ) represent the first examples of norursane-type triterpenoids acylated with a p -coumaroyl moiety. The potential anti-inflammatory and protein tyrosine phosphatase 1B inhibitory activities of all the isolates were evaluated. Compounds 3, 7: , and 8: at 10 µM showed potent inhibitory activities on lipopolysaccharide-induced nitric oxide production in BV-2 microglial cells, with nitric oxide levels decreasing to 31.5, 41.9, and 27.1%, respectively, while compounds 3, 4, 7: , and 8: exhibited notable inhibitory activities against protein tyrosine phosphatase 1B, with IC 50 values ranging from 1.7 to 18.2 µM. Interestingly, compounds 3: and 8: , bearing a C-3 trans - p -coumaroyl group, showed not only more potent anti-inflammatory effects, but also exhibited stronger protein tyrosine phosphatase 1B inhibition than their respective stereoisomers (2: and 7: ) with a cis - p -coumaroyl group., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

In our ongoing research program on the proapoptotic function of saponins, two previously undescribed saponins, named zygiaosides E (1: ) and F (2: ), were isolated from the leaves of Albizia zygia . Their structures were established based on extensive analysis of 1D and 2D NMR data, HR-ESI-MS analysis, and by chemical degradation. The proapoptotic effect of zygiaoside E (1: ) was evaluated on human malignant melanoma (A375), human epidermoid cancer (A431), and normal Homo sapiens skin tissue (TE 353.SK.) cell lines by cytometric analysis. Zygiaoside E (1: ) induced apoptosis of the two human cancer cell lines (A375 and A431) in a dose-dependent manner at 1 µM but did not induce apoptosis in noncancerous skin cells (TE 353.Sk), even when treated with concentrations up to 15 µM. The underlying mechanism of the apoptosis induction activity of zygiaoside E (1: ) on the mitochondrial membrane potential status in A375 cells was further assessed by monitoring the uptake rate of DiOC6, a mitochondrial specific and voltage-dependent fluorescent dye. The number of malignant melanoma cells emitting high fluorescence levels was decreased when cells were treated with 3 or 5 µM of zygiaoside E (1: ) during either 12 or 24 h, thereby revealing a drop of mitochondrial membrane potential in A375 cells upon treatment, which indicated mitochondrial perturbation., Competing Interests: The authors declare that they have no conflict of interest. The findings described herein are a consolidation of independent research carried out in the laboratories of the authors. As such, none of its content in any shape or form is deemed liable to any other individual or organization., (Thieme. All rights reserved.)

Alzheimer's disease is a growing general health concern with huge implications for individuals and society. Beta boswellic acid, a major compound of the Boswellia serrata plant, has long been used for the treatment of various inflammatory diseases. The exact mechanism of beta boswellic acid action in Alzheimer's disease pathogenesis remains unclear. In the current study, the protective effect of beta boswellic acid on streptozotocin-induced sporadic Alzheimer's disease was surveyed. Alzheimer's disease model was induced using streptozotocin followed by an assessment of the treatment effects of beta boswellic acid in the presence of streptozotocin. The prevention effect of beta boswellic acid on Alzheimer's disease induction by streptozotocin was evaluated. Behavioral activities in the treated rats were evaluated. Histological analysis was performed. Phosphorylation of tau protein at residues Ser396 and Ser404 and the expression of reelin protein were determined. Glial fibrillary acidic protein immunofluorescence staining was applied in the hippocampus regions. Our findings indicated that beta boswellic acid decreased traveled distance and escape latency in the prevention (beta boswellic acid + streptozotocin) and treatment (streptozotocin + beta boswellic acid) groups compared to control during the acquisition test. It increased "time spent" (%) in the target quadrant. Reelin level was enhanced in rats treated with beta boswellic acid. Tau hyperphosphorylation (p-tau404) and glial fibrillary acidic protein were decreased in the prevention group while the expression of reelin protein in both groups was increased. We could suggest that the anti-inflammatory property of beta boswellic acid is one of the main factors involving in the improvement of learning and memory in rats. Therefore the antineurodegenerative effect of beta boswellic acid may be due to its ability to reactivate reelin protein., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Retinal diseases are a leading cause of impaired vision and blindness but some lack effective treatments. New therapies are required urgently to better manage retinal diseases. Natural pentacyclic triterpenoids and their derivatives have a wide range of activities, including antioxidative, anti-inflammatory, cytoprotective, neuroprotective, and antiangiogenic properties. Pentacyclic triterpenoids have great potential in preventing and/or treating retinal pathologies. The pharmacological effects of pentacyclic triterpenoids are often mediated through the modulation of signalling pathways, including nuclear factor erythroid-2 related factor 2, high-mobility group box protein 1, 11 β -hydroxysteroid dehydrogenase type 1, and Src homology region 2 domain-containing phosphatase-1. This review summarizes recent in vitro and in vivo evidence for the pharmacological potential of pentacyclic triterpenoids in the prevention and treatment of retinal diseases. The present literature supports the further development of pentacyclic triterpenoids. Future research should now attempt to improve the efficacy and pharmacokinetic behaviour of the agents, possibly by the use of medicinal chemistry and targeted drug delivery strategies., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Centella asiatica , a triterpene-rich medicinal herb, is traditionally used to treat various types of diseases including neurological, dermatological, and metabolic diseases. A few articles have previously reviewed a broad range of pharmacological activities of C. asiatica , but none of these reviews focuses on the use of C. asiatica in cardiovascular diseases. This review aims to summarize recent findings on protective effects of C. asiatica and its active constituents (asiatic acid, asiaticoside, madecassic acid, and madecassoside) in cardiovascular diseases. In addition, their beneficial effects on conditions associated with cardiovascular diseases were also reviewed. Articles were retrieved from electronic databases such as PubMed and Google Scholar using keywords " Centella asiatica ," "asiatic acid," "asiaticoside," "madecassic acid," and "madecassoside." The articles published between 2004 and 2018 that are related to the aforementioned topics were selected. A few clinical studies published beyond this period were also included. The results showed that C. asiatica and its active compounds possess potential therapeutic effects in cardiovascular diseases and cardiovascular disease-related conditions, as evidenced by numerous in silico, in vitro, in vivo , and clinical studies. C. asiatica and its triterpenes have been reported to exhibit cardioprotective, anti-atherosclerotic, antihypertensive, antihyperlipidemic, antidiabetic, antioxidant, and anti-inflammatory activities. In conclusion, more clinical and pharmacokinetic studies are needed to support the use of C. asiatica and its triterpenes as therapeutic agents for cardiovascular diseases. Besides, elucidation of the molecular pathways modulated by C. asiatica and its active constituents will help to understand the mechanisms underlying the cardioprotective action of C. asiatica ., Competing Interests: The authors declare that they have no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Triterpenoids are distributed widely in higher plants and are of interest because of their structural diversity and broad range of bioactivities. In particular, there is a very large literature on the propensity of a variety of triterpenoids to act as potential anticancer agents. In the present review, the anticancer potential is summarized for naturally occurring triterpenoids and their semi-synthetic derivatives, including examples of lupane-, oleanane-, ursane-, and cucurbitane-type pentacyclic triterpenoids, along with dammarane-type tetracyclic triterpenes including ginsenosides and their sapogenins and dichapetalins, which have been characterized as antitumor leads from higher plants. Preliminary structure-activity relationships and reported mechanisms of the antineoplastic-related activity are included. Prior studies for triterpenoids of plant origin are supportive of additional work being conducted on the more detailed biological and mechanistic evaluation for the progression of this type of natural products as possible cancer chemotherapeutic agents., Competing Interests: The authors declare no conflict of interest, financial or otherwise., (Georg Thieme Verlag KG Stuttgart · New York.)

Targeted isolation based on a combination of NMR and HPLC-PDA-MS of a dichloromethane extract of Thymus vulgaris Varico 3 aerial parts afforded one new p -cymene dimer, 6,3',4'-trihydroxy-5,5'-diisopropyl-2,2'-dimethylbiphenyl (1: ), together with two known p -cymene derivatives (2: and 3: ), as well as five known compounds, namely, thymol (4: ), oleanolic acid (5: ), ursolic acid (6: ), cirsimaritin (7: ), and xanthomicrol (8: ). The structural elucidation of all compounds was performed by spectroscopic analyses, including 1D and 2D NMR, and HRESIMS experiments. The biphenyls were assayed for their inhibitory activity on tyrosinase. Compounds 2: and 3: showed negligible activity on tyrosinase, while compound 1: effectively inhibited the enzyme with 35% (± 0.3) inhibitory activity, higher than the inhibition of the reference compound kojic acid (18.6 ± 0.02)., Competing Interests: The authors declare that they have no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Two new arborinane-type triterpenes, myrotheols A (1: ) and B (2: ), two new arborinane-type glycosides, myrothesides C (3: ) and D (4: ), together with four known diterpenes (5:  - 8: ) were isolated from the ethyl acetate extract of the endolichenic fungus Myrothecium inundatum . The structures of new compounds 1:  - 4: were elucidated by NMR and MS analyses. The absolute configuration of 1: was assigned by a single-crystal X-ray diffraction experiment. Compounds 3: and 4: represent the first two natural 4-O-methyl- α -D-mannosides. Compounds 1:  - 8: exhibited cytotoxicity against K562 and RKO human cancer cell lines., Competing Interests: The authors declare no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Damulin B, a dammarane-type saponin from steamed Gynostemma pentaphyllum , exhibits the strongest activity against human lung carcinoma A549 cells among the isolated active saponins. In this study, the structure-activity relationship of a series of saponin compounds was discussed. The inhibitory effect of damulin B on human lung cancer A549 and H1299 cells was investigated from apoptosis, cell cycle, and migration aspects. In vitro , human lung cancer cells were more susceptible to damulin B treatment than human normal fibroblasts. Damulin B exhibited a strong cytotoxic effect, as evidenced by the increase of apoptosis rate, reduction of mitochondrial membrane potential (MMP), generation of reactive oxygen species, and G0/G1 phase arrest. Furthermore, damulin B activated the following: both intrinsic and extrinsic apoptosis pathways along with early G1 phase arrest via the upregulation of the Bax, Bid, tBid, cleaved caspase-8, and p53 expression levels; downregulation of the procaspase-8/-9, CDK4, CDK6, and cyclin D1 expression levels; and more release of cytochrome c in the cytoplasm. In addition, antimigratory activities and suppressive effects on metastasis-related factors, such as MMP-2 and MMP-9, accompanied by the upregulation of IL-24 were revealed. Altogether, the results proved that damulin B could inhibit human lung cancer cells by inducing apoptosis, blocking the cell cycle at early G0/G1 phase and suppressing the migration. Hence, damulin B has potential therapeutic efficacy against lung cancer., Competing Interests: The authors declare no conflict interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Hibiscus sabdariffa is a medicinal plant consumed as a diuretic and anti-obesity remedy. Several pharmacological studies have shown its beneficial effects in metabolism. Peroxisome proliferator-activated receptors δ and γ may play a role in the actions of H. sabdariffa. These nuclear receptors regulate lipid and glucose metabolism and are therapeutic targets for type 2 diabetes. This research aimed to perform a phytochemical study guided by a bioassay from H. sabdariffa to identify compounds with peroxisome proliferator-activated receptor δ and peroxisome proliferator-activated receptor γ agonist activity, supported by messenger ribonucleic acid expression, molecular docking, lipid accumulation, and an antihyperglycemic effect. An oral glucose tolerance test in mice with the aqueous extract of H. sabdariffa and the dichloromethane extract of H. sabdariffa was performed. The dichloromethane extract of H. sabdariffa exhibited an antihyperglycemic effect. The dichloromethane extract of H. sabdariffa was fractioned, and four fractions were evaluated in 3T3-L1 adipocytes on peroxisome proliferator-activated receptor δ , peroxisome proliferator-activated receptor γ , fatty acid transporter protein, and glucose transporter type 4 messenger ribonucleic acid expression. Fraction F3 exhibited peroxisome proliferator-activated receptor δ / γ dual agonist activity, and a further fractionation yielded two subfractions, F3-1 and F3-2, which also increased peroxisome proliferator-activated receptor δ and peroxisome proliferator-activated receptor γ expression. Subfractions were analyzed by GC/MS. The main compounds identified in F3-1 were linoleic acid, oleic acid, and palmitic acid, while in F3-2, the main compounds identified were α -amyrin and lupeol. These molecules were subjected to molecular docking analysis. α -Amyrin and lupeol showed the highest affinity. Moreover, both produced an increase in peroxisome proliferator-activated receptor δ , peroxisome proliferator-activated receptor γ , fatty acid transporter protein, and glucose transporter type 4 expression. Additionally, α -amyrin and lupeol decreased lipid accumulation in 3T3-L1 adipocytes and blood glucose in mice. Until now, α -amyrin and lupeol have not been reported with activity on peroxisome proliferator-activated receptors. This study provides evidence that α -amyrin and lupeol possess antidiabetic effects through a peroxisome proliferator-activated receptor δ / γ dual agonist action., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Georg Thieme Verlag KG Stuttgart · New York.)

Breast cancer is a complex disease driven by multiple factors including both genetic and epigenetic alterations. Recent studies revealed that abnormal gene expression induced by epigenetic changes including aberrant promoter methylation plays a critical role in human breast carcinogenesis. Cucurbitacin B has antiproliferative activity against various human breast cancer cells, but the molecular mechanism is not completely understood. In this study, we explore the influence of cucurbitacin B from Trichosanthes cucumerina on the methylation status at the promoter of oncogenes c-Myc, cyclin D1, and survivin in breast cancer cell lines. Growth inhibitory effect of cucurbitacin B on breast cancer cells was assessed by MTT assay and colony formation assay. Methylation status of genomic DNA was determined by methylation-specific PCR. Gene and protein expression levels of all genes studied were analyzed by real-time RT-PCR and western blot. The results indicated that cucurbitacin B could inhibit cell growth in breast cancer cells. The oncogene promoters are usually hypomethylated in cancer cells. Upon cucurbitacin B treatment, upregulation of DNMT1 and obvious heavy methylation in the promoters of c-Myc, cyclin D1, and survivin, which consequently downregulated the expression of all these oncogenes, were observed. Hence, cucurbitacin B proved to be a potential cancer therapeutic agent, in part by inducing hypermethylation and silences the oncogenic activation., Competing Interests: The authors declare no conflicts of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Ginseng is a perennial herb that contains various medicinal substances. The major active constituents of ginseng are ginsenosides, which have multifarious biological activities. Some pharmacological activities are closely dependent on the stereoisomers derived from the configuration at C20. In this study, the in vitro anti-inflammatory activity of C20 epimeric ocotillol-type triterpenes (2, 3, 9: , and 10: ) and protopanaxadiol [20( S / R )-protopanaxadiol] were investigated. Epimers 2: and 3: were prepared starting from 20( S )-protopanaxadiol. Epimers 9: and 10: were synthesized from 20( R )-3-acetylprotopanaxadiol (7: ). The anti-inflammatory activity of 2, 3, 9, 10: , 20( S )-protopanaxadiol, and 20( R )-protopanaxadiol was evaluated in cultured mouse macrophage RAW 264.7 cells. The MTT assay was used to measure the cytotoxicity. RAW 264.7 cells were stimulated by lipopolysaccharide to release the inflammatory mediators nitric oxide, prostaglandin E 2 , TNF- α , and interleukin-6 and anti-inflammatory mediator interleukin-10. The effect of the compounds on the overproduction of nitric oxide, prostaglandin E 2 , TNF- α , interleukin-6, and interleukin-10 was determined using Griess and ELISA methods. The results demonstrated that the in vitro anti-inflammatory activities of C20 epimeric ocotillol-type triterpenes and protopanaxadiol were different. Both the 20 S -epimers (2: and 3: ) and 20 R -epimers (9: and 10: ) inhibited the release of inflammatory mediator nitric oxide, while mainly the 20 S -epimers inhibited the release of inflammatory mediator prostaglandin E 2 , and the 20 R -epimers inhibited the release of inflammatory cytokine TNF- α . Both the 20 S -epimers [2, 3: , and 20( S )-protopanaxadiol] and 20 R -epimers [9, 10: , and 20( R )-protopanaxadiol] inhibited the release of inflammatory cytokine interleukin-6, but mainly the 20 S -epimers [2, 3: , and 20( S )-protopanaxadiol] increased the release of anti-inflammatory mediator interleukin-10., Competing Interests: The authors have no conflicts of interest to declare., (Georg Thieme Verlag KG Stuttgart · New York.)

In an in vitro screening for anti-influenza agents from European polypores, the fruit body extract of Gloeophyllum odoratum dose-dependently inhibited the cytopathic effect of the H3N2 influenza virus A/Hong Kong/68 (HK/68) in Madin Darby canine kidney cells with a 50% inhibitory concentration (IC 50 ) of 15 µg/mL, a noncytotoxic concentration. After a chromatographic work-up, eight lanostane triterpenes (1: -8: ) were isolated and their structures were elucidated based on high-resolution electrospray ionization mass spectrometry analyses, and one- and two-dimensional nuclear magnetic resonance experiments. Constituents 1: (gloeophyllin K) and 2: (gloeophyllin L) are reported here for the first time, and compounds 5: , 7: , and 8: have not been described for the investigated fungal material so far. The highest activity was determined for trametenolic acid B (3: ) against HK/68 and the 2009 pandemic H1N1 strain A/Jena/8178/09 with IC 50 values of 14 and 11 µM, respectively. In a plaque reduction assay, this compound was able to bind to cell-free viruses and to neutralize their infectivity., Competing Interests: The authors declare no conflicts of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

The collateral sensitivity effect is among the most promising strategies for overcoming multidrug resistance in cancer. In this work, 28 cucurbitane-type triterpenoids (1: -28: ), previously isolated from the African medicinal plant Momordica balsamina and its derivatives, were evaluated for their collateral sensitivity effect on three different human cancer entities, gastric (EPG85-257), pancreatic (EPP85-181), and colon (HT-29), each with two different multidrug-resistant variants. One was selected for its resistance to daunorubicin (EPG85-257RDB, EPP85-181RDB, HT-29RDB) and the other was selected for its resistance to mitoxantrone (EPG85-257RNOV, EPP85-181RNOV, HT-29RNOV). On gastric cell lines, the best results were obtained for compounds 3: and 10: , which exhibited a collateral sensitivity effect together with high antiproliferative activity. In turn, on colon cancer cell lines, the best multidrug resistance-selective antiproliferative effects were observed for derivatives 11, 13: , and 15: , which showed collateral sensitivity effects against both resistant variants. Compounds 11: and 3: were also the most selective against the multidrug resistance pancreatic cells lines. Some compounds, such 6, 10, 11: and 15: , were previously found to be strong P-glycoprotein modulators, thus highlighting their potential as promising leads for overcoming multidrug resistance in cancer cells., Competing Interests: The authors declare no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Madecassoside (MS) and asiaticoside (AS) along with their aglycones, madecassic acid (MA) and asiatic acid (AA), are considered the major neuroactive triterpenoid constituents of Centella asiatica . In this study, we aimed to compare MS, AS, MA, and AA for their neurite outgrowth activities and mechanisms in Neuro-2a cells. Immunofluorescent cell staining showed MS and AS significantly increased the percentage of neurite-bearing cells (%NBC) and the neurite length with higher potency than MA and AA. The triterpenoid glycosides induced sustained extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) phosphorylation, while their aglycones activated only transient signaling of ERK1/2. Suppression of ERK1/2 activation significantly abolished not only cAMP response element-binding protein (CREB) phosphorylation but also the increment of %NBC and neurite length in MS- and AS-treated cells. Inhibition of ERK phosphorylation did not produce similar blockage of CREB activation and neurite outgrowth in MA- and AA-treated cells. On the other hand, inactivation of protein kinase B (Akt) resulted in a suppression of neurite lengthening in all studied triterpenoids. This is the first study discerning the different signaling pathways of neurite outgrowth activity induced by C. asiatica triterpenoid glycosides and aglycones. Neurite outgrowth activity of the glycosides MS and AS was found to involve the activation of sustained ERK phosphorylation leading to CREB activation, while ERK activation was not associated with MA- and AA-induced neurite outgrowth. In addition, Akt activation was evident to be more involved in neurite elongation process., Competing Interests: The authors declare no conflicts of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

The Hyacinthaceae family ( sensu APGII), with approximately 900 species in around 70 genera, plays a significant role in traditional medicine in Africa as well as across Europe and the Middle and Far East. The dichloromethane extract of the bulbs of Massonia pustulata (Hyacinthaceae sensu APGII) yielded two known homoisoflavonoids, ( R )-5-hydroxy-3-(4-hydroxybenzyl)-7-methoxy-4-chromanone 1: and 5-hydroxy-3-(4-hydroxybenzyl)-7-methoxy-4-chromone 2: and four spirocyclic nortriterpenoids, eucosterol 3: , 28-hydroxyeucosterol 4: and two previously unreported triterpenoid derivatives, ( 17S,23S )-17 α ,23-epoxy-3 β ,22 β ,29-trihydroxylanost-8-en-27,23-olide 5: , and ( 17S, 23S )-17 α ,23-epoxy-28,29-dihydroxylanost-8-en-3-on-27,23-olide 6: . Compounds 1, 2, 3: , and 5: were assessed for cytotoxicity against CaCo-2 cells using a neutral red uptake assay. Compounds 1, 2: , and 5: reduced cell viability by 70% at concentrations of 30, 100, and 100 µM, respectively. Massonia bifolia yielded three known homoisoflavonoids, ( R ) - (4'-hydroxy)-5-hydroxy-7-methoxy-4-chromanone 1: , ( R )-(4'-hydroxy)-5,7-dihydroxy-4-chromanone 7: and ( R ) - (3'-hydroxy-4'-methoxy)-5,7-dihydroxy-4-chromanone 9: , two previously unreported homoisoflavonoids, ( E ) - 3-benzylidene-(3',4'-dihydroxy)-5-hydroxy-7-methoxy-4-chromanone 8: and ( R ) - (3',4'-dihydroxy)-5-hydroxy-7-methoxy-4-chromanone 10,: and a spirocyclic nortriterpenoid, 15-deoxoeucosterol 11: . Compounds 1, 1AC, 7, 8, 9,: and 10: were screened for antiangiogenic activity against human retinal microvascular endothelial cells. Some compounds showed dose-dependent antiproliferative activity and blocked endothelial tube formation, suggestive of antiangiogenic activity., Competing Interests: The authors declare there is no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

The aerial parts of Guarea guidonia afforded three new tirucallane-type triterpenoids: 3,4- seco -tirucalla-4(28),8(9),24(25)-trien-7α,11α-dihydroxy-21,23-epoxy-3,11-olide, named guareolide (1: ), 3,4- seco -tirucalla-4(28),7(8),24(25)-trien-21-hydroxy-21,23-epoxy-3-oic acid, named guareoic acid A (2: ), and 3,4- seco -tirucalla-4(28),7(8),24(25)-trien-21,23-epoxy-3-oic acid, named guareoic acid B (3: ), of which 1: possessed an unusual seven-membered lactone ring. Seven known terpenes were also isolated and characterized as flindissone, 7-acetyldihydronomilin, picroquassin E, boscartol C, and cneorubins A, B, and X. Their structures were determined by spectroscopic methods including one-dimensional and two-dimensional nuclear magnetic resonance analysis and high-resolution mass spectrometry. The isolates were investigated for their potential cytotoxic activity on Jurkat, HeLa, and MCF7 cancer cell lines. Flindissone and compound 2: showed an antiproliferative activity in all cell lines. Further studies revealed that flindissone, the most active compound, induced in Jurkat and HeLa cells both cytostatic and cytotoxic responses., Competing Interests: The authors declare no conflicts of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Betulinic acid is a naturally occurring pentacyclic lupane-type triterpenoid usually isolated from birch trees, but present in many other botanical sources. It is found in different plant organs, both as a free aglycon and as glycosyl derivatives. A wide range of pharmacological activities has been described for this triterpenoid, including antiviral and antitumor effects. In addition, several other interesting properties have been identified in the fields of immunity and metabolism, namely antidiabetic, antihyperlipidemic, and anti-inflammatory activities. Taken together, these latter three properties make betulinic acid a highly interesting prospect for treating metabolic syndrome. The present review focuses on the therapeutic potential of this agent, along with several of its semisynthetic derivatives, which could open new frontiers in the use of natural product-based medicines., Competing Interests: Conflict of Interest: The authors state no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Boswellic acids constitute a group of unique pentacyclic triterpene acids from Boswellia serrata with multiple pharmacological activities that confer them anti-inflammatory and anti-tumoral properties. A subgroup of boswellic acids, characterized by an 11-keto group, elevates intracellular Ca 2+ concentrations [Ca 2+ ] i and causes moderate aggregation of human platelets. How different BAs and their mixtures in pharmacological preparations affect these parameters in activated platelets has not been addressed, so far. Here, we show that boswellic acids either antagonize or induce Ca 2+ mobilization and platelet aggregation depending on defined structural determinants with inductive effects predominating for a B. serrata gum resin extract. 3- O -Acetyl-11-keto- β -boswellic acid potently suppressed Ca 2+ mobilization (IC 50  = 6 µM) and aggregation (IC 50  = 1 µM) when platelets were activated by collagen or the thromboxane A 2 receptor agonist U-46619, but not upon thrombin. In contrast, β -boswellic acid and 3- O -acetyl- β -boswellic acid, which lack the 11-keto moiety, were weak inhibitors of agonist-induced platelet responses, but instead they elicited elevation of [Ca 2+ ] i and aggregation of platelets (≥ 3 µM). 11-Keto- β -boswellic acid, the structural intermediate between 3- O -acetyl-11-keto- β -boswellic acid and β -boswellic acid, was essentially inactive independent of the experimental conditions. Together, our study unravels the complex agonizing and antagonizing properties of boswellic acids on human platelets in pharmacologically relevant preparations of B. serrata gum extracts and prompts for careful evaluation of the safety of such extracts as herbal medicine in cardiovascular risk patients., Competing Interests: Conflict of Interest: The authors have no conflicts of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

Two new triterpenes and five new triterpene saponins, named ilexpusons A-G ( 1 - 7 ), as well as eight known compounds were isolated from Ilex pubescens . The structures of the new compounds were established by a combination of chemical and spectroscopic methods, including HRESIMS, 1 H-NMR, 13 C-NMR, 1 H- 1 H COSY, HSQC, HMBC, and NOESY. Additionally, the biological activity of compounds 1  -  15 against adenosine diphosphate-induced platelet aggregation in rabbit plasma was determined. Among the tested compounds, 1, 2, 5, 6, 8, 13, 14 , and 15 exhibited significant inhibition of platelet aggregation in vitro ., Competing Interests: Conflict of Interest: The authors declare that no competing financial interests., (Georg Thieme Verlag KG Stuttgart · New York.)

Five new triterpenoid saponins ( 1 - 5 ) and four known triterpenoid saponins, ginsenoside Re 5 ( 6 ), majonoside R 1 ( 7 ), 24( R )-majonoside R 1 ( 8 ), and ginsenoside Rf ( 9 ), were isolated from the rhizomes of Panacis majoris . The structures of new compounds were elucidated as (20 S ,24 S ,25 R *)-6-O-[ β -D-glucopyranosyl-(1 → 2)- β -D-glucopyranosyl]-dammar-20,24-epoxy-3 β ,6 α ,12 β ,25,26-pentaol ( 1 ), (20 S ,24 R ,25 R )-6-O-[ β -D-glucopyranosyl-(1 → 2)- β -D-glucopyranosyl]-dammar-20,24-epoxy-3 β ,6 α ,12 β ,25,26-pentaol ( 2 ), (20 S )-6-O-[ β -D-glucopyranosyl-(1 → 2)- β -D-glucopyranosyl]-dammar-20,25-epoxy-3 β ,6 α ,12 β ,24 α -tetraol ( 3 ), 6-O-[ β -D-glucopyranosyl-(1 → 2)- β -D-glucopyranosyl]-dammar-3 β ,6 α ,12 β ,20 S ,24 R ,25-hexaol ( 4 ), and 6-O-[ β -D-glucop-yranosyl-(1 → 2)- β -D-glucopyranosyl]-dammar-25(26)-ene-3 β ,6 α ,12 β ,20 S ,24 R -pentaol ( 5 ) on the basis of extensive spectral analysis and chemical methods. Ginsenoside Re 5 was isolated from the plant for the first time. The similarities of the nine compounds lie in the fact that their aglycones are conjoined with the same glucopyranose moieties, the same linkage of the glycosyl chains, and the same glycosylation sites, while they have a varied C-17 side chain. Compounds 3 and 5 exhibited moderate antiplatelet aggregation activities induced by adenosine diphosphate with IC 50 values of 23.24 and 18.43 µM, respectively. Compound 5 displayed moderate inhibition of arachidonic acid-induced platelet aggregation with an IC 50 value of 30.11 µM., (Georg Thieme Verlag KG Stuttgart · New York.)

Two lupane and hopane caffeates ( 1 and 4 ) and two hopane coumarates ( 2 and 3 ) along with eight known compounds ( 5 - 12 ) were isolated from stems and roots of Lepisanthes senegalensis . Their structures were established on the basis of spectroscopic techniques. The structure of compound 2 was confirmed by single-crystal X-ray diffraction analysis. Triterpenes 1 and 4 - 6 showed cytotoxicity against the NCI-H187 cell line with IC 50 values of 31.5, 28.5, 16.2, and 4.0 µM, respectively. However, these compounds also showed cytotoxicity against Vero cells, with IC 50 values of 75.5, 16.6, 8.9, and 5.0 µM, respectively. In addition, compound 6 exhibited a moderate antimalarial activity with an IC 50 value of 4.5 µM., (Georg Thieme Verlag KG Stuttgart · New York.)

The purpose of this study was to observe the protective effects of α-boswellic acids on hypoxia-induced pulmonary vascular structural remodeling in pulmonary arterial smooth muscle cells in a hypertensive rat model. Pulmonary arterial smooth muscle cells were cultured and then randomly divided into four groups: normoxia, hypoxia (3 % O2; 24 h), hypoxia plus α-boswellic acids, and hypoxia plus DMSO (as a positive control), according to the different concentrations of α-boswellic acids (21.90 µM, 43.79 µM, and 87.58 µM). Apoptosis and proliferation of pulmonary arterial smooth muscle cells significantly decreased in the hypoxia plus α-boswellic acids group compared with the hypoxia and hypoxia plus DMSO groups (n = 8, p < 0.05). The mRNA and protein phosphorylation levels of c-Jun N-terminal kinase 1 and extracellular regulated protein kinase 1 were significantly elevated in hypoxic cells compared with normal cells. However, the mRNA and protein phosphorylation levels of c-Jun N-terminal kinase 1 and extracellular regulated protein kinase 1 markedly decreased in the hypoxia plus α-boswellic acids group compared with the hypoxia plus DMSO group (n = 8, p < 0.05; n = 13, p < 0.05, respectively). Our findings suggest that α-boswellic acids can inhibit inappropriate apoptosis and excessive proliferation of pulmonary arterial smooth muscle cells and pulmonary vascular remodeling by repressing the expression of c-Jun N-terminal kinase 1 and extracellular regulated protein kinase 1 under hypoxic conditions., (Georg Thieme Verlag KG Stuttgart · New York.)

Saponins are used in medicine due to their pharmacological and immunological effects. To better understand interactions of saponins with model membranes and natural membranes of, for example, erythrocytes, Langmuir film balance experiments are well established. For most saponins, a strong interaction with cholesterol was demonstrated in dependence of both the aglycone part and the sugar moieties and is suggested to be correlated with a strong hemolytic activity, high toxicity, and high surface activity, as was demonstrated for the steroid saponin digitonin. In general, changes in the sugar chain or in substituents of the aglycone result in a modification of the saponin properties. A promising saponin with regard to fairly low hemolytic activity and high adjuvant effect is α -tomatine, which still shows a high affinity for cholesterol. An interaction with cholesterol and lipids has also been proven for the Quillaja saponin from the bark of Quillaja saponaria Molina. This triterpene saponin was approved in marketed vaccines as an adjuvant due to the formation of immunostimulating complexes. Immunostimulating complexes consist of a Quillaja saponin, cholesterol, phospholipids, and a corresponding antigen. Recently, another saponin from Quillaja brasiliensis was successfully tested in immunostimulating complexes, too. Based on the results of interaction studies, the formation of drug delivery systems such as immunostimulating complexes or similar self-assembled colloids is postulated for a variety of saponins., (Georg Thieme Verlag KG Stuttgart · New York.)

Triterpene saponins are secondary metabolites typical for higher plants. They possess a wide range of pharmaceutical and biological activities. These include anti-inflammatory, vasoprotective, expectorant, and antitumor properties. In particular, the ability of saponins to enhance the cytotoxicity of chemotherapeutic drugs has opened new perspectives for their application in combined cancer chemotherapy. In this study, the biological activity of the saponin fraction isolated from Lysimachia ciliata (denoted as CIL-1/2) was evaluated to assess its chemosensitizing activity in prostate cancer cell lines (DU-145, PC-3). No cytotoxic or cytostatic effect of the CIL-1/2 fraction administered at the concentration of 0.5 µg/mL was observed. In contrast, cocktails of CIL-1/2 and mitoxantrone (a drug commonly used in prostate cancer therapy) exerted synergistic cytostatic and proapoptotic effects. Furthermore, the synergy of proapoptotic activities of the analyzed cocktails is accompanied by their synergistic effects on prostate cancer cell movement and invasiveness. The significantly weaker impact of this cocktail on normal prostate cells additionally adds to the significance of our data and confirms that the CIL-1/2 fraction might be considered a potent adjuvant for prostate cancer chemotherapy., (Georg Thieme Verlag KG Stuttgart · New York.)

Within an ongoing research program on saponins with potential antileishmanial activity, four previously undescribed saponins were isolated from Maesa argentea leaves and identified by LC-MS/MS, GC-MS, and 1D and 2D NMR spectroscopy as 3 β - O -{([ β -D-glucopyranosyl-(1 → 2)- α -L-rhamnopyranosyl-(1 → 2)- β -D-galactopyranosyl-(1 → 3)]-[ β -D-galactopyranosyl-(1 → 2)]- β -D-glucuronopyranosyl)}-21 β -angeloyloxy-22 α -butanoyloxy-13 β ,28-oxidoolean-16 α ,28 α -diol ( 1 ), 3 β - O -{([ β -D-glucopyranosyl-(1 → 2)- α -L-rhamnopyranosyl-(1 → 2)- β -D-galactopyranosyl-(1 → 3)]-[ β -D-galactopyranosyl-(1 → 2)]- β -D-glucuronopyranosyl)}-21 β ,22 α -angeloyloxy-13 β ,28-oxidoolean-16 α ,28 α -diol ( 2 ), 3 β - O -{([ β -D-glucopyranosyl-(1 → 2)- α -L-rhamnopyranosyl-(1 → 2)- β -D-galactopyranosyl-(1 → 3)]-[ β -D-galactopyranosyl-(1 → 2)]- β -D-glucuronopyranosyl)}-21 β -angeloyloxy-22 α -( E )-cinnamoyloxy-13 β ,28-oxidoolean-16 α ,28 α -diol ( 3 ), and 3 β - O -{([ α -L-rhamnopyranosyl-(1 → 2)- β -D-galactopyranosyl-(1 → 3)]-[ β -D-galactopyranosyl-(1 → 2)]- β -D-glucuronopyranosyl)}-21 β -angeloyloxy-22 α -( E )-cinnamoyloxy-13 β ,28-oxidoolean-16 α ,28 α -diol ( 4 ). Leaf material was obtained from a germinated seed that was clonally propagated using in vitro tissue culturing. Compounds 1 - 4 showed structural similarity with maesasaponins and maesabalides reported before from other Maesa spp. All four compounds showed in vitro activity against Plasmodium falciparum K1 and Leishmania infantum at micromolar concentrations. However, the observed inhibitory action must be considered nonspecific since they were also cytotoxic in the same concentration range., (Georg Thieme Verlag KG Stuttgart · New York.)

The oral bioavailability of drugs is often limited due to the presence of the P-glycoprotein, an efflux pump strongly expressed on the luminal side of the intestinal barrier. In an attempt to circumvent drug efflux, strategies consisting in the coadministration of drugs with surface-active agents have been found to be promising. In this context, the role of saponins on the intestinal permeability of a P-glycoprotein substrate was investigated. The P-glycoprotein inhibition activity of three triterpenoid saponins extracted from several plants of the Caryophyllaceae family was evaluated using an intestinal barrier model comprised of Caco-2 cell lines. The results showed a strong effect of two saponins on P-glycoprotein-mediated transport. At a concentration of 15 µM, the efflux ratio was close to 1 for both saponins, thus suggesting a total inhibition of the efflux pump in contrast to verapamil HCl, a conventional P-glycoprotein inhibitor. In addition, measurements of the transepithelial electrical resistance revealed that the integrity of the monolayers was not altered at such concentrations, thereby reducing potential adverse effects. The presence of acetylated sugars in the saponin structure could possibly facilitate interactions with the efflux pump by an ATP-dependent mechanism or by fluidization of cell membranes., (Georg Thieme Verlag KG Stuttgart · New York.)

The seeds of Carapa procera are exploited extensively in West African ethnopharmacy for the treatment of several pathologies, including inflammation. They also are effective as insect antifeedants and as a mosquito repellent. With the aim of identifying bioactive principles, an ethyl acetate extract of the defatted seeds was made and fractionated. Two principle compounds were isolated. One of these, 5,6-dehydro-7-deacetoxy-7-oxogedunin (1), while known from another genus of the Meliaceae, is newly identified from the genus Carapa and its X-ray structure is described for the first time. In addition, 1 displayed strong anti-clonogenic activity at 10 µM. The other compound, mexicanolide (2), is known from this species and showed neither cytotoxicity nor anti-clonogenicity. These differences in efficacy are discussed in relation to known structure-activity relationships of limonoids., (Georg Thieme Verlag KG Stuttgart · New York.)

Fractionation of an acetone extract of the aerial parts of Salvia urmiensis led to the isolation of a new (1) and a known (2) E-seco-ursane-type triterpenoid, together with four other known compounds. Their structures were established by 1D and 2D nuclear magnetic resonance as well as high-resolution electrospray ionization mass spectrometry. The effect of compounds 1 and 2 on cell viability of HeLa and HepG2 cells was investigated with the MTT assay. We also report the mechanism of action of compound 2 as a potential anticancer agent in HeLa cells. Bcl-2, Bax, and caspases signaling pathway expression in HeLa cells was analyzed. HeLa cells treated with compound 2 were assayed for the cleavage of poly-(ADP-ribose)-polymerase and DNA fragmentation resulting in nuclear shrinkage. Taken together, these results suggest that treatment of HeLa cells with compound 2 can induce apoptosis by regulating Bcl-2 family members and by suppressing caspase cascade activation., (Georg Thieme Verlag KG Stuttgart · New York.)

Five new lupane triterpene coumaroyl esters (1-5), together with betulin (6) and a known Buxus alkaloid, N-3-benzoyldihydrocyclomicrophylline F (7), were isolated from a CHCl3-soluble partition of a methanol extract of Buxus cochinchinensis Pierre ex Gagnep. (Buxaceae) collected in Vietnam. Isolation work was monitored using human colon cancer cells (HT-29). The structures of the new compounds (1-5) were determined on the basis of spectroscopic data interpretation. In addition to their cytotoxicity against HT-29 cells and nuclear factor-kappa B (p65) inhibitory activity in an enzyme-linked immunosorbent assay, all isolates as well as two semisynthetic compounds derived from betulin and 5, respectively, were also evaluated for their in vitro antiplasmodial activities against the drug-resistant Dd2 strain of Plasmodium falciparum and antifungal effects on the growth of the pathogenic yeast Candida albicans. The new lupane triterpene coumaroyl esters (1-5), along with a betulin derivative and the known Buxus alkaloid, were found to show significant in vitro antimalarial activities, with IC50 values ranging from 0.26 to 2.07 µM., (Georg Thieme Verlag KG Stuttgart · New York.)

In traditional medicine, the oleoresinous gum of Pistacia lentiscus var. chia, so-called mastic gum, has been used to treat multiple conditions such as coughs, sore throats, eczema, dyslipidemia, and diabetes. Mastic gum is rich in triterpenes, which have been postulated to exert antidiabetic effects and improve lipid metabolism. In fact, there is evidence of oleanonic acid, a constituent of mastic gum, acting as a peroxisome proliferator-activated receptor γ agonist, and mastic gum being antidiabetic in mice in vivo. Despite these findings, the exact antidiabetic mechanism of mastic gum remains unknown. Glucocorticoids play a key role in regulating glucose and fatty acid metabolism, and inhibition of 11β-hydroxysteroid dehydrogenase 1 that converts inactive cortisone to active cortisol has been proposed as a promising approach to combat metabolic disturbances including diabetes. In this study, a pharmacophore-based virtual screening was applied to filter a natural product database for possible 11β-hydroxysteroid dehydrogenase 1 inhibitors. The hit list analysis was especially focused on the triterpenoids present in Pistacia species. Multiple triterpenoids, such as masticadienonic acid and isomasticadienonic acid, main constituents of mastic gum, were identified. Indeed, masticadienonic acid and isomasticadienonic acid selectively inhibited 11β-hydroxysteroid dehydrogenase 1 over 11β-hydroxysteroid dehydrogenase 2 at low micromolar concentrations. These findings suggest that inhibition of 11β-hydroxysteroid dehydrogenase 1 contributes to the antidiabetic activity of mastic gum., (Georg Thieme Verlag KG Stuttgart · New York.)

Five new cucurbitacins, kuguacins II-VI (1-5), along with five known analogues (6-10), were obtained from the fruit of Momordica charantia. Structures of the new compounds were elucidated as 5β,19-epoxycucurbit-23-en-7-on-3β,25-diol (1), 5β,19-epoxycucurbit-7,23-dion-3β,25-diol (2), 5β,19-epoxycucurbit-6-en-19,23-dion-3β,25-diol (3), 5β,19-epoxy-23,24,25,26,27-pentanorcucurbit-6-en-7,19-dion-3β,22-diol (4), and cucurbit-5-en-7,23-dion-3β,19,25-triol (5) by extensive spectroscopic and single-crystal X-ray diffraction analyses. Some cucurbitane compounds from this species were screened for their potential antidiabetic properties in terms of antigluconeogenic activity. As a result, compounds 1, 10, 11, and 12 (at 25-100 µM) showed concentration-dependent inhibition on glucose production from liver cells. In addition, compounds 11 and 12 (at 100 µM) showed around 20-30 % inhibition on PEPCK activity., (Georg Thieme Verlag KG Stuttgart · New York.)

Boswellic acids have long been considered the main bioactive components of frankincense, and many studies in vitro and in animals as well as several clinical studies have confirmed their various bioactivities. In particular, a large number of mechanistic studies have confirmed their anti-inflammatory and antitumor activities. However, not every boswellic acid exhibits a satisfactory pharmacological performance, which depends on the chemical structure and functional groups of the acid. To enhance the pharmacological values of boswellic acids, derivatization has been specifically applied with the aim of discovering more active derivatives of BAs. In addition, the preliminary pharmacokinetic studies of these compounds using various standard methods show their poor bioavailability in humans and rodents, which has led to questions of their pharmacological relevance and potentially limits their use in clinical practice and pharmaceutical development. To improve these effects, some approaches have shown some improvements in effectiveness, and the new formula compatibility approach is considered a very reasonable method for improving the bioavailability of boswellic acids., (Georg Thieme Verlag KG Stuttgart · New York.)

Cancer cells may rapidly acquire multidrug resistance, mainly due to the presence of adenosine triphosphate-binding cassette transporters, epidermal growth factor receptor, or mutations in the p53 tumor suppressor gene. This work was designed to assess the cytotoxicity of the methanol crude extracts and compounds from the fruits of Uapaca togoensis, namely, β-amyryl acetate (1), 11-oxo-α-amyryl acetate (2), lupeol (3), pomolic acid (4), futokadsurin B (5), arborinin (6), and 3-O-β-D-glucopyranosyl sitosterol (7) against nine drug sensitive and multidrug-resistant cancer cell lines. The resazurin reduction assay was used to evaluate the cytotoxicity of the fruits of U. togoensis and compounds, whilst the caspase-Glo assay was used to detect the activation of caspase enzymes by the fruits of U. togoensis and compound 6. Cell cycle, mitochondrial membrane potential, and levels of reactive oxygen species were all analyzed via flow cytometry. The acridone alkoid 6 and the crude extract from the fruits of U. togoensis were active on all of the nine tested cancer lines with IC50 values below 32 µM and 30 µg/mL, respectively. Compounds 2 and 5 showed selective activities and IC50 values below 99 µM or 42 µM, respectively, which were obtained towards 3/9 and 6/9 tested cancer cell lines. Compound 6 displayed IC50 values below 10 µM towards seven of the nine tested cancer cell lines. The IC50 values ranged from 3.55 µM (against CEM/ADR5000 cells) to 31.77 µM (against CCRF-CEM cells) for alkaloid 6 and from 0.20 µM (against CCRF-CEM cells) to 195.12 µM (against CEM/ADR5000 cells) for doxorubicin. The crude extract of the fruits of U. togoensis induced apoptosis in the CCRF-CEM leukemia cells, which was mediated by the disruption of the mitochondrial membrane potential. Compound 6 also strongly induced apoptosis in CCRF-CEM cells and cell cycle arrest in the G0/G1 and S phases. The crude extract from the fruits of this plant as well as aborinin are potential antiproliferative natural products that deserve further investigation to develop novel cytotoxic drugs to fight sensitive and otherwise drug-resistant phenotypes., (Georg Thieme Verlag KG Stuttgart · New York.)

Five new 5β,19-epoxycucurbitane triterpenoids, taikugausins A-E (1-5), together with 5β,19-epoxy-25-methoxycucurbita-6,23-diene-3β,19-diol (6), have been isolated and characterized from the 70 % EtOH extract of the fresh fruits of Momordica charantia. The chemical structures of compounds 1-6 were elucidated on the basis of extensive spectroscopic analyses, especially 2D NMR (HMQC, HMBC, and NOESY) experiments and HRESIMS data. The relationship between NMR chemical shifts and the configuration of C-19 with an OMe group in 5β,19-epoxycucurbitane are described. Among them, compounds 3 and 4 exhibited remarkable anti-inflammatory activities by the inhibition of nitric oxide production at the concentration of 10 µg/mL. In addition, 3 and 4 also showed moderate cytotoxicity against WiDr, Hep G2, MCF-7, and HEp-2 human tumor cell lines., (Georg Thieme Verlag KG Stuttgart · New York.)

Two lanostane triterpenes, 3β-hydroxylanosta-9,24-dien-21-oic acid (1) and methyl-3β-hydroxylanosta-9,24-dien-21-oate (2), were isolated from the stem bark of Protorhus longifolia. Their structures were deduced on the basis of spectroscopic analysis (NMR, HRMS, IR). This study investigated the in vitro anti-adipogenic activity of the two triterpenes. Their inhibitory activity was evaluated on selected lipid digestive enzymes (pancreatic lipase and cholesterol esterase). The inhibitory activity of the compounds on hormone-sensitive lipase and their ability to bind bile acids were also evaluated. The effect of the compounds on glucose uptake in C2C12 muscle cells and 3T3-L1 adipocytes, and on triglyceride accumulation in 3T3-L1 adipocytes was investigated. The triterpenes effectively inhibited the activities of the enzymes with IC50 values ranging from 0.04 to 0.31 mg/mL. The compounds showed a high affinity for secondary bile acids. Both compounds stimulated glucose uptake in C2C12 muscle cells and 3T3-L1 adipocytes. Compound 1 significantly reduced triglyceride accumulation in mature differentiated 3T3-L1 adipocytes. It is apparent that these lanostane triterpenes enhance glucose uptake and suppress adipogenesis, which together with their inhibitory effects on lipid digestive enzymes suggests that they have antihyperlipidemic potential., (Georg Thieme Verlag KG Stuttgart · New York.)

Nausea and vomiting are the most distressing and common side effects of cancer chemotherapy which often result in patient noncompliance. In the present study, standardized methanolic and n-butanolic fractions of Bacopa monnieri were evaluated against cisplatin-induced emesis in the pigeon in relation to their activity on central and intestinal neurotransmitters levels. Cisplatin (7.0 mg/kg, i. v.) induced reproducible emesis without lethality in healthy pigeons. The methanolic (10-40 mg/kg) and the bacoside-rich n-butanolic fractions of B. monnieri (5-20 mg/kg), as well as the antioxidant N-(2-mercaptopropionyl) glycine (10 mg/kg), attenuated cisplatin-induced emesis by 66.3% (p < 0.05), 71.6% (p < 0.001), and 76.5% (p < 0.001), respectively, where the standard antiemetic metoclopramide (30 mg/kg) produced a 48.9% reduction (p < 0.01). The methanolic and n-butanolic fractions of B. monnieri at all of the doses tested significantly reduced the serotonin concentration (p < 0.001) in the brain stem and intestine 3 h after cisplatin administration, while at the 18th h, B. monnieri treatments attenuated not only the dopamine upsurge in the area postrema and brain stem (p < 0.05-0.001), but also the intestinal 5-HT concentration (p < 0.01-0.001). B. monnieri treatments alone did not alter the basal neurotransmitters or their metabolites in the brain areas and intestine. The prolonged suppressive effect of B. monnieri treatments on the behavioral signs of cisplatin-induced emesis, the subsequent supportive neural evidence, and the safety and tolerability profile suggest that B. monnieri methanolic and bacoside-rich n-butanolic fractions might be a valuable adjunct in the treatment of emetogenic chemotherapy, and this warrants further study in other models of emesis., (Georg Thieme Verlag KG Stuttgart · New York.)

Eight new triterpenoid saponins, the saikosaponin homologs comastomasaponins A-H (1-8), as well as a known triterpenoid (9) and eight known saponins (10-17) were isolated from the aerial portions of Comastoma pedunculatum. The structures of these compounds were elucidated spectroscopically, and their hepatoprotective activity and cytotoxic activity were evaluated against five human tumor cell lines in vitro. Compounds 1, 5-12, 14, 15, and 17 exhibited potent hepatoprotective activity, and compound 11 displayed cytotoxic activity against HCT-8, Bel-7402, BGC-825, A549, and A2780 human tumor cell lines., (Georg Thieme Verlag KG Stuttgart · New York.)

Plants belonging to the genus Maytenus are routinely used in folk medicine for the treatment of pain diseases. Our previous phytochemical study of the roots of Maytenus imbricata resulted in the isolation and characterization of tingenone, a pentacyclic triterpene. Natural triterpenoids are of growing interest because they have several biological activities, including analgesic properties. The present study assessed the involvement of the opiodergic pathway in the tingenone-induced antinociceptive effect against hyperalgesia induced by prostaglandin E2 (2 µg) in the peripheral pathway. We evaluated the effect of several antagonists to opioid receptors using the mouse paw pressure test. Tingenone administered into the right hind paw induced a local antinociceptive effect that was antagonized by naloxone, a nonselective antagonist to opioid receptors. Clocinnamox, naltrindole, and nor-binaltorphimine are selective antagonists to µ, δ, and κ receptors, respectively, which reverted the peripheral antinociception induced by tingenone. Bestatine acts as an inhibitor of aminopeptidase, an enzyme that degrades endogenous opioid peptides, and was shown to intensify the antinociceptive effect of tingenone. The results suggest that the opioidergic system participates in the peripheral antinociception induced by tingenone., (Georg Thieme Verlag KG Stuttgart · New York.)

Chemical investigation of the ethanol extract of the whole plant of Megacodon stylophorus led to the isolation and identification of two new seco-hopane triterpenoids, 2,3-seco-22(29)-hopene-2-carboxyl-3-aldehyde (1) and 2,3-seco-4(23),22(29)-hopene-2-carboxyl-3-aldehyde (2), along with 10 known compounds, 3-12. All the isolates were reported from this plant for the first time. The structures of compounds 1 and 2 were determined by detailed analysis of their spectral data including 1D and 2D NMR. In addition, compound 1 was further analyzed by X-ray crystallography. Compounds 1-3 were evaluated for their in vitro anti-proliferative activities on HeLa, MCF-7, and Hep-G2 tumor cell lines. Compound 2 was active against the three cell lines with IC50 values of 3.6, 7.5, and 13.6 µM, respectively, while compound 1 exhibited cytotoxicity on MCF-7 (IC50 14.0 µM) and HeLa (IC50 18.2 µM) cell lines. Antimicrobial activities of compounds 1-2 (minimum inhibitory concentration values in the range of 3.12-12.50 mg/mL) were also observed., (Georg Thieme Verlag KG Stuttgart · New York.)

The reinvestigation of the n-BuOH extract of the roots of Clematis argentilucida led to the isolation of four new oleanane-type triterpenoid saponins, 1-4, four known saponins, 5-8, first isolated from the species, together with ten saponins, 9-18, reported in the preceding papers. The structures of saponins 1-8 were elucidated by extensive spectroscopic analysis and chemical evidences. The cytotoxicity of all the saponins were evaluated against human tumor HL-60, HepG-2, and SGC-7901 cell lines. The monodesmosidic saponins 4, 7, 8, and 14-18 exhibited cytotoxic activity against the three cell lines with IC50 values in the range of 0.87-19.48 µM., (Georg Thieme Verlag KG Stuttgart · New York.)

Ten new triterpene saponins (1-10) have been isolated from the stems of Entada phaseoloides. Their structures were elucidated by spectroscopic analysis and chemical methods. Among these compounds, the aglycons of 6-10 are being reported for the first time, in this study, including 3β,15α,16α-trihydroxy-11α,12α-epoxy olean-28,13β-olide (6), 3β,15α,16α-trihydroxy-11-oxo-olean-12-en-28-oic acids (7 and 8), and 3β,15α,16α-trihydroxy-oleana-11,13(18)-dien-28-oic acids (9 and 10). The cytotoxic activities of all of these compounds were evaluated against HepG-2, A549, and Ec-1 cell lines., (Georg Thieme Verlag KG Stuttgart · New York.)

Eight new triterpenoid saponins, oleiferosides A-H (1-8), were isolated from the EtOH extract of the roots of Camellia oleifera. Their structures were elucidated by a combination of 1D and 2D NMR techniques, mass spectrometry, and chemical methods. All were characterized to be oleanane-type saponins with sugar moieties linked to C-3 of the aglycone. Cytotoxic activities of these saponins were evaluated against four human tumor cell lines (A549, B16, BEL-7402, and MCF-7) by using the MTT in vitro assay. Compound 3 exhibited potent cytotoxic activitiy against all the tested cell lines with IC50 values < 10 µM. Compounds 1, 2, 4, and 5 showed moderate cytotoxic activities toward the tested cell lines., (Georg Thieme Verlag KG Stuttgart · New York.)

Based on the fact that Synadenium grantii is used in folk medicine for the treatment of peptic ulcers and inflammatory diseases, this work describes its chemical and pharmacological properties. Pharmacological investigation of the crude bark extract showed a high antioxidant activity over several scavenger systems, such as 2,2'-azino-bis (3-ethylenebenzothiazoline-6-sulfonic acid)• +, 1-diphenyl-2-picrylhydrazyl•, O2 • - , and HOCl, as well as an enzymatic system with human myeloperoxidase and an ex vivo hemolysis system. Furthermore, the oral administration of the crude bark extract was able to reduce carrageenan-induced rat paw edema as effectively as ibuprofen. These biological activities may be associated with the presence of flavonoids and terpenes, as revealed by HPLC and NMR analyses of the crude stem bark extract. The phytochemical investigations in this study resulted in the isolation of friedelin and 3β-friedelinol for the first time, while euphol and lanosterol were also isolated., (Georg Thieme Verlag KG Stuttgart · New York.)

In this study, a diverse set of triterpenoid saponins was evaluated to assess their chemosensitizing activity in two human liver cancer cells (Bel-7402 and HepG2) and non-neoplastic HL-7702 liver cells. Cyclamin, a 13,28-epoxy oleanane-type triterpenoid saponin from Ardisia japonica, was identified as a potent chemosensitizer. A low cytotoxic level of cyclamin synergistically enhances the growth inhibitory effect of 5-fluorouracil (from 41.3 ± 1.1% to 64.5 ± 2.3%), cisplatin (from 57.1 ± 1.5% to 79.6 ± 2.7%), and epirubicin (from 62.6 ± 1.2% to 74.9 ± 1.8%) on Bel-7402 cells, but not HL-7702 cells. Flow cytometric analysis shows that cyclamin synergistically enhances the apoptosis and cell cycle arrest induction effects of 5-fluorouracil by 69.4% and 22.2%, respectively. The mechanism of action could be through the activation of caspase-3, -8, and -9, the upregulation of cyclin-dependent kinase 2, the cell division cycle 25 homolog A expression level, or the Bax/B-cell lymphoma 2 ratio. Furthermore, a lactate dehydrogenase release assay demonstrated that cyclamin markedly increases the membrane permeability of Bel-7402 cells, which may also contribute to the mechanism of the chemosensitizing activity of cyclamin. These findings indicate the potential usefulness of cyclamin for the chemoprevention and treatment of liver cancer., (Georg Thieme Verlag KG Stuttgart · New York.)

Seven new triterpenoid saponins, schekwangsiensides A-G (1-7), and a new triterpenoid, schekwangsienin (8), together with nine known triterpenoids and saponins (9-17), were isolated from the aerial parts of Schefflera kwangsiensis. The structures of these compounds were elucidated on the basis of spectroscopic data analysis and chemical evidence. Furthermore, in in vitro assays, compounds 4, 8, 9, and 15 (10 µM) exhibited moderate hepatoprotective activities against D-galactosamine-induced HL-7702 cell damage., (Georg Thieme Verlag KG Stuttgart · New York.)

It is considered that natural products used in folk medicine can potentiate the effect of drugs. The aim of this study was to evaluate the pharmacological interaction between ursolic acid, a triterpene isolated from herbal medicines to treat pain, and the analgesics diclofenac or tramadol. Individual dose-response curves of the antinociceptive effect of these compounds were built to calculate the ED50, as well as the pharmacological interaction, by using isobolographic analysis. All treatments decreased significantly and in a dose-dependent manner the writhing behavior with ED50 values of 103.50 ± 19.66, 20.54 ± 6.05, and 9.60 ± 1.69 mg/kg, for ursolic acid, diclofenac, and tramadol, respectively. An isobolographic analysis allowed the characterization of the pharmacological interaction produced by a fixed ratio combination of 1 : 1 and 1 : 3 of equi-effective doses of these compounds. Theoretical antinociceptive ED50 values of ursolic acid-diclofenac were 62.12 ± 10.28 and 41.43 ± 6.69 mg/kg, respectively, not statistically different from those obtained experimentally (44.52 ± 5.25 and 44.89 ± 49.05 mg/kg, respectively), reporting an additive interaction. Theoretical antinociceptive ED50 values of ursolic acid-tramadol (56.56 ± 9.87 and 33.08 ± 5.07 mg/kg, respectively) were significantly lower than those observed experimentally (138.36 ± 49.05 and 67.34 ± 18.98 mg/kg, respectively) reporting antagonism in this interaction. Antinociceptive response obtained from isobolograms in the writhing test was corroborated by using formalin test in mice. Adverse effects such as gastric damage in the ursolic acid-diclofenac combination did not increase in an additive form similarly as with antinociception. Conversely, sedative response was significantly increased in the ursolic acid-tramadol combination. As observed in the formalin test, the antagonism on the antinociceptive response between ursolic acid and tramadol (1 : 1) was not reverted in the presence of the opioid antagonist naltrexone (1 mg/kg, i. p.). These results provide evidence for a differential pharmacological interaction, in which ursolic acid does not interfere with the antinociceptive effect of diclofenac but antagonizes that obtained with tramadol in an independent opioid mechanism. Therefore, medicinal plants containing abundant presence of ursolic acid may also modify efficacy in the alternative combinations for the pain therapy., (Georg Thieme Verlag KG Stuttgart · New York.)

Galphimia glauca, commonly known as "flor de estrella", is a plant species used in Mexican traditional medicine for the treatment of different diseases that have an acute or chronic inflammatory process in common. Aerial parts of this plant contain nor-seco-triterpenoids with anxiolytic properties, which have been denominated galphimines. Other compounds identified in the plant are tetragalloyl-quinic acid, gallic acid, and quercetin, which are able to inhibit the bronchial obstruction induced by platelet-activating factor. The objective of this work was to evaluate the anti-inflammatory effect of crude extracts from G. glauca and, by means of bioguided chemical separation, to identify the compounds responsible for this pharmacological activity. n-Hexane, ethyl acetate, dichloromethane, and methanol extracts showed an important anti-inflammatory effect. Chemical separation of the active methanol extract allowed us to identify the nor-seco-triterpenes galphimine-A (1) and galphimine-E (3) as the anti-inflammatory principles. Analysis of structure-activity relationships evidenced that the presence of an oxygenated function in C6 is absolutely necessary to show activity. In this work, the isolation and structural elucidation of two new nor-seco-triterpenes denominated as galphimine-K (4) and galphimine-L (5), together with different alkanes, fatty acids, as well as three flavonoids (17-19), are described, to our knowledge for the first time, from Galphimia glauca., (Georg Thieme Verlag KG Stuttgart · New York.)