A perspective review on the biosynthesis of plant-based secondary metabolites and their application as potent drugs

Many phytochemicals and their derived metabolites produced by plants are extensively employed in commercial goods,pharmaceutical products as well as in the environmental and medicalfields.However,these secondary metabolites obtained from plants are in low amounts,and it is difficult to synthesize them at the industrial level.Despite these challenges,they may be utilized for a variety of medicinal products that are either available in the market or are being researched and tested.Secondary metabolites are complex compounds that exhibit chirality.Further,under controlled conditions with elicitors,desired secondary metabolites may be produced from plant cell cultures.This review emphasizes the various aspects of secondary metabolites including their types,synthesis,and applications as medicinal products.The article aims to promote the use of plant secondary metabolites in the management and treatment of various diseases.

Secondary Metabolites of Entomopathogenic Fungi, Biological Alternative for the Control of Agricultural Pests and Disease: Present and Perspectives

The use of entomopathogenic fungi (EF) in recent years has been highly effective against the different orders of insects considered pests of agricultural importance and their conidia have been commonly applied, but it has been reported that these are sensitive to the environmental conditions. For this reason, biopesticides products have been formulated based on secondary metabolites, recently. These biomolecules participate as biological control agent, such as: cyclic depsipeptides, amino acids, polyketides, polyphenols and terpenoids, affecting their morphology, life cycle and insect behavior. The use of secondary metabolites of entomopathogenic fungi opens the possibility of application in a more efficient way for the control of agricultural pests in a compatible with the environment and human health;therefore, it is important to know, analyzing the type of molecules, their effects, and their different methods of application.

Metabolic and transcriptomic analyses elucidate a novel insight into the network for biosynthesis of carbohydrate and secondary metabolites in the stems of a medicinal orchid Dendrobium nobile

Dendrobium nobile is an important medicinal and nutraceutical herb.Although the ingredients of D.nobile have been identified as polysaccharides,alkaloids,amino acids,flavonoids and bibenzyls,our understanding of the metabolic pathways that regulate the synthesis of these compounds is limited.Here,we used transcriptomic and metabolic analyses to elucidate the genes and metabolites involved in the biosynthesis of carbohydrate and several secondary metabolites in the stems of D.nobile.A total of 1005 metabolites and 31,745 genes were detected in the stems of D.nobile.The majority of these metabolites and genes were involved in the metabolism of carbohydrates(fructose,mannose,glucose,xylulose and starch),while some were involved in the metabolism of secondary metabolites(alkaloids,β-tyrosine,ferulic acid,4-hydroxybenzoate and chrysin).Our predicted regulatory network indicated that five genes(AROG,PYK,DXS,ACEE and HMGCR) might play vital roles in the transition from carbohydrate to alkaloid synthesis.Correlation analysis identified that six genes(ALDO,PMM,BGLX,EGLC,XYLB and GLGA) were involved in carbohydrate metabolism,and two genes(ADT and CYP73A) were involved in secondary metabolite biosynthesis.Our analyses also indicated that phosphoenol-pyruvate(PEP) was a crucial bridge that connected carbohydrate to alkaloid biosynthesis.The regulatory network between carbohydrate and secondary metabolite biosynthesis established will provide important insights into the regulation of metabolites and biological systems in Dendrobium species.

The role of sound stimulation in production of plant secondary metabolites

Sound vibration is one of natural stimuli trigging physiological changes in plants.Recent studies showed that sound waves stimulated production of a variety of plant secondary metabolites,including flavonoids,in order to enhance seed germination,flowering,growth or defense.In this review,we examine the potential role of sound stimulation on the biosynthesis of secondary metabolites and the followed cascade of physiological changes in plants,from the perspective of transcriptional regulation and epigenetic regulation for the first time.A systematic summary showed that a wide range of factors may regulate the production of secondary metabolites,including plant species,growth stage,sound types,sound frequency,sound intensity level and exposure time,etc.Biochemical and physiological changes due to sound stimulation were thoroughly summarized as well,for secondary metabolites can also act as a free radical scavenger,or a hormone signaling molecule.We also discussed the limits of previous studies,and the future application of sound waves in biosynthesis of plant secondary metabolites.

Selenium: A Game Changer in Plant Development, Growth, and Stress Tolerance, via the Modulation in Gene Expression and Secondary Metabolite Biosynthesis

The presence of selenium(Se)is not widely established as crucial for crops,although it is commonly recognized as an important nutrient for animals as well as humans.Even so,it is inevitably accepted that Se usually contributes positively to the life cycle of plants.Previousfindings suggested that small amounts of Se seem to have a productive role in growth and production.As a result,Se is assumed to function in multiple ways,primarily by influencing a variety of biochemical and physiological functions.Also,Se also acts as a plant antioxidant and pro-oxidant and confers tolerance against different abiotic stresses,including salinity,drought,extreme temperature,and toxic metals/metalloids stresses.It reflects a defensive barrier against stress by increasing chlorophyll content synthesis,photosynthesis,oxygen supply,osmoprotectant concentration,and secondary metabolite acquisition.One other crucial role of Se is its ability to strengthen antioxidant performance in plants,thereby decreasing the concentration of reactive-oxygen-species(ROS).Furthermore,Se generates and modifies genes and proteins that respond situationally to stress,and the presence of high Se concentrations in the growth-medium can cause phytotoxic conditions via excessive ROS production,and through pro-oxidative Se occurrence,suppression of chlorophyll contents in the biosynthetic pathway,and the inhibition of plant developmental and normal physiological functions.Like a phytofortifier,the correct amount of Se can indeed enhance the nutrient quality of both crop and fodder production.Furthermore,crops have naturally developed ways to combat Se-deficiency and Se-toxicity.The current review focuses on recent advances in understanding the dynamics of Se,the positive and negative roles of Se in crop management,and its efficiency in countering abiotic stress.

Study on Marine actinomycetes and analysis of their secondary metabolites

Actinomycetes are relatively prevalent bacteria in the ocean,constituting 9% of the total number of marine bacteria.The advancement of science and technology has led to a more profound exploration of marine actinomycetes.These studies hold immense significance in comprehending the distribution and adaptation of marine actinomycetes within the oceanic environment,as well as uncovering new secondary metabolites.Based on differing lifestyles,marine actinomycetes can be categorized as free-living or co-epiphytic.The activity and metabolism of actinomycetes vary across diverse marine settings,including the deep sea,benthic regions,and marine organisms.Due to their distinctive biological traits and genetic background,these marine actinomycetes inevitably generate metabolites possessing unique structures.Research methodologies concerning marine actinomycetes predominantly encompass traditional pure culture techniques,molecular biology approaches,and the integration of metagenomics and bioinformatics.The exploration of varied methodologies proves pivotal for the analysis of metabolite processes.Through the cultivation of marine actinomycetes,numerous compounds featuring novel structures and significant activities have been isolated,furnishing a substantial foundation for new drug investigations.These encompass,but are not restricted to,peptides,antibiotics,terpenoids,ketones,quinones,macrolides,and pigments.The potential applications of marine actinomyces and their secondary metabolites extend beyond antibacterial and anti-tumor effects,exhibiting promising prospects in antifungal and antiviral domains.This paper provides a comprehensive review of the classification,resources,research methodologies,and habitats of marine actinomycetes.Furthermore,it delves into the classification of secondary metabolites and their functional activities,facilitating a more exhaustive analysis of the secondary metabolites produced by marine actinomycetes.

Effect of Different Concentrations of Pesticide-Imidacloprid on the Main Secondary Metabolites of Fruit and Polysaccharide of Chinese Wolfberry

[Objective] The aim was to seek the appropriate utilization methods for imidacloprid pesticide in the production of Chinese wolfberry,as well as to provide scientific basis for the rational use of imidacloprid pesticide. [Method] The effect of different concentrations and spraying times of 10% WP of imidacloprid on the main secondary metabolites such as carotenoid and flavone,as well as the polysaccharide and total sugar content was studied in field. [Result] The effect of different concentrations of imidacloprid on the secondary metabolites and the content of polysaccharide of Chinese wolfberry was significant. After imidacloprid spraying,the contents of flavone,polysaccharide and total sugar on the 1st,7th and 14th d showed increasing trend,while the content of carotenoid showed decreasing trend. With the dilution times increasing,the content of the flavone,polysaccharide and total sugar showed increasing trend,while the content of carotenoid decreased,in which the highest content of the secondary metabolites and polysaccharide appeared in 1 800 times. [Conclusion] The dilution ratio of 1 800 times should be selected as the appropriate dosage of 10% WP of imidacloprid.

Changes of main secondary metabolites in leaves of Ginkgo biloba in response to ozone fumigation

To investigate the effect of elevated 03 on the accumulation of main secondary metabolites in leaves of Ginkgo biloba L., four-year- old trees were exposed in open-top chambers with ambient air and the air with twice ambient 03 concentration in Shenyang in 2006. Elevated 03 increased the concentrations of terpenes, but decreased the concentrations of phenolics in G. biloba leaves. The results showed that secondary compounds from G. biloba leaves responded to the elevated 03 exposure in a different way when compared to previous studies which showed elevated 03 increased the concentrations of phenolics but had no effect on the terpenes in leaves of other deciduous trees. Furthermore, reduced synthesis of phenolics may decrease the resistance of G. biloba to 03 and other environmental factors. On the other hand, the induced synthesis of terpenes may enhance the antioxidant abilities in G. biloba leaves at the end of 03 fumigation.

Identification and Bioactivities of Secondary Metabolites Derived from Endophytic Fungi Isolated from Ethnomedicinal Plants of Tujia in Hubei Province:A Review

Tujia is a national minority,inhabiting in the mountainous Wuling area in China.Since 1978,Tujia medicine has been studied,summarized and developed,leading to numerous achievements by Chinese researchers,such as the publishing of approximately 30 monographs of Tujia medicine.These publications are focused on summarizing and improving the theory of Tujia medicine and developing clinical therapies from this system of medicine.The shortage of natural medicinal plants used in Tujia medicine has created the need to discover new resources to replace them and protect endangered natural plant species.Endophytic fungi are one of the conservation options,are considered a source of new bioactive natural products,and are a renewable and inexhaustible source of new drugs and agrochemicals.This review summarizes 260 compounds from endophytic fungi that have been previously isolated from the medicinal plants of Tujia.These compounds include steroids,terpenoids,meroterpenoids,polyketides,alkaloids,peptides,aliphatic compounds,aromatic compounds,and heterocyclic compounds.

Secondary metabolites of rice sheath blight pathogen Rhizoctonia solani Kühn and their biological activities

Eight compounds were isolated from the fermentation cultures of rice sheath blight pathogen Rhizoctonia solani Kuhn. They were identified as ergosterol （1）, 6β-hydroxysitostenone （2）, sitostenone （3）, m-hydroxyphenylacetic acid （4）, methyl m-hydroxyphenylacetate （5）, m-hydroxymethylphenyl pentanoate （6）, （Z）-3-methylpent-2-en-1,5-dioic acid （7） and 3-methoxyfuran-2-carboxylic acid （8） by means of physicochemical and spectroscopic analysis. Among them, 2, 3, 5-8 were isolated from R. solani for the first time. All the compounds were evaluated for their biological activities. 4-6 and 8 showed their inhibitory activities on the radical and germ elongation of rice seeds. 1,4 and 7 showed moderate antibacterial activity to some bacteria. 4, 7 and 8 exhibited weak inhibitory activities on spore germination of Magnaporthe oryzae. 8 showed moderate antioxidant activity with the 1,1-diphenyl-2-picryhydrazyl （DPPH） andβ-carotene-linoleic acid assays. This is the first time to reveal compounds 5, 6 and 8 from rice sheath blight pathogen R. solani to have in vitro phytotoxic activity.

Secondary Metabolites of a Deep Sea Derived Fungus Aspergillus versicolor CXCTD-06-6a and Their Bioactivity

In order to obtain novel secondary metabolites, a deep sea inhabiting fungus Aspergillus versicolor CXCTD-06-6a was investigated. One new diketopiperazine brevianamide W(1a), as well as five known diketopiperazine alkaloids, diketopiperazine V(1b), brevianamide Q(2), brevianamide R(3), brevianamide K(4), and brevianamide E(5), were isolated from the Et OAc extract of the fermentation broth. Their structures were elucidated by spectroscopy techniques(NMR, MS). The six compounds exhibited moderate radical scavenging activity against DPPH with clearance ratio of 55.0%(1a and 1b), 53.7%(2), 46.2%(3), 61.4%(4) and 19.3%(5) at a concentration of 13.9 μmol L-1, respectively; while the positive control ascorbic acid showed a ratio of 70.3% at the concentration of 28.4 μmol L-1.

The Bioactive Secondary Metabolites from Talaromyces species

The focus of this review is placed on the chemical structures from the species of the genus Talaromyces reported with reference to their biological activities.221 secondary metabolites,including 43 alkaloids and peptides,88 esters,31 polyketides,19 quinones,15 steroid and terpenoids,and 25 other structure type compounds,have been included,and 66 references are cited.

Nitrogen Sources Affect Streptolydigin Production and Related Secondary Metabolites Distribution of Streptomyces lydicus AS 4.2501

The effects of nitrogen sources on streptolydigin production and distribution of secondary metabolites were investigated for flask cultured S.lydicus AS 4.2501.When peptone,asparamide,and glutamic acid were ex- amined as the nitrogen source,respectively,liquid chromatography-mass spectrometry(LC-MS)and photodiode array(PDA)analyses revealed the formation of two analogues of streptolydigin in the fermentation broth.When soybean meal was used as the source of nitrogen,three analogues of streptolydigin were detected.The use of am- monium sulfate as a source of nitrogen resulted in a lower pH value of the fermentation system,thus inhibiting streptolydigin biosynthesis and changing the metabolic profiling.Among the nitrogen sources that were made use of,glutamic acid was most favorable to the formation of streptolydigin.Simultaneously,this study also showed that the changing nitrogen sources resulted in altering the production and relative ratios of streptolydigin and its analogues.

Plant-derived secondary metabolites as the main source of efflux pump inhibitors and methods for identification

The upsurge of multiple drug resistance(MDR)bacteria substantially diminishes the effectiveness of antibiotic arsenal and therefore intensifies the rate of therapeutic failure.The major factor in MDR is efflux pump-mediated resistance.A unique pump can make bacteria withstand a wide range of structurally diverse compounds.Therefore,their inhibition is a promising route to eliminate resistance phenomenon in bacteria.Phytochemicals are excellent alternatives as resistance-modifying agents.They can directly kill bacteria or interact with the crucial events of pathogenicity,thereby decreasing the ability of bacteria to develop resistance.Numerous botanicals display noteworthy efflux pumps inhibitory activities.Edible plants are of growing interest.Likewise,some plant families would be excellent sources of efflux pump inhibitors(EPIs)including Apocynaceae,Berberidaceae,Convolvulaceae,Cucurbitaceae,Fabaceae,Lamiaceae,and Zingiberaceae.Easily applicable methods for screening plant-derived EPIs include checkerboard synergy test,berberine uptake assay and ethidium bromide test.In silico highthroughput virtual detection can be evaluated as a criterion of excluding compounds with efflux substrate-like characteristics,thereby improving the selection process and extending the identification of EPIs.To ascertain the efflux activity inhibition,real-time PCR and quantitative mass spectrometry can be applied.This review emphasizes on efflux pumps and their roles in transmitting bacterial resistance and an update plant-derived EPIs and strategies for identification.

Secondary metabolite credentials ofEvolvulus alsinoides by high performance thin layer chromatography(HPTLC)

Plants and plant-based products are the bases of many modern pharmaceuticals that are current in use today for various diseases.The aim of the study was to investigate the biochemical constituents and high performance thin layer chromatography（HPTLC） finger printing of the ethanolic extract of Evolvulus alsinoides.Phytochemical screening was done by standard procedures and HPTLC method was also established to analyze alkaloids,flavonoids and phenolic compounds from the ethanolic extract of Evolvulus alsinoides.Preliminary phytochemical screening showed that ethanol extracted more secondary metabolites than other solvents.HPTLC fingerprinting analysis showed the presence of various alkaloids,flavonoids and phenols（quercetin） in the ethanolic extract.It can be concluded that Evolvulus alsinoides may serve as a source of potent antioxidants that may be used in the prevention of various diseases such as cancer,diabetes and cardiovascular diseases due to the presence of phenolic compounds.HPTLC finger print of Evolvulus alsinoides may be useful in the differentiation of the species from adulterants and act as a biochemical marker for this medicinally important plant in the pharmaceutical industry and plant systematic studies.

Effects of Barium Stress in Brassica juncea and Cakile maritima:The Indicator Role of Some Antioxidant Enzymes and Secondary Metabolites

Soil contamination by toxic trace metal elements,like barium(Ba),may stimulate various undesirable changes in the metabolic activity of plants.The plant responses are fast and with,direct or indirect,generation of reactive oxygen species(ROS).To cope with the stress imposed by the ROS production,plants developed a dual cellular system composed of enzymatic and non-enzymatic players that convert ROS,and their by-products,into stable nontoxic molecules.To assess the Ba stress response of two Brassicaceae species(Brassica juncea,a glycophyte,and Cakile maritime,a halophyte),plants were exposure to different Ba concentrations(0,100,200,300 and 500µM).The plants response was evaluated through their morphology and development,the determination of plant leaves antioxidant enzymatic activities and by the production of plants secondary metabolites.Results indicated that the two Brassicaceae species have the ability to survive in an environment containing Ba(even at 500µM).The biomass production of C.maritima was slightly affected whereas an increase in biomass B.juncea was noticed.The stress imposed by Ba activated the antioxidant defense system in the two species,noticed by the changes in the leaves activity of catalase(CAT),ascorbate peroxidase(APX)and guaicol peroxidase(GPX),and of the secondary metabolites,through the production of total phenols and flavonoids.The enzymatic response was not similar within the two plant species:CAT and APX seem to have a more important role against the oxidative stress in C.maritima while in B.juncea is GPX.Overall,total phenols and flavonoids production was more significant in the plants aerial part than in the roots,of the both species.Although the two Brassicaceae species response was different,in both plants catalytic and non-catalytic transformation of ROS occurs,and both were able to overcome the Ba toxicity and prevent the cell damage.

Secondary Metabolites from the Endophytic Fungus Xylaria sp.hg1009

A detailed chemical investigation of the secondary metabolites produced by the endophytic fungus Xylaria sp.isolated from the stems of Isodon sculponeatus afforded six new compounds,xylariahgins A-F(1-6),two new natural products(7 and 8),along with two known compounds(9 and 10)(Fig.1).The structures of all compounds were unambiguously established by analyzing their spectroscopic data or referring to pertinent literature.Compounds 1-8 were tested for their cytotoxic activity against five human tumor cell lines.

The comparative analysis and identification of secondary metabolites between Tibet wild and cultivated pomegranates(Punica granatum L.)in China

Secondary metabolites are closely related to the nutritional quality and health functions of plants.We investigated the secondary metabolites of both wild(n=23)and cultivated(n=27)pomegranate plants(Punica granatum L.)growing in China.The total flavonoid(TF)and tannin(TT)contents from the peel and juice were determined and the secondary metabolites in the peel(ZLP)and juice(ZLZ)of‘Zela 4’were identified using liquid chromatography–electrospray ionization tandem mass spectrometry(LC–ESI-MS/MS).Analysis of variance(P<0.05)showed that there were significant differences in the TF content of peel(TF(P))and juice(TF(J)),and the TT content of peel(TT(P))and juice(TT(J))among different pomegranate accessions.Pearson correlation analysis showed that latitude and altitude might be the main environmental factors affecting TF and TT contents in pomegranates.In this study,279 secondary metabolites were identified in the ZLP and ZLZ.In addition,we report for the first time 227 secondary metabolites in pomegranates.Using orthogonal partial least squares discriminant analysis,90 differential metabolites were identified in ZLP and ZLZ.In addition,we screened eight specific germplasms(high-TF(P),‘Junyong 3’;low-TF(P),‘Yanzhihong’;high-TF(J),‘Zela 4’;low-TF(J),‘Yudazi’,high-TT(P),‘Junyong 4’;low-TT(P),‘Anba 1’;high-TT(J),‘Yeba 1’;and low-TT(J),‘Baihuayushizi’).The results of our study provide a reference for the development and utilization of wild pomegranate resources and pomegranate breeding in China.

Effect of salinity on the growth,biological activity and secondary metabolites of some marine fungi

The study investigated the effects of salinity on growth, antimicrobial activities and secondary metabolites of 47 marine filamentous fungi isolated from the East China Sea near the western shore of the Taiwan Straits. The results indicate that NaCl promoted the growth up to 91.5% of test strains. However, only 14.9% of them showed a significant increase of antimicrobial activity against Candida albicans. When incubated in different concentrations of NaCl, the colony growth, antimicrobial activities and composition of secondary metabolites of the strain Ty01b-8 of Penicillium sp. varied. Treatment with KCl also showed a similar effect. An alkaloid isolated from the fermentation broth of Ty01b-8 was identified as chrysogine, inhibition activity of which against Hela cells was 15.05% at 20μg/ml, and yield was 4.4 and 4.9 times higher in 3 percent and 6 percent NaCl treatments, respectively, compared with the non-salt culture condition. These findings prove that salinity is an important factor influencing growth and secondary metabolites of some marine fungi, which can be used to screen for new metabolites from marine fungi, and to enhance their metabolites production in industrial fermentation.

Antimicrobial and antiproliferative prospective of kosinostatin-a secondary metabolite isolated from Streptomyces sp.

Cancer is a communal health hazard worldwide. The present investigation attempts to evaluate anti- microbial and anticancer potential of kosinostatin on mammary carcinoma cell line （MCF-7）. The anticancer and antiproliferative activities of kosinostatin were analyzed on MCF cell line by MTT assay and cytotoxicity assays like lactate dehydrogenase （LDH） and glutathione （GSH）. The secondary metabolite kosinostatin exhibited its apoptotic nature by expressing p53 protein. Collectively, the results acquired from this study promise that kosinostatin shows the potent anticancer activity.