Evaluation of Real-World Tumor Response Derived From Electronic Health Record Data Sources: A Feasibility Analysis in Patients With Metastatic Non-Small Cell Lung Cancer Treated With Chemotherapy.

PURPOSE: Real-world data (RWD) holds promise for ascribing a real-world (rw) outcome to a drug intervention; however, ascertaining rw-response to treatment from RWD can be challenging. Friends of Cancer Research formed a collaboration to assess available data attributes related to rw-response across RWD sources to inform methods for capturing, defining, and evaluating rw-response. MATERIALS AND METHODS: This retrospective noninterventional (observational) study included seven electronic health record data companies (data providers) providing summary-level deidentified data from 200 patients diagnosed with metastatic non-small cell lung cancer (mNSCLC) and treated with first-line platinum doublet chemotherapy following a common protocol. Data providers reviewed the availability and frequency of data components to assess rw-response (ie, images, radiology imaging reports, and clinician response assessments). A common protocol was used to assess and report rw-response end points, including rw-response rate (rwRR), rw-duration of response (rwDOR), and the association of rw-response with rw-overall survival (rwOS), rw-time to treatment discontinuation (rwTTD), and rw-time to next treatment (rwTTNT). RESULTS: The availability and timing of clinician assessments was relatively consistent across data sets in contrast to images and image reports. Real-world response was analyzed using clinician response assessments (median proportion of patients evaluable, 77.5%), which had the highest consistency in the timing of assessments. Relative consistency was observed across data sets for rwRR (median 46.5%), as well as the median and directionality of rwOS, rwTTD, and rwTTNT. There was variability in rwDOR across data sets. CONCLUSION: This collaborative effort demonstrated the feasibility of aligning disparate data sources to evaluate rw-response end points using clinician-documented responses in patients with mNSCLC. Heterogeneity exists in the availability of data components to assess response and related rw-end points, and further work is needed to inform drug effectiveness evaluation within RWD sources.

Inhibition of glycosphingolipid synthesis with eliglustat in combination with immune checkpoint inhibitors in advanced cancers: preclinical evidence and phase I clinical trial.

Glycosphingolipids (GSLs) are abundantly expressed in cancer cells. The effects of GSL-targeted immunotherapies are not fully understood. Here, we show that the inhibition of GSL synthesis with the UDP-glucose ceramide glucosyltransferase inhibitor eliglustat can increase the exposure of the major histocompatibility complex (MHC) and tumour antigen peptides, enhancing the antitumour response of CD8+ T cells in a range of tumour models. We therefore conducted a proof-of-concept phase I trial on the combination of eliglustat and an anti-PD-1 antibody for the treatment of advanced cancers (NCT04944888). The primary endpoints were safety and feasibility, and the secondary endpoint was antitumor activity. All prespecified endpoints were met. Among the 31 enrolled patients, only 1 patient experienced a grade 3 adverse event (AE), and no grade 4 AEs were observed. The objective response rate was 22.6% and the disease control rate reached 71%. Of the 8 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer, one achieved complete response and two each had partial response and stable disease. In summary, inhibiting the synthesis of GSLs might represent an effective immunotherapy approach.

Metabolomic analysis revealed the inflammatory and oxidative stress regulation in response to Vibrio infection in Plectropomus leopardus.

Frequent outbreaks of infectious diseases in aquaculture have led to significant economic losses. The leopard coral grouper (Plectropomus leopardus) often suffers from vibriosis. Improving host immunity presents a superior strategy for disease control, with minimal side effects compared to the use of antibiotics, highlighting the necessity of exploring the mechanisms underlying the fish's response to pathogen infections. Here, we conducted a comparative metabolomic analysis on the livers of the P. leopardus infected with Vibrio harveyi. A total of 1124 differential metabolites (DMs) were identified, with 190, 218, 359, and 353 DMs being identified at 6, 12, 24, and 48 h post-infection (hpi), respectively. Then, based on the time series analysis, we found that the lipid metabolism pathways were modulated in response to the Vibrio infection, with an increase in the quantity of eicosanoids and gycerophospholipids (GPLs), as well as a decrease in the quantity of bile acids (BAs), vitamin D, and sex hormones. Furthermore, 13 enriched pathways involving 31 DMs were identified through KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analyses. We identified histamine, 15(S)-HpETE, and anandamide in the transient receptor potential (TRP) channels pathway, as well as (7S,8S)-DiHODE, 5S,8R-DiHODE, and 13(S)-HpODE in the linoleic acid (LA) metabolism pathway. The DM levels increased, which may be attributed to inflammation. The DMs in the thyroid hormone synthesis pathway were identified, and the contents of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) decreased, which may be crucial in antioxidants. Our findings highlighted the dynamic adjustments in lipid metabolism and the response to inflammation and oxidative stress during the infection of V. harveyi in P. leopardus. This study not only deepens our understanding of the metabolic underpinnings of fish immune responses but also lays the groundwork for research into functional metabolomics and mechanisms of disease resistance.

BMAL1/PGC1α4-FNDC5/irisin axis impacts distinct outcomes of time-of-day resistance exercise.

BACKGROUND: Resistance exercise leads to improved muscle function and metabolic homeostasis. Yet how circadian rhythm impacts exercise outcomes and its molecular transduction remains elusive. METHODS: Human volunteers were subjected to 4 weeks of resistance training protocols at different times of day to assess training outcomes and their associations with myokine irisin. Based on rhythmicity of Fibronectin type III domain containing 5 (FNDC5/irisin), we trained wild type and FNDC5 knockout mice at late active phase (high FNDC5/irisin level) or late rest phase (low FNDC5/irisin level) to analyze exercise benefits on muscle function and metabolic homeostasis. Molecular analysis was performed to understand the regulatory mechanisms of FNDC5 rhythmicity and downstream signaling transduction in skeletal muscle. RESULTS: In this study, we showed that regular resistance exercises performed at different times of day resulted in distinct training outcomes in humans, including exercise benefits and altered plasma metabolomics. We found that muscle FNDC5/irisin levels exhibit rhythmicity. Consistent with human data, compared to late rest phase (low irisin level), mice trained chronically at late active phase (high irisin level) gained more muscle capacity along with improved metabolic fitness and metabolomics/lipidomics profiles under a high-fat diet, whereas these differences were lost in FNDC5 knockout mice. Mechanistically, Basic helix-loop-helix ARNT like 1 (BMAL1) and Peroxisome proliferative activated receptor, gamma, coactivator 1 alpha 4 (PGC1α4) induce FNDC5/irisin transcription and rhythmicity, and the signaling is transduced via αV integrin in muscle. CONCLUSION: Together, our results offered novel insights that exercise performed at distinct times of day determines training outcomes and metabolic benefits through the rhythmic regulation of the BMAL1/PGC1α4-FNDC5/irisin axis.

An insoluble cellulose nanofiber with robust expansion capacity protects against obesity.

An imbalance between energy intake and energy expenditure predisposes obesity and its related metabolic diseases. Soluble dietary fiber has been shown to improve metabolic homeostasis mainly via microbiota reshaping. However, the application and metabolic effects of insoluble fiber are less understood. Herein, we employed nanotechnology to design citric acid-crosslinked carboxymethyl cellulose nanofibers (CL-CNF) with a robust capacity of expansion upon swelling. Supplementation with CL-CNF reduced food intake and delayed digestion rate in mice by occupying stomach. Besides, CL-CNF treatment mitigated diet-induced obesity and insulin resistance in mice with enhanced energy expenditure, as well as ameliorated inflammation in adipose tissue, intestine and liver and reduced hepatic steatosis, without any discernible signs of toxicity. Additionally, CL-CNF supplementation resulted in enrichment of probiotics such as Bifidobacterium and decreased in the relative abundances of deleterious microbiota expressing bile salt hydrolase, which led to increased levels of conjugated bile acids and inhibited intestinal FXR signaling to stimulate the release of GLP-1. Taken together, our findings demonstrate that CL-CNF administration protects mice from diet-induced obesity and metabolic dysfunction by reducing food intake, enhancing energy expenditure and remodeling gut microbiota, making it a potential therapeutic strategy against metabolic diseases.

Multi-organ transcriptomic profiles and gene-regulation network underlying vibriosis resistance in tongue sole.

Vibrio spp. are major pathogens responsible for mortality and disease in various marine aquaculture organisms. Effective disease control and genetic breeding strategies rely heavily on understanding host vibriosis resistance mechanisms. The Chinese tongue sole (Cynoglossus semilaevis) is economically vital but suffers from substantial mortalities due to vibriosis. Through continuous selective breeding, we have successfully obtained vibriosis-resistant families of this species. In this study, we conducted RNA-seq analysis on three organs, including liver, spleen and intestine from selected resistant and susceptible tongue soles. Additionally, we integrated these data with our previously published RNA-seq datasets of skin and gill, enabling the construction of organ-specific transcriptional profiles and a comprehensive gene co-expression network elucidating the differences in vibriosis resistance. Furthermore, we identified 12 modules with organ-specific functional implications. Overall, our findings provide a valuable resource for investigating the molecular basis of vibriosis resistance in fish, offering insights into target genes and pathways essential for molecular selection and genetic manipulation to enhance vibriosis resistance in fish breeding programs.

Immune and regulative characterization of complement-related gene cfhl5 in response to Vibrio harveyi challenge in Cynoglossus semilaevis.

Complement factor H-related protein (CFHR) plays an important role in regulating complement activation and defensive responses. The function of CFHR2 (complement factor H related 2), a member of the CFHR family, in fish remains unclear. Here, we report the genetic relationship, expression characteristics and regulatory mechanism of cfhl5 (complement factor H like 5) gene, which encodes CFHR2 in Chinese tongue sole. We observed that the cfhl5 gene was widely expressed in several tissues, such as brain, heart and immune organs, and was most abundantly expressed in liver. After injection with Vibrio harveyi, the expression of cfhl5 was up-regulated significantly in liver, spleen and kidney at 12 or 24 hours post infection (hpi), suggesting an involvement of this gene in the acute immune response. Knockdown of cfhl5 in liver cells significantly up-regulated the expression of the pro-inflammatory cytokines tnf-α (tumor necrosis factor-alpha) and il1ß (interleukin-1beta), the immunomodulatory factor il10 (interleukin-10) and the lectin complement pathway gene masp1 (MBL-associated serine protease 1), and down-regulated the expression of complement components c3 (complement 3) and cfi (complement factor I). In our previous work, we found that cfhl5 gene was significantly higher methylated and lower expressed in the resistant family compared with the susceptible family. Therefore, we used dual-luciferase reporter system to determine the effect of DNA methylation on this gene and found that DNA methylation could inhibit the promoter activity to reduce its expression. These results demonstrated that the expression of cfhl5 is regulated by DNA methylation, and this gene might play an important role in the immune response by regulating the expression of cytokines and complement components genes in Chinese tongue sole.

FOXA3 regulates cholesterol metabolism to compensate for low uptake during the progression of lung adenocarcinoma.

Cholesterol metabolism is vital for multiple cancer progression, while how cholesterol affects lung, a low-cholesterol tissue, for cancer metastasis and the underlying mechanism remain unclear. In this study, we found that metastatic lung adenocarcinoma cells acquire cellular dehydrocholesterol and cholesterol by endogenous cholesterol biosynthesis, instead of uptake upon cholesterol treatment. Besides, we demonstrated that exogenous cholesterol functions as signaling molecule to induce FOXA3, a key transcription factor for lipid metabolism via GLI2. Subsequently, ChIP-seq analysis and molecular studies revealed that FOXA3 transcriptionally activated Hmgcs1, an essential enzyme of cholesterol biosynthesis, to induce endogenous dehydrocholesterol and cholesterol level for membrane composition change and cell migration. Conversely, FOXA3 knockdown or knockout blocked cholesterol biosynthesis and lung adenocarcinoma metastasis in mice. In addition, the potent FOXA3 inhibitor magnolol suppressed metastatic gene programs in lung adenocarcinoma patient-derived organoids (PDOs). Altogether, our findings shed light onto unique cholesterol metabolism and FOXA3 contribution to lung adenocarcinoma metastasis.

Inhibition of OGG1 ameliorates pulmonary fibrosis via preventing M2 macrophage polarization and activating PINK1-mediated mitophagy.

BACKGROUND: 8-Oxoguanine DNA glycosylase (OGG1), a well-known DNA repair enzyme, has been demonstrated to promote lung fibrosis, while the specific regulatory mechanism of OGG1 during pulmonary fibrosis remains unclarified. METHODS: A bleomycin (BLM)-induced mouse pulmonary fibrosis model was established, and TH5487 (the small molecule OGG1 inhibitor) and Mitochondrial division inhibitor 1 (Mdivi-1) were used for administration. Histopathological injury of the lung tissues was assessed. The profibrotic factors and oxidative stress-related factors were examined using the commercial kits. Western blot was used to examine protein expression and immunofluorescence analysis was conducted to assess macrophages polarization and autophagy. The conditional medium from M2 macrophages was harvested and added to HFL-1 cells for culture to simulate the immune microenvironment around fibroblasts during pulmonary fibrosis. Subsequently, the loss- and gain-of function experiments were conducted to further confirm the molecular mechanism of OGG1/PINK1. RESULTS: In BLM-induced pulmonary fibrosis, OGG1 was upregulated while PINK1/Parkin was downregulated. Macrophages were activated and polarized to M2 phenotype. TH5487 administration effectively mitigated pulmonary fibrosis, M2 macrophage polarization, oxidative stress and mitochondrial dysfunction while promoted PINK1/Parkin-mediated mitophagy in lung tissues of BLM-induced mice, which was partly hindered by Mdivi-1. PINK1 overexpression restricted M2 macrophages-induced oxidative stress, mitochondrial dysfunction and mitophagy inactivation in lung fibroblast cells, and OGG1 knockdown could promote PINK1/Parkin expression and alleviate M2 macrophages-induced mitochondrial dysfunction in HFL-1 cells. CONCLUSION: OGG1 inhibition protects against pulmonary fibrosis, which is partly via activating PINK1/Parkin-mediated mitophagy and retarding M2 macrophage polarization, providing a therapeutic target for pulmonary fibrosis.

Effectiveness of Yijinjing on cognitive and motor functions in patients with Parkinson's disease: study protocol for a randomized controlled trial.

Background: Parkinson's disease (PD) is a common neurodegenerative disorder that affects motor and non-motor functions, significantly reducing patients' quality of life. No effective drug-based treatments are known to solve this problem. Non-drug therapies such as Yijinjing exercise have shown potential in improving cognitive and motor functions in PD patients. However, solid evidence must still be provided to support their clinical efficacy. This study aims to evaluate the clinical efficacy of Yijinjing exercise interventions in PD patients and explore the underlying mechanisms between the cognitive and motor functions in PD. Methods: This is a single-center randomized controlled trial in which 96 eligible PD patients will be randomly assigned to receive either Yijinjing exercise group or brisk walking group or control group in a ratio of 1:1:1. Interventions (Yijinjing exercise or brisk walking training, 40 min per session) will be provided in 3 sessions per week (Monday, Wednesday, Friday) for 12 weeks, with a total of 36 sessions. After the treatment, there will be a 1-month follow-up period. The primary outcomes will be measured using the Montreal Cognitive Assessment (MoCA) and the Unified Parkinson's Disease Rating Scale motor section (UPDRS-III). Secondary outcomes include balance function, executive function, walking function, sleep quality, and quality of life. Additionally, the prefrontal cerebral and sensorimotor cortex blood oxygen signal level will be collected to explore the underlying mechanisms. All outcomes will be assessed at baseline, at the end of 12 weeks of treatment and after an additional 1-month follow-up period. Discussion: The results of the study protocol will provide high-quality evidence for the potential of intervention measures based on the Yijinjing exercise to improve the cognitive and activity levels of Parkinson's disease patients. We envision the Yijinjing exercise as a non-pharmacological family activity that can provide a new and more effective method for the treatment of Parkinson's disease patients or those at risk. Clinical trial registration: This study was approved by the Ethics Committee of the Second Rehabilitation Hospital of Shanghai (2020-05-01). The trial has been registered in the China Clinical Trials Registry (ChiCTR2200055636).

CD146, a therapeutic target involved in cell plasticity.

Since its identification as a marker for advanced melanoma in the 1980s, CD146 has been found to have multiple functions in both physiological and pathological processes, including embryonic development, tissue repair and regeneration, tumor progression, fibrosis disease, and inflammations. Subsequent research has revealed that CD146 is involved in various signaling pathways as a receptor or co-receptor in these processes. This correlation between CD146 and multiple diseases has sparked interest in its potential applications in diagnosis, prognosis, and targeted therapy. To better comprehend the versatile roles of CD146, we have summarized its research history and synthesized findings from numerous reports, proposing that cell plasticity serves as the underlying mechanism through which CD146 contributes to development, regeneration, and various diseases. Targeting CD146 would consequently halt cell state shifting during the onset and progression of these related diseases. Therefore, the development of therapy targeting CD146 holds significant practical value.

Cross-Modal Retrieval With Noisy Correspondence via Consistency Refining and Mining.

The success of existing cross-modal retrieval (CMR) methods heavily rely on the assumption that the annotated cross-modal correspondence is faultless. In practice, however, the correspondence of some pairs would be inevitably contaminated during data collection or annotation, thus leading to the so-called Noisy Correspondence (NC) problem. To alleviate the influence of NC, we propose a novel method termed Consistency REfining And Mining (CREAM) by revealing and exploiting the difference between correspondence and consistency. Specifically, the correspondence and the consistency only be coincident for true positive and true negative pairs, while being distinct for false positive and false negative pairs. Based on the observation, CREAM employs a collaborative learning paradigm to detect and rectify the correspondence of positives, and a negative mining approach to explore and utilize the consistency. Thanks to the consistency refining and mining strategy of CREAM, the overfitting on the false positives could be prevented and the consistency rooted in the false negatives could be exploited, thus leading to a robust CMR method. Extensive experiments verify the effectiveness of our method on three image-text benchmarks including Flickr30K, MS-COCO, and Conceptual Captions. Furthermore, we adopt our method into the graph matching task and the results demonstrate the robustness of our method against fine-grained NC problem. The code is available on https://github.com/XLearning-SCU/2024-TIP-CREAM.

Iron overload in hypothalamic AgRP neurons contributes to obesity and related metabolic disorders.

Iron overload is closely associated with metabolic dysfunction. However, the role of iron in the hypothalamus remains unclear. Here, we find that hypothalamic iron levels are increased, particularly in agouti-related peptide (AgRP)-expressing neurons in high-fat-diet-fed mice. Using pharmacological or genetic approaches, we reduce iron overload in AgRP neurons by central deferoxamine administration or transferrin receptor 1 (Tfrc) deletion, ameliorating diet-induced obesity and related metabolic dysfunction. Conversely, Tfrc-mediated iron overload in AgRP neurons leads to overeating and adiposity. Mechanistically, the reduction of iron overload in AgRP neurons inhibits AgRP neuron activity; improves insulin and leptin sensitivity; and inhibits iron-induced oxidative stress, endoplasmic reticulum stress, nuclear factor κB signaling, and suppression of cytokine signaling 3 expression. These results highlight the critical role of hypothalamic iron in obesity development and suggest targets for treating obesity and related metabolic disorders.

Zinc finger protein ZNF638 regulates triglyceride metabolism via ANGPTL8 in an estrogen dependent manner.

BACKGROUND AND AIM: Triglyceride (TG) levels are closely related to obesity, fatty liver and cardiovascular diseases, while the regulatory factors and mechanism for triglyceride homeostasis are still largely unknown. Zinc Finger Protein 638 (ZNF638) is a newly discovered member of zinc finger protein family for adipocyte function in vitro. The aim of the present work was to investigate the role of ZNF638 in regulating triglyceride metabolism in mice. METHODS: We generated ZNF638 adipose tissue specific knockout mice (ZNF638 FKO) by cross-breeding ZNF638 flox to Adiponectin-Cre mice and achieved adipose tissue ZNF638 overexpression via adenoviral mediated ZNF638 delivery in inguinal adipose tissue (iWAT) to examined the role and mechanisms of ZNF638 in fat biology and whole-body TG homeostasis. RESULTS: Although ZNF638 FKO mice showed similar body weights, body composition, glucose metabolism and serum parameters compared to wild-type mice under chow diet, serum TG levels in ZNF638 FKO mice were increased dramatically after refeeding compared to wild-type mice, accompanied with decreased endothelial lipoprotein lipase (LPL) activity and increased lipid absorption of the small intestine. Conversely, ZNF638 overexpression in iWAT reduced serum TG levels while enhanced LPL activity after refeeding in female C57BL/6J mice and obese ob/ob mice. Specifically, only female mice exhibited altered TG metabolism upon ZNF638 expression changes in fat. Mechanistically, RNA-sequencing analysis revealed that the TG regulator angiopoietin-like protein 8 (Angptl8) was highly expressed in iWAT of female ZNF638 FKO mice. Neutralizing circulating ANGPTL8 in female ZNF638 FKO mice abolished refeeding-induced TG elevation. Furthermore, we demonstrated that ZNF638 functions as a transcriptional repressor by recruiting HDAC1 for histone deacetylation and broad lipid metabolic gene suppression, including Angptl8 transcription inhibition. Moreover, we showed that the sexual dimorphism is possibly due to estrogen dependent regulation on ZNF638-ANGPTL8 axis. CONCLUSION: We revealed a role of ZNF638 in the regulation of triglyceride metabolism by affecting Angptl8 transcriptional level in adipose tissue with sexual dimorphism.

Transferrin receptor levels and its rare variant are associated with human obesity.

AIM: Iron homeostasis is critical for functional respiratory chain complex of mitochondrial, thus potentially contributing to fat biology and energy homeostasis. Transferrin receptor (Tfrc) binds to transferrin for extracellular iron uptake and is recently reported to be involved in brown fat development and functionality. However, whether TFRC levels and variants are associated with human obesity is unknown. METHODS: To investigate the association of TFRC levels and variants with human obesity, fat biopsies were obtained from surgery. Exon-sequencing and genetic assessments were conducted of a case-control study. For TFRC levels assessment in fat biopsy, 9 overweight and 12 lean subjects were involved. For genetic study, obese (n = 1271) and lean subjects (n = 1455) were involved. TFRC levels were compared in abdominal mesenteric fat of pheochromocytoma patients versus control subjects, and overweight versus lean subjects. For genetic study, whole-exome sequencing of obese and matched control subjects were conducted and analyzed. In addition, the possible disruption in protein stability of TFRC variant was assessed by structural and molecular analysis. RESULTS: TFRC levels are increased in human browning adipose tissue and decreased in fat of overweight patients. Besides, TFRC levels are negatively correlated with body mass index and positively correlated with uncoupling protein 1 levels. Furthermore, a rare heterozygous missense variant p.I337V in TFRC shows a tendency to enrich in obese subjects. Structural and functional study reveals impaired protein stability of the TFRC variant compared to wild-type. CONCLUSIONS: Reduced TFRC levels and its rare variant p.I337V with protein instability are associated with human obesity.

Highly sensitive determination of multiple pesticide residues in foods by supercritical fluid chromatography coupled with ion mobility quadrupole time-of-flight mass spectrometry.

This experiment aimed to establish a green, simple and highly sensitive method (supercritical fluid chromatography (SFC) coupled with ion mobility quadrupole time-of-flight mass spectrometry (IM-Q-TOF/MS)) for the detection of multiple pesticides in foods. During the experiments, several important SFC parameters, such as stationary phase, modifier, make-up solution, back-temperature and back-pressure were optimized. Here, single-field collision cross section (CCS) values and multifield CCS values of 20 pesticides were examined by IM-Q-TOF/MS as highly specific parameters with excellent experimental precision. In addition, based on accurate mass matching and fragment ion comparison, mass fragments were obtained by IM-Q-TOF/MS, which elucidated the regularities of compound structure and characteristic fragment ions. Under the optimized conditions, satisfactory linearity (R2 ≥ 0.9989) and recoveries (79.60 % to 112.97 %) were obtained. The intra- and interday precisions were favorable, with RSDs lower than 4.91 and 7.65 %, respectively. Additionally, the method showed low limits of detection (0.1-8.8 ng/mL). The proposed method has been successfully applied to the highly sensitive detection of phenylurea herbicide, triazine herbicides, organophosphorus pesticide, pyrethroid insecticide and acaricide in yam and potato.

Characterisation of forkhead box protein A3 as a key transcription factor for hepatocyte regeneration.

Background & Aims: Liver regeneration is vital for the recovery of liver function after injury, yet the underlying mechanism remains to be elucidated. Forkhead box protein A3 (FOXA3), a member of the forkhead box family, plays important roles in endoplasmic reticulum stress sensing, and lipid and glucose homoeostasis, yet its functions in liver regeneration are unknown. Methods: Here, we explored whether Foxa3 regulates liver regeneration via acute and chronic liver injury mice models. We further characterised the molecular mechanism by chromatin immunoprecipitation sequencing and rescue experiments in vivo and in vitro. Then, we assessed the impact of Foxa3 pharmacological activation on progression and termination of liver regeneration. Finally, we confirmed the Foxa3-Cebpb axis in human liver samples. Results: Foxa3 is dominantly expressed in hepatocytes and cholangiocytes and is induced upon partial hepatectomy (PH) or carbon tetrachloride (CCl4) administration. Foxa3 deficiency in mice decreased cyclin gene levels and delayed liver regeneration after PH, or acute or chronic i.p. CCl4 injection. Conversely, hepatocyte-specific Foxa3 overexpression accelerated hepatocytes proliferation and attenuated liver damage in an CCl4-induced acute model. Mechanistically, Foxa3 directly regulates Cebpb transcription, which is involved in hepatocyte division and apoptosis both in vivo and in vitro. Of note, Cebpb overexpression in livers of Foxa3-deficient mice rescued their defects in cell proliferation and regeneration upon CCl4 treatment. In addition, pharmacological induction of Foxa3 via cardamonin speeded up hepatocyte proliferation after PH, without interfering with liver regeneration termination. Finally, Cebpb and Ki67 levels had a positive correlation with Foxa3 expression in human chronic disease livers. Conclusions: These data characterise Foxa3 as a vital regulator of liver regeneration, which may represent an essential factor to maintain liver mass after liver injury by governing Cebpb transcription. Impact and Implications: Liver regeneration is vital for the recovery of liver function after chemical insults or hepatectomy, yet the underlying mechanism remains to be elucidated. Herein, via in vitro and in vivo models and analysis, we demonstrated that Forkhead box protein A3 (FOXA3), a Forkhead box family member, maintained normal liver regeneration progression by governing Cebpb transcription and proposed cardamonin as a lead compound to induce Foxa3 and accelerate liver repair, which signified that FOXA3 may be a potential therapeutic target for further preclinical study on treating liver injury.

Facile fabrication of CoAl-LDH nanosheets for efficient rhodamine B degradation via peroxymonosulfate activation.

Layered double hydroxides (LDHs) have been extensively investigated as promising peroxymonosulfate (PMS) activators for the degradation of organic pollutants. However, bulk LDHs synthesized using conventional methods possess a closely stacked layered structure, which seriously blocks active sites and yields low intrinsic activity. In this study, we exfoliated bulk CoAl-LDHs to fabricate CoAl-LDH nanosheets by alkali-etching and Ostwald ripening via a simple hydrothermal process in a KOH solution. The exfoliated LDHs possessed the typical nanosheet structure with more exposed active sites for PMS activation, and hence, boosted the degradation of the pollutants. CoAl-1 exhibited an outstanding catalytic performance as the PMS activator for rhodamine B (RhB) degradation with the apparent rate constant of 0.1687 min-1, which was about 3.63 and 5.02 times higher than that of commercial nano-Co3O4 and bulk CoAl-LDH, respectively. The maximum RhB degradation of 93.1% was achieved at the optimal reaction conditions: catalyst dose 0.1 g L-1, PMS concentration 0.3 mM, pH 7, and temperature 298 K. Further analysis of RhB degradation mechanism illustrated that singlet oxygen (1O2) dominated RhB degradation in the CoAl-1/PMS system, while ˙OH, ˙O2-, and ˙SO4- may mainly serve as the intermediates for the generation of 1O2 and were indirectly involved in the degradation. This study provides a promising strategy for developing two-dimensional LDH nanosheets for wastewater remediation.

Genome-wide DNA methylation mediates the resistance to vibriosis in Cynoglossus semilaevis.

Chinese tongue sole (Cynoglossus semilaevis) is an economically important marine fish in China. However, vibriosis has caused huge mortality and economic losses in its culturing industry. To reveal the effect of DNA methylation on the resistance to vibriosis in tongue sole, we conducted RNA sequencing and whole genome bisulfite sequencing (WGBS), and compared the gene expressions and DNA methylation patterns between the resistant and susceptible families. We identified a total of 741 significantly differentially expressed genes (DEGs) in kidney and 17460 differentially methylated genes (DMGs), which were both enriched in immune-related pathways, such as "cAMP signaling pathway" and "NOD-like receptor signaling pathway". Through the correlation analysis of DEGs and DMGs, we identified two important immune pathways, including "complement and coagulation cascades", and "cytokine-cytokine receptor interaction", which played important roles in regulating the inflammation level and immune homeostasis. For example, the expression of proinflammatory cytokine il17c was down-regulated under the regulation of DNA methylation; in addition, the expression of protease-activated receptor 3 (par3) was up-regulated, which could induce the up-expressionof il8. These results demonstrated that the regulation of DNA methylation on the genes involved in immune responses might contribute to the resistance to vibriosis in tongue sole, and provided a basis for the control of diseases in fish aquaculture.