The melanocortin receptor accessory protein 2 (MRAP2) plays an essential role in the regulation of metabolic homeostasis and deletion of which results in severe obesity syndrome in mice and human. Mam Show more
The melanocortin receptor accessory protein 2 (MRAP2) plays an essential role in the regulation of metabolic homeostasis and deletion of which results in severe obesity syndrome in mice and human. Mammalian MRAP2 is recognized as an endogenous physiological mediator through the potentiation of the MC4R signaling in vivo. Two isoforms of MRAP2 are identified in zebrafish genome, zMRAP2a and zMRAP2b. However, the mechanism of assembling dual topology and the regulatory roles of each complex on the melanocortin cascades remains unclear. In this study, we showed the bidirectional homo- and hetero-dimeric topologies of two zebrafish MRAP2 isoforms on the plasma membrane. Orientation fixed chimeric proteins could affect the trafficking and pharmacological properties of zMC4R signaling. Reciprocal replacement of zMRAP2a and zMRAP2b proteins elucidated the major participation of the carboxyl terminal as the functional domain for modulating zMC4R signaling. Our findings revealed the complex and dynamic conformational regulation of dual zebrafish MRAP2 proteins in vitro. Show less
The biological functions of circular RNAs in liver tumorigenesis have been well demonstrated by a number of studies. Nevertheless, to the best of our knowledge, the role and mechanism of action of hsa Show more
The biological functions of circular RNAs in liver tumorigenesis have been well demonstrated by a number of studies. Nevertheless, to the best of our knowledge, the role and mechanism of action of hsa_circ₀₀₀₈₅₃₇ (circ₀₀₀₈₅₃₇₎ in liver cancer pathogenesis remain undetermined. In the present study, circ₀₀₀₈₅₃₇ expression was associated with the GLI3 gene and was markedly increased in liver cancer tissue specimens and cells. High expression levels of circ₀₀₀₈₅₃₇ exhibited a poor prognosis. In addition, circ₀₀₀₈₅₃₇ overexpression resulted in an increased proliferation, migration and invasion of liver cancer cells, whereas circ₀₀₀₈₅₃₇ knockdown exhibited opposite effects. circ₀₀₀₈₅₃₇ acted as a sponge of microRNA‑153‑3p (miR‑153‑3p), and a negative correlation was observed between circ₀₀₀₈₅₃₇ and miR‑153‑3p expression in liver cancer. Transfection with miR‑153‑3p further abolished the effects of circ₀₀₀₈₅₃₇ on the malignant behavior of liver cancer cells. Furthermore, circ₀₀₀₈₅₃₇ indirectly affected the expression levels of pro‑survival protein myeloid cell leukemia 1 (MCL1) and snail family zinc finger 1 (Snail1) via miR‑153‑3p in liver cancer cells. In conclusion, the data indicated that circ₀₀₀₈₅₃₇ facilitated liver carcinogenesis by indirectly regulating miR‑153‑3p and leading to the release of MCL1 and Snail1. Show less
Hepatocellular carcinoma (HCC) is a globally prevailing cancer with a low 5-year survival rate. Little is known about its intricate gene expression profile. Single-cell RNA sequencing is an indispensa Show more
Hepatocellular carcinoma (HCC) is a globally prevailing cancer with a low 5-year survival rate. Little is known about its intricate gene expression profile. Single-cell RNA sequencing is an indispensable tool to explore the genetic characteristics of HCC at a more detailed level. In this study, we profiled the gene expression of single cells from human HCC tumor and para-tumor tissues using the Smart-seq 2 sequencing method. Based on differentially expressed genes, we identified heterogeneous subclones in HCC tissues, including five HCC and two hepatocyte subclones. We then carried out hub-gene co-network and functional annotations analysis followed pseudo-time analysis with regulated transcriptional factor co-networks to determine HCC cellular trajectory. We found that MLX interacting protein like (MLXIPL) was commonly upregulated in the single cells and tissues and associated with a poor survival rate in HCC. Mechanistically, MLXIPL activation is crucial for promoting cell proliferation and inhibits cell apoptosis by accelerating cell glycolysis. Taken together, our work identifies the heterogeneity of HCC subclones, and suggests MLXIPL might be a promising therapeutic target for HCC. Show less
The therapeutic outcome of hepatocellular carcinoma (HCC) remains unsatisfactory because of poor response and acquired drug resistance. To better elucidate the molecular mechanisms of HCC, here we use Show more
The therapeutic outcome of hepatocellular carcinoma (HCC) remains unsatisfactory because of poor response and acquired drug resistance. To better elucidate the molecular mechanisms of HCC, here we used three Gene Expression Omnibus datasets to identify potential oncogenes, and thereby identified small nuclear ribonucleoprotein polypeptide C (SNRPC). We report that SNRPC is highly up-regulated in HCC tissues as determined using immunohistochemistry assays of samples from a cohort of 224 patients with HCC, and overexpression of SNRPC was correlated with multiple tumors, advanced stage, and poor outcome. Kaplan-Meier analysis confirmed that patients with high SNRPC expression exhibited shorter survival in four independent HCC cohorts (all P < 0.05). Furthermore, SNRPC mutations are significantly more frequent in HCC tissues than in normal liver tissues and are an early event in the development of HCC. Functional network analysis suggested that SNRPC is linked to the regulation of ribosome, spliceosome, and proteasome signaling. Subsequently, gain- and loss-of-function assays showed that SNRPC promotes the motility and epithelial-mesenchymal transition of HCC cells in vitro. SNRPC expression was negatively correlated with the infiltration of CD4 Show less
Macroautophagy/autophagy is a conserved catabolic pathway that targets cytoplasmic components for their degradation and recycling in an autophagosome-dependent lysosomal manner. Under physiological co Show more
Macroautophagy/autophagy is a conserved catabolic pathway that targets cytoplasmic components for their degradation and recycling in an autophagosome-dependent lysosomal manner. Under physiological conditions, this process maintains cellular homeostasis. However, autophagy can be stimulated upon different forms of cellular stress, ranging from nutrient starvation to exposure to drugs. Thus, this pathway can be seen as a central component of the integrated and adaptive stress response. Here, we report that even brief induction of autophagy is coupled Show less
Previous genotyping-based assays have identified non-coding variants of several interleukins (ILs) being associated with genetic susceptibility to leprosy. However, understanding of the involvement of Show more
Previous genotyping-based assays have identified non-coding variants of several interleukins (ILs) being associated with genetic susceptibility to leprosy. However, understanding of the involvement of coding variants within all IL family genes in leprosy was still limited. To obtain the full mutation spectrum of all ILs in leprosy, we performed a targeted deep sequencing of coding regions of 58 ILs genes in 798 leprosy patients (age 56.2 ± 14.4; female 31.5%) and 990 healthy controls (age 38.1 ± 14.0; female 44.3%) from Yunnan, Southwest China. mRNA expression alterations of ILs in leprosy skin lesions or in response to M. leprae treatment were estimated by using publicly available expression datasets. Two coding variants in IL27 (rs17855750, p.S59A, p = 4.02 × 10 Show less
Patients with non-small cell lung cancer (NSCLC) initially responding to tyrosine kinase inhibitors (TKIs) eventually develop resistance due to accumulating mutations in the EGFR and additional lesser Show more
Patients with non-small cell lung cancer (NSCLC) initially responding to tyrosine kinase inhibitors (TKIs) eventually develop resistance due to accumulating mutations in the EGFR and additional lesser investigated mechanisms such as the participation of the tumor microenvironment (TME). Here, we examined the potential for MET inhibitor capmatinib for the treatment of osimertinib-resistant NSCLCs and normalizing the TME. We first established that HCC827 and H1975 cells showed increased resistance against osimertinib when co-cultured with CAFs isolated from osimertinib-resistant patients. Additionally, we showed that CAFs promoted epithelial-mesenchymal transition (EMT) and self-renewal ability in both HCC827 and H1975 cells. We subsequently found that both CAF-cultured HCC827 and H1975 showed a significantly higher expression of MET, Akt, Snail and IL-1β, which were associated with survival and inflammatory responses. These cells in turn, promoted the generation of CAFs from normal lung fibroblasts. Subsequently, we observed that the treatment of capmatinib resulted in the re-sensitization of CAF-co-cultured H1975 and HCC827 to osimertinib, in association with reduced EMT and self-renewal ability. MET-silencing experiment using siRNA supported the observations made with capmatinib while with a greater magnitude. MET-silenced cell exhibited a severely hindered expression of inflammatory markers, IL-1β and NF-κB; EMT markers, Snail and Vimentin, while increased E-cadherin. Finally, we demonstrated that the combination of capmatinib and osimertinib led to an increased tumor inhibition and significantly lower number of CAFs within the patient derived xenograft (PDX) model. Taken together, our findings suggested that an increased MET/Akt/Snail signaling was induced between the NSCLC cells and their TME (CAFs), resulting in osimertinib resistance. Suppression of this pathway by capmatinib may bypass the EGFR activating mutation and overcomes osimertinib resistance by targeting both tumor cells and CAFs. Show less
The etiology of hypertriglyceridemia (HTG) and acute pancreatitis (AP) is complex. Herein, we dissected the underlying etiology in a patient with HTG and AP. The patient had a 20-year history of heavy Show more
The etiology of hypertriglyceridemia (HTG) and acute pancreatitis (AP) is complex. Herein, we dissected the underlying etiology in a patient with HTG and AP. The patient had a 20-year history of heavy alcohol consumption and an 8-year history of mild HTG. He was hospitalized for alcohol-triggered AP, with a plasma triglyceride (TG) level up to 21.4 mmol/L. A temporary rise in post-heparin LPL concentration (1.5-2.5 times of controls) was noted during the early days of AP whilst LPL activity was consistently low (50∼70% of controls). His TG level rapidly decreased to normal in response to treatment, and remained normal to borderline high during a ∼3-year follow-up period during which he had abstained completely from alcohol. Sequencing of the five primary HTG genes (i.e., Show less
Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the Unite Show more
Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein-coupled receptors ( 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-4 Show more
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
Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic component of metabolic syndrome and has attracted widespread attention due to its increased prevalence. Daily dietary management is a Show more
Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic component of metabolic syndrome and has attracted widespread attention due to its increased prevalence. Daily dietary management is an effective strategy for the prevention of NAFLD. Quinoa, a nutritious pseudocereal, is abundant in antioxidative bioactive phytochemicals. In the present study, the effects of different amounts of quinoa on the progression of NAFLD and the related molecular mechanism were investigated. Male SD rats were simultaneously administered a high fat diet (HF) and different amounts of quinoa (equivalent to 100 g/day and 300 g/day of human intake, respectively). After 12 weeks of the intervention, hepatic TG (triglyceride) and TC (total cholesterol) as well as serum antioxidative parameters were determined, and hematoxylin-eosin staining (H&E) staining was used to evaluate hepatic steatosis. Differential metabolites in serum and hepatic tissue were identified using UPLC-QTOF-MS Low amounts of quinoa (equivalent to 100 g/d of human intake) effectively controlled the weight of rats fed a high-fat diet. In addition, quinoa effectively inhibited the increase in hepatic TG and TC levels, mitigated pathological injury, promoted the increase in SOD and GSH-Px activities, and decreased MDA levels. Nontarget metabolic profile analysis showed that quinoa regulated lipid metabolites in the circulation system and liver such as LysoPC and PC. RNA-Seq and RT-PCR verification revealed that a high amount of quinoa more effectively upregulated genes related to lipid metabolism [Apoa (apolipoprotein)5, Apoa4, Apoc2] and downregulated genes related to the immune response [lrf (interferon regulatory factor)5, Tlr6 (Toll-like receptor), Tlr10, Tlr11, Tlr12]. Quinoa effectively prevented NAFLD by controlling body weight, mitigating oxidative stress, and regulating the lipid metabolic profile and the expression of genes related to lipid metabolism and the immune response. Show less
It is widely accepted that circular RNA (circRNA) plays an important role in cardiovascular diseases. Therefore, this experiment aimed to investigate the pathogenesis of circMACF1 in acute myocardial Show more
It is widely accepted that circular RNA (circRNA) plays an important role in cardiovascular diseases. Therefore, this experiment aimed to investigate the pathogenesis of circMACF1 in acute myocardial infarction (AMI). qRT-PCR and immunoblotting were used to detect the expression levels of circMACF1, miR-500b-5p, and epithelial membrane protein 1 (EMP1). The role of circMACF1, miR-500b-5p, and EMP1 in cardiomyocyte apoptosis was assessed using annexin V-FITC/PI. Echocardiographic assessment, serum creatine kinase MB (CK-MB) and lactate dehydrogenase (LDH), myocardial infarct size, and TUNEL staining were applied in our research. In the MI group, the expression levels of circMACF1 and EMP1 were decreased with the increasing expression level of miR-500b-5p. CircMACF1 upregulated the expression of EMP1 as a sponge of miR-500b-5p, and circMACF1 was a direct target of miR-500b-5p. CircMACF1 impaired the progression of AMI by modulating the miR-500b-5p/EMP1 axis. CircMACF1 may be a potential therapeutic target for treating AMI. Graphical Abstract CircMACF1 upregulated EMP1 expression by sponge miR-500b-5p. Show less
Emerging evidence suggests the involvement of caudal-related homoeobox transcription factor 2 (CDX2) in tumorigenesis of various cancers. Although CDX2 functions in cancer invasion and metastasis, few Show more
Emerging evidence suggests the involvement of caudal-related homoeobox transcription factor 2 (CDX2) in tumorigenesis of various cancers. Although CDX2 functions in cancer invasion and metastasis, fewer studies focus on the role of CDX2 during the induction of epithelial-mesenchymal transition (EMT) in colorectal cancer (CRC). Immunohistochemical analysis of CDX2 was performed. A series of in vitro and in vivo experiments were conducted to reveal the role of CDX2 in the invasion and metastasis of CRC. CDX2 was downregulated in CRC tissues and reduced CDX2 correlated with poor prognosis. Knockdown of CDX2 promoted colon cancer cell invasion in vitro and facilitated liver metastasis in vivo with inducing EMT phenotypes. Further investigation indicated that CDX2 retarded Akt and GSK-3β phosphorylation, and thereby diminished Snail expression, β-catenin stabilisation and nuclear translocation. The depletion of β-catenin neutralised the regulation of Slug and ZEB1 by CDX2 knockdown. Mechanistically, CDX2 antagonised PI3K/Akt activity in CRC by modulating PTEN expression. CDX2 directly bound to the promoter of PTEN and transactivated its expression. Our study first uncovered that CDX2 inhibits EMT and metastasis of CRC by regulation of Snail expression and β-catenin stabilisation via transactivation of PTEN expression. Show less
Ocular surface changes may develop in patients with chronic renal failure (CRF) undergoing hemodialysis. In recent years, an association of CRF with dry eye syndrome has been emphasized. However, tear Show more
Ocular surface changes may develop in patients with chronic renal failure (CRF) undergoing hemodialysis. In recent years, an association of CRF with dry eye syndrome has been emphasized. However, tear proteomics of CRF patients has not been analyzed. Here, we performed systematic profiling of the tear film proteins in CRF patients through use of isobaric tags for relative and absolute quantitative (iTRAQ) MS/MS, aiming to identify associations between dry eye symptoms and expression of tear proteomic changes in patients with CRF undergoing hemodialysis. Twenty CRF patients and ten healthy subjects underwent a series of ophthalmic examinations. Tear samples from the participants were analyzed by iTRAQ approach. A total of 1139 tear proteins were screened, and 212 differentially expressed proteins were identified. The pattern changes included 77 whose expression levels were upregulated (fold increase >1.2) whereas 135 others that were downregulated (fold decrease <1/1.2). Bioinformatics analysis showed that these proteins were significantly enriched in lipid metabolism, inflammatory, and immune response pathways. Furthermore, APOA1, APOA4, APOB, APOE, S100A8, S100A9, S100A4, HSP90B and other molecules were significantly changed. Our study elucidated the characteristics of tear dynamics and protein markers in CRF patients undergoing hemodialysis. Significance: Despite the association of chronic renal failure (CRF) with dry eye disease, there are no reports describing potentially important differentially expressed tear proteins in CRF patients undergoing hemodialysis. It is still a challenge to obtain a comprehensive description of the pathogenesis of dry eye in CRF patients which hinders establishing a patient specific therapeutic scheme. Our study is the first iTRAQ proteomics analysis of the tears of patients with CRF, which reveals the changes in the protein expression profile in CRF patients afflicted with dry eye disease. The identity was verified of some relevant differentially expressed proteins, and they may be candidate diagnostic markers of dry eye disease in patients with CRF. These tear film protein constituents found in hemodialysis patients can be of important clinical significance in treating this condition. SIGNIFICANCE: Despite the association of chronic renal failure (CRF) with dry eye disease, there are no reports describing potentially important differentially expressed tear proteins in CRF patients undergoing hemodialysis. It is still a challenge to obtain a comprehensive description of the pathogenesis of dry eye in CRF patients which hinders establishing a patient specific therapeutic scheme. Our study is the first iTRAQ proteomics analysis of the tears of patients with CRF, which reveals the changes in the protein expression profile in CRF patients afflicted with dry eye disease. The identity was verified of some relevant differentially expressed proteins, and they may be candidate diagnostic markers of dry eye disease in patients with CRF. These tear film protein constituents found in hemodialysis patients can be of important clinical significance in treating this condition. Show less
Digestive system carcinoma is one of the most devastating diseases worldwide. Lack of valid clinicopathological parameters as prognostic factors needs more accurate and effective biomarkers for high-c Show more
Digestive system carcinoma is one of the most devastating diseases worldwide. Lack of valid clinicopathological parameters as prognostic factors needs more accurate and effective biomarkers for high-confidence prognosis that guide decision-making for optimal treatment of digestive system carcinoma. The aim of the present study was to establish a novel model to improve prognosis prediction of digestive system carcinoma, with a particular interest in transcription factors (TFs). A TF-related prognosis model of digestive system carcinoma with data from TCGA database successively were processed by univariate and multivariate Cox regression analyses. Then, for evaluating the prognostic prediction value of the model, ROC curve and survival analysis were performed by external data from GEO database. Furthermore, we verified the expression of TFs expression by qPCR in digestive system carcinoma tissue. Finally, we constructed a TF clinical characteristics nomogram to furtherly predict digestive system carcinoma patient survival probability with TCGA database. By Cox regression analysis, a panel of 17 TFs (NFIC, YBX2, ZBTB47, ZNF367, CREB3L3, HEYL, FOXD1, TIGD1, SNAI1, HSF4, CENPA, ETS2, FOXM1, ETV4, MYBL2, FOXQ1, ZNF589) was identified to present with powerful predictive performance for overall survival of digestive system carcinoma patients based on TCGA database. A nomogram that integrates TFs was established, allowing efficient prediction of survival probabilities and displaying higher clinical utility. The 17-TF panel is an independent prognostic factor for digestive system carcinoma, and 17 TFs based nomogram might provide implication an effective approach for digestive system carcinoma patient management and treatment. Show less
Epithelial ovarian cancer (EOC) is a highly fatal gynecological cancer. A long noncoding RNA (lncRNA) gastric cancer-associated lncRNA1 (GClnc1) has been revealed to play critical roles in metastasis. Show more
Epithelial ovarian cancer (EOC) is a highly fatal gynecological cancer. A long noncoding RNA (lncRNA) gastric cancer-associated lncRNA1 (GClnc1) has been revealed to play critical roles in metastasis. Therefore, the present study aims to explore the correlation between GClnc1 and the metastasis and progression of EOC. First, 57 paired EOC and paracancerous tissues were collected to detect GClnc1 expression by RT-qPCR. Subsequently, OVC1 and SKOV3 cells with GClnc1 silencing/overexpression were developed to detect changes in cell activity, apoptosis, migration and invasion abilities. Then, the subcellular localization of GClnc1 was detected by nuclear/cytoplasmic fractionation, ISH and FISH assays. The binding relationships between GClnc1 and forkhead box protein C2 (FOXC2), and between FOXC2 and NOTCH1 were predicted and verified. GClnc1 was significantly overexpressed in EOC tissues, and knockdown of GClnc1 inhibited cell viability and promoted apoptosis. Moreover, GClnc1 in the nucleus bound to the transcription factor FOXC2, thereby activating the transcription of NOTCH1. NOTCH1 overexpression enhanced the proliferation and epithelial-mesenchymal transition of SKOV3 and OVC1 cells. Moreover, NOTCH1 activated the NF-κB/Snail signaling. Finally, in vivo experiments demonstrated that GClnc1 knockdown suppressed the growth and metastasis of SKOV3 and OVC1 cells in vivo. GClnc1 promoted NOTCH1 transcription by recruiting FOXC2, thereby activating the NF-κB/Snail signaling and promoting EOC cell growth and metastasis. Show less
Endothelial glycocalyx loss is integral to increased pulmonary vascular permeability in sepsis-related acute lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is a novel macrophage-de Show more
Endothelial glycocalyx loss is integral to increased pulmonary vascular permeability in sepsis-related acute lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is a novel macrophage-derived lipid mediator exhibiting potential anti-inflammatory and pro-resolving benefits. PCTR1 was administrated intraperitoneally with 100 ng/mouse after lipopolysaccharide (LPS) challenged. Survival rate and lung function were used to evaluate the protective effects of PCTR1. Lung inflammation response was observed by morphology and inflammatory cytokines level. Endothelial glycocalyx and its related key enzymes were measured by immunofluorescence, ELISA, and Western blot. Afterward, related-pathways inhibitors were used to identify the mechanism of endothelial glycocalyx response to PCTR1 in mice and human umbilical vein endothelial cells (HUVECs) after LPS administration. In vivo, we show that PCTR1 protects mice against lipopolysaccharide (LPS)-induced sepsis, as shown by enhanced the survival and pulmonary function, decreased the inflammatory response in lungs and peripheral levels of inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β. Moreover, PCTR1 restored lung vascular glycocalyx and reduced serum heparin sulphate (HS), syndecan-1 (SDC-1), and hyaluronic acid (HA) levels. Furthermore, we found that PCTR1 downregulated heparanase (HPA) expression to inhibit glycocalyx degradation and upregulated exostosin-1 (EXT-1) protein expression to promote glycocalyx reconstitution. Besides, we observed that BAY11-7082 blocked glycocalyx loss induced by LPS in vivo and in vitro, and BOC-2 (ALX antagonist) or EX527 (SIRT1 inhibitor) abolished the restoration of HS in response to PCTR1. PCTR1 protects endothelial glycocalyx via ALX receptor by regulating SIRT1/NF-κB pathway, suggesting PCTR1 may be a significant therapeutic target for sepsis-related acute lung injury. Show less
Dendritic cells (DCs) are key in the initiation of the adaptive T cell responses to tailor adequate immunity that corresponds to the type of pathogen encountered. Oppositely, DCs control the resolutio Show more
Dendritic cells (DCs) are key in the initiation of the adaptive T cell responses to tailor adequate immunity that corresponds to the type of pathogen encountered. Oppositely, DCs control the resolution phase of inflammation and are able to induce tolerance after receiving anti-inflammatory cytokines or upon encounter of self-associated molecular patterns, such as α2-3 linked sialic acid (α2-3sia). We here investigated whether α2-3sia, that bind immune inhibitory Siglec receptors, would alter signaling and reprogramming of LPS-stimulated human monocyte-derived DCs (moDCs). Transcriptomic analysis of moDCs stimulated with α2-3sia-conjugated dendrimers revealed differentially expressed genes related to metabolic pathways, cytokines, and T cell differentiation. An increase in genes involved in ATPase regulator activity, oxidoreductase activity, and glycogen metabolic processes was detected. Metabolic extracellular flux analysis confirmed a more energetic moDC phenotype upon α2-3sia binding as evidenced by an increase in both glycolysis and mitochondrial oxidative phosphorylation. T In conclusion, we demonstrate that α2-3sia binding to moDCs, phosphorylates Siglec-9, alters metabolic pathways, cytokine signaling, and T cell differentiation processes in moDCs and promotes regulatory T cells. The sialic acid-Siglec axis on DCs is therefore, a novel target to induce tolerance and to explore for immunotherapeutic interventions aimed to restore inflammatory processes. Show less
Metastasis and chemoresistance are major causes of poor prognosis in patients with esophageal squamous cell carcinoma (ESCC), manipulated by multiple factors including deubiquitinating enzyme (DUB). D Show more
Metastasis and chemoresistance are major causes of poor prognosis in patients with esophageal squamous cell carcinoma (ESCC), manipulated by multiple factors including deubiquitinating enzyme (DUB). DUB PSMD14 is reported to be a promising therapeutic target in various cancers. Here, we explored the antitumor activity of Thiolutin (THL), the PSMD14 inhibitor, as a new therapy strategy in ESCC. Show less
Sleeve gastrectomy (SG) is the most widely used bariatric procedures globally, which could improve glucose and lipid metabolism dramatically. Circular RNAs (circRNAs) are being increasingly implicated Show more
Sleeve gastrectomy (SG) is the most widely used bariatric procedures globally, which could improve glucose and lipid metabolism dramatically. Circular RNAs (circRNAs) are being increasingly implicated in numerous pathophysiological processes. However, for diabetes mellitus (DM), the expression and function of circRNAs remain largely undetermined, in particular, whether circRNAs mediate the amelioration of DM observed after SG. Using a diabetic rat model, we subjected liver tissue from SG and sham-operated rats to RNA sequencing. Amongst the 103 differentially regulated circRNAs identified in diabetic rats after SG, we focused on circDOCK7, a highly expressed circRNA derived from the back-splicing of the DOCK7 gene. Silencing of circDOCK7 significantly inhibited cellular proliferation and induction of apoptosis in insulin-resistant rat hepatocytes. Further analysis indicated circDOCK7 harbored binding sites for miR-139-3p and regulated the expression of minichromosome maintenance 3 (MCM3) through sequestration of miR-139-3p. Our findings therefore demonstrate a novel regulatory pathway involving circDOCK7 that regulates cellular proliferation and apoptosis through increasing the expression of MCM3. Overall, our study establishes a list of specific circRNAs expressed in diabetic rat liver after SG including circDOCK7 which serve as potential biomarkers and treatment targets for DM patients. Show less
Substantial evidence indicated that maternal malnutrition could increase the susceptibility to obesity, insulin resistance, and type 2 diabetes in adulthood. It is increasingly apparent that the brain Show more
Substantial evidence indicated that maternal malnutrition could increase the susceptibility to obesity, insulin resistance, and type 2 diabetes in adulthood. It is increasingly apparent that the brain, especially the hypothalamus, plays a critical role in glucose homeostasis. However, little information is known about the mechanisms linking maternal protein restriction combined with post-weaning high-fat (HF) feeding with altered expression of brain neurotransmitters, and investigations into the epigenetic modifications of hypothalamus in offspring have not been fully elucidated. Our objective was to explore the effects of maternal protein restriction combined with post-weaning HF feeding on glucose metabolism and hypothalamic POMC methylation in male offspring mice. C57/BL6 mice were fed on either low-protein (LP) or normal chow (NC) diet throughout gestation and lactation. Then, the male offspring were randomly weaned to either NC or high-fat (HF) diet until 32 weeks of age. Gene expressions and DNA methylation of hypothalamic proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) were determined in male offspring. The results showed that birth weights and body weights at weaning were both significantly lower in male offspring mice of the dams fed with a LP diet. Maternal protein restriction combined with post-weaning high-fat feeding, predisposes higher body weight, persistent glucose intolerance (from weaning to 32 weeks of age), hyperinsulinemia, and hyperleptinemia in male offspring mice. POMC and MC4R expressions were significantly increased in offspring mice fed with maternal LP and postnatal high-fat diet ( Show less
The objective was to perform a proof-of-principle study to evaluate the effects of methionine (Met) and arginine (Arg) supply on protein abundance of amino acid, insulin signaling, and glutathione met Show more
The objective was to perform a proof-of-principle study to evaluate the effects of methionine (Met) and arginine (Arg) supply on protein abundance of amino acid, insulin signaling, and glutathione metabolism-related proteins in subcutaneous adipose tissue (SAT) explants under ceramide (Ce) challenge. SAT from four lactating Holstein cows was incubated with one of the following media: ideal profile of amino acid as the control (IPAA; Lys:Met 2.9:1, Lys:Arg 2:1), increased Met (incMet; Lys:Met 2.5:1), increased Arg (incArg; Lys:Arg 1:1), or incMet plus incArg (Lys:Met 2.5:1 Lys:Arg 1:1) with or without 100 μM exogenous cell-permeable Ce ( Show less
Gastric cancer (GC) is one of the most common cancers, with most patients often succumbing to death as a result of tumor metastasis. Recent work has demonstrated that gastrin is closely associated wit Show more
Gastric cancer (GC) is one of the most common cancers, with most patients often succumbing to death as a result of tumor metastasis. Recent work has demonstrated that gastrin is closely associated with GC metastasis. However, the specific molecular mechanisms underlying this relationship remain to be unveiled. In this study, we assessed the impact of gastrin and the Wnt/β-catenin inhibitor XAV939 on the epithelial-mesenchymal transition (EMT) of the SGC-7901 and MKN45 GC cell lines, and we determined that gastrin-17 significantly decreased E-cadherin expression and upregulated the expression of Snail1 and N-cadherin in GC cells. In addition, gastrin 17 also significantly increased the expression of Wnt3α in a dose-dependent manner. Consistent with these results, gastrin-17 promoted GC cell invasion, proliferation, and migration in a dose-dependent fashion, and these effects were inhibited by XAV939. Together, these results indicated that gastrin-17 induced GC cell EMT, migration, and invasion via the Wnt/β-catenin signaling pathway, which suggests that this gastrin/Wnt/β-catenin signaling axis may represent a therapeutic target for the prevention of GC metastasis. Show less
Skeletal muscle has a remarkable ability to regenerate owing to its resident stem cells (also called satellite cells, SCs). SCs are normally quiescent; when stimulated by damage, they activate and exp Show more
Skeletal muscle has a remarkable ability to regenerate owing to its resident stem cells (also called satellite cells, SCs). SCs are normally quiescent; when stimulated by damage, they activate and expand to form new fibers. The mechanisms underlying SC proliferative progression remain poorly understood. Here we show that DHX36, a helicase that unwinds RNA G-quadruplex (rG4) structures, is essential for muscle regeneration by regulating SC expansion. DHX36 (initially named RHAU) is barely expressed at quiescence but is highly induced during SC activation and proliferation. Inducible deletion of Dhx36 in adult SCs causes defective proliferation and muscle regeneration after damage. System-wide mapping in proliferating SCs reveals DHX36 binding predominantly to rG4 structures at various regions of mRNAs, while integrated polysome profiling shows that DHX36 promotes mRNA translation via 5'-untranslated region (UTR) rG4 binding. Furthermore, we demonstrate that DHX36 specifically regulates the translation of Gnai2 mRNA by unwinding its 5' UTR rG4 structures and identify GNAI2 as a downstream effector of DHX36 for SC expansion. Altogether, our findings uncover DHX36 as an indispensable post-transcriptional regulator of SC function and muscle regeneration acting through binding and unwinding rG4 structures at 5' UTR of target mRNAs. Show less
Severe negative energy balance around parturition is an important contributor to ketosis, a metabolic disorder that occurs most frequently in the peripartal period. Autophagy and mitophagy are importa Show more
Severe negative energy balance around parturition is an important contributor to ketosis, a metabolic disorder that occurs most frequently in the peripartal period. Autophagy and mitophagy are important processes responsible for breaking down useless or toxic cellular material, and in particular damaged mitochondria. However, the role of autophagy and mitophagy during the occurrence and development of ketosis is unclear. The objective of this study was to investigate autophagy and mitophagy in the livers of cows with subclinical ketosis (SCK) and clinical ketosis (CK). We assessed autophagy by measuring the protein abundance of microtubule-associated protein 1 light chain 3-II (LC3-II; encoded by MAP1LC3) and sequestosome-1 (p62, encoded by SQSTM1), as well as the mRNA abundance of autophagy-related genes 5 (ATG5), 7 (ATG7), and 12 (ATG12), beclin1 (BECN1), and phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3). Mitophagy was evaluated by measuring the protein abundance of the mitophagy upstream regulators PTEN-induced putative kinase 1 (PINK1) and Parkin. Liver and blood samples were collected from healthy cows [n = 15; blood β-hydroxybutyrate (BHB) concentration <1.2 mM], cows with SCK (n = 15; blood BHB concentration 1.2 to 3.0 mM) and cows with CK (n = 15; blood BHB concentration >3.0 mM with clinical signs) with similar lactation numbers (median = 3, range = 2 to 4) and days in milk (median = 6, range = 3 to 9). The serum activity of aspartate aminotransferase and alanine aminotransferase was greater in cows with CK than in healthy cows. Levels of oxidative stress biomarkers malondialdehyde and hydrogen peroxide were also higher in liver tissue from ketotic cows (SCK and CK) than from healthy cows. Compared with cows with CK and healthy cows, the hepatic mRNA abundance of MAP1LC3, SQSTM1, ATG5, ATG7, ATG12, and PIK3C3 was upregulated in cows with SCK. Compared with healthy cows, cows with SCK had a lower abundance of p62 and a greater abundance of LC3-II, but levels of both were higher in cows with CK. The mRNA abundance of ATG12 was lower in cows with CK than in healthy cows. Furthermore, the hepatic protein abundance of PINK1 and Parkin was greater in cows with SCK and slightly lower in cows with CK than in healthy cows. These data demonstrated differences in the hepatic activities of autophagy and mitophagy in cows with SCK compared with cows with CK. Although the precise mechanisms for these differences could not be discerned, autophagy and mitophagy seem to be involved in ketosis. Show less
Chemoresistance is a severe clinical challenge in breast cancer. Hypoxia and cancer stem cells (CSCs) contribute to the paclitaxel (PTX) resistance, but the molecular mechanisms are still elusive. Mic Show more
Chemoresistance is a severe clinical challenge in breast cancer. Hypoxia and cancer stem cells (CSCs) contribute to the paclitaxel (PTX) resistance, but the molecular mechanisms are still elusive. MicorRNAs (miRNA) have been considered a promising therapeutic strategy in various cancers. Here, we identified the crucial function of miR-526b-3p in regulating PTX resistance and CSC properties. Our data demonstrated that miR-526b-3p mimic repressed the cell viability of breast cancer cells. The counts of Edu-positive cells were reduced by miR-526b-3p in breast cancer cells. Meanwhile, the apoptosis of breast cancer cells was induced by miR-526b-3p. Tumorigenicity analysis in the nude mice confirmed that miR-526b-3p attenuated the breast cancer cell growth Show less