Vacancy Engineering in 2D Transition Metal Chalcogenide Photocatalyst: Structure Modulation, Function and Synergy Application.

Transition metal chalcogenides (TMCs) are widely used in photocatalytic fields such as hydrogen evolution, nitrogen fixation, and pollutant degradation due to their suitable bandgaps, tunable electronic and optical properties, and strong reducing ability. The unique 2D malleability structure provides a pre-designed platform for customizable structures. The introduction of vacancy engineering makes up for the shortcomings of photocorrosion and limited light response and provides the greatest support for TMCs in terms of kinetics and thermodynamics in photocatalysis. This work reviews the effect of vacancy engineering on photocatalytic performance based on 2D semiconductor TMCs. The characteristics of vacancy introduction strategies are summarized, and the development of photocatalysis of vacancy engineering TMCs materials in energy conversion, degradation, and biological applications is reviewed. The contribution of vacancies in the optical range and charge transfer kinetics is also discussed from the perspective of structure manipulation. Vacancy engineering not only controls and optimizes the structure of the TMCs, but also improves the optical properties, charge transfer, and surface properties. The synergies between TMCs vacancy engineering and atomic doping, other vacancies, and heterojunction composite techniques are discussed in detail, followed by a summary of current trends and potential for expansion.

Systematic tracking of nitrogen sources in complex river catchments: Machine learning approach based on microbial metagenomics.

Tracking nitrogen pollution sources is crucial for the effective management of water quality; however, it is a challenging task due to the complex contaminative scenarios in the freshwater systems. The contaminative pattern variations can induce quick responses of aquatic microorganisms, making them sensitive indicators of pollution origins. In this study, the soil and water assessment tool, accompanied by a detailed pollution source database, was used to detect the main nitrogen pollution sources in each sub-basin of the Liuyang River watershed. Thus, each sub-basin was assigned to a known class according to SWAT outputs, including point source pollution-dominated area, crop cultivation pollution-dominated area, and the septic tank pollution-dominated area. Based on these outputs, the random forest (RF) model was developed to predict the main pollution sources from different river ecosystems using a series of input variable groups (e.g., natural macroscopic characteristics, river physicochemical properties, 16S rRNA microbial taxonomic composition, microbial metagenomic data containing taxonomic and functional information, and their combination). The accuracy and the Kappa coefficient were used as the performance metrics for the RF model. Compared with the prediction performance among all the input variable groups, the prediction performance of the RF model was significantly improved using metagenomic indices as inputs. Among the metagenomic data-based models, the combination of the taxonomic information with functional information of all the species achieved the highest accuracy (0.84) and increased median Kappa coefficient (0.70). Feature importance analysis was used to identify key features that could serve as indicators for sudden pollution accidents and contribute to the overall function of the river system. The bacteria Rhabdochromatium marinum, Frankia, Actinomycetia, and Competibacteraceae were the most important species, whose mean decrease Gini indices were 0.0023, 0.0021, 0.0019, and 0.0018, respectively, although their relative abundances ranged only from 0.0004 to 0.1 %. Among the top 30 important variables, functional variables constituted more than half, demonstrating the remarkable variation in the microbial functions among sites with distinct pollution sources and the key role of functionality in predicting pollution sources. Many functional indicators related to the metabolism of Mycobacterium tuberculosis, such as K24693, K25621, K16048, and K14952, emerged as significant important factors in distinguishing nitrogen pollution origins. With the shortage of pollution source data in developing regions, this suggested approach offers an economical, quick, and accurate solution to locate the origins of water nitrogen pollution using the metagenomic data of microbial communities.

Evaluation of the effects of three different processing methods of aconite on rat metabolites based on high-coverage pseudotargeted metabolomics.

Aconite is the processed product of the seed root of Aconitum carmichaelii Debx. Aconite is a commonly used traditional Chinese medicine, which is generally used after processing. Black aconite, light aconite, and salted aconite are three different processed aconite products. They have the effects of restoring yang and saving energy enemy, dispersing cold, and relieving pain. However, clinical aconite poisoning cases have frequently been reported. In our study, we investigated the effects of three different processed aconite products on the changes of metabolites in vivo. A total of 42 rats were randomly divided into seven groups with six rats in each group. After three consecutive days of intragastric administration of 2.7 g/kg of the aconite-processed product, rat serums were obtained. The rat metabolites were detected using liquid chromatography-tandem mass spectrometry. The altered metabolites related to aconite-processed products were discovered by statistical analysis using metaboanalyst software. Our study is the first time to comprehensively evaluate the effects of three different processed aconite products on rat metabolites based on pseudotargeted metabolomics.

Oral magnesium prevents acetaminophen-induced acute liver injury by modulating microbial metabolism.

Acetaminophen overuse is a common cause of acute liver failure (ALF). During ALF, toxins are metabolized by enzymes such as CYP2E1 and transformed into reactive species, leading to oxidative damage and liver failure. Here, we found that oral magnesium (Mg) alleviated acetaminophen-induced ALF through metabolic changes in gut microbiota that inhibit CYP2E1. The gut microbiota from Mg-supplemented humans prevented acetaminophen-induced ALF in mice. Mg exposure modulated Bifidobacterium metabolism and enriched indole-3-carboxylic acid (I3C) levels. Formate C-acetyltransferase (pflB) was identified as a key Bifidobacterium enzyme involved in I3C generation. Accordingly, a Bifidobacterium pflB knockout showed diminished I3C generation and reduced the beneficial effects of Mg. Conversely, treatment with I3C or an engineered bacteria overexpressing Bifidobacterium pflB protected against ALF. Mechanistically, I3C bound and inactivated CYP2E1, thus suppressing formation of harmful reactive intermediates and diminishing hepatocyte oxidative damage. These findings highlight how interactions between Mg and gut microbiota may help combat ALF.

An engineered Escherichia coli Nissle strain prevents lethal liver injury in a mouse model of tyrosinemia type 1.

BACKGROUND & AIMS: Hereditary tyrosinemia type 1 (HT1) results from the loss of fumarylacetoacetate hydrolase (FAH) activity and can lead to lethal liver injury. Therapeutic options for HT1 remain limited. In this study, we aimed to construct an engineered bacterium capable of reprogramming host metabolism and thereby provide a potential alternative approach for the treatment of HT1. METHODS: Escherichia coli Nissle 1917 (EcN) was engineered to express genes involved in tyrosine metabolism in the anoxic conditions that are characteristic of the intestine (EcN-HT). Bodyweight, survival rate, plasma (tyrosine/liver function), H&E staining and RNA sequencing were used to assess its ability to degrade tyrosine and protect against lethal liver injury in Fah-knockout (KO) mice, a well-accepted model of HT1. RESULTS: EcN-HT consumed tyrosine and produced L-DOPA (levodopa) in an in vitro system. Importantly, in Fah-KO mice, the oral administration of EcN-HT enhanced tyrosine degradation, reduced the accumulation of toxic metabolites, and protected against lethal liver injury. RNA sequencing analysis revealed that EcN-HT rescued the global gene expression pattern in the livers of Fah-KO mice, particularly of genes involved in metabolic signaling and liver homeostasis. Moreover, EcN-HT treatment was found to be safe and well-tolerated in the mouse intestine. CONCLUSIONS: This is the first report of an engineered live bacterium that can degrade tyrosine and alleviate lethal liver injury in mice with HT1. EcN-HT represents a novel engineered probiotic with the potential to treat this condition. IMPACT AND IMPLICATIONS: Patients with hereditary tyrosinemia type 1 (HT1) are characterized by an inability to metabolize tyrosine normally and suffer from liver failure, renal dysfunction, neurological impairments, and cancer. Given the overlap and complementarity between the host and microbial metabolic pathways, the gut microbiome provides a potential chance to regulate host metabolism through degradation of tyrosine and reduction of byproducts that might be toxic. Herein, we demonstrated that an engineered live bacterium, EcN-HT, could enhance tyrosine breakdown, reduce the accumulation of toxic tyrosine byproducts, and protect against lethal liver injury in Fah-knockout mice. These findings suggested that engineered live biotherapeutics that can degrade tyrosine in the gut may represent a viable and safe strategy for the prevention of lethal liver injury in HT1 as well as the mitigation of its associated pathologies.

Aggregation behavior of polystyrene nanoplastics: Role of surface functional groups and protein and electrolyte variation.

Aggregation kinetics of plastics are affected by the surface functional groups and exposure orders (electrolyte and protein) with kinds of mechanisms in aquatic environment. This study investigates the aggregation of polystyrene nanoplastics (PSNPs) with varying surface functional groups in the presence of common electrolytes (NaCl, CaCl2, Na2SO4) and bovine serum albumin (BSA). It also examines the impact of different exposure orders, namely BSA + NaCl (adding them together), BSA → NaCl (adding BSA firstly and then NaCl), and NaCl → BSA (adding NaCl firstly and then BSA), on PSNPs aggregation. The presence of BSA decreased the critical coagulation concentration in NaCl (CCCNa+) of the non-modified PS-Bare from 222.17 to 142.81 mM (35.72%), but increased that of the carboxyl-modified PS-COOH from 157.34 to 160.03 mM (1.71%). This might be ascribed to the thicker absorbed layer of BSA onto the PS-Bare surface, known from Ohshima's soft particle theory. Their aggregation in CaCl2 was both increased because of Ca2+ bridging. Different from the monotonous effects of BSA on PS-Bare and PS-COOH, BSA initially facilitated PS-NH2 aggregation via patch-charge attraction, then inhibited it at higher salt levels through steric repulsion. Furthermore, exposure orders had no significant effect on PS-Bare and PS-COOH, but had a NaCl concentration-dependent impact on PS-NH2. At the low NaCl concentrations (10 and 100 mM), no obvious influence could be observed. While, at 300 mM NaCl, the high concentrations of BSA could not totally stabilize the salt-induced aggregates in NaCl → BSA, but could achieve it in the other two orders. These might be attributed to the electrical double layer compression by NaCl, "patch-charge" force and steric hindrance by BSA. These experimental findings shed light on the potential fate and transport of nanoparticles in aquatic environments.

Quinary RuRhPdPtAu high-entropy alloy as an efficient electrocatalyst for the hydrogen evolution reaction.

Quinary RuRhPdPtAu high-entropy alloy nanoparticles (HEA-NPs) were prepared for the first time from a deep eutectic solvent by an electrochemical method. Owing to the benefits of high entropy and abundant surface active sites, the RuRhPdPtAu HEA-NPs exhibit outstanding electrocatalytic performance for the hydrogen evolution reaction.

Engineering RsDddA as mitochondrial base editor with wide target compatibility and enhanced activity.

Double-stranded DNA-specific cytidine deaminase (DddA) base editors hold great promise for applications in bio-medical research, medicine, and biotechnology. Strict sequence preference on spacing region presents a challenge for DddA editors to reach their full potential. To overcome this sequence-context constraint, we analyzed a protein dataset and identified a novel DddAtox homolog from Ruminococcus sp. AF17-6 (RsDddA). We engineered RsDddA for mitochondrial base editing in a mammalian cell line and demonstrated RsDddA-derived cytosine base editors (RsDdCBE) offered a broadened NC sequence compatibility and exhibited robust editing efficiency. Moreover, our results suggest the average frequencies of mitochondrial genome-wide off-target editing arising from RsDdCBE are comparable to canonical DdCBE and its variants.

Sonochemically assisted the synthesis and catalytic application of bismuth-based photocatalyst: A mini review.

Recently, bismuth (Bi)-based photocatalysts have been a well-deserved hotspot in the field of photocatalysis owning to their photoelectrochemical properties driven by the distortion of the Bi 6 s orbital, while their narrow band gap and poor quantum efficiency still restrict their application. With the development of ultrasonic technology, it is expected to become a broom to clear the application obstacles of Bi-based photocatalysts. The special forces and environmental conditions brought by ultrasonic irradiation play beneficial roles in the preparation, modification and performance releasement of Bi-based photocatalysts. In this review, the role and influencing factors of ultrasound in the preparation and modification of Bi-based photocatalysts were introduced. Crucially, the mechanism of the improving the performance for various types of Bi-based photocatalysts by ultrasound in the whole process of photocatalysis was deeply analyzed. Then, the application of ultrasonic synergistic Bi-based photocatalysts in contaminants treatment and energy conversion was briefly introduced. Finally, based on an unambiguous understanding of ultrasonic technology in assisting Bi-based photocatalysts, the future directions and possibilities for ultrasonic synergistic Bi-based photocatalysts are explored.

Virus Infection and mRNA Nuclear Export.

Gene expression in eukaryotes begins with transcription in the nucleus, followed by the synthesis of messenger RNA (mRNA), which is then exported to the cytoplasm for its translation into proteins. Along with transcription and translation, mRNA export through the nuclear pore complex (NPC) is an essential regulatory step in eukaryotic gene expression. Multiple factors regulate mRNA export and hence gene expression. Interestingly, proteins from certain types of viruses interact with these factors in infected cells, and such an interaction interferes with the mRNA export of the host cell in favor of viral RNA export. Thus, these viruses hijack the host mRNA nuclear export mechanism, leading to a reduction in host gene expression and the downregulation of immune/antiviral responses. On the other hand, the viral mRNAs successfully evade the host surveillance system and are efficiently exported from the nucleus to the cytoplasm for translation, which enables the continuation of the virus life cycle. Here, we present this review to summarize the mechanisms by which viruses suppress host mRNA nuclear export during infection, as well as the key strategies that viruses use to facilitate their mRNA nuclear export. These studies have revealed new potential antivirals that may be used to inhibit viral mRNA transport and enhance host mRNA nuclear export, thereby promoting host gene expression and immune responses.

SHIP1 modulates antimalarial immunity by bridging the crosstalk between type I IFN signaling and autophagy.

Stringent control of the type I interferon (IFN-I) signaling is critical for host immune defense against infectious diseases, yet the molecular mechanisms that regulate this pathway remain elusive. Here, we show that Src homology 2 containing inositol phosphatase 1 (SHIP1) suppresses IFN-I signaling by promoting IRF3 degradation during malaria infection. Genetic ablation of Ship1 in mice leads to high levels of IFN-I and confers resistance to Plasmodium yoelii nigeriensis (P.y.) N67 infection. Mechanistically, SHIP1 promotes the selective autophagic degradation of IRF3 by enhancing K63-linked ubiquitination of IRF3 at lysine 313, which serves as a recognition signal for NDP52-mediated selective autophagic degradation. In addition, SHIP1 is downregulated by IFN-I-induced miR-155-5p upon P.y. N67 infection and severs as a feedback loop of the signaling crosstalk. This study reveals a regulatory mechanism between IFN-I signaling and autophagy, and verifies SHIP1 can be a potential target for therapeutic intervention against malaria and other infectious diseases. IMPORTANCE Malaria remains a serious disease affecting millions of people worldwide. Malaria parasite infection triggers tightly controlled type I interferon (IFN-I) signaling that plays a critical role in host innate immunity; however, the molecular mechanisms underlying the immune responses are still elusive. Here, we discover a host gene [Src homology 2-containing inositol phosphatase 1 (SHIP1)] that can regulate IFN-I signaling by modulating NDP52-mediated selective autophagic degradation of IRF3 and significantly affect parasitemia and resistance of Plasmodium-infected mice. This study identifies SHIP1 as a potential target for immunotherapies in malaria and highlights the crosstalk between IFN-I signaling and autophagy in preventing related infectious diseases. SHIP1 functions as a negative regulator during malaria infection by targeting IRF3 for autophagic degradation.

A prime editor efficiently repaired human induced pluripotent stem cells with AR gene mutation (c.2710G > A; p. V904M).

Prime Editor (PE) is a precise genome manipulation technology based on the CRISPR-Cas9 system, while its application in human induced pluripotent stem cells (iPSCs) remains limited. Here, we established a repaired hiPS cell line (SKLRMi001-A-1) from hiPSCs with androgen receptor (AR) mutation (c.2710G > A; p.V904M). The repaired iPSC line expressed pluripotency markers, retained normal karyotype, showed the capability of differentiating into three germ layers and was absence of mycoplasma infection. The repaired iPSC line will help to elucidate the mechanism of androgen insensitivity syndrome (AIS) and benefit treatment for AIS in the future.

Effectiveness of Pentavalent Rotavirus Vaccine in Shanghai, China: A Test-Negative Design Study.

OBJECTIVE: To evaluate vaccine effectiveness (VE) of a live oral pentavalent rotavirus vaccine (RotaTeq, RV5) among young children in Shanghai, China, via a test-negative design study. STUDY DESIGN: We consecutively recruited children visiting a tertiary children's hospital for acute diarrhea from November 2021 to February 2022. Information on clinical data and rotavirus vaccination was collected. Fresh fecal samples were obtained for rotavirus detection and genotyping. To evaluate VE of RV5 against rotavirus gastroenteritis among young children, unconditional logistic regression models were conducted to compare ORs for vaccination between rotavirus-positive cases and test-negative controls. RESULTS: A total of 390 eligible children with acute diarrhea were enrolled, including 45 (11.54%) rotavirus-positive cases and 345 (88.46%) test-negative controls. After excluding 4 cases (8.89%) and 55 controls (15.94%) who had received the Lanzhou lamb rotavirus vaccine, 41 cases (12.39%) and 290 controls (87.61%) were included for the evaluation of RV5 VE. After adjustment for potential confounders, the 3-dose RV5 vaccination showed 85% (95% CI, 50%-95%) VE against mild to moderate rotavirus gastroenteritis among children aged 14 weeks to ≤4 years and 97% (95% CI, 83%-100%) VE among children aged 14 weeks to ≤2 years with genotypes G8P8, G9P8, and G2P4 represented 78.95%, 18.42%, and 2.63% of circulation strains, respectively. CONCLUSIONS: A 3-dose vaccination of RV5 is highly protective against rotavirus gastroenteritis among young children in Shanghai. The G8P8 genotype prevailled in Shanghai after RV5 introduction.

Structure Modification of Ginsenoside Rh2 and Cytostatic Activity on Cancer Cells.

Ginsenoside Rh2 (Rh2) is one of the most effective anticancer components extracted from red ginseng, but the poor solubility limits its clinical application. In this paper, ginsenoside Rh2 was modified with maleimidocaproic acid or maleimidoundecanoic acid with functional groups at both ends. The structures of derivatives were determined by analysis of 1D and 2D nuclear magnetic resonance, Fourier transform infrared, and high-resolution mass spectrometry. Antiproliferative cell experiments showed that Rh2 modified with maleimidocaproic acid (C-Rh2) displayed higher cytostatic activity against different tumor cells compared with Rh2, while Rh2 modified with maleimidoundecanoic acid (U-Rh2) did not exhibit obvious cytotoxicity. The results suggest that the length of the spacer arm may play an important role in the cytostatic activity of the Rh2 derivatives.

Mussel-inspired magnetic adsorbent MnO2/PDA@Fe3O4 for removing heavy metal ions contaminants in single and mixed systems.

Heavy metal pollution has been a magnificent concern for a long period. A novel magnetic material, MnO2/PDA@Fe3O4, was prepared in this paper. With the assistance of multiple characterization methods, it was confirmed that polydopamine coated the magnetic nucleus and acted as a dense intermediate layer for MnO2 attachment. Having superior adsorption performance, MnO2/PDA@Fe3O4 could remove heavy metal cations efficiently no matter in single or mixed systems. The maximum adsorption capacities calculated by the Langmuir model for Pb(II), Cu(II), and Cd(II) were 295.01 mg/g, 130.30 mg/g, and 115.16 mg/g, respectively. In mixed systems, the adsorbent showed obvious selectivity for Pb(II). And the variation of Cu(II) concentration was more responsible for Pb(II) adsorption than that of Cd(II). The kinetic and thermodynamic data revealed that the polluted ions immobilizations by MnO2/PDA@Fe3O4 were chemisorption and were endothermic, entropy increase, spontaneous process. The presence of humic acid and coexisting ions induced only a very limited interference. In addition, MnO2/PDA@Fe3O4 maintained excellent adsorption performance and stability after five cycles of adsorption and removed 98.33% Pb(II) and 71.24% Cu(II) from actual water, respectively. This study confirmed that the MnO2/PDA@Fe3O4 had great potential and broad prospects to remediate the heavy metal contaminants in water.

The aggregation of natural inorganic colloids in aqueous environment: A review.

Natural inorganic colloids (NICs) are the most common and dominant existence in the ecosystem, with high concentration and wide variety. In spite of the low toxicity, they can alter activity and mobility of hazardous engineered nanoparticles (ENPs) through different interactions, which warrants the necessity to understand and predict the fate and transport of NICs in aquatic ecosystems. Here, this review summarized NICs properties and behaviors, interaction mechanisms and environmental factors at the first time. Various representative NICs and their physicochemical properties were introduced across the board. Then, the aggregation and sedimentation behaviors were discussed systematically, mainly concerning the heteroaggregation between NICs and ENPs. To speculate their fate and elucidate the corresponding mechanisms, the classical Derjaguin-Landau-Verwey-Overbeek (DLVO) and extended DLVO (X-DLVO) theories were focused. Furthermore, a range of intrinsic and extrinsic factors was presented in different perspective. Last but not the least, this paper pointed out theoretical and analytical gaps in current researches, and put forward suggestions for further research, aiming to provide a more comprehensive and original perspective in the fields of natural occurring colloids.

Sertraline Is an Effective SARS-CoV-2 Entry Inhibitor Targeting the Spike Protein.

The global spread of the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the continuously emerging new variants underscore an urgent need for effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). Here, we screened several FDA-approved amphiphilic drugs and determined that sertraline (SRT) exhibits potent antiviral activity against infection of SARS-CoV-2 pseudovirus (PsV) and authentic virus in vitro. It effectively inhibits SARS-CoV-2 spike (S)-mediated cell-cell fusion. SRT targets the early stage of viral entry. It can bind to the S1 subunit of the S protein, especially the receptor binding domain (RBD), thus blocking S-hACE2 interaction and interfering with the proteolysis process of S protein. SRT is also effective against infection with SARS-CoV-2 PsV variants, including the newly emerging Omicron. The combination of SRT and other antivirals exhibits a strong synergistic effect against infection of SARS-CoV-2 PsV. The antiviral activity of SRT is independent of serotonin transporter expression. Moreover, SRT effectively inhibits infection of SARS-CoV-2 PsV and alleviates the inflammation process and lung pathological alterations in transduced mice in vivo. Therefore, SRT shows promise as a treatment option for COVID-19. IMPORTANCE The study shows SRT is an effective entry inhibitor against infection of SARS-CoV-2, which is currently prevalent globally. SRT targets the S protein of SARS-CoV-2 and is effective against a panel of SARS-CoV-2 variants. It also could be used in combination to prevent SARS-CoV-2 infection. More importantly, with long history of clinical use and proven safety, SRT might be particularly suitable to treat infection of SARS-CoV-2 in the central nervous system and optimized for treatment in older people, pregnant women, and COVID-19 patients with heart complications, which are associated with severity and mortality of COVID-19.

The Pseudotargeted Metabolomics Study on the Toxicity of Fuzi Using Ultraperformance Liquid Chromatography Tandem Mass Spectrometry.

Fuzi is commonly used in traditional Chinese medicine. Clinical Fuzi poisoning cases have frequently been reported. Glycyrrhizae Radix is often used to alleviate Fuzi's toxicity. However, the poisoning mechanism of Fuzi and the detoxication mechanism of Glycyrrhizae Radix are still not clear. We identified the chemical components of Fuzi at different decoction times (0.5, 1, 2, 4, and 6 h) using ultrahigh performance liquid chromatography quadrupole time-of-flight mass spectrometry. A total of 35 compounds were detected in the Fuzi decoction, including diester alkaloids, monoester alkaloids, amino acids, phenolic acids, organic acids, glycosides, and sugars among others. The content of diester alkaloids (i.e., subaconitine, neoaconitine, and aconitine) in the Fuzi decoction decreased after 2 h of decoction time, while the content of monoester alkaloids (i.e., benzoyl aconitine and benzoyl subaconitine) reached a peak at 2 h. A total of 32 rats were randomly divided into four groups, including 8 cases in the low-dosage Fuzi decoction group A, 8 cases in the high-dosage Fuzi decoction group B, 8 cases in the Fuzi and glycyrrhizae decoction group C, and 8 cases in the control group D. The decoction was administered orally for 7 days. Then, a serum was obtained. The metabolites' changes were analyzed in serum metabolomics using liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Statistical analysis and pathway analysis were used to assess the effects of glycyrrhizae on the metabolic changes induced by Fuzi. The behavioral and biochemical characteristics indicated that Fuzi exhibited toxic effects on rats and their metabolic profiles changed. However, the metabolic profiles of the glycyrrhizae group became similar to those of the control group. These profiles showed that glycyrrhizae can effectively improve Fuzi poisoning rats. Our study demonstrated that the established pseudotargeted metabolomics is a powerful approach for investigating the mechanisms of herbal toxicity.

Discovery of novel benzbromarone analogs with improved pharmacokinetics and benign toxicity profiles as antihyperuricemic agents.

Benzbromarone (BM) is a potent URAT1 inhibitor approved for the treatment of gout. However, the low URAT1-selectivity and hepatotoxcity limit its clinical use. To solve these problems, we rationally designed and synthesized a series of BM derivatives by chemotype hybridization and bioisosteric replacement. Most compounds exhibited potent inhibitory activities against URAT1 with IC50 values ranging from 5.83 µM to 0.80 µM. Among them, JNS4 exhibited the highest URAT1 inhibitory activity with an IC50 of 0.80 µM, comparable to that of BM (IC50 = 0.53 µM). Molecular dynamic simulations showed that JNS4 formed π-cation interaction with R477, the same as BM. Different from BM, JNS4 bound to W357 and H245 via π-π interactions and formed a hydrogen bond with S35, which might contribute to the high URAT1 binding affinity of JNS4. JNS4 hardly inhibited GLUT9 (IC50 > 20 µM), another urate reabsorption transporter. In addition, JNS4 showed little inhibitory effects against OAT1 and ABCG2 with IC50 of 4.04 µM and 10.16 µM, respectively. Importantly, JNS4 displayed higher in vivo urate-lowering effects at doses of 1-4 mg/kg in a mouse model of hyperuricemia, as compared to BM and lesinurad. Furthermore, JNS4 possessed favorable pharmacokinetic properties with an oral bioavailability of 55.28%, significantly higher than that of BM (36.11%). Moreover, JNS4 demonstrated benign toxicity profiles (no cytotoxicities against HepG2 and HK2 cells; no hepatic and renal toxicities observed in vivo). Collectively, these results suggest that JNS4 represents a novel, safe and selective URAT1 inhibitor with excellent druggabilities and is worthy of further investigation as an anti-hyperuricemic agent.