Iminyl-Radical-Mediated Formation of Covalent Au-N Bonds for Molecular Junctions.

The interaction between organic radicals and transition metals plays a crucial role in radical-mediated chemical reactions, functional devices, and biocatalysis. Characterizing such interactions, however, remains a long-standing challenge due to the inherently high reactivity of radical species. Here, using a scanning tunneling microscope breaking junction (STM-BJ) technique, we are able to detect the interaction mode between iminyl radicals and the gold surface at a single molecule level. We show that the free iminyl radicals generated through photochemical N-O bond homolysis of oxime esters react toward the gold electrode surface and produce covalent Au-N bonds. Intriguingly, we find that the Au-N bonding reactions lead to the formation of robust and highly conductive single-molecule junctions. These findings provide not only insights into the mechanism of iminyl-radical-involved reactions but also a facile photolysis method to create a new type of covalent electrode-molecule bonding contact for molecular devices.

Promotion of healthy adipose tissue remodeling ameliorates muscle inflammation in a mouse model of sarcopenic obesity.

A large subset of elders is classified as having sarcopenic obesity, a prevalence of obesity in combination with sarcopenia which places an aging population at the risk of adverse health consequences from both conditions. However, its complex etiology has restrained the development of effective therapeutic strategies. Recent progress has highlighted that the mode by which adipose tissue (AT) remodels is a determinant of metabolic health in the context of obesity. Healthy AT remodeling confers metabolic protection including insulin-sensitizing and anti-inflammatory effects to non-adipose tissues including skeletal muscle. Here, we employed a doxycycline-inducible adipocyte Hif1a knockout system to evaluate the muscle-protective effects associated with HIF1α inactivation-induced healthy AT remodeling in a model of sarcopenic obesity. We found that adipocyte HIF1α inactivation leads to improved AT metabolic health, reduced serum levels of lipids and pro-inflammatory cytokines, and increase of circulating adipokine (APN) in ovariectomized obese mice fed with obesogenic high-fat diet (HFD). Concomitantly, muscle inflammation is evidently lower in obese OVX mice when adipocyte HIF1α is inactivated. Furthermore, these protective effects against muscle inflammation can be mimicked by the administration of adiponectin receptor agonist AdipoRon. Collectively, our findings underscore the importance of AT metabolic health in the context of concurrent sarcopenia and obesity, and promotion of healthy AT remodeling may represent a new therapeutic strategy to improve muscle health in sarcopenic obesity.

Molecular Mechanisms of Oxidative Stress Relief by CAPE in ARPE-19 Cells.

Caffeic acid phenylethyl ester (CAPE) is an antioxidative agent originally derived from propolis. Oxidative stress is a significant pathogenic factor in most retinal diseases. Our previous study revealed that CAPE suppresses mitochondrial ROS production in ARPE-19 cells by regulating UCP2. The present study explores the ability of CAPE to provide longer-term protection to RPE cells and the underlying signal pathways involved. ARPE-19 cells were given CAPE pretreatment followed by t-BHP stimulation. We used in situ live cell staining with CellROX and MitoSOX to measure ROS accumulation; Annexin V-FITC/PI assay to evaluate cell apoptosis; ZO-1 immunostaining to observe tight junction integrity in the cells; RNA-seq to analyze changes in gene expression; q-PCR to validate the RNA-seq data; and Western Blot to examine MAPK signal pathway activation. CAPE significantly reduced both cellular and mitochondria ROS overproduction, restored the loss of ZO-1 expression, and inhibited apoptosis induced by t-BHP stimulation. We also demonstrated that CAPE reverses the overexpression of immediate early genes (IEGs) and activation of the p38-MAPK/CREB signal pathway. Either genetic or chemical deletion of UCP2 largely abolished the protective effects of CAPE. CAPE restrained ROS generation and preserved the tight junction structure of ARPE-19 cells against oxidative stress-induced apoptosis. These effects were mediated via UCP2 regulation of p38/MAPK-CREB-IEGs pathway.

In situ synthesis of a Bi2O3 quantum dot decorated BiOCl heterojunction with superior photocatalytic capability for organic dye and antibiotic removal.

As a decoration method, coupling a photocatalyst with semiconductor quantum dots has been proven to be an efficient strategy for enhanced photocatalytic performance. Herein, a novel BiOCl nanosheet decorated with Bi2O3 quantum dots (QDs) was first synthesized by a facile one-step in situ chemical deposition method at room temperature. The as-prepared materials were characterized by multiple means of analysis. The Bi2O3QDs with an average diameter of about 8.0 nm were uniformly embedded on the surface of BiOCl nanosheets. The obtained Bi2O3QDs/BiOCl exhibited significantly enhanced photocatalytic performance on the degradation of the rhodamine B and ciprofloxacin, which could be attributed to the band alignment, the photosensitization effect and the strong coupling between Bi2O3 and BiOCl. In addition, the dye photosensitization effect was demonstrated by the monochromatic photodegradation experiments. The radical trapping experiments and the ESR testing demonstrated the type II charge transfer route of the heterojunction. Finally, a reasonable photocatalytic mechanism based on the relative band positions was discussed to illustrate the photoreaction process. These findings provide a good choice for the design and potential application of BiOCl-based photocatalysts in water remediation.

Brønsted Acid-Catalyzed Reaction of N-arylnaphthalen-2-amines with Quinone Esters for the Construction of Carbazole and C-N Axially Chiral Carbazole Derivatives.

We demonstrated here an efficient synthetic method of carbazole derivatives from readily available N-arylnaphthalen-2-amines and quinone esters catalyzed by Brønsted acid. With this strategy, a series of carbazole derivatives were obtained in good to excellent yields (76 to >99) under mild conditions. Large scale reaction illustrated the synthetic utility of this protocol. Meanwhile, a series of C-N axially chiral carbazole derivatives were also constructed in moderate to good yields (36-89% yield) with moderate to excellent atroposelectivities (44-94% ee) by using chiral phosphoric acid as a catalyst, which provides a novel strategy for the atroposelective construction of C-N axially chiral compounds and a new member of the C-N atropisomers.

CTD Sensors for Ocean Investigation Including State of Art and Commercially Available.

Over 70% of the earth's surface is covered by oceans; globally, oceans provides a huge source of wealth to humans. In the literature, several sensors have been developed to investigate oceans. Electrical conductivity temperature depth (CTD) sensors were used frequently and extensively. Long-term accurate CTD data is important for the study and utilization of oceans, e.g., for weather forecasting, ecological evolution, fishery, and shipping. Several kinds of CTD sensors based on electrics, optical, acoustic wave and radio waves have been developed. CTD sensors are often utilized by measuring electrical signals. The latest progress of CTD sensors will be presented in order of performance. The principles, structure, materials and properties of many CTD sensors were discussed in detail. The commercially available CTD sensors were involved and their respective performances were compared. Some possible development directions of CTD sensors for ocean investigation are proposed.

p-Terphenyl-based rigid stationary phases with embedded polar groups for liquid chromatography.

Terphenyls are important building blocks for a wide range of functional molecules. Among the three isomers, p-terphenyl (C18H14) is particularly useful for the construction of optical devices on account of its unique structure. Herein, two rigid stationary phases bearing p-terphenyl as an external moiety and variable embedded carbamate groups (p-TerC with one embedded carbamate group and p-TerC2 with two embedded carbamate group) were presented. The proposed stationary phases were characterized by various means and evaluated in reversed-phase (RP) mode, using different classes of analytes, including polycyclic aromatic hydrocarbons (PAHs), alkylbenzenes, 4-alkylbiphenyls, substituted ureas, sulfonylureas, substituted sulfanilamides and aromatic acids. The comparison with conventional C18, several other polar-embedded aromatic and C18 equivalents indicated p-terphenyl-based stationary phases were featured by multiple retention mechanisms, involving π-π interaction, charge-transfer interaction, hydrogen-bonding and hydrophobic interaction in RP mode. A unusually high specificity to the analytes with linear structures was observed, as exemplified by an irreversible adsorption of tetracene and a readily separation of tetraphene and chrysene. The aliphatic linker used in the proposed stationary phases was an influential factor for retentivity, selectivity and column efficiency. Interestingly, p-TerC2 was operable in normal-phase mode for the separation of certain PAHs through polar-related interactions. The linear, rigid polyphenyl structure of p-terphenyl endowed the new stationary phase with distinctive chromatographic properties, in contrast to those of the preceding counterparts bonded with alkyl and/or polynuclear aromatic moieties.

Co-inducible Catabolism of 2-Naphthol Initiated by Hydroxylase CehC1C2 in Rhizobium sp. X9 Removed Its Ecotoxicity.

2-Naphthol, which originates from various industrial activities, is widely disseminated through the discharge of industrial wastewater and is, thus, harmful to the water ecosystem, agricultural production, and human health. In this study, the carbaryl degrading strain Rhizobium sp. X9 was proven to be able to degrade 2-naphthol and reduce its toxicity to rice (Oryza sativa) and Chlorella ellipsoidea. Two-component hydroxylase CehC1C2 is responsible for the initial step of degradation and generates 1,2-dihydroxynaphthalene, which is further degraded by the ceh cluster. The transcription of gene cluster cehC1C2 could be induced when both 2-naphthol and glucose were added. A bioinformatic analysis revealed that two transcriptional regulators, the inhibitor CehR2 and the activator CehR3, could be involved in this process. Our study elucidated the molecular mechanism of microbial degradation of 2-naphthol and provided an effective strategy for the in situ remediation of 2-naphthol contamination in the environment.

Real-World Outcome and Prognostic Factors Among HER2-Positive Metastatic Breast Cancer Patients Receiving Pyrotinib-Based Therapy: A Multicenter Retrospective Analysis.

Purpose: To explore the efficacy, safety, and potential factors influencing efficacy and outcome of pyrotinib-based therapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) in complex clinical practice. Methods: Real-world data for HER2-positive MBC patients treated with pyrotinib-based regimens from 6 hospitals in Northern Anhui, China, from September 2018 to February 2022, were retrospectively collected, and clinicopathological features, efficacy, prognosis, and safety were analyzed. Potential influencing factors including baseline serum vascular endothelial growth factor-A (VEGF-A) for evaluating pyrotinib's treatment response and outcome were also explored. Results: A total of 169 patients with HER2-positive MBC were enrolled. The objective response rate (ORR), disease control rate (DCR), and median progression-free survival (mPFS) of the overall cohort were 65.1%, 87.6%, and 12.4 months, respectively. Pyrotinib is highly beneficial as different treatment lines and appears to be a feasible strategy both in combination with chemotherapeutic drugs and alone. The mPFS values were 16.5 months, 12.4 months, and 9.3 months in the first, second, and third-or-higher lines of anti-HER2 therapy, respectively (P=0.027). The most common adverse event (AE) was diarrhea (88.2%), and patients with < grade 3 diarrhea achieved a longer mPFS than patients with ≥ grade 3 diarrhea (13.3 months vs 6.9 months, P=0.007). Among the patients with available baseline VEGF-A data, the ORR was 43.5% in patients with a high level of VEGF-A, compared to 81.5% in patients with a low level of VEGF-A (P=0.005). Moreover, patients in the VEGF-A-high group exhibited a shorter mPFS time than those in the VEGF-A-low group (7.8 months vs 19.1 months, P=0.004). Further analysis demonstrated AE of diarrhea and VEGF-A at baseline to be independent prognostic factors for PFS. Conclusion: Pyrotinib-based regimens showed promising efficacy, with manageable tolerance, and AE occurrence of severe diarrhea and baseline level of serum VEGF-A are helpful in predicting the treatment outcome of pyrotinib in HER2-positive MBC.

Carbon sequestration from refractory dissolved organic carbon produced by biodegradation of Saccharina japonica.

Using macroalgae cultures to sequester carbon has been proposed in recent years. Yet the key mechanism of carbon sequestration-how carbon in degrading biomass is converted into refractory dissolved organic carbon (RDOC) remains poorly understood. The process of producting RDOC via biomass degradation of Saccharina japonica, the most productive algae in China, was thus studied in the laboratory. Most of the carbon in the kelp biomass was converted to dissolved inorganic carbon (DIC) by bacterial respiration. Only 7.8% of the carbon in the kelp biomass was converted into labile DOC, semi-labile or semi-refractory DOC, and refractory DOC in turn. The enrichment of DIC resulted in hypoxic conditions in the water. For the hypoxia in the experiment, the sulfur-degrading bacteria Campylobacteria and Bacteroidia became the dominant bacterial classes, which were the key drivers for the transformation of labile DOC to semi-labile or semi-refractory DOC. Then, semi-labile or semi-refractory DOC was converted to RDOC, driven by the sulfite-reducing bacteria Clostridia and Kapabacteria. Finally, 0.3% of the carbon content in kelp was transformed into RDOC. The resulting RDOC, which was rich in sulfur and nitrogen elements, increased the molecular diversity and average molecular weight in the water. An important finding was that the production of RDOC may be accompanied by the environmental risk of hypoxia.

Self-supporting photocatalyst of 2D Bi2O3 anchored on carbon paper for degradation pollutants.

Two-dimensional vertically aligned Bi2O3 nanosheets over carbon paper (CP) were prepared via an in situ growth approach. Bi2O3/CP exhibits a robust photocatalytic activity, as well as renewability and flexibility. With Rhodamine B and 2,4-dichlorophenol used as target pollutants, the rate constant of Bi2O3/CP was 3.72 × 10-3 min-1 and 6.93 × 10-3 min-1 under visible-light irradiation for 2 h, respectively. The improved activity was attributed to the synergistic effects of the hierarchical structure of Bi2O3 and the conductive substrate, CP; the former provided efficient catalytic sites for the pollutants and absorbed more of the light scattered among the nanosheets, while the latter is beneficial to the photogenerated electron transfer.

Plasma metabolomics provides new insights into the relationship between metabolites and outcomes and left ventricular remodeling of coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is a metabolically perturbed pathological condition. However, the knowledge of metabolic signatures on outcomes of CAD and their potential causal effects and impacts on left ventricular remodeling remains limited. We aim to assess the contribution of plasma metabolites to the risk of death and major adverse cardiovascular events (MACE) as well as left ventricular remodeling. RESULTS: In a prospective study with 1606 Chinese patients with CAD, we have identified and validated several independent metabolic signatures through widely-targeted metabolomics. The predictive model respectively integrating four metabolic signatures (dulcitol, ß-pseudouridine, 3,3',5-Triiodo-L-thyronine, and kynurenine) for death (AUC of 83.7% vs. 76.6%, positive IDI of 0.096) and metabolic signatures (kynurenine, lysoPC 20:2, 5-methyluridine, and L-tryptophan) for MACE (AUC of 67.4% vs. 59.8%, IDI of 0.068) yielded better predictive value than trimethylamine N-oxide plus clinical model, which were successfully applied to predict patients with high risks of death (P = 0.0014) and MACE (P = 0.0008) in the multicenter validation cohort. Mendelian randomisation analysis showed that 11 genetically inferred metabolic signatures were significantly associated with risks of death or MACE, such as 4-acetamidobutyric acid, phenylacetyl-L-glutamine, tryptophan metabolites (kynurenine, kynurenic acid), and modified nucleosides (ß-pseudouridine, 2-(dimethylamino) guanosine). Mediation analyses show that the association of these metabolites with the outcomes could be partly explained by their roles in promoting left ventricular dysfunction. CONCLUSIONS: This study provided new insights into the relationship between plasma metabolites and clinical outcomes and its intermediate pathological process left ventricular dysfunction in CAD. The predictive model integrating metabolites can help to improve the risk stratification for death and MACE in CAD. The metabolic signatures appear to increase death or MACE risks partly by promoting adverse left ventricular dysfunction, supporting potential therapeutic targets of CAD for further investigation.

Transcriptome analysis of malate-induced Schizochytrium sp. FJU-512 reveals a novel pathway for biosynthesis of docosahexaenoic acid with enhanced expression of genes responsible for acetyl-CoA and NADPH accumulation.

Schizochytrium is one of the few oleaginous microalgae that produce docosahexaenoic acid (DHA)-rich lipids. In this study, global changes in gene expression levels of Schizochytrium sp. FJU-512 cultured with malate in a 15 l-bioreactor was analyzed using comparative transcriptomics. The changes were found mainly in the genes involved in oxidative phosphorylation, ß-oxidation, and pentose phosphate pathways. Consequently, the global changes in genes associated with the pathways could lead to an increase in the influx throughputs of pyruvate, branched-chain amino acids, fatty acids, and vitamin B6. Our transcriptome analysis indicated pyruvate dehydrogenase E2 component and acetolactate synthase I/II/III large subunit as major contributors to acetyl-CoA biosynthesis, whereas glucose-6-phosphate dehydrogenase was indicated as the major contributor to the biosynthesis of NADPH. An increase in DHA titer of up to 22% was achieved with the addition of malate to the fed-batch culture of Schizochytrium sp. FJU-512. This study provides an alternate method to enhance DHA production in Schizochytrium sp. FJU-512 through malate induced upregulation of genes responsible for acetyl-CoA and NADPH biosynthesis.

The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK.

The activity of 5'-adenosine monophosphate-activated protein kinase (AMPK) is inversely correlated with the cellular availability of glucose. When glucose levels are low, the glycolytic enzyme aldolase is not bound to fructose-1,6-bisphosphate (FBP) and, instead, signals to activate lysosomal AMPK. Here, we show that blocking FBP binding to aldolase with the small molecule aldometanib selectively activates the lysosomal pool of AMPK and has beneficial metabolic effects in rodents. We identify aldometanib in a screen for aldolase inhibitors and show that it prevents FBP from binding to v-ATPase-associated aldolase and activates lysosomal AMPK, thereby mimicking a cellular state of glucose starvation. In male mice, aldometanib elicits an insulin-independent glucose-lowering effect, without causing hypoglycaemia. Aldometanib also alleviates fatty liver and nonalcoholic steatohepatitis in obese male rodents. Moreover, aldometanib extends lifespan and healthspan in both Caenorhabditis elegans and mice. Taken together, aldometanib mimics and adopts the lysosomal AMPK activation pathway associated with glucose starvation to exert physiological roles, and might have potential as a therapeutic for metabolic disorders in humans.

Association of thyroid autoimmunity with the presence and severity of coronary atherosclerosis in patients undergoing coronary angiography.

Studies on the association of thyroid autoimmunity with cardiometabolic risk and coronary artery disease (CAD) have produced conflicting results. This study aimed to investigate the relationship of thyroid autoimmune bodies (thyroid peroxidase antibody [TPOAb] and thyroglobulin antibody [TgAb]) with CAD in euthyroid subjects undergoing coronary angiography. A total of 307 subjects who underwent coronary angiography were included. The severity of coronary atherosclerosis was evaluated by using Gensini score. Serum TSH, total T3, total T4, TPOAb, TgAb, lipid levels et al were measured and compared between the groups with and without CAD. Logistic multivariate regression analysis were performed to assess the associations. Levels of thyroid hormones were comparable between the two groups. The positive percentage of anti-Tg antibodies was higher in non-CAD group (15.22% vs 7.91%, χ2 = 3.95, p = .047) while no significant difference was observed for anti-TPO antibodies (19.57% vs 17.21%, χ2 = 0.243, p = .622). The natural log-transformed Gensini score (ln (Gensini score)) was lower in the TgAb+ group (2.94 ± 1.11 vs 2.41 ± 1.18, P = .015). There was no significant difference for ln (Gensini score) between TPOAb- and TPOAb+ group (2.90 ± 1.14 vs 2.85 ± 1.09, P = .782). Logistical regression analysis revealed that positive TgAb was inversely associated with the presence of CAD (OR: 0.387, 95% CI: 0.157-0.952, p = .039) independent of other risk factors. The results showed that TgAb positivity might be an independent protective factor for CAD.

Comparative Genomic Analysis of Carbofuran-Degrading Sphingomonads Reveals the Carbofuran Catabolism Mechanism in Sphingobium sp. Strain CFD-1.

The worldwide use of the carbamate insecticide carbofuran has caused considerable concern about its environmental fate. Degradation of carbofuran by Sphingobium sp. strain CFD-1 is initiated via the hydrolysis of its ester bond by carbamate hydrolase CehA to form carbofuran phenol. In this study, another carbofuran-degrading strain, Sphingobium sp. CFD-2, was isolated. Subsequently, a cfd gene cluster responsible for the catabolism of carbofuran phenol was predicted by comparing the genomes of strains CFD-1, CFD-2, and Novosphingobium sp. strain KN65.2. The key genes verified to be involved in the catabolism of carbofuran phenol within the cfd cluster include the hydroxylase gene cfdC, epoxide hydrolase gene cfdF, and ring cleavage dioxygenase gene cfdE and are responsible for the successive conversion of carbofuran phenol, resulting in complete ring cleavage. These carbofuran-catabolic genes (cehA and the cfd cluster) are distributed on two plasmids in strain CFD-1 and are highly conserved among the carbofuran-degrading sphingomonad strains. The mobile genetic element IS6100 flanks cehA and the cfd gene cluster, indicating the importance of horizontal gene transfer in the formation of carbofuran degradation gene clusters. The elucidation of the molecular mechanism of carbofuran catabolism provides insights into the evolutionary scenario of the conserved carbofuran catabolic pathway. IMPORTANCE Owing to the extensive use of carbofuran over the past 50 years, bacteria have evolved catabolic pathways to mineralize this insecticide, which plays an important role in eliminating carbofuran residue in the environment. In this study, the cfd gene cluster, responsible for the catabolism of carbofuran phenol, was predicted by comparing sphingomonad genomes. The function of key enzymatic genes in this gene cluster was identified. Furthermore, the carbamate hydrolase gene cehA and the cfd gene cluster are highly conserved in different carbofuran-degrading strains. Additionally, the horizontal gene transfer elements flanking the cfd gene cluster were investigated. These findings help elucidate the molecular mechanism of microbial carbofuran degradation and enhance our understanding of the evolutionary mechanism of the carbofuran catabolic pathway.

An effective method to reduce lymphatic drainage post-lateral cervical lymph node dissection of differentiated thyroid cancer: a retrospective analysis.

BACKGROUND: Lymph or chyle leak (LL/CL) is severe complications after lateral cervical lymph node dissection (LLND), mainly due to iatrogenic injury of the lymphatic duct. Efficient and well-operated methods to reduce postoperative drainage are still lacking. This was a feasibility study to evaluate a new method of preventing LL/CL compared to conventional treatment. METHOD: We retrospectively analyzed 20 consecutive patients who used the "pedicled omohyoid flap covering (POFC)" method during LLND from January 2019 to December 2021 in our center as an observation group. Another 20 consecutive patients used the conventional method during LLND in this period as a control group. The clinical and pathological features of the two groups were compared, and the related factors that affected postoperative lymphatic drainage were analyzed with Cox proportional hazards models. RESULTS: The drainage volume per 24 h and the incidence of LL/CL in the control group were both higher than that in the observation group (all P < 0.05), and the number of lymph nodes dissected in the IV region > 10 and the use of the POFC method were the independent risk factors that significantly affected the incidence of LL/CL post LLND (all P < 0.05). CONCLUSIONS: POFC is a safe and useful method for reducing drainage and preventing LL/CL post-LLND, especially for patients with heavy metastasis of the lymph nodes in the IV region.

Isoandrographolide from Andrographis paniculata ameliorates tubulointerstitial fibrosis in ureteral obstruction-induced mice, associated with negatively regulating AKT/GSK-3ß/ß-cat signaling pathway.

Tubulointerstitial fibrosis (TIF) is a prominent pathological manifestation for the progression of almost all chronic kidney diseases (CKDs) to end-stage renal failure. However, there exist few efficient therapies to cure TIF. Our recent results showed that (8R, 12S)-isoandrographolide (ISA), a diterpenoid lactone ingredient of traditional Chinese herbal Andrographis paniculata (Burm.f.) Nees, exhibited anti-pulmonary fibrosis in silica-induced mice. Herein, we investigated the therapeutic effect of ISA on TIF, using mice subjected to unilateral ureteral obstruction (UUO) and human kidney proximal tubular epithelial (HK-2) cells treated with transforming growth factor-ß1 (TGF-ß1) or tumor necrosis factor-α (TNF-α). The pathological changes and collagen deposition results displayed that ISA administration significantly attenuated inflammatory response, ameliorated TIF, and protected the kidney injury. Interestingly, ISA revealed much lower cytotoxicity on HK-2 cells, but exhibited stronger inhibitory effect on tubular epithelial mesenchymal transformation (EMT) and inflammation, as compared to andrographolide (AD), the major ingredient of A. paniculata extract that has been reported to ameliorate TIF in diabetic nephropathy mice. It was further clarified that the amelioration of TIF by ISA was associated with suppressing the aberrant activation of AKT/GSK-3ß/ß-catenin pathway through network pharmacology analysis and experimental validation. Taken together, these findings indicate that ISA is a promising lead compound for development of anti-TIF, and even broad-spectrum anti-fibrotic drugs.

Small-molecule activators specific to adenine base editors through blocking the canonical TGF-ß pathway.

Adenine base editors (ABEs) catalyze A-to-G conversions, offering therapeutic options to treat the major class of human pathogenic single nucleotide polymorphisms (SNPs). However, robust and precise editing at diverse genome loci remains challenging. Here, using high-throughput chemical screening, we identified and validated SB505124, a selective ALK5 inhibitor, as an ABE activator. Treating cells with SB505124 enhanced on-target editing at multiple genome loci, including epigenetically refractory regions, and showed little effect on off-target conversion on the genome. Furthermore, SB505124 facilitated the editing of disease-associated genes in vitro and in vivo. Intriguingly, SB505124 served as a specific activator by selectively promoting ABE activity. Mechanistically, SB505124 promotes ABE editing, at least in part, by enhancing ABE expression and modulating DNA repair-associated genes. Our findings reveal the role of the canonical transforming growth factor-ß pathway in gene editing and equip ABEs with precise chemical control.