Integrated metabolomic and transcriptomic analyses provide insights into regulation mechanisms during bulbous stem development in the Chinese medicinal herb plant, Stephania kwangsiensis.

BACKGROUND: Stephania kwangsiensis Lo (Menispermaceae) is a well-known Chinese herbal medicine, and its bulbous stems are used medicinally. The storage stem of S. kwangsiensis originated from the hypocotyls. To date, there are no reports on the growth and development of S. kwangsiensis storage stems. RESULTS: The bulbous stem of S. kwangsiensis, the starch diameter was larger at the stable expanding stage (S3T) than at the unexpanded stage (S1T) or the rapidly expanding stage (S2T) at the three different time points. We used ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and Illumina sequencing to identify key genes involved in bulbous stem development. A large number of differentially accumulated metabolites (DAMs) and differentially expressed genes (DEGs) were identified. Based on the differential expression profiles of the metabolites, alkaloids, lipids, and phenolic acids were the top three differentially expressed classes. Compared with S2T, significant changes in plant signal transduction and isoquinoline alkaloid biosynthesis pathways occurred at both the transcriptional and metabolic levels in S1T. In S2T compared with S3T, several metabolites involved in tyrosine metabolism were decreased. Temporal analysis of S1T to S3T indicated the downregulation of phenylpropanoid biosynthesis, including lignin biosynthesis. The annotation of key pathways showed an up-down trend for genes and metabolites involved in isoquinoline alkaloid biosynthesis, whereas phenylpropanoid biosynthesis was not completely consistent. CONCLUSIONS: Downregulation of the phenylpropanoid biosynthesis pathway may be the result of carbon flow into alkaloid synthesis and storage of lipids and starch during the development of S. kwangsiensis bulbous stems. A decrease in the number of metabolites involved in tyrosine metabolism may also lead to a decrease in the upstream substrates of phenylpropane biosynthesis. Downregulation of lignin synthesis during phenylpropanoid biosynthesis may loosen restrictions on bulbous stem expansion. This study provides the first comprehensive analysis of the metabolome and transcriptome profiles of S. kwangsiensis bulbous stems. These data provide guidance for the cultivation, breeding, and harvesting of S. kwangsiensis.

Characterization of CYP82 genes involved in the biosynthesis of structurally diverse benzylisoquinoline alkaloids in Corydalis yanhusuo.

Benzylisoquinoline alkaloids (BIAs) represent a significant class of secondary metabolites with crucial roles in plant physiology and substantial potential for clinical applications. CYP82 genes are involved in the formation and modification of various BIA skeletons, contributing to the structural diversity of compounds. In this study, Corydalis yanhusuo, a traditional Chinese medicine rich in BIAs, was investigated to identify the catalytic function of CYP82s during BIA formation. Specifically, 20 CyCYP82-encoding genes were cloned, and their functions were identified in vitro. Ten of these CyCYP82s were observed to catalyze hydroxylation, leading to the formation of protopine and benzophenanthridine scaffolds. Furthermore, the correlation between BIA accumulation and the expression of CyCYP82s in different tissues of C. yanhusuo was assessed their. The identification and characterization of CyCYP82s provide novel genetic elements that can advance the synthetic biology of BIA compounds such as protopine and benzophenanthridine, and offer insights into the biosynthesis of BIAs with diverse structures in C. yanhusuo.

The effects of green and chemically-synthesized copper oxide nanoparticles on the production and gene expression of morphinan alkaloids in Oriental poppy.

Oriental poppy (Papaver orientale L.) belonging to the Papaveraceae family, has the capacity to synthesize a wide range of benzylisoquinoline alkaloids (BIAs). This experiment was conducted to investigate the effects of green and chemical copper oxide nanoparticles (CuO NPs) elicitors on oxidative stress and the BIAs biosynthesis pathway in the cell suspension culture of P. orientale. This research shows that both green and chemical CuO NPs at concentrations of 20 mg/L and 40 mg/L, induce oxidative stress in the cell suspension of P. orientale by increasing the production of H2O2 and the activity of antioxidant enzymes. The comparison of treatments revealed that utilizing a lower concentration of CuO NPs (20 mg/L) and extending the duration of cell suspension incubation (up to 48 h) play a more influential role in inducing the expression of the BIAs biosynthesis pathway genes (PsWRKY, TYDC, SalSyn, SalR, SalAT, T6ODM, COR and CODM) and increasing the production of morphinan alkaloids (thebaine, codeine, and morphine). The overarching results indicate that the concentration of CuO NPs and the duration of cell treatment have a more significant impact than the nature of CuO NPs in inducing oxidative stress and stimulating the expression of the BIAs pathway genes.

Oxymatrine protects articular chondrocytes from IL-1ß-induced damage through autophagy activation via AKT/mTOR signaling pathway inhibition.

BACKGROUND: Osteoarthritis (OA) is a common degenerative joint disease characterized by persistent articular cartilage degeneration and synovitis. Oxymatrine (OMT) is a quinzolazine alkaloid extracted from the traditional Chinese medicine, matrine, and possesses anti-inflammatory properties that may help regulate the pathogenesis of OA; however, its mechanism has not been elucidated. This study aimed to investigate the effects of OMT on interleukin-1ß (IL-1ß)-induced damage and the potential mechanisms of action. METHODS: Chondrocytes were isolated from Sprague-Dawley rats. Toluidine blue and Collagen II immunofluorescence staining were used to determine the purity of the chondrocytes. Thereafter, the chondrocytes were subjected to IL-1ß stimulation, both in the presence and absence of OMT, or the autophagy inhibitor 3-methyladenine (3-MA). Cell viability was assessed using the MTT assay and SYTOX Green staining. Additionally, flow cytometry was used to determine cell apoptosis rate and reactive oxygen species (ROS) levels. The protein levels of AKT, mTOR, LC3, P62, matrix metalloproteinase-13, and collagen II were quantitatively analyzed using western blotting. Immunofluorescence was used to assess LC3 expression. RESULTS: OMT alleviated IL-1ß-induced damage in chondrocytes, by increasing the survival rate, reducing the apoptosis rates of chondrocytes, and preventing the degradation of the cartilage matrix. In addition, OMT decreased the ROS levels and inhibited the AKT/mTOR signaling pathway while promoting autophagy in IL-1ß treated chondrocytes. However, the effectiveness of OMT in improving chondrocyte viability under IL-1ß treatment was limited when autophagy was inhibited by 3-MA. CONCLUSIONS: OMT decreases oxidative stress and inhibits the AKT/mTOR signaling pathway to enhance autophagy, thus inhibiting IL-1ß-induced damage. Therefore, OMT may be a novel and effective therapeutic agent for the clinical treatment of OA.

Molecular regulation of the key specialized metabolism pathways in medicinal plants.

The basis of modern pharmacology is the human ability to exploit the production of specialized metabolites from medical plants, for example, terpenoids, alkaloids, and phenolic acids. However, in most cases, the availability of these valuable compounds is limited by cellular or organelle barriers or spatio-temporal accumulation patterns within different plant tissues. Transcription factors (TFs) regulate biosynthesis of these specialized metabolites by tightly controlling the expression of biosynthetic genes. Cutting-edge technologies and/or combining multiple strategies and approaches have been applied to elucidate the role of TFs. In this review, we focus on recent progress in the transcription regulation mechanism of representative high-value products and describe the transcriptional regulatory network, and future perspectives are discussed, which will help develop high-yield plant resources.

Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.

Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1-3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid4, NAD+ levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD+ pool and increases NAD+ levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss-Handler pathway5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD+-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.

Bioactivity and mechanism of action of sanguinarine and its derivatives in the past 10 years.

Sanguinarine is a quaternary ammonium benzophenanthine alkaloid found in traditional herbs such as Chelidonium, Corydalis, Sanguinarum, and Borovula. It has been proven to possess broad-spectrum biological activities, such as antitumor, anti-inflammatory, antiosteoporosis, neuroprotective, and antipathogenic microorganism activities. In this paper, recent progress on the biological activity and mechanism of action of sanguinarine and its derivatives over the past ten years is reviewed. The results showed that the biological activities of hematarginine and its derivatives are related mainly to the JAK/STAT, PI3K/Akt/mTOR, NF-κB, TGF-ß, MAPK and Wnt/ß-catenin signaling pathways. The limitations of using sanguinarine in clinical application are also discussed, and the research prospects of this subject are outlined. In general, sanguinarine, a natural medicine, has many pharmacological effects, but its toxicity and safety in clinical application still need to be further studied. This review provides useful information for the development of sanguinarine-based bioactive agents.

Ruminant metabolism of zygacine, the major toxic alkaloid in foothill death camas (Zigadenuspaniculatus).

Death Camas (Zigadenus spp.) are common poisonous plants distributed throughout North America. The toxic alkaloids in foothill death camas are zygadenine and a series of zygadenine esters, with zygacine, the 3-acetyl ester of zygadenine, being the most abundant. Both cattle and sheep can be poisoned by grazing death camas, however, sheep consume death camas more readily and are most often poisoned. We hypothesized that the presence of enzymes, including esterases present in the rumen, liver, and blood of livestock would metabolize zygacine. The objective of this study was to investigate the metabolism of zygacine in sheep and cattle using in-vitro and in-vivo systems. Results from experiments where zygacine was incubated in rumen culture, plasma, liver S9 fractions, and liver microsomes and from the analysis of rumen and sera from sheep and cattle dosed death camas plant material demonstrated that zygacine is metabolized to zygadenine in the rumen, liver and blood of sheep and cattle. The results from this study indicate that diagnosticians should analyze for zygadenine, and not zygacine, in the rumen and sera for the diagnosis of livestock suspected to have been poisoned by foothill death camas.

Alkaloid uptake pathways in renal tubular epithelial cells from different processed products of Phellodendri chinensis Cortex.

This study aimed to investigate the absorption of alkaloids from Phellodendri chinensis Cortex (PC) by human renal tubular epithelial cells (HK-2). Cellular uptake and affinity ultrafiltration assays were employed to determine the alkaloid uptake pathway in HK-2 cells. Stemming from the hypothesis that salt-water processed PC introduces these alkaloids into the kidney at a cellular level, this research focused on different processed products of PC that are tailored for renal targeting. Utilizing the UPLC-QqQ-MS method, we quantified variations in the uptake capacity of phellodendrine, magnoflorine, jatrorrhizine, berberrubine, and berberine from raw Phellodendri chinensis Cortex (RPC), salt-water processed Phellodendri chinensis Cortex (SPC), and wine processed Phellodendri chinensis Cortex (WPC) in HK-2 cells. This study also tracked the concentration changes of these five alkaloids in HK-2 cells during the administration phase. Further, we evaluated the influence of two inhibitors on the absorption of these five alkaloids from PC and its processed products into HK-2 cells: the organic anion transporters (OATs) inhibitor-probenecid (PRO), and the organic cationic transporters (OCTs) inhibitor-tetraethylammonium chloride (TEAC). A pivotal component of this research was an investigation into the effects of PC and its processed products on the expression levels of OCT2, OAT1, and OAT3 proteins in HK-2 cells, facilitated by Western blot analysis. Finally, we appraised the binding affinity of PC's alkaloids to OCT2, OAT1, and OAT3 proteins using an ultrafiltration centrifugation technique. The uptake of different processed products of PC by HK-2 cells showed the following trend: SPC group > RPC group > WPC group. When considering inhibitor uptake in HK-2 cells, the group treated with PRO (an OATs inhibitor) demonstrated a higher uptake than the group treated with TEAC (an OCTs inhibitor). It was observed that different processed products of PC elevated the expression of OCT2 and OAT1 proteins in HK-2 cells. Specifically, both the SPC and berberrubine groups displayed enhanced expression of these proteins, with a marked increase noted for OCT2. Through affinity ultrafiltration assays, it was determined that the binding affinity of alkaloids from different processed products of PC to OCT2 and OAT1 significantly exceeded that to OAT3. These results indicate that PC-derived alkaloids are absorbed by HK-2 cells, predominantly through transport mechanisms mediated by OCT2 and OAT1, with OCT2 serving as the dominant transporter. The higher intake of alkaloids in SPC group can likely be linked to the amplified activity of kidney uptake transporters.

Genome sequencing and functional analysis of a multipurpose medicinal herb Tinospora cordifolia (Giloy).

Tinospora cordifolia (Willd.) Hook.f. & Thomson, also known as Giloy, is among the most important medicinal plants that have numerous therapeutic applications in human health due to the production of a diverse array of secondary metabolites. To gain genomic insights into the medicinal properties of T. cordifolia, the genome sequencing was carried out using 10× Genomics linked read and Nanopore long-read technologies. The draft genome assembly of T. cordifolia was comprised of 1.01 Gbp, which is the genome sequenced from the plant family Menispermaceae. We also performed the genome size estimation for T. cordifolia, which was found to be 1.13 Gbp. The deep sequencing of transcriptome from the leaf tissue was also performed. The genome and transcriptome assemblies were used to construct the gene set, resulting in 17,245 coding gene sequences. Further, the phylogenetic position of T. cordifolia was also positioned as basal eudicot by constructing a genome-wide phylogenetic tree using multiple species. Further, a comprehensive comparative evolutionary analysis of gene families contraction/expansion and multiple signatures of adaptive evolution was performed. The genes involved in benzyl iso-quinoline alkaloid, terpenoid, lignin and flavonoid biosynthesis pathways were found with signatures of adaptive evolution. These evolutionary adaptations in genes provide genomic insights into the presence of diverse medicinal properties of this plant. The genes involved in the common symbiosis signalling pathway associated with endosymbiosis (Arbuscular Mycorrhiza) were found to be adaptively evolved. The genes involved in adventitious root formation, peroxisome biogenesis, biosynthesis of phytohormones, and tolerance against abiotic and biotic stresses were also found to be adaptively evolved in T. cordifolia.

Piperlongumine, a Piper longum-derived amide alkaloid, protects mice from ovariectomy-induced osteoporosis by inhibiting osteoclastogenesis via suppression of p38 and JNK signaling.

Postmenopausal osteoporosis (PMOP) is a metabolic bone disease that results from overproduction and hyperactivation of osteoclasts caused by insufficient estrogen in women after menopause. Current therapeutic strategies are mainly focused on treating PMOP patients who have already developed severe bone loss or even osteoporotic fractures. Obviously, a better strategy is to prevent PMOP from occurring in the first place. However, such reagents are largely lacking. Piperlongumine (PLM), an amide alkaloid extracted from long pepper Piper longum, exhibits the anti-osteoclastogenic effect in normal bone marrow macrophages (BMMs) and the protective effect against osteolysis induced by titanium particles in mice. This study examined the preventive effect of PLM on PMOP and explored the potential mechanism of this effect using both ovariectomized mice and their primary cells. The result showed that PLM (5 and 10 mg kg-1) administered daily for 6 weeks ameliorated ovariectomy-induced bone loss and osteoclast formation in mice. Further cell experiments showed that PLM directly suppressed osteoclast formation, F-actin ring formation, and osteoclastic resorption pit formation in BMMs derived from osteoporotic mice, but did not obviously affect osteogenic differentiation of bone marrow stromal cells (BMSCs) from these mice. Western blot analysis revealed that PLM attenuated maximal activation of p38 and JNK pathways by RANKL stimulation without affecting acute activation of NF-κB, AKT, and ERK signaling. Furthermore, PLM inhibited expression of key osteoclastogenic transcription factors NFATc1/c-Fos and their target genes (Dcstamp, Atp6v0d2, Acp5, and Oscar). Taken together, our findings suggest that PLM inhibits osteoclast formation and function by suppressing RANKL-induced activation of the p38/JNK-cFos/NFATc1 signaling cascade, thereby preventing ovariectomy-induced osteoporosis in mice. Thus, PLM can potentially be used as an anti-resorption drug or dietary supplement for the prevention of PMOP.

Unlocking the hidden potential: Enhancing the utilization of stems and leaves through metabolite analysis and toxicity assessment of various parts of Aconitum carmichaelii.

ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum carmichaelii is widely used in traditional Chinese medicine clinics as a bulk medicinal material. It has been used in China for more than two thousand years. Nevertheless, the stems and leaves of this plant are usually discarded as non-medicinal parts, even though they have a large biomass and exhibit therapeutic properties. Thus, it is crucial to investigate metabolites of different parts of Aconitum carmichaelii and explore the relationship between metabolites and toxicity to unleash the utilization potential of the stems and leaves. AIM OF THE STUDY: Using plant metabolomics, we aim to correlate different metabolites in various parts of Aconitum carmichaelii with toxicity, thereby screening for toxicity markers. This endeavor seeks to offer valuable insights for the development of Aconitum carmichaelii stem and leaf-based applications. MATERIALS AND METHODS: UHPLC-Q-Orbitrap MS/MS-based plant metabolomics was employed to analyze metabolites of the different parts of Aconitum carmichaelii. The cardiotoxicity and hepatotoxicity of the extracts from different parts of Aconitum carmichaelii were also investigated using zebrafish as animal model. Toxicity markers were subsequently identified by correlating toxicity with metabolites. RESULTS: A total of 113 alkaloids were identified from the extracts of various parts of Aconitum carmichaelii, with 64 different metabolites in stems and leaves compared to daughter root (Fuzi), and 21 different metabolites in stems and leaves compared to mother root (Wutou). The content of aporphine alkaloids in the stems and leaves of Aconitum carmichaelii is higher than that in the medicinal parts, while the content of the diester-diterpenoid alkaloids is lower. Additionally, the medicinal parts of Aconitum carmichaelii exhibited cardiotoxicity and hepatotoxicity, while the stems and leaves have no obvious toxicity. Finally, through correlation analysis and animal experimental verification, mesaconitine, deoxyaconitine, and hypaconitine were used as toxicity markers. CONCLUSION: Given the low toxicity of the stems and leaves and the potential efficacy of aporphine alkaloids, the stems and leaves of Aconitum carmichaelii hold promise as a valuable medicinal resource warranting further development.

Corydalis saxicolaBunting total alkaloid eliminates Porphyromonas gingivalis strain 33277 internalized into macrophages by inhibition of TLR2.

OBJECTIVE: This study aimed to investigate the impact of Corydalis Saxicola Bunting Total Alkaloid (CSBTA) on Porphyromonas gingivalis internalization within macrophages and explore the potential role of Toll-Like Receptor 2 (TLR2) in this process. METHODS: We established a P. gingivalis internalization model in macrophages by treating P. gingivalis-infected macrophages (MOI=100:1) with 200 µg/mL metronidazole and 300 µg/mL gentamicin for 1 h. Subsequently, the model was exposed to CSBTA at concentrations of 0.02 g/L or 1 µg/mL Pam3CSK4. After a 6 h treatment, cell lysis was performed with sterile water to quantify bacterial colonies. The mRNA expressions of TLR2 and interleukin-8 (IL-8) in macrophages were analyzed using RT-qPCR, while their protein levels were assessed via Western blot and ELISA respectively. RESULTS: P. gingivalis could internalize into macrophages and enhance the expression of TLR2 and IL-8. Activation of TLR2 by Pam3CSK4 contributed to P. gingivalis survival within macrophages and increased TLR2 and IL-8 expression. Conversely, 0.02 g/L CSBTA effectively cleared intracellular P. gingivalis, achieving a 90 % clearance rate after 6 h. Moreover, it downregulated the expression of TLR2 and IL-8 induced by P. gingivalis. However, the inhibitory effect of CSBTA on the internalized P. gingivalis model was attenuated by Pam3CSK4. CONCLUSION: CSBTA exhibited the ability to reduce the presence of live intracellular P. gingivalis and lower IL-8 expression in macrophages, possibly by modulating TLR2 activity.

Aporphine and amide alkaloids from Illigera parviflora.

Three undescribed alkaloids (+)-9-hydroxy-N-acetylnordicentrine (1), illigeparvinine (2), and deca-(2E,4Z)-2,4-dienoic acid 4-hydroxy-2-phenethyl amide (3), along with 19 known analogues (4-22), were isolated from the ethnic medicinal plant Illigera parviflora. Their structures were established using NMR, MS, and other spectroscopic analyses as well as X-ray diffraction. Moderate inhibition of human gastric carcinoma (MGC-803) and breast adenocarcinoma (T-47D) cell lines proliferation was observed for actinodaphnine (4) with IC50 values of 28.74 and 11.65 µM, respectively. These findings contribute new anticancer potential compounds and expand the chemical diversity known from the valuable traditional medicinal plant I. parviflora.

O- and N-Methyltransferases in benzylisoquinoline alkaloid producing plants.

BACKGROUND: Secondary metabolites such as benzylisoquinoline alkaloids (BIA) have attracted considerable attention because of their pharmacological properties and potential therapeutic applications. Methyltransferases (MTs) can add methyl groups to alkaloid molecules, altering their physicochemical properties and bioactivity, stability, solubility, and recognition by other cellular components. Five types of O-methyltransferases and two types of N-methyltransferases are involved in BIA biosynthesis. OBJECTIVE: Since MTs may be the source for the discovery and development of novel biomedical, agricultural, and industrial compounds, we performed extensive molecular and phylogenetic analyses of O- and N-methyltransferases in BIA-producing plants. METHODS: MTs involved in BIA biosynthesis were isolated from transcriptomes of Berberis koreana and Caulophyllum robustum. We also mined the methyltransferases of Coptis japonica, Papaver somniferum, and Nelumbo nucifera from the National Center for Biotechnology Information protein database. Then, we analyzed the functional motifs and phylogenetic analysis. RESULT: We mined 42 O-methyltransferases and 8 N-methyltransferases from the five BIA-producing plants. Functional motifs for S-adenosyl-L-methionine-dependent methyltransferases were retained in most methyltransferases, except for the three O-methyltransferases from N. nucifera. Phylogenetic analysis revealed that the methyltransferases were grouped into four clades, I, II, III and IV. The clustering patterns in the phylogenetic analysis suggested a monophyletic origin of methyltransferases and gene duplication within species. The coexistence of different O-methyltransferases in the deep branch subclade might support some cases of substrate promiscuity. CONCLUSIONS: Methyltransferases may be a source for the discovery and development of novel biomedical, agricultural, and industrial compounds. Our results contribute to further understanding of their structure and reaction mechanisms, which will require future functional studies.

Exploring toxicological interactions in a changing sea: The case of the alkaloids caffeine and caulerpin.

The bisindolic alkaloid caulerpin (CAU) is a bioactive compound isolated from green algae of the genus Caulerpa that are highly invasive in the Mediterranean Sea. On the other side, the purine alkaloid caffeine (CAF) is one of the most globally consumed psychoactive substances and a widespread anthropogenic water pollutant. Both compounds display a large panel of biological properties and are well known to accumulate in the tissues of aquatic organisms and, in certain circumstances, co-occur in the human diet. On this premise, the present study aimed to investigate possible synergistic interactions between CAU and CAF by using the bivalve Mytilus galloprovincialis as a model organism. Mussels were exposed to CAF via medium while they were fed with food enriched with CAU. After treatments, biochemical analysis confirmed the toxic potential of CAF, with increased AChE activity and lipid peroxidation. Also, histopathological alterations were observed in the gills and digestive tubules. The NMR-based metabolomics analysis detected higher levels of free amino acids under CAF treatments. Conversely, the food administration of CAU did not affect the above toxicological biomarkers. In addition, we did not observe any cumulative effect between CAF and CAU toward increased cellular damage and neurotoxicity. On the other hand, a possible action of CAU in decreasing CAF toxicity could be hypothesized based on our results. This hypothesis is supported by the activity of CAU as an agonist of peroxisome proliferator-activated receptors (PPARs). PPARs mediate xenobiotic detoxification via cytochromes P450, which is involved in CAF metabolism. Overall, the results obtained not only rule out any cumulative adverse effects of CAF and CAU but also encourage further research to evaluate the possible use of CAU, a compound easily obtained through the valorization of biomass from invasive species, as a food additive to improve the clearance of xenobiotics.

Bioactive alkaloids from the venom of Dendrobatoidea Cope, 1865: a scoping review.

Bioactive compounds derived from secondary metabolism in animals have refined selectivity and potency for certain biological targets. The superfamily Dendrobatoidea is adapted to the dietary sequestration and secretion of toxic alkaloids, which play a role in several biological activities, and thus serve as a potential source for pharmacological and biotechnological applications. This article constitutes a scoping review to understand the trends in experimental research involving bioactive alkaloids derived from Dendrobatoidea based upon scientometric approaches. Forty-eight (48) publications were found in 30 journals in the period of 60 years, between 1962 and 2022. More than 23 structural classes of alkaloids were cited, with 27.63% for batrachotoxins, 13.64% for pyridinics, with an emphasis on epibatidine, 16.36% for pumiliotoxins, and 11.82% for histrionicotoxins. These tests included in vivo (54.9%), in vitro (39.4%), and in silico simulations (5.6%). Most compounds (54.8%) were isolated from skin extracts, whereas the remainder were obtained through molecular synthesis. Thirteen main biological activities were identified, including acetylcholinesterase inhibitors (27.59%), sodium channel inhibitors (12.07%), cardiac (12.07%), analgesic (8.62%), and neuromuscular effects (8.62%). The substances were cited as being of natural origin in the "Dendrobatidae" family, genus "Phyllobates," "Dendrobates," and seven species: Epipedobates tricolor, Phyllobates aurotaenia, Oophaga histrionica, Oophaga pumilio, Phyllobates terribilis, Epipedobates anthonyi, and Ameerega flavopicta. To date, only a few biological activities have been experimentally tested; hence, further studies on the bioprospecting of animal compounds and ecological approaches are needed.

Pharmacokinetics, dynamics, toxicology and molecular docking of bioactive alkaloid vasicine from Adhatoda vasica: a promising toxin binder against aflatoxin B1 and ochratoxin A.

Vasicine from Adhatoda vasica was investigated in the management of aflatoxicosis and ochratoxicosis by in silico molecular docking approach. The computational analysis was carried out using Discovery Studio Autodock 4.5 tool. Absorption, distribution, metabolism, and excretion (ADME), pharmacodynamics and toxicity studies were also carried out using Swiss ADME and PASS online server, respectively. The standard drug compound used was silymarin and the structure were retrieved from the protein data bank for both the test compound vasicine and the standard drug. Vasicine interacted with aflatoxin B1 at 10 different poses and the maximum dock score was found to be 83.04 and the binding energy was -37.54 kcal/mol. Silymarin interacted with aflatoxin B1 at 10 different poses and the maximum dock score was found to be 143.578 and the binding energy was -67.32 kcal/mol. Vasicine interacted with ochratoxin A at 10 different poses and the maximum dock score was found to be 73.75 and the binding energy was -56.20 kcal/mol. Silymarin interacted with ochratoxin A at 10 different poses and the maximum dock score was found to be 89.23 and the binding energy was -98.86 kcal/mol. The compounds possess good gastro intestinal absorption with antioxidant property and exhibits minimum adverse effects. The obtained results support the toxin mitigating potential of the test compound with minimum adverse effects and hence vasicine can be regarded as a potential toxin binder of aflatoxin B1 and ochratoxin A, wherein it can be implemented for alleviating aflatoxicosis and ochratoxicosis.

Interplay between Amaryllidaceae alkaloids, the bacteriome and phytopathogens in Lycoris radiata.

Alkaloids are a large group of plant secondary metabolites with various structures and activities. It is important to understand their functions in the interplay between plants and the beneficial and pathogenic microbiota. Amaryllidaceae alkaloids (AAs) are unique secondary metabolites in Amaryllidaceae plants. Here, we studied the interplay between AAs and the bacteriome in Lycoris radiata, a traditional Chinese medicinal plant containing high amounts of AAs. The relationship between AAs and bacterial composition in different tissues of L. radiata was studied. In vitro experiments revealed that AAs have varying levels of antimicrobial activity against endophytic bacteria and pathogenic fungi, indicating the importance of AA synthesis in maintaining a balance between plants and beneficial/pathogenic microbiota. Using bacterial synthetic communities with different compositions, we observed a positive feedback loop between bacteria insensitive to AAs and their ability to increase accumulation of AAs in L. radiata, especially in leaves. This may allow insensitive bacteria to outcompete sensitive ones for plant resources. Moreover, the accumulation of AAs enhanced by insensitive bacteria could benefit plants when challenged with fungal pathogens. This study highlights the functions of alkaloids in plant-microbe interactions, opening new avenues for designing plant microbiomes that could contribute to sustainable agriculture.