👤 X Meng

White matter hyperintensity (WMH) is an important factor leading to cognitive impairment, and the mechanism has not been clarified. In recent years, studies have found that circular RNA (circRNA) has differential expression in cerebrovascular diseases. This study aims to analyze the expression profile of circRNA in peripheral blood mononuclear cell (PBMC) of patients with WMH with cognitive impairment, to screen the differentially expressed circRNA, and to explore the possible role of circRNA in WMH with cognitive impairment. CircRNA microarray was used to detect the circRNA expression profile of PBMC in patients with WMH with cognitive impairment, and in patients with WMH without cognitive impairment as well as in normal controls (3 cases each, male to female ratio of 2꞉1). The differentially expressed circRNA in patients with WMH with cognitive impairment was screened. The screening criteria for differentially expressed circRNA was fold change (FC) ≥2.0 (|log Compared with the control group, there were 5 significantly up-regulated circRNA and 3 down-regulated circRNA in the WMH with cognitive impairment group; 8 circRNA were significantly up-regulated and 2 were down-regulated in the WMH without cognitive impairment group. When compared with the WMH with cognitive impairment group, no co-differentially expressed circRNA was found in WMH without cognitive impairment group and control group. Compared with the control group, the expression of hsa_circ₀₀₉₂₂₂₂ was up-regulated and the expressions of hsa_circ₀₀₀₀₆₆₂ and hsa_circ₀₀₈₃₇₇₃ were down-regulated in the WMH with cognitive impairment group and the WMH without cognitive impairment group, and there was no significant difference between the 2 groups (all The circRNA expression profile of patients with WMH is changed significantly. The differentially expressed circRNA may be the cause of WMH; Hsa_circ₀₀₉₂₂₂₂, hsa_circ₀₀₀₀₆₆₂, and hsa_circ₀₀₈₃₇₇₃ may regulate the expression of target genes by targeting adsorption of the target miRNA, leading to brain white matter damage through Janus kinase 2 (JAK2)/signal transducers and activators of transcription (STAT3) signal pathway and Wnt signal pathway.There is no significant difference in circRNA expression profile between WMH with or without cognitive impairment. Cognitive impairment in patients with WMH may have other reasons. Show less

Bardet-Biedl syndrome (BBS; OMIM 209900) is a rare genetic disease causing damage to multiple organs and affecting patients' quality of life in late adolescence or early adulthood. In this study, the ocular characteristics including morphology and function, were analyzed in 12 BBS patients from 10 Chinese families by molecular diagnostics. A total of five known and twelve novel variants in four Show less

DEAD (Glu-Asp-Ala-Glu) box RNA helicases have been proven to contribute to antiviral innate immunity. The DDX21 RNA helicase was identified as a nuclear protein involved in rRNA processing and RNA unwinding. DDX21 was also proven to be the scaffold protein in the complex of DDX1-DDX21-DHX36, which senses double-strand RNA and initiates downstream innate immunity. Here, we identified that DDX21 undergoes caspase-dependent cleavage after virus infection and treatment with RNA/DNA ligands, especially for RNA virus and ligands. Caspase-3/6 cleaves DDX21 at D126 and promotes its translocation from the nucleus to the cytoplasm in response to virus infection. The cytoplasmic cleaved DDX21 negatively regulates the interferon beta (IFN-β) signaling pathway by suppressing the formation of the DDX1-DDX21-DHX36 complex. Thus, our data identify DDX21 as a regulator of immune balance and most importantly uncover a potential role of DDX21 cleavage in the innate immune response to virus. Show less

MiR-452-5p plays an essential role in the development of a variety of tumors, but little is known about its biological function and mechanism in colorectal cancer (CRC). The expression levels of miR-452-5p in CRC tissues and cells were detected by real-time quantitative PCR (qRT-PCR). Besides, the biological effects of miR-452-5p on CRC were investigated by functional experiments The expression level of miR-452-5p was up-regulated in CRC tissues. MiR-452-5p promoted CRC cell proliferation, cell cycle transition and chemoresistance, and inhibited cell apoptosis. Moreover, miR-452-5p directly targeted PKN2 and DUSP6 and subsequently activated the ERK/MAPK signaling pathway, and it was transcriptionally regulated by c-Jun. To conclude, miR-452-5p expression is up-regulated in CRC, which promotes the progression of CRC by activating the miR-452-5p-PKN2/DUSP6-c-Jun positive feedback loop. These findings indicate that miR-452-5p may act as a potential therapeutic target and clinical response biomarker for CRC. Show less

Elucidating virus-cell interactions is fundamental to understanding viral replication and identifying targets for therapeutic control of viral infection. The extracellular signal-regulated kinase (ERK) pathway has been shown to regulate pathogenesis during many viral infections, but its role during coronavirus infection is undetermined. Infectious bronchitis virus is the representative strain of Gammacoronavirus, which causes acute and highly contagious diseases in the poultry farm. In this study, we investigated the role of ERK1/2 signaling pathway in IBV infection. We found that IBV infection activated ERK1/2 signaling and the up-regulation of phosphatase DUSP6 formed a negative regulation loop. Pharmacological inhibition of MEK1/2-ERK1/2 signaling suppressed the expression of DUSP6, promoted cell death, and restricted virus replication. In contrast, suppression of DUSP6 by chemical inhibitor or siRNA increased the phosphorylation of ERK1/2, protected cells from apoptosis, and facilitated IBV replication. Overexpression of DUSP6 decreased the level of phospho-ERK1/2, promoted apoptosis, while dominant negative mutant DUSP6-DN lost the regulation function on ERK1/2 signaling and apoptosis. In conclusion, these data suggest that MEK-ERK1/2 signaling pathway facilitates IBV infection, probably by promoting cell survival; meanwhile, induction of DUSP6 forms a negative regulation loop to restrict ERK1/2 signaling, correlated with increased apoptosis and reduced viral load. Consequently, components of the ERK pathway, such as MEK1/2 and DUSP6, represent excellent targets for the development of antiviral drugs. Show less

Immune thrombocytopenia (ITP) is an autoimmune-mediated disease characterized by decreased platelet counts. Cytokines play important roles in modulating the immune response and are involved in the pathogenesis of many autoimmune diseases. This study aimed at exploring the serum levels of a core set of cytokines that exert immune-regulatory functions in newly diagnosed ITP patients (both before and after treatment) and splenectomized ITP patients. Using the Bio-Plex suspension array system and ELISA, the serum levels of IL-10, IL-21, IL-27, IL-33, IL-35, IL-37, and TGF-β Show less

To understand the inflammatory microenvironment and microbiome factors for prognosis of chronic rhinosinusitis with polyps (CRSwNP), we explored the difference in characteristics of the microbiome of the nasal sinuses and inflammatory cytokines between recurrent and non-recurrent groups. We collected nasal secretions and polyp tissue from 77 CRSwNP patients. Then, we extracted microbial DNA from cotton swabs, performed high-throughput sequencing based on 16S rRNA to detect bacterial community composition, and analyzed cytokines such as IL-5, IL-8, IL-17a, IL-17e, IL-18, IL-27 and INF-gamma from polyp tissue using Luminex. The eosinophil and neutrophil cells in the peripheral blood and polyp tissue were counted. Postoperative follow-up of patients with CRSwNP for 1 year was conducted to record the recurrence of nasal polyps and analyze the correlation between the recurrence of nasal polyps and the characteristics of inflammatory cytokines, inflammatory cell count and nasal microbial diversity. After 1 year of follow-up, there were 12 recurrent patients, including 5 males and 7 females. Postoperative recurrence of nasal polyps was not significantly correlated with age, sex, asthma, allergic rhinitis or other allergic diseases in CRSwNP patients. In terms of the total nasal symptom score, the recurrent group was significantly higher than the non-recurrent group. In nasal polyp tissues, eosinophils (40.83/HP) and neutrophils (30.83/HP) in patients with CRSwNP in the recurrent group were significantly higher than those in the non-recurrent group (13.72/HP), and neutrophils (18.5/HP) were also significantly higher in the recurrent group than the non-recurrent group. The expression levels of IFN-, IL-17A, IL-17E and IL-18 were significantly higher in the recurrent group than in the non-recurrent group, and the positive rates were not different. In Southwest China, Enterobacteria and anaerobic bacteria may be correlated with the inflammatory pattern expression of nasal polyps. The neutrophil-mediated inflammatory response plays an important role in patients with CRSwNP in Southwest China and is correlated with nasal polyp recurrence. Recurrence of nasal polyps after endoscopic sinus surgery may be potentially associated with a reduced abundance of protective microorganisms and an increased number of pathogenic microorganisms. Show less

Alternative splicing is a critical process to generate protein diversity. However, whether and how alternative splicing regulates autophagy remains largely elusive. Here we systematically identify the splicing factor SRSF1 as an autophagy suppressor. Specifically, SRSF1 inhibits autophagosome formation by reducing the accumulation of LC3-II and numbers of autophagosomes in different cell lines. Mechanistically, SRSF1 promotes the splicing of the long isoform of Bcl-x that interacts with Beclin1, thereby dissociating the Beclin1-PIK3C3 complex. In addition, SRSF1 also directly interacts with PIK3C3 to disrupt the interaction between Beclin1 and PIK3C3. Consequently, the decrease of SRSF1 stabilizes the Beclin1 and PIK3C3 complex and activates autophagy. Interestingly, SRSF1 can be degraded by starvation- and oxidative stresses-induced autophagy through interacting with LC3-II, whereas reduced SRSF1 further promotes autophagy. This positive feedback is critical to inhibiting Gefitinib-resistant cancer cell progression both in vitro and in vivo. Consistently, the expression level of SRSF1 is inversely correlated to LC3 level in clinical cancer samples. Our study not only provides mechanistic insights of alternative splicing in autophagy regulation but also discovers a new regulatory role of SRSF1 in tumorigenesis, thereby offering a novel avenue for potential cancer therapeutics. Show less

Etomidate (ETO) is a commonly used intravenous anesthetic that has been reported to exert a tumor suppressive effect in several types of cancer. The present study aimed to investigate the effect of ETO on cell proliferation and apoptosis in non-small cell lung cancer (NSCLC) cells and elucidate its potential mechanism of action. Therefore, Cell Counting Kit-8 assay was performed to evaluate the effect of different concentrations of ETO (0, 1, 2 or 3 µg/ml) on A549 cell viability. In addition, the possible interaction between ETO and WW domain containing E3 ubiquitin protein ligase 2 (WWP2) was predicted using the STITCH database. Additionally, a stable WWP2-overexpressing A549 cell line was constructed by transfecting A549 cells with the pcDNA3.1-WWP2 plasmid. Cell proliferation and apoptosis were assessed using colony formation and TUNEL assays, respectively. The mRNA and protein expression levels of the apoptosis-related proteins Bcl-2, Bax, caspase 3 and cleaved-caspase 3 were determined by reverse transcription-quantitative PCR and western blotting. In addition, the expression and phosphorylation levels of proliferation-associated genes (PCNA and Ki-67) and proteins in the PI3K/Akt pathway were analyzed by western blotting. The results showed that treatment with ETO attenuated the cell viability and proliferation of A549 cells. ETO also promoted cell apoptosis and decreased the expression of the anti-apoptotic protein Bcl-2, whilst increasing that of pro-apoptotic proteins Bax and cleaved caspase 3 in a dose-dependent manner. Furthermore, ETO was found to negatively regulate the expression of WWP2, such that WWP2 overexpression reversed the potentiating effects of ETO on cell apoptosis. In addition, ETO promoted the expression of PTEN and reduced the phosphorylation levels of the PI3K/AKT pathway-related proteins. These effects aforementioned could also be reversed by WWP2 overexpression. Therefore, data from the present study suggest that ETO can attenuate the progression of NSCLC through by the PI3K/AKT pathway, specifically by targeting WWP2. These findings may provide a novel target for the treatment of NSCLC. Show less

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone involved in regulating glucose and lipid metabolism. GIP receptor (GIPR) antagonism is believed to offer therapeutic potential for various metabolic diseases. Pharmacological intervention of GIPR, however, has limited success due to lack of effective antagonistic reagents. Previously we reported the discovery of two mouse anti-murine GIPR monoclonal antibodies (mAbs) with distinctive properties in rodent models. Here, we report the detailed structural and biochemical characterization of these two antibodies, mAb1 and mAb2. Show less

Traditional Chinese medicine Tongxinluo (TXL) has been widely used to treat coronary artery disease in China, since it could reduce myocardial infarct size and ischemia/reperfusion injury in both non-diabetic and diabetic conditions. It has been shown that TXL could regulate peroxisome proliferator activated receptor-α (PPAR-α), a positive modulator of angiopoietin-like 4 (Angptl4), in diabetic rats. Endothelial junction substructure components, such as VE-cadherin, are involved in the protection of reperfusion injury. Thus, we hypothesized cell-intrinsic and endothelial-specific Angptl4 mediated the protection of TXL on endothelial barrier under high glucose condition against ischemia/reperfusion-injury via PPAR-α pathway. Incubated with high glucose medium, the human cardiac microvascular endothelial cells (HCMECs) were then exposed to oxygen-glucose-serum deprivation (2 hours) and restoration (2 hours) stimulation, with or without TXL, insulin, or rhAngptl4 pretreatment. TXL, insulin, and rhAngptl4 had similar protective effects on the endothelial barrier. TXL treatment reversed the endothelial barrier breakdown in HCMECs significantly as identified by decreasing endothelial permeability, upregulating the expression of JAM-A, VE-cadherin, and integrin-α5 and increasing the membrane location of VE-cadherin and integrin-α5, and these effects of TXL were as effective as insulin and rhAngptl4. However, Angptl4 knock-down with small interfering RNA (siRNA) interference and PPAR-α inhibitor MK886 partially abrogated these beneficial effects of TXL. Western blotting also revealed that similar with insulin, TXL upregulated the expression of Angptl4 in HCMECs, which could be inhibited by Angptl4 siRNA or MK886 exposure. TXL treatment increased PPAR-α activity, which could be diminished by MK886 but not by Angptl4 siRNA. These data suggest cell-intrinsic and endothelial-specific Angptl4 mediates the protection of TXL against endothelial barrier breakdown during oxygen-glucose-serum deprivation and restoration under high glucose condition partly via the PPAR-α/Angptl4 pathway. Show less

Carotid atherosclerosis disease (CAD) is generally associated with the occurrence of cardiovascular and cerebrovascular accidents. However, CAD has not been taken seriously enough in the clinic, which, coupled with the single treatment and prevention of CAD, has led to a generally low level of patient compliance. Therefore, acupuncture is expected to be a safe and effective therapy that can be maintained in the long term for patients with CAD. The study objective is to evaluate the efficiency and reliability of acupuncture to relieve CAD and provide a new therapeutic idea for the clinical treatment of CAD. This is a three-arm randomized clinical trial in China. Three groups (TA, SA, and MC) will be randomly allocated at a 1:1:1 ratio. The study will enrol 105 cervical atherosclerosis plaque patients in total on a voluntary basis, with 35 patients in each group. The treatment will last for 12 weeks, with two treatments per week for twenty-four treatments in total. Two 3D ultrasound indicators will be measured as the primary outcomes: the total plaque volume (PV) of the carotid artery on each side and the grey-scale median (GSM). The secondary outcomes will include intima-media thickness (IMT), lipid levels, apolipoprotein A-IV level, platelet count (PLT), fibrinogen (FIB), and platelet aggregation rate (PAR). All the outcomes will be assessed before treatment, after treatment, and after a 12-week follow-up period. This study will utilize per-protocol (PP) and intention-to-treat (ITT) analysis principles. This trial is to evaluate the efficacy and reliability of acupuncture in relieving carotid atherosclerotic plaques by establishing acupuncture (TA), sham acupuncture (SA), and medication (MC) groups. This study was approved by the Institutional Ethics Committee of Guangdong Provincial Hospital of Traditional Chinese Medicine (no. YF2018-107-01). All data and findings will be provided by the principal investigator via email. ChiCTR, ChiCTR1800019259 . Registered on 1 November 2018-retrospectively registered, http://www.chictr.org.cn/index.aspx. Show less

Transformation of follicular lymphoma (FL) into B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) is rare and results in greatly increased aggressiveness of clinical course. Here we present extensive molecular analysis of this unusual transformation, including immunoglobulin (Ig) gene rearrangement studies, cytogenetic analysis, and whole-exome sequencing (WES) of the patient's FL, B-ALL/LBL, and normal cells. Although FL showed marked somatic hypermutation (SHM) of the Ig genes, SHM appeared to be even more extensive in B-ALL/LBL. Cytogenetically, at least three translocations were identified in the B-ALL/LBL involving the Show less

Fatty acids are involved in the development and progression of colorectal cancer (CRC). However, genetic effects of fatty acid biosynthesis pathway on CRC outcome are unclear. Cox regression model was used to evaluate genetic effects on CRC overall survival (OS) and progression-free survival (PFS), accompanied by calculating hazard ratios (HRs) and confidence intervals (CIs). Differential expression analysis, expression quantitative trait loci analysis, dual-luciferase reporter assay and chromatin immunoprecipitation assay were performed to explore the genetically biological mechanism. The rs10838164 C>T in HSD17B12 was significantly associated with an increased risk of death and progression of CRC (OS, HR = 2.12, 95% CI = 1.40-3.22, P = 4.03 × 10 Show less

To establish a secondary hemophagocytic lymphohistiocytosis(HLH) mouse model, and to investigate the effect of ruxolitinib on the disease manifestation of model mice. Wild type C57BL/6 mice were randomly divided into 4 groups: two groups of mice were intraperitoneally injected with CpG oligodeoxynucleotide 1826 (CpG-ODN1826) every other day to induce HLH, and other two groups were control groups. One group of the CpG-ODN1826 groups and one of the control groups were given ruxolitinib, and other two groups were given the same amount of PBS. Blood samples, serum ferritin and hepatic/spleen weights of experimental mice were detected and serum cytokine levels were measured by ELISA. Compared with the control groups, the levels of white blood cells, hemoglobin and platelets in the CpG-ODN1826 groups were significantly lower (P＜0.05); and liver/body weight, spleen/body weight, serum ferritin, sCD25, IL-10, IL-1β, IFN-Ƴ, IL-12p70, GM-CSF, TNF-α and IL-18 levels significantly increased (P＜0.05). There was no significant difference in the levels of IL-2, IL-4, IL-5, IL-6, IL-22, IL-13, IL-27 and IL-23 between the two groups (P＞0.05). The spleen in CpG group had disordered internal structure, expanding red pulp and hyperplastic nucleated cells. The liver had severe perivascular inflammations. The spleen/weight of the ruxolitinib-treated mice in the CpG-ODN1826 group was significantly smaller than that of the unapplied ruxolitinib (P＜0.05). The CpG-ODN1826 can induce secondary HLH symptoms in wild type C57BL/6 mice. Ruxolitinib can alleviate the symptoms of splenomegaly in HLH model mice. Show less

Myeloid-derived growth factor (MYDGF), which is produced by bone marrow-derived cells, mediates cardiac repair following myocardial infarction by inhibiting cardiac myocyte apoptosis to subsequently reduce the infarct size. However, the function of MYDGF in the incretin system of diabetes is still unknown. Here, loss-of-function and gain-of-function experiments in mice revealed that MYDGF maintains glucose homeostasis by inducing glucagon-like peptide-1 (GLP-1) production and secretion and that it improves glucose tolerance and lipid metabolism. Treatment with recombinant MYDGF increased the secretion and production of GLP-1 in STC-1 cells in vitro. Mechanistically, the positive effects of MYDGF are potentially attributable to the activation of protein kinase A/glycogen synthase kinase 3β/β-catenin (PKA/GSK-3β/β-catenin) and mitogen-activated protein kinase (MAPK) kinases/extracellular regulated protein kinase (MEK/ERK) pathways. Based on these findings, MYDGF promotes the secretion and production of GLP-1 in intestinal L-cells and potentially represents a potential therapeutic medication target for type 2 diabetes. Show less

Establishing a genetic diagnosis for individuals with intellectual disability (ID) benefits patients and their families as it may inform the prognosis, lead to appropriate therapy, and facilitate access to medical and supportive services. Exome sequencing has been successfully applied in a diagnostic setting, but most clinical exome referrals are pediatric patients, with many adults with ID lacking a comprehensive genetic evaluation. Our unique recruitment strategy involved partnering with service and education providers for individuals with ID. We performed exome sequencing and analysis, and clinical variant interpretation for each recruited family. All five families enrolled in the study opted-in for the return of genetic results. In three out of five families exome sequencing analysis identified pathogenic or likely pathogenic variants in KANSL1, TUSC3, and MED13L genes. Families discussed the results and any potential medical follow-up in an appointment with a board certified clinical geneticist. Our study suggests high yield of exome sequencing as a diagnostic tool in adult patients with ID who have not undergone comprehensive sequencing-based genetic testing. Research studies including an option of return of results through a genetic clinic could help minimize the disparity in exome diagnostic testing between pediatric and adult patients with ID. Show less

Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. The overexpression of COUP-TFII has been observed in several types of malignancies. However, its role in ICC progression remains unclear. In this study, we found that the protein level of COUP-TFII was increased, but the mRNA level was unchanged in ICC tissues. High protein expression was positively associated with tumor size, lymph node metastasis, and poor prognosis in ICC patients. Furthermore, the overexpression of COUP-TFII promoted the proliferation, migration, and invasion of ICC cells in vitro and enhanced tumor growth and metastasis in nude mouse models. Mechanistic studies revealed that COUP-TFII induced epithelial-to-mesenchymal transition in ICC cells by upregulating Snail expression. Moreover, the activation of PI3K/AKT signaling led to the upregulation of COUP-TFII protein expression in ICC. Together, these findings indicate that COUP-TFII promotes epithelial-to-mesenchymal transition and metastasis in ICC and suggest that this protein is a potential target for adjuvant therapy for these patients. Show less

Existing evidence has shown that circulating Epstein-Barr virus (EBV)-miR-BART13-3p is highly expressed in plasma of nasopharyngeal carcinoma (NPC) patients, especially among patients with advanced diseases. However, the exact role that EBV-miR-BART13-3p plays in the development of NPC remains poorly understood. Here we show that up-regulated expression of EBV-miR-BART13-3p leads to increased capacity in migration and invasion of NPC cells Show less

Cancer cells undergo significant lipid metabolic reprogramming to ensure sufficient energy supply for survival and progression. However, how cancer cells integrate lipid metabolic signaling with cancer progression is not well understood. In the present study, we demonstrated that C/EBPδ, a critical lipid metabolic regulator, is a TGF-β1 downstream gene and promotes lung adenocarcinoma metastasis. Importantly, C/EBPδ caused significant oscillations in both lipid metabolic and epithelial to mesenchymal transition (EMT) gene networks. Mechanistically, we demonstrated that C/EBPδ recruited oncogene NCOA3 to transcriptionally activate Slug, a canonical EMT transcription factor, which in turn induced oxLDL receptor-1 (Lox1) expression and enhanced oxLDL uptake to promote cancer metastasis, which could be blocked with LOX1 neutralizing antibody. In summary, our results unveiled a previously unappreciated interplay between lipid metabolic and metastatic program, as well as the existence of a pivotal C/EBPδ-Slug-Lox1 transcription axis to promote oxLDL levels and cancer metastasis. Show less

Increased circulating branched-chain amino acids (BCAAs) have been involved in the pathogenesis of obesity and insulin resistance (IR). However, evidence relating berberine (BBR), gut microbiota, BCAAs, and IR is limited. Here, we showed that BBR could effectively rectify steatohepatitis and glucose intolerance in high-fat diet (HFD)-fed mice. BBR reorganized gut microbiota populations under both the normal chow diet (NCD) and HFD. Particularly, BBR noticeably decreased the relative abundance of BCAA-producing bacteria, including order Clostridiales; families Streptococcaceae, Clostridiaceae, and Prevotellaceae; and genera Streptococcus and Prevotella. Compared with the HFD group, predictive metagenomics indicated a reduction in the proportion of gut microbiota genes involved in BCAA biosynthesis but the enrichment genes for BCAA degradation and transport by BBR treatment. Accordingly, the elevated serum BCAAs of HFD group were significantly decreased by BBR. Furthermore, the Western blotting results implied that BBR could promote the BCAA catabolism in the liver and epididymal white adipose tissues of HFD-fed mice by activation of the multienzyme branched-chain α-ketoacid dehydrogenase complex (BCKDC), whereas by inhibition of the phosphorylation state of BCKDHA (E1α subunit) and branched-chain α-ketoacid dehydrogenase kinase (BCKDK). The ex vivo assay further confirmed that BBR could increase BCAA catabolism in both AML12 hepatocytes and 3T3-L1 adipocytes. Finally, data from healthy subjects and diabetics confirmed that BBR could improve glycemic control and modulate circulating BCAAs. Together, our findings clarified BBR improving IR associated not only with gut microbiota alteration in BCAA biosynthesis but also with BCAA catabolism in liver and adipose tissues. Show less

Via promoting synovitis, pannus growth and cartilage/bone destruction, fibroblast-like synovial cells (FLSs) play a significant role in the pathogenesis of rheumatoid arthritis (RA). In our study, rats were induced with complete freund's adjuvant (CFA) to be animal models for studying the RA pathogenesis. Microtubule-associated Serine/Threonine-protein kinase 3 (MAST3) has been documented to play a critical role in regulating the immune response of IBD (Inflammatory bowel disease) and involved in the process of cytoskeleton organization, intracellular signal transduction and peptidyl-serine phosphorylation, but its role in the progression of RA remains unknown and is warranted for investigation. So, we tried our best to investigate the mechanism and signaling pathway of MAST3 in RA progression. In the synovial tissue and FLSs of AA rats, we have found that MAST3 was significantly up-regulated than normal. Furthermore, MAST3 overexpression could promote proliferation and inflammatory response of FLSs. In the aspect of mechanism, we discovered that the expression of MAST3 might involve in NF-κB signaling pathway in RA. On the whole, our results suggested that MAST3 might promote the proliferation and inflammation of FLSs by regulating NF-κB signaling pathway. Show less

The glucose-responsive transcription factor carbohydrate response element-binding protein (ChREBP) critically promotes aerobic glycolysis and cell proliferation in colorectal cancer cells. It has been reported that ubiquitination may be important in the regulation of ChREBP protein levels and activities. However, the ChREBP-specific E3 ligase and molecular mechanism of ChREBP ubiquitination remains unclear. Using database exploration and expression analysis, we found here that levels of the E3 ligase SMURF2 (Smad-ubiquitination regulatory factor 2) negatively correlate with those of ChREBP in cancer tissues and cell lines. We observed that SMURF2 interacts with ChREBP and promotes ChREBP ubiquitination and degradation via the proteasome pathway. Interestingly, ectopic SMURF2 expression not only decreased ChREBP levels but also reduced aerobic glycolysis, increased oxygen consumption, and decreased cell proliferation in colorectal cancer cells. Moreover, SMURF2 knockdown increased aerobic glycolysis, decreased oxygen consumption, and enhanced cell proliferation in these cells, mostly because of increased ChREBP accumulation. Furthermore, we identified Ser/Thr kinase AKT as an upstream suppressor of SMURF2 that protects ChREBP from ubiquitin-mediated degradation. Taken together, our results indicate that SMURF2 reduces aerobic glycolysis and cell proliferation by promoting ChREBP ubiquitination and degradation via the proteasome pathway in colorectal cancer cells. We conclude that the SMURF2-ChREBP interaction might represent a potential target for managing colorectal cancer. Show less

Induced pluripotent stem cells (iPSC) derived from healthy individuals are important controls for disease-modeling studies. Here we apply precision health to create a high-quality resource of control iPSCs. Footprint-free lines were reprogrammed from four volunteers of the Personal Genome Project Canada (PGPC). Multilineage-directed differentiation efficiently produced functional cortical neurons, cardiomyocytes and hepatocytes. Pilot users demonstrated versatility by generating kidney organoids, T lymphocytes, and sensory neurons. A frameshift knockout was introduced into MYBPC3 and these cardiomyocytes exhibited the expected hypertrophic phenotype. Whole-genome sequencing-based annotation of PGPC lines revealed on average 20 coding variants. Importantly, nearly all annotated PGPC and HipSci lines harbored at least one pre-existing or acquired variant with cardiac, neurological, or other disease associations. Overall, PGPC lines were efficiently differentiated by multiple users into cells from six tissues for disease modeling, and variant-preferred healthy control lines were identified for specific disease settings. Show less

Currently, cisplatin (DDP) is the first-line chemotherapeutic agent used for treatment of ovarian cancer, but gradually acquired drug resistance minimizes its therapeutic outcomes. We aimed to identify crucial genes associated with DDP resistance in ovarian cancer and uncover potential mechanisms. Two sets of gene expression data were downloaded from Gene Expression Omnibus, and bioinformatics analysis was conducted. In our study, the differentially expressed genes between DDP-sensitive and DDP-resistant ovarian cancer were screened in GSE15709 and GSE51373 database, and chromosome condensation 2 regulator (RCC2) and nucleoporin 160 were identified as 2 genes that significantly up-regulated in DDP-resistant ovarian cancer cell lines compared with DDP-sensitive cell lines. Moreover, RCC2, Ral small GTPase (RalA), and Ral binding protein-1 (RalBP1) expression was found to be significantly higher in DDP-resistant ovarian cancer tissues than in DDP-sensitive tissues. RCC2 plays a positive role in cell proliferation, apoptosis, and migration in DDP-resistant ovarian cancer cell lines in vitro and in vivo. Furthermore, RCC2 could interact with RalA, thus promoting its downstream effector RalBP1. RalA knockdown could reverse the effects of RCC2 overexpression on DDP-resistant ovarian cancer cell proliferation, apoptosis, and migration. Similarly, RalA overexpression could alleviate the effects of RCC2 knockdown in DDP-resistant ovarian cancer cells. Taken together, RCC2 may function as an oncogene, regulating the RalA signaling pathway, and intervention of RCC2 expression might be a promising therapeutic strategy for DDP-resistant ovarian cancer.-Gong, S., Chen, Y., Meng, F., Zhang, Y., Wu, H., Li, C., Zhang, G. RCC2, a regulator of the RalA signaling pathway, is identified as a novel therapeutic target in cisplatin-resistant ovarian cancer. Show less

Acute pancreatitis (AP) is a severe inflammatory disease. Caerulin induces significant pro-inflammatory responses in macrophages, causing serve damage to pancreatic acinar cells. The potential role of Rab GTPase 21 (Rab21) in this process was tested in this study. In murine bone marrow-derived macrophages (BMDMs), caerulin induced Rab21-TRAF3-MKK3 complex association. Rab21 silencing (by targeted shRNAs) or knockout (by CRISPR/Cas9 method) largely inhibited caerulin-induced MKK3-TRAF3 association, downstream MKK3-p38 activation and production of several pro-inflammatory cytokines (IL-1β, TNF-α and IL-17). Conversely, ectopic Rab21 overexpression in BMDMs potentiated caerulin-induced MKK3-TRAF3 association and pro-inflammatory cytokines production. The cytotoxicity of caerulin-activated BMDMs to co-cultured pancreatic acinar cells was alleviated by Rab21 knockdown or knockout, but exacerbated with Rab21 overexpression. In vivo, administration of Rab21 shRNA lentivirus significantly attenuated pancreatic and systemic inflammations in caerulin-injected AP mice. Collectively, our results suggest that Rab21 mediates caerulin-induced MKK3-p38 activation and pro-inflammatory responses. Show less

Family with sequence similarity 83, member A (FAM83A), as a potential tumor promoter, was reported to contribute to the progression of several malignant tumors. However, the significance of FAM83A in invasion and metastasis of non-small cell lung cancer (NSCLC) remains largely unknown. In this study, we found that FAM83A expression was significantly increased in NSCLC tissues. High expression of FAM83A was positively associated with tumor metastasis and poor survival of NSCLC patients. Functional experiments revealed that FAM83A knockdown could suppress NSCLC cell migration and invasion both Show less

Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) has been identified in multiple genome-wide association studies (GWAS) as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). On the basis of this genetic evidence, we developed anti-GIPR antagonistic antibodies as a potential therapeutic strategy for the treatment of obesity and observed that a mouse anti-murine GIPR antibody (muGIPR-Ab) protected against body weight gain, improved multiple metabolic parameters, and was associated with reduced food intake and resting respiratory exchange ratio (RER) in DIO mice. We replicated these results in obese nonhuman primates (NHPs) using an anti-human GIPR antibody (hGIPR-Ab) and found that weight loss was more pronounced than in mice. In addition, we observed enhanced weight loss in DIO mice and NHPs when anti-GIPR antibodies were codosed with glucagon-like peptide-1 receptor (GLP-1R) agonists. Mechanistic and crystallographic studies demonstrated that hGIPR-Ab displaced GIP and bound to GIPR using the same conserved hydrophobic residues as GIP. Further, using a conditional knockout mouse model, we excluded the role of GIPR in pancreatic β-cells in the regulation of body weight and response to GIPR antagonism. In conclusion, these data provide preclinical validation of a therapeutic approach to treat obesity with anti-GIPR antibodies. Show less