Cellular communication network factor 1 promotes retinal leakage in diabetic retinopathy via inducing neutrophil stasis and neutrophil extracellular traps extrusion.

BACKGROUND: Diabetic retinopathy (DR) is a major cause of blindness and is characterized by dysfunction of the retinal microvasculature. Neutrophil stasis, resulting in retinal inflammation and the occlusion of retinal microvessels, is a key mechanism driving DR. These plugging neutrophils subsequently release neutrophil extracellular traps (NETs), which further disrupts the retinal vasculature. Nevertheless, the primary catalyst for NETs extrusion in the retinal microenvironment under diabetic conditions remains unidentified. In recent studies, cellular communication network factor 1 (CCN1) has emerged as a central molecule modulating inflammation in pathological settings. Additionally, our previous research has shed light on the pathogenic role of CCN1 in maintaining endothelial integrity. However, the precise role of CCN1 in microvascular occlusion and its potential interaction with neutrophils in diabetic retinopathy have not yet been investigated. METHODS: We first examined the circulating level of CCN1 and NETs in our study cohort and analyzed related clinical parameters. To further evaluate the effects of CCN1 in vivo, we used recombinant CCN1 protein and CCN1 overexpression for gain-of-function, and CCN1 knockdown for loss-of-function by intravitreal injection in diabetic mice. The underlying mechanisms were further validated on human and mouse primary neutrophils and dHL60 cells. RESULTS: We detected increases in CCN1 and neutrophil elastase in the plasma of DR patients and the retinas of diabetic mice. CCN1 gain-of-function in the retina resulted in neutrophil stasis, NETs extrusion, capillary degeneration, and retinal leakage. Pre-treatment with DNase I to reduce NETs effectively eliminated CCN1-induced retinal leakage. Notably, both CCN1 knockdown and DNase I treatment rescued the retinal leakage in the context of diabetes. In vitro, CCN1 promoted adherence, migration, and NETs extrusion of neutrophils. CONCLUSION: In this study, we uncover that CCN1 contributed to retinal inflammation, vessel occlusion and leakage by recruiting neutrophils and triggering NETs extrusion under diabetic conditions. Notably, manipulating CCN1 was able to hold therapeutic promise for the treatment of diabetic retinopathy.

The effects of repeated freezing and thawing on bovine sperm morphometry and function.

Refreezing the remaining genetic resources after in vitro fertilization (IVF) can conserve genetic materials. However, the precise damage inflicted by repeated freezing and thawing on bovine sperm and its underlying mechanism remain largely unexplored. Thus, this study investigates the impact of repeated freeze-thaw cycles on sperm. Our findings indicate that such cycles significantly reduce sperm viability and motility. Furthermore, the integrity of the sperm plasma membrane and acrosome is compromised during this process, exacerbating the advanced apoptosis triggered by oxidative stress. Additionally, transmission electron microscopy exposed severe damage to the plasma membranes of both the sperm head and tail. Notably, the "9 + 2" structure of the tail was disrupted, along with a significant decrease in the level of the axonemal protein DNAH10, leading to reduced sperm motility. IVF outcomes revealed that repeated freeze-thaw cycles considerably impair sperm fertilization capability, ultimately reducing the blastocyst rate. In summary, our research demonstrates that repeated freeze-thaw cycles lead to a decline in sperm viability and motility, attributed to oxidative stress-induced apoptosis and DNAH10-related dynamic deficiency. As a result, the utility of semen is compromised after repeated freezing.

An Artificial LiSiOx Nociceptor with Neural Blockade and Self-Protection Abilities.

An artificial nociceptor, as a critical and special bionic receptor, plays a key role in a bioelectronic device that detects stimuli and provides warnings. However, fully exploiting bioelectronic applications remains a major challenge due to the lack of the methods of implementing basic nociceptor functions and nociceptive blockade in a single device. In this work, we developed a Pt/LiSiOx/TiN artificial nociceptor. It had excellent stability under the 104 endurance test with pulse stimuli and exhibited a significant threshold current of 1 mA with 1 V pulse stimuli. Other functions such as relaxation, inadaptation, and sensitization were all realized in a single device. Also, the pain blockade function was first achieved in this nociceptor with over a 25% blocking degree, suggesting a self-protection function. More importantly, an obvious depression was activated by a stimulus over 1.6 V due to the cooperative effects of both lithium ions and oxygen ions in LiSiOx and the dramatic accumulation of Joule heat. The conducting channel ruptured partially under sequential potentiation, thus achieving nociceptive blockade, besides basic functions in one single nociceptor, which was rarely reported. These results provided important guidelines for constructing high-performance memristor-based artificial nociceptors and opened up an alternative approach to the realization of bioelectronic systems for artificial intelligence.

Design, synthesis and biological evaluation of indole-2-carboxylic acid derivatives as novel HIV-1 integrase strand transfer inhibitors.

Integrase plays an important role in the life cycle of HIV-1, and integrase strand transfer inhibitors (INSTIs) can effectively impair the viral replication. However, drug resistance mutations have been confirmed to decrease the efficacy of INSTI during the antiviral therapy. Herein, indole-2-carboxylic acid (1) was found to inhibit the strand transfer of integrase, and the indole nucleus of compound 1 was observed to chelate with two Mg2+ ions within the active site of integrase. Through optimization of compound 1, a series of indole-2-carboxylic acid derivatives were designed and synthesized, and compound 17a was proved to markedly inhibit the effect of integrase, with IC50 value of 3.11 µM. Binding mode analysis of 17a demonstrated that the introduced C6 halogenated benzene ring could effectively bind with the viral DNA (dC20) through π-π stacking interaction. These results indicated that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.

Unveiling Sb3+ Doping and Tricolor Luminescence from Intrinsic Self-Trapped Excitons in Cs2ZnCl4 Crystals.

Zero-dimensional (0D) lead-free halide perovskites have lately received significant interest owing to their captivating broadband emissions. An in-depth understanding of the luminescence mechanism of self-trapped excitons (STEs) and realization of effective regulation of luminescence properties have become a major challenge in the research of lead-free metal halides. Herein, we have synthesized the Cs2ZnCl4 and Sb3+-doped Cs2ZnCl4 crystals and conducted a comprehensive investigation into their distinct electronic structures and optical characteristics. The findings from both experimental and theoretical investigations indicate that the tricolor luminescence in Cs2ZnCl4 and blue emission in Sb3+-doped Cs2ZnCl4 stem from intrinsic STEs, and the near-infrared emission originates from extrinsic STEs associated with the Sb3+ ion in Sb3+-doped Cs2ZnCl4. Sb3+ doping increases the quantum yield of Cs2ZnCl4 to a large extent. In addition, intersystem crossing, exciton self-trapping, and lattice relaxation are the main reasons for the large Stokes shift. The present study is expected to provide a novel perspective for researchers in comprehending the luminescent mechanism of STEs and advancing the utilization of 0D lead-free metal halides in optoelectronic applications.

Light-Mediated Multilevel Flexible High-Efficiency Perovskite Resistive Switching Memory Based on Mn:CsPbCl3 Nanocrystals.

Herein, the electrical characteristics, photoelectric properties, resistive switching (RS) mechanism, and flexible storage application of Ag/PMMA&Mn:CsPbCl3/ITO (PMMA = poly(methyl methacrylate)) devices are studied by using the photoelectric material Mn:CsPbCl3 nanocrystals (NCs) embedded in PMMA as the RS layer. The devices exhibit bipolar RS behavior with low operating voltage, excellent cycling endurance (>1000 times), long retention time (≥104 s), high ON/OFF ratio (≈104), and good environmental stability. The flexible memory devices have demonstrated reliable mechanical stability of consecutive 1000 bending cycles. In addition, multilevel data storage is realized by introducing the UV light, and the adjustive resistive switching characteristics is achieved through photoelectric synergistic work. The resistive switching mechanism under the excitation of light has been studied comprehensively. This work may pave a new way for developing the next generation of high-density data storage and photoelectric memristor.

The effects of non-invasive brain stimulation on disorder of consciousness in patients with brain injury: A systematic review and meta-analysis of randomized controlled trial.

INTRODUCTION: Disorders of consciousness (DOC) result from neural system injury and manifest as changes in arousal or awareness. This systematic review and meta-analysis aimed to investigate the therapeutic effects of non-invasive brain stimulation (NIBS) techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), on consciousness dysfunction in patients with brain disorders. METHODS: Literature was systematically searched in Medline, Embase, Cochrane database, Web of Science, EBSCO from inception to May 2023. Only randomized controlled trial with NIBS as an intervention and participants with DOC were included. RESULTS: A total of 7 studies with 313 participants were included for meta-analysis. Compared with sham- or placebo-stimulation, NIBS can improve the Coma Recovery Scale-Revised scores significantly (mean difference [MD] = 1.96, 95 % confidence interval [CI] = [1.49; 2.43], P <.0001). CONCLUSION: NIBS has a significant positive effect in enhancing the symptoms of DOC. Nevertheless, it is imperative for further investigations comprising high-quality research designs and larger sample sizes in order to comprehensively elucidate the effects of NIBS techniques on diverse targets of stimulation within the population of individuals suffering from DOC.

A Kr*-Rb cold collision apparatus based on atom trap.

A cold collision between atoms and molecules (<1 K) is one of the hot research fields in atomic and molecular physics. At low temperatures, the number of partial waves participating in the collision process decreases dramatically, and quantum phenomena start to emerge. The reaction is often dominated by quantum tunneling, and pronounced resonances can exist on collision cross sections. Here, we report on an apparatus designed for studying cold collisions between metastable noble gas atoms and alkali atoms. Our apparatus features a combined Magneto-Optical-Trap (MOT) and velocity map imaging (VMI) system. The center of a Rb MOT is overlapped with the VMI system. Cold Kr* atoms are launched toward the Rb atoms to induce Kr* + Rb reactions. The collision energy between the two species can be varied from 100 mK to 20 K. With this setup, we are planning to explore the quantum phenomena in Kr* + Rb cold collisions, including the shape resonance and stereodynamics in the reaction.

The Discovery of Indole-2-carboxylic Acid Derivatives as Novel HIV-1 Integrase Strand Transfer Inhibitors.

As an important antiviral target, HIV-1 integrase plays a key role in the viral life cycle, and five integrase strand transfer inhibitors (INSTIs) have been approved for the treatment of HIV-1 infections so far. However, similar to other clinically used antiviral drugs, resistance-causing mutations have appeared, which have impaired the efficacy of INSTIs. In the current study, to identify novel integrase inhibitors, a set of molecular docking-based virtual screenings were performed, and indole-2-carboxylic acid was developed as a potent INSTI scaffold. Indole-2-carboxylic acid derivative 3 was proved to effectively inhibit the strand transfer of HIV-1 integrase, and binding conformation analysis showed that the indole core and C2 carboxyl group obviously chelated the two Mg2+ ions within the active site of integrase. Further structural optimizations on compound 3 provided the derivative 20a, which markedly increased the integrase inhibitory effect, with an IC50 value of 0.13 µM. Binding mode analysis revealed that the introduction of a long branch on C3 of the indole core improved the interaction with the hydrophobic cavity near the active site of integrase, indicating that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.

RING box protein-1(RBX1), a key component of SCF E3 ligase, induced multiple myeloma cell drug-resistance though suppressing p27.

Multiple myeloma (MM) is a clonal disease of plasma cells that remains, for the most part, incurable despite the advent of several novel therapeutics. The elevated expression of p27 and its association with cell-cycle arrest is speculated to be one of the major mechanisms by which MM cells escape the cytotoxic effects of therapeutic agents. In this study, we demonstrated that RBX1 silencing could inhibit MM cell growth and promote cell drug resistance. RBX1 directly interacted with and triggered the ubiquitination and degradation of p27, ultimately causing p27 reduction. Additionally, cell growth and apoptosis analysis indicated that the role of RBX1 in regulating myeloma cell proliferation and drug resistance resulted from p27 accumulation, which occurred in a Thr187 phosphorylation-dependent manner. Furthermore, the cell-cycle analysis demonstrated that RBX1 overexpression induced cells to enter the cell cycle (S-phase) and partially inhibited chemotherapeutic drugs-mediated cell cycle arrest. Notably, the forced expression of RBX1 also inhibited the cell adhesion-mediated elevation of p27 and induced the accumulation of adherent cells in apoptosis, especially the proteolytic cleavage of caspase-3. Additionally, RBX1 knockdown significantly inhibited myeloma development in SCID-Hu mice and in a human MM xenotransplant model. Overall, these in vitro and in vivo experiments indicated that the RBX1-p27 axis could be a central molecular mechanism by which RBX1 functions as a tumor promoter and stimulates cell growth in chemotherapeutic drugs treated MM cells.

Identification of disulfidptosis related subtypes, characterization of tumor microenvironment infiltration, and development of DRG prognostic prediction model in RCC, in which MSH3 is a key gene during disulfidptosis.

Disulfidptosis is a newly discovered mode of cell death induced by disulfide stress. However, the prognostic value of disulfidptosis-related genes (DRGs) in renal cell carcinoma (RCC) remains to be further elucidated. In this study, consistent cluster analysis was used to classify 571 RCC samples into three DRG-related subtypes based on changes in DRGs expression. Through univariate regression analysis and LASSO-Cox regression analysis of differentially expressed genes (DEGs) among three subtypes, we constructed and validated a DRG risk score to predict the prognosis of patients with RCC, while also identifying three gene subtypes. Analysis of DRG risk score, clinical characteristics, tumor microenvironment (TME), somatic cell mutations, and immunotherapy sensitivity revealed significant correlations between them. A series of studies have shown that MSH3 can be a potential biomarker of RCC, and its low expression is associated with poor prognosis in patients with RCC. Last but not least, overexpression of MSH3 promotes cell death in two RCC cell lines under glucose starvation conditions, indicating that MSH3 is a key gene in the process of cell disulfidptosis. In summary, we identify potential mechanism of RCC progression through DRGs -related tumor microenvironment remodeling. In addition, this study has successfully established a new disulfidptosis-related genes prediction model and discovered a key gene MSH3. They may be new prognostic biomarkers for RCC patients, provide new insights for the treatment of RCC patients, and may inspire new methods for the diagnosis and treatment of RCC patients.

Loss of function of GATA3 regulates FRA1 and c-FOS to activate EMT and promote mammary tumorigenesis and metastasis.

Basal-like breast cancers (BLBCs) are among the most aggressive cancers, partly due to their enrichment of cancer stem cells (CSCs). Breast CSCs can be generated from luminal-type cancer cells via epithelial-mesenchymal transition (EMT). GATA3 maintains luminal cell fate, and its expression is lost or reduced in BLBCs. However, deletion of Gata3 in mice or cells results in early lethality or proliferative defects. It is unknown how loss-of-function of GATA3 regulates EMT and CSCs in breast cancer. We report here that haploid loss of Gata3 in mice lacking p18Ink4c, a cell cycle inhibitor, up-regulates Fra1, an AP-1 family protein that promotes mesenchymal traits, and downregulates c-Fos, another AP-1 family protein that maintains epithelial fate, leading to activation of EMT and promotion of mammary tumor initiation and metastasis. Depletion of Gata3 in luminal tumor cells similarly regulates Fra1 and c-Fos in activation of EMT. GATA3 binds to FOSL1 (encoding FRA1) and FOS (encoding c-FOS) loci to repress FOSL1 and activate FOS transcription. Deletion of Fra1 or reconstitution of Gata3, but not reconstitution of c-Fos, in Gata3 deficient tumor cells inhibits EMT, preventing tumorigenesis and/or metastasis. In human breast cancers, GATA3 expression is negatively correlated with FRA1 and positively correlated with c-FOS. Low GATA3 and FOS, but high FOSL1, are characteristics of BLBCs. Together, these data provide the first genetic evidence indicating that loss of function of GATA3 in mammary tumor cells activates FOSL1 to promote mesenchymal traits and CSC function, while concurrently repressing FOS to lose epithelial features. We demonstrate that FRA1 is required for the activation of EMT in GATA3 deficient tumorigenesis and metastasis.

Achieving adjustable digital-to-analog conversion in memristors with embedded Cs2AgSbBr6 nanoparticles.

In this work, the proportions of Cs2AgSbBr6 nanoparticles (NPs) mixed in a PMMA film are adjusted to the digital and analog types of resistive switching (RS) behaviors in Ag/PMMA&Cs2AgSbBr6-NPs/ITO memristor devices. It is confirmed that when the concentration of NPs doped in the PMMA film is about 5 wt%, the memristor devices demonstrate bipolar digital RS behaviors with excellent electrical characteristics such as low operating voltage, high ON/OFF ratio (>500), good endurance (>800 cycles), and stable retention ability (>104 s). However, the devices showed a transition to analog-type memristive behavior when the concentration of NPs doped in the PMMA film is around 10 wt%, and several artificial synapse behaviors are successfully simulated. The device model simulation is also used to explore the effect of the NPs on the local electric field and growing filaments. Our work provides an opportunity to explore next-generation artificial synapse devices based on lead-free halide perovskites.

Organocatalytic radical relay trifunctionalization of unactivated alkenes by a combination of cyano migration and alkylacylation.

The first N-heterocyclic carbene organocatalytic three-component radical relay trifunctionalization of unactivated alkenes through the combination of remote 1,4-cyano migration and alkylacylation was reported. This protocol features mild reaction conditions, readily available materials, excellent regioselectivity, and capability of late-stage functionalization.

Bibliometric and visualized analysis of scientific publications on rehabilitation of rotator cuff injury based on web of science.

Background: Since the discovery of rehabilitation as an intervention for rotator cuff injury, its impact on the recovery of rotator cuff injury has attracted crucial attention, and the number of related studies is increasing worldwide. There were no bibliometric and visualized analysis studies in this field. This study aimed to investigate the research hotpots and trends in the rehabilitation of rotator cuff injury via bibliometric and visualized analysis and to identify the future development of clinical practice. Method: The publications regarding rehabilitation of rotator cuff injury from inception to December 2021 were obtained from the Web of Science Core Collection database. The trends of publications, co-authorship and co-occurrence analysis and visualized analysis were carried out using Citespace, VOSviewer, Scimago Graphica software, and R Project. Results: A total of 795 publications were included in this study. The number of publications significantly increased yearly. The United States published the highest number of related papers and the papers published by the United States had the highest citations. The University of Laval, the University of Montreal and Keele University were the top 3 most contributive institutions. Additionally, the Journal of Shoulder and Elbow Surgery was the journal with the highest number of publications. The most common keywords were "rotator cuff", "rehabilitation", "physical therapy", "management", and "telerehabilitation". Conclusion: The total number of publications has shown a steady upward trend. The cooperation between countries globally was still relatively lacking, and therefore it is necessary to strengthen cooperation between different countries and regions to provide conditions for multi-center, large sample, and high-quality research. In addition to the relatively mature rehabilitation of rotator cuff injury such as passive motion or exercise therapy, telerehabilitation has also attracted much attention with the progress of science.

Highly Thermally Sensitive Cascaded Wannier-Mott Exciton Ionization/Carrier Localization in Manganese-Doped Perovskite Nanocrystals.

Transition-metal doping in perovskite nanocrystals strongly alters the photophysical properties of these nanocrystals. However, the details of the underlying thermal and optical processes within such an intriguing symmetry-breaking nanosystem are far from clear. Herein, we study the sensitively temperature-dependent and highly competent delocalized exciton and transition-metal ion-captured carrier recombination processes in manganese-doped CsPbBr0.6Cl2.4 nanocrystals. The combined experimental and theoretical studies reveal that both the exciton ionization and capture of the band-edge carriers by the manganese ions play the dominant roles in determining the proportion of the manganese ions-dominated recombination process. A density functional theory calculation of the temporal fluctuation of the manganese ions-accommodated localized orbitals further confirms that the thermally enhanced nonadiabatic electron-phonon coupling promotes the probability of the carrier localization. These findings reveal the respective crucial roles of the exciton ionization and carrier capture in the localized recombination process in the transition-metal-doped semiconductor nanocrystals.

Spatiotemporal variations, influence factors, and simulation of global cooling degree days.

The cooling degree days (CDDs) can indicate the hot climatic impacts on energy consumption and thermal environment comfort effectively. Nevertheless, seldom studies focused on the spatiotemporal characteristics, influence factors, and simulation of global CDDs. This study analyzed the spatial-temporal characteristics of global CDDs from 1970 to 2018 and in the future, explored five determinants, and simulated CDDs and their interannual changing rates. The results showed that the global CDDs were generally higher at lower latitudes and altitudes. Many places experienced significant positive changes of CDDs (p < 0.05), and the rates became larger at lower latitudes and attitudes. In the future, most CDDs had the sustainability trends. Besides, significant negative partial correlations existed between not only CDDs but also their variation rates with latitude, altitude, and average enhanced vegetation index in the summer, while positive with the annual PM2.5, distance to large waterbodies (p = 0.000). Moreover, the values and variation rates of CDDs can be deduced using the generalized regression neural network method. The root-mean-square errors were 231.73 °C * days and 1.71 °C * days * year-1, respectively. These conclusions were helpful for the energy-saving for cooling with the climate change and optimization of thermal environment.

Tetrabromobisphenol Exposure Impairs Bovine Oocyte Maturation by Inducing Mitochondrial Dysfunction.

Tetrabromobisphenol (TBBPA) is the most widely used brominated flame retardant in the world and displays toxicity to humans and animals. However, few studies have focused on its impact on oocyte maturation. Here, TBBPA was added to the culture medium of bovine cumulus-oocyte complexes (COCs) to examine its effect on oocytes. We found that TBBPA exposure displayed an adverse influence on oocyte maturation and subsequent embryonic development. The results of this study showed that TBBPA exposure induced oocyte meiotic failure by disturbing the polar-body extrusion of oocytes and the expansion of cumulus cells. We further found that TBBPA exposure led to defective spindle assembly and chromosome alignment. Meanwhile, TBBPA induced oxidative stress and early apoptosis by mediating the expression of superoxide dismutase 2 (SOD2). TBBPA exposure also caused mitochondrial dysfunction, displaying a decrease in mitochondrial membrane potential, mitochondrial content, mtDNA copy number, and ATP levels, which are regulated by the expression of pyruvate dehydrogenase kinase 3 (PDK3). In addition, the developmental competence of oocytes and the quality of blastocysts were also reduced after TBBPA treatment. These results demonstrated that TBBPA exposure impaired oocyte maturation and developmental competence by disrupting both nuclear and cytoplasmic maturation of the oocyte, which might have been caused by oxidative stress induced by mitochondrial dysfunction.

Enhanced Resistive Switching Performance through Air-Stable Cu2AgSbI6 Thin Films for Flexible and Multilevel Storage Application.

Herein, the lead-free halide perovskite films with different Cu-to-Ag ratios (Cu3-xAgxSbI6, x = 0, 1, 2, or 3) have been prepared by a spin-coating method at low temperature. The enhanced resistive switching (RS) performance of more uniform SET/RESET voltages and the endurance up to at least 1600 cycles are found in the RS memory with a device structure of Ag/PMMA/Cu2AgSbI6/ITO. The device performance is not degraded under different bending angles and after 103 bending cycles, which is beneficial for flexible memory applications. The appropriately increased activation energy of the perovskites with the partial substitution of Ag atoms, which would lead to a more robust filament formed, is proposed to explain the enhanced RS mechanism. Importantly, the effective size and number of filaments measured by conductive AFM are introduced to confirm the multilevel storage effect of Cu2AgSbI6. The multilevel storage characteristics with four resistance levels are demonstrated by various compliance currents. Moreover, the Cu2AgSbI6 memory devices still exhibit enhanced RS properties and multilevel storage after 75 days of exposure to ambient conditions. Our study provides a strategy for improving the stability and high-density storage applications of halide perovskite RS memory devices.

Comprehensive analysis of endoplasmic reticulum-related and secretome gene expression profiles in the progression of non-alcoholic fatty liver disease.

Endoplasmic reticulum (ER) is the principal organelle for protein synthesis, such as hepatokines and transmembrane proteins, and is critical for maintaining physiological function. Dysfunction of ER is associated with metabolic disorders. However, the role of ER homeostasis as well as hepatokines in the progression of non-alcoholic fatty liver disease (NAFLD) remains to be elucidated. Here we comprehensively analyzed the RNA-seq profiles of liver biopsies from 206 NAFLD patients and 10 controls from dataset GSE135251. The co-expression modules were constructed based on weighted gene co-expression network analysis and six co-expression modules were identified, of which brown module stood out to be significantly associated with fibrosis stage and NAFLD activity score (NAS). Subsequently, cytoscape with cytoHubba plugin was applied to identify hub genes in the brown module. GO and KEGG enrichment analysis of the top 20 hub genes were performed and showed the involvement of extracellular matrix formation, collagen synthesis and decomposition, etc. Further, the expression of the top 20 hub genes were found to be a consistent increasing trend as the fibrosis stages and NAS increased, which have been validated both in HFD fed and HFHC fed mice. Among these genes, THY1, PTGDS, TMPRSS3, SPON1, COL1A2, RHBDF1, COL3A1, COL5A1, COL1A1 and IGFBP7 performed well in distinguishing fibrosis stage, while COL1A2, COL3A1, THY1, RHBDF1 and COL1A2 exhibited good capacity to discriminate NAS. Besides, RHBDF1, COL3A1, QSOX1, STING1, COL5A1, IGFBP7, COL4A2, COL1A1, FKBP10 and COL1A2 also showed a strong power in the diagnosis of NAFLD. In addition, COL1A1, COL1A2, COL3A1, COL8A2, IGFBP7, PGF, PTGDS, SPON1, THY1 and TIMP1 were identified as secretome genes from the top 20 hub genes. Of them, circulated THY1 and collagen III level were validated to be significantly elevated in the MCD diet-induced mice. Thus, we provided a systemic view on understanding the pathological roles and mechanisms of ER as well as secretome in NAFLD progression. THY1, COL1A1, COL1A2, COL3A1 and RHBDF1 could be served as candidate biomarkers to evaluate the progression of NAFLD.