ROS-responsive carboxymethyl chitosan nanoparticles loaded with astaxanthin for alleviating oxidative damage in intestinal cells.

The controlled release of antioxidant substances at the intestinal oxidative damage site is crucial for alleviating intestine-related diseases. Herein, the novel ROS-responsive carrier was synthesized through simple amidation reaction between carboxymethyl chitosan (CMC) and methionine (Met), a natural organic compound containing ROS-responsive linkages (thioether). Initially, astaxanthin (AXT) nanoparticles (AXT2@CMT) with excellent stability and drug loading capacity (39.68 ± 0.23 µg/mL) were prepared by optimizing various reaction conditions. In the simulated high-concentration ROS environment of the intestine, CMT achieved a transition from hydrophobic groups (thioether) into hydrophilic groups (sulfone), which was conducive to the controlled release of AXT. In vitro cell experiments revealed that AXT2@CMT could effectively alleviate the oxidative damage in intestinal epithelioid cell line No. 6 (IEC-6 cell) caused by H2O2. This study achieved a straightforward preparation of ROS-responsive nanocarrier through food ingredients, offering a theoretical foundation for the controlled release of AXT at the intestinal oxidative damage site.

Enantioselectivity regulation of antibody against chiral herbicide metolachlor based on interaction at chiral center.

Enantioselective antibodies have emerged as great potential biomaterials in the fields of immunoassays and chiral separation. However, cross-reactivity of antibodies to the distomer may severely restrict the application. Comprehending the interaction mechanism between antibodies and enantiomers could be beneficial to produce superior enantioselective antibodies. In this study, a pair of recombinant antibodies (RAbs) against metolachlor enantiomers at chiral carbon (αSS-MET and αSR-MET) were generated and characterized. The αSS-MET-RAb and αSR-MET-RAb showed comparable sensitivity and specificity to the parental monoclonal antibodies by icELISA, with IC50 values of 3.45 and 223.77 ng/mL, respectively. Moreover, the complex structures of RAbs and corresponding eutomer were constructed and analyzed, and site-specific mutagenesis was utilized to verify the reliability of the enantioselective mechanism elucidated. It demonstrated that the strength of the interaction between the chiral center region of eutomer and the antibody was the key factor for the enantioselectivity of antibody. Increasing this interaction could limit the conformational adjustment of the distomer in a specific chiral recognition cavity, thus decreasing the affinity of the antibody to the distomer. This work provided the in-depth analysis of enantioselective mechanism for two RAbs and paved the way to regulate antibody enantioselective performance for immunoassays of chiral compounds.

Targeting histone demethylases JMJD3 and UTX: selenium as a potential therapeutic agent for cervical cancer.

BACKGROUND: The intriguing connection between selenium and cancer resembles a captivating puzzle that keeps researchers engaged and curious. While selenium has shown promise in reducing cancer risks through supplementation, its interaction with epigenetics in cervical cancer remains a fascinating yet largely unexplored realm. Unraveling the intricacies of selenium's role and its interaction with epigenetic factors could unlock valuable insights in the battle against this complex disease. RESULT: Selenium has shown remarkable inhibitory effects on cervical cancer cells in various ways. In in vitro studies, it effectively inhibits the proliferation, migration, and invasion of cervical cancer cells, while promoting apoptosis. Selenium also demonstrates significant inhibitory effects on human cervical cancer-derived organoids. Furthermore, in an in vivo study, the administration of selenium dioxide solution effectively suppresses the growth of cervical cancer tumors in mice. One of the mechanisms behind selenium's inhibitory effects is its ability to inhibit histone demethylases, specifically JMJD3 and UTX. This inhibition is observed both in vitro and in vivo. Notably, when JMJD3 and UTX are inhibited with GSK-J4, similar biological effects are observed in both in vitro and in vivo models, effectively inhibiting organoid models derived from cervical cancer patients. Inhibiting JMJD3 and UTX also induces G2/M phase arrest, promotes cellular apoptosis, and reverses epithelial-mesenchymal transition (EMT). ChIP-qPCR analysis confirms that JMJD3 and UTX inhibition increases the recruitment of a specific histone modification, H3K27me3, to the transcription start sites (TSS) of target genes in cervical cancer cells (HeLa and SiHa cells). Furthermore, the expressions of JMJD3 and UTX are found to be significantly higher in cervical cancer tissues compared to adjacent normal cervical tissues, suggesting their potential as therapeutic targets. CONCLUSIONS: Our study highlights the significant inhibitory effects of selenium on the growth, migration, and invasion of cervical cancer cells, promoting apoptosis and displaying promising potential as a therapeutic agent. We identified the histone demethylases JMJD3 and UTX as specific targets of selenium, and their inhibition replicates the observed effects on cancer cell behavior. These findings suggest that JMJD3 and UTX could be valuable targets for selenium-based treatments of cervical cancer.

Nanoscale detection of carbon dots-induced changes in actin skeleton of neural cells.

Understanding the cytotoxicity of fluorescent carbon dots (CDs) is crucial for their applications, and various biochemical assays have been used to study the effects of CDs on cells. Knowledge on the effects of CDs from a biophysical perspective is integral to the recognition of their cytotoxicity, however the related information is very limited. Here, we report that atomic force microscopy (AFM) can be used as an effective tool for studying the effects of CDs on cells from the biophysical perspective. We achieve this by integrating AFM-based nanomechanics with AFM-based imaging. We demonstrate the performance of this method by measuring the influence of CDs on living human neuroblastoma (SH-SY5Y) cells at the single-cell level. We find that high-dose CDs can mechanically induce elevated normalized hysteresis (energy dissipation during the cell deformation) and structurally impair actin skeleton. The nanomechanical change highly correlates with the alteration of actin filaments, indicating that CDs-induced changes in SH-SY5Y cells are revealed in-depth from the AFM-based biophysical aspect. We validate the reliability of the biophysical observations using conventional biological methods including cell viability test, fluorescent microscopy, and western blot assay. Our work contributes new and significant information on the cytotoxicity of CDs from the biophysical perspective.

Central Chirality and Axial Chirality Recognition of the Enantioselective Antibodies to Herbicide Metolachlor.

Enantioselective antibodies have emerged as efficient tools in the field of chiral chemical detection and separation. However, it is complicated to obtain a highly stereoselective antibody due to the unclear recognition mechanism. In this study, the hapten of metolachlor was synthesized and enantio-separated. The absolute configuration of the four haptens obtained was identified by the computed and experimental electronic circular dichroism comparison. Five polyclonal antibodies against the Rac-metolachlor and its enantiomers were generated by immunization. The cross-activity of all the 5 antibodies with 44 structural analogues, including metolachlor enantiomers, was tested. It demonstrated that antibodies have higher specificity to recognize central chirality than axial chirality. Especially, αRR-MET-Ab exhibited excellent specificity and stereoselectivity. Accordingly, 3D-QSAR models were constructed and revealed that paired stereoisomers exhibited opposite interactions with the antibodies. It is the first time that the antibodies against four stereoisomers were prepared and analyzed, which will be conducive to the rational design of the stereoselective antibodies.

Fractional CO2 Laser for Vulvar Tissue Rejuvenation: A Prospective Study.

Objective: Aging and changes in hormone levels influence the appearance of the vulva, including the texture, pigmentation, and other manifestations, all of which may largely affect the physical and mental health of women. This study aimed to evaluate the efficacy and safety of fractional carbon dioxide (CO2) laser treatment for vulvar rejuvenation in Chinese women. Background: The limited options currently available for vulvar rejuvenation raise concerns. There is insufficient evidence to determine whether the fractional CO2 laser can safely and effectively rejuvenate the vulvar area for women of various ages and races. Methods: The study included 17 patients (mean age = 36.4 years) treated three times by continuous fractional CO2 laser with an interval of 1 month between each session. The primary outcomes were changes in vulva texture and pigmentation. Treatment was evaluated using images of the patients. Baseline and posttreatment images were collected and evaluated using a scoring system from 0 to 3 to grade the vulvar texture and pigmentation changes. In addition, patients rated their degree of vaginal rejuvenation after the treatment using a scoring system from 0 to 3. Results: Fractional CO2 laser treatment effectively and significantly increased vulvar texture and decreased vulvar pigmentation after three sessions (p < 0.05). Patients also self-reported noticeable improvement. There were no adverse reactions during the treatment and follow-up. Conclusions: Fractional CO2 laser treatment is a safe and effective method for vulvar rejuvenation in women.

Maintaining the working state of firefighters by utilizing self-concept clarity as a resource.

The working state of firefighters is important for their own safety as well as that of the general public. The purpose of this study is to investigate the correlations between self-concept clarity, resilience, work engagement, and job burnout among firefighters, as well as the impacts of self-concept clarity and resilience as resources that can maintain their working state. Based on data from 2,156 firefighters, analysis showed that self-concept clarity was negatively associated with job burnout and positively associated with work engagement. The results also showed that self-concept clarity had a direct effect on job burnout and work engagement, and an indirect effect by improving the firefighters' resilience. Maintaining and improving their self-concept clarity and resilience promises to be an effective strategy for guaranteeing the working state of firefighters.

Green synthesis of Zn2+ nanocarriers from Auricularia auricula fermentation broth with excellent antioxidant activity.

Nanoparticles (NPs) possessing nanoscale dimensions and remarkable antioxidant activity were synthesized via a green hydrothermal method utilizing Auricularia auricula fermentation broth, referred to as AFNPs. The functional groups on the surface of the AFNPs significantly contributed to the formation of AFNPs-Zn2+. The AFNPs-Zn2+ appeared a zinc retention rate of 40.80 % after gastrointestinal digestion. When compared to typical zinc supplements, AFNPs-Zn2+ did not exhibit visible cytotoxicity or hemolysis. Furthermore, AFNPs-Zn2+ demonstrated the ability to mitigate cell damage resulting from zinc deficiency. In vivo experiments showed that AFNPs-Zn2+ were mainly observed in the stomach, intestine, kidney, and testis after oral administration. In vivo distribution experiments indicated predominant presence of AFNPs-Zn2+ in the stomach, intestine, kidney, and testis following oral administration. This study highlights the potential for Auricularia auricula NPs to serve as the efficient, stable, and safe nanocarriers for Zn2+.

Diabetes Mellitus to Accelerated Atherosclerosis: Shared Cellular and Molecular Mechanisms in Glucose and Lipid Metabolism.

Diabetes is one of the critical independent risk factors for the progression of cardiovascular disease, and the underlying mechanism regarding this association remains poorly understood. Hence, it is urgent to decipher the fundamental pathophysiology and consequently provide new insights into the identification of innovative therapeutic targets for diabetic atherosclerosis. It is now appreciated that different cell types are heavily involved in the progress of diabetic atherosclerosis, including endothelial cells, macrophages, vascular smooth muscle cells, dependence on altered metabolic pathways, intracellular lipids, and high glucose. Additionally, extensive studies have elucidated that diabetes accelerates the odds of atherosclerosis with the explanation that these two chronic disorders share some common mechanisms, such as endothelial dysfunction and inflammation. In this review, we initially summarize the current research and proposed mechanisms and then highlight the role of these three cell types in diabetes-accelerated atherosclerosis and finally establish the mechanism pinpointing the relationship between diabetes and atherosclerosis.

Advances of Predicting Allosteric Mechanisms Through Protein Contact in New Technologies and Their Application.

Allostery is an intriguing phenomenon wherein the binding activity of a biological macromolecule is modulated via non-canonical binding site, resulting in synchronized functional changes. The mechanics underlying allostery are relatively complex and this review is focused on common methodologies used to study allostery, such as X-ray crystallography, NMR spectroscopy, and HDXMS. Different methodological approaches are used to generate data in different scenarios. For example, X-ray crystallography provides high-resolution structural information, NMR spectroscopy offers dynamic insights into allosteric interactions in solution, and HDXMS provides information on protein dynamics. The residue transition state (RTS) approach has emerged as a critical tool in understanding the energetics and conformational changes associated with allosteric regulation. Allostery has significant implications in drug discovery, gene transcription, disease diagnosis, and enzyme catalysis. Enzymes' catalytic activity can be modulated by allosteric regulation, offering opportunities to develop novel therapeutic alternatives. Understanding allosteric mechanisms associated with infectious organisms like SARS-CoV and bacterial pathogens can aid in the development of new antiviral drugs and antibiotics. Allosteric mechanisms are crucial in the regulation of a variety of signal transduction and cell metabolism pathways, which in turn govern various cellular processes. Despite progress, challenges remain in identifying allosteric sites and characterizing their contribution to a variety of biological processes. Increased understanding of these mechanisms can help develop allosteric systems specifically designed to modulate key biological mechanisms, providing novel opportunities for the development of targeted therapeutics. Therefore, the current review aims to summarize common methodologies that are used to further our understanding of allosteric mechanisms. In conclusion, this review provides insights into the methodologies used for the study of allostery, its applications in in silico modeling, the mechanisms underlying antibody allostery, and the ongoing challenges and prospects in advancing our comprehension of this intriguing phenomenon.

Dandelion (Taraxacum mongolicum) Extract Alleviated H2O2-Induced Oxidative Damage: The Underlying Mechanism Revealed by Metabolomics and Lipidomics.

Dandelion has received wide attention in food and medicine fields due to its excellent antioxidant properties. Nonetheless, the underlying mechanism of this action has not yet been fully clarified, particularly at the metabolic level. Herein, the effects of dandelion extract (DE) on H2O2-induced oxidative damage was investigated. The results indicate that the DE alleviated H2O2-induced cell damage (increased by 14.5% compared to H2O2 group), reduced the reactive oxygen species (ROS) level (decreased by 80.1% compared to H2O2 group), maintained the mitochondrial membrane potential (MMP) level, and increased antioxidant-related enzyme activities. Importantly, the metabolic response of PC12 cells indicates that H2O2 disturbed phospholipid metabolism and damaged cell membrane integrity. In addition, energy metabolism, the central nervous system, and the antioxidant-related metabolism pathway were perturbed. In contrast, DE rescued the H2O2-induced metabolic disorder and further alleviated oxidative damage. Collectively, these findings provide valuable stepping stones for a discussion of the mechanism and show the promise of DE as a suitable additive for functional food products.

Based on the Cancer Genome Atlas Database Development of a prognostic model of RNA binding protein in stomach adenocarcinoma.

The purpose of this study was to identify potential RNA binding proteins associated with the survival of gastric adenocarcinoma, as well as the corresponding biological characteristics and signaling pathways of these RNA binding proteins. RNA sequencing and clinical data were obtained from the cancer genome map (N = 32, T = 375) and the comprehensive gene expression database (GSE84437, N = 433). The samples in The Cancer Genome Atlas were randomly divided into a development group and a test group. A total of 1495 RNA binding protein related genes were extracted. Using nonparametric tests to analyze the difference of RNA binding protein related genes, 296 differential RNA binding proteins were obtained, 166 were up-regulated and 130 were down regulated. Twenty prognosis-related RNA binding proteins were screened using Cox regression, including 14 high-risk genes (hazard ratio > 1.0) and 6 low-risk genes (hazard ratio < 1.0). Seven RNA binding protein related genes were screened from the final prognostic model and used to construct a new prognostic model. Using the development group and test group, the model was verified with survival analysis, receiver operating characteristics curves and prognosis analysis curves. A prediction nomogram was finally developed and showed good prediction performance.

Lymphography using microbubbles and contrast-enhanced ultrasound (CEUS) before lymphatic supermicrosurgery for severe lymphorrhea of lower extremity.

Lymphaticovenous anastomosis (LVA) is an effective surgical treatment for lymphorrhea. However, the traditional indocyanine green (ICG) fluorescent lymphography mapping for lymphatic vessels has limitations, it can only depict the initial capillary lymphatic network localized in the dermis of the skin, which cannot visualize lymphatics deeper than 1.5 cm. A new mapping technique, microbubbles and contrast-enhanced ultrasound (CEUS) can address the problem. In one case of lymphocutaneous fistula, for the first time, we used microbubbles and CEUS technique for preoperative localization for LVAs. Microbubbles and CEUS can identify deep lymphatic vessels and better evaluate the function of lymphatic vessels. The patient's symptoms of edema and lymphorrhea improved clinically. Microbubbles and CEUS is an effective methods for identifying lymphatic vessels in lower limbs.

Fibroblast growth factor 1 ameliorates thin endometrium in rats through activation of the autophagic pathway.

Background: Thin endometrium is a reproductive disorder that affects embryo implantation. There are several therapies available for this disease, however they are not so effective. Fibroblast growth factor 1 (FGF1) is a member of fibroblast growth factor superfamily (FGFs), and it has been demonstrated that FGF1 expression was altered in samples collected from patients with thin endometrium. However, it is unclear if FGF1 could improve thin endometrium. The aim of this study was to investigate whether FGF1 have a therapeutic effect on thin endometrium. Methods: A model of thin endometrium induced by ethanol was constructed to investigate the effect and mechanism of action of FGF1 in thin endometrium. In the characterization experiments, 6-8 weeks female rats (n = 40) were divided into four groups: i) Control group; ii) Sham group; iii) Injured group; (iv) FGF1 therapy group. Endometrial tissues would be removed after three sexuel cycles after molding. Morphology and histology of the endometrium were evaluated by visual and hematoxylin and eosin staining. Masson staining and expression of α-SMA in endometrium showed the degree of endometrial fibrosis. Western blotting (PCNA、vWF and Vim) and immunohistochemistry (CK19 and MUC-1) demonstrated the effect of FGF1 on cell proliferation and angiogenesis. Moreover, immunohistochemistry (ER and PR) was used to explore the function of endometrium. The remaining rats (n = 36) were divided into three groups: i) Injured group; ii) FGF1 therapy group; and iii) 3-methyladenine. Western blotting (p38、p-p38、PI3K 、SQSTM1/p62、beclin-1 and LC3) was used to explore the mechanisms of FGF1. Results: In FGF1 therapy group, the morphology and histology of endometrium improved compared with the model group. Masson staining and the expression level of α-SMA showed that FGF1 could decrease the fibrotic area of endometrium. Besides, changes in ER and PR expression in the endometrium suggested that FGF1 could restore endometrium-related functions. Western blotting and immunohistochemistry revealed that PCNA, vWF, Vim, CK19 and MUC-1 were significantly increased after FGF1 treatment compared with the thin endometrium. In addition, Western blotting showed that p38, p-p38, PI3K, SQSTM1/p62, beclin-1 and LC3 levels were higher in FGF1 group than in the injured group. Conclusion: FGF1 application cured the thin endometrium caused by ethanol through autophagy mechanism.

Perinatal outcomes of twin emergency cerclage: comparison with expectant treatment and singleton emergency cerclage.

The present study aimed to evaluate the perinatal outcomes and influencing factors in twin pregnancies undergoing emergency cervical cerclage. The present retrospective cohort study included clinical data that were recorded between January 2015 and December 2021 at The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (China). The study included data from 103 pregnancies (26 twin and 77 singleton pregnancies) that underwent emergency cerclage and 17 twin pregnancies that underwent expectant treatment. The median gestational age of twin emergency cerclage was significantly lower than that of singleton emergency cerclage, but higher than that of expectant treatment (28.5, 34.0 and 24.0 weeks, respectively). The median interval to delivery of twin emergency cerclage was significantly lower than that of singleton emergency cerclage, but significantly higher than that of expectantly treated twin pregnancies (37.0, 78.0 and 7.0 days, respectively).IMPACT STATEMENTWhat is already known on this subject? An important cause of premature birth is cervical insufficiency. Cervical cerclage extends the gestational period of women with cervical insufficiency. According to 2019 SOGC's No. 373-Cervical Insufficiency and Cervical Cerclage, both twin and single pregnancies benefit from emergency cerclage. However, there is minimal information about the pregnancy outcomes of emergency cerclage in twin pregnancies.What the results of this study add? This study shows that the outcomes of pregnancy in twin pregnancies undergoing emergency cerclage were better than that of expectant treatment but worse than that in singleton pregnancies undergoing emergency cerclage.What the implications are of these findings for clinical practice and/or further research? In this study, pregnant women with cervical insufficiency in twin pregnancies can benefit from emergency cerclage, we should treat those pregnant women as early as possible.

A prognostic and immunological analysis of 7B-containing Kelch structural domain (KLHDC7B) in pan-cancer: a potential target for immunotherapy and survival.

PURPOSE: KLHDC7B is a member of Kelch family, with a Kelch domain in the C-terminal half, which plays a role in various cellular events, such as cytoskeletal arrangement, protein degradation, gene expression. Although there is increasing evidence supporting KLHDC7B's vital role in tumorigenesis, a systematic analysis of KLHDC7B in cancers remains lacking. Therefore, we intended to investigate the prognostic value for KLHDC7B across 33 cancer types and explore its potential immunological function. METHODS: GEO (Gene Expression Omnibus database) and TCGA (The Cancer Genome Atla) database were used to explore the role of KLHDC7B in 33 cancers. TIMER2, GEPIA2 and Kaplan-Meier plotter were utilized to explore the KLHDC7B expression level and prognostic value in different cancers. The pan cancer genetic variation and DNA methylation of KLHDC7B were analyzed by cBioPortal and MEXPRESS. TIMER2 was employed to investigate the correlation between KLHDC7B expression and immune infiltration. The relationship of KLHDC7B expression with TMB (tumor mutational burden) and MSI (microsatellite instability) were evaluated using Spearman correlation analysis. Finally, by GO and KEGG enrichment analysis, the underlying mechanisms of KLHDC7B in tumor pathophysiology were further investigated. RESULTS: KLHDC7B expression level was related to pathological stages, MSI, TMB, immune checkpoint and immune cell infiltration in most cancers. Especially, we found that the KLHDC7B expression was negatively correlated with the immune infiltration of Myeloid derived suppressor cells into TGCT and GBM. Additionally, survival analysis showed that the expression of KLHDC7B was connected with overall survival (OS) in 3 cancers and disease-free survival (DFS) in 5 cancers. Furthermore, the enrichment analysis revealed that the KLHDC7B collecting genes and binding proteins are related to the function of proteins and immune response. CONCLUSION: KLHDC7B demonstrates strong clinical utility as markers of prognostic and immune response in pan-cancer.

Transcription factor CncC potentially regulates cytochrome P450 CYP321A1-mediated flavone tolerance in Helicoverpa armigera.

Insect P450s play crucial roles in metabolizing insecticides and toxic plant allelochemicals. In this study, our results demonstrate that Helicoverpa armigera can adapt to a lower concentration of flavone (a flavonoid phytochemical), and P450 activities and CYP321A1 transcript levels significantly increase after exposure to flavone. RNAi-mediated knockdown of CYP321A1 significantly reduced the tolerance of H. armigera larvae to flavone. In addition, the regulatory mechanisms driving CYP321A1 induction following exposure to flavone were investigated. Flavone exposure significantly increased H2O2 generation in the larval midgut. The mRNA levels of HaCncC and HaMaf-s significantly increased in the midgut of H. armigera after exposure to flavone. Knockdown of HaCncC significantly inhibited expression of flavone-induced CYP321A1 and resulted in a decrease in flavone induction of CYP321A1. HaCncC knockdown significantly reduced the tolerance of H. armigera larvae to flavone. Taken together, these results indicate that HaCncC regulates expression of the CYP321A1 gene responsible for flavone tolerance in H. armigera.

Enhancement of organics and nutrient removal and microbial mechanism in vertical flow constructed wetland under a static magnetic field.

Low and unstable pollutant removal is regarded as the bottleneck problem in constructed wetlands (CWs) for wastewater treatment. This study investigated the effect of static magnetic field (MF) on enhancing the purification efficiency and microbial mechanism in vertical flow CW systems for treating domestic wastewater. The results showed that MF-CWs outperformed control systems in terms of treatment performance, with average removal efficiencies of COD, NH4+-N, TN, and TP reaching 92.58%, 73.58%, 72.53%, and 95.83%, respectively. The change of malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD) activity indicated that MF application was beneficial for plant health. Additionally, higher ammonia monooxygenase (AMO) activity in MF-CWs suggested the removal of NH4+-N was facilitated. The high-throughput sequencing results demonstrated that MF application could enrich the functional bacteria such as Patescibacteria phylum, mainly, including Gammaproteobacteria, Betaproteobacteria, and Alphaproteobacteria, which further accelerated pollutants transformation. These findings would be beneficial in understanding pollutant removal processes and their mechanism in CWs with MF application.

Intestinal peroxisome proliferator-activated receptor α-fatty acid-binding protein 1 axis modulates nonalcoholic steatohepatitis.

BACKGROUND AND AIMS: Peroxisome proliferator-activated receptor α (PPARα) regulates fatty acid transport and catabolism in liver. However, the role of intestinal PPARα in lipid homeostasis is largely unknown. Here, intestinal PPARα was examined for its modulation of obesity and NASH. APPROACH AND RESULTS: Intestinal PPARα was activated and fatty acid-binding protein 1 (FABP1) up-regulated in humans with obesity and high-fat diet (HFD)-fed mice as revealed by using human intestine specimens or HFD/high-fat, high-cholesterol, and high-fructose diet (HFCFD)-fed C57BL/6N mice and PPARA -humanized, peroxisome proliferator response element-luciferase mice. Intestine-specific Ppara or Fabp1 disruption in mice fed a HFD or HFCFD decreased obesity-associated metabolic disorders and NASH. Molecular analyses by luciferase reporter assays and chromatin immunoprecipitation assays in combination with fatty acid uptake assays in primary intestinal organoids revealed that intestinal PPARα induced the expression of FABP1 that in turn mediated the effects of intestinal PPARα in modulating fatty acid uptake. The PPARα antagonist GW6471 improved obesity and NASH, dependent on intestinal PPARα or FABP1. Double-knockout ( Ppara/Fabp1ΔIE ) mice demonstrated that intestinal Ppara disruption failed to further decrease obesity and NASH in the absence of intestinal FABP1. Translationally, GW6471 reduced human PPARA-driven intestinal fatty acid uptake and improved obesity-related metabolic dysfunctions in PPARA -humanized, but not Ppara -null, mice. CONCLUSIONS: Intestinal PPARα signaling promotes NASH progression through regulating dietary fatty acid uptake through modulation of FABP1, which provides a compelling therapeutic target for NASH treatment.