Effects of tillage patterns and stover mulching on N2O production, nitrogen cycling genes and microbial dynamics in black soil.

Stover-covered no-tillage (NT) is of great significance to the rational utilization of stover resources and improvement of cultivated land quality, and also has a profound impact on ensuring groundwater, food and ecosystem security. However, the effects of tillage patterns and stover mulching on soil nitrogen turnover remain elusive. Based on the long-term conservation tillage field experiment in the mollisol area of Northeast China since 2007, the shotgun metagenomic sequencing of soils and microcosm incubation were combined with physical and chemical analyses, alkyne inhibition analysis to elucidate the regulatory mechanisms of NT and stover mulching on the farmland soil nitrogen emissions and microbial nitrogen cycling genes. Compared with conventional tillage (CT), NT stover mulching significantly reduced the emission of N2O instead of CO2, especially when 33% mulching was adopted, and correspondingly the nitrate nitrogen of NT33 was higher than that of other mulching amounts. The stover mulching was associated with higher total nitrogen, soil organic carbon and pH. The abundance of AOB (ammonia-oxidizing bacteria)-amoA (ammonia monooxygenase subunit A) was substantially increased by stover mulching, while the abundance of denitrification genes was reduced in most cases. Under alkyne inhibition, the tillage mode, treatment time, gas condition and interactions between them noticeably influenced the N2O emission and nitrogen transformation. In CT, NT0 (no mulching) and NT100 (full mulching), the relative contribution of AOB to N2O production was markedly higher than that of ammonia oxidizing archaea. Different tillage modes were associated with distinct microbial community composition, albeit NT100 was closer to CT than to NT0. Compared with CT, the co-occurrence network of microbial communities was more complex in NT0 and NT100. Our findings suggest that maintaining a low-quantity stover mulching could regulate soil nitrogen turnover toward proficiently enhancing soil health and regenerative agriculture, and coping with global climate change.

Evaluating Potentials of Species Rich Taxonomic Groups in Cosmetics and Dermatology: Clustering and Dispersion of Skin Efficacy of Asteraceae and Ranunculales Plants on the Species Phylogenetic Tree.

BACKGROUND: The medicinal properties of plants can be predicted by virtue of phylogenetic methods, which nevertheless have not been utilized to explore the regularity of skin-related bioactivities of ethnomedicinal plants. We aim to investigate the distribution of skin efficacy of Asteraceae and Ranunculales plants on the species-level Tree of Life. METHODS: The clinical efficacy data of 551 ethnomedicinal species belonging to Ranunculales, as well as 579 ethnomedicinal species of Asteraceae, were systematically collected and collated; these therapeutic data fell into 15 categories, including skin disease/cosmeceutical. The large phylogenetic tree of all China angiosperm species was used to detect the phylogenetic signals of ethnomedicinal plants by calculating the D statistic, phylogenetic diversity (PD), net relatedness index (NRI), and nearest taxon index (NTI). Of all Chinese ethnomedicinal plants of Ranunculales and Asteraceae, 339 (61.5% of all ethnomedicinal species) and 382 (66.0% of all) are used for skin problems. In Ranunculales, a clustered structure was suggested by the NRI value for skin uses. In Asteraceae, the skin utility was not clustered; Artemisia, Aster, Cremanthodium, Ligularia, and Saussurea are the most used Asteraceae genera for skin issues. RESULTS: The clustering structure was identified in Artemisia, and the skin efficacy in other genera was of overdispersion (NRI < 0). NTI values and D statistics largely agree with NRI. When compared with PD values of different therapeutic categories, the PD value of the skin category was relatively high in Cremanthodium, Ranunculales, Asteraceae, and Artemisia, suggesting the enormous efficacy space in the new taxa of these taxonomic groups. CONCLUSION: By resolving the distribution of therapeutic effects of Ranunculales/Asteraceae taxa, the importance of phylogenetic methods in mining botanical resources with skin utilities is validated.

The genus Chrysanthemum: Phylogeny, biodiversity, phytometabolites, and chemodiversity.

The ecologically and economically important genus Chrysanthemum contains around 40 species and many hybrids and cultivars. The dried capitulum of Chrysanthemum morifolium (CM) Ramat. Tzvel, i.e., Flos Chrysanthemi, is frequently used in traditional Chinese medicine (TCM) and folk medicine for at least 2,200 years. It has also been a popular tea beverage for about 2,000 years since Han Dynasty in China. However, the origin of different cultivars of CM and the phylogenetic relationship between Chrysanthemum and related Asteraceae genera are still elusive, and there is a lack of comprehensive review about the association between biodiversity and chemodiversity of Chrysanthemum. This article aims to provide a synthetic summary of the phylogeny, biodiversity, phytometabolites and chemodiversity of Chrysanthemum and related taxonomic groups, focusing on CM and its wild relatives. Based on extensive literature review and in light of the medicinal value of chrysanthemum, we give some suggestions for its relationship with some genera/species and future applications. Mining chemodiversity from biodiversity of Chrysanthemum containing subtribe Artemisiinae, as well as mining therapeutic efficacy and other utilities from chemodiversity/biodiversity, is closely related with sustainable conservation and utilization of Artemisiinae resources. There were eight main cultivars of Flos Chrysanthemi, i.e., Hangju, Boju, Gongju, Chuju, Huaiju, Jiju, Chuanju and Qiju, which differ in geographical origins and processing methods. Different CM cultivars originated from various hybridizations between multiple wild species. They mainly contained volatile oils, triterpenes, flavonoids, phenolic acids, polysaccharides, amino acids and other phytometabolites, which have the activities of antimicrobial, anti-viral, antioxidant, anti-aging, anticancer, anti-inflammatory, and closely related taxonomic groups could also be useful as food, medicine and tea. Despite some progresses, the genetic/chemical relationships among varieties, species and relevant genera have yet to be clarified; therefore, the roles of pharmacophylogeny and omics technology are highlighted.

Mining Therapeutic Efficacy from Treasure Chest of Biodiversity and Chemodiversity: Pharmacophylogeny of Ranunculales Medicinal Plants.

Ranunculales, comprising of 7 families that are rich in medicinal species frequently utilized by traditional medicine and ethnomedicine, represents a treasure chest of biodiversity and chemodiversity. The phylogenetically related species often have similar chemical profile, which makes them often possess similar therapeutic spectrum. This has been validated by both ethnomedicinal experiences and pharmacological investigations. This paper summarizes molecular phylogeny, chemical constituents, and therapeutic applications of Ranunculales, i.e., a pharmacophylogeny study of this representative medicinal order. The phytochemistry/metabolome, ethnomedicine and bioactivity/pharmacology data are incorporated within the phylogenetic framework of Ranunculales. The most studied compounds of this order include benzylisoquinoline alkaloid, flavonoid, terpenoid, saponin and lignan, etc. Bisbenzylisoquinoline alkaloids are especially abundant in Berberidaceae and Menispermaceae. The most frequent ethnomedicinal uses are arthritis, heat-clearing and detoxification, carbuncle-abscess and sore-toxin. The most studied bioactivities are anticancer/cytotoxic, antimicrobial, and anti-inflammatory activities, etc. The pharmacophylogeny analysis, integrated with both traditional and modern medicinal uses, agrees with the molecular phylogeny based on chloroplast and nuclear DNA sequences, in which Ranunculales is divided into Ranunculaceae, Berberidaceae, Menispermaceae, Lardizabalaceae, Circaeasteraceae, Papaveraceae, and Eupteleaceae families. Chemical constituents and therapeutic efficacy of each taxonomic group are reviewed and the underlying connection between phylogeny, chemodiversity and clinical uses is revealed, which facilitate the conservation and sustainable utilization of Ranunculales pharmaceutical resources, as well as developing novel plant-based pharmacotherapy.

Distribution patterns and industry planning of commonly used traditional Chinese medicinal plants in China.

Medicinal plants are the primary material basis for disease prevention and treatment in traditional Chinese medicine (TCM). The conservation and sustainable utilization of these medicinal plants is critical for the development of the TCM industry. However, wild medicinal plant resources have sharply declined in recent decades. To ameliorate the shortage of medicinal plant resources, it is essential to explore the development potential of the TCM industry in different geographical regions. For this purpose, we examined the spatial distribution of commonly used medicinal plants in China, the number of Chinese medicinal material markets, and the number of TCM decoction piece enterprises. Specifically, multispecies superimposition analysis and Thiessen polygons were used to reveal the optimal range for planting bulk medicinal plants and the ideal regions for building Chinese medicinal material markets, respectively. Furthermore, we quantitatively analyzed mismatches between the spatial distribution of commonly used medicinal plant richness, Chinese medicinal material markets, and TCM decoction piece enterprises. We found that the areas suitable for growing commonly used medicinal plants in China were mainly distributed in Hengduan Mountain, Nanling Mountain, Wuling Mountain, and Daba Mountain areas. The Thiessen polygon network based on Chinese medicinal material market localities showed there are currently fewer markets in southwestern, northwestern, and northeastern China than in central and southern China. TCM decoction piece enterprises are concentrated in a few provinces, such as Hebei and Jiangxi. We found that the distribution of commonly used medicinal plants, Chinese medicinal material markets and TCM decoction piece enterprises are mismatched in Henan, Shaanxi, Hunan, Hubei, Zhejiang, Fujian, Chongqing, and Xizang. We recommend strengthening development of the TCM industry in Henan, Hunan, Zhejiang, Shaanxi, Hubei, Chongqing, Fujian, and Xizang; building more Chinese medicinal material markets in southwestern, northwestern, and northeastern China; and establishing medicinal plant nurseries in resource-rich provinces to better protect and domesticate local medicinal plants.

Impact of Drug Metabolism/Pharmacokinetics and its Relevance Considering Traditional Medicine-based Anti-COVID-19 Drug Research.

BACKGROUND: The representative anti-COVID-19 herbs, i.e., Poriacocos, Pogostemon, Prunus, and Glycyrrhiza plants, are commonly used in the prevention and treatment of COVID-19, a pandemic caused by SARSCoV- 2. Diverse medicinal compounds with favorable anti-COVID-19 activities are abundant in these plants, and their unique pharmacological/pharmacokinetic properties have been revealed. However, the current trends in Drug Metabolism/Pharmacokinetic (DMPK) investigations of anti-COVID-19 herbs have not been systematically summarized. METHODS: In this study, the latest awareness, as well as the perception gaps regarding DMPK attributes, in the anti- COVID-19 drug development and clinical usage was critically examined and discussed. RESULTS: The extracts and compounds of P.cocos, Pogostemon, Prunus, and Glycyrrhiza plants show distinct and diverse absorption, distribution, metabolism, excretion, and toxicity (ADME/T) properties. The complicated herbherb interactions (HHIs) and herb-drug interactions (HDIs) of anti-COVID-19 Traditional Chinese Medicine (TCM) herb pair/formula dramatically influence the PK/pharmacodynamic (PD) performance of compounds thereof, which may inspire researchers to design innovative herbal/compound formulas for optimizing the therapeutic outcome of COVID-19 and related epidemic diseases. The ADME/T of some abundant compounds in anti-COVID-19 plants have been elucidated, but DMPK studies should be extended to more compounds of different medicinal parts, species, and formulations and would be facilitated by various omics platforms and computational analyses. CONCLUSION: In the framework of pharmacology and pharmacophylogeny, the DMPK knowledge base would promote the translation of bench findings into the clinical practice of anti-COVID-19 and speed up the anti-COVID-19 drug discovery and development.

Distribution of Therapeutic Efficacy of Ranunculales Plants Used by Ethnic Minorities on the Phylogenetic Tree of Chinese Species.

The medicinal properties of plants can be evolutionarily predicted by phylogeny-based methods, which, however, have not been used to explore the regularity of therapeutic effects of Chinese plants utilized by ethnic minorities. This study aims at exploring the distribution law of therapeutic efficacy of Ranunculales plants on the phylogenetic tree of Chinese species. We collected therapeutic efficacy data of 551 ethnomedicinal species belonging to five species-rich families of Ranunculales; these therapeutic data were divided into 15 categories according to the impacted tissues and organs. The phylogenetic tree of angiosperm species was used to analyze the phylogenetic signals of ethnomedicinal plants by calculating the net relatedness index (NRI) and nearest taxon index (NTI) in R language. The NRI results revealed a clustered structure for eight medicinal categories (poisoning/intoxication, circulatory, gastrointestinal, eyesight, oral, pediatric, skin, and urinary disorders) and overdispersion for the remaining seven (neurological, general, hepatobiliary, musculoskeletal, otolaryngologic, reproductive, and respiratory disorders), while the NTI metric identified the clustered structure for all. Statistically, NRI and NTI values were significant in 5 and 11 categories, respectively. It was found that Mahonia eurybracteata has therapeutic effects on all categories. iTOL was used to visualize the distribution of treatment efficacy on species phylogenetic trees. By figuring out the distribution of therapeutic effects of Ranunculales medicinal plants, the importance of phylogenetic methods in finding potential medicinal resources is highlighted; NRI, NTI, and similar indices can be calculated to help find taxonomic groups with medicinal efficacy based on the phylogenetic tree of flora in different geographic regions.

A Global Analysis of Alternative Splicing of Dichocarpum Medicinal Plants, Ranunculales.

Background: The multiple isoforms are often generated from a single gene via Alternative Splicing (AS) in plants, and the functional diversity of the plant genome is significantly increased. Despite well-studied gene functions, the specific functions of isoforms are little known, therefore, the accurate prediction of isoform functions is exceedingly wanted. Methods: Here we perform the first global analysis of AS of Dichocarpum, a medicinal genus of Ranunculales, by utilizing full-length transcriptome datasets of five Chinese endemic Dichocarpum taxa. Multiple software were used to identify AS events, the gene function was annotated based on seven databases, and the protein-coding sequence of each AS isoform was translated into an amino acid sequence. The self-developed software DIFFUSE was used to predict the functions of AS isoforms. Results: Among 8,485 genes with AS events, the genes with two isoforms were the most (6,038), followed by those with three isoforms and four isoforms. Retained intron (RI, 551) was predominant among 1,037 AS events, and alternative 3' splice sites and alternative 5' splice sites were second. The software DIFFUSE was effective in predicting functions of Dichocarpum isoforms, which have not been unearthed. When compared with the sequence alignment-based database annotations, DIFFUSE performed better in differentiating isoform functions. The DIFFUSE predictions on the terms GO:0003677 (DNA binding) and GO: 0010333 (terpene synthase activity) agreed with the biological features of transcript isoforms. Conclusion: Numerous AS events were for the first time identified from full-length transcriptome datasets of five Dichocarpum taxa, and functions of AS isoforms were successfully predicted by the self-developed software DIFFUSE. The global analysis of Dichocarpum AS events and predicting isoform functions can help understand the metabolic regulations of medicinal taxa and their pharmaceutical explorations.

Dissection of full-length transcriptome and metabolome of Dichocarpum (Ranunculaceae): implications in evolution of specialized metabolism of Ranunculales medicinal plants.

Several main families of Ranunculales are rich in alkaloids and other medicinal compounds; many species of these families are used in traditional and folk medicine. Dichocarpum is a representative medicinal genus of Ranunculaceae, but the genetic basis of its metabolic phenotype has not been investigated, which hinders its sustainable conservation and utilization. We use the third-generation high-throughput sequencing and metabolomic techniques to decipher the full-length transcriptomes and metabolomes of five Dichocarpum species endemic in China, and 71,598 non-redundant full-length transcripts were obtained, many of which are involved in defense, stress response and immunity, especially those participating in the biosynthesis of specialized metabolites such as benzylisoquinoline alkaloids (BIAs). Twenty-seven orthologs extracted from trancriptome datasets were concatenated to reconstruct the phylogenetic tree, which was verified by the clustering analysis based on the metabolomic profile and agreed with the Pearson correlation between gene expression patterns of Dichocarpum species. The phylogenomic analysis of phytometabolite biosynthesis genes, e.g., (S)-norcoclaurine synthase, methyltransferases, cytochrome p450 monooxygenases, berberine bridge enzyme and (S)-tetrahydroprotoberberine oxidase, revealed the evolutionary trajectories leading to the chemodiversity, especially that of protoberberine type, aporphine type and bis-BIA abundant in Dichocarpum and related genera. The biosynthesis pathways of these BIAs are proposed based on full-length transcriptomes and metabolomes of Dichocarpum. Within Ranunculales, the gene duplications are common, and a unique whole genome duplication is possible in Dichocarpum. The extensive correlations between metabolite content and gene expression support the co-evolution of various genes essential for the production of different specialized metabolites. Our study provides insights into the transcriptomic and metabolomic landscapes of Dichocarpum, which will assist further studies on genomics and application of Ranunculales plants.

Ethnopharmacology, chemodiversity, and bioactivity of Cephalotaxus medicinal plants.

Cephalotaxus is the only genus of Cephalotaxaceae family, and its natural resources are declining due to habitat fragmentation, excessive exploitation and destruction. In many areas of China, folk herbal doctors traditionally use Cephalotaxus plants to treat innominate swollen poison, many of which are cancer. Not only among Han people, but also among minority ethnic groups, Cephalotaxus is used to treat various diseases, e.g., cough, internal bleeding and cancer in Miao medicine, bruises, rheumatism and pain in Yao medicine, and ascariasis, hookworm disease, scrofula in She medicine, etc. Medicinal values of some Cephalotaxus species and compounds are acknowledged officially. However, there is a lack of comprehensive review summarizing the ethnomedicinal knowledge of Cephalotaxus, relevant medicinal phytometabolites and their bioactivities. The research progresses in ethnopharmacology, chemodiversity, and bioactivities of Cephalotaxus medicinal plants are reviewed and commented here. Knowledge gaps are pinpointed and future research directions are suggested. Classic medicinal books, folk medicine books, herbal manuals and ethnomedicinal publications were reviewed for the genus Cephalotaxus (Sanjianshan in Chinese). The relevant data about ethnobotany, phytochemistry, and pharmacology were collected as comprehensively as possible from online databases including Scopus, NCBI PubMed, Bing Scholar, and China National Knowledge Infrastructure (CNKI). "Cephalotaxus", and the respective species name were used as keywords in database search. The obtained articles of the past six decades were collated and analyzed. Four Cephalotaxus species are listed in the official medicinal book in China. They are used as ethnomedicines by many ethnic groups such as Miao, Yao, Dong, She and Han. Inspirations are obtained from traditional applications, and Cephalotaxus phytometabolites are developed into anticancer reagents. Cephalotaxine-type alkaloids, homoerythrina-type alkaloids and homoharringtonine (HHT) are abundant in Cephalotaxus, e.g., C. lanceolata, C. fortunei var. alpina, C. griffithii, and C. hainanensis, etc. New methods of alkaloid analysis and purification are continuously developed and applied. Diterpenoids, sesquiterpenoids, flavonoids, lignans, phenolics, and other components are also identified and isolated in various Cephalotaxus species. Alkaloids such as HHT, terpenoids and other compounds have anticancer activities against multiple types of human cancer. Cephalotaxus extracts and compounds showed anti-inflammatory and antioxidant activities, immunomodulatory activity, antimicrobial activity and nematotoxicity, antihyperglycemic effect, and bone effect, etc. Drug metabolism and pharmacokinetic studies of Cephalotaxus are increasing. We should continue to collect and sort out folk medicinal knowledge of Cephalotaxus and associated organisms, so as to obtain new enlightenment to translate traditional tips into great therapeutic drugs. Transcriptomics, genomics, metabolomics and proteomics studies can contribute massive information for bioactivity and phytochemistry of Cephalotaxus medicinal plants. We should continue to strengthen the application of state-of-the-art technologies in more Cephalotaxus species and for more useful compounds and pharmacological activities.

The Utility of Electrochemical Systems in Microbial Degradation of Polycyclic Aromatic Hydrocarbons: Discourse, Diversity and Design.

Polycyclic aromatic hydrocarbons (PAHs), especially high molecular weight PAHs, are carcinogenic and mutagenic organic compounds that are difficult to degrade. Microbial remediation is a popular method for the PAH removal in diverse environments and yet it is limited by the lack of electron acceptors. An emerging solution is to use the microbial electrochemical system, in which the solid anode is used as an inexhaustible electron acceptor and the microbial activity is stimulated by biocurrent in situ to ensure the PAH removal and avoid the defects of bioremediation. Based on the extensive investigation of recent literatures, this paper summarizes and comments on the research progress of PAH removal by the microbial electrochemical system of diversified design, enhanced measures and functional microorganisms. First, the bioelectrochemical degradation of PAHs is reviewed in separate and mixed PAH degradation, and the removal performance of PAHs in different system configurations is compared with the anode modification, the enhancement of substrate and electron transfer, the addition of chemical reagents, and the combination with phytoremediation. Second, the key functional microbiota including PAH degrading microbes and exoelectrogens are overviewed as well as the reduced microbes without competitive advantage. Finally, the typical representations of electrochemical activity especially the internal resistance, power density and current density of systems and influence factors are reviewed with the correlation analysis between PAH removal and energy generation. Presently, most studies focused on the anode modification in the bioelectrochemical degradation of PAHs and actually more attentions need to be paid to enhance the mass transfer and thus larger remediation radius, and other smart designs are also proposed, especially that the combined use of phytoremediation could be an eco-friendly and sustainable approach. Additionally, exoelectrogens and PAH degraders are partially overlapping, but the exact functional mechanisms of interaction network are still elusive, which could be revealed with the aid of advanced bioinformatics technology. In order to optimize the efficacy of functional community, more advanced techniques such as omics technology, photoelectrocatalysis and nanotechnology should be considered in the future research to improve the energy generation and PAH biodegradation rate simultaneously.

Pharmaceutical resource discovery from traditional medicinal plants: Pharmacophylogeny and pharmacophylogenomics.

The worldwide botanical and medicinal culture diversity are astonishing and constitute a Pierian spring for innovative drug R&D. Here, the latest awareness and the perspectives of pharmacophylogeny and pharmacophylogenomics, as well as their expanding utility in botanical drug R&D, are systematically summarized and highlighted. Chemotaxonomy is based on the fact that closely related plants contain the same or similar chemical profiles. Correspondingly, it is better to combine morphological characters, DNA markers and chemical markers in the inference of medicinal plant phylogeny. Medicinal plants within the same phylogenetic groups may have the same or similar therapeutic effects, thus forming the core of pharmacophylogeny. Here we systematically review and comment on the versatile applications of pharmacophylogeny in (1) looking for domestic resources of imported drugs, (2) expanding medicinal plant resources, (3) quality control, identification and expansion of herbal medicines, (4) predicting the chemical constituents or active ingredients of herbal medicine and assisting in the identification and determination of chemical constituents, (5) the search for new drugs sorting out, and (6) summarizing and improving herbal medicine experiences, etc. Such studies should be enhanced within the context of deeper investigations of molecular biology and genomics of traditional medicinal plants, phytometabolites and metabolomics, and ethnomedicine-based pharmacological activity, thus enabling the sustainable conservation and utilization of traditional medicinal resources.

Interspecies variation of clopidogrel hydrolysis in liver microsomes from various mammals.

Clopidogrel, a clinically used antiplatelet agent, can be readily hydrolyzed by human carboxylesterase 1A (CES1A) to release an inactive metabolite clopidogrel carboxylic acid (CCA). In this study, clopidogrel was used as a tool substrate to investigate the interspecies variation of clopidogrel hydrolysis in hepatic microsomes from various mammals including human and six laboratory animals (such as mouse, rat, rabbit, beagle dog, minipig and cynomolgus monkey). The results demonstrated that clopidogrel could be hydrolyzed into CCA by all tested hepatic microsomes from human or other mammals, but the hydrolytic rates greatly varied among species. Inhibition assays demonstrated that BNPP (an inactivator of mammalian CES) strongly inactivated clopidogrel hydrolytic activity in all tested hepatic microsomes, suggested that mammalian CES were major contributor(s) responsible for clopidogrel hydrolysis in hepatic preparations from all above-mentioned species. By contrast, the response of a reversible inhibitor of human CES1A on clopidogrel hydrolysis in these liver preparations varied significantly among different species. Moreover, the enzymatic kinetics and the apparent kinetic parameters of clopidogrel hydrolysis in hepatic microsomes from various animal species were evaluated and compared to each other. These findings provide crucial information for deeply understanding the differences in catalytic behaviors of mammalian CES, which will be very helpful for choosing suitable laboratory animal(s) for whole tests of CES1A substrate-drugs.

Impact of Drug Metabolism/Pharmacokinetics and their Relevance Upon Traditional Medicine-based Cardiovascular Drug Research.

BACKGROUND: The representative cardiovascular herbs, i.e. Panax, Ligusticum, Carthamus, and Pueraria plants, are traditionally and globally used in the prevention and treatment of various cardiovascular diseases. Modern phytochemical studies have found many medicinal compounds from these plants, and their unique pharmacological activities are being revealed. However, there are few reviews that systematically summarize the current trends of Drug Metabolism/Pharmacokinetic (DMPK) investigations of cardiovascular herbs. METHODS: Here, the latest understanding, as well as the knowledge gaps of the DMPK issues in drug development and clinical usage of cardiovascular herbal compounds, was highlighted. RESULTS: The complicated herb-herb interactions of cardiovascular Traditional Chinese Medicine (TCM) herb pair/formula significantly impact the PK/pharmacodynamic performance of compounds thereof, which may inspire researchers to develop a novel herbal formula for the optimized outcome of different cardiovascular diseases. While the Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME/T) of some compounds has been deciphered, DMPK studies should be extended to more cardiovascular compounds of different medicinal parts, species (including animals), and formulations, and could be streamlined by versatile omics platforms and computational analyses. CONCLUSION: In the context of systems pharmacology, the DMPK knowledge base is expected to translate bench findings to clinical applications, as well as foster cardiovascular drug discovery and development.

Inhibition of human carboxylesterases by ginsenosides: structure-activity relationships and inhibitory mechanism.

BACKGROUND: Human carboxylesterases (hCES) are key serine hydrolases responsible for the hydrolysis of a wide range of endogenous and xenobiotic esters. Although it has been reported that some ginsenosides can modulate the activities of various enzymes, the inhibitory effects of ginsenosides on hCES have not been well-investigated. METHODS: In this study, more than 20 ginsenosides were collected and their inhibitory effects on hCES1A and hCES2A were assayed using the highly specific fluorescent probe substrates for each isoenzyme. Molecular docking simulations were also performed to investigate the interactions between ginsenosides and hCES. RESULTS: Among all tested ginsenosides, Dammarenediol II (DM) and 20S-O-ß-(d-glucosyl)-dammarenediol II (DMG) displayed potent inhibition against both hCES1A and hCES2A, while protopanaxadiol (PPD) and protopanaxatriol (PPT) exhibited strong inhibition on hCES2A and high selectivity over hCES1A. Introduction of O-glycosyl groups at the core skeleton decreased hCES inhibition activity, while the hydroxyl groups at different sites might also effect hCES inhibition. Inhibition kinetic analyses demonstrated that DM and DMG functioned as competitive inhibitors against hCES1A-mediated d-luciferin methyl ester (DME) hydrolysis. In contrast, DM, DMG, PPD and PPT inhibit hCES2A-mediated fluorescein diacetate (FD) hydrolysis via a mixed manner. CONCLUSION: The structure-inhibition relationships of ginsenosides as hCES inhibitors was investigated for the first time. Our results revealed that DM and DMG were potent inhibitors against both hCES1A and hCES2A, while PPD and PPT were selective and strong inhibitors against hCES2A.

Traditional Tibetan medicinal plants: a highlighted resource for novel therapeutic compounds.

Around 70-80% of drugs used in traditional Tibetan medicine (TTM) come from Qinghai Tibet Plateau, the majority of which are plants. The biological and medicinal culture diversity on Qinghai Tibet Plateau are amazing and constitute a less tapped resource for innovative drug research and development. Meanwhile, the problem of the exhausting Tibetan medicine resources is worrying. Here, the latest awareness, as well as the gaps of the traditional Tibetan medicinal plant issues in drug development and clinical usage of TTM compounds, was systematically reviewed and highlighted. The TTM resource studies should be enhanced within the context of deeper and more extensive investigations of molecular biology and genomics of TTM plants, phytometabolites and metabolomics and ethnopharmacology-based bioactivity, thus enabling the sustainable conservation and exploitation of Tibetan medicinal resource.

Functional and Transcriptomic Characterization of a Dye-decolorizing Fungus from Taxus Rhizosphere.

We isolated three laccase-producing fungus strains from Taxus rhizosphere. Myrotheium verrucaria strain DJTU-sh7 had the highest laccase activity of 216.2 U/ml, which was increased to above 300 U/ml after optimization. DJTU-sh7 had the best decolorizing effect for three classes of reactive dyes. The DJTU-sh7-containing fungal consortium displayed the robust decolorizing ability. Both color removal efficiency and chemical oxygen demand were increased in the consortium mediated biotransformation. Transcriptome changes of M. verrucaria elicited by azo dye and phenolic were quantified by the high throughput transcriptome sequencing, and the activities of the selected oxidases and reductases were determined. The possible involvement of oxidases and reductases, especially laccase, aryl alcohol oxidase, and ferric reductase in the biotransformation of dye and phenolic compounds was revealed at both transcriptomic and phenotypic levels. Revealing the transcriptomic mechanisms of fungi in dealing with organic pollutants facilitates the fine-tuned manipulation of strains in developing novel bioremediation and biodegradation strategies.We isolated three laccase-producing fungus strains from Taxus rhizosphere. Myrotheium verrucaria strain DJTU-sh7 had the highest laccase activity of 216.2 U/ml, which was increased to above 300 U/ml after optimization. DJTU-sh7 had the best decolorizing effect for three classes of reactive dyes. The DJTU-sh7-containing fungal consortium displayed the robust decolorizing ability. Both color removal efficiency and chemical oxygen demand were increased in the consortium mediated biotransformation. Transcriptome changes of M. verrucaria elicited by azo dye and phenolic were quantified by the high throughput transcriptome sequencing, and the activities of the selected oxidases and reductases were determined. The possible involvement of oxidases and reductases, especially laccase, aryl alcohol oxidase, and ferric reductase in the biotransformation of dye and phenolic compounds was revealed at both transcriptomic and phenotypic levels. Revealing the transcriptomic mechanisms of fungi in dealing with organic pollutants facilitates the fine-tuned manipulation of strains in developing novel bioremediation and biodegradation strategies.