Improved Charge Separation and CO2 Affinity of In2O3 by K Doping with Accompanying Oxygen Vacancies for Boosted CO2 Photoreduction.

The CO2 photocatalytic conversion efficiency of the semiconductor photocatalyst is always inhibited by the sluggish charge transfer and undesirable CO2 affinity. In this work, we prepare a series of K-doped In2O3 catalysts with concomitant oxygen vacancies (OV) via a hydrothermal method, followed by a low-temperature sintering treatment. Owing to the synergistic effect of K doping and OV, the charge separation and CO2 affinity of In2O3 are synchronously promoted. Particularly, when P/P0 = 0.010, at room temperature, the CO2 adsorption capacity of the optimal K-doped In2O3 (KIO-3) is 2336 cm3·g-1, reaching about 6000 times higher than that of In2O3 (0.39 cm3·g-1). As a result, in the absence of a cocatalyst or sacrificial agent, KIO-3 exhibits a CO evolution rate of 3.97 µmol·g-1·h-1 in a gas-solid reaction system, which is 7.6 times that of pristine In2O3 (0.52 µmol·g-1·h-1). This study provides a novel approach to the design and development of efficient photocatalysts for CO2 conversion by element doping.

Oxygen-deficient AgIO3 for efficiently photodegrading organic contaminants under natural sunlight.

Defect engineering is regarded as an effective strategy to boost the photo-activity of photocatalysts for organic contaminants removal. In this work, abundant surface oxygen vacancies (Ov) are created on AgIO3 microsheets (AgIO3-OV) by a facile and controllable hydrogen chemical reduction approach. The introduction of surface Ov on AgIO3 broadens the photo-absorption region from ultraviolet to visible light, accelerates the photoinduced charges separation and migration, and also activates the formation of superoxide radicals (•O2-). The AgIO3-OV possesses an outstanding degradation rate constant of 0.035 min-1, for photocatalytic degrading methyl orange (MO) under illumination of natural sunlight with a light intensity is 50 mW/cm2, which is 7 and 3.5 times that of the pristine AgIO3 and C-AgIO3 (AgIO3 is calcined in air without generating Ov). In addition, the AgIO3-OV also exhibit considerable photoactivity for degrading other diverse organic contaminants, including azo dye (rhodamine B (RhB)), antibiotics (sulflsoxazole (SOX), norfloxacin (NOR), chlortetracycline hydrochloride (CTC), tetracycline hydrochloride (TC) and ofloxacin (OFX)), and even the mixture of organic contaminants (MO-RhB and CTC-OFX). After natural sunlight illumination for 50 min, 41.4% of total organic carbon (TOC) for MO-RhB mixed solution can be decreased over AgIO3-OV. In a broad range of solution pH from 3 to 11 or diverse water bodies of MO solution, AgIO3-OV exhibits attractive activity for decomposing MO. The MO photo-degradation process and mechanism over AgIO3-OV under natural sunlight irradiation has been systemically investigated and proposed. The toxicities of MO and its degradation intermediates over AgIO3-OV are compared using Toxicity Estimation Software (T.E.S.T.). Moreover, the non-toxicity of both AgIO3-OV catalyst and treated antibiotic solution (CTC-OFX mixture) are confirmed by E. coli DH5a cultivation test, supporting the feasibility of AgIO3-OV catalyst to treat organic contaminants in real water under natural sunlight illumination.

Biotechnological production and potential applications of hypocrellins.

Hypocrellins (HYPs), a kind of natural perylenequinones (PQs) with an oxidized pentacyclic core, are important natural compounds initially extracted from the stromata of Hypocrella bambusae and Shiraia bambusicola. They have been widely concerned for their use as anti-microbial, anti-cancers, and anti-viral photodynamic therapy agents in recent years. Considering the restrictions of natural stromal resources, submerged fermentation with Shiraia spp. has been viewed as a promising alternative biotechnology for HYP production, and great efforts have been made to improve HYP production over the past decade. This article reviews recent publications about the mycelium fermentation production of HYPs, and their bioactivities and potential applications, and especially summarizes the progresses toward manipulation of fermentation conditions. Also, their chemical structure and analytic methods are outlined. Herein, it is worth mentioning that the gene arrangement in HYP gene cluster is revised; previous unknown genes in HYP and CTB gene clusters with correct function annotation are deciphered; the homologous sequences of HYP, CTB, and elc are systematically aligned, and especially the biosynthetic pathway of HYPs is full-scale proposed. KEY POINTS: • The mycelial fermentation process and metabolic regulation of hypocrellins are reviewed. • The bioactivities and potential applications of hypocrellins are summarized. • The biosynthesis pathway and regulatory mechanisms of hypocrellins are outlined.

Correction to: Activation and enhancement of caerulomycin A biosynthesis in marine-derived Actinoalloteichus sp. AHMU CJ021 by combinatorial genome mining strategies.

An amendment to this paper has been published and can be accessed via the original article.

Activation and enhancement of caerulomycin A biosynthesis in marine-derived Actinoalloteichus sp. AHMU CJ021 by combinatorial genome mining strategies.

BACKGROUND: Activation of silent biosynthetic gene clusters (BGCs) in marine-derived actinomycete strains is a feasible strategy to discover bioactive natural products. Actinoalloteichus sp. AHMU CJ021, isolated from the seashore, was shown to contain an intact but silent caerulomycin A (CRM A) BGC-cam in its genome. Thus, a genome mining work was preformed to activate the strain's production of CRM A, an immunosuppressive drug lead with diverse bioactivities. RESULTS: To well activate the expression of cam, ribosome engineering was adopted to treat the wild type Actinoalloteichus sp. AHMU CJ021. The initial mutant strain XC-11G with gentamycin resistance and CRM A production titer of 42.51 ± 4.22 mg/L was selected from all generated mutant strains by gene expression comparison of the essential biosynthetic gene-camE. The titer of CRM A production was then improved by two strain breeding methods via UV mutagenesis and cofactor engineering-directed increase of intracellular riboflavin, which finally generated the optimal mutant strain XC-11GUR with a CRM A production titer of 113.91 ± 7.58 mg/L. Subsequently, this titer of strain XC-11GUR was improved to 618.61 ± 16.29 mg/L through medium optimization together with further adjustment derived from response surface methodology. In terms of this 14.6 folds increase in the titer of CRM A compared to the initial value, strain XC-GUR could be a well alternative strain for CRM A development. CONCLUSIONS: Our results had constructed an ideal CRM A producer. More importantly, our efforts also had demonstrated the effectiveness of abovementioned combinatorial strategies, which is applicable to the genome mining of bioactive natural products from abundant actinomycetes strains.

Genome mining and metabolic profiling illuminate the chemistry driving diverse biological activities of Bacillus siamensis SCSIO 05746.

Bacillus spp. are important producers of bioactive natural products with potential applications in medicine and agriculture. Bacillus sp. SCSIO 05476 from a deep-sea sediment exhibits broad-spectrum antimicrobial activities and strong cytotoxic activity. Here, an integrative approach combining genome mining and metabolic profiling has been applied to decipher the chemical origins of this strain's varied and significant biological activities. First, genome mining revealed 19 candidate gene clusters encoding the biosynthesis of diverse secondary metabolites. Then, a series of bacillibactins, fengycins, bacillomycins, surfactins, bacillaenes, macrolactins, and related species were found by LC-DAD-MS. Finally, three new linear bacillibactins, linbacillibactins A-C (1-3), along with 11 known secondary metabolites, bacillibactin (4), normal-C13 Val7 surfactin (5), anteiso-C13 Leu7 surfactin (6), iso-C14 Leu7 surfactin (7), normal-C14 Leu7 surfactin (8), anteiso-C14 Leu7 surfactin (9), macrolactin D (10), normal-C14 bacillomycin D (11), iso-C16 bacillomycin D (12), normal-C17 bacillomycin D (13), and iso-C17 bacillomycin D (14), were obtained and elucidated by bioactivity and structure-guided isolation from the fermentation of strain SCSIO 05746. Among them, new compounds 1-3 show significant siderophore activities comparable to that of bacillibactin (4), compounds 13 and 14 exhibit strong cytotoxic activity. At the same time, the strain classification status was confirmed by genomic analyses, and the complete genome sequence of Bacillus siamensis was presented firstly. This study provides a foundation for understanding the mechanisms driving SCSIO 05746's multiple bioactivities and demonstrates a successful way of discovering bioactive metabolites using a combination of genome mining and metabolic profiling methods.

Enhancement of marinacarboline A biosynthesis by optimizing the riboflavin supplement in marine derived Nocardiopsis flavescens CGMCC 4.5723.

OBJECTIVES: To improve the bioproductivity of secondary metabolites of marine derived Nocardiopsis flavescens CGMCC 4.5723 by enhancing its riboflavin supplement. RESULTS: The NfRibA, type II guanosine triphosphate (GTP) cyclohydrolase (GCH II) of Nocardiopsis flavescens CGMCC 4.5723, was biochemically identified and showed that NfRibA could efficiently catalyze the first step of riboflavin biosynthesis to hydrolyze GTP into 2, 5-diamino-6-ribosylamino-4(3H)-pyrimidinedione 5'-phosphate (DARPP) with Km value of 160.11 ± 26.81 µM in vitro. The overexpression of NfribA could obviously increase riboflavin bioproduction to the titers of 0.41 ± 0.19 mg/l by comparing with the wild type counterpart. Consequently, this rise of riboflavin bioproduction did not disturb the expression of genes involved in marinacarboline A biosynthesis, but could significantly enhance its bioproduction with the titer of 5.5 ± 0.17 mg/l through comparing with wild type control. CONCLUSIONS: Optimization of riboflavin supplement could be a new promising strategy in actinomycetic marinacarboline A exploitation.

Identification of the Actinomycin D Biosynthetic Pathway from Marine-Derived Streptomyces costaricanus SCSIO ZS0073.

Bioactive secondary metabolites from Streptomycetes are important sources of lead compounds in current drug development. Streptomyces costaricanus SCSIO ZS0073, a mangrove-derived actinomycete, produces actinomycin D, a clinically used therapeutic for Wilm's tumor of the kidney, trophoblastic tumors and rhabdomyosarcoma. In this work, we identified the actinomycin biosynthetic gene cluster (BGC) acn by detailed analyses of the S. costaricanus SCSIO ZS0073 genome. This organism produces actinomycin D with a titer of ~69.8 µg mL-1 along with traces of actinomycin Xoß. The acn cluster localized to a 39.8 kb length region consisting of 25 open reading frames (ORFs), including a set of four genes that drive the construction of the 4-methyl-3-hydroxy-anthranilic acid (4-MHA) precursor and three non-ribosomal peptide synthetases (NRPSs) that generate the 4-MHA pentapeptide semi-lactone, which, upon dimerization, affords final actinomycin D. Furthermore, the acn cluster contains four positive regulatory genes acnWU4RO, which were identified by in vivo gene inactivation studies. Our data provide insights into the genetic characteristics of this new mangrove-derived actinomycin D bioproducer, enabling future metabolic engineering campaigns to improve both titers and the structural diversities possible for actinomycin D and related analogues.

Cytotoxic Polyketides Isolated from the Deep-Sea-Derived Fungus Penicillium chrysogenum MCCC 3A00292.

The chemical examination of the solid cultures of the deep-sea-derived fungus Penicillium chrysogenum MCCC 3A00292 resulted in the isolation of three new versiol-type analogues, namely peniciversiols A-C (1-3), and two novel lactone derivatives, namely penicilactones A and B (6 and 7), along with 11 known polyketides. The planar structures of the new compounds were determined by the comprehensive analyses of the high-resolution electrospray ionization mass spectroscopy (HRESIMS) and nuclear magnetic resonance (NMR) data, while their absolute configurations were resolved on the basis of comparisons of the experimental electronic circular dichroism (ECD) spectra with the calculated ECD data. Compound 1 is the second example of versiols featuring a 2,3-dihydropyran-4-one ring. Additionally, compounds 6 and 7 are the first representatives of γ-lactone derivatives constructed by a 1,3-dihydroxy-5-methylbenzene unit esterifying with the α-methyl-γ-hydroxy-γ-acetic acid α,ß-unsaturated-γ-lactone moiety and α-hydroxy-γ-methyl-γ-acetic acid α,ß-unsaturated-γ-lactone unit, respectively. All of the isolated compounds were evaluated for their cytotoxic activities against five human cancer cell lines of BIU-87, ECA109, BEL-7402, PANC-1, and Hela-S3. Compound 1 exhibited a selective inhibitory effect against the BIU-87 cell line (IC50 = 10.21 µM), while compounds 4, 5, 8, and 12-16 showed inhibitory activities against the ECA109, BIU-87, and BEL-7402 cell lines with the IC50 values ranging from 7.70 to > 20 µM.

Identification and utilization of two important transporters: SgvT1 and SgvT2, for griseoviridin and viridogrisein biosynthesis in Streptomyces griseoviridis.

BACKGROUND: Griseoviridin (GV) and viridogrisein (VG, also referred as etamycin), both biosynthesized by a distinct 105 kb biosynthetic gene cluster (BGC) in Streptomyces griseoviridis NRRL 2427, are a pair of synergistic streptogramin antibiotics and very important in treating infections of many multi-drug resistant microorganisms. Three transporter genes, sgvT1-T3 have been discovered within the 105 kb GV/VG BGC, but the function of these efflux transporters have not been identified. RESULTS: In the present study, we have identified the different roles of these three transporters, SgvT1, SgvT2 and SgvT3. SgvT1 is a major facilitator superfamily (MFS) transporter whereas SgvT2 appears to serve as the sole ATP-binding cassette (ABC) transporter within the GV/VG BGC. Both proteins are necessary for efficient GV/VG biosynthesis although SgvT1 plays an especially critical role by averting undesired intracellular GV/VG accumulation during biosynthesis. SgvT3 is an alternative MFS-based transporter that appears to serve as a compensatory transporter in GV/VG biosynthesis. We also have identified the γ-butyrolactone (GBL) signaling pathway as a central regulator of sgvT1-T3 expression. Above all, overexpression of sgvT1 and sgvT2 enhances transmembrane transport leading to steady production of GV/VG in titers ≈ 3-fold greater than seen for the wild-type producer and without any notable disturbances to GV/VG biosynthetic gene expression or antibiotic control. CONCLUSIONS: Our results shows that SgvT1-T2 are essential and useful in GV/VG biosynthesis and our effort highlight a new and effective strategy by which to better exploit streptogramin-based natural products of which GV and VG are prime examples with clinical potential.

Bioimaging of Intravenous Polymeric Micelles Based on Discrimination of Integral Particles Using an Environment-Responsive Probe.

One of the biggest challenges in bioimaging of nanoparticles is how to identify integral particles from bulk signals of probes. Signals of free probes are always mistakenly counted into total signals of particles. In this study, in vivo fate of intravenous polymeric micelles (PMs, mPEG2.5k-PDLLA2.5k) was explored using a highly sensitive near-infrared environment-responsive fluorescent probe. This probe is able to emit fluorescence when embedded in nanocarriers but quench spontaneously and absolutely upon release into water, based on the aggregation-caused quenching effect, which means that the interference generated by free probes can be completely diminished. Analysis of blood-borne fluorescence reveals rapid clearance of PMs from blood following a tricompartmental pharmacokinetic model. Live imaging shows pervasive distribution of PMs throughout the body, and a tendency of accumulation to extremities with fluorescence density 3-5 times higher than the trunk. Ex vivo examination reveals that most PMs are found in vital organs following an order of lung > liver > spleen > heart > kidney in concentration, but an order of liver > lung > spleen > heart ≈ kidney in total amount. The distribution to other organs and tissues is even lower, and to brain, negligible. It is concluded that the biodistribution of PMs to vital organs and extremities warns of potential toxicity and can be translated to explain the toxicity of its commercial counterpart with similar chain lengths.

Controlling Release of Integral Lipid Nanoparticles Based on Osmotic Pump Technology.

PURPOSE: To achieve controlled release of integral nanoparticles by the osmotic pump strategy using nanostructured lipid carriers (NLCs) as model nanoparticles. METHODS: NLCs was prepared by a hot-homogenization method, transformed into powder by lyophilization, and formulated into osmotic pump tablets (OPTs). Release of integral NLCs was visualized by live imaging after labeling with a water-quenching fluorescent probe. Effects of formulation variables on in vitro release characteristics were evaluated by measuring the model drug fenofibrate. Pharmacokinetics were studied in beagle dogs using the core tablet and a micronized fenofibrate formulation as references. RESULTS: NLCs are released through the release orifices of the OPTs as integral nanoparticles. Near zero-order kinetics can be achieved by optimizing the influencing variables. After oral administration, decreased C max and steady drug levels for as long as over 24 h are observed. NLC-OPTs show an oral bioavailability of the model drug fenofibrate similar to that of the core tablets, which is about 1.75 folds that of a fast-release formulation. CONCLUSION: Controlled release of integral NLCs is achieved by the osmotic pump strategy.

Synchronous microencapsulation of multiple components in silymarin into PLGA nanoparticles by an emulsification/solvent evaporation method.

The development of polymeric carriers loaded with extracts suffers from the drawback not to be able to incorporate simultaneously various pharmacological compounds into the formulation. The aim of this study was therefore to achieve synchronous microencapsulation of multiple components of silymarin into poly (lactic-co-glycolic acid) nanoparticle, the most commonly used polymeric carrier with biodegradability and safety. The main strategy taken was to improve the overall entrapment efficiency and to reduce the escaping ratio of the components of different physicochemical properties. The optimized nanoparticles were spherical in morphology with a mean particle size of 150 ± 5 nm. Under common preparative conditions, silybin and isosilybin were entrapped in high efficiency, whereas taxifolin, silychristin and silydianin, especially taxifolin, showed less entrapment because they were more hydrophilic. By changing the pH of the outer aqueous phase and saturating it with silymarin, the entrapment efficiency of taxifolin, silychristin and silydianin could be significantly improved to over 90%, the level similar to silybin and isosilybin, thereby achieving synchronous encapsulation. It could be concluded that synchronous encapsulation of multiple components of silymarin was achieved by optimizing the preparative variables.

Environment-responsive aza-BODIPY dyes quenching in water as potential probes to visualize the in vivo fate of lipid-based nanocarriers.

Environment-responsive near-infrared (NIR) aza-BODIPY dyes capable of fluorescence quenching in water were explored to visualize the in vivo fate of model lipid-based nanocarriers, solid lipid nanoparticles (SLNs). The water-quenching effect of the dyes was confirmed to be sensitive and remained stable for at least 24h. In vitro lipolysis measured by fluorescence quenching completed within 20min, which was in correlation with alkaline compensation results. In vivo live imaging indicated predominant digestion of SLNs within 2h and complete digestion within 4h, which correlated well to in vitro data. Rekindling of quenched dyes by mixed micelles was observed in vitro, but not in vivo. In sharp contrast, SLNs encapsulating another NIR dye DiR showed persistent fluorescence both in vitro and in vivo despite significant lipolysis. It was envisaged that water-quenching fluorescence dyes can be used as probes to monitor the in vivo fate of lipid-based nanocarriers. FROM THE CLINICAL EDITOR: Lipid-based drug delivery systems can provide an excellent nanocarrier platform for the delivery of poorly water-soluble drugs. Nonetheless, the mechanism of oral absorption and subsequent kinetics is poorly understood. In this article, the authors studied the novel use of near-infrared (NIR) aza-BODIPY dyes to visualize the fate of these lipid-based nanocarriers. The positive finding means that this approach may be useful for in-vivo monitoring of lipid-based nanocarriers.

Involvement of SgvP in carbon-sulfur bond formation during Griseoviridin biosynthesis.

Griseoviridin (GV) is an A-type streptogramin antibiotic displaying antimicrobial activity and acting synergistically with viridogrisein (VG). Bioinformatic analyses reveal SgvP as the sole cytochrome P450 enzyme in the GV/VG gene cluster. To explore the role of SgvP in the GV/VG pathway, we inactivated the sgvP gene. The resulting ΔsgvP mutant generated two new products: GV-1 and GV-2, both lacking the CS bridge. In trans complementation of the sgvP gene into the ΔsgvP mutant strain partially restores GV production. Feeding [1-(13) C]-labeled cysteine to the wild-type strain led to enrichment of C-7 in the GV scaffold, thus verifying that the CS bond in GV is formed through direct coupling of the free SH group provided by the side chain of cysteine. The above results highlight the significance of SgvP in CS bond formation in griseoviridin biosynthesis.

Insights into the molecular network underlying phytotoxicity and phytoaccumulation of ciprofloxacin.

Ciprofloxacin (CIP) is frequently detected in agricultural soils and can be accumulated by crops, causing phytotoxicities and food safety concerns. However, the molecular basis of its phytotoxicity and phytoaccumulation is hardly known. Here, we analyzed physiological and molecular responses of choysum (Brassica parachinensis) to CIP stress by comparing low CIP accumulation variety (LAV) and high accumulation variety (HAV). Results showed that the LAV suffered more severe inhibition of growth and photosynthesis than the HAV, exhibiting a lower tolerance to CIP toxicity. Integrated transcriptome and proteome analyses suggested that more differentially expressed genes/proteins (DEGs/DEPs) involved in basic metabolic processes were downregulated to a larger extent in the LAV, explaining its lower CIP tolerance at molecular level. By contrast, more DEGs/DEPs involved in defense responses were upregulated to a larger extent in the HAV, showing the molecular basis of its stronger CIP tolerance. Further, a CIP phytotoxicity-responsive molecular network was constructed for the two varieties to better understand the molecular mechanisms underlying the variety-specific CIP tolerance and accumulation. The results present the first comprehensive molecular profile of plant response to CIP stress for molecular-assisted breeding to improve CIP tolerance and minimize CIP accumulation in crops.

Biodegradation of phthalate acid esters and whole-genome analysis of a novel Streptomyces sp. FZ201 isolated from natural habitats.

Di-n-butyl phthalate (DBP) is one of the most extensively used phthalic acid esters (PAEs) and is considered to be an emerging, globally concerning pollutant. The genus Streptomyces holds promise as a degrader of various organic pollutants, but PAE biodegradation mechanisms by Streptomyces species remain unsolved. In this study, a novel PAE-degrading Streptomyces sp. FZ201 isolated from natural habitats efficiently degraded various PAEs. FZ201 had strong resilience against DBP and exhibited immediate degradation, with kinetics adhering to a first-order model. The comprehensive biodegradation of DBP involves de-esterification, ß-oxidation, trans-esterification, and aromatic ring cleavage. FZ201 contains numerous catabolic genes that potentially facilitate PAE biodegradation. The DBP metabolic pathway was reconstructed by genome annotation and intermediate identification. Streptomyces species have an open pangenome with substantial genome expansion events during the evolutionary process, enabling extensive genetic diversity and highly plastic genomes within the Streptomyces genus. FZ201 had a diverse array of highly expressed genes associated with the degradation of PAEs, potentially contributing significantly to its adaptive advantage and efficiency of PAE degradation. Thus, FZ201 is a promising candidate for remediating highly PAE-contaminated environments. These findings enhance our preliminary understanding of the molecular mechanisms employed by Streptomyces for the removal of PAEs.

Improving key gene expression and di-n-butyl phthalate (DBP) degrading ability in a novel Pseudochrobactrum sp. XF203 by ribosome engineering.

Di-n-butyl phthalate (DBP) is one of the important phthalates detected commonly in soils and crops, posing serious threat to human health. Pseudochrobactrum sp. XF203 (XF203), a new strain related with DBP biodegradation, was first identified from a natural habitat lacking human disturbance. Genomic analysis coupled with gene expression comparison assay revealed this strain harbors the key aromatic ring-cleaving gene catE203 (encoding catechol 2,3-dioxygenase/C23O) involved DBP biodegradation. Following intermediates identification and enzymatic analysis also indicated a C23O dependent DBP lysis pathway in XF203. The gene directed ribosome engineering was operated and to generate a desirable mutant strain XF203R with highest catE203 gene expression level and strong DBP degrading ability. The X203R removed DBP in soil jointly by reassembling bacterial community. These results demonstrate a great value of XF203R for the practical DBP bioremediation application, highlighting the important role of the key gene-directed ribosome engineering in mining multi-pollutants degrading bacteria from natural habitats where various functional genes are well conserved.

Madecassoside alleviates acute kidney injury by regulating JNK-mediated oxidative stress and programmed cell death.

BACKGROUND: Acute kidney injury (AKI) has high morbidity and mortality, which is manifested by inflammation and apoptosis. Effective treatment methods for AKI are currently lacking. OBJECTIVE: This study demonstrated the protecting effects of Madecassoside (MA) in the cisplatin- and hypoxia-reoxygenation-induced renal tubular epithelial cells in vitro and AKI mice in vivo. METHODS: In vivo AKI mouse models were established by inducing them with cisplatin and renal ischemia-reperfusion. In vitro injury models of mouse renal tubular epithelial cells were established by inducing them with cisplatin and hypoxia and reoxygenation, respectively. The mechanism of MA effects was further explored using molecular docking and RNA-sequencing. RESULTS: MA could significantly reduce kidney injury in the cisplatin-and renal ischemia-reperfusion (IRI)-induced AKI. Further validation in the two cellular models also showed that MA had protect effects. MA can alleviate AKI in vitro and in vivo by inhibiting inflammation, cell apoptosis, and oxidative stress. MA exhibited high permeability across the Caco-2 cell, can enter cells directly. Through RNA-seq and molecular docking analysis, this study further demonstrated that MA inhibits its activity by directly binding to JNK kinase, thereby inhibiting c-JUN mediated cell apoptosis and improving AKI. In addition, MA has better renal protective effects compared to curcumin and JNK inhibitor SP600125. CONCLUSION: The results demonstrate that MA might be a potential drug for the treatment of AKI and act through the JNK/c-JUN signaling pathway.

[Substrate specificity of 3-hydroxypicolinic acid unit in the viridogrisein biosynthetic pathway].

OBJECTIVE: To explore the role of sgvS in the biosynthesis of 3-hydroxypicolinic acid moiety of viridogrsein, and to analyze the substrate specificity of 3-hydroxypicolinic acid moiety in the viridogrsein biosynthetic pathway. METHODS: Through gene insertion inactivation and in trans complementation strategies, we obtained the gene inactivation mutant sgvS andits complementation mutant deltasgvS :: sgvS. Meanwhile, we fed 3-hydroxypicolinic acid, picolinic acid, 2-piperidinecarboxylic acid, 3-chloropyridinecarboxylic acid, 4-chloropyridinecarboxylic acid, 3,5-chloropyridinecarboxylic acid, nicotinic acid, 2-chloronicotinic acid, 2-fluoronicotinic acid acid, 5-fluoronicotinic acid and 6-fluoronicotinic acid to the sgvS mutant, respectively. The fermentation extracts were analyzed by HPLC. RESULTS: sgvS mutant abolished the viridogrsein production; viridogrsein production was restored through in trans complementation of sgvS mutant or by feeding 3-hydroxypicolinic acid to the sgvS mutant. No new viridogrsein analogues were observed by feeding other above mentioned 3-hydroxypicolinic acid analogues tothe deltasgvS mutant. CONCLUSION: sgvS is necessary for the biosynthesis of 3-hydroxypicolinic acid moiety. The biosynthetic protein, SgvD1, activates 3-hydroxypicolinic acid, showing strict substrate specificity en route to the viridogrsein biosynthesis.