Production Of Bioactive Metabolites Research Articles

Marine Cyanobacteria-Assisted Metallic Nanoparticles: A Review on Anticancer Activity and Mechanism of Action

Marine cyanobacteria, known as blue-green algae, are ancient microorganisms with oxygenic photosynthetic capability. They have diverse biochemical capabilities, including production of bioactive secondary metabolites. We studied the anti-cancer properties of cyanobacterial nanoparticles through various literatures. We focused on mechanistic studies of the anticancer properties of metal and metal oxide nanoparticles. Our research gathered information from patent databases, conference abstracts, publications, and news releases, as well as PubMed searches for peer-reviewed articles and Google searches for gray literature. We used strict criteria for selecting sources, and our search ended on 30 October, 2022. Metal nanoparticles, such as gold and silver, have unique physicochemical properties, making them suitable for therapeutic applications in nanomedicine. Cyanobacteria-assisted synthesis is environmentally sustainable and results in mild reaction conditions and minimal toxic byproducts. These nanoparticles have potential applications in cancer therapy, including drug delivery systems and targeted therapies. This study further explored the mechanistic aspects of cancer development, emphasising the role of genetic mutations, uncontrolled cell growth, and metastasis. Cyanobacterial biogenic nanoparticles demonstrate cytotoxicity, apoptosis induction, ROS generation, and immunomodulation, contributing to their anticancer efficacy. Additionally, these nanoparticles serve as carriers for drug delivery, enabling the targeted and controlled release of therapeutic agents. The review ends by emphasising how crucial it is to comprehend how cyanobacteria extract assists metallic nanoparticles. Cyanobacterial biogenic synthesis using microemulsion synthesis methods, UV-initiated photoreduction, microwave assistance, and polymer/polysaccharide-mediated approaches was investigated. The field of marine cyanobacteria, biogenic metal nanoparticles, and their anticancer potential is dynamic and has important implications for future therapeutic approaches.

Diversity, distribution and phytotoxic and anti-Trypanosoma activities of cultivable fungi associated with Magellan sub-Antarctic strait and Maritime Antarctic macroalgae.

We isolated and characterized the community of cultivable fungi associated with marine macroalgae present in the Magellan sub-Antarctic straits and the South Shetland Islands, Maritime Antarctica, and evaluated their production of bioactive metabolites. A total of 201 filamentous fungal isolates were obtained. The genera Antarctomyces, Pseudogymnoascus, Microdochium, Trichoderma, Cladosporium, Penicillium, Neoascochyta, Entomortierella and Linnemannia were associated with Antarctic macroalgae, with Neoascochyta paspali being the most abundant taxon. In contrast, 12 taxa representing Cadophora, Microdochium, Penicillium, Pseudogymnoascus were associated with macroalgae from the Magellan sub-Antarctic, with Penicillium dominating the assemblages. The diversity indices of the fungal communities associated with macroalgae in the two regions were similar. Among 177 fungal extracts assessed for metabolite production, 31 (17.5%) showed strong phytotoxicactivity and 17 (9.6%) showed anti-Trypanosoma cruzi activity. Penicillium showed the highest phytotoxic and anti-Trypanosoma activity values. The detection of taxa in common between the polar and cold temperate zones reinforces the need for further investigations of the distribution of species in these distinct ecoregions. The detection of bioactive extracts produced particularly by Penicillium representatives reinforces the potential to obtain active molecules that can be explored as natural products or as sources of bioactive compounds with application in agriculture and biomedicine.

Arabinoxylan Alleviates Obesity by Regulating Gut Microbiota and Bile Acid Metabolism.

Overweight and obesity are major and increasingly global public health concern. High intake of dietary fiber is negatively correlated with obesity and obesity-related metabolic diseases. Here, we investigated the impact of arabinoxylan on obesity based on the modification of gut microecology. Arabionxylan reduced body weight and improved glucose metabolism, as well as intestinal barrier function and metabolic endotoxemia in obese mice. Supplementation with arabinoxylan increased the relative abundance of Prevotellaceae_UCG_001, Lachnospiraceae_NK4A136_group, Clostridia_UCG_014, Alistipes, Bacteroides, and Ruminococcus, which was associated with the upregulated 7α-dehydroxylation function and production of secondary bile acids (deoxycholic acid and lithocholic acid). The modification of gut microbiota by arabinoxylan also influenced the production of SCFAs, genistein, daidzein, indolelactic acid, and indoleacetic acid, contributing to the amelioration of obesity. Our study highlights the antiobesity effects of arabinoxylan through the modification of gut microbiota and the production of bioactive metabolites.

Phenolic Bisabolane Sesquiterpene Derivatives from an Arctic Marine-derived Fungus Aspergillus sydowii MNP-2

Background:: Filamentous fungi in the genus Aspergillus are well known for their important roles in production of bioactive secondary metabolites with diversely chemical structures and potential application in pharmaceutical industry. Objective:: The present study aimed to investigate the phenolic bisabolane sesquiterpene (PBS) derivatives from an Arctic marine-derived fungus Aspergillus sydowii MNP-2. Methods:: In this study, antimicrobial activities were carried out according to the broth microdilution assay, nitric oxide (NO) production in mouse macrophages (RAW264.7) and BV2 microglial cells was used to detect the inhibitory effect of compounds in inflammatory reactions, and in vitro inhibitory cell proliferation activity was determined by the cell counting kit-8 (CCK-8) assay. Results:: In this work, chemical investigation of an Arctic marine-derived strain A. sydowii MNP-2 led to the isolation of 11 PBSs (1-11) using various chromatographic methods. Their chemical structures were unambiguously determined by 1H NMR spectroscopy and mass spectrometry analyses as well as comparison with literature data. It is noteworthy that compounds 1, 7 and 11 were firstly obtained from A. sydowii. Antimicrobial assay showed that these chemicals had no potent inhibitory effect on Staphylococcus aureus, Escherichia coli, and Candida albicans with MIC values > 16 μg/mL. Additionally, the inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)- induced inflammation in mouse macrophages (RAW264.7) and BV2 microglial cells were all below 10% for compounds 4-6 and 8, indicating almost negligible anti-inflammatory efficacy. Among the tested compounds 4-6 and 8 for tumor-cell proliferation inhibition activities, compound 5 demonstrated the strongest inhibitory effect against human acute promyelocytic leukemia cells (HL-6) with a 44.76% inhibition rate. Conclusion:: In the present study, 11 PBS derivatives were purified and characterized from the solidand liquid-state fermentations of the Arctic marine-derived fungus A. sydowii MNP-2. Unfortunately, none of these metabolites had significant antimicrobial, anti-inflammatory, or tumor-cell proliferation inhibition activities.

Light-Regulated Growth, Anatomical, Metabolites Biosynthesis and Transcriptional Changes in Angelica sinensis

Angelica sinensis is an alpine medicinal plant that has been widely used as a general blood tonic and gynecological indications over 2000 years, which depend on the bioactive metabolites (e.g., volatile oils, organic acids, and flavonoids). Although the accumulation of these metabolites is significantly affected by the environmental factors (e.g., altitude, temperature, and sunshine) as found in previous studies, the regulatory mechanism of different lights has not been clearly revealed. Here, growth parameters, contents of bioactive metabolites, and expression levels of related genes were examined when A. sinensis was exposed to different white-light (WL) and UV-B radiation treatments. The results showed that the differences in growth parameters (e.g., plant height, root length, and plant biomass) and leaf tissue characteristics (e.g., leaf thickness, stomatal density and shape, and chloroplast density) were observed under different light treatments. The contents of Z-ligustilide and ferulic acid elevated with the increase of WL (50 to 150 µmol·m2/s) and maximized under the combination of WL-100 and UV-B (107 µW/m2, UV-107) radiation, while the total flavonoids and polysaccharides contents, as well as in vitro antioxidant capacity, elevated with the increasing of WL and UV-B. mRNA transcripts encoding for the biosynthesis of volatile oils, ferulic acid, flavonoids, and polysaccharides were found to be differentially regulated under the different WL and UV-B treatments. These morphological, anatomical, and transcriptional changes are consistent with the elevated bioactive metabolites in A. sinensis under the combination of WL and UV-B. These findings will provide useful references for improving bioactive metabolite production via the cultivation and bioengineering of A. sinensis.

Lactiplantibacillus plantarum Interstrain Variability in the Production of Bioactive Phenolic Metabolites from Flavan-3-ols.

Flavan-3-ols intake is associated with numerous health benefits, but these are influenced by their conversion into smaller phenolic metabolites by the gut microbiota. Thus, the identification of bacteria that metabolize flavan-3-ols could lead to targeted interventions to enhance their benefits. To this end, we screened 47 Lactiplantibacillus plantarum strains for their ability to metabolize (+)-catechin, a flavan-3-ol. Then, we assessed these strains for their capacity to convert various flavan-3-ol structures. Out of the 47 isolates, 12 released 3-(3',4'-dihydroxyphenyl)-1-(2,4,6-trihydroxyphenyl)-propan-2-ol (a form of diphenylpropan-2-ol) from (+)-catechin. All strains metabolized (+)-catechin, (-)-epicatechin, (-)-epigallocatechin, but only a subset transformed (-)-gallocatechin. Among these simple flavan-3-ol structures, (-)-epicatechin was metabolized the most. A hierarchical cluster analysis identified two groups of flavan-3-ol-metabolizing strains categorized as having "high" and "low" production of diphenylpropan-2-ols. Notably, the strains that produced higher levels of diphenylpropan-2-ol from (+)-gallocatechin and (+)-catechin also performed better with a camu-camu extract, which was studied as a complex source of flavan-3-ols and predominantly contained these two flavan-3-ols. These results demonstrate the interstrain variability in L. plantarum metabolism, which may be useful for developing tailored formulations to enhance the production of flavan-3-ols bioactive metabolites.

Exploring quorum sensing for inducing bioactives overproduction in the dinoflagellate microalga Amphidinium carterae

The dinoflagellate Amphidinium carterae is a promising source of unique bioactive compounds with potential applications in diverse industries. Abiotic strategies for increasing bioactive cell quota have been preferred for cost-effectiveness, controllability, and existing knowledge. The supernatants of Heterosigma akashiwo and Pavlova sp. enhanced haemolytic activity of A. carterae by 2.3 times and improved its final biomass by 10 % when added to the growth medium. Prymnesium parvum supernatant increased the total lipid content of A. carterae by 50 %, while Pleurochrysis roscoffensis supernatant boosted its total carotenoid content by 40 %. This study demonstrated a rapid screening strategy for evaluating growth responses and highlights the potential of using allelopathic strategies to enhance bioactive metabolite production. Utilizing supernatants for the formulation of growth media fosters a circular economy by repurposing resources, minimizing waste, and promoting sustainability in the microalgal biotechnological industry.

Enhancement of Forskolin Production Using Aeroponic Cultivation of Coleus forskohlii and the Impact on the Plant Phytochemistry.

Accessing plant resources to extract compounds of interest can sometimes be challenging. To facilitate access and limit the environmental impact, innovative cultivation strategies can be developed. Forskolin is a molecule of high interest, mainly found in the roots of Coleus forskohlii. The aim of this study was to develop aeroponic cultivation methods to provide a local source of Coleus forskohlii and to study the impact of abiotic stress on forskolin and bioactive metabolite production. Three cultivation itineraries (LED lighting, biostimulant, and hydric stress) along with a control itinerary were established. The forskolin content in the plant roots was quantified using HPLC-ELSD, and the results showed that LED treatment proved to be the most promising, increasing root biomass and the total forskolin content recovered at the end of the cultivation period threefold (710.1 ± 21.3 mg vs. 229.9 ± 17.7 mg). Statistical analysis comparing the LED itinerary to the control itinerary identified stress-affected metabolites, showing that LEDs positively influence mainly the concentration of phenolic compounds in the roots and diterpenes in the aerial parts of Coleus forskohlii. Moreover, to better define the phytochemical composition of Coleus forskohlii cultivated in France using aeroponic cultivation, an untargeted metabolomic analysis was conducted using UHPLC-HRMS/MS analysis and molecular networks on both the root and aerial parts. This study demonstrates that aeroponic cultivation, especially with the application of an LED treatment, could be a very promising alternative for a local source of Coleus forskohlii leading to easy access to the roots and aerial parts rich in forskolin and other bioactive compounds.

Whole genome–based comparative analysis of the genus Streptomyces reveals many misclassifications

Streptomyces species are experts in the production of bioactive secondary metabolites; however, their taxonomy has fallen victim of the tremendous interest shown by the scientific community, evident in the discovery of numerous synonymous in public repositories. Based on genomic data from NCBI Datasets and nomenclature from the LPSN database, we compiled a dataset of 600 Streptomyces species along with their annotations and metadata. To pinpoint the most suitable taxonomic classification method, we conducted a comprehensive assessment comparing multiple methodologies, including analysis of 16S rRNA, individual housekeeping genes, multilocus sequence analysis (MLSA), and Fast Average Nucleotide Identity (FastANI) on a subset of 409 species with complete data. Due to insufficient resolution of 16S rRNA and inconsistency observed in individual housekeeping genes, we performed a more in-depth analysis, comparing only FastANI and MLSA, which expanded our dataset to include 502 species. With FastANI validated as the preferred method, we conducted pairwise analysis on the entire dataset identifying 59 non-unique species among the 600, and subsequently refined the dataset to 541 unique species. Additionally, we collected data on 724 uncharacterized Streptomyces strains to investigate the uniqueness potential of the unannotated fraction of the Streptomyces genus. Utilizing FastANI, 289 strains could be successfully classified into one of the 541 Streptomyces species.Key points• Evaluation of taxonomic classification methods for Streptomyces species.• Whole genome analysis, specifically FastANI, has been chosen as preferred method.• Various reclassifications are proposed within the Streptomyces genus.Graphical abstract

A Close View of the Production of Bioactive Fungal Metabolites Mediated by Chromatin Modifiers.

Secondary metabolites produced by fungi are well known for their biological properties, which play important roles in medicine. These metabolites aid in managing infections and treating chronic illnesses, thereby contributing substantially to human health improvement. Despite this extensive knowledge, the vast biodiversity and biosynthetic potential of fungi is still largely unexplored, highlighting the need for further research in natural products. In this review, several secondary metabolites of fungal origin are described, emphasizing novel structures and skeletons. The detection and characterization of these metabolites have been significantly facilitated by advancements in analytical systems, particularly modern hyphenated liquid chromatography/mass spectrometry. These improvements have primarily enhanced sensitivity, resolution, and analysis flow velocity. Since the in vitro production of novel metabolites is often lower than the re-isolation of known metabolites, understanding chromatin-based alterations in fungal gene expression can elucidate potential pathways for discovering new metabolites. Several protocols for inducing metabolite production from different strains are discussed, demonstrating the need for uniformity in experimental procedures to achieve consistent biosynthetic activation.

Genomic Analysis of Aspergillus Section Terrei Reveals a High Potential in Secondary Metabolite Production and Plant Biomass Degradation.

Aspergillus terreus has attracted interest due to its application in industrial biotechnology, particularly for the production of itaconic acid and bioactive secondary metabolites. As related species also seem to possess a prosperous secondary metabolism, they are of high interest for genome mining and exploitation. Here, we present draft genome sequences for six species from Aspergillus section Terrei and one species from Aspergillus section Nidulantes. Whole-genome phylogeny confirmed that section Terrei is monophyletic. Genome analyses identified between 70 and 108 key secondary metabolism genes in each of the genomes of section Terrei, the highest rate found in the genus Aspergillus so far. The respective enzymes fall into 167 distinct families with most of them corresponding to potentially unique compounds or compound families. Moreover, 53% of the families were only found in a single species, which supports the suitability of species from section Terrei for further genome mining. Intriguingly, this analysis, combined with heterologous gene expression and metabolite identification, suggested that species from section Terrei use a strategy for UV protection different to other species from the genus Aspergillus. Section Terrei contains a complete plant polysaccharide degrading potential and an even higher cellulolytic potential than other Aspergilli, possibly facilitating additional applications for these species in biotechnology.

Stimulating Novel and Bioactive Metabolite Production by Cocultivation of Two Fungi─Aspergillus oryzae and Epicoccum dendrobii.

Fungi produce various bioactive secondary metabolites (SMs) as protective and weaponized tools to enhance survival in shared ecological niches. By mimicking a competitive ecosystem, cocultivation has been proven to be particularly successful in stimulating SM discovery. Here, we reported the identification of four novel metabolites, epiclactones A and B, epioxochromane and aoergostane, from the coculture of two biotechnologically important strains, Aspergillus oryzae and Epicoccum dendrobii. Transcriptome and metabolome analyses revealed widespread silent gene activation during fungal-fungal interaction. The majority of differentially expressed gene clusters were summarized for both strains. Based on these highly activated biosynthetic pathways, we suggested that a bidirectional chemical defense occurred under cocultivation. E. dendrobii enhanced the production of the spore inhibitor, fumigermin. Moreover, A. oryzae highly accumulated the antifungal agent kojic acid with a yield of up to 1.10 g/L. This study provides an excellent example for the discovery of hidden natural products by cocultivation.

An Overview on Nocardiopsis Species Originating From North African Biotopes as a Promising Source of Bioactive Compounds and In Silico Genome Mining Analysis of Three Sequenced Genomes.

Actinobacteria are renowned for their prolific production of diverse bioactive secondary metabolites. In recent years, there has been an increasing focus on exploring "rare" genera within this phylum for biodiscovery purposes, notably the Nocardiopsis genus, which will be the subject of the present study. Recognizing the absence of articles describing the research process of finding bioactive molecules from the genus Nocardiopsis in North African environments. We, therefore, present a historical overview of the discoveries of bioactive molecules of the genus Nocardiopsis originating from the region, highlighting their biological activities and associated reported molecules, providing a snapshot of the current state of the field, and offering insights into future opportunities and challenges for drug discovery. Additionally, we present a genome mining analysis of three genomes deposited in public databases that have been reported to be bioactive. A total of 36 biosynthetic gene clusters(BGCs) were identified, including those known to encode bioactive molecules. Notably, a substantial portion of the BGCsshowed little to no similarity to those previously described, suggesting the possibility that the analyzed strains could be potential producers of new compounds. Further research on these genomes is essential to fully uncovering their biotechnological potential. Moving forward, we discuss the experimental designs adopted in the reported studies, as well as new avenues to guide the exploration of the Nocardiopsis genus in North Africa.

A Genomics-Based Discovery of Secondary Metabolite Biosynthetic Gene Clusters in the Potential Novel Strain Streptomyces sp. 21So2-11 Isolated from Antarctic Soil.

Streptomyces species are attractive sources of secondary metabolites that serve as major sources of antibiotics and other drugs. In this study, genome mining was used to determine the biosynthetic potential of Streptomyces sp. 21So2-11 isolated from Antarctic soil. 16S rRNA gene sequencing revealed that this strain is most closely related to Streptomyces drozdowiczii NBRC 101007T, with a similarity of 98.02%. Genome comparisons based on average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) showed that strain 21So2-11 represents a novel species of the genus Streptomyces. In addition to a large number of genes related to environmental adaptation and ecological function, a total of 28 putative biosynthetic gene clusters (BGCs) responsible for the biosynthesis of known and/or novel secondary metabolites, including terpenes, lantipeptides, polyketides, nonribosomal peptides, RiPPs and siderophores, were detected in the genome of strain 21So2-11. In addition, a total of 1456 BGCs were predicted to contribute to the biosynthesis of more than 300 secondary metabolites based on the genomes of 47 Streptomyces strains originating from polar regions. The results indicate the potential of Streptomyces sp. 21So2-11 for bioactive secondary metabolite production and are helpful for understanding bacterial adaptability and ecological function in cold terrestrial environments.

Brightening microalgal potential: A study on organic fluorescent dyes to increase photosynthetic active radiation

Microalgae hold promise for sustainable biomass and bioactive metabolite production, yet their commercial viability faces challenges due to low productivity, often linked to inefficient light utilisation. Algae absorb light primarily in the 400–500 nm (blue) and 600–700 nm (red) range termed photosynthetically active radiation (PAR), leaving excess light untapped. Optimising incident light spectra is vital for high biomass production. Recent advancements have utilised fluorescent dyes as spectral converters to improve PAR availability in algae. The current study evaluated the solubility and spectral profiles of Diphenylanthracene [DPA], Diphenyloxazole [DPO], Rhodamine 6G [R6G], Rhodamine 8G [R8G], Rhodamine 800 [R800], Fluorescein Isothiocyanate [FITC], Lumogen Yellow [LY], and Lumogen Red [LR] in methanol, ethanol, and acetone across varying concentrations. DPA and DPO absorbed UV light and emitted in violet/blue wavelengths. In contrast, R8G emitted light in the blue-green region (450–500 nm), which could potentially stimulate pigment and lipid production in algae. LY exhibited peaks covering green to red PAR wavelengths. LR dye displayed an excitation/emission range of 320–400 and 590–660 nm, whereas R6G, R800, and FITC showed no PAR-related emissions. Most dyes showed higher fluorescence at 10 mgL−1 in methanol. DPA, LY, and R8G displayed the highest energy emissions, with LR emitting 9.56 × 10−18 J·photon−1, suggesting its potential to supply ample energy for supporting algal growth. This spectral conversion strategy shows promise for enhancing microalgae growth and metabolite production, reducing reliance on artificial light, and potentially cutting energy and cultivation costs. The study contributes to advancing sustainable practices in algal biotechnology.

In vitro plant regeneration and bioactive metabolite production of endangered medicinal plant Fritillaria cirrhosa

The bulb of Fritillaria cirrhosa D. Don is widely used for the anti-asthmatic, anti-tussive, and anti-cancer agents, etc., while the yield is limited by an endangered status, a long juvenile phase, and restricted growth habitat. Ancillary approaches to improve the bulb yield by micropropagation and bioactive metabolites production by bioreactor have not been established. Here is reported the plant regeneration, suspension cell culture, and bioactive metabolite production at different treatments. The embryogenic calli were successfully induced via the histomorphological identification. The highest proliferation times (4.11-fold) were observed with a select combination of hormones [NAA (0.2 mg/L) + 6-BA (1.0 mg/L) + GA3 (1.0 mg/L)] and culture conditions (red light and 20 °C), the highest content of imperialine (0.13 mg/g) was observed under blue light, total phenolic (0.52 mg/g) under red light, polysaccharides (36.57 mg/g) and total flavonoids (2.67 mg/g) as well as antioxidant capacity under white light. The plantlets were regenerated within 125 d from the induced embryogenic calli to acclimation and transplantation of seedlings. For the suspension cell culture, a 6.30-, 1.78-, 1.37-, and 1.51-fold increase of proliferation times, imperialine, polysaccharides, and total phenolic contents was observed at 40 d, respectively. Based on the above observations, an effective and complete in vitro approach has been proposed to regenerate plants and produce bioactive metabolites in F. cirrhosa.

Gymnascella thermotolerans-GTE-21, an Endophytic Fungus in Euphorbia geniculata as a Versatile Producer of Bioactive Metabolites

Gymnascella thermotolerans-GTE-21, an Endophytic Fungus in Euphorbia geniculata as a Versatile Producer of Bioactive Metabolites

In vitro Antibacterial Activity and Secondary Metabolite Profiling of Endolichenic Fungi Isolated from Genus Parmotrema.

The endolichenic fungi are an unexplored group of organisms for the production of bioactive secondary metabolites. The aim of the present study is to determine the antibacterial potential of endolichenic fungi isolated from genus Parmotrema. The study is continuation of our previous work, wherein a total of 73 endolichenic fungi were isolated from the lichenized fungi, which resulted in 47 species under 23 genera. All the isolated endolichenic fungi were screened for preliminary antibacterial activity. Five endolichenic fungi-Daldinia eschscholtzii, Nemania diffusa, Preussia sp., Trichoderma sp. and Xylaria feejeensis, were selected for further antibacterial activity by disc diffusion method. The zone of inhibition ranged from 14.3 ± 0.1 to 23.2 ± 0.1. The chemical composition of the selected endolichenic fungi was analysed through GC-MS, which yielded a total of 108 compounds from all the selected five endolichenic fungi. Diethyl phthalate, 1-hexadecanol, dibutyl phthalate, n-tetracosanol-1, 1-nonadecene, pyrrol[1,2-a] pyrazine-1,4-dione, hexahydro-3-(2-methyl) and tetratetracontane were found to be common compounds among one or the other endolichenic fungi, which possibly were responsible for antibacterial activity. GC-MS data were further analysed through Principal Component Analysis which showed D. eschscholtzii to be with unique pattern of expression of metabolites. Compound confirmation test revealed coumaric acid to be responsible for antibacterial activity in D. eschscholtzii. So, the study proves that endolichenic fungi that inhabit lichenized fungal thalli could be a source of potential antibacterial compounds.

Alteration of Hepatic Cytochrome P450 Expression and Arachidonic Acid Metabolism by Arsenic Trioxide (ATO) in C57BL/6 Mice.

The success of arsenic trioxide (ATO) in acute promyelocytic leukemia has driven a plethora studies to investigate its efficacy in other malignancies. However, the inherent toxicity of ATO limits the expansion of its clinical applications. Such toxicity may be linked to ATO-induced metabolic derangements of endogenous substrates. Therefore, the primary objective of this study was to investigate the effectof ATO on the hepatic formation of arachidonic acid (AA) metabolites, hydroxyeicosatetraenoic acids (HETEs), as well as their most notable producing machinery, cytochrome P450 (CYP) enzymes. For this purpose, C57BL/6 mice were intraperitoneally injected with 8 mg/kg ATO for 6 and 24 h. Total RNA was extracted from harvested liver tissues for qPCR analysis of target genes. Hepatic microsomal proteins underwent incubation with AA, followed by identification/quantification of the produced HETEs. ATO downregulated Cyp2e1, while induced Cyp2j9 and most of Cyp4a and Cyp4f, and this has resulted in a significant increase in 17(S)-HETE and 18(R)-HETE, while significantly decreased 18(S)-HETE. Additionally, ATO induced Cyp4a10, Cyp4a14, Cyp4f13, Cyp4f16, and Cyp4f18, resulting in a significant elevation in 20-HETE formation. In conclusion, ATO altered hepatic AA metabolites formation through modulating the underlying network of CYP enzymes. Modifying the homeostatic production of bioactive AA metabolites, such as HETEs, may entail toxic events that can, at least partly, explain ATO-induced hepatotoxicity. Such modification can also compromise the overall body tolerability to ATO treatment in cancer patients.

Studies and Enhancement of Natural Bioactive Compounds Content through Media Optimization

In these studies, endophyte bacteria were isolated from a medicinal plant root of Adhathoda beddomei (adosa). The antimicrobial activity was demonstrated against different pathogenic and nonpathogenic bacteria. Identification of endophytes was done based on external morphological characteristics with the help of a Scanning Electron Microscope (SEM). another challenging problem in this regard is that the efficiency of the endophytic bacteria to produce bioactive compounds is not as high as expected because, in many previous works in literature, it has been reported that yields are generally meagre. Through this study, we have tried to enhance the production of bioactive metabolites using media optimization and Resonance Surface Methodology (RSM). These are generally from µg/l to less than mg/l and are therefore not yet appropriate for fermentative production on an industrial level.