A novel GSK3ß inhibitor 5n attenuates acute kidney injury.

Acute kidney injury (AKI) is a clinical syndrome with high morbidity and mortality caused by various factor. The specific strategies for AKI are still lacking. GSK3ß is widely expressed in the kidneys. In acute models of injury, GSK3ß promotes the systemic inflammatory response, increases the proinflammatory release of cytokines, induces apoptosis, and alters cell proliferation. We screened a series of 3-(4-pyridyl)-5-(4-sulfamido-phenyl)-1,2,4-oxadiazole derivatives which are recognized as new GSK3ß inhibitors, and found that 5n had the least toxicity and the best cell protection. We then tested the anti-inflammatory and reno-protective effect of 5n in cisplatin-treated tubular epithelial cells. 5n had anti-inflammation effect indicated by phosphor-NF-κB detection. Finally, we found that 5n ameliorated renal injury and inflammation in cisplatin-induced AKI mouse model. Silencing GSK3ß inhibited cell injury and inflammation induced by cisplatin. We found that GSK3ß interacted with PP2Ac to modulate the activity of NF-κB. In conclusion, 5n, the novel GSK3ß inhibitor, protects against AKI via PP2Ac-dependent mechanisms which may provide a potential strategy for the treatment of AKI in clinic.

The role of circadian clock in regulating cell functions: implications for diseases.

The circadian clock system orchestrates daily behavioral and physiological rhythms, facilitating adaptation to environmental and internal oscillations. Disruptions in circadian rhythms have been linked to increased susceptibility to various diseases and can exacerbate existing conditions. This review delves into the intricate regulation of diurnal gene expression and cell function by circadian clocks across diverse tissues. . Specifically, we explore the rhythmicity of gene expressions, behaviors, and functions in both immune and non-immune cells, elucidating the regulatory effects and mechanisms imposed by circadian clocks. A detailed discussion is centered on elucidating the complex functions of circadian clocks in regulating key cellular signaling pathways. We further review the circadian regulation in diverse diseases, with a focus on inflammatory diseases, cancers, and systemic diseases. By highlighting the intimate interplay between circadian clocks and diseases, especially through clock-controlled cell function, this review contributes to the development of novel disease intervention strategies. This enhanced understanding holds significant promise for the design of targeted therapies that can exploit the circadian regulation mechanisms for improved treatment efficacy.

Motility and tumor infiltration are key aspects of invariant natural killer T cell anti-tumor function.

Dysfunction of invariant natural killer T (iNKT) cells contributes to immune resistance of tumors. Most mechanistic studies focus on their static functional status before or after activation, not considering motility as an important characteristic for antigen scanning and thus anti-tumor capability. Here we show via intravital imaging, that impaired motility of iNKT cells and their exclusion from tumors both contribute to the diminished anti-tumor iNKT cell response. Mechanistically, CD1d, expressed on macrophages, interferes with tumor infiltration of iNKT cells and iNKT-DC interactions but does not influence their intratumoral motility. VCAM1, expressed by cancer cells, restricts iNKT cell motility and inhibits their antigen scanning and activation by DCs via reducing CDC42 expression. Blocking VCAM1-CD49d signaling improves motility and activation of intratumoral iNKT cells, and consequently augments their anti-tumor function. Interference with macrophage-iNKT cell interactions further enhances the anti-tumor capability of iNKT cells. Thus, our findings provide a direction to enhance the efficacy of iNKT cell-based immunotherapy via motility regulation.

Adsorption Behavior and Kinetics of 1,4-Dioxane by Carbon Aerogel.

1,4-dioxane is a potential carcinogen in water and is difficult to deal with due to its robust cycloether bond and complete miscibility with water. To remove 1,4-dioxane in an economically viable and environmentally friendly way, a series of carbon aerogels were synthesized as adsorbents for 1,4-dioxane. The experiment results showed that adsorption performances were closely related to the preparation conditions of carbon aerogels, such as the molar ratio, heating rate, pyrolysis temperature and residence time, which were carefully controlled. Scanning electron microscope analysis revealed the presence of a three-dimensional porous network structure in carbon aerogels. Brunauer-Emmett-Teller analysis results demonstrated an increase in specific surface area (673.89 m2/g) and total pore volume after carbonization, with an increase in mesoporous porosity and a decrease in microporosity. When considering each variable individually, the highest specific surface area of prepared carbon aerogels was achieved at a pyrolysis temperature of 800 °C, a holding time of 1 h, and a heating rate of 2 °C/min. Under optimal experimental conditions, the adsorption removal of 1,4-dioxane by carbon aerogels exceeded 95%, following quasi-second-order kinetics and Langmuir isothermal adsorption isotherms, indicating that monolayer adsorption on the surface of carbon aerogels occurred. The maximum adsorption capacity obtained was 67.28 mg/g at a temperature of 318 K, which was attributed to the presence of a large proportion of mesopores and abundant micropores simultaneously in carbon aerogels. Furthermore, with the interference of chlorinated solvents such as trichloroethylene (TCE), the removal efficiency of 1,4-dioxane had no obvious inhibition effect. Regeneration experiments showed that after five continuous cycles, the carbon aerogels still kept a comparable adsorption capacity, which illustrates its potential application in 1,4-dioxane-polluted water purification.

DNA barcoding of the genus Gampsocleis (Orthoptera, Tettigoniidae) from China.

DNA barcoding is a useful addition to the traditional morphology-based taxonomy. A ca. 650 bp fragment of the 5' end of mitochondrial cytochrome c oxidase subunit I (hereafter COI-5P) DNA barcoding was sued as a practical tool for Gampsocleis species identification. DNA barcodes from 889 specimens belonging to 8 putative Gampsocleis species was analyzed, including 687 newly generated DNA barcodes. These barcode sequences were clustered/grouped into Operational Taxonomic Units (OTUs) using the criteria of five algorithms, namely Barcode Index Number (BIN) System, Assemble Species by Automatic Partitioning (ASAP), a Java program uses an explicit, determinate algorithm to define Molecular Operational Taxonomic Unit (jMOTU), Generalized Mixed Yule Coalescent (GMYC), and Bayesian implementation of the Poisson Tree Processes model (bPTP). The Taxon ID Tree grouped sequences of morphospecies and almost all MOTUs in distinct nonoverlapping clusters. Both long- and short-winged Gampsocleis species are reciprocally monophyletic in the Taxon ID Tree. In BOLD, 889 barcode sequences are assigned to 17 BINs. The algorithms ASAP, jMOTU, bPTP and GMYC clustered the barcode sequences into 6, 13, 10, and 23 MOTUs, respectively. BIN, ASAP, and bPTP algorithm placed three long-winged species, G. sedakovii, G. sinensis and G. ussuriensis within the same MOTU. All species delimitation algorithms split two short-winged species,G. fletcheri and G. gratiosa into at least two MOTUs each, except for ASAP algorithm. More detailed molecular and morphological integrative studies are required to clarify the status of these MOTUs in the future.

Aflibercept Loaded Eye-Drop Hydrogel Mediated with Cell-Penetrating Peptide for Corneal Neovascularization Treatment.

Corneal neovascularization (CoNV) is a major cause of visual impairment worldwide. Currently, available treatment options have limited efficacy and are associated with adverse effects due to biological barriers and clearance mechanisms. To address this challenge, a novel topical delivery system is developed-Gel 2_1&Eylea-an aflibercept-loaded eye-drop hydrogel mediated with cell-penetrating peptide 1. Gel 2_1&Eylea demonstrates superior membrane permeability, increased stability, and prolonged drug retention time on the ocular surface, and thus may improve drug efficacy. In a rabbit CoNV model, Gel 2_1&Eylea significantly reduces the density of neovascularization with no adverse effects on normal corneoscleral limbal vessels, demonstrating high efficacy and biocompatibility. This work identifies a promising treatment for CoNV which has the potential to benefit other ocular neovascular diseases.

Vaccarin alleviates cisplatin-induced acute kidney injury via decreasing NOX4-derived ROS.

Cisplatin is a chemotherapeutant widely used in treating solid tumors, with the common side effect of acute kidney injury (AKI). Developing effective useful agent for preventing or treating cisplatin-induced AKI is of great importance. In this study, we investigate the protective effect of vaccarin, a chemical entity of flavonoid glycoside, against cisplatin-induced AKI. Cisplatin-treated C57BL/6J mice and human kidney-2 (HK-2) cells were used as the model of cisplatin-induced AKI. The levels of blood urea nitrogen (BUN) and creatine (Cr) levels and periodic acid-Schiff staining (PAS) scores decreased when vaccarin was administrated. Vaccarin had no impact on renal platinum accumulation, which was detected by the ICP-MS 6 h after cisplatin injection. Moreover, vaccarin can significantly alleviate the product of reactive oxygen species and the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) in cisplatin-induced AKI, both in vivo and in vitro. In addition, vaccarin decreased the receptor-interacting protein kinase 1 (RIPK1) related programmed necrosis (necroptosis), cell apoptosis (shown by the protein levels of cleaved-caspase3 and flow cytometry) and inflammation (shown by the decreased levels of NLRP3, p-P65 and the mRNA of several inflammatory factors). NOX4 inhibitor GLX351322 (GLX) and NOX4 kowndown by siRNA have equivalent protective effect of vaccarin in vitro. When vaccarin was administered together with GLX or NOX4 siRNA, this protective effect of vaccarin did not further increase, as indicating by the index of oxidative stress, cell viability, necroptosis and apoptosis. In conclusion, vaccarin can alleviate cisplatin-induced AKI via inhibiting NOX4.

Activation and Denitrosylation of Procaspase-3 in KA-induced Excitotoxicity.

BACKGROUND: It has been reported that activation of glutamate kainate receptor subunit 2 (GluK2) subunit-containing glutamate receptors and the following Fas ligand(FasL) up-regulation, caspase-3 activation, result in delayed apoptosis-like neuronal death in hippocampus CA1 subfield after cerebral ischemia and reperfusion. Nitric oxide-mediated S-nitrosylation might inhibit the procaspase activation, whereas denitrosylation might contribute to cleavage and activation of procaspases. OBJECTIVES: The study aimed to elucidate the molecular mechanisms underlying procaspase-3 denitrosylation and activation following kainic acid (KA)-induced excitotoxicity in rat hippocampus. METHODS: S-nitrosylation of procaspase-3 was detected by biotin-switch method. Activation of procaspase-3 was shown as cleavage of procaspase-3 detected by immunoblotting. FasL expression was detected by immunoblotting. Cresyl violets and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining were used to detect apoptosis-like neuronal death in rat hippocampal CA1 and CA3 subfields. RESULTS: KA led to the activation of procaspase-3 in a dose- and time-dependent manner, and the activation was inhibited by KA receptor antagonist NS102. Procaspase-3 was denitrosylated at 3 h after kainic acid administration, and the denitrosylation was reversed by SNP and GSNO. FasL ASODNs inhibited the procaspase-3 denitrosylation and activation. Moreover, thioredoxin reductase (TrxR) inhibitor auranofin prevented the denitrosylation and activation of procaspase-3 in rat hippocampal CA1 and CA3 subfields. NS102, FasL AS-ODNs, and auranofin reversed the KAinduced apoptosis and cell death in hippocampal CA1 and CA3 subfields. CONCLUSIONS: KA led to denitrosylation and activation of procaspase-3 via FasL and TrxR. Inhibition of procaspase-3 denitrosylation by auranofin, SNP, and GSNO played protective effects against KA-induced apoptosis-like neuronal death in rat hippocampal CA1 and CA3 subfields. These investigations revealed that the procaspase-3 undergoes an initial denitrosylation process before becoming activated, providing valuable insights into the underlying mechanisms and possible treatment of excitotoxicity.

Two-dimensional materials for high density, safe and robust metal anodes batteries.

With a high specific capacity and low electrochemical potentials, metal anode batteries that use lithium, sodium and zinc metal anodes, have gained great research interest in recent years, as a potential candidate for high-energy-density storage systems. However, the uncontainable dendrite growth during the repeated charging process, deteriorates the battery performance, reduces the battery life and more importantly, raises safety concerns. With their unique properties, two-dimensional (2D) materials, can be used to modify various components in metal batteries, eventually mitigating the dendrite growth, enhancing the cycling stability and rate capability, thus leading to safe and robust metal anodes. In this paper, we review the recent advances of 2D materials and summarize current research progress of using 2D materials in the applications of (i) anode design, (ii) separator engineering, and (iii) electrolyte modifications by guiding metal ion nucleation, increasing ion conductivity, homogenizing the electric field and ion flux, and enhancing the mechanical strength for safe metal anodes. The 2D material modifications provide the ultimate solution for obtaining dendrite-free metal anodes, realizes the high energy storage application, and indicates the importance of 2D materials development. Finally, in-depth understandings of subsequent metal growth are lacking due to research limitations, while more advanced characterizations are welcome for investigating the metal deposition mechanism. The more facile and simplified preparation of 2D materials possess great prospects in high energy density metal anode batteries, and thus fulfils the development of EVs.

HIVEP3 inhibits fate decision of CD8+ invariant NKT cells after positive selection.

CD8+ invariant natural killer T (iNKT) cells are functionally different from other iNKT cells and are enriched in human but not in mouse. To date, their developmental pathway and molecular basis for fate decision remain unclear. Here, we report enrichment of CD8+ iNKT cells in neonatal mice due to their more rapid maturation kinetics than CD8- iNKT cells. Along developmental trajectories, CD8+ and CD8- iNKT cells separate at stage 0, following stage 0 double-positive iNKT cells, and differ in HIVEP3 expression. HIVEP3 is lowly expressed in stage 0 CD8+ iNKT cells and negatively controls their development, whereas it is highly expressed in stage 0 CD8- iNKT cells and positively controls their development. Despite no effect on IFN-γ, HIVEP3 inhibits granzyme B but promotes interleukin-4 production in CD8+ iNKT cells. Together, we reveal that, as a negative regulator for CD8+ iNKT fate decision, low expression of HIVEP3 in stage 0 CD8+ iNKT cells favors their development and T helper 1-biased cytokine responses as well as high cytotoxicity.

Carbon Nitride-Based siRNA Vectors with Self-Produced O2 Effects for Targeting Combination Therapy of Liver Fibrosis via HIF-1α-Mediated TGF-ß1/Smad Pathway.

Hypoxia is an important feature, which can upregulate the hypoxia-inducible factor-1α (HIF-1α) expression and promote the activation of hepatic stellate cells (HSCs), leading to liver fibrosis. Currently, effective treatment for liver fibrosis is extremely lacking. Herein, a safe and effective method is established to downregulate the expression of HIF-1α in HSCs via targeted delivery of VA-PEG-modified CNs-based nanosheets-encapsulated (VA-PEG-CN@GQDs) HIF-1α small interfering RNA (HIF-1α-siRNA). Due to the presence of lipase in the liver, the reversible release of siRNA can be promoted to complete the transfection process. Simultaneously, VA-PEG-CN@GQD nanosheets enable trigger the water splitting process to produce O2 under near-infrared (NIR) irradiation, thereby improving the hypoxic environment of the liver fibrosis site and maximizing the downregulation of HIF-1α expression to improve the therapeutic effect, as demonstrated in liver fibrosis mice. Such combination therapy can inhibit the activation of HSCs via HIF-1α-mediated TGF-ß1/Smad pathway, achieving outstanding therapeutic effects in liver fibrosis mice. In conclusion, this study proposes a novel strategy for the treatment of liver fibrosis by regulating the hypoxic environment and the expression of HIF-1α at lesion site.

[Expression of antigens of foot-and-mouth disease virus in plants: a review].

Foot-and-mouth disease (FMD) is an acute, severe, and highly contagious infectious disease caused by foot-and-mouth disease virus (FMDV), which seriously endangers the development of animal husbandry. The inactivated FMD vaccine is the main product for the prevention and control of FMD, which has been successfully applied to control the pandemic and outbreak of FMD. However, the inactivated FMD vaccine also has problems, such as the instability of antigen, the risk of spread of the virus due to incomplete inactivation during vaccine production, and the high cost of production. Compared with traditional microbial and animal bioreactors, production of antigens in plants through transgenic technology has some advantages including low cost, safety, convenience, and easy storage and transportation. Moreover, since antigens produced from plants can be directly used as edible vaccines, no complex processes of protein extraction and purification are required. But, there are some problems for the production of antigens in plants, which include low expression level and poor controllability. Thus, expressing the antigens of FMDV in plants may be an alternative mean for production of FMD vaccine, which has certain advantages but still need to be continuously optimized. Here we review the main strategies for expressing active proteins in plants, as well as the research progress on the expression of FMDV antigens in plants. We also discuss the current problems and challenges encountered, with the aim to facilitate related research.

Identification and clinical significance of tsRNAs and miRNAs in PBMCs of treatment-requiring retinopathy of prematurity.

The aim of the study is to reveal the expression profiling and clinical significance of peripheral blood mononuclear cell (PBMC) tRNA-derived small RNAs (tsRNAs) and microRNAs (miRNAs) of premature infants with treatment-requiring retinopathy of prematurity (ROP). Significantly altered tsRNAs and miRNAs were screened using small RNA sequencing. RT-qPCR was used to verify the altered RNAs identified by small RNA transcriptomics. The target genes, their enriched functions, and possibly involved signaling pathways were identified by bioinformatics analyses. According to the small RNA sequencing, 125 tsRNAs and 205 miRNAs were significantly altered in PBMCs obtained from infants with treatment-requiring ROP compared with the premature controls without retinopathy. We preliminarily validated the significant alterations of 6 tsRNAs and 9 miRNAs. The target genes for those tsRNAs were enriched for cellular macromolecule metabolic process, intracellular anatomical structure, transcription regulatory region nucleic acid binding, and Th17 cell differentiation; those of the altered miRNAs were enriched for the developmental process, cell junction, DNA-binding transcription activator activity, and FoxO signaling pathway. By verification with the extended sample size, we identified tsRNAs and miRNAs that could be potential biomarkers with clinical values. The study recognized the alterations and clinical significance of changed tsRNA/miRNA profiles in PBMCs from premature infants with ROP. These significantly altered tsRNAs and miRNAs might be useful as potential diagnostic biomarkers and molecular targets for treatment-requiring ROP.

Fundus image classification using Inception V3 and ResNet-50 for the early diagnostics of fundus diseases.

Purpose: We aim to present effective and computer aided diagnostics in the field of ophthalmology and improve eye health. This study aims to create an automated deep learning based system for categorizing fundus images into three classes: normal, macular degeneration and tessellated fundus for the timely recognition and treatment of diabetic retinopathy and other diseases. Methods: A total of 1,032 fundus images were collected from 516 patients using fundus camera from Health Management Center, Shenzhen University General Hospital Shenzhen University, Shenzhen 518055, Guangdong, China. Then, Inception V3 and ResNet-50 deep learning models are used to classify fundus images into three classes, Normal, Macular degeneration and tessellated fundus for the timely recognition and treatment of fundus diseases. Results: The experimental results show that the effect of model recognition is the best when the Adam is used as optimizer method, the number of iterations is 150, and 0.00 as the learning rate. According to our proposed approach we, achieved the highest accuracy of 93.81% and 91.76% by using ResNet-50 and Inception V3 after fine-tuned and adjusted hyper parameters according to our classification problem. Conclusion: Our research provides a reference to the clinical diagnosis or screening for diabetic retinopathy and other eye diseases. Our suggested computer aided diagnostics framework will prevent incorrect diagnoses caused by the low image quality and individual experience, and other factors. In future implementations, the ophthalmologists can implement more advanced learning algorithms to improve the accuracy of diagnosis.

Hollow mesoporous organosilica nanoparticles reduced graphene oxide based nanosystem for multimodal image-guided photothermal/photodynamic/chemo combinational therapy triggered by near-infrared.

Developing a nanosystem that can perform multimodal imaging-guided combination therapy is highly desirable but challenging. In this study, we introduced multifunctional nanoparticles (NPs) consisting of graphene oxide-grafted hollow mesoporous organosilica loaded with the drug doxorubicin (DOX) and photosensitizers tetraphenylporphyrin (TPP). These NPs were encapsulated by thermosensitive liposomes that release their contents once the temperature exceeds a certain threshold. Metal oxide NPs grown on the graphene oxide (GO) surface served multiple roles, including enhancing photothermal efficiency, acting as contrast agents to improve magnetic resonance imaging, increasing the sensitivity and specificity of photoacoustic imaging, and catalysing hydrogen peroxide for the generation of reactive oxygen species (ROS). When locally injected, the HMONs-rNGO@Fe3 O4 /MnOx@FA/DOX/TPP NPs effectively enriched in subcutaneous Hela cell tumour of mice. The photothermal/photodynamic/chemo combination therapy triggered by near-infrared (NIR) successfully suppressed the tumour without noticeable side effects. This study presented a unique approach to develop multimodal imaging-guided combination therapy for cancer.

m6A modifications of circular RNAs in ischemia-induced retinal neovascularization.

Ischemia-induced pathological neovascularization in the retina is a leading cause of blindness in various age groups. The purpose of the current study was to identify the involvement of circular RNAs (circRNAs) methylated by N6-methyladenosine (m6A), and predict their potential roles in oxygen-induced retinopathy (OIR) in mice. Methylation assessment via microarray analysis indicated that 88 circRNAs were differentially modified by m6A methylation, including 56 hyper-methylated circRNAs and 32 hypo-methylated circRNAs. Gene ontology enrichment analysis predicted that the enriched host genes of the hyper-methylated circRNAs were involved in cellular process, cellular anatomical entity, and protein binding. Host genes of the hypo-methylated circRNAs were enriched in the regulation of cellular biosynthetic process, the nucleus, and binding. According to the Kyoto Encyclopedia of Genes and Genomes analysis, those host genes were involved in the pathways of selenocompound metabolism, salivary secretion, and lysine degradation. MeRIP-qPCR verified significant alterations in m6A methylation levels of mmu_circRNA_33363, mmu_circRNA_002816, and mmu_circRNA_009692. In conclusion, the study revealed the m6A modification alterations in OIR retinas, and the findings above shed light on the potential roles of m6A methylation in circRNA regulatory functions in the pathogenesis of ischemia-induced pathological retinal neovascularization.

Safety, tolerability, and pharmacokinetics of fluoropezil (DC20), a novel acetylcholinesterase inhibitor: A phase I study in healthy young and elderly Chinese subjects.

The present study evaluated the safety, tolerability, and pharmacokinetics of fluoropezil (DC20), a novel acetylcholinesterase inhibitor under development for the treatment of Alzheimer's disease (AD) in otherwise healthy young and elderly Chinese subjects. The study of young subjects included the multiple ascending dose (MAD) arm (2 and 6 mg, N = 24) and the food effect arm (4 mg, N = 12) and was followed by the study of elderly subjects who were given (2 and 4 mg, N = 11). The noncompartmental analysis method was used to determine the pharmacokinetic parameters. The pharmacokinetics of fed versus fasted dose administration in the same subjects was assessed by 90% confidence interval. In the MAD arm, the accumulation ratios of DC20 in vivo were 2.29 and 2.15, respectively. In the food effect arm, compared with fasting administration, an area under the concentration-time curve from zero to t after a standard and high-fat diet orally administered slightly increased by about 19% and 29%, and the time to maximum concentration (Tmax ) was delayed by around 1 h. For elderly study subjects, Tmax was 1.5 and 1.25 h, and terminal half-life (t1/2 ) was 77.1 and 74.2 h, respectively. There were no serious adverse events (AEs), whereas gastrointestinal reactions were the most common AEs associated with the study drug. We predicted the safety risks of DC20 in the clinical treatment of AD, which were well-tolerated by the healthy young and elderly subjects. The elimination of DC20 from the body was slower in elderly subjects than in young subjects. This study was approved by the Center for Drug Evaluation, National Medical Products Administration (CTR20181428, CTR20190664, CTR20191878, and CTR20192724).

scm6A-seq reveals single-cell landscapes of the dynamic m6A during oocyte maturation and early embryonic development.

N6-methyladenosine (m6A) has been demonstrated to regulate RNA metabolism and various biological processes, including gametogenesis and embryogenesis. However, the landscape and function of m6A at single cell resolution have not been extensively studied in mammalian oocytes or during pre-implantation. In this study, we developed a single-cell m6A sequencing (scm6A-seq) method to simultaneously profile the m6A methylome and transcriptome in single oocytes/blastomeres of cleavage-stage embryos. We found that m6A deficiency leads to aberrant RNA clearance and consequent low quality of Mettl3Gdf9 conditional knockout (cKO) oocytes. We further revealed that m6A regulates the translation and stability of modified RNAs in metaphase II (MII) oocytes and during oocyte-to-embryo transition, respectively. Moreover, we observed m6A-dependent asymmetries in the epi-transcriptome between the blastomeres of two-cell embryo. scm6A-seq thus allows in-depth investigation into m6A characteristics and functions, and the findings provide invaluable single-cell resolution resources for delineating the underlying mechanism for gametogenesis and early embryonic development.

Dysregulated hepatic UDP-glucuronosyltransferases and flavonoids glucuronidation in experimental colitis.

Glucuronidation catalyzed by UDP-glucuronosyltransferases (UGTs) is one of the most important phase II mechanisms, facilitating drug clearance via conjugation of glucuronic acid with polar groups of xenobiotics. Accumulating evidence suggests that IBDs impact drug disposition, but whether and how IBDs regulate UGTs and drug glucuronidation remains undefined. In this study, we aim to investigate the expression of UGTs and drug glucuronidation in experimental colitis. Given that glucuronidation occurs primarily in the liver, we analyzed the mRNA changes in hepatic UGTs with a DSS-induced mouse colitis model. Twelve UGTs were downregulated in the liver of colitis mice including UGT1A1 and UGT1A9 (two representative UGTs). Colitis in mice downregulated UGT1A1 and UGT1A9 in the liver but not in small intestine, colon, and kidney. We also established that the downregulation of UGTs was attributed to the disease itself rather than the DSS compound. Moreover, colitis-reduced UGT1A1 and UGT1A9 lead to dampened baicalein and puerarin glucuronidation. PXR was the only UGT regulator significantly downregulated in colitis mice, suggesting dysregulation of PXR is associated with the downregulation of UGT1A1 and UGT1A9, thereby potentially resulting in dysfunction of baicalein and puerarin glucuronidation. Collectively, we establish that UGTs and glucuronidation are dysregulated in colitis, and this effect may cause variation in drug responsiveness in IBDs.