👤 Zhe Piao

Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompletely defined. Here, we found that BAF60a functions as a chromatin regulator that sustains biphasic GSIS and preserves β cell function under metabolic stress conditions. BAF60a was downregulated in β cells from obese and diabetic mice, monkeys, and humans. β cell-specific inactivation of BAF60a in adult mice impaired GSIS, leading to hyperglycemia and glucose intolerance. Conversely, restoring BAF60a expression improved β cell function and systemic glucose homeostasis. Mechanistically, BAF60a physically interacted with Nkx6.1 to selectively modulate chromatin accessibility and transcriptional activity of target genes critical for GSIS coupling in islet β cells. A BAF60a V278M mutation associated with decreased β cell GSIS function was identified in human donors. Mice carrying this mutation, which disrupted the interaction between BAF60a and Nkx6.1, displayed β cell dysfunction and impaired glucose homeostasis. In addition, GLP-1R and GIPR expression was significantly reduced in BAF60a-deficient islets, attenuating the insulinotropic effect of GLP-1R agonists. Together, these findings support a role for BAF60a as a component of the epigenetic machinery that shapes the chromatin landscape in β cells critical for glucose sensing and insulin secretion. Show less

Small dense low-density lipoprotein cholesterol (sdLDL-C), as an emerging atherogenic factor of cardiovascular diseases, requires additional tests. We aimed to establish a sdLDL-C equation using standard lipid profile and evaluate its capacity of identifying the residual cardiovascular risk beyond LDL-C and apolipoprotein B (ApoB). This cross-sectional study included 25 435 participants from Health Management Cohort and 11 628 participants from China Health and Retirement Longitudinal Study (CHARLS) to construct and evaluate the sdLDL-C equation by least-squares regression model. The equation for sdLDL-C depended on low-density lipoprotein cholesterol (LDL-C) and an interaction term between LDL-C and the natural log of triglycerides (TG). The modified equation (sdLDL-C = 0.14*ln(TG)*LDL-C - 0.45*LDL-C + 10.88) was more accurate than the original equation in validation set (slope = 0.783 vs. 0.776, MAD = 5.228 vs. 5.396). Using the 80th percentile (50 mg/dL) as a risk-enhancer rule for sdLDL-C, accuracy of the modified equation was higher than the original equation in validation set (90.47% vs. 89.73%). The estimated sdLDL-C identified an additional proportion of high-risk individuals in BHMC (4.93%) and CHARLS (1.84%). The newly developed equation in our study provided an accurate tool for estimating sdLDL-C level among the Chinese population as a potential cardiovascular risk-enhancer. Show less

RNA-binding proteins (RBPs) are powerful and versatile regulators in living creatures, playing fundamental roles in organismal development, metabolism, and various diseases by the regulation of gene expression at multiple levels. The requirements of deep research on RBP function have promoted the rapid development of RBP-RNA interplay detection methods. Recently, the detection method of fusing RNA modification enzymes (RME) with RBP of interest has become a hot topic. Here, we reviewed RNA modification enzymes in adenosine deaminases that act on RNA (ADAR), terminal nucleotidyl transferase (TENT), and activation-induced cytosine deaminase/ApoB mRNA editing enzyme catalytic polypeptide-like (AID/APOBEC) protein family, regarding the biological function, biochemical activity, and substrate specificity originated from enzyme selves, their domains and partner proteins. In addition, we discussed the RME activity screening system, and the RME mutations with engineered enzyme activity. Furthermore, we provided a systematic overview of the basic principles, advantages, disadvantages, and applications of the RME-based and cross-linking and immunopurification (CLIP)-based RBP target profiling strategies, including targets of RNA-binding proteins identified by editing (TRIBE), RNA tagging, surveying targets by APOBEC-mediated profiling (STAMP), CLIP-seq, and their derivative technology. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition RNA Processing > RNA Editing and Modification. Show less

Previous studies on the endotyping of chronic rhinosinusitis (CRS) that were based on inflammatory factors have broadened our understanding of the disease. However, the endotype of CRS combined with inflammatory and remodeling features has not yet been clearly elucidated. We sought to identify the endotypes of patients with CRS according to inflammatory and remodeling factors. Forty-eight inflammatory and remodeling factors in the nasal mucosal tissues of 128 CRS patients and 24 control subjects from northern China were analyzed by Luminex, ELISA, and ImmunoCAP. Sixteen factors were used to perform the cluster analysis. The characteristics of each cluster were analyzed using correlation analysis and validated by immunofluorescence staining. Patients were classified into 5 clusters. Clusters 1 and 2 showed non-type 2 signatures with low biomarker concentrations, except for IL-19 and IL-27. Cluster 3 involved a low type 2 endotype with the highest expression of neutrophil factors, such as granulocyte colony-stimulating factor, IL-8, and myeloperoxidase, and remodeling factors, such as matrix metalloproteinases and fibronectin. Cluster 4 exhibited moderate type 2 inflammation. Cluster 5 exhibited high type 2 inflammation, which was associated with relatively higher levels of neutrophil and remodeling factors. The proportion of CRS with nasal polyps, asthma, allergies, anosmia, aspirin sensitivity, and the recurrence of CRS increased from clusters 1 to 5. Diverse inflammatory mechanisms result in distinct CRS endotypes and remodeling profiles. The explicit differentiation and accurate description of these endotypes will guide targeted treatment decisions. Show less

Clinically, hypoxia is associated with increased distant metastasis and poor survival in gastric cancer (GC). In this study, we set out from the cellular interaction to further explain the molecular mechanism of invasion in GC cells under hypoxic conditions. Gastric cancer cells were cultured under 1% O HGC-medium induced NGC dissociated. Long non-coding RNA (lncRNA) prostate cancer gene expression marker 1 (PCGEM1) was specifically expressed in HGC exosomes. HGC-derived PCGEM1-riched exosomes could promote the invasion and migration of NGC. On the mechanism, PCGEM1 maintained stability and reduced the degradation of SNAI1, which could induce the epithelial-mesenchymal transition of GC. LncRNA PCGEM1 was overexpressed in GC cells. And part of the PCGEM1 can be encapsulated into exosomes. These exosomes promoted invasion and migration of other GC cells. We considered PCGEM1 might act as a "scaffold" combined with SNAI1 and prompt the invasion and migration of GC. Show less

Erythrocyte membrane protein band 4.1-like 3 (EPB41L3) is an important membrane skeletal protein that may interact with numerous membrane proteins. Loss of EPB41L3 is reported in multiple cancer types, and it is originally identified as a tumor suppressor. In this study, through analyzing expression profiling retrieved from the Gene Expression Omnibus (GEO) dataset, we find that EPB41L3 is upregulated in primary osteosarcoma (OS) and osteosarcoma cell lines. Importantly, EPB41L3 may promote osteosarcoma cell proliferation and suppress osteosarcoma cell migration and invasion. Reduced EPB41L3 leads to a decrease of E-cadherin as well as an increase of N-cadherin and Vimentin, implying a prominent epithelial-to-mesenchymal transition. Furthermore, we demonstrate that EPB41L3 inhibits the epithelial-to-mesenchymal transition through destabilizing the Snai1 protein, one of the most important transcription factors of the epithelial-to-mesenchymal transition process. Collectively, our study has first established the complex and vital roles of EPB41L3 and implicated EPB41L3 as a potential biomarker in osteosarcoma. Show less

Cyclovirobuxine D (CVB‑D) is an alkaloid, which is mainly derived from Buxus microphylla. It has been reported that CVB‑D has positive effects on breast cancer, gastric cancer and other malignant tumors. However, to the best of our knowledge, there are no reports regarding the effects of CVB‑D on colorectal cancer (CRC). The purpose of the present study was to determine the anticancer effects of CVB‑D and further elucidate its molecular mechanism(s). DLD‑1 and LoVo cell lines were selected to evaluate the antitumor effect of CVB‑D. Cytotoxicity, viability and proliferation were evaluated by the MTT and colony formation assays. Flow cytometry was used to detect the effects on apoptosis and the cell cycle in CVB‑D‑treated CRC cells. The migration and invasion abilities of CRC cells were examined by wound healing and Transwell assays. In addition, RNA sequencing, bioinformatics analysis and western blotting were performed to investigate the target of drug action and clarify the molecular mechanisms. A xenograft model was established using nude mice, and ultrasound was employed to assess the preclinical therapeutic effects of CVB‑D in vivo. It was identified that CVB‑D inhibited the proliferation, migration, stemness, angiogenesis and epithelial‑mesenchymal transition of CRC cells, and induced apoptosis and S‑phase arrest. In addition, CVB‑D significantly inhibited the growth of xenografts. It is notable that CVB‑D exerted anticancer effects in CRC cells partly by targeting collagen triple helix repeat containing 1 (CTHRC1), which may be upstream of the AKT and ERK pathways. CVB‑D exerted anticancer effects through the CTHRC1‑AKT/ERK‑Snail signaling pathway. Targeted therapy combining CTHRC1 with CVB‑D may offer a promising novel therapeutic approach for CRC treatment. Show less

UVRAG (UV radiation resistance associated) is an important regulator of mammalian macroautophagy/autophagy by interacting with BECN1, PIK3C3, and RUBCN. Phosphorylation of UVRAG by MTORC1 negatively regulates autophagosome maturation under nutrient-enriched conditions. However, how UVRAG ubiquitination is regulated is still unknown. Here we report that UVRAG is ubiquitinated by SMURF1 at lysine residues 517 and 559, which decreases the association of UVRAG with RUBCN and promotes autophagosome maturation. However, the deubiquitinase ZRANB1 specifically cleaves SMURF1-induced K29 and K33-linked polyubiquitin chains from UVRAG, thereby increasing the binding of UVRAG to RUBCN and inhibiting autophagy flux. We also demonstrate that CSNK1A1-mediated UVRAG phosphorylation at Ser522 disrupts the binding of SMURF1 to UVRAG through PPxY motif and blocks UVRAG ubiquitination-mediated autophagosome maturation. Interestingly, ZRANB1 is phosphorylated at Thr35, and Ser209 residues by CSNK1A1, and this phosphorylation activates its deubiquitinating activity. Importantly, we provide Show less

Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death. Mutations in the MYBPC3 gene represent the cause of HCM in ~35% of patients with HCM. However, genetic testing in clinic setting has been limited due to the cost and relatively time-consuming by Sanger sequencing. Here, we developed a HCM Molecular Diagnostic Kit enabling ultra-low-cost targeted gene resequencing in a large cohort and investigated the mutation spectrum of MYBPC3. In a cohort of 114 patients with HCM, a total of 20 different mutations (8 novel and 12 known mutations) of MYBPC3 were identified from 25 patients (21.9%). We demonstrated that the power of targeted resequencing in a cohort of HCM patients, and found that MYBPC3 is a common HCM-causing gene in Chinese patients. Phenotype-genotype analyses showed that the patients with double mutations (n = 2) or premature termination codon mutations (n = 12) showed more severe manifestations, compared with patients with missense mutations (n = 11). Particularly, we identified a recurrent truncation mutation (p.Y842X) in four unrelated cases (4/25, 16%), who showed severe phenotypes, and suggest that the p.Y842X is a frequent mutation in Chinese HCM patients with severe phenotypes. Show less

We aimed to investigate the effects of LXRα, ChREBP and Elovl6 in the development of insulin resistance-induced by medium- and long-chain fatty acids. Sprague Dawley rats were fed a standard chow diet (Control group) or a high-fat, high sucrose diet with different fat sources (coconut oil, lard, sunflower and fish oil) for 8 weeks. These oils were rich in medium-chain saturated fatty acids (MCFA group), long-chain saturated fatty acids (LCFA group), n-6 and n-3 long-chain polyunsaturated fatty acids (n-6 PUFA and n-3 PUFA groups), respectively, which had different chain lengths and degrees of unsaturation. Hyperinsulinemic-euglycemic clamp with [6-(3)H] glucose infusion was performed in conscious rats to assess hepatic insulin sensitivity. LCFA and n-6 PUFA groups induced hepatic insulin resistance and increased liver X receptor α (LXRα), carbohydrate response element binding protein (ChREBP) and long-chain fatty acid elongase 6 (Elovl6) expression in liver and white adipose tissue (WAT). Furthermore, LCFA and n-6 PUFA groups suppressed Akt serine 473 phosphorylation in liver and WAT. By contrast, in liver and WAT, MCFA and n-3 PUFA groups decreased LXRα, ChREBP and Elovl6 expression and improved insulin signaling and insulin resistance, but Akt serine 473 phosphorylation was not restored by MCFA group in WAT. This study demonstrated that the mechanism of the different effects of medium- and long-chain fatty acids on hepatic insulin resistance involves LXRα, ChREBP and Elovl6 alternations in liver and WAT. It points to a new strategy for ameliorating insulin resistance and diabetes through intervention on Elovl6 or its control genes. Show less

Hepatocellular carcinoma (HCC) is one of the most common human tumors in Asia and Africa. The molecular genetic changes involving both protooncogenes and tumor suppressor genes are known to be involved in hepatocarcinogenesis, but the roles of the known tumor suppressor genes in hepatocarcinogenesis are not fully elucidated. In this study, the authors analyzed the loss of heterozygosity (LOH) of known tumor suppressor genes in HCC and evaluated the relationship between LOH of tumor suppressor genes and clinicopathologic features. The authors assessed the LOH of the 10 known tumor suppressor genes (VHL, APC, EXT1, WT1, Rb1, p53, BRCA1, nm23, DPC4, and DCC) with microsatellite markers in 29 consecutively resected HCC specimens. The authors found frequent LOH of tumor suppressor genes in HCC. Twenty five of 29 cases (86%) had LOH of tumor suppressor genes and 17 cases (59%) had LOHs involving 2-4 tumor suppressor genes. Among the tumor suppressor genes, frequent LOH was noted in the p53 (66%), Rb1 (33%), EXT1 (33%), and APC (20%) genes. LOH of the p53 gene and multiple LOH of the tumor suppressor genes were more frequent in poorly differentiated HCCs (P = 0.02). The LOH of tumor suppressor genes is frequent in HCCs and LOH of the p53 gene and accumulated LOHs are related to poorly differentiated HCC. Abnormalities of the p53 gene or the accumulated abnormalities of the tumor suppressor genes may play a role in the aggressive progression of HCC. Show less