Two novel C29-5beta-sterols from the stems of Opuntia dillenii

Two novel C29-5beta-sterols, opuntisterol [(24R)-24-ethyl-5beta-cholest-9-ene-6beta,12alpha-diol] (1) and opuntisteroside [(24R)-24-ethyl-6beta-[(beta-d-glucopyranosyl)oxy]-5beta-cholest-9-ene-12alpha-ol] (2), together with nine known compounds, beta-sitosterol (3), taraxerol (4), friedelin (5), methyl linoleate (6), 7-oxositosterol (7), 6beta-hydroxystigmast-4-ene-3-one (8), daucosterol (9), methyl eucomate (10) and eucomic acid (11), were isolated from the stems of Opuntia dillenii collected in Guizhou Province, China. Their structures were elucidated mainly by spectroscopic analysis. The absolute configuration of 1 were deduced from comparative 1H NMR data of the (S)- and (R)-methoxyphenyl acetate derivatives. Compounds 6-8, 10 and 11 were isolated from O. dillenii for the first time.     

靶向肿瘤血管生成的天然产物研究进展

血管生成在肿瘤的发生发展过程中起着非常重要的作用.促血管生成因子及其受体可以通过调节血管生成促进肿瘤发生发展.因此,发现和开发靶向血管生成因子药物已经成为治疗肿瘤的重要策略.近年来,天然产物因其结构多样、毒副作用低及作用机制独特等优势已然成为开发抗肿瘤药物的主要来源.本文归纳阐述了近年来靶向血管生成因子具有抗肿瘤活性的...     

A novel link between autophagy and the ubiquitin-proteasome system

Autophagy and the ubiquitin-proteasome system (UPS) are the major routes for intracellular protein degradation. These two pathways were previously thought to be largely distinct. Here we summarize our recent work that demonstrates that long-term autophagy inhibition slows the clearance of short-lived UPS-specific substrates, like p53. This is caused by the accumulation of p62 after autophagy inhibition. These data suggest that the ramifications of a block in autophagy may be much wider than what was previously thought. Rather than simply decreasing clearance of autophagic substrates, while UPS flux is undisturbed, the cell will have to contend with a decrease in clearance by both major routes.     

Establishing a link between oncogenes and tumor angiogenesis.

We have tried to stress that mutant oncogenes or overexpressed, nonmutated proto-oncogenes, in addition to their direct affect on promoting aberrant tumor cell proliferation (and survival), may possess a crucial indirect means of stimulating tumor cell growth through regulation of angiogenesis. This effect would never be observed in tissue culture studies of oncogene function using pure cultures of tumor cells, which probably helps explain why the pro-angiogenic function of oncogenes has not been appreciated until only relatively recently. Indeed, the very first indication of a possible contributory role of oncogenes, such as ras and myc, to tumor angiogenesis was first reported by Thompson et al. in 1989, who used reconstituted organ cultures of the mouse prostate gland for their studies (69). This potentially important contribution of oncogenes to tumor growth and development may prove to have an impact on how various signal transduction inhibitors that are now in early phase clinical trials, e.g., monoclonal neutralizing antibodies to the human EGF receptor (70), function in vivo as anti-tumor agents.     

Apolipoprotein(a), a link between atherosclerosis and tumor angiogenesis

Lipoprotein (a) [Lp(a)] is a LDL-like particle with one apolipoprotein(a) [apo(a)] covalently bound to apolipoprotein B, the structural protein of Low Density Lipoprotein (LDL). Lewis Lung Carcinoma (LL/2) cells exhibited delayed growth and reduced angiogenesis in apo(a) transgenic mice, expressing a recombinant apo(a) [r-apo(a)] with 18 kringle 4 repeats. The mean microvessel density of subcutaneous LL/2 tumors from apo(a) transgenic mice was significantly lower than that of tumors from control wild type mice. CHO cells secreting a truncated apo(a) protein with only six kringle 4 repeats did not exhibit delayed tumor growth nor did it impair angiogenesis. These data point to an unappreciated role of human apo(a) in angiogenesis and cancer biology. As angiogenesis is necessary for reendothelialization following vascular injury, suppression of angiogenesis by apo(a) may also contribute to the atherogenicity of apo(a). The differences between the truncated apo(a) and r-apo(a) are consistent with the higher atherogenicity of higher molecular weight isoforms.     

Biological effects of toxic products from Trichothecium roseum link

Extracts of rice cultures of 8 of 16 isolates ofTrichothecium roseum killed one or more ducklings or mice or both. One of the isolates (MC-156) obtained from shelled corn was the most toxigenic; extracts of this isolate killed all treated ducklings and mice.Doses of purified toxic fraction TR-1 of 166 mg/kg body weight given intraperitoneally killed all test mice but none of the mice given 100 mg/kg doses died. However, a partially purified fraction (Fraction VII), from which toxic fraction TR-1 was derived, killed two of three mice given 78 mg/kg doses.Crude ether extracts of rice cultures ofT. roseum (MC-156) produced death when injected intraperitoneally in rabbits and a 19-day-old pig and also produced dermal necrosis when applied to the skin of rabbits. The latter phenomenon was not observed when 5 mg of toxic fraction TR-1 was applied to the skin of rabbits.The greatest production of toxin occurred in rice cultures when incubated at 28° C and with 20 % (ml/g) water added to the rice. Incubation of rice cultures ofT. roseum (MC-156) under CO₂ tension suppressed toxin production.

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Zusammenfassung Auszüge von Reiskulturen von acht der 16 Stämme vonTrichothecium roseum haben mehrere Entchen und/oder Mäuse getötet. Einer der Auszüge (MC-156) von abgeschälten Mais war das toxischste; Auszüge dieses Isolates hat alle Entchen und Mäuse getötet. Dosen der gereinigten toxischen Fraktion TR-1, 166 mg/Kg Körpergewicht, intraperitonial verabreicht, haben alle Mäuse getötet, aber keine der Mäuse starb mit der Dose von 100 mg/Kg. Jedoch hat eine teilweise gereinigte Fraktion (Fraktion VII), von welcher die toxische Fraktion TR-1 gewonnen war, zwei von drei Mäusen mit 78 mg/Kg Dose getötet. Ungereinigte Ätherauszüge vonT. roseum (MC-156) waren tödlich, wenn sie in Kaninchen, in ein 19 Tage altes Schweinchen intraperitonel injiziert worden sind. Sie haben auch eine Hautnekrose hervorgerufen, wenn sie auf die Haut von Kaninchen gebracht worden sind. Das letztere Phänomen war nicht beobachtet, wenn 5 mg der toxischen Fraktion TR-1 an Kaninchenhaut gebracht worden ist. Die größte Produktion des Toxins fand in Reiskulturen statt, wenn sie bei 28° C und mit 20 Perzent (ml/g) Wasser bebrütet worden sind. Inkubation von Reiskulturen vonT. roseum (MC-156) unter CO₂-Druck hat die Toxinproduktion unterdrückt.

     

Drug development from natural products: exploiting synergistic effects

Drug development in phytomedicine has been focused in the past on the discovery and analysis of new structures from natural products. The search aimed at the determination of the single "active principle" in plants, based on the assumption that a plant has one or a few ingredients which determine its therapeutic effects. But traditional systems of medicines like Ayurveda, traditional Chinese medicine or the European phytotherapy generally assume that a synergy of all ingredients of the plants will bring about the maximum of therapeutic efficacy. This approach has for long been impossible to investigate since adequate methods to standardize complex plant mixtures as well as to rationalize complex mode of actions were lacking. The introduction of high throughput technologies provides the opportunity to determine profiles of plants and to systematically explore the mode of action of combinatory drug regimes. The present review highlights the concept of synergy and gives examples of synergistic effects of plant constituents. It elaborates on how the high throughput technologies can be used in drug development from natural products with the aim of creating evidence-based plant medications in prevention and treatment of different diseases in the form of new single treatments or new combinatory drug regimes while exploiting synergy-effects.     

A novel cyclin provides a link between dopamine and RNA processing.

Regulation of gene expression by dopamine may play an important role in learning, reward, and addiction. Hyman and colleagues now report the characterization of ania-6, a novel cyclin that associates with RNA polymerase II and is induced by dopamine or cocaine in the neostriatum. Ania-6 may thus provide a link between dopamine and gene expression at the level of mRNA processing.     

A novel link between a rab GTPase and Rvs proteins: the yeast amphiphysin homologues

The BAR proteins are a well-conserved family of proteins including Rvsp in yeast, amphiphysins and Bin proteins in mammals. In yeast, as in mammals, BAR proteins are known to be implicated in vesicular traffic. The Gyp5p (Ypl249p) and Ymr192p proteins interact in two-hybrid tests with both Rvs161p and Rvs167p. Gyp5p is a Ypt/Rab-specific GAP and Ymr192p is highly similar to Gyp5p. To specify the interaction between Rvsp and Gyp5p, we used two-hybrid tests to determine the domains necessary for these interactions. The specific SH3 domain of Rvs167p interacted with the N-terminal domain of Gyp5p. Moreover, Gyp5p could form a homodimer. Fus2 protein is a specific partner of Rvs161p in two-hybrid tests. To characterize the functional relationships between these five proteins, we have studied cellular phenotypes in single, double and triple mutant strains for which rvs mutants present defects, such as polarity, cell fusion and meiosis. Phenotypic analysis showed that Gyp5p, Ymr192p and Fus2p were involved in bipolar budding pattern and in meiosis. Specific epistasis or suppressive phenomena were found between the five mutations. Finally, The Gyp5p-GFP fusion protein was localized at the bud tip during apical growth and at the mother-bud neck during cytokinesis. Moreover, Rvs167p and Rvs161p were shown to be essential for the correct localization of Gyp5p. Altogether, these data support the hypothesis that both Rvsp proteins act in vesicular traffic through physical and functional interactions with Ypt/Rab regulators.     

Beneficial effects of natural products on female sexual dysfunction: A systematic review and meta-analysis

BackgroundFemale sexual dysfunction (FSD) includes female orgasmic disorder, female sexual interest or arousal disorder, and genito-pelvic pain or penetration disorder. FSD affects 40% of women worldwide, but it is understudied and likely undertreated. Natural products are frequently used by women to treat FSD, but scientific evidence of their efficacy is lacking.ObjectiveThis systematic review and meta-analysis focused on the study of the efficacy of natural products on FSD.Study designSystematic review and meta-analysis of existing studies on natural products in the treatment of FSD.MethodsThe literature search included MEDLINE, EMBASE, PsycINFO, and the Cochrane Central Register of Controlled Trial databases for studies published from January 2000 to February 2020. The quality and the level of evidence of the studies were assessed. The association between natural products and FSD was summarized using standardized mean differences (SMD) with a 95% confidence interval (CI).ResultsA total of 536 studies were identified, with 20 of them meeting the criteria. According to this meta-analysis, Tribulus terrestris showed a significant positive effect in improving overall female sexual function (SMD = 1.12, 95% CI = 0.46 - 1.79, p = 0.001) and individual sexual arousal (SMD = 1.03, 95% CI = 0.22 - 1.84, p = 0.013), sexual desire (SMD = 1.08, 95% CI = 0.52 - 1.63, p ≤ 0.001) and sexual orgasm (SMD = 0.51, 95% CI = 0.02 - 1.00, p = 0.040) domains compared to placebo. Panax ginseng was found to be effective in treating sexual arousal (SMD = 0.54, 95% CI = 0.11 - 0.97, p = 0.014) and sexual desire (SMD = 0.59, 95% CI = 0.27 - 0.90, p < 0.001) compared to placebo. Meanwhile, other natural products reviewed in this study, such as Trifolium pretense, did not differ significantly from placebo in terms of improving FSD.ConclusionPreliminary evidence suggests that Tribulus terrestris and Panax ginseng may be effective as alternative treatments for FSD in a clinical setting.     

Hybrid peptide-polyketide natural products: biosynthesis and prospects toward engineering novel molecules

The structural and catalytic similarities between modular nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) inspired us to search for hybrid NRPS-PKS systems. By examining the biochemical and genetic data known to date for the biosynthesis of hybrid peptide-polyketide natural products, we show (1) that the same catalytic sites are conserved between the hybrid NRPS-PKS and normal NRPS or PKS systems, although the ketoacyl synthase domain in NRPS/PKS hybrids is unique, and (2) that specific interpolypeptide linkers exist at both the C- and N-termini of the NRPS and PKS proteins, which presumably play a critical role in facilitating the transfer of the growing peptide or polyketide intermediate between NRPS and PKS modules in hybrid NRPS-PKS systems. These findings provide new insights for intermodular communications in hybrid NRPS-PKS systems and should now be taken into consideration in engineering hybrid peptide-polyketide biosynthetic pathways for making novel "unnatural" natural products.     

A possible mechanism for link between advanced glycation end products and the development of osteoarthritis

The age-dependent accumulation of advanced glycation end products (AGEs) has proposed to be involved in the mechanism for the accelerated development of osteoarthritis (OA). Although numerous studies have been made on the effects of extracelluar AGEs and AGEs/RAGE mediated signaling pathway, few attention was paid to the intracellular AGEs. Recently, ERM proteins (ezrin, radixin and moesin) have been identified as novel receptors of intracellular AGEs. Recent analyses of the structure and functions of ERM proteins have revealed that these molecules are involved not only in cytoskeletal organization but also in signal transduction. The ERM phosphorylation induced by many stimuli plays a crucial role in the actin cytoskeleton arrangement, cell shape alterations, cell attachment and adhesion. Therefore, we hypothesize that the intracellular AGE–ERM interaction may be a possible mechanism for link between advanced glycation end products and the accelerated development of osteoarthritis. Furthermore, we would like to propose the possible ways to test our hypotheses for outlining a theoretic framework for future studies.     

Cardiac arrhythmia and thyroid dysfunction: A novel genetic link

Inherited Long QT Syndrome (LQTS), a cardiac arrhythmia that predisposes to the often lethal ventricular fibrillation, is commonly linked to mutations in KCNQ1. The KCNQ1 voltage-gated K⁺ channel α subunit passes ventricular myocyte K⁺ current that helps bring a timely end to each heart-beat. KCNQ1, like many K⁺ channel α subunits, is regulated by KCNE β subunits, inherited mutations in which also associate with LQTS. KCNQ1 and KCNE mutations are also associated with atrial fibrillation. It has long been known that thyroid status strongly influences cardiac function, and that thyroid dysfunction causes abnormal cardiac structure and rhythm. We recently discovered that KCNQ1 and KCNE2 form a thyroid-stimulating hormone-stimulated K⁺ channel in the thyroid that is required for normal thyroid hormone biosynthesis. Here, we review this novel genetic link between cardiac and thyroid physiology and pathology, and its potential influence upon future therapeutic strategies in cardiac and thyroid disease.     

Uridine natural products: Challenging targets and inspiration for novel small molecule inhibitors

Nucleoside derivatives, in particular those featuring uridine, are familiar components of the nucleoside family of bioactive natural products. The structural complexity and biological activities of these compounds have inspired research from organic chemistry and chemical biology communities seeking to develop novel approaches to assemble the challenging molecular targets, to gain inspiration for enzyme inhibitor development and to fuel antibiotic discovery efforts. This review will present recent case studies describing the total synthesis and biosynthesis of uridine natural products, and de novo synthetic efforts exploiting features of the natural products to produce simplified scaffolds. This research has culminated in the development of complementary strategies that can lead to effective uridine-based inhibitors and antibiotics. The strengths and challenges of the juxtaposing methods will be illustrated by examining select uridine natural products. Moreover, structure–activity relationships (SAR) for each natural product-inspired scaffold will be discussed, highlighting the impact on inhibitor development, with the aim of future uridine-based small molecule expansion.