Phytochemical Information and Biological Activities of Quinolizidine Alkaloids in Sophora: A Comprehensive Review.

Quinolizidine alkaloids, a main form of alkaloids found in the genus Sophora, have been shown to have many pharmacological effects. This review aims to summarize the photochemical reports and biological activities of quinolizidine alkaloids in Sophora. The collected information suggested that a total of 99 quinolizidine alkaloids were isolated and detected from different parts of Sophora plants, represented by lupinine-type, cytisine-type, sparteine-type, and matrine-type. However, quality control needs to be monitored because it could provide basic information for the reasonable and efficient use of quinolizidine alkaloids as medicines and raw materials. The nonmedicinal parts may be promising to be used as a source of quinolizidine alkaloid raw materials and to reduce the waste of resources and environmental pollution. In addition, the diversity of chemical compounds based on the alkaloid scaffold to make a biological compound library needs to be extended, which may reduce toxicity and find new bioactivities of quinolizidine alkaloids. The bioactivities most reported are in the fields of antitumor activity along with the effects on the cardiovascular system. However, those studies rely on theoretical research, and novel drugs based on quinolizidine alkaloids are expected.

Molecular mechanisms involved in drug-induced liver injury caused by urate-lowering Chinese herbs: A network pharmacology study and biology experiments.

As an important part of the comprehensive treatment methods, the urate-lowering Chinese herbs could provide favorable clinical effects on hyperuricemia in its ability to invigorate spleen and remove dampness. Owing to the long-term duration, it brought up the potential adverse reactions (ADRs) and concerns about the drug-induced liver injury from these herbs. To address this problem, the bioinformatics approaches which combined the network pharmacology, computer simulation and molecular biology experiments were undertaken to elucidate the underlying drug-induced liver injury molecular mechanisms of urate-lowering Chinese herbs. Several electronic databases were searched to identify the potential liver injury compounds in published research. Then, the putative target profile of liver injury was predicted, and the interaction network was constructed based on the links between the compounds, corresponding targets and core pathways. Accordingly, the molecular docking simulation was performed to recognize the representative compounds with hepatotoxicity. Finally, the cell experiments were conducted to investigate the biochemical indicators and expression of the crucial protein that were closely associated with liver injury. In conclusion, the current research revealed that the compounds with potential liver injury including diosgenin, baicalin, saikosaponin D, tetrandrine, rutaecarpine and evodiamine from urate-lowering Chinese herbs, could lead to decline the survival rate of L-02 cell, increase the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) in cell-culture medium, enhance the expression of p-p38/p38, while the p38 inhibitor could achieve the trend of regulating and controlling liver injury. These research findings bring further support to the growing evidence that the mechanism of the liver injury induced by the compounds from urate-lowering Chinese herbs may be associated with the activation of p38α.

Exploiting the Sensitivity of Nutrient Transporter Deletion Strains in Discovery of Natural Product Antimetabolites.

Actinomycete secondary metabolites are a renowned source of antibacterial chemical scaffolds. Herein, we present a target-specific approach that increases the detection of antimetabolites from natural sources by screening actinomycete-derived extracts against nutrient transporter deletion strains. On the basis of the growth rescue patterns of a collection of 22 Escherichia coli (E. coli) auxotrophic deletion strains representative of the major nutrient biosynthetic pathways, we demonstrate that antimetabolite detection from actinomycete-derived extracts prepared using traditional extraction platforms is masked by nutrient supplementation. In particular, we find poor sensitivity for the detection of antimetabolites targeting vitamin biosynthesis. To circumvent this and as a proof of principle, we exploit the differential activity of actinomycete extracts against E. coli ΔyigM, a biotin transporter deletion strain versus wildtype E. coli. We achieve more than a 100-fold increase in antimetabolite sensitivity using this method and demonstrate a successful bioassay-guided purification of the known biotin antimetabolite, amiclenomycin. Our findings provide a unique solution to uncover the full potential of naturally derived antibiotics.

[Secondary Metabolites from Marine Microorganisms. I. Secondary Metabolites from Marine Actinomycetes].

Review represents data on new active metabolites isolated from marine actinomycetes published in 2007 to 2014. Marine actinomycetes are an unlimited source of novel secondary metabolites with various biological activities. Among them there are antibiotics, anticancer compounds, inhibitors of biochemical processes.

Hypouricemic actions of exopolysaccharide produced by Cordyceps militaris in potassium oxonate-induced hyperuricemic mice.

The hypouricemic actions of exopolysaccharide produced by Cordyceps militaris (EPCM) in potassium oxonate-induced hyperuricemia in mice were examined. Hyperuricemic mice were administered intragastrically with EPCM (200, 400 and 800 mg/kg body weight) or allopurinol (5 mg/kg body weight) once daily. Serum uric acid, blood urea nitrogen and liver xanthine oxidase (XOD) activities of each treatment were measured after administration for 7 days. EPCM showed dose-dependent uric acid-lowering actions. EPCM at a dose of 400 mg/kg body weight and allopurinol showed the same effect in serum uric acid, blood urea nitrogen and liver XOD activities in hyperuricemic mice. An increase in liver XOD activities was observed in hyperuricemic mice due to administration of EPCM at a dose of 200 mg/kg body weight. EPCM at a dose of 800 mg/kg body weight did not show significant effects on serum uric acid and XOD activities. We conclude that EPCM has a hypouricemic effect caused by decreases in urate production and the inhibition of XOD activities in hyperuricemic mice, and this natural product exhibited more potential efficacy than allopurinol in renal protection.

Components of cancer metabolism and therapeutic interventions.

All forms of life share a common indispensible need of energy. The requirement of energy is necessary for an organism not only to survive but also to thrive. The metabolic activities in normal cells rely predominately on mitochondrial oxidative phophorylation for energy generation in the form of ATP. On the contrary, cancer cells predominately rely on glycolysis rather than oxidative phosphorylation. It is long believed that an impairment of mitochondrial oxidative phosphorylation is the cause of this glycolytic phenotype observed in cancers. However, studies in cancer metabolism have revealed that mitochondrial function in many cancers is intact. It has also been observed that cancers utilize various forms of metabolism. The various metabolic phenotypes that are employed by cancer cells have a common purpose, to balance macromolecular biosynthesis and sufficient ATP production in order to support the rapid proliferation rate characteristic of these aberrant cells. These metabolic pathways are attractive targets for possible therapeutic interventions and currently research is underway to meet this end. More importantly, normal cells have essentially the same metabolic requirements as cancer cells so finding an approach to target these metabolic pathways without incurring detrimental effects on normal tissues remains the challenge.

Speculative strategies for new antibacterials: all roads should not lead to Rome.

In concert with improvements in personal hygiene and public sanitation, the discovery and development of antibiotics during the latter half of the last century has reduced substantially the morbidity and mortality associated with bacterial diseases. However, the past decade has witnessed a sharp reduction in interest in antibacterial drug development by 'big pharma', compounded by a decline in the breadth of chemical space for new antibacterial molecules and a failure to exploit the plethora of cellular processes potentially targetable by novel classes of antibacterial molecules. This review focuses on some strategies relating to antibacterial chemotherapy, paths less trodden, which the author considers worthy of further exploration.

Inhibitory effect of melanogenesis by 5-pentyl-2-furaldehyde isolated from Clitocybe sp.

In the continued search for melanogenesis inhibitors from microbial metabolites, we found that the culture broth of Clitocybe sp. MKACC 53267 inhibited melanogenesis in B16F10 melanoma cells. The active component was purified by solvent extraction, silica gel chromatography, Sephadex LH-20 column chromatography, and finally by preparative HPLC. Its structure was determined as 5- pentyl-2-furaldehyde on the basis of the UV, NMR, and MS spectroscopic analysis. The 5-pentyl-2-furaldehyde potently inhibited melanogenesis in B16F10 cells with an IC50 value of 8.4 microgram/ml, without cytotoxicity.

Capsaicin, a potential inhibitor of cholera toxin production in Vibrio cholerae.

The use of natural compounds as inhibitory agents for virulence factor production is a new approach to overcome increased antimicrobial resistance in pathogenic bacteria. In this study, we examined whether red chilli (Capsicum annuum) contains any such compound(s) that can repress the cholera toxin (CT) production in Vibrio cholerae. We found that the methanol extract of red chilli could inhibit CT production in recently emerged V. cholerae O1 El Tor variant strains without affecting their viability. Interestingly, capsaicin, a well-studied active component of red chilli, also drastically inhibited CT production in V. cholerae strains belonging to various serogroups including variants. Real-time quantitative reverse transcription-PCR assay revealed that capsaicin effectively repressed the transcription of ctxA, tcpA and toxT genes, but not of toxR and toxS genes. On the contrary, capsaicin significantly enhanced the transcription of the hns gene, the product of which is known to regulate negatively the transcription of ctxAB, tcpA and toxT genes. These results suggest that capsaicin might act as a potent repressor for CT production possibly by enhancing the transcription of hns.

Yokonolide A, a new inhibitor of auxin signal transduction, from Streptomyces diastatochromogenes B59.

Bio-probes that inhibit the action of auxin are useful tools for the study of auxin signaling. To screen for specific inhibitors of auxin signaling, we used an Arabidopsis transgenic line harboring the auxin-inducible promoter derived from PS-IAA4/5 and the reporter gene, GUS (beta-glucuronidase). In this transgenic plant, the exogenous auxin specifically enhanced the expression of the GUS reporter gene. A novel 22-membered spiroketal-macrolide, yokonolide A (1), and related previously known compound, A82548A (2), were isolated from Streptomyces diastatochromogenes B59 as inhibitors of auxin inducible gene expression. The absolute structure of I was determined by detailed spectral analyses and chemical derivatization. 1 and 2 completely inhibited the auxin-induced transcription of the reporter gene at 5 and 1 microm, respectively. In contrast, 1 and 2 did not affect the translation of GUS reporter transcripts. In addition, 1 and 2 did not inhibit the gibberellin-induced alpha-amylase expression at 100 microM in barley aleurone cells. These results suggest that 1 and 2 specifically inhibit auxin signaling leading to auxin-mediated gene expression.

Lachnellins A, B, C, D, and naphthalene-1,3,8-triol, biologically active compounds from a Lachnellula species (ascomycetes).

In the course of our search for new biologically active metabolites, lachnellin A (1), a metabolite with high cytotoxic and antimicrobial activities, the structurally related lachnellins B, C and D (3, 4, 7), and naphthalene-1,3,8-triol (8), an inhibitor of malate synthase (EC 4.1.3.2), were isolated from submerged cultures of the ascomycete Lachnellula sp. A 32-89. The antimicrobial, cytotoxic and phytotoxic activities of lachnellin A depended on its reactivity and could be abolished by the addition of cysteine. The enzyme inhibiting activity of (8) was due to reactive intermediates during melanization and was no longer observed in the presence of serum albumin. In addition, rac-scytalone (9), (+)-trans-3,4-dihydro-3,4,8-trihydroxy-1 (2H)-naphthalenone (10), 2,5-dihydroxytoluene (11), and (R)-(-)-5-methylmellein (12) were obtained from the same source and biologically characterized.

Biosynthesis of fluorothreonine and fluoroacetic acid by the thienamycin producer, Streptomyces cattleya.

An antimetabolite, THX, was isolated from fermentation broths of the thienamycin producer, Streptomyces cattleya, when the organism was grown in the presence of a fluorine-containing substrate. THX was subsequently identified as one of the four possible stereoisomers of 4-fluorothreonine. Inorganic fluoride or any one of a number of organofluorine compounds can be used as precursors of 4-fluorothreonine. In addition, 19F NMR has provided evidence that the organism synthesizes fluoroacetate under the same fermentation conditions. The in vitro antibacterial spectrum of 4-fluorothreonine is also presented.

Antimutagenic unusual amino acids from plants.

Five unusual amino acids were identified as antimutagens against spontaneous mutation of Salmonella typhimurium TA100: L-azetidine-2-carboxylic acid (1) from Liliaceae plants, alpha-(methylenecyclopropyl)glycine (2) from Litchi chinensis seeds, and 2-amino-4-methylhex-5-ynoic acid (3), hypoglycin A (4), and (2S,4R)-2-amino-4-hydroxyhept-6-ynoic acid (5) from Euphoria longana seeds. The absolute stereochemistry of 5 was determined by its chiral synthesis from L-allylglycine, proving that 5 is the C-4 epimer of the amino acid previously isolated from dried longan seeds.

Metabolic products from microorganisms. 230. Amiclenomycin-peptides, new antimetabolites of biotin. Taxonomy, fermentation and biological properties.

Four new and two known peptide antibiotics containing amiclenomycin (Acm) have been isolated from a culture of Streptomyces venezuelae Tü 2460: L-MeIle-L-Acm (1), L-Ile-L-Acm (2), L-MeVal-L-Acm (3), L-MeIle-L-Acm-L-Gln (4), L-Ile-L-Acm-L-Gln (5) and L-Val-L-Acm-L-Gln (6). These di- and tripeptides exhibited antimicrobial activity on a minimal medium against Gram-negative bacteria, which could be reversed by biotin. It was shown that the antibiotics were decomposed by peptidases to provide amiclenomycin (7) after their uptake into cells of Escherichia coli via peptide-permeases. The antimicrobial activity of the amiclenomycin-peptides was the inhibition of DAPA-aminotransferase by the amiclenomycin-warhead, however, amiclenomycin itself was hardly transported into the cells. Since the amiclenomycin peptides misuse general transport systems, they are presented here as examples for the illicit transport concept.

beta-methylnorleucine, an antimetabolite produced by Serratia marcescens.

An amino acid was formed by alpha-aminobutyrate-resistant mutants of Serratia marcescens grown in a medium containing norvaline. This amino acid was identified as erythro-beta-methyl-L-norleucine [(2S,3S)-2-amino-3-methylhexanoic acid] by instrumental analyses. beta-Methylnorleucine inhibited the growth of several bacteria in synthetic medium.

Microbial production of vitamin B12 antimetabolites. IV. Isolation and identification of 4-keto-5-amino-6-hydroxyhexanoic acid.

4-Keto-5-amino-6-hydroxyhexanoic acid was isolated from Bacillus cereus 102804 fermentations and found to inhibit the growth of Gram-positive and Gram-negative bacteria, when grown in a chemically defined medium. The mechanism appeared to be the inhibition of delta-aminolevulinic acid dehydratase. The Ki value of 4-keto-5-amino-6-hydroxyhexanoic acid in an enzyme preparation of Propionibacterium shermanii was 0.72 microM. Similar test conditions with 4-keto-5-aminohexanoic acid resulted in Ki of 12.1 microM. In both cases competitive inhibition was found. The structure of 4-keto-5-amino-6-hydroxyhexanoic acid was determined.