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Auxin signaling regulates growth and developmental processes in plants. The core of nuclear auxin signaling relies on just three components: TIR1/AFBs, Aux/IAAs, and ARFs. Each component is itself made up of several domains, all of which contribute to the regulation of auxin signaling. Studies of the structural aspects of these three core signaling components have deepened our understanding of auxin signaling dynamics and regulation. In addition to the structured domains of these components, intrinsically disordered regions within the proteins also impact auxin signaling outcomes. New research is beginning to uncover the role intrinsic disorder plays in auxin-regulated degradation and subcellular localization. Structured and intrinsically disordered domains affect auxin perception, protein degradation dynamics, and DNA binding. Taken together, subtle differences within the domains and motifs of each class of auxin signaling component affect signaling outcomes and specificity.

Paraquat is one of the most widely used nonselective herbicides in agriculture. Due to its wide use, paraquat resistant weeds have emerged and is becoming a potential threat to agriculture. The molecular mechanisms of paraquat resistance in weeds remain largely unknown. Physiological studies indicated that the impaired translocation of paraquat and enhanced antioxidation could improve paraquat resistance in plants. However, the detoxification of paraquat via active metabolism by plants has not been reported to date. Here we report that an activated expression of At1g01600 encoding the P450 protein CYP86A4 confers paraquat resistance as revealed by the gain-of-function mutant paraquat tolerance 11D (pqt11D), in which a T-DNA with four 35S enhancers was inserted at 1646 bp upstream the ATG of At1g01600. The paraquat resistance can be recapitulated in Arabidopsis wild type by overexpressing AtPQT11 (At1g01600), while its knockout mutant is hypersensitive to paraquat. Moreover, AtPQT11 also confers paraquat resistance in E. coli when overexpressed. We further demonstrate that AtPQT11 has P450 enzyme activity that converts paraquat to N-demethyl paraquat nontoxic to Arabidopsis, therefore detoxifying paraquat in plants. Taken together, our results unequivocally demonstrate that AtPQT11/ CYP86A4 detoxifies paraquat via active metabolism, thus revealing a novel molecular mechanism of paraquat resistance in plants and providing a means potentially enabling crops to resist paraquat.

Riboflavin is an essential micronutrient for humans and must be obtained exogenously from foods or supplements. Numerous studies have suggested a major role of riboflavin in the prevention and treatment of various diseases. There are mainly three strategies for riboflavin synthesis, including total chemical synthesis, chemical semi-synthesis, and microbial fermentation, the latter being currently the most promising strategy. In recent years, flavinogenic microbes have attracted increasing attention. Fungi, including Eremothecium ashbyii and Ashbya gossypii, and bacteria, including Bacillus subtilis, Escherichia coli, and lactic acid bacteria, are ideal cell factories for riboflavin overproduction. Thus they are good candidates for enhancing the level of riboflavin in fermented foods or designing novel riboflavin bio-enriched foods with improved nutritional value and/or beneficial properties for human health. This review briefly describes the role of riboflavin in human health and the historical process of its industrial production, and then highlights riboflavin biosynthesis in bacteria and fungi, and finally summarizes the strategies for riboflavin overproduction based on both the optimization of fermentation conditions and the development of riboflavin-overproducing strains via chemical mutagenesis and metabolic engineering. Overall, this review provides an updated understanding of riboflavin biosynthesis and can promote the research and development of fermented food products rich in riboflavin.

Aflatoxin contamination of almond kernels, caused by Aspergillus flavus and A. parasiticus, is a severe concern for growers because of its high toxicity. In California, the global leader of almond production, aflatoxin can be managed by applying the biological control strain AF36 of A. flavus and selecting resistant cultivars. Here, we classified the almond genotypes by K-Means cluster analysis into three groups (susceptible [S], moderately susceptible [MS], or resistant [R]) based on aflatoxin content of inoculated kernels. The protective effects of the shell and seedcoat in preventing aflatoxin contamination were also examined. The presence of intact shells reduced aflatoxin contamination >100-fold. The seedcoat provided a layer of protection but not complete protection. In kernel inoculation assays, none of the studied almond genotypes showed a total resistance to the pathogen. However, nine traditional cultivars and four advanced selections were classified as R. Because these advanced selections contained germplasm derived from peach, we compared the kernel resistance of three peach cultivars to that shown by kernels of an R (Sonora) and an S (Carmel) almond cultivar and five pistachio cultivars. Overall, peach kernels were significantly more resistant to the pathogen than almond kernels, which were more resistant than pistachio kernels. Finally, we studied the combined effect of the cultivar resistance and the biocontrol strain AF36 in limiting aflatoxin contamination. For this, we coinoculated almond kernels of R Sonora and S Carmel with AF36 72 h before or 48 h after inoculating with an aflatoxin-producing strain of A. flavus. The percentage of aflatoxin reduction by AF36 strain was greater in kernels of Carmel (98%) than in those of Sonora (83%). Cultivar resistance also affected the kernel colonization by the biological control strain. AF36 strain limited aflatoxin contamination in almond kernels even when applied 48 h after the aflatoxin-producing strain. Our results show that biocontrol combined with the use of cultivars with resistance to aflatoxin contamination can result in a more robust protection strategy than the use of either practice in isolation.

Background: Maternal subclinical hypothyroidism (SCH) has been associated with adverse pregnancy outcomes. This study aimed to explore whether SCH in the first trimester contributed to the developm...

Infections caused by virus are one of the foremost causes of morbidity and mortality in the world. Although a number of antiviral drugs are currently used for treatment of various kinds of viral infection diseases, there is still no available therapeutic agent for the most of virus in clinical practice. Coumarin is a chemical compound which is found naturally in a variety of plants, as well as it can be synthetically produced possessing diverse biological effects. More recently, reports have highlighted the potential role of coumarin derivatives as antiviral agents. This review outlines the advances in coumarin-based compounds against various viruses including human immunodeficiency virus, hepatitis virus, herpes simplex virus, Chikungunya virus and Enterovirus 71, the structure activity relationship and the possible mechanism of action of the most potent coumarin derivatives are also discussed.

Plants produce many secondary metabolites showing considerable inter- and intraspecific diversity of concentration and composition as a strategy to cope with environmental stresses. The evolution of plant defenses against herbivores and pathogens can be unraveled by understanding the mechanisms underlying chemical diversity. Pyrrolizidine alkaloids are a class of secondary metabolites with high diversity. We performed a qualitative and quantitative analysis of 80 pyrrolizidine alkaloids with liquid chromatography-tandem mass spectrometry of leaves from 17 Jacobaea species including one to three populations per species with 4–10 individuals per population grown under controlled conditions in a climate chamber. We observed large inter- and intraspecific variation in pyrrolizidine alkaloid concentration and composition, which were both species-specific. Furthermore, we sequenced 11 plastid and three nuclear regions to reconstruct the phylogeny of the 17 Jacobaea species. Ancestral state reconstruction at the species level showed mainly random distributions of individual pyrrolizidine alkaloids. We found little evidence for phylogenetic signals, as nine out of 80 pyrrolizidine alkaloids showed a significant phylogenetic signal for Pagel's λ statistics only, whereas no significance was detected for Blomberg's K measure. We speculate that this high pyrrolizidine alkaloid diversity is the result of the upregulation and downregulation of specific pyrrolizidine alkaloids depending on ecological needs rather than gains and losses of particular pyrrolizidine alkaloid biosynthesis genes during evolution.

Camptothecin (CPT) and its analogs are gaining prominence for its promising anti-cancer activity and are used throughout the world for the treatment of colorectal, breast, and lung cancers in particular. Nothapodytes nimmoniana (J. Graham) Mabb. (Olacaceae), a plant native to India's Western Ghats, has been harnessed for the production of CPT. The endangered nature of its wild population has urged plant tissue culture and engineering techniques to increase CPT production in multifold levels by adapting elicitation methods using chemical stress-inducing substances called elicitors. The main objective of this study is to increase the CPT production through in vitro cell suspension culture of N. nimmoniana by treating it with 5 different biotic elicitors such as chitin, chitosan, pullulan, glutathione, and jasmonic acid. The preliminary quantification of CPT in methanolic extracts of wild N. nimmoniana revealed that the bark extracts showed higher level of CPT than the leaf extracts. Further, column chromatography technique was employed to obtain CPT with 99.25 % purity. The elemental composition and structure of the purified compound was confirmed through HR-MS and Proton NMR spectroscopy. Shake flask in vitro elicitation of CPT was observed at a maximum level in 10 % chitin treated elicited culture with a yield of 15.06 μg/150 ml culture followed by 5 % jasmonic acid amounting to 6.025 μg/150 ml of culture as compared with other elicitors and control. LC-MS/MS fragmentation analysis was utilized for the structural confirmation of CPT. In conclusion, the biotic elicitor chitin 10 % treated suspension cells of N. nimmoniana showed maximum level (11.48-fold) of CPT elicitation followed by 4.65-fold in 5 % jasmonic acid treatment as compared with other elicitors and control suspension cells.

The lipid peroxidation product malondialdehyde and the DNA peroxidation product base-propenal react with dG to generate the exocyclic adduct, M1dG. This mutagenic lesion has been found in human genomic and mitochondrial DNA. M1dG in genomic DNA is enzymatically oxidized to 6-oxo-M1dG, a lesion of currently unknown mutagenic potential. Here, we report the synthesis of an oligonucleotide containing 6-oxo-M1dG and the results of extension experiments aimed at determining the effect of the 6-oxo-M1dG lesion on the activity of human polymerase iota (hPol ι). For this purpose, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed to obtain reliable quantitative data on the utilization of poorly incorporated nucleotides. Results demonstrate that hPol ι primarily incorporates deoxycytidine triphosphate (dCTP) and thymidine triphosphate (dTTP) across from 6-oxo-M1dG with approximately equal efficiency, whereas deoxyadenosine triphosphate (dATP) and deoxyguanosine triphosphate (dGTP) are poor substrates. Following the incorporation of a single nucleotide opposite the lesion, 6-oxo-M1dG blocks further replication by the enzyme.

Flavonoids have been shown to target aromatase, suppressing the transformed cells' proliferation and growth. Such experimental data further promoted the usage of flavonoids as an aromatase inhibitor and helps prevent cancer, specifically breast and lung cancer. Conversely, flavonoids have certain limitations like low absorption, potency, and some side effects in addition to their tremendous advantages. The pharmacokinetics and toxicity of flavonoids are now being addressed by using advanced nanotechnological approaches. This review discusses the comprehensive aromatase signaling pathway in normal and cancer cells. It also draws attention to how do flavonoids modulate aromatase signaling pathways. Also, different flavonoid groups inhibiting aromatase activities are discussed and listed in the Table comprising flavonoids group, cancer type, clinical trials, IC50, and the assay employed. Moreover, nanoparticles-mediated improvement in the pharmacokinetics and toxicity issues of flavonoids in targeting aromatase are also deliberated. In conclusion, flavonoids act as a potential anticancer agent via targeting aromatase. Besides, nanotechnological approaches are useful in addressing the pharmacokinetics and toxicity of flavonoids.

Sorafenib is a first-line molecular-target drug for advanced hepatocellular carcinoma (HCC), and reducing sorafenib resistance is an important issue to be resolved for the clinical treatment of HCC. In the current study, we identified that ABCC5 is a critical regulator and a promising therapeutic target of acquired sorafenib resistance in human hepatocellular carcinoma cells. The expression of ABCC5 was dramatically induced in sorafenib-resistant HCC cells and was remarkably associated with poor clinical prognoses. The down-regulation of ABCC5 expression could significantly reduce the resistance of sorafenib to HCC cells. Importantly, activation of PI3K/AKT/NRF2 axis was essential for sorafenib to induce ABCC5 expression. ABCC5 increased intracellular glutathione (GSH) and attenuated lipid peroxidation accumulation by stabilizing SLC7A11 protein, which inhibited ferroptosis. Additionally, the inhibition of ABCC5 enhanced the anti-cancer activity of sorafenib in vitro and in vivo. These findings demonstrate a novel molecular mechanism of acquired sorafenib resistance and also suggest that ABCC5 is a new regulator of ferroptosis in HCC cells.

Aspergillus flavus (A. flavus) is one of the most important model environmental fungi which can produce a potent toxin and carcinogen known as aflatoxin. Aflatoxin contamination causes massive agricultural economic loss and a critical human health issue each year. Although a functional vacuole has been highlighted for its fundamental importance in fungal virulence, the molecular mechanisms of the vacuole in regulating the virulence of A. flavus remain largely unknown. Here, we identified a novel vacuole-related protein in A. flavus, the ortholog of phosphatidylinositol-3-phosphate-5-kinase (Fab1) in Saccharomyces cerevisiae. This kinase was located at the vacuolar membrane, and loss of fab1 function was found to affect the growth, conidia and sclerotial development, cellular acidification and metal ion homeostasis, aflatoxin production and pathogenicity of A. flavus. Further functional analysis revealed that Fab1 was required to maintain the vacuole size and cell morphology. Additional quantitative proteomic analysis suggested that Fab1 was likely to play an important role in maintaining vacuolar/cellular homeostasis, with vacuolar dysregulation upon fab1 deletion leading to impaired aflatoxin synthesis in this fungus. Together, these results provide insight into the molecular mechanisms by which this pathogen produces aflatoxin and mediates its pathogenicity, and may facilitate dissection of the vacuole-mediated regulatory network in A. flavus.

Natural substances are known to have strong protective effects against neurodegenerative diseases. Among them, phenolic compounds, especially flavonoids, come to the fore with their neuroprotective effects. Since quercetin, which is found in many medicinal plants and foods, is also taken through diet, its physiological effects on humans are imperative. Many studies have been published up to date on the neuroprotective properties of quercetin, a flavanol derivative. However, there is no review published so far summarizing the effect of quercetin on the cholinesterase (ChE) enzymes related to the cholinergic hypothesis, which is one of the pathological mechanisms of Alzheimer's Disease (AD). However, ChE inhibitors, regardless of natural or synthetic, play a vital role in the treatment of AD. Although the number of studies on the ChE inhibitory effect of quercetin is limited, it deserves to be discussed in a review article. With this sensitivity, the neuroprotective effect of quercetin against AD through ChE inhibition was scrutinized in the current review study. In addition, studies on the bioavailability of quercetin and its capacity to cross the blood-brain barrier and how this capacity and bioavailability can be increased were given. Generally, studies containing data published in recent years were obtained from search engines such as PubMed, Scopus, and Medline and included herein. Consequently, quercetin should not be considered as a fashionable natural compound and should be identified as a promising compound, especially with increased bioavailability, for the treatment of AD.

The medicinal plant C. roseus synthesizes biologically active alkaloids via the terpenoid indole alkaloid (TIAs) biosynthetic pathway. Most of these alkaloids have high therapeutic value, such as vinblastine and vincristine. Plant signaling components, plant hormones, precursors, growth hormones, prenylated proteins, and transcriptomic factors regulate the complex networks of TIA biosynthesis. For many years, researchers have been evaluating the scientific value of the TIA biosynthetic pathway and its potential in commercial applications for market opportunities. Metabolic engineering has revealed the major blocks in metabolic pathways regulated at the molecular level, unknown structures, metabolites, genes, enzyme expression, and regulatory genes. Conceptually, this information is necessary to create transgenic plants and microorganisms for the commercial production of high-value dimer alkaloids, such as vinca alkaloids, vinblastine, and vincristine In this review, we present current knowledge of the regulatory mechanisms of these components in the C. roseus TIA pathway, from genes to metabolites.

Paraquat is one of the most widely used nonselective herbicides and has elicited the emergence of paraquat-resistant weeds. However, the molecular mechanisms of paraquat resistance are not completely understood. Here we report the Arabidopsis gain-of-function mutant pqt15-D with significantly enhanced resistance to paraquat and the corresponding gene PQT15, which encodes the Multidrug and Toxic Extrusion (MATE) transporter DTX6. A point mutation at +932 bp in DTX6 causes a G311E amino acid substitution, enhancing the paraquat resistance of pqt15-D, and overexpression of DTX6/PQT15 in the wild-type plants also results in strong paraquat resistance. Moreover, heterologous expression of DTX6 and DTX6-D in Escherichia coli significantly enhances bacterial resistance to paraquat. Importantly, overexpression of DTX6-D enables Arabidopsis plants to tolerate 4 mM paraquat, a near-commercial application level. DTX6/PQT15 is localized in the plasma membrane and endomembrane, and functions as a paraquat efflux transporter as demonstrated by paraquat efflux assays with isolated protoplasts and bacterial cells. Taken together, our results demonstrate that DTX6/PQT15 is an efflux transporter that confers paraquat resistance by exporting paraquat out of the cytosol. These findings reveal a molecular mechanism of paraquat resistance in higher plants and provide a promising candidate gene for engineering paraquat-resistant crops.

Evodiamine (Evo) is a quinazolinocarboline alkaloid found in Evodia rutaecarpa and exhibits moderate antiproliferative activity. Herein, we report using a scaffold-hopping approach to identify a series of novel polycyclic heterocyclic derivatives based on Evo as the topoisomerase I (Top1) inhibitor for the treatment of triple-negative breast cancer (TNBC), which is an aggressive subtype of breast cancer with limited treatment options. The most potent compound 7f inhibited cell growth in a human breast carcinoma cell line (MDA-MB-231) with an IC50 value of 0.36 μM. Further studies revealed that Top1 was the target of 7f, which directly induced irreversible Top1-DNA covalent complex formation or induced an oxidative DNA lesion through an indirect mechanism mediated by reactive oxygen species. More importantly, in vivo studies showed that 7f exhibited potent antitumor activity in a TNBC-patient-derived tumor xenograft model. These results suggest that compound 7f deserves further investigation as a promising candidate for the treatment of TNBC.

Coumarins, a heterocyclic benzo-α-pyrones and naturally occurring ring structure that possess significant pharmacological properties, have attracted the attention of researchers and medicinal chemists to reveal the suitability of both natural and synthetic coumarins as drugs. Many compounds have been synthesized utilizing the basic coumarin structure. The diverse synthetic methods resulted in the synthesis of important coumarin derivatives that offer a wide range of biological properties as antimicrobial, anticancer, anti-inflammatory, antioxidant, antidiabetic and antidepressant that make them potential drug candidates. With a particular interest in ulcers, coumarins have shown potential inhibition against urease enzyme. In recent years, scientists have emphasized the anti-urease activity of coumarins due to their low toxicity. The aim of this review is to compile data from recent research about anti-urease activities of coumarins and structure-activity relationship studies of the coumarin ring structure. Investigation of different structural substitutions in coumarin rings may help researchers to design new compounds with strong and effective anti- urease abilities.

A unique prenylated bicarbazole alkaloid, clausanisumine (1), and two biogenetically related known monomer carbazole alkaloids, mukonal (2) and 3-methylcarbazole (3), were isolated from the fruits of Clausena anisum-olens. Clausanisumine (1) was an uncommon prenylated bicarbazole alkaloid, possessing an unprecedented carbon skeleton, which was composed of a simple carbazole alkaloid and a prenylated carbazole alkaloid. The chemical structure of 1 was established by a combination of comprehensive spectral methods. A plausible biosynthetic pathway of 1 was also proposed. Additionally, the potential anti-HIV activities of all isolates 1-3in vitro were evaluated. Compound 1 exhibited remarkable anti-HIV-1 reverse transcriptase effects showing an EC50 value of 18.58 nM. The discovery of the prenylated bicarbazole alkaloid from C. anisum-olens with notable anti-HIV activity would be meaningful to discovering and developing new anti-HIV drugs.

Aberrant activity of the histone methyltransferase polycomb repressive complex 2 (PRC2) has been linked to several cancers, with small-molecule inhibitors of the catalytic subunit of the PRC2 enhancer of zeste homologue 2 (EZH2) being recently approved for the treatment of epithelioid sarcoma (ES) and follicular lymphoma (FL). Compounds binding to the EED subunit of PRC2 have recently emerged as allosteric inhibitors of PRC2 methyltransferase activity. In contrast to orthosteric inhibitors that target EZH2, small molecules that bind to EED retain their efficacy in EZH2 inhibitor-resistant cell lines. In this paper we disclose the discovery of potent and orally bioavailable EED ligands with good solubilities. The solubility of the EED ligands was optimized through a variety of design tactics, with the resulting compounds exhibiting in vivo efficacy in EZH2-driven tumors.

Melilotus species are used as green manure and rotation crops worldwide and contain abundant pharmacologically active coumarins. However, there is a paucity of information on its genome and coumarin production and function. Here, we reported a chromosome-scale assembly of Melilotus albus genome with 1.04 Gb in eight chromosomes, containing 71.42% repetitive elements. Long terminal repeat retrotransposon bursts coincided with declining of population sizes during the Quaternary glaciation. Resequencing of 94 accessions enabled insights into genetic diversity, population structure, and introgression. Melilotus officinalis had relatively larger genetic diversity than that of M. albus. The introgression existed between M. officinalis group and M. albus group, and gene flows was from M. albus to M. officinalis. Selection sweep analysis identified candidate genes associated with flower colour and coumarin biosynthesis. Combining genomics, BSA, transcriptomics, metabolomics, and biochemistry, we identified a β-glucosidase (BGLU) gene cluster contributing to coumarin biosynthesis. MaBGLU1 function was verified by overexpression in M. albus, heterologous expression in Escherichia coli, and substrate feeding, revealing its role in scopoletin (coumarin derivative) production and showing that nonsynonymous variation drives BGLU enzyme activity divergence in Melilotus. Our work will accelerate the understanding of biologically active coumarins and their biosynthetic pathways, and contribute to genomics-enabled Melilotus breeding.

Background Hepatocellular carcinoma (HCC) is a major contributor to the worldwide cancer burden. Recent studies on HCC have demonstrated dramatic alterations in expression of several cytochrome P450 (CYP) family members that play a crucial role in biotransformation of many drugs and other xenobiotics; however, the mechanisms responsible for their deregulation remain unclear. Methods We investigated a potential involvement of miRNAs in downregulation of expression of CYPs observed in HCC tumors. We compared miRNA expression profiles (TaqMan Array Human MicroRNA v3.0 TLDA qPCR) between HCC human patient tumors with strong (CYP-) and weak/no (CYP+) downregulation of drug-metabolizing CYPs. The role of significantly deregulated miRNAs in modulation of expression of the CYPs and associated xenobiotic receptors was then investigated in human liver HepaRG cells transfected with relevant miRNA mimics or inhibitors. Results We identified five differentially expressed miRNAs in CYP- versus CYP+ tumors, namely miR-29c, miR-125b1, miR-505, miR-653 and miR-675. The two most-upregulated miRNAs found in CYP- tumor samples, miR-29c and miR-653, were found to act as efficient suppressors of CYP1A2 or AHR expression. Conclusions Our results revealed a novel role of miR-653 and miR-29c in regulation of expresion of CYPs involved in crucial biotransformation processes in liver, which are often deregulated during liver cancer progression.

Cyclic AMP (cAMP) acts as a second messenger and is involved in the regulation of various physiological responses. Recently, we identified the cAMP-synthesis/hydrolysis enzyme CAPE, which contains the two catalytic domains adenylyl cyclase (AC) and cAMP phosphodiesterase (PDE) from the liverwort Marchantia polymorpha. Here we characterize the PDE domain of M. polymorpha CAPE (MpCAPE-PDE) using the purified protein expressed in E. coli. The Km and Vmax of MpCAPE-PDE were 30 µM and 5.8 nmol min−1 mg−1, respectively. Further, we investigated the effect of divalent cations on PDE activity and found that Ca2+ enhanced PDE activity, suggesting that Ca2+ may be involved in cAMP signaling through the regulation of PDE activity of CAPE. Among the PDE inhibitors tested, only dipyridamole moderately inhibited PDE activity by approximately 40% at high concentrations. Conversely, 3-isobutyl-1-methylxanthine (IBMX) did not inhibit PDE activity.

In plant tissue culture, callus forms from detached explants in response to a high-auxin-to-low-cytokinin ratio on callus-inducing medium. Callus is a group of pluripotent cells because it can regenerate either roots or shoots in response to a low level of auxin on root-inducing medium or a high-cytokinin-to-low-auxin ratio on shoot-inducing medium, respectively1. However, our knowledge of the mechanism of pluripotency acquisition during callus formation is limited. On the basis of analyses at the single-cell level, we show that the tissue structure of Arabidopsis thaliana callus on callus-inducing medium is similar to that of the root primordium or root apical meristem, and the middle cell layer with quiescent centre-like transcriptional identity exhibits the ability to regenerate organs. In the middle cell layer, WUSCHEL-RELATED HOMEOBOX5 (WOX5) directly interacts with PLETHORA1 and 2 to promote TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS1 expression for endogenous auxin production. WOX5 also interacts with the B-type ARABIDOPSIS RESPONSE REGULATOR12 (ARR12) and represses A-type ARRs to break the negative feedback loop in cytokinin signalling. Overall, the promotion of auxin production and the enhancement of cytokinin sensitivity are both required for pluripotency acquisition in the middle cell layer of callus for organ regeneration.

Most fruits and vegetables contain flavonoids, a type of phytonutrient. As well as carotenoids, they're responsible for fruits and vegetable brilliant hues. Some other phytonutrients such as flavonoids are strong antioxidants with anti-inflammatory and immune properties. There are many flavonoids, including anthocyanins, flavones, flavonols, flavonoids, and isoflavonoids. Quercetin and chrysin were chosen for the investigation. Humans and other animals can contract Helminthiasis (helminthiases), sometimes known as worm infection. Tapeworms, roundworms, and flukes are only a few of the parasites that exist. Skeletal muscle relaxants are used to treat spasticity caused by upper motor neuron syndromes and muscle discomfort or musculoskeletal spasms created by peripheral disturbances. Samples of quercetin and chrysin were generated in the presence of 0.5% SCMC suspension at concentrations of 10, 20, 30, and 40 mg/ml, and then analyzed. To keep track of photocell beam disruptions, a six-digit counter was utilized (locomotor activity). It was time to turn on the actophotometer and examine the locomotor behavior of each rat for five minutes. The basal activity levels of all the animals were recorded. Keywords: Flavonoids, Anthelmintic, Skeletal Muscle relaxant, animal models

Riboflavin is a feed additive, food additive, and clinical drug, with a significant annual demand of nearly 8000 tons. Fermentation using recombinant Bacillus subtilis is currently one of the most important industrial production method for riboflavin. First, a suitable medium was selected and the expression of the ureABC operon was modified. The ykgB gene was overexpressed in B. subtilis RX10, the production of the derivative strain RX20 was increased to 4.61 g l-1 riboflavin, and the yield was increased to 52 mg riboflavin g-1 glucose. The relative transcription level of pyr operon in RX20 was reduced to 71%, the production of the derivative strain RX21 was increased to 5.82 g l-1 riboflavin, and the yield was 76 mg riboflavin g-1 glucose. The start codon of the pyrE gene in RX21 was modified to "TTG", the production of the derivative strain RX22 was increased to 7.01 g l-1 riboflavin, and the yield was 89 mg riboflavin g-1 glucose. These results indicated that overexpression of the ykgB gene and reduction of the metabolic flux of de novo synthesis of pyrimidine nucleotides were beneficial to the synthesis of riboflavin.

Plant hormone cytokinins are important regulators of plant development, response to environmental stresses and interplay with other plant hormones. Cytokinin dehydrogenases (CKXs) are proteins responsible for the irreversible break-down of cytokinins to the adenine and aldehyde. Even though plant CKXs have been extensively studied, homologous proteins from other taxa remain mainly uncharacterised. Here we present our study on the molecular evolution and divergence of the CKX from bacteria, fungi, amoeba and viridiplantae. Although CKXs are present in eukaryotes and prokaryotes, they are missing in algae and metazoan taxa. The prevalent domain architecture consists of the FAD-binding and cytokinin binding domains, whereas some bacteria appear to have only cytokinin binding domain proteins. The CKXs play important role in the various aspects of plant life including control of plant development, response to biotic and abiotic stress, influence nutrition. Results of our study suggested that CKX originates from the FAD-linked C-terminal oxidase and has a defence-oriented function. The obtained results significantly extend the current understanding of the cytokinin dehydrogenases structure–function from the relationship to homologues from other taxa and provide a starting point baseline for their future functional characterization.

Phyllanthus is a large genus of shrubs, trees and rare herbs of the family Euphorbiaceae, comprising more than 600 species [1]. The aim of this project was to identify the phytochemicals present in P. niruri and the antidiabetic activity of the ethanolic extracts of the plant. The phytochemical analysis for alkaloids, flavonoids, anthraquinone, phenols, saponins, tannins, alkaloids, total phenolics, total flavonoids, carbohydrates and amino acids were made by following standard procedures. The antidiabetic property of the plant extract was evaluated using insulin as standards through inhibition of alphaamylase enzyme activity. The presence of saponins, alkaloids, tannins, flavonoids, phenols, terpenoids, carbohydrates, coumarins, anthraquinones and amino acids was observed. The total phenolic content in the extract was measured using catechol (standard) and a graph was plotted with concentration on X axis and absorbance on the Y axis. The total phenolic content was calculated. The calibration curves of α-amylase inhibition of Insulin and P. niruri was used to calculate the IC50 value.

The cytochrome P450 (Cyp) proteins Cyp1A1 and Cyp1A2 are strongly induced in the mouse liver by the potent environmental toxicant 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), acting through the aryl hydrocarbon receptor (AHR). The induction of Cyp1A1 is localized within the centrilobular regions of the mouse liver at low doses of TCDD, progressing to pan-lobular induction at higher doses. Even without chemical perturbation, metabolic functions and associated genes are basally zonated in the liver lobule along the central-to-portal axis. To investigate the mechanistic basis of spatially restricted gene induction by TCDD, we have developed a multiscale computational model of the mouse liver lobule with single-cell resolution. The spatial location of individual hepatocytes in the model was calibrated from previously published high-resolution images. A systems biology model of the network of biochemical signaling pathways underlying Cyp1A1 and Cyp1A2 induction was then incorporated into each hepatocyte in the model. Model simulations showed that a negative feedback loop formed by binding of the induced Cyp1A2 protein to TCDD, together with cooperative gene induction by the β-catenin/AHR/TCDD transcription factor complex and β-catenin, help produce the spatially localized induction pattern of Cyp1A1. Although endogenous WNT regulates the metabolic zonation of many genes, it was not a driver of zonal Cyp1A1 induction in our model. Conclusion: In this work, we used data-driven computational modeling to identify the mechanistic basis of zonally restricted gene expression induced by the potent and persistent environmental pollutant TCDD. The multiscale model and derived results clarify the mechanisms of dose-dependent hepatic gene induction responses to TCDD. Additionally, this work contributes to our broader understanding of spatial gene regulation along the liver lobule.

Riboflavin is an essential nutrient for humans and animals, and its derivatives flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) are cofactors in the cells. Therefore, riboflavin and its derivatives are widely used in the food, pharmaceutical, nutraceutical and cosmetic industries. Advances in biotechnology have led to a complete shift in the commercial production of riboflavin from chemical synthesis to microbial fermentation. In this review, we provide a comprehensive review of biotechnologies that enhance riboflavin production in microorganisms, as well as representative examples. Firstly, the synthesis pathways and metabolic regulatory processes of riboflavin in microorganisms; and the current strategies and methods of metabolic engineering for riboflavin production are systematically summarized and compared. Secondly, the using of systematic metabolic engineering strategies to enhance riboflavin production is discussed, including laboratory evolution, histological analysis and high-throughput screening. Finally, the challenges for efficient microbial production of riboflavin and the strategies to overcome these challenges are prospected.

Legumes balance nitrogen acquisition from soil nitrate with symbiotic nitrogen fixation. Nitrogen fixation requires establishment of a new organ, which is a cytokinin dependent developmental process in the root. We found cytokinin biosynthesis is a central integrator, balancing nitrate signalling with symbiotic acquired nitrogen. Low nitrate conditions provide a permissive state for induction of cytokinin by symbiotic signalling and thus nodule development. In contrast, high nitrate is inhibitory to cytokinin accumulation and nodule establishment in the root zone susceptible to nodule formation. This reduction of symbiotic cytokinin accumulation was further exacerbated in cytokinin biosynthesis mutants, which display hypersensitivity to nitrate inhibition of nodule development, maturation and nitrogen fixation. Consistent with this, cytokinin application rescues nodulation and nitrogen fixation of biosynthesis mutants in a concentration dependent manner. These inhibitory impacts of nitrate on symbiosis occur in a Nlp1 and Nlp4 dependent manner and contrast with the positive influence of nitrate on cytokinin biosynthesis that occurs in species that do not form symbiotic root nodules. Altogether this shows that legumes, as exemplified by Lotus japonicus, have evolved a different cytokinin response to nitrate compared to non-legumes., Nodule development in legumes is a cytokinin dependent process. Here the authors show that high nitrate supply, which limits nodulation, suppresses cytokinin biosynthesis in Lotus japonicus which contrasts with the positive effect of nitrate on cytokinin biosynthesis in non-legumes

Inactivation of the phytohormone auxin plays important roles in plant development, and several enzymes have been implicated in auxin inactivation. In this study, we show that the predominant natural auxin, indole-3-acetic acid (IAA), is mainly inactivated via the GH3-ILR1-DAO pathway. IAA is first converted to IAA-amino acid conjugates by GH3 IAA-amidosynthetases. The IAA-amino acid conjugates IAA-aspartate (IAA-Asp) and IAA-glutamate (IAA-Glu) are storage forms of IAA and can be converted back to IAA by ILR1/ILL amidohydrolases. We further show that DAO1 dioxygenase irreversibly oxidizes IAA-Asp and IAA-Glu into 2-oxindole-3-acetic acid-aspartate (oxIAA-Asp) and oxIAA-Glu, which are subsequently hydrolyzed by ILR1 to release inactive oxIAA. This work established a complete pathway for the oxidative inactivation of auxin and defines the roles played by auxin homeostasis in plant development.

Mimosa pigra L. (Fabaceae), commonly known as giant mimosa, is one of the major invasive species, constituting a serious threat to agricultural crops and other plants in the biodiversity. With this study, we aimed to investigate the mechanism underlying the effects on plant growth and development upon exposure to two coumarins. Protein solutions were obtained from giant mimosa seedlings that had been exposed to the coumarins, and they were analyzed with the shotgun proteomic method by liquid chromatography–tandem mass spectrometry (LC–MS/MS). The proteins were identified in seedlings treated with coumarins. The control plants expressed 621 proteins, the plants treated with isoscopoletin expressed 613 proteins, and the plants treated with umbelliferone expressed 640 proteins. The classification of proteins by PANTHER software found that the coumarins interfered with proteins involved in cellular component organization or biogenesis and metabolic processes. STITCH analysis of protein expression after treatment with coumarins confirmed that CUL4, ESF, LNG2 and SCD2 played a role in plant growth and development. WAK1 and WAT1 were involved in cell wall and cell surface responses. At3g61030 and CIP111 were related to Ca2+ accumulation and CAND1, CUL4 and ML5 were linked with programmed cell death. It is worthwhile to mention that coumarins increased morphological changes in the epidermis, Ca2+ accumulation in the roots and protein expression in plant growth and development, morphological changes, Ca2+ accumulation as well as in programmed cell death.

Flavonoids are important metabolites of pigeon pea in relation to its stress resistance. However, the molecular basis and regulatory mechanisms of flavonoids in pigeon pea remain unclear. Methyl jasmonate (MeJA) is a signaling molecule associated with biosynthesis of flavonoids. In this study, after exogenous treatment of 10 mg/L MeJA, infection of pathogenic fungi to pigeon pea was alleviated and the content of flavonoids was increased. Results of gene expression and metabolic changes that were respectively analyzed by transcriptome sequencing and high performance liquid chromatography (HPLC) showed that (1) concentrations of various flavonoids, such as genistein, apigenin, vitexin and biochanin A were significantly up-regulated; (2) 13675 differentially expressed genes were produced, mainly enriched in signal transduction and isoflavone biosynthesis pathways: (3) the expression levels of key synthase genes (CcI2′H, CcHIDH, Cc7-IOMT) in the flavonoid biosynthesis pathway were significantly up-regulated; (4) Overexpression of CcbHLH35 significantly induced upregulation of flavonoid synthase genes and accumulation of genistein, vitexin and apigenin. Our findings reveals the pivotal roles of MeJA in synthesis and functioning of flavonoids in pigeon pea, which provide a basis for further studies on flavonoid-mediated defense responses.

Quercetin, widely distributed in fruits and vegetables, is a flavonoid known for its antioxidant, antiviral, antimicrobial, and antiinflammatory properties. Several studies highlight the potential use of quercetin as an antiviral, due to its ability to inhibit the initial stages of virus infection, to be able to interact with proteases important for viral replication, and to reduce inflammation caused by infection. Quercetin could also be useful in combination with other drugs to potentially enhance the effects or synergistically interact with them, in order to reduce their side effects and related toxicity. Since there is no comprehensive compilation about antiviral activities of quercetin and derivates, the aim of this review is providing a summary of their antiviral activities on a set of human viral infections along with mechanisms of action. Thus, the following family of viruses are examined: Flaviviridae, Herpesviridae, Orthomyxoviridae, Coronaviridae, Hepadnaviridae, Retroviridae, Picornaviridae, Pneumoviridae, and Filoviridae.

Auxin/indoleacetic acid (Aux/IAA) family genes respond to the hormone auxin, which have been implicated in the regulation of multiple biological processes. In this study, all 25 Aux/IAA family genes were identified in Tartary buckwheat (Fagopyrum tataricum) by a reiterative database search and manual annotation. Our study provided comprehensive information of Aux/IAA family genes in buckwheat, including gene structures, chromosome locations, phylogenetic relationships, and expression patterns. Aux/IAA family genes were nonuniformly distributed in the buckwheat chromosomes and divided into seven groups by phylogenetic analysis. Aux/IAA family genes maintained a certain correlation and a certain species-specificity through evolutionary analysis with Arabidopsis and other grain crops. In addition, all Aux/IAA genes showed a complex response pattern under treatment of indole-3-acetic acid (IAA). These results provide valuable reference information for dissecting function and molecular mechanism of Aux/IAA family genes in buckwheat.

Flavonoids have a variety of biological activities that are beneficial to human health. However, owing to low bioavailability, most flavonoids exert beneficial effects in the intestine through metabolism by the flora into a variety of structurally different derivatives. Also, flavonoids can modulate the type and structure of intestinal microorganisms to improve human health. It has been reported that the development of depression is accompanied by changes in the type and number of intestinal microorganisms, and gut microbes can significantly improve depressive symptoms through the gut-brain axis. Therefore, the interaction between flavonoids and intestinal microbes to alleviate depression is discussed. © 2021 Society of Chemical Industry.

Background and Aims Initiation of cluster roots in white lupin (Lupinus albus) under phosphorus (P) deficiency requires auxin signalling, whereas flavonoids inhibit auxin transport. However, little information is available about the interactions between P deficiency and flavonoids in terms of cluster-root formation in white lupin. Methods Hydroponic and aeroponic systems were used to investigate the role of flavonoids in cluster-root formation, with or without 75 μm P supply. Key Results Phosphorus-deficiency-induced flavonoid accumulation in cluster roots depended on developmental stage, based on in situ determination of fluorescence of flavonoids and flavonoid concentration. LaCHS8, which codes for a chalcone synthase isoform, was highly expressed in cluster roots, and silencing LaCHS8 reduced flavonoid production and rootlet density. Exogenous flavonoids suppressed cluster-root formation. Tissue-specific distribution of flavonoids in roots was altered by P deficiency, suggesting that P deficiency induced flavonoid accumulation, thus fine-tuning the effect of flavonoids on cluster-root formation. Furthermore, naringenin inhibited expression of an auxin-responsive DR5:GUS marker, suggesting an interaction of flavonoids and auxin in regulating cluster-root formation. Conclusions Phosphorus deficiency triggered cluster-root formation through the regulation of flavonoid distribution, which fine-tuned an auxin response in the early stages of cluster-root development. These findings provide valuable insights into the mechanisms of cluster-root formation under P deficiency.

Machine learning (ML) methods have attracted increasing interest in chemistry as in all fields of science in recent years. This method is of great importance for the design of targeted bioactive compounds, especially by avoiding loss of time, money, and chemicals. There are lots of online web-based platforms such as LibSVM and OCHEM for the application of ML methods. In this paper, it has been examined the literature data on the activity predictions of heterocyclic compounds, biological activity results such as antiurease, HIV-1 Integrase, E. Coli DNA Gyrase B, and antifungal, pharmacophore-based studies, synthesis, and finding possible inhibitors using different machine learning methods.

Cytochrome P450 selectively hydroxylates the ω and ω-1 positions of fatty acids. Among synthetic oxidizing catalysts, Suslick’s bis-pocket porphyrin Mn or Fe complex achieved ω oxidation for the fi...

Quercetin is a dietary flavonoid that can affect the balance between anti-oxidant defense system and oxidative stress. A number of studies showed the positive effects of quercetin on diabetes mellitus and related metabolic disorders

In Dictyostelium, chemoattractants induce a fast cGMP response that mediates myosin filament formation in the rear of the cell. The major cGMP signaling pathway consists of a soluble guanylyl cyclase sGC, a cGMP-stimulated cGMP-specific phosphodiesterase, and the cGMP-target protein GbpC. Here we combine published experiments with many unpublished experiments performed in the past 45 years on the regulation and function of the cGMP signaling pathway. The chemoattractants stimulate heterotrimeric G alpha beta gamma and monomeric Ras proteins. A fraction of the soluble guanylyl cyclase sGC binds with high affinity to a limited number of membrane binding sites, which is essential for sGC to become activated by Ras and G alpha proteins. sGC can also bind to F-actin; binding to branched F-actin in pseudopods enhances basal sGC activity, whereas binding to parallel F-actin in the cortex reduces sGC activity. The cGMP pathway mediates cell polarity by inhibiting the rear: in unstimulated cells by sGC activity in the branched F-actin of pseudopods, in a shallow gradient by stimulated cGMP formation in pseudopods at the leading edge, and during cAMP oscillation to erase the previous polarity and establish a new polarity axis that aligns with the direction of the passing cAMP wave.

Application of atoxigenic strains of Aspergillus flavusto soils is the most successful aflatoxin biological control approach. The objective of this study was to evaluate the efficacies of native non-aflatoxin producing (atoxigenic) strains as a biocontrol agent in peanut field in China. The competitive atoxigenic A. flavus strains (JS4, SI1and SXN) isolated from different crops, in China were used for field evaluation. The strains applied during the growing season (June – October, 2016) in the field at rate of 25 kg inoculum/hectare. The colonization of these biocontrol agents has been investigated and the population of A. flavus communities in soil were determined. The incidences of toxin producing (toxigenic) A. flavus strains and aflatoxin contamination in peanuts were also determined. Treated plots produced significant reductions in the incidence of toxigenic isolates of A. flavus in soil. However, the total fungal densities were not significantly different (p > 0.05) after treatments. Large percentage of aflatoxin reductions, ranging from 82.8% (SXN) up to 87.2% (JS4) were recorded in treated plots. Generally, the results suggest that the strategy can be used to control aflatoxin contamination and continuous evaluation should be done.

Ma-chao Li,1,* Jie Lu,2,* Yao Lu,1,3,* Tong-yang Xiao,4,* Hai-can Liu,1 Shi-qiang Lin,5 Da Xu,1 Gui-lian Li,1 Xiu-qin Zhao,1 Zhi-guang Liu,1 Li-li Zhao,1 Kang-lin Wan1 1State Key Laboratory of Infectious Disease Prevention and Control, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People’s Republic of China; 2Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China; 3School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, People’s Republic of China; 4Guangdong Key Laboratory for Diagnosis & Treatment of Emerging Infectious Diseases, Shenzhen Third People’s Hospital, Southern University of Science and Technology, Shenzhen, People’s Republic of China; 5Department of Bioinformatics, College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li-li Zhao; Kang-lin WanNational Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, P.O. Box 5, Changping, Beijing, 102206, People’s Republic of ChinaTel/Fax +86 10 58900779Email zhaolili@icdc.cn; wankanglin@icdc.cnObjective: To investigate the mutations within the whole rpoB gene of Mycobacterium tuberculosis and analyze their effects on rifampin (RIF) resistance based on crystal structure.Methods: We sequenced the entire rpoB gene in 175 tuberculosis isolates and quantified their minimum inhibitory concentrations using microplate-based assays. Additionally, the structural interactions between wild-type/mutant RpoB and RIF were also analyzed.Results: Results revealed that a total of 34 mutations distributed across 17 different sites within the whole rpoB gene were identified. Of the 34 mutations, 25 could alter the structural interaction between RpoB and RIF and contribute to RIF resistance. Statistical analysis showed that S450L, H445D, H445Y and H445R mutations were associated with high-level RIF resistance, while D435V was associated with moderate-level RIF resistance.Conclusion: Some mutations within the rpoB gene could affect the interaction between RpoB and RIF and thus are associated with RIF resistance. These findings could be helpful to design new antibiotics and develop novel diagnostic tools for drug resistance in TB.Keywords: Mycobacterium tuberculosis, rifampin resistance, structure, mutation

Cytochrome P450 1A1 (CYP1A1) is a member of a subfamily of enzymes involved in the metabolism of both endogenous and exogenous substrates and the chemical activation of xenobiotics to carcinogenic derivatives. Here, the effects of nicotine, a major psychoactive compound present in cigarette smoke, on CYP1A1 expression and human hepatocellular carcinoma (HepG2) cell proliferation were investigated. Nicotine stimulated CYP1A1 expression via the transcription factors, activator protein 1, nuclear factor-kappa B, and the aryl hydrocarbon receptor (AhR) signaling pathway. Pharmacological inhibition and mutagenesis studies indicated that p38 mitogen-activated protein kinase, as well as RelA (or p65), mediated the upregulation of CYP1A1 of nicotine in HepG2 cells. The antioxidant compound, N-acetyl-cysteine, abrogated nicotine-activated production of reactive oxygen species and inhibited CYP1A1 expression by nicotine. Furthermore, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was inhibited by diphenyleneiodonium (an NADPH oxidase inhibitor). Thus, these results demonstrated that AhR played an important role in nicotine-induced CYP1A1 expression. Additionally, liver hepatocellular carcinoma HepG2 cells treated with nicotine exhibited markedly enhanced proliferation via CYP1A1 expression and Akt activation.

Members of the cytochrome p450 (CYP) enzyme family are abundantly expressed in insect olfactory tissues, where they are thought to act as Odorant Degrading Enzymes (ODEs). However, their contribution to olfactory signaling in vivo is poorly understood. This is due in part to the challenge of identifying which of the dozens of antennal-expressed CYPs might inactivate a given odorant. Here, we tested a high-throughput deorphanization strategy in Drosophila to identify CYPs that are transcriptionally induced by exposure to odorants. We discovered three CYPs selectively upregulated by geranyl acetate using transcriptional profiling. Although these CYPs are broadly expressed in the antenna in non-neuronal cells, electrophysiological recordings from CYP mutants did not reveal any changes in olfactory neuron responses to this odorant. Neurons were desensitized by pre-exposing flies to the odorant, but this effect was similar in CYP mutants. Together, our data suggest that the induction of a CYP gene by an odorant does not necessarily indicate a role for that CYP in neuronal responses to that odorant. We go on to show that some CYPs have highly restricted expression patterns in the antenna, and suggest that such CYPs may be useful candidates for further studies on olfactory CYP function.

The aim of this work was to evaluate the effectiveness of quercetin addition to the treatment regimen for patients with COVID-19 associated pneumonia. Materials and methods. The effectiveness of two dosage forms of quercetin was studied in 200 patients, who were divided equally into the main and control groups. The main group patients received quercetin in addition to the basic therapy: intravenous drip of Quercetin/Polyvinylirolidone during the first 10 days followed by oral administration of Quercetin/Pectin over the next 10 days. Patients from the control group received only the basic therapy drugs. The study evaluated the dynamics of the disease symptoms (saturation level, respiratory rate, body temperature, cough, general weakness), as well as laboratory markers (C-reactive protein (CRP), ferritin, D-dimer). Results. Two dosage forms of quercetin consistently used in addition to the basic therapy improve pulmonary gas exchange and accelerate the lung function recovery. This is evidenced by a statistically significant majority of patients with positive dynamics in the symptoms of “Saturation level” and “Cough” as well as the meeting a complex indicator of the therapy effectiveness 2 days earlier than in the control group. The treatment regimen applied also helps to stabilize the level of D-dimer in the blood of the main group patients. Conclusions. The use of two dosage forms of quercetin in addition to the basic therapy accelerates the recovery of patients with coronavirus disease associated pneumonia and can help to prevent the progression of COVID-19 associated coagulopathy.

Aflatoxins are potent carcinogens, mutagens and teratogens, and are harmful to both humans and animals. As many as 30 genes are involved in aflatoxin biosynthesis. Among them, aflM (ver-1) gene was predicted to encode a 28-kDa NADPH-dependent ketoreductase (AFLM), which catalyzed middle enzymatic steps in aflatoxin biosynthetic pathway. AFLM (Ver-1) was proved to be necessary for conversion of versicolorin A (VERA) to demethylsterigmatocystin (DMST) in aflatoxin B1 (AFB1) biosynthesis. For these reasons, aflM gene was cloned and specific monoclonal antibodies for AFLM was developed to better define potential pathways of AFLM involved in AFB1 biosynthesis. Monoclonal antibodies 11B2-1D7 and 3G5-4E7 were successfully screened out by immunizing mouse. Immunoblot analysis revealed that both had high sensitivity and specificity to identify native AFLM protein in A. flavus with detection limit of 11 ​ng/mL and 8 ​ng/mL respectively. These results showed that it was suitable for quantitative detection of AFLM in A. flavus isolate. Further investigation revealed that aflatoxin accumulations of various A. flavus were not dependent on AFLM biosynthesis. Overall, this is the first report for development for AFLM monoclonal antibody development and application in A. flavus quantitative detection.

Alzheimer���s disease (AD) is an age-related neurodegenerative disorder, the incidence of which is climbing with ever-growing aged population, but no cure is hitherto available. The epidemiological studies unveiled that chronic intake of flavonoids was negatively associated with AD risk. Flavonoids, a family of natural polyphenols widely distributed in human daily diets, were readily conjugated by phase II drug metabolizing enzymes after absorption in vivo, and glucuronidation could occur in 1 min following intravenous administration. Recently, as many as 191 metabolites were obtained after intragastric administration of a single flavonoid, indicating that other bioactive metabolites, besides conjugates, might be formed and account for the contradiction between efficacy of flavonoids in human or animal models and low systematic exposure of flavonoid glycosides or aglycones. In this review, metabolism of complete 68 flavonoid monomers potential for AD treatment, grouped in flavonoid O-glycosides, flavonoid aglycones, flavonoid C-glycosides, flavonoid dimers, flavonolignans and prenylated flavonoids according to their common structural elements, respectively, has been systematically retrospected, summarized and discussed, including their unequivocally identified metabolites, metabolic interconversions, metabolic locations, metabolic sites (regio- or stereo-selectivity), primarily involved metabolic enzymes or intestinal bacteria, and interspecies correlations or differences in metabolism, and their bioactive metabolites and the underlying mechanism to reverse AD pathology were also reviewed, providing whole perspective about advances on extensive metabolism of diverse potent flavonoids in vivo and in vitro up to date and aiming at elucidation of mechanism of actions of flavonoids on AD or other central nervous system (CNS) disorders.