The relationship between triglyceride-glucose index and prospective key clinical outcomes in patients hospitalised for coronary artery disease.

BACKGROUND: The triglyceride-glucose (TyG) index is regarded as a dependable alternative for assessing insulin resistance (IR), given its simplicity, cost-effectiveness, and strong correlation with IR. The relationship between the TyG index and adverse outcomes in patients with coronary heart disease (CHD) is not well established. This study examines the association of the TyG index with long-term adverse outcomes in hospitalized CHD patients. METHODS: In this single-center prospective cohort study, 3321 patients hospitalized with CHD were included. Multivariate Cox regression models were employed to assess the associations between the TyG index and the incidence of all-cause mortality and major adverse cardiovascular events (MACEs). To examine potential nonlinear associations, restricted cubic splines and threshold analysis were utilized. RESULTS: During a follow-up period of 9.4 years, 759 patients (22.9%) succumbed to mortality, while 1291 (38.9%) experienced MACEs. Threshold analysis demonstrated a significant "U"-shaped nonlinear relationship with MACEs, with different hazard ratios observed below and above a TyG index of 8.62 (below: HR 0.71, 95% CI 0.50-0.99; above: HR 1.28, 95% CI 1.10-1.48). Notably, an increased risk of all-cause mortality was observed only when the TyG index exceeded 8.77 (HR 1.53, 95% CI 1.19-1.96). CONCLUSIONS: This study reveals a nonlinear association between the TyG index and both all-cause mortality and MACEs in hospitalized CHD patients with CHD. Assessing the TyG index, particularly focusing on individuals with extremely low or high TyG index values, may enhance risk stratification for adverse outcomes in this patient population.

Diagnostic performance of Node Reporting and Data System (Node-RADS) for assessing mesorectal lymph node in rectal cancer by CT.

BACKGROUND: To compare the diagnostic performance of the Node-RADS scoring system and lymph node (LN) size in preoperative LN assessment for rectal cancer (RC), and to investigate whether the selection of size as the primary criterion whereas morphology as the secondary criterion for LNs can be considered the preferred method for clinical assessment. METHODS: Preoperative CT data of 146 RC patients treated with radical resection surgery were retrospectively analyzed. The Node-RADS score and short-axis diameter of size-prioritized LNs and the morphology-prioritized LNs were obtained. The correlations of Node-RADS score to the pN stage, LNM number and lymph node ratio (LNR) were investigated. The performances on assessing pathological lymph node metastasis were compared between Node-RADS score and short-axis diameter. A nomogram combined the Node-RADS score and clinical features was also evaluated. RESULTS: Node-RADS score showed significant correlation with pN stage, LNM number and LNR (Node-RADS of size-prioritized LN: r = 0.600, 0.592, and 0.606; Node-RADS of morphology-prioritized LN: r = 0.547, 0.538, and 0.527; Node-RADSmax: r = 0.612, 0.604, and 0.610; all p < 0.001). For size-prioritized LN, Node-RADS achieved an AUC of 0.826, significantly superior to short-axis diameter (0.826 vs. 0.743, p = 0.009). For morphology-prioritized LN, Node-RADS exhibited an AUC of 0.758, slightly better than short-axis diameter (0.758 vs. 0.718, p = 0.098). The Node-RADS score of size-prioritized LN was significantly better than that of morphology-prioritized LN (0.826 vs. 0.758, p = 0.038). The nomogram achieved the best diagnostic performance (AUC = 0.861) than all the other assessment methods (p < 0.05). CONCLUSIONS: The Node-RADS scoring system outperforms the short-axis diameter in predicting lymph node metastasis in RC. Size-prioritized LN demonstrates superior predictive efficacy compared to morphology-prioritized LN. The nomogram combined the Node-RADS score of size-prioritized LN with clinical features exhibits the best diagnostic performance. Moreover, a clear relationship was demonstrated between the Node-RADS score and the quantity-dependent pathological characteristics of LNM.

GLP-1 signaling-regulated SNAP25 is involved in improved insulin secretion in diabetic GK rats after Roux-en-Y gastric bypass surgery.

BACKGROUND: Roux-en-Y gastric bypass surgery (RYGB) improves glucose-stimulated insulin secretion (GSIS) in type 2 diabetes (T2D) patients. SNAP25 plays an essential role in GSIS. Clinical studies indicate that enhanced GLP-1 signaling is an important contributor to the improved ß-cell function in T2D. We aimed to explore whether GLP-1-regulated SNAP25 is involved in the enhanced secretory function of ß-cells in diabetic Goto-Kakizaki (GK) rats after RYGB. METHODS AND RESULTS: RYGB or sham surgery was conducted in GK rats. mRNA and protein expression of SNAP25 was assessed by qPCR and Western blot, respectively. Occupancy of CREB and acetyltransferase CBP and acetylation of histone H3 (ACH3) at the Snap25 promoter were determined using ChIP assay. RYGB led to increased SNAP25 expression and CREB phosphorylation in islets from GK rats. Increased SNAP25 improved GSIS in ß-cells cultured in high glucose conditions. Consistent with increased plasma GLP-1 after RYGB, GLP-1R agonist exendin4 increased SNAP25 expression and CREB phosphorylation in ß-cells. Mechanistically, exendin4 promoted the recruitment of CREB and CBP, thereby increasing ACH3 at the Snap25 promoter. Consistently, inhibition of CBP attenuated the effect of exendin4 on SNAP25 expression. Furthermore, the knockdown of SNAP25 diminished the increase of GSIS potentiated by chronic GLP-1 culture in INS-1 832/13 cells. CONCLUSIONS: Our findings unravel the novel mechanisms of RYGB-enhanced SNAP25 expression in ß-cells, and SNAP25 may contribute to the improved ß-cell secretory function induced by RYGB.

Establishment of the Diagnostic Signature of Ferroptosis Genes in Multiple Sclerosis.

Ferroptosis is a novel form of membrane-dependent cell death that differs from other cell death modalities such as necrosis, apoptosis, and autophagy. Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system primarily affecting brain and spinal cord neurons. Although the pathogenesis of these two conditions may seem unrelated, recent studies have indicated a connection between ferroptosis and multiple sclerosis. In fact, ferroptosis plays a significant role in the development of MS, as evidenced by the presence of elevated iron levels and iron metabolism abnormalities in the brains, spinal cords, and other neurons of MS patients. These abnormalities disrupt iron homeostasis within cells, leading to the occurrence of ferroptosis. However, there is currently a lack of research on the diagnostic value of ferroptosis-related genes in multiple sclerosis. In this study, we employed bioinformatics methods to identify ferroptosis-related genes (ATM, GSK3B, HMGCR, KLF2, MAPK1, NFE2L1, NRAS, PCBP1, PIK3CA, RPL8, VDAC3) associated with the diagnosis of multiple sclerosis and constructed a diagnostic model. The results demonstrated that the diagnostic model accurately identified the patients' condition. Subsequently, subgroup analysis was performed based on the expression levels of ferroptosis-related genes, dividing patients into high and low expression groups. The results showed differences in immune function and immune cell infiltration between the two groups. Our study not only confirms the correlation between ferroptosis and multiple sclerosis but also demonstrates the diagnostic value of ferroptosis-related genes in the disease. This provides guidance for clinical practice and direction for further mechanistic research.

Laser Processing of Crumpled Porous Graphene/MXene Nanocomposites for a Standalone Gas Sensing System.

Integrating wearable gas sensors with energy harvesting and storage devices can create self-powered systems for continuous monitoring of gaseous molecules. However, the development is still limited by complex fabrication processes, poor stretchability, and sensitivity. Herein, we report the low-cost and scalable laser scribing of crumpled graphene/MXenes nanocomposite foams to combine stretchable self-charging power units with gas sensors for a fully integrated standalone gas sensing system. The crumpled nanocomposite designed in island-bridge device architecture allows the integrated self-charging unit to efficiently harvest kinetic energy from body movements into stable power with adjustable voltage/current outputs. Meanwhile, given the stretchable gas sensor with a large response of ∼1% ppm-1 and an ultralow detection limit of ∼5 ppb to NO2/NH3, the integrated system provides real-time monitoring of the exhaled human breath and the local air quality. The innovations in materials and structural designs pave the way for the future development of wearable electronics.

Comparative Analysis of the Anti-Inflammatory Effects of Liraglutide and Dulaglutide.

Inflammation plays a pathophysiological role in atherosclerosis and its clinical consequences. In addition to glycemic control, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are of wide concern for cardioprotective effects. The structure, half-life, homology, and clinical efficacy of GLP-1RAs exhibit remarkable disparity. Several studies have compared the disparities in anti-inflammatory effects between daily and weekly GLP-1RAs. This study aimed to compare the similarities and differences between liraglutide and dulaglutide in terms of inhibiting atherosclerotic inflammation and improving co-cultured endothelial cell function. The expression of inflammation markers was examined by immunofluorescence, Western blotting, and real-time PCR. The tube-forming ability of endothelial cells was tested on Matrigel. The results verify that 10/50/100 nmol/L liraglutide and 100 nmol/L dulaglutide markedly suppressed the expression of inflammatory factors in LPS-induced atherosclerosis after 24 and 72 hours, respectively. Moreover, they promoted the polarization of M1 macrophages toward the M2 phenotype and improved the function of co-cultured endothelial cells. Both liraglutide and dulaglutide ameliorate atherosclerosis development. The difference between the two resided in the extended intervention duration required to observe the effect of dulaglutide, and liraglutide demonstrated a superior dose-dependent manner. We provide a potential strategy to understand the dynamics of drug action and possible timing administration.

Crosstalk between 5-methylcytosine and N6-methyladenosine machinery defines disease progression, therapeutic response and pharmacogenomic landscape in hepatocellular carcinoma.

BACKGROUND: Accumulated evidence highlights the significance of the crosstalk between epigenetic and epitranscriptomic mechanisms, notably 5-methylcytosine (5mC) and N6-methyladenosine (m6A). Herein, we conducted a widespread analysis regarding the crosstalk between 5mC and m6A regulators in hepatocellular carcinoma (HCC). METHODS: Pan-cancer genomic analysis of the crosstalk between 5mC and m6A regulators was presented at transcriptomic, genomic, epigenetic, and other multi-omics levels. Hub 5mC and m6A regulators were summarized to define an epigenetic and epitranscriptomic module eigengene (EME), which reflected both the pre- and post-transcriptional modifications. RESULTS: 5mC and m6A regulators interacted with one another at the multi-omic levels across pan-cancer, including HCC. The EME scoring system enabled to greatly optimize risk stratification and accurately predict HCC patients' clinical outcomes and progression. Additionally, the EME accurately predicted the responses to mainstream therapies (TACE and sorafenib) and immunotherapy as well as hyper-progression. In vitro, 5mC and m6A regulators cooperatively weakened apoptosis and facilitated proliferation, DNA damage repair, G2/M arrest, migration, invasion and epithelial-to-mesenchymal transition (EMT) in HCC cells. The EME scoring system was remarkably linked to potential extrinsic and intrinsic immune escape mechanisms, and the high EME might contribute to a reduced copy number gain/loss frequency. Finally, we determined potential therapeutic compounds and druggable targets (TUBB1 and P2RY4) for HCC patients with high EME. CONCLUSIONS: Our findings suggest that HCC may result from a unique synergistic combination of 5mC-epigenetic mechanism mixed with m6A-epitranscriptomic mechanism, and their crosstalk defines therapeutic response and pharmacogenomic landscape.

Altered Brain Function in Pediatric Patients With Complete Spinal Cord Injury: A Resting-State Functional MRI Study.

BACKGROUND: Injury to the spinal cord of children may cause potential brain reorganizations, affecting their rehabilitation. However, the specific functional alterations of children after complete spinal cord injury (CSCI) remain unclear. PURPOSE: To explore the specific functional changes in local brain and the relationship with clinical characteristics in pediatric CSCI patients, clarifying the impact of CSCI on brain function in developing children. STUDY TYPE: Prospective. SUBJECTS: Thirty pediatric CSCI patients (7.83 ± 1.206 years) and 30 age-, gender-matched healthy children as controls (HCs) (8.77 ± 2.079 years). FIELD STRENGTH/SEQUENCE: 3.0 T/Resting-state functional MRI (rs-fMRI) using echo-planar-imaging (EPI) sequence. ASSESSMENT: Amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and regional homogeneity (ReHo) were used to characterize regional neural function. STATISTICAL TESTS: Two-sample t-tests were used to compare the ALFF, fALFF, ReHo values of the brain between pediatric CSCI and HCs (voxel-level FWE correction, P < 0.05). Spearman correlation analyses were performed to analyze the associations between the ALFF, fALFF, ReHo values in altered regions and the injury duration, sensory motor scores of pediatric CSCI patients (P < 0.05). Then receiver operating characteristic (ROC) analysis was conducted to identify possible sensitive imaging indicators for clinical therapy. RESULTS: Compared with HCs, pediatric CSCI showed significantly decreased ALFF in the right postcentral gyrus (S1), orbitofrontal cortex, and left superior temporal gyrus (STG), increased ALFF in bilateral caudate nucleus, thalamus, middle cingulate gyrus, and cerebellar lobules IV-VI, and increased ReHo in left cerebellum Crus II and Brodmann area 21. The ALFF value in the right S1 negatively correlated with the pinprick and light touch sensory scores of pediatric CSCI. When the left STG was used as an imaging biomarker for pediatric CSCI, it achieved the highest area under the curve of 0.989. CONCLUSIONS: These findings may provide potential neural mechanisms for sensory motor and cognitive-emotional deficits in children after CSCI. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 5.

Insight into the mechanism of direct N-C coupling in selective catalytic reduction of NO by CO over Ni(111)-supported graphene.

Selective catalytic reduction (SCR) of NO using CO as a reducing agent is a straightforward and promising approach to the simultaneous removal of NO and CO. Herein, a novel mechanism of N-C direct coupling of gaseous NO and CO into ONCO and subsequent hydrogenation of *ONCO to nitrogen-containing compounds over Ni(111)-supported graphene ((Gr/Ni(111)) is reported. The results indicate that Gr/Ni(111) can not only trigger direct N-C coupling of NO and CO to form ONCO with a low activation energy barrier of 0.11 eV, but also enable the key intermediate of *ONCO to be stable. The *ONCO chemisorbed on Gr/Ni(111) exhibits negative univalent [ONCO]- and is more stable than neutral ONCO. The hydrogenation pathways show that HNCO preferably forms through a kinetically favorable initial N-C coupling due to the lowest free-energy barrier of 0.18 eV, while NH2CH3 is a considerably competitive product because its free-energy barrier is only 0.20 eV higher than that of HNCO. Our results provide a fundamental insight into the novel reaction mechanism of the SCR of NO and also suggest that nickel-supported graphene is a potential and high-efficient catalyst for eliminating CO and NO harmful gases.

Rational targeting of autophagy in colorectal cancer therapy: From molecular interactions to pharmacological compounds.

The abnormal progression of tumors has been a problem for treatment of cancer and therapeutic should be directed towards targeting main mechanisms involved in tumorigenesis in tumors. The genomic mutations can result in changes in biological mechanisms in human cancers. Colorectal cancer is one of the most malignant tumors of gastrointestinal tract and its treatment has been faced some difficulties due to development of resistance in tumor cells and also, their malignant behavior. Hence, new therapeutic modalities for colorectal cancer are being investigated. Autophagy is a "self-digestion" mechanism that is responsible for homeostasis preserving in cells and its aberrant activation/inhibition can lead to tumorigenesis. The current review focuses on the role of autophagy mechanism in colorectal cancer. Autophagy may be associated with increase/decrease in progression of colorectal cancer due to mutual function of this molecular mechanism. Pro-survival autophagy inhibits apoptosis to increase proliferation and survival rate of colorectal tumor cells and it is also involved in cancer metastasis maybe due to EMT induction. In contrast, pro-death autophagy decreases growth and invasion of colorectal tumor cells. The status of autophagy (upregulation and down-regulation) is a determining factor for therapy response in colorectal tumor cells. Therefore, targeting autophagy can increase sensitivity of colorectal tumor cells to chemotherapy and radiotherapy. Interestingly, nanoparticles can be employed for targeting autophagy in cancer therapy and they can both induce/suppress autophagy in tumor cells. Furthermore, autophagy modulators can be embedded in nanostructures in improving tumor suppression and providing cancer immunotherapy.

Development of convenient crystallization inhibition assays for structure-activity relationship studies in the discovery of crystallization inhibitors.

Kidney stone diseases are increasing globally in prevalence and recurrence rates, indicating an urgent medical need for developing new therapies that can prevent stone formation. One approach we have been working on is to develop small molecule inhibitors that can interfere with the crystallization process of the chemical substances that form the stones. For these drug discovery efforts, it is critical to have available easily accessible assay methods to evaluate the potential inhibitors and rank them for structure-activity relationship studies. Herein, we report a convenient, medium-to-high throughput assay platform using, as an example, the screening and evaluation of inhibitors of L-cystine crystallization for the prevention of kidney stones in cystinuria. The assay involves preparing a supersaturated solution, followed by incubating small volumes (<1 mL) of the supersaturated solution with test inhibitors for 72 hours, and finally measuring L-cystine concentrations in the supernatants after centrifugation using either a colorimetric or fluorometric method. Compared to traditional techniques for studying crystallization inhibitors, this miniaturized multi-well assay format is simple to implement, cost-effective, and widely applicable in determining and distinguishing the activities of compounds that inhibit crystallization. This assay has been successfully employed to discover L-cystine diamides as highly potent inhibitors of L-cystine crystallization such as LH708 with an EC50 of 0.058 µM, 70-fold more potent than L-CDME (EC50 = 4.31 µM).

Safety and efficacy of treating post-burn pathological scars with extracorporeal shock wave therapy: A meta-analysis of randomised controlled trials.

The clinical application of shockwave therapy has expanded to the treatment of pathological scars. The objective of this systematic review and meta-analysis is to quantitatively evaluate the efficacy and safety of extracorporeal shockwave therapy combined with comprehensive rehabilitation therapy on post-burn pathological scars compared to comprehensive rehabilitation therapy alone. The randomised controlled trials of extracorporeal shockwave therapy for post-burn pathological scars published in English and Chinese languages before October 2021 were included. The methodological quality and risk of bias of the selected articles were assessed with the Cochrane Collaboration's 'risk of bias' tool. RevMan software was applied for data analysis. This is the first systematic review and meta-analysis considering the effectiveness and safety of extracorporeal shockwave therapy on post-burn pathological scars. And nine randomised controlled trials involving 422 patients were included in this meta-analysis. The meta-analysis results showed that, compared with comprehensive rehabilitation therapy alone, extracorporeal shockwave therapy combined with comprehensive rehabilitation therapy was more effective in relieving pain (standardized mean difference [SMD] = -0.59, 95% confidence interval [CI]: [-0.87 to -0.31], p < 0.0001) and pruritus related to pathological scars (SMD = -0.94; 95% CI: [-1.25 to -0.63], p = 0.004), improving scars' appearance (SMD = -1.78, 95% CI: [-3.37 to -0.19], p = 0.03) and elasticity (SMD = 0.25, 95% CI: [0.29-0.21], p < 0.00001), decreasing scars thickness (SMD = -0.13, 95% CI: [-0.25 to -0.01], p = 0.04) and promoting the maturation status of scars (SMD = -2.86, 95% CI: [-3.96 to -1.76], p < 0.00001). There were no reported serious adverse events during and after extracorporeal shockwave therapy in the included studies. Available data preliminarily suggested that the combination of extracorporeal shockwave therapy and comprehensive rehabilitation therapy had better therapeutic effect on post-burn pathological scars than comprehensive rehabilitation therapy alone, without obvious side effects. However, further clinical well-controlled randomised controlled trials are needed. Systematic review registration ID: PROSPERO CRD42022297573.

A robust method for protein depletion based on gene editing.

The technology of clustered regularly interspaced short palindromic repeats (CRISPR)-associated nuclease Cas9 (CRISPR-Cas9) is a powerful system for protein depletion resulting from insertions and deletions following Cas9 cleavage of genome at specific site in vitro and in vivo. We herein present a relatively standard protocol for protein depletion in a step-by-step procedure, including guide RNA designation and vector construction, lentivirus production, cell selection, and experimentally validate the function of targeted protein. We exemplified this approach by editing PDGFRß in human epithelial cells, and expected that this simplified and detailed protocol will be more broadly applied on specific genes to aid understanding gene functions.

Progression and application of CRISPR-Cas genomic editors.

Base editing technology is an efficient tool for genome editing, particularly in the correction of base mutations. Diverse base editing systems were developed according to the dCas9 or nCas9 linked with different deaminase or reverse transcriptase in the editors, including ABEs, CBEs, PEs and dual-functional of base editor (such as CGBE1, A&C-BEmax, ACBE, etc.). Currently, Base editing technology has been widely applied to various fields such as microorganisms, plants, animals and medicine for basic research and therapeutics. Here, we reviewed the advancement of base editing technology. We also discussed the application of base editors in different areas in the future.

AAV-mediated in vivo genome editing in vascular endothelial cells.

In vivo genome editing meets numerous challenges including efficiency and safety. Here we describe an efficient in vivo genome editing method of delivering CRISPR-Cas9 into vascular endothelial cells with adeno-associated viruses (AAVs). In this system, expression of SpCas9 is driven by a specific endothelial promoter of intercellular adhesion molecule 2 (pICAM2) to restrict this foreign enzyme in vascular endothelial cells, which can be efficiently infected by AAV1. We exemplify this approach by editing VEGFR2 in retinal vascular endothelial cells in a mouse model of oxygen-induced retinopathy, and expect that this simplified protocol can be expanded to other researches on editing endothelial genome in vivo.

TRIM16 overexpression inhibits the metastasis of colorectal cancer through mediating Snail degradation.

Tripartite motif containing 16 (TRIM16) is a member of the tripartite motif protein family and functions as a potential tumor suppressor in several cancers. However, the specific function and clinical significance of TRIM16 in colorectal cancer (CRC) remains unclear. In this study, we observed that low TRIM16 expression was detected frequently in primary colorectal cancer (CRC) tissues and was closely associated with a better prognosis. Functional studies demonstrate that TRIM16 overexpression notably inhibits the metastasis abilities of CRC in vivo and in vitro. Mechanistically, our results demonstrated that TRIM16 directly bound and ubiquitinated Snail family transcriptional repressor 1 (Snail), an important transcriptional factor of the epithelial-mesenchymal transition (EMT) process suppressing the EMT in CRC. Additionally, our data revealed that the inhibition effect of TRIM16 on cancer metastasis was dependent on Snail degradation. Collectively, our study is the first to report that TRIM16 plays a crucial anti-tumor role in CRC tumorigenesis. We also provided novel evidence that TRIM16 might act as a prognostic and therapeutic target to assess and inhibit CRC progression.

Internalization and membrane activity of the antimicrobial peptide CGA-N12.

Antimicrobial peptides (AMPs) are conventional antibiotic alternatives due to their broad-spectrum antimicrobial activities and special mechanisms of action against pathogens. The antifungal peptide CGA-N12 was originally derived from human chromogranin A (CGA) and consists of the 65th to 76th amino acids of the CGA N-terminal region. In the present study, we found that CGA-N12 had fungicidal activity and exhibited time-dependent inhibition activity against Candida tropicalis. CGA-N12 entered the cells to exert its antagonist activity. The internalization of CGA-N12 was energy-dependent and accompanied by actin cytoskeleton-, clathrin-, sulfate proteoglycan-, endosome-, and lipid-depleting agent-mediated endocytosis. Moreover, the CGA-N12 internalization pathway was related to the peptide concentration. The effects of CGA-N12 on the cell membrane were investigated. CGA-N12 at a low concentration less than 4 × MIC100 did not destroy the cell membrane. While with increasing concentration, the damage to the cell membrane caused by CGA-N12 became more serious. At concentrations greater than 4 × MIC100, CGA-N12 destroyed the cell membrane integrity. Therefore, the membrane activity of CGA-N12 is concentration dependant.

Recent progress in heterogeneous metal and metal oxide catalysts for direct dehydrogenation of ethane and propane.

Catalytic non-oxidative direct dehydrogenation of light alkanes serves as an effective reinforcement to selectively produce the corresponding olefins, and the heterogeneous metals and metal oxides, not limited to the commercially used Pt- and Cr-based catalysts, are widely investigated to enhance the efficiency. In this review, we outline the progress of these dehydrogenation catalysts that have been mainly developed in the past five years. For different classes of the most-promising catalysts in the selective dehydrogenation of ethane-to-ethylene and propane-to-propylene, their syntheses, structural information, catalytic properties and mechanisms are comparatively summarized.

FXR-mediated epigenetic regulation of GLP-1R expression contributes to enhanced incretin effect in diabetes after RYGB.

In this study, we investigated how Roux-en-Y gastric bypass (RYGB) enhances glucagon-like peptide 1 (GLP-1) response in GK rats and explored the potential link between RYGB-stimulated BAs/FXR signalling and GLP-1R-linked signalling in ß-cells, a key pathway that regulates glucose-stimulated insulin secretion (GSIS). Here we show that RYGB restores GLP-1R expression in GK rat islets. This involves increased total BAs as well as chenodeoxycholic acid (CDCA), leading to FXR activation, increasing FXR binding to the promoter of Glp-1r and enhancing occupancy of histone acetyltransferase steroid receptor coactivator-1 (SRC1), thus increasing histone H3 acetylation at the promoter. These coordinated events bring about increased GLP-1R expression, resulting in greater GLP-1 response in ß-cells. Moreover, ablation of FXR suppressed the stimulatory effects of GLP-1. Thus, this study unravels the crucial role of the BAs/FXR/SRC1 axis-controlled GLP-1R expression in ß-cells, which results in enhanced incretin effect and normalized blood glucose of GK rats after RYGB.

Chalcomoracin prevents vitreous-induced activation of AKT and migration of retinal pigment epithelial cells.

Retinal pigment epithelial (RPE) cells are the major cell type in the epi- or sub-retinal membranes in the pathogenesis of proliferative vitreoretinopathy (PVR), which is a blinding fibrotic eye disease and still short of effective medicine. The purpose of this study is to demonstrate whether Chalocomoracin (CMR), a novel purified compound from fungus-infected mulberry leaves, is able to inhibit vitreous-induced signalling events and cellular responses intrinsic to PVR. Our studies have revealed that the CMR IC50 for ARPE-19 cells is 35.5 µmol/L at 72 hours, and that 5 µmol/L CMR inhibits vitreous-induced Akt activation and p53 suppression; in addition, we have discovered that this chemical effectively blocks vitreous-stimulated proliferation, migration and contraction of ARPE-19 cells, suggesting that CMR is a promising PVR prophylactic.