Nanoconfined polymerization limits crack propagation in hysteresis-free gels.

Consecutive mechanical loading cycles cause irreversible fatigue damage and residual strain in gels, affecting their service life and application scope. Hysteresis-free hydrogels within a limited deformation range have been created by various strategies. However, large deformation and high elasticity are inherently contradictory attributes. Here we present a nanoconfined polymerization strategy for producing tough and near-zero-hysteresis gels under a large range of deformations. Gels are prepared through in situ polymerization within nanochannels of covalent organic frameworks or molecular sieves. The nanochannel confinement and strong hydrogen bonding interactions with polymer segments are crucial for achieving rapid self-reinforcement. The rigid nanostructures relieve the stress concentration at the crack tips and prevent crack propagation, enhancing the ultimate fracture strain (17,580 ± 308%), toughness (87.7 ± 2.3 MJ m-3) and crack propagation strain (5,800%) of the gels. This approach provides a general strategy for synthesizing gels that overcome the traditional trade-offs of large deformation and high elasticity.

Biocompatible Tough Ionogels with Reversible Supramolecular Adhesion.

Cohesive and interfacial adhesion energies are difficult to balance to obtain reversible adhesives with both high mechanical strength and high adhesion strength, although various methods have been extensively investigated. Here, a biocompatible citric acid/L-(-)-carnitine (CAC)-based ionic liquid was developed as a solvent to prepare tough and high adhesion strength ionogels for reversible engineered and biological adhesives. The prepared ionogels exhibited good mechanical properties, including tensile strength (14.4 MPa), Young's modulus (48.1 MPa), toughness (115.2 MJ m-3), and high adhesion strength on the glass substrate (24.4 MPa). Furthermore, the ionogels can form mechanically matched tough adhesion at the interface of wet biological tissues (interfacial toughness about 191 J m-2) and can be detached by saline solution on demand, thus extending potential applications in various clinical scenarios such as wound adhesion and nondestructive transfer of organs.

Towards Stabilized Few-Shot Object Detection with Less Forgetting via Sample Normalization.

Few-shot object detection is a challenging task aimed at recognizing novel classes and localizing with limited labeled data. Although substantial achievements have been obtained, existing methods mostly struggle with forgetting and lack stability across various few-shot training samples. In this paper, we reveal two gaps affecting meta-knowledge transfer, leading to unstable performance and forgetting in meta-learning-based frameworks. To this end, we propose sample normalization, a simple yet effective method that enhances performance stability and decreases forgetting. Additionally, we apply Z-score normalization to mitigate the hubness problem in high-dimensional feature space. Experimental results on the PASCAL VOC data set demonstrate that our approach outperforms existing methods in both accuracy and stability, achieving up to +4.4 mAP@0.5 and +5.3 mAR in a single run, with +4.8 mAP@0.5 and +5.1 mAR over 10 random experiments on average. Furthermore, our method alleviates the drop in performance of base classes. The code will be released to facilitate future research.

Low-Hysteresis and High-Toughness Hydrogels Regulated by Porous Cationic Polymers: the Effect of Counteranions.

Service life and range of polymer materials is heavily reliant on their elasticity and mechanical stability under long-term loading. Slippage of chain segments under load leads to significant hysteresis of the hydrogels, limiting its repeatability and mechanical stability. Achieving the desired elasticity exceeding that of rubber is a great challenge for hydrogels, particularly when subjected to large deformations. Here, low-hysteresis and high-toughness hydrogels were developed through controllable interactions of porous cationic polymers (PCPs) with adjustable counteranions, including reversible bonding of PCP frameworks/polymer segments (polyacrylamide, PAAm) and counteranions/PAAm. This strategy reduces chain segment slippage under load, endowing the PCP-based hydrogels (PCP-gels) with good elasticity under large deformations (7 % hysteresis at a strain ratio of 40). Furthermore, due to the enlarged chain segments entanglement by PCP, the PCP-gels exhibit large strain (13000 %), significantly enhanced toughness (68 MJ m-3 ), high fracture energy (43.1 kJ m-2 ), and fatigue resistance. The unique properties of these elastic PCP-gels have promising applications in the field of flexible sensors.

Incidence and risk factors for cholelithiasis after bariatric surgery: a systematic review and meta-analysis.

BACKGROUND: Obesity has been identified as an independent risk factor for cholelithiasis. As a treatment for obesity, bariatric surgery may increase the incidence of cholelithiasis. The risk factors for cholelithiasis after bariatric surgery remain uncertain. The purpose of this study was to explore the risk factors for postoperative cholelithiasis after weight-loss surgery and propose suggestions for clinical decision making. METHODS: Four databases, PubMed, EMBASE, Web of Science and Cochrane, were systematically searched for all reports about cholelithiasis after bariatric surgery, and literature screening was performed following prespecified inclusion criteria. The included studies were all evaluated for quality according to the NOS scale. Data extraction was followed by analysis using Reviewer Manager 5.4 and StataSE 15. RESULTS: A total of 19 articles were included in this meta-analysis, and all studies were of high quality. A total of 20,553 patients were included in this study. Sex [OR = 0.62, 95% CI (0.55, 0.71), P < 0.00001] and race [OR = 1.62, 95% CI (1.19, 2.19), P = 0.002] were risk factors for cholelithiasis after bariatric surgery. Surgical procedure, preoperative BMI, weight-loss ratio, smoking, hypertension, diabetes mellitus, and dyslipidemia were neither protective nor risk factors for cholelithiasis after bariatric surgery. CONCLUSION: Caucasian race and female sex are risk factors for developing cholelithiasis after bariatric surgery; surgical procedure, BMI, weight loss ratio, hypertension, diabetes mellitus, dyslipidemia, and smoking are not risk factors for cholelithiasis after bariatric surgery.

Unsupervised Learning-Guided Accelerated Discovery of Alkaline Anion Exchange Membranes for Fuel Cells.

Without insight into the correlation between the structure and properties, anion exchange membranes (AEMs) for fuel cells are developed usually using the empirical trial and error method or simulation methods. Here, a virtual module compound enumeration screening (V-MCES) approach, which does not require the establishment of expensive training databases and can search the chemical space containing more than 4.2×105 candidates was proposed. The accuracy of the V-MCES model was considerably improved when the model was combined with supervised learning for the feature selection of molecular descriptors. Techniques from V-MCES, correlating the molecular structures of the AEMs with the predicted chemical stability, generated a ranking list of potential high stability AEMs. Under the guidance of V-MCES, highly stable AEMs were synthesized. With understanding of AEM structure and performance by machine learning, AEM science may enter a new era of unprecedented levels of architectural design.

Liquid biopsy at the frontier of detection, prognosis and progression monitoring in colorectal cancer.

Colorectal cancer (CRC) is one of the most common cancers worldwide and a leading cause of carcinogenic death. To date, surgical resection is regarded as the gold standard by the operator for clinical decisions. Because conventional tissue biopsy is invasive and only a small sample can sometimes be obtained, it is unable to represent the heterogeneity of tumor or dynamically monitor tumor progression. Therefore, there is an urgent need to find a new minimally invasive or noninvasive diagnostic strategy to detect CRC at an early stage and monitor CRC recurrence. Over the past years, a new diagnostic concept called "liquid biopsy" has gained much attention. Liquid biopsy is noninvasive, allowing repeated analysis and real-time monitoring of tumor recurrence, metastasis or therapeutic responses. With the advanced development of new molecular techniques in CRC, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), exosomes, and tumor-educated platelet (TEP) detection have achieved interesting and inspiring results as the most prominent liquid biopsy markers. In this review, we focused on some clinical applications of CTCs, ctDNA, exosomes and TEPs and discuss promising future applications to solve unmet clinical needs in CRC patients.

Uncovering the gene regulatory network of type 2 diabetes through multi-omic data integration.

BACKGROUND: Type 2 diabetes (T2D) onset is a complex, organized biological process with multilevel regulation, and its physiopathological mechanisms are yet to be elucidated. This study aims to find out the key drivers and pathways involved in the pathogenesis of T2D through multi-omics analysis. METHODS: The datasets used in the experiments comprise three groups: (1) genomic (2) transcriptomic, and (3) epigenomic categories. Then, a series of bioinformatics technologies including Marker set enrichment analysis (MSEA), weighted key driver analysis (wKDA) was performed to identify key drivers. The hub genes were further verified by the Receiver Operator Characteristic (ROC) Curve analysis, proteomic analysis, and Real-time quantitative polymerase chain reaction (RT-qPCR). The multi-omics network was applied to the Pharmomics pipeline in Mergeomics to identify drug candidates for T2D treatment. Then, we used the drug-gene interaction network to conduct network pharmacological analysis. Besides, molecular docking was performed using AutoDock/Vina, a computational docking program. RESULTS: Module-gene interaction network was constructed using MSEA, which revealed a significant enrichment of immune-related activities and glucose metabolism. Top 10 key drivers (PSMB9, COL1A1, COL4A1, HLA-DQB1, COL3A1, IRF7, COL5A1, CD74, HLA-DQA1, and HLA-DRB1) were selected by wKDA analysis. Among these, COL5A1, IRF7, CD74, and HLA-DRB1 were verified to have the capability to diagnose T2D, and expression levels of PSMB9 and CD74 had significantly higher in T2D patients. We further predict the co-expression network and transcription factor (TF) binding specificity of the key driver. Besides, based on module interaction networks and key driver networks, 17 compounds are considered to possess T2D-control potential, such as sunitinib. CONCLUSIONS: We identified signature genes, biomolecular processes, and pathways using multi-omics networks. Moreover, our computational network analysis revealed potential novel strategies for pharmacologic interventions of T2D.

Revisional large gastric pouch with Roux-en-Y gastric bypass for patients with type 2 diabetes and a body mass index less than 35 kg/m2: a cause and effect analysis.

PURPOSE: To evaluate the long-term efficacy of large gastric pouch surgery and revisional surgery in patients with a body mass index (BMI) < 35 kg/m2 and type 2 diabetes mellitus (T2DM). METHODS: We conducted a retrospective review of patients who underwent laparoscopic Roux-en-Y gastrojejunostomy with a large gastric pouch in our hospital. The clinical pre- and post-surgery data, including BMI, waist circumference, fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), lipid metabolism-related indicators, homoeostatic model assessment of insulin resistance (HOMA-IR), and major complications, were recorded and analyzed. RESULTS: Twenty-four patients were included in the analysis, 12 of whom underwent revisional surgery. At their 5-year-follow-up after the primary surgery, the BMI and waist circumference of the patients with T2DM were lower than their baseline values. The BMI, HbA1c, HOMA-IR, FPG and waist circumference also decreased after the revisional surgery. The rates of remission of diabetes after the primary vs. after the revisional surgery were 4.17% vs. 41.70%, respectively (P < 0.05). CONCLUSION: Roux-en-Y gastrojejunostomy with a large gastric pouch is not effective in the long term and, therefore, is unsuitable for Chinese patients with T2DM and a BMI < 35 kg/m2. Conversely, revisional surgery has a definite effect on these patients.

TyG Index Performs Better Than HOMA-IR in Chinese Type 2 Diabetes Mellitus with a BMI < 35 kg/m2: A Hyperglycemic Clamp Validated Study

Background and objectives: Chinese type 2 diabetes mellitus (T2DM) patients are characterized by a low body mass index (BMI), and significant insulin resistance (IR). The triglyceride glucose (TyG) index has not been studied as a means of assessing IR in Chinese T2DM patients with a BMI < 35 kg/m2. Materials and Methods: An open-label cross-sectional study recruited 102 Chinese T2DM patients with a BMI < 35 kg/m2. The hyper-insulinemic euglycemic clamp, homeostatic model assessment of IR (HOMA-IR), and TyG index were used to determine the level of IR. Based on Pearson's correlations, glucose disposal rate (GDR), TyG index, and HOMA-IR were analyzed. HOMA-IR and TyG index for IR were evaluated using multiple linear regression and multivariate logistic regression analyses. On the basis of the receiver operating characteristic (ROC) curve, the sensitivity, specificity, and optimal cut-off value of HOMA-IR and the TyG index were determined. Results: The mean values of GDR, HOMA-IR, and TyG index were 4.25 ± 1.81, 8.05 ± 7.98, and 8.12 ± 0.86 mg/kg/min, respectively. Pearson's correlation coefficient was −0.418 between GDR and TyG index and −0.324 between GDR and HOMA-IR. ROC curve analysis showed that, among both sexes, the TyG index was a better discriminator of IR than HOMA-IR. The area under the ROC curve (AUC) of the TyG index (0.785, 0.691−0.879) was higher than that of HOMA-IR (0.73, 0.588−0.873) in all genders. The optimal cut-off values of the TyG index and HOMA-IR were 7.99 and 3.39, respectively. Conclusions: The TyG index showed more effectiveness in identifying IR in Chinese T2DM patients with a BMI < 35 kg/m2 compared to HOMA-IR.

Ultra-Tough and Recyclable Ionogels Constructed by Coordinated Supramolecular Solvents.

The mechanical properties of most hydrogels (ionogels) are considerably affected by covalently cross-linked networks. However, the interactions between solvent/solvent molecules and solvent/polymer chains are usually ignored. Herein, a series of ultra-tough ionogels were prepared via a supramolecular solvent, halometallate ionic liquid, in which cations and coordinating anions form a 3D supramolecular network. The linear polymer chains are physically cross-linked with supramolecular solvents synergistically enhancing the strength (14.3 MPa), toughness (78 MJ m-3 ), and Young's modulus (55 MPa) of ionogels, effectively dispersing the stress concentration under load, and obtaining better fatigue resistance and higher fracture energy (198 kJ m-2 ). Furthermore, the reversible cross-linking enables green recovery and recycling of ionogels, simply by water. This strategy shows broad applicability based on a variety of supramolecular solvents and coordinatable polymers.

Identification of the differences in olfactory system between male and female oriental tobacco budworm Helicoverpa assulta.

The olfactory system of insects facilitates their search for host and mates, hence it plays an essential role for insect survival and reproduction. Insects recognize odor substances through olfactory neurons and olfactory genes. Previous studies showed that there are significant sex-specific differences in how insects identify odorant substances, especially sex pheromones. However, whether the sex-specific recognition of odorant substances is caused by differences in the expression of olfaction-related genes between males and females remains unclear. To clarify this problem, the whole transcriptome sequence of the adult Helicoverpa assulta, an important agricultural pest of tobacco and other Solanaceae plants, was obtained using Pacbio sequencing. RNA-seq analysis showed that there were 27 odorant binding proteins (OBPs), 24 chemosensory proteins, 4 pheromone-binding proteins (PBPs), 68 odorant receptors and 2 sensory neuron membrane proteins (SNMPs) genes, that were expressed in the antennae of male and female H. assulta. Females had significantly higher expression of General odorant-binding protein 1-like, OBP, OBP3, PBP3 and SNMP1 than males, while males had significantly higher expression of GOBP1, OBP7, OBP13, PBP2 and SNMP2. These results improve our understanding of mate search and host differentiation in H. assulta.

Robot-assisted sleeve gastrectomy in patients with obesity with a novel Chinese domestic MicroHand SII surgical system.

BACKGROUND: A new device has been added to the Chinese MicroHand surgical robot family, developed based on the successful application of control algorithms. As a benefit of using these specialized control algorithms, the motion mapping relation can be accommodated into the system without the help of a built-in image system, resulting in a novel Chinese domestic surgical robot with two arms called MicroHand SII, which is different from the former MicroHand S and da Vinci systems. In this study, we investigate the performance of a novel MicroHand SII robotic platform in patients with obesity. METHODS: From March 2018 to April 2019, a total of 7 patients whose BMI ranged from 29.9 to 49.8 kg/m2 were operated on with the robot-assisted technique using the MicroHand SII surgical system. Data regarding demography, surgical procedure and the 3-month outcome postoperation were collected. RESULTS: There were 2 female and 5 male patients with a median age (range) of 35 (20-51) years. The median operative time was 160 (149-195) minutes. None were converted to open surgery. All anthropometry indices improved significantly (p < 0.05) at 3 months postoperatively. There were no cases of surgical site infection, gastrointestinal/abdominal bleeding, or conversion to an open operation. CONCLUSIONS: The initial experience showed that the Chinese domestic robot surgical system MicroHand SII could be feasibly and safely applied in sleeve gastrectomy in patients with obesity. Because of the unique design of this system such as a two-hand robot, an array of master-slave motion strategies, and a roll joint at the end of the instruments that allows 7 degrees of freedom, this robotic platform has presented its own obvious advantages.

Laparoscopic Roux-en-Y gastric bypass in Type 2 diabetes mellitus patient with low body mass index and gastric stromal tumor: A case report. / 低体重指数2åž‹ç³–å°¿ç— å¹¶èƒƒé—´è´¨ç˜¤æ‚£è€ è ¹è ”é•œä¸‹è¡ŒRoux-en-Y胃旁路术1例.

Laparoscopic Roux-en-Y gastric bypass (LRYGB) has been proved to be a safe and effective treatment for Type 2 diabetes mellitus (T2DM) patients with body mass index (BMI) >27.5 kg/m2 in China. The incidence of gastrointestinal stromal tumor (GIST) is very low, whereas the relevant studies on GIST and LRYGB are few. This is the first report of GIST associated with LRYGB in low BMI Chinese patient with T2DM.A male patient with GIST and T2DM, whose body weight and height were 67 kg and 175 cm, respectively,and the calculated BMI was 21.9 kg/m2. He was diagnosed by gastroscopy and enhanced CT scan. We used LRYGB to treat GIST and T2DM at the same time. After the operation, the GIST was removed successfully. Both the blood glucose levels and glycosylated hemoglobin were normal at 4 months and 1 year later. The patient received follow-up gastroscopy and abdominal CT scan and did not find out local recurrence and metastasis. LRYGB may be the best choice in treating GIST in T2DM with low BMI.

Effect of laparoscopic Roux-en-Y gastric bypass on improvement of insulin resistance in Type 2 diabetic patients evaluated by hyperinsulinemic-euglycemic clamp. / é«˜èƒ°å²›ç´ -正葡萄糖钳夹实验评价Roux-en-Y胃旁路术对2åž‹ç³–å°¿ç— æ‚£è€ èƒ°å²›ç´ æŠµæŠ—çš„æ”¹å–„ä½œç”¨.

OBJECTIVES: With the increase of people's living standards increasing year by year, Type 2 diabetes has brought great economic and living burden to the society and patients. Bariatric surgery can improve metabolic indicators in patients with diabetes, but specific mechanisms are still under study. This study aims to evaluate the effect of Roux-en-Y gastric bypass (RYGB) on insulin resistance in patients with Type 2 diabetes by hyperinsulinemic-euglycemic clamp. METHODS: The peripheral glucose uptake (M value) of 40 patients undergoing laparoscopic Roux-en-Y gastric bypass surgery before and 6 months after the operation were analyzed hyperinsulinemic euglycemic clamp. Fasting blood glucose, glycosylated hemoglobin, triglycerides, andlow-density lipoprotein cholesterol levels as well as body mass index were also analyzed. RESULTS: M value of patients after laparoscopic Roux-en-Y gastric bypass was significantly higher than that before the operation, while indexes such as fasting blood glucose, glycosylated hemoglobin, triglycerides, and low-density lipoprotein cholesterol levels as well as body mass index were lower than those before the operation (all P<0.05). CONCLUSIONS: Laparoscopic Roux-en-Y gastric bypass surgery significantly improves insulin resistance in patients with Type 2 diabetes, decreases blood sugar and blood lipid, and can exert a positive effect on the treatment of Type 2 diabetes.

A Superstrong and Reversible Ionic Crystal-Based Adhesive Inspired by Ice Adhesion.

In this study, we developed a superstrong and reversible adhesive, which can possess a high bonding strength in the "adhesive" state and detach with the application of heating. An ionic crystal (IC) gel, in which an IC was immobilized within a soft-polymer matrix, were synthesized via in situ photo-crosslinking of a precursor solution composed of N, N-dimethyl acrylamide (DMAA) and a melted IC. The obtained IC gel is homogenous and transparent at melt point. When cooled to the phase transition temperature of the IC, the gel turns into the adhesive with the adhesion strength of 5.82 MPa (on glasses), due to the excellent wetting of melted gel and a thin layer of crystalline IC with high cohesive strength formed on the substrates. The synergistic effects between IC, polymer networks and substrates were investigated by solid state 1 H NMR and molecular dynamics simulation. Such an adhesive layer is reversable and can be detached by heating and subsequent re-adhesion via cooling. This study proposed the new design of removable adhesives, which can be used in dynamic and complex environments.

Effect of sleeve gastrectomy on gastroesophageal reflux in patients with metabolic syndrome. / è¢–çŠ¶èƒƒåˆ‡é™¤æœ¯å¯¹ä»£è°¢ç»¼åˆå¾æ‚£è€ èƒƒé£Ÿç®¡åæµç—‡çŠ¶çš„å½±å“.

OBJECTIVES: To investigate the incidence of gastroesophageal reflux disease (GERD) after sleeve gastrectomy and the effect of sleeve gastrectomy in treating the symptom of gastroesophageal reflux in patients with metabolic syndrome. METHODS: We retrospectively analyzed 60 patients with metabolic syndrome who received laparoscopy sleeve gastrectomy in the Department of Bariatric and Metabolic Surgery, Third Xiangya Hospital of Central South University from April 2018 to May 2019, and assessed the changes of symptoms before and after surgery. RESULTS: The study included 31 men and 29 women. The age of these patients was 16-46 (29.17±7.23) years, ranging from 16 to 46 years. The weight and body mass index (BMI) of the patients decreased from (116.02±31.96) kg and (39.67±8.90) kg/m2 to (98.32±25.22) kg and (34.4±7.85) kg/m2 at 1 month after the surgery, respectively. The number of patients with gastroesophageal reflux was 37(61.67%) before the surgery, and 18(30.00%) at 1 month after the surgery, respectively. The number of asymptomatic patients before the surgery while had gastroesophageal reflux symptoms within 1 month after the surgery was 4(6.67%). Among the 37 patients, 6(16.62%) had persisted or worsen symptoms with gastroesophageal reflux symptoms before the surgery, 23(62.16%) had no symptoms, and 8 patients (21.62%) showed improvement of gastroesophageal reflux 1 month after the surgery. Some scores of the GERD-Health-Related Quality of Life Scale (such as reflux after dinner) were significantly lower after the surgury than those before the surgery (P<0.05). CONCLUSIONS: The symptoms of GERD are effectively improved after surgery. Sleeve gastrectomy is a feasible, safe and effective treatment for obesity with GERD.

Leukemia inhibitory factor inhibits the proliferation of gastric cancer by inducing G1-phase arrest.

Leukemia inhibitory factor (LIF), a member of the interleukin-6 cytokine family, plays a complex role in cancer. LIF inhibits the proliferation and survival of several myeloid leukemia cells but promotes tumor progression and metastasis in many solid tumors. However, the relationship between LIF and gastric cancer has not been well understood. LIF was downregulated in gastric cancer as detected by western blot analysis and immunohistochemistry (IHC). Notably, LIF was downregulated in approximately 70% (56/80) of primary gastric cancers, in which it was significantly associated with advanced clinical stage, lymph node metastasis, and poor overall survival (median 5-year survival = 26 vs. 43 months for patients with high LIF expression and low LIF expression gastric cancer, respectively). To study the potential function of LIF in the downregulation of gastric cancer, we monitored the behavior using proliferation, cell cycle, and flow cytometry analysis. Overexpression of LIF inhibited the gastric cancer cell cycle in the G1 phase. In our experiment, overexpression of LIF by lentivirus upregulated P21 and downregulated cyclin D1. Recombinant human LIF also downregulated P21 and cyclin D1 at various times. A further in vivo tumor formation study in nude mice indicated that overexpression of LIF in gastric cancer significantly delayed the progress of tumor formation. These findings indicate that LIF may serve as a negative regulator of gastric cancer.

Farnesoid X receptor interacts with cAMP response element binding protein to modulate glucagon-like peptide-1 (7-36) amide secretion by intestinal L cell.

Type II diabetes is a complex, chronic, and progressive disease. Glucagon-like peptide-1 (7-36) amide (GLP-1) is a gut hormone released from the L cells which stimulate insulin secretion and promotes insulin gene expression and ß-cell growth and differentiation. Elevated levels of hormones secreted by L cells are an essential reason for diabetes improvement. GLP-1 secretion has been reported to be regulated by farnesoid X receptor (FXR), a transcriptional sensor for bile acids which also acts on glucose metabolism. Herein, we attempted to evaluate the effect of FXR on GLP-1 secretion in mouse enteroendocrine L cell line, namely STC-1, and to investigate the underlying mechanism. FXR inversely regulated GLP-1 secretion in STC-1. A total of 24 nonredundant human proteins were shown to be related to FXR by BioGRID; KEGG pathway analysis revealed that FXR was related to glucagon signaling pathway, particularly with the transcriptional activators CREB, PGC1α, Sirt1, and CBP. CREB could positively regulate GLP-1 secretion in STC-1 cells. FXR combined with CREB to inhibit its transcriptional activity, thus inhibiting proprotein convertase subtilisin/kexin type 1 protein level and GLP-1 secretion. In the present study, we demonstrated a negative regulation of GLP-1 secretion by FXR in L cell line, STC-1; FXR exerts its function in L cells through interacting with CREB, a crucial transcriptional regulator of cAMP-CREB signaling pathway, to inhibit its transcriptional activity. Targeting FXR to rescue GLP-1 secretion may be a promising strategy for type II diabetes.

A novel epigenetic mechanism of FXR inhibiting GLP-1 secretion via miR-33 and its downstream targets.

Type II diabetes is a complex, chronic, and progressive disease. Previously, we demonstrate that FXR inhibits GLP-1 secretion via interacting with CREB to inhibit the transcriptional activity of CREB, thus promoting the development of type II diabetes. Epigenetic modifications, such as DNA methylation, histone acetylation, and post-transcriptional RNA regulation, are essential mediators contributing to diabetes-associated morbidity and mortality. Thus, we attempted to investigate the epigenetic mechanisms of FXR modulating GLP-1 secretion. Firstly, the involvement of histone acetylation, DNA methylation, and post-transcriptional regulation in FXR inhibiting GLP-1 secretion was verified. As FXR overexpression significantly inhibited the activity of GCG 3'-UTR, we hypothesize that miRNA might participate in the mechanism. Two online tools and real-time PCR revealed that FXR promoted miR-33 expression. Moreover, miR-33 inhibited the expression of GCG and CREB1 through direct targeting in STC-1 cells. FXR overexpression in STC-1 cells significantly reduced the mRNA expression and protein levels of both GCG and CREB1, as well as the secretion of GLP-1; miR-33 inhibition exerted opposing effects. More importantly, the effects of FXR overexpression were significantly reversed by miR-33 inhibition, indicating that FXR inhibited GLP-1 secretion through promoting miR-33 expression, therefore inhibiting the expression of miR-33 targets, GCG and CREB1. In conclusion, we provide a novel epigenetic mechanism by which FXR inhibits the secretion of GLP-1 through miR-33 and its two downstream targets, GCG and CREB1. These findings might provide innovative strategies for improving type II diabetes, which needs further in vivo and clinical investigation.