Beyond transcription, aryl hydrocarbon receptor plays a protective role in periodontitis by interacting with CaMKII.

BACKGROUND: The aryl hydrocarbon receptor (AhR) has been studied as an intracellular pattern recognition receptor that can identify bacterial pigments. To identify a potential therapeutic target for periodontitis, we investigated the expression of AhR in periodontitis and its role in the pathogenesis of periodontitis. METHODS: First, we analyzed AhR expression in a single-cell dataset from human periodontal tissue. Quantitative polymerase chain reaction (qPCR), immunofluorescence, and immunohistochemistry were used to verify the AhR level. Later, we determined the phenotypes of ligature-induced periodontitis in myeloid-specific AhR-deficient mice (Lyz2-Cre+/- AhRfx/fx), after which RNA sequencing (RNA-seq), qPCR, Western blot, immunofluorescence, and immunohistochemistry were used to investigate the impacts of AhR on periodontitis and its mechanism. Finally, we determined the therapeutic effect of AhR agonist 6-Formylindolo[3,2-b]carbazole (FICZ) administration on murine periodontitis and verified the effects of FICZ on macrophage polarization in vitro. RESULTS: AhR expression was enhanced in macrophages from periodontitis patients. Deletion of AhR from macrophages aggravated ligature-induced periodontitis and promoted the inflammatory response. Calcium/calmodulin-stimulated protein kinase II (CaMKII) phosphorylation was accelerated in AhR-deficient macrophages. Inhibiting CaMKII phosphorylation ameliorated periodontitis in Lyz2-Cre+/- AhRfx/fx mice. FICZ treatment blocked alveolar bone loss and relieved periodontal inflammation. FICZ diminished M1 macrophage polarization and promoted M2 macrophage polarization upon M1 macrophage induction. CONCLUSION: AhR played a protective role in the pathogenesis of periodontitis by orchestrating macrophage polarization via interacting with the CaMKII signaling pathway.

Advances in microbial self-healing concrete: A critical review of mechanisms, developments, and future directions.

The self-healing bioconcrete, or bioconcrete as concrete containing microorganisms with self-healing capacities, presents a transformative strategy to extend the service life of concrete structures. This technology harnesses the biological capabilities of specific microorganisms, such as bacteria and fungi, which are integral to the material's capacity to autonomously mend cracks, thereby maintaining structural integrity. This review highlights the complex biochemical pathways these organisms utilize to produce healing compounds like calcium carbonate, and how environmental parameters, such as pH, temperature, oxygen, and moisture critically affect the repair efficacy. A comprehensive analysis of recently published peer-reviewed literature, and contemporary experimental research forms the backbone of this review with a focus on microbiological aspects of the self-healing process. The review assesses the challenges facing self-healing bioconcrete, including the longevity of microbial spores and the cost implications for large-scale implementation. Further, attention is given to potential research directions, such as investigating alternative biological agents and optimizing the concrete environment to support microbial activity. The culmination of this investigation is a call to action for integrating self-healing bioconcrete in construction on a broader scale, thereby realizing its potential to fortify infrastructure resilience and sustainability.

Engineering "three-in-one" fluorescent nanozyme of Ce-Au NCs for on-site visual detection of Hg2.

Hg2+ contamination poses a serious threat to the environment and human health. Although gold nanoclusters (Au NCs) have been utilized as fluorescence probes or colorimetric nanozymes for performing Hg2+ assays by using a single method, designing multifunctional nanoclusters as fluorescent nanozyme remains challenging. Herein, Ce-aggregated gold nanoclusters (Ce-Au NCs) were reported with "three in one" functions to generate strong fluorescence, excellent peroxidase-like activity, and the highly specific recognition of Hg2+ via its metallophilic interaction. A portable fluorescence and colorimetric dual-mode sensing device based on Ce-Au NCs was developed for on-site visual analysis of Hg2+. In the presence of Hg2+, fluorescence was effectively quenched and the paper-based chips gradually darkened from green till they became completely absent, while peroxidase-like activity was significantly enhanced. Two independent signals were captured by one identification unit, which provided self-validation to improve reliability and accuracy. Therefore, this work presents a simple synthesis of a multifunctional fluorescent nanozyme, and the developed portable device for on-site visual detection has considerable potential for application in the rapid on-site analysis of heavy metal ions in the environment.

Adaptive Expression and ncRNA Regulation of Genes Related to Digestion and Metabolism in Stomach of Red Pandas during Suckling and Adult Periods.

Red pandas evolved from carnivores to herbivores and are unique within Carnivora. Red pandas and carnivorous mammals consume milk during the suckling period, while they consume bamboo and meat during the adult period, respectively. Red pandas and carnivorous mammal ferrets have a close phylogenetic relationship. To further investigate the molecular mechanisms of dietary changes and nutrient utilization in red pandas from suckling to adult, comparative analysis of the whole transcriptome was performed on stomach tissues from red pandas and ferrets during the suckling and adult periods. The main results are as follows: (1) we identified ncRNAs for the first time in stomach tissues of both species, and found significant expression changes of 109 lncRNAs and 106 miRNAs in red pandas and 756 lncRNAs and 109 miRNAs in ferrets between the two periods; (2) up-regulated genes related to amino acid transport regulated by lncRNA-miRNA-mRNA networks may efficiently utilize limited bamboo amino acids in adult red pandas, while up-regulated genes related to amino acid degradation regulated by lncRNAs may maintain the balance of amino acid metabolism due to larger daily intakes in adult ferrets; and (3) some up-regulated genes related to lipid digestion may contribute to the utilization of rich nutrients in milk for the rapid growth and development of suckling red pandas, while up-regulated genes associated with linoleic acid metabolism regulated by lncRNA-miRNA-mRNA networks may promote cholesterol decomposition to reduce health risks for carnivorous adult ferrets. Collectively, our study offers evidence of gene expression adaptation and ncRNA regulation in response to specific dietary changes and nutrient utilization in red pandas during suckling and adult periods.

Circulating Levels of T-Cell Traits and the Risk of Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study.

Amyotrophic lateral sclerosis (ALS) represents a rare and potentially fatal neurodegenerative disease. Diverse T-cell subsets could potentially exert diametrically opposite impacts upon ALS development. A two-sample Mendelian randomization (MR) analysis was performed to investigate the correlation between 244 T-cell subsets and ALS risk. Genetic instrumental variables were procured from a standard genome-wide association study (GWAS) that encompassed 244 T-cell subsets in 3757 individuals of European lineage. ALS-related data were collected from a GWAS comprising 20,806 ALS instances and 59,804 European control participants. Multiple sensitivity analyses were performed to verify the robustness of the significant results. Reverse MR analysis was used for delineating the effects of ALS on the characteristics of T-cells. After multiple comparison corrections, 24 out of the 244 subtypes demonstrated a potential association with ALS risk. Significantly, 75% of these associations encompassed the expression of the CD3 on diverse T-cell subtypes, revealing a highly consistent inverse relation to ALS risk. The proportion of T regulatory cells (Tregs) in CD4+ T cells and secreting Tregs in CD4+ T cells demonstrated negative associations with the risk of ALS. CCR7 expression on naive CD4+ T cells and CCR7 expression on naive CD8+ T cells showed positive associations with ALS risk. Certain T-cell subsets, particularly those identified by CD3 expression on terminally differentiated CD8+ T cells, proportions of Tregs, and CCR7 expression, indicated an association with ALS risk. These findings harmonize with and extend previous observational studies investigating the involvement of T lymphocyte subset-induced immunological processes in ALS.

Enhancing root physiology for increased yield in water-saving and drought-resistance rice with optimal irrigation and nitrogen.

Objectives: Water-saving and drought-resistance rice (WDR) plays a vital role in the sustainable development of agriculture. Nevertheless, the impacts and processes of water and nitrogen on grain yield in WDR remain unclear. Methods: In this study, Hanyou 73 (WDR) and Hyou 518 (rice) were used as materials. Three kinds of nitrogen fertilizer application rate (NFAR) were set in the pot experiment, including no NFAR (nitrogen as urea applied at 0 g/pot), medium NFAR (nitrogen as urea applied at 15.6 g/pot), and high NFAR (nitrogen as urea applied at 31.2 g/pot). Two irrigation regimes, continuous flooding cultivation and water stress, were set under each NFAR. The relationships between root and shoot morphophysiology and grain yield in WDR were explored. Results: The results demonstrated the following: 1) under the same irrigation regime, the grain yield of two varieties increased with the increase of NFAR. Under the same NFAR, the reduction of irrigation amount significantly reduced the grain yield in Hyou 518 (7.1%-15.1%) but had no substantial influence on the grain yield in Hanyou 73. 2) Under the same irrigation regime, increasing the NFAR could improve the root morphophysiology (root dry weight, root oxidation activity, root bleeding rate, root total absorbing surface area, root active absorbing surface area, and zeatin + zeatin riboside contents in roots) and aboveground physiological indexes (leaf photosynthetic rate, non-structural carbohydrate accumulation in stems, and nitrate reductase activity in leaves) in two varieties. Under the same NFAR, increasing the irrigation amount could significantly increase the above indexes in Hyou 518 (except root dry weight) but has little effect on Hanyou 73. 3) Analysis of correlations revealed that the grain yield of Hyou 518 and Hanyou 73 was basically positively correlated with aboveground physiology and root morphophysiology, respectively. Conclusion: The grain yield could be maintained by water stress under medium NFAR in WDR. The improvement of root morphophysiology is a major factor for high yield under the irrigation regime and NFAR treatments in WDR.

Integrated transcriptomic and metabolomic analysis provides insights into cold tolerance in lettuce (Lactuca sativa L.).

The popular leafy vegetable lettuce (Lactuca sativa L.) is susceptible to cold stress during the growing season, which slows growth rate, causes leaf yellowing and necrosis, and reduced yield and quality. In this study, transcriptomic and metabolomic analyses of two cold-resistant lettuce cultivars (GWAS-W42 and F11) and two cold-sensitive lettuce cultivars (S13K079 and S15K058) were performed to identify the mechanisms involved in the cold response of lettuce. Overall, transcriptome analysis identified 605 differentially expressed genes (DEGs), including significant enrichment of genes involved in the flavonoid and flavonol (CHS, CHI, F3H, FLS, CYP75B1, HCT, etc.) biosynthetic pathways related to oxidation-reduction and catalytic activity. Untargeted metabolomic analysis identified fifteen flavonoid metabolites and 28 other metabolites potentially involved in the response to cold stress; genistein, quercitrin, quercetin derivatives, kaempferol derivatives, luteolin derivatives, apigenin and their derivatives accumulate at higher levels in cold-resistant cultivars. Moreover, MYBs, bHLHs, WRKYs and Dofs also play positive role in the low temperature response, which affected the expression of structural genes contributing to the variation of metabolites between the resistant and sensitive. These results provide valuable evidence that the metabolites and genes involved in the flavonoid biosynthetic pathway play important roles in the response of lettuce to cold stress.

Mechanistic Insights into 1,2-bis(2,4,6-tribromophenoxy)ethane-Induced Male Reproductive Toxicity in Zebrafish.

The novel brominated flame retardant, 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), has increasingly been detected in environmental and biota samples. However, limited information is available regarding its toxicity, especially at environmentally relevant concentrations. In the present study, adult male zebrafish were exposed to varying concentrations of BTBPE (0, 0.01, 0.1, 1, and 10 µg/L) for 28 days. The results demonstrated underperformance in mating behavior and reproductive success of male zebrafish when paired with unexposed females. Additionally, a decline in sperm quality was confirmed in BTBPE-exposed male zebrafish, characterized by decreased total motility, decreased progressive motility, and increased morphological malformations. To elucidate the underlying mechanism, an integrated proteomic and phosphoproteomic analysis was performed, revealing a predominant impact on mitochondrial functions at the protein level and a universal response across different cellular compartments at the phosphorylation level. Ultrastructural damage, increased expression of apoptosis-inducing factor, and disordered respiratory chain confirmed the involvement of mitochondrial impairment in zebrafish testes. These findings not only provide valuable insights for future evaluations of the potential risks posed by BTBPE and similar chemicals but also underscore the need for further research into the impact of mitochondrial dysfunction on reproductive health.

Factors Influencing Seed Dormancy and Germination and Advances in Seed Priming Technology.

Seed dormancy and germination play pivotal roles in the agronomic traits of plants, and the degree of dormancy intuitively affects the yield and quality of crops in agricultural production. Seed priming is a pre-sowing seed treatment that enhances and accelerates germination, leading to improved seedling establishment. Seed priming technologies, which are designed to partially activate germination, while preventing full seed germination, have exerted a profound impact on agricultural production. Conventional seed priming relies on external priming agents, which often yield unstable results. What works for one variety might not be effective for another. Therefore, it is necessary to explore the internal factors within the metabolic pathways that influence seed physiology and germination. This review unveils the underlying mechanisms of seed metabolism and germination, the factors affecting seed dormancy and germination, as well as the current seed priming technologies that can result in stable and better germination.

Morphology and phylogeny of four new species within Polycephalomycetaceae (Hypocreales) parasitising Ophiocordyceps species.

Species of the family Polycephalomycetaceae grow on insects or entomopathogenic fungi and are distributed from tropical to subtropical regions. This study proposed four new species of hyperparasitic fungi from China based on six molecular markers (ITS, SSU, LSU, TEF-1α, RPB1 and RPB2) phylogenetic analyses and morphological characteristics. The four new species, i.e. Pleurocordycepslitangensis, Polycephalomycesjinghongensis, Po.multiperitheciatae and Po.myrmecophilus, were described and illustrated. Pl.litangensis, exhibiting a hyperparasitic lifestyle on Ophiocordycepssinensis, differed from Pleurocordyceps other species in producing subulate ß-phialides and ovoid or elliptic α-conidia. Po.jinghongensis was distinct from Polycephalomyces other species, being parasitic on Ophiocordyceps sp., as producing oval or long oval-shaped α-conidia and columns of ß-conidia. Po.multiperitheciatae differed from Polycephalomyces other species as having synnemata with fertile head, linear ß-conidia and parasitic on Ophiocordycepsmultiperitheciata. Po.myrmecophilus was distinct from Polycephalomyces other species, being parasitic on the fungus Ophiocordycepsacroasca, as producing round or ovoid α-conidia and elliptical ß-conidia without synnemata from the colonies. These four species were clearly distinguished from other species in the family Polycephalomycetaceae by phylogenetic and morphological characteristics. The morphological features were discussed and compared to relevant species in the present paper.

Characterization of the metabolic contributions of cytochrome P450 isoforms to bicyclol using the relative activity factor method.

Bicyclol is a hepatoprotective agent widely used for treating chronic hepatitis and drug-induced liver injuries in clinics. The purpose of the study was to elucidate the contribution of CYP450 enzymes to the metabolism of bicyclol using the relative activity factor approach. After incubation with human liver microsomes and recombinant human liver CYP450 enzymes, the calculated contribution of CYP3A4 and 2C19 to the metabolism of bicyclol was 85.6-90.3% and 9.2-9.7%, respectively. The metabolism was interrupted in the presence of CYP3A4 and 2C19 selective inhibitors. These findings help to predict or avoid metabolic drug-drug interactions or toxicity in clinical applications of bicyclol.

Molecular Phylogenetic and Comparative Genomic Analysis of Pleurocordyceps fusiformispora sp. nov. and Perennicordyceps elaphomyceticola in the Family Polycephalomycetaceae.

Several Pleurocordyceps species have been reported as hyperparasitic fungi. A new species, Pleurocordyceps fusiformispora, and a known species, Perennicordyceps elaphomyceticola, are described here based on morphology and phylogenetic evidence from six genes (ITS, SSU, LSU, TET1-α, RPB1, and RPB2). Pl. fusiformispora differed from the other Pleurocordyceps species by producing flaky colonies, ovoid or elliptic α-conidia, and fusiform or long fusiform ß-conidia. Both full genomes of Pe. elaphomyceticola and Pl. fusiformispora were sequenced, annotated, and compared. The antiSMASH and local BLAST analyses revealed significant differences in the number and types of putative secondary metabolite biosynthetic gene clusters, i.e., NPPS, PKS, and hybrid PKS-NRPS domains, between the two species. In addition, the putative BGCs of six compounds, namely ε-poly lysine, 4-epi-15-epi-brefeldin A, Monorden D/monocillin IV/monocillin VII/pochonin M/monocillin V/monocillin II, Tolypyridone, Piperazine, and Triticone DABFC, were excavated in the present study. This study motivates the use of heterologous expression and gene knockout methods to discover novel biologically active SMs from Polycephalomycetaceae.

Genomic comparative analysis of Ophiocordyceps unilateralis sensu lato.

Ophiocordyceps unilateralis sensu lato is a common pathogenic fungus of ants. A new species, O. fusiformispora, was described based on morphology and phylogenetic evidence from five genes (SSU, LSU, TEF1α, RPB1, and RPB2). The whole genomes of O. fusiformispora, O. contiispora, O. subtiliphialida, O. satoi, O. flabellata, O. acroasca, and O. camponoti-leonardi were sequenced and annotated and compared with whole genome sequences of other species in O. unilateralis sensu lato. The basic genome-wide characteristics of the 12 species showed that the related species had similar GC content and genome size. AntiSMASH and local BLAST analyses revealed that the number and types of putative SM BGCs, NPPS, PKS, and hybrid PKS-NRPS domains for the 12 species differed significantly among different species in the same genus. The putative BGC of five compounds, namely, NG-391, lucilactaene, higginsianin B, pyripyropene A, and pyranonigrin E were excavated. NG-391 and lucilactaene were 7-desmethyl analogs of fusarin C. Furthermore, the 12 genomes had common domains, such as KS-AT-DH-MT-ER-KR-ACP and SAT-KS-AT-PT-ACP-ACP-Te. The ML and BI trees of SAT-KS-AT-PT-ACP-ACP-Te were highly consistent with the multigene phylogenetic tree in the 12 species. This study provided a method to obtain the living culture of O. unilateralis sensu lato species and its asexual formed on the basis of living culture, which was of great value for further study of O. unilateralis sensu lato species in the future, and also laid a foundation for further analysis of secondary metabolites of O. unilateralis sensu lato.

Zeolitic imidazolate framework derived Fe catalyst electrocatalytic-driven atomic hydrogen for efficient reduction of nitrate to N2.

Excessive discharge of nitrogen-containing chemical products into the natural water environment leads to the serious environmental problem of nitrate-nitrogen pollution, threatening the ecological balance and human health. In this study, we propose an efficient denitrification electrochemical method utilizing iron-doped zeolite imidazolium framework derived defective nitrogen-doped carbon (d-FeNC) catalysts. The d-FeNC catalyst exhibited 97 % nitrate removal efficiency and 94 % total nitrogen (TN) removal, and the reaction rate constant was increased from 0.73 h-1 of the Fe-undoped electrocatalyst (d-NC) to 1.11 h-1. The successful synthesis of d-FeNC with carbon defect sites and encapsulated Fe was confirmed by in-depth characterization. In situ electron paramagnetic resonance (EPR) analysis in conjunction with cyclic voltammetry (CV) tests confirmed the carbon substrates with defect enhanced the trapping of atomic hydrogen (H*) on the catalyst surface. Density functional theory (DFT) calculations clarified the doping of Fe facilitated the adsorption of nitrate, resulting in contact of H* with nitrate on the catalyst surface. In the synergy of the defective state organic framework and metal Fe, H* and nitrate realized a collision process. The electrochemical denitrification system achieved an excellent nitrate removal capacity of 7587 mgN·g-1cat in high-concentration nitrate solution and showed excellent stability under various conditions. Overall, this study underscores the potential of defective iron-doped carbon catalysts for efficient electrocatalytic denitrification, providing a promising approach for sustainable wastewater treatment.

Proline-derived quinoline formamide compounds as human urate transporter 1 inhibitors with potent uric acid-lowering activities.

We report the design and synthesis of a series of proline-derived quinoline formamide compounds as human urate transporter 1 (URAT1) inhibitors via a ligand-based pharmacophore approach. Structure-activity relationship studies reveal that the replacement of the carboxyl group on the polar fragment with trifluoromethanesulfonamide and substituent modification at the 6-position of the quinoline ring greatly improve URAT1 inhibitory activity compared with lesinurad. Compounds 21c, 21e, 24b, 24c, and 23a exhibit potent activities against URAT1 with IC50 values ranging from 0.052 to 0.56 µM. Furthermore, compound 23a displays improved selectivity towards organic anion transporter 1 (OAT1), good microsomal stability, low potential for genotoxicity and no inhibition of the hERG K+ channel. Compounds 21c and 23a, which have superior pharmacokinetic properties, also demonstrate significant uric acid-lowering activities in a mouse model of hyperuricemia. Notably, 21c also exhibits moderate anti-inflammatory activity related to the gout inflammatory pathway. Compounds 21c and 23a with superior druggability are potential candidates for the treatment of hyperuricemia and gout.

BBR affects macrophage polarization via inhibition of NF-κB pathway to protect against T2DM-associated periodontitis.

BACKGROUND AND OBJECTIVE: Periodontitis is intimately associated with the development of various systemic diseases, among which type 2 diabetes mellitus (T2DM) has a bidirectional relationship with the pathogenesis of periodontitis. The objective of the present work was to investigate the role of berberine (BBR) in periodontitis with T2DM and related mechanisms. METHODS: The mRNA expression of macrophage polarization-related factors in the microenvironment of periodontal inflammation was detected using real-time quantitative PCR (RT-qPCR). The experimental periodontitis model was constructed in wild-type (WT) and T2DM (db/db) mice, which were administered BBR after 7 days of modeling. Alveolar bone loss (ABL) in each group of mice was measured utilizing micro-computed tomography images. RT-qPCR was performed to analyze the levels of macrophage polarization-related factors in mouse gingiva. Lastly, using western blotting and RT-qPCR, the signaling pathway of BBR affecting macrophage polarization in the microenvironment of periodontitis was explored. RESULTS: BBR inhibited M1 polarization and stimulated M2 polarization in the periodontitis microenvironment. BBR decreased ABL in the WT and T2DM periodontitis models. And BBR reduced the production of proinflammatory cytokines and increased anti-inflammatory cytokine expression in the gingiva of WT and T2DM model mice. Ultimately, BBR mediates its anti-inflammatory effects on periodontitis through inhibition of the NF-κB pathway. CONCLUSIONS: BBR had a therapeutic effect on T2DM-associated periodontitis via inhibiting the NF-κB pathway to affect macrophage polarization, which may have implications for the new pharmacological treatment of T2DM-associated periodontitis.

Clinical features and genetic spectrum of a multicenter Chinese cohort with myotonic dystrophy type 1.

BACKGROUND: As the most common subtype of adult muscular dystrophy worldwide, large cohort reports on myotonic dystrophy type I (DM1) in China are still lacking. This study aims to analyze the genetic and clinical characteristics of Chinese Han DM1 patients. METHODS: Based on the multicenter collaborating effort of the Pan-Yangtze River Delta Alliance for Neuromuscular Disorders, patients with suspected clinical diagnoses of DM1 were genetically confirmed from January 2020 to April 2023. Peak CTG repeats in the DMPK gene were analyzed using triplet repeat-primed PCR (TP-PCR) and flanking PCR. Time-to-event analysis of onset age in females and males was performed. Additionally, detailed clinical features and longitudinal changes from the disease onset in 64 DM1 patients were retrospectively collected and analyzed. The Epworth Sleepiness Scale and Fatigue Severity Scale were used to quantify the severity of daytime sleepiness and fatigue. RESULTS: Among the 211 genetically confirmed DM1 patients, the mean age at diagnosis was 40.9 ± 12.2 (range: 12-74) with a male-to-female ratio of 124:87. The average size of CTG repeats was 511.3 (range: 92-1945). Among the DM1 patients with comprehensive clinical data (n = 64, mean age 41.0 ± 12.0), the age at onset was significantly earlier in males than in females (4.8 years earlier, p = 0.026). Muscle weakness (92.2%), myotonia (85.9%), and fatigue (73.4%) were the most prevalent clinical features. The predominant involved muscles at onset are hands (weakness or myotonia) (52.6%) and legs (walking disability) (42.1%). Of them, 70.3% of patients had daytime sleepiness, 14.1% had cataract surgery, 7.8% used wheelchairs, 4.7% required ventilatory support, and 1.6% required gastric tubes. Regarding the comorbidities, 4.7% of patients had tumors, 17.2% had diabetes, 23.4% had dyspnea, 28.1% had intermittent insomnia, 43.8% experienced dysphagia, and 25% exhibited cognitive impairment. Chinese patients exhibited smaller size of CTG repeats (468 ± 139) than those reported in Italy (613 ± 623), the US (629 ± 386), and Japan (625 [302, 1047]), and milder phenotypes with less multisystem involvement. CONCLUSION: The Chinese Han DM1 patients presented milder phenotypes compared to their Caucasian and Japanese counterparts. A male predominance and an early age of onset were identified in male Chinese Han DM1 patients.

The Active Glucuronide Metabolite of the Brain Protectant IMM-H004 with Poor Blood-Brain Barrier Permeability Demonstrates a High Partition in the Rat Brain via Multiple Mechanisms.

BACKGROUND: Glucuronidation is an essential metabolic pathway for a variety of drugs. IMM-H004 is a novel neuroprotective agent against ischemic stroke, and its glucuronide metabolite IMM-H004G exhibits similar pharmacological activity. Despite possessing a higher molecular weight and polarity, brain exposure of IMM-H004G is much higher than that of IMM-H004. This study aimed to investigate the brain metabolism and transport mechanisms of IMM-H004 and IMM-H004G. METHODS: First, the possibility of IMM-H004 glucuronidation in the brain was evaluated in several human brain cell lines and rat homogenate. Subsequently, the blood-brain barrier carrier-mediated transport mechanism of IMM-H004 and IMM-H004G was studied using overexpression cell models. In addition, intracerebroventricular injection, in situ brain perfusion model, and microdialysis/microinjection techniques were performed to study the distribution profiles of IMM-H004 and IMM-H004G. RESULTS: IMM-H004 could be metabolized to IMM-H004G in both rat brain and HEB cells mediated by UGT1A7. However, IMM-H004G could not be hydrolyzed back into IMM-H004. Furthermore, the entry and efflux of IMM-H004 in the brain were mediated by the pyrilamine-sensitive H+/OC antiporter and P-gp, respectively, while the transport of IMM-H004G from the blood to the brain was facilitated by OATP1A2 and OATP2B1. Ultimately, stronger concentration gradients and OATP-mediated uptake played a critical role in promoting greater brain exposure of IMM-H004G. CONCLUSIONS: The active glucuronide metabolite of the brain protectant IMM-H004 with poor blood-brain barrier permeability demonstrates a high partition in the rat brain via multiple mechanisms, and our findings deepen the understanding of the mechanisms underlying the blood-brain barrier metabolism and transport of active glucuronide conjugates.

Design, Synthesis, and Bioevaluation of Novel Reversibly Photoswitchable PI3K Inhibitors Based on Phenylazopyridine Derivatives toward Light-Controlled Cancer Treatment.

Photopharmacology is an emerging approach for achieving light-controlled drug activity. Herein, we design and synthesize a novel series of photoswitchable PI3K inhibitors by replacing a sulfonamide moiety with an azo group in a 4-methylquinazoline-based scaffold. Through structure-activity relationship studies, compound 6g is identified to be effectively switched between its trans- and cis-configuration under irradiation with proper wavelengths. Molecular docking studies show the cis-isomer of 6g is favorable to bind to the PI3K target, supporting compound 6g in the PSS365 (cis-isomer enriched) was more potent than that in the PSSdark (trans-isomer dominated) in PI3K enzymatic assay, cell antiproliferative assay, Western blotting analysis on PI3K downstream effectors, cell cycle analysis, colony formation assay, and wound-healing assay. Relative to the cis-isomer, the trans-isomer is more metabolically stable and shows good pharmacokinetic properties in mice. Moreover, compound 6g inhibits tumor growth in nude mice and a zebrafish HGC-27 xenograft model.

Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate Enhances foxo1-Mediated Lipophagy to Remodel Lipid Metabolism in Zebrafish Liver.

An emerging environmental contaminant, bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH), can bioaccumulate in the liver and affect hepatic lipid metabolism. However, the in-depth mechanism has yet to be comprehensively explored. In this study, we utilized transgenic zebrafish Tg (Apo14: GFP) to image the interference of TBPH on zebrafish liver development and lipid metabolism at the early development stage. Using integrated lipidomic and transcriptomic analyses to profile the lipid remodeling effect, we uncovered the potential effects of TBPH on lipophagy-related signaling pathways in zebrafish larvae. Decreased lipid contents accompanied by enhanced lipophagy were confirmed by the measurements of Oil Red O staining and transmission electron microscopy in liver tissues. Particularly, the regulatory role of the foxo1 factor was validated via its transcriptional inhibitor. Double immunofluorescence staining integrated with biochemical analysis indicated that the enhanced lipophagy and mitochondrial fatty acid oxidation induced by TBPH were reversed by the foxo1 inhibitor. To summarize, our study reveals, for the first time, the essential role of foxo1-mediated lipophagy in TBPH-induced lipid metabolic disorders and hepatoxicity, providing new insights for metabolic disease studies and ecological health risk assessment of TBPH.