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The Cucurbitaceae family is an extensive group of fruits and vegetables that exhibit common characteristics; for example, they are farmed on a global scale and exhibit a wide range of applications, including fresh consumption and use in various food and beverage products. As is frequent, many species or genera share a common name, and this can lead to some confusion when looking for information about a specific variety. In this review, we describe the findings about the biological activity, like antibacterial, antiviral, antidiabetic, and anticancer properties, of two genera of this family, Cucumis and Momordica, which have been characterized and evaluated in several research studies and regarding which information is readily accessible. Those activities rely on the various physicochemical qualities and nutritional content of each variety, including factors like ß-carotene and polyphenols, among others. The goal of this review is to provide a rapid search for each activity examined in the literature, enabling future research on their potential uses in functional foods and nutraceutical supplements.
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Anthocyanins (ACNs) are phytochemicals with numerous bioactivities, e.g., antioxidant and anti-inflammatory. Health benefits from consuming ACN-rich foods, extracts, and supplements have been studied in clinical trials (CT). However, the individual effect of single ACNs and their correlation with doses and specific bioactivities or molecular targets have not been thoroughly analyzed. This review shows a recompilation of single anthocyanins composition and concentrations used in CT, conducted to investigate the effect of these anti-inflammatory derivatives in obese condition. Single anthocyanin doses with changes in the levels of frequently monitored markers were correlated. In addition, the analysis was complemented with reports of studies made in vitro with single ACNs. Anthocyanins' efficacy in diseases with high baseline obesity-related inflammation markers was evidenced. A poor correlation was found between most single anthocyanin doses and level changes of commonly monitored markers. Correlations between cyanidin, delphinidin, and pelargonidin derivatives and specific molecular targets were proposed. Our analysis showed that knowledge of specific compositions and anthocyanin concentrations determined in future studies would provide more information about mechanisms of action.
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Cynara cardunculus L. var. scolymus, known as the artichoke, originated in the Mediterranean region and is now cultivated in several countries. The artichoke has leaves, a stem, and a head, also called a floral capitulum, covered with green and pointed bracts. It is rich in polyphenols, flavonoids, anthocyanins, phenolic compounds, inulin, coumarins, terpenes, dietary fibre, enzymes, polysaccharides, minerals and vitamins, and therefore has a wide range of uses, including in the food industry, medicine and biofuels. Several studies have shown that artichokes have properties such as antioxidant, anti-inflammatory, antimicrobial, anticancer, hypocholesterolaemic, anti-HIV, cardioprotective, hepatoprotective and lipid-lowering effects. The aim of this study is to provide a literature review on the phytochemical composition, bioactivity and applications, focusing on the methods of extraction, purification and concentration of enzymes present in artichoke.
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In this study, the leaves of Kalanchoe fedtschenkoi were consecutively macerated with hexane, chloroform, and methanol. These extracts were used to assess the bioactivities of the plant. The antimicrobial activity was tested against a panel of Gram-positive and -negative pathogenic bacterial and fungal strains using the microdilution method. The cytotoxicity of K. fedtschenkoi extracts was investigated using human-derived macrophage THP-1 cells through the MTT assay. Finally, the anti-inflammatory activity of extracts was studied using the same cell line by measuring the secretion of IL-10 and IL-6. The phytoconstituents of hexane and chloroform extracts were evaluated using gas chromatography-mass spectrometry (GC/MS). In addition, high-performance liquid chromatography (HPLC) was used to study the phytochemical content of methanol extract. The total flavonoid content (TFC) of methanol extract is also reported. The chemical composition of K. fedtschenkoi extracts was evaluated using Fourier-transform infrared spectroscopy (FTIR). Results revealed that the chloroform extract inhibited the growth of Pseudomonas aeruginosa at 150 µg/mL. At the same concentration, methanol extract inhibited the growth of methicillin-resistant Staphylococcus aureus (MRSA). Regarding their cytotoxicity, the three extracts were highly cytotoxic against the tested cell line at IC50 < 3 µg/mL. In addition, the chloroform extract significantly stimulated the secretion of IL-10 at 50 µg/mL (p < 0.01). GC/MS analyses revealed that hexane and chloroform extracts contain fatty acids, sterols, vitamin E, and triterpenes. The HPLC analysis demonstrated that methanol extract was constituted by quercetin and kaempferol derivatives. This is the first report in which the bioactivities and chemical profiles of K. fedtschenkoi are assessed for non-polar and polar extracts.
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This study involves aporphine alkaloids identified through 13C Nuclear Magnetic Resonance (NMR) spectroscopic data. For the present publication, articles were selected from several databases on aporphine alkaloids from 1994 to 2021. In this class, more than 700 compounds have been registered, with 221 were included in this section, among which 122 were characterized for the first time in the investigated period. The study also addresses their biosynthetic pathways, classifying substances according to their structural characteristics based on established literature. Furthermore, pharmacological activities related to the aporphine alkaloids highlighted in this section are also presented, giving an overview of the various applications of these compounds.
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Alcaloides , Aporfinas , Alcaloides/farmacologia , Alcaloides/química , Aporfinas/farmacologia , Aporfinas/química , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
Protein hydrolysates are a promising source of bioactive peptides. One strategy by which they can be obtained is fermentation. This method uses the proteolytic system of microorganisms to hydrolyze the parental protein. Fermentation is a little-explored method for obtaining protein hydrolysates from amaranth. Different strains of lactic acid bacteria (LAB) and Bacillus species isolated from goat milk, broccoli, aguamiel, and amaranth flour were used in this work. First, the total protein degradation (%TPD) of amaranth demonstrated by the strains was determined. The results ranged from 0 to 95.95%, the strains that produced a higher %TPD were selected. These strains were identified by molecular biology and were found to correspond to the genera Enterococcus, Lactobacillus, Bacillus, and Leuconostoc. Fermentation was carried out with amaranth flour and the selected strains. After this process, water/salt extracts (WSE) containing the released protein hydrolysates were obtained from amaranth doughs. The peptide concentration was measured by the OPA method. The antioxidant, antihypertensive and antimicrobial activity of the WSE was evaluated. In the FRAP test, the best WSE was LR9 with a concentration of 1.99 µMTE/L ± 0.07. In ABTS, 18C6 obtained the highest concentration with 19.18 µMTE/L ± 0.96. In the DPPH test, there was no significant difference. In terms of antihypertensive activity, inhibition percentages ranging from 0 to 80.65% were obtained. Some WSE were found to have antimicrobial properties against Salmonella enterica and Listeria monocytogenes. Fermentation of amaranth with LAB and Bacillus spp. allowed the release of protein hydrolysates with antioxidant, antihypertensive, and antimicrobial activity.
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Santalum genus belongs to the family of Santalaceae, widespread in India, Australia, Hawaii, Sri Lanka, and Indonesia, and valued as traditional medicine, rituals and modern bioactivities. Sandalwood is reported to possess a plethora of bioactive compounds such as essential oil and its components (α-santalol and ß-santalol), phenolic compounds and fatty acids. These bioactives play important role in contributing towards biological activities and health-promoting effects in humans. Pre-clinical and clinical studies have shown the role of sandalwood extract as antioxidant, anti-inflammatory, antibacterial, antifungal, antiviral, neuroleptic, antihyperglycemic, antihyperlipidemic, and anticancer activities. Safety studies on sandalwood essential oil (EO) and its extracts have proven them as a safe ingredient to be utilized in health promotion. Phytoconstituents, bioactivities and traditional uses established sandalwood as one of the innovative materials for application in the pharma, food, and biomedical industry.
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Óleos Voláteis , Santalum , Humanos , Santalum/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologiaRESUMO
Enzymatic hydrolysis is the most prominent strategy to release bioactive peptides from different food proteins and protein-rich by-products. Unconventional microbial proteases (UMPs) have gaining increased attention for such purposes, particularly from the 2010s. In this review, we present and discuss aspects related to UMPs production, and their use to obtain bioactive protein hydrolysates. Antioxidant and anti-hypertensive potentials, commonly evaluated through in vitro testing, are mainly reported. The in vivo bioactivities of protein hydrolysates and peptides produced through UMPs action are highlighted. In addition to bioactivities, enzymatic hydrolysis acts by modulating the functional properties of proteins for potential food uses. The compiled literature indicates that UMPs are promising biocatalysts to generate bioactive protein hydrolysates, adding up to commercially available enzymes. From the recent interest on this topic, continuous and in-depth research is needed to advance toward the applicability and commercial utility of both UMPs and obtained hydrolysates.
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The Brazilian Cerrado is home to a large number of native and endemic species of enormous potential, among which we can highlight the cagaita, gabiroba, jatobá-do-cerrado, lobeira, and mangaba. In this review, we report the nutritional and phenolic composition, as well as bioactivities of these five Brazilian Cerrado fruits. The compiled data indicated that these fruits have high nutritional, functional, and economic potential and contribute to the daily intake of macro- and micronutrients, energy, and phenolic compounds by inhabitants of the Cerrado region. Phenolic-rich extracts obtained from these fruits have shown several bioactivities, including antioxidant, anti-inflammatory, antidyslipidemic, antidiabetic, analgesic, anticarcinogenic, hepatoprotective, gastrointestinal protective, and antimicrobial properties. Therefore, these fruits can be explored by the food industry as a raw material to develop food products of high value-added, such as functional foods, and can also be employed as plant sources to obtain bioactive compounds for food, cosmetic, and pharmaceutical purposes.
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Plants are the main sources of bioactive compounds (nutraceuticals) that function under different mechanisms of action for the benefit of human health. Mexico ranks fifth in the world in biodiversity, offering opportunities for healthy food. An important variety of crops are produced in the state of Hidalgo, e.g., based on the 2021 production, alfalfa, oats, maguey, and corn. The present review presents the latest findings of these crops, regarding the benefits they provide to health (bioactivity, nutraceuticals), and presents the compounds and mechanisms identified by which the benefit is provided. The knowledge compiled here is for the benefit of the recovery of the crops, the recognition of their bioactivities, in search of identifying the best routes of action for prevention, treatment and possible cure of chronic degenerative diseases (thereby promoting crop valorization). Exhaustive bibliographic research was carried out by means of engines and scientific databases. Articles published between 2001 and 2022 that included specific keywords (Scopus, EMBASE, EBSCO, PubMed, Science Direct, Web of Science, Google Scholar). Outstanding activities have been identified for the compounds in the crops, such as antiinflammatory, anticholesterolemic, antihypertensive, antidiabetic, anticancer, antimicrobial, antioxidant, and chelating. The compounds that provide these properties are total phenols, phenolic acids, tannins, anthocyanins, carotenoids, iso-flavones, phytosterols, saponins, fructans, glycosides, glucans, avenanthramides, and polysaccharides.
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Chia seed peptides (CSP) can be a source of multifunctional biopeptides to treat non-communicable diseases. However, interactions and binding affinity involved in targeting specific receptors remains unexplored. In this study, molecular simulation techniques were used as virtual screening of CSP to determine drug-like candidates using a multi-target-directed ligand approach. CSP fraction with the best bioactivities in vitro was sequenced. Then, a prediction model was built using physicochemical descriptors (hydrophobicity, hydrophilicity, intestinal stability, antiangiogenic, antihypertensive, and anti-inflammatory) to calculate potential scores and rank possible biopeptides. Furthermore, molecular dynamics simulations (MDS) and ensemble molecular docking analysis were carried out using four human protein targets (ACE, angiotensin converting enzyme; VEGF, vascular endothelial growth factor; GLUC, glucocorticoid and MINC, mineralocorticoid receptors). Five known-sequence peptides (NNVFYPF, FNIVFPG, SRPWPIDY, QLQRWFR, GSRFDWTR) and five de novo peptides (DFKF, DLRF, FKAF, FRSF, QFRF) had the lowest energy score and higher affinity for ACE and VEGF. The therapeutic effects of these selected peptides can be related to the inhibition of the enzymes involved in angiogenesis and hypertension, due to formation of stable complexes with VEGF and ACE binding sites, respectively. The application of MDS is a good resource for identifying bioactive peptides for future experimental validation.
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Salvia hispanica , Salvia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peptídeos/química , Extratos Vegetais , Salvia/química , Fator A de Crescimento do Endotélio VascularRESUMO
Species of Burkholderia are highly versatile being found not only abundantly in soil, but also as plants and animals' commensals or pathogens. Their complex multireplicon genomes harbour an impressive number of polyketide synthase (PKS) and nonribosomal peptide-synthetase (NRPS) genes coding for the production of antimicrobial secondary metabolites (SMs), which have been successfully deciphered by genome-guided tools. Moreover, genome metrics supported the split of this genus into Burkholderia sensu stricto (s.s.) and five new other genera. Here, we show that the successful antimicrobial SMs producers belong to Burkholderia s.s. Additionally, we reviewed the occurrence, bioactivities, modes of action, structural, and biosynthetic information of thirty-eight Burkholderia antimicrobial SMs shedding light on their diversity, complexity, and uniqueness as well as the importance of genome-guided strategies to facilitate their discovery. Several Burkholderia NRPS and PKS display unusual features, which are reflected in their structural diversity, important bioactivities, and varied modes of action. Up to now, it is possible to observe a general tendency of Burkholderia SMs being more active against fungi. Although the modes of action and biosynthetic gene clusters of many SMs remain unknown, we highlight the potential of Burkholderia SMs as alternatives to fight against new diseases and antibiotic resistance.
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Anti-Infecciosos , Burkholderia , Anti-Infecciosos/farmacologia , Burkholderia/química , Burkholderia/genética , Genômica , Família Multigênica , Policetídeo Sintases/genética , Metabolismo SecundárioRESUMO
Exploratory factor analysis was applied to determine the chemical differences between fruitbodies of three Agaricus subrufescens mushroom strains [from Japan (JP), Brazil (ABZ), and Belgium (T2)] grown with handmade and commercial supplements. The composition of the ABZ strain cultivated with agro-industrial waste supplement presented a high nutritional composition regarding the amounts of fibre and protein, similar to mushrooms cultivated with the commercial supplement. The chromatographic fingerprints obtained for T2 and JP strains grown with commercial supplements presented similar profiles compared to those cultivated with the supplement based on peanut and the mix of supplements. The chromatographic analysis also showed that the similarities are correlated with the relative abundance of antioxidant compounds annotated by HPLC-MS, such as vanillic acid deoxyhexoside, caffeic acid hexoside, catechin hexosemalonate, digallic acid, cinnamic acid derivative, and p-coumaroylmalic acid. This study showed that handmade supplements based on agro-industrial waste could be viable alternatives for replacing high-cost supplements.
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Agaricus , Antioxidantes , Fibras na Dieta , Suplementos NutricionaisRESUMO
Large amounts of by-products are generated during fish processing. The study aimed to assess whether tilapia scales are a potential source for obtaining glycosaminoglycans, as well as to determine their anticoagulant and cytotoxic/antiproliferative activities, against different tumor lines. The glycosaminoglycans were extracted, purified, and fractionated. The fractions that indicated the presence of uronic acid and sulfated GAGs were characterized by electrophoresis, NMR, and degree of sulfation (DS). The extraction process using the papain enzyme had a yield of 0.86%. Fraction V (FV) revealed the presence of chondroitin sulfate chains CS-A and CS-C, with DS of 0.146. FV demonstrated anticoagulant potential, as it was able to increase aPTT time. FV showed a cytotoxic effect for HTC metabolizing cells at 24, 48, and 72 h. However, it did not show activity for neuroblastoma cells in any of the evaluated times. The results indicate that the tilapia scales are a possible source for obtaining chondroitin sulfate, with potential use as anticoagulant and cytotoxic/antitumor.
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Ciclídeos , Tilápia , Animais , Anticoagulantes/farmacologia , Sulfatos de Condroitina , GlicosaminoglicanosRESUMO
Amongst functional foods, garlic and its by-products stand out given their rich phytochemical profile. A comprehensive analytical approach becomes necessary to fully address garlic preparations health-promoting activities, considering the coexistence of several active ingredients from different chemical families. For this, we developed a multi-phytochemical protocol combining Ultrasound and Dispersive Liquid-Liquid Microextraction, coupled to Liquid Chromatography, for the determination of flavonols, organosulfur compounds, and inulin. Hydrophilic interaction chromatography showed an adequate resolution of flavonols and sugars in a shorter time. The protocol showed a suitable performance and acceptable quantitative yields for garlic powder, cooked garlic, black garlic, and liquid garlic flavouring samples. Additionally, the proposed methodology represented a useful tool to assess how the different garlic products related to functional properties, taking into account the various phytochemical families present in each sample. This is the first time a comprehensive and multi-phytochemical validated analysis of garlic preparations is proposed.
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Cromatografia Líquida/métodos , Suplementos Nutricionais/análise , Alho/química , Microextração em Fase Líquida/métodos , Compostos Fitoquímicos/análise , Flavonóis/análise , Análise de Alimentos/métodos , Alimento Funcional/análise , Interações Hidrofóbicas e Hidrofílicas , Inulina/análise , Compostos de Enxofre/análise , UltrassomRESUMO
Bioactive compounds can provide health benefits beyond the nutritional value and are originally present or added to food matrices. However, because they are part of the food matrices, most bioactive compounds remain in agroindustrial by-products. Agro-industrial by-products are generated in large quantities throughout the food production chain and can-when not properly treated-affect the environment, the profit, and the proper and nutritional distribution of food to people. Thus, it is important to adopt processes that increase the use of these agroindustrial by-products, including biological approaches, which can enhance the extraction and obtention of bioactive compounds, which enables their application in food and pharmaceutical industries. Biological processes have several advantages compared to nonbiological processes, including the provision of extracts with high quality and bioactivity, as well as extracts that present low toxicity and environmental impact. Among biological approaches, extraction from enzymes and fermentation stand out as tools for obtaining bioactive compounds from various agro-industrial wastes. In this sense, this article provides an overview of the main bioactive components found in agroindustrial by-products and the biological strategies for their extraction. We also provide information to enhance the use of these bioactive compounds, especially for the food and pharmaceutical industries.
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Caesalpinia ferrea C. Mart., popularly known as "Jucá" or "Pau-ferro", belongs to the Fabaceae family, and is classified as a native and endemic species in Brazil. Numerous studies that portray its ethnobotany, chemical composition, and biological activities exist in the literature. The present study aimed to systematically review publications addressing the botanical aspects, uses in popular medicine, phytochemical composition, and bioactivities of C. ferrea. The searches focused on publications from 2015 to March 2020 using the Scopus, Periódicos Capes, PubMed, Google Scholar, and ScienceDirect databases. The leaves, fruits, seeds, and bark from C. ferrea are used in popular medicine to treat disorders affecting several systems, including the circulatory, immune, cardiovascular, digestive, respiratory, genitourinary, musculoskeletal, and conjunctive systems. The most commonly found chemical classes in phytochemical studies are flavonoids, polyphenols, terpenoids, tannins, saponins, steroids, and other phenolic compounds. The biological properties of the extracts and isolated compounds of C. ferrea most cited in the literature were antibacterial, antifungal, antioxidant, antiproliferative, anti-inflammatory, and healing potential. However, further studies are still needed to clarify a link between its traditional uses, the active compounds, and the reported pharmacological activities, as well as detailed research to determine the toxicological profile of C. ferrea.
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Anti-Infecciosos , Anti-Inflamatórios , Antioxidantes , Caesalpinia/química , Compostos Fitoquímicos , Extratos Vegetais , Animais , Anti-Infecciosos/química , Anti-Infecciosos/uso terapêutico , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Antioxidantes/química , Antioxidantes/uso terapêutico , Etnobotânica , Etnofarmacologia , Humanos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/uso terapêutico , Fitoterapia , Extratos Vegetais/química , Extratos Vegetais/uso terapêuticoRESUMO
ABSTRACT Gracilariopsis lemaneiformis is a type of red alga that contains seaweed polysaccharide agar. In this study, a novel non-agar seaweed polysaccharide fraction named GCP (short of crude polysaccharide obtained from Gracilariopsis lemaneiformis) was isolated from Gracilariopsis lemaneiformis. Structural analysis showed that GCP shows triple helical chain conformation when dissolved in water and has many branches and long side chains. Also, 1→3 linkage is the major linkage and the sugar structures are galactopyranose configurations linked by β-type glycosidic linkages. Two macromolecular substance fractions (GCP-1 and GCP-2) were purified by DEAE Sepharose Fast Flow column chromatography. Moreover, a splenocyte damage assay and splenocyte proliferation assay were used to analyse the bioactivities of GCP, GCP-1 and GCP-2. It was demonstrated that polysaccharides could protect splenocyte damaged by H2O2; GCP-2 shows a greatest protection rate, that is, 92.8%, which significantly enhanced the splenocyte proliferation, and GCP showed the highest proliferation rate, 9.30%. The results suggested that this type of novel non-agar polysaccharide displayed remarkable antioxidant and immunomodulatory activities and early alkali treatment could decrease the activities. It may represent a potential material for health food and clinical medicines.
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Animais , Ratos , Polissacarídeos/química , Alga Marinha/química , Rodófitas/química , Polissacarídeos/isolamento & purificação , Valores de Referência , Ensaio de Imunoadsorção Enzimática , Linfócitos/efeitos dos fármacos , Microscopia Eletrônica de Varredura , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Cromatografia Líquida de Alta Pressão , Espectroscopia de Infravermelho com Transformada de Fourier , Ácido Periódico/química , Proliferação de Células/efeitos dos fármacos , Peso MolecularRESUMO
Curcuma, a valuable genus in the family Zingiberaceae, includes approximately 110 species. These plants are native to Southeast Asia and are extensively cultivated in India, China, Sri Lanka, Indonesia, Peru, Australia, and the West Indies. The plants have long been used in folk medicine to treat stomach ailments, stimulate digestion, and protect the digestive organs, including the intestines, stomach, and liver. In recent years, substantial progress has been achieved in investigations regarding the chemical and pharmacological properties, as well as in clinical trials of certain Curcuma species. This review comprehensively summarizes the current knowledge on the chemistry and briefly discusses the biological activities of Curcuma species. A total of 720 compounds, including 102 diphenylalkanoids, 19 phenylpropene derivatives, 529 terpenoids, 15 flavonoids, 7 steroids, 3 alkaloids, and 44 compounds of other types isolated or identified from 32 species, have been phytochemically investigated. The biological activities of plant extracts and pure compounds are classified into 15 groups in detail, with emphasis on anti-inflammatory and antitumor activities.
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Curcuma/química , Extratos Vegetais/farmacologia , Alcaloides/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Austrália , Linhagem Celular Tumoral , Fenômenos Químicos , China , Ensaios Clínicos como Assunto , Curcuma/classificação , Modelos Animais de Doenças , Flavonoides/química , Humanos , Índia , Indonésia , Peru , Compostos Fitoquímicos/química , Extratos Vegetais/química , Sri Lanka , Esteroides/química , Terpenos/químicaRESUMO
Background: Hyalodendriella sp. Ponipodef12, an endophytic fungus from a poplar hybrid, was a high producer of botrallin and TMC-264 with various bioactivities. In this study, the influences of eight metal ions (i.e.,Mn2+,Na+, Mg2+,Zn2+,Cu2+,Fe2+,Fe3+ and Al3+) on botrallin and TMC-264 production in liquid culture of the endophytic fungus Hyalodendriella sp. Ponipodef12 were investigated. Results: Three most effective metal ions (Zn2+,Cu2+ and Mg2+) along with their optimum concentrations were screened. The optimum addition time and concentrations of Zn2+,Cu2+ and Mg2+ were further obtained respectively for improving botrallin and TMC-264 production. The combination effects of Zn2+,Cu2+ and Mg2+ on the production of botrallin and TMC-264 by employing statistical method based on the central composite design (CCD) and response surface methodology (RSM) were evaluated, and two quadratic predictive models were developed for botrallin and TMC-264 production. The yields of botrallin and TMC-264, which were predicted as 144.12 mg/L and 36.04 mg/L respectively, were validated to be 146.51 mg/L and 36.63 mg/L accordingly with the optimum concentrations of Zn2+ at 0.81 mmol/L, Cu2+ at 0.20 mmol/L, and Mg2+ at 0.13 mmol/L in medium. Conclusion: The results indicated that the enhancement of botrallin and TMC-264 accumulation in liquid culture of the endophytic fungus Hyalodendriella sp. Ponipodef12 by the metal ions and their combination should be an effective strategy.