In day-to-day life, we often must choose between pursuing familiar behaviors or adjusting behaviors when new strategies might be more fruitful. The dorsomedial striatum (DMS) is indispensable for arbi Show more
In day-to-day life, we often must choose between pursuing familiar behaviors or adjusting behaviors when new strategies might be more fruitful. The dorsomedial striatum (DMS) is indispensable for arbitrating between old and new action strategies. To uncover molecular mechanisms, we trained mice to generate nose poke responses for food, then uncoupled the predictive relationship between one action and its outcome. We then bred the mice that failed to rapidly modify responding. This breeding created offspring with the same tendencies, failing to inhibit behaviors that were not reinforced. These mice had less post-synaptic density protein 95 in the DMS. Also, densities of the melanocortin-4 receptor (MC4R), a high-affinity receptor for α-melanocyte-stimulating hormone, predicted individuals' response strategies. Specifically, high MC4R levels were associated with poor response inhibition. We next found that reducing Mc4r in the DMS in otherwise typical mice expedited response inhibition, allowing mice to modify behavior when rewards were unavailable or lost value. This process required inputs from the orbitofrontal cortex, a brain region canonically associated with response strategy switching. Thus, MC4R in the DMS appears to propel reward-seeking behavior, even when it is not fruitful, while moderating MC4R presence increases the capacity of mice to inhibit such behaviors. Show less
To investigate the treating effect of Yiqi-Bushen-Tiaozhi (YBT) recipe on nonalcoholic steatohepatitis (NASH) mice, determine whether the outcome was associated with gut microbiota, and clarify the re Show more
To investigate the treating effect of Yiqi-Bushen-Tiaozhi (YBT) recipe on nonalcoholic steatohepatitis (NASH) mice, determine whether the outcome was associated with gut microbiota, and clarify the regulating mechanism. NASH mice were induced by high-fat and high-fructose diets (HFFD). In the fifth week, mice in the YBT group were orally administrated YBT (22.12g·kg Results of the pathological and biochemical index showed that YBT could improve NASH mice. Compared with improving inflammation and hepatocyte damage, YBT may be more focused on enhancing metabolic disorders in mice, such as increasing HDL-c level. The diversity and richness of the gut microbiota of NASH mice induced by HFFD are significantly different from the normal control (NC) group. After YBT treatment, the diversity and richness of the mice microbiota will be increased to similar NC mice. YBT could treat NASH mice by improving the diversity and richness of gut microbiota and further the improvement of ALA metabolism. Show less
The effects of cholamine, a raw material for synthesis of some active lipids, are unknown in poultry. To address this, 180 52-wk-old Hyline laying hens were randomly divided into 3 groups (20 replicat Show more
The effects of cholamine, a raw material for synthesis of some active lipids, are unknown in poultry. To address this, 180 52-wk-old Hyline laying hens were randomly divided into 3 groups (20 replicates per group with three hens per replicate). The control group and the treatment groups (treatment 1 and 2) were fed basal diet and the diet supplemented with 500 or 1,000 mg of cholamine per kilogram of the diet for 35 d, respectively. The data showed that supplementary cholamine significantly lowered egg production, daily feed intake, serum high-density lipoprotein cholesterol level, liver index, and the percentages of C15:0 and C20:0 in fatty acid composition of liver, significantly elevated hepatic triglyceride content, the ratio of villus height to crypt depth (P < 0.05), and the percentage of C18:2n-6 and the ratio of n-6 to n-3 polyunsaturated fatty acids in liver fat (P < 0.10). Moreover, supplementary cholamine altered the relative abundance of some intestinal bacteria with a decrease in the alpha biodiversity (P < 0.10). Additionally, transcriptome analysis on the livers of the treatment vs. the control groups identified 1,151 up- and 914 down-regulated differentially expressed genes (DEGs), and pathway analysis revealed that the suppressed Notch signaling pathway and the enhanced Oxidative phosphorylation pathway were enriched with DEGs. Particularly, fat absorption, transport and oxidative phosphorylation-related DEGs (e.g., FABP1, APOA4, and PCK1) were significantly induced, but fatty acid synthesis, and lipid package and secretion-related DEGs (e.g., FASN, SCD, and MTTP) were not. In conclusion, supplementary cholamine may lower egg production by promoting hepatic lipid deposition and reducing abundances of beneficial intestinal bacteria and microfloral biodiversity in laying hens. Show less
Differentiation blockade is a hallmark of acute myeloid leukemia (AML). A strategy to overcome such a blockade is a promising approach against the disease. The lack of understanding of the underlying Show more
Differentiation blockade is a hallmark of acute myeloid leukemia (AML). A strategy to overcome such a blockade is a promising approach against the disease. The lack of understanding of the underlying mechanisms hampers development of such strategies. Dysregulated ribonucleotide reductase (RNR) is considered a druggable target in proliferative cancers susceptible to deoxynucleoside triphosphate (dNTP) depletion. Herein, we report an unanticipated discovery that hyperactivating RNR enables differentiation and decreases leukemia cell growth. We integrate pharmacogenomics and metabolomics analyses to identify that pharmacologically (eg, nelarabine) or genetically upregulating RNR subunit M2 (RRM2) creates a dNTP pool imbalance and overcomes differentiation arrest. Moreover, R-loop-mediated DNA replication stress signaling is responsible for RRM2 activation by nelarabine treatment. Further aggravating dNTP imbalance by depleting the dNTP hydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) enhances ablation of leukemia stem cells by RRM2 hyperactivation. Mechanistically, excessive activation of extracellular signal-regulated kinase (ERK) signaling downstream of the imbalance contributes to cellular outcomes of RNR hyperactivation. A CRISPR screen identifies a synthetic lethal interaction between loss of DUSP6, an ERK-negative regulator, and nelarabine treatment. These data demonstrate that dNTP homeostasis governs leukemia maintenance, and a combination of DUSP inhibition and nelarabine represents a therapeutic strategy. Show less
Developmental dysplasia of the hip (DDH) is a common anomaly leading to adult osteoarthritis. Environmental and genetic factors contribute to DDH, but its exact genetic mechanism is unclear. In this s Show more
Developmental dysplasia of the hip (DDH) is a common anomaly leading to adult osteoarthritis. Environmental and genetic factors contribute to DDH, but its exact genetic mechanism is unclear. In this study, we used whole exome sequencing to identify the causative gene of a DDH pedigree. A rare missense variant in KANSL1 (c.C767T; p.S256F) was identified as the pathogenic cause of DDH. Subsequent mutation screening showed another missense variant in 1 of 200 sporadic patients. Kansl1-mutated mice showed reduced chondrocytes in the acetabulum and a decrease in the cartilage matrix, which may be DDH phenotype-related abnormalities. Furthermore, functional studies showed that cell proliferation was delayed and Mmp13 expression was abnormally upregulated in chondrocytes differentiated from Kansl1 mutant mouse embryonic stem cells. In conclusion, our findings suggest that KANSL1 is a novel pathogenic gene for DDH. The identification of KANSL1 variants has great diagnostic value for identifying individuals with DDH. KEY MESSAGES: Developmental dysplasia of the hip (DDH) is a common anomaly causing adult osteoarthritis. Environmental and genetic factors contribute to DDH, but its exact genetic mechanism is unclear. Using high-throughput whole exome sequencing, we found a novel variant in KANSL1 that was co-inherited by all severely affected individuals diagnosed with DDH from a three-generation family. Further analysis revealed that a Kansl1 variant in mice reduced the number of chondrocytes and decreased cartilage matrix, and mouse embryonic stem differentiation assay showed cartilage defects. These findings indicate a direct association between KANSL1 and hip development, expanding the pathogenic gene spectrum in DDH and providing insight into potential new targets for diagnosing and treating hip dysplasia. Show less
Rong Li, Wenqiang Zhu, Piaopiao Huang+4 more · 2022 · Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · added 2026-04-24
Long-term treatment of olanzapine, the most widely-prescribed second-generation antipsychotic, remarkably increases the risk of non-alcoholic fatty liver disease (NAFLD), whereas the mechanism for ola Show more
Long-term treatment of olanzapine, the most widely-prescribed second-generation antipsychotic, remarkably increases the risk of non-alcoholic fatty liver disease (NAFLD), whereas the mechanism for olanzapine-induced NAFLD remains unknown. Excessive hepatic fat accumulation is the basis for the pathogenesis of NAFLD, which results from the disturbance of TG metabolism in the liver. Apolipoprotein A5 (ApoA5) is a key regulator for TG metabolism in vivo that promotes TG accumulation in hepatocytes, thereby resulting in the development of NAFLD. However, there are no data indicating the role of apoA5 in olanzapine-induced NAFLD. Therefore, this study aims to investigate the role of apoA5 in olanzapine-induced NAFLD. This study was carried out via animal studies, cell experiment, and ApoA5 gene knockdown experiment. Six-week-old male C57BL/6J mice were randomized into a control group, a low-dose group, and a high-dose group, which were treated by 10% DMSO, 3 mg/(kg·d) olanzapine, and 6 mg/(kg·d) olanzapine, respectively for 8 weeks. The lipid levels in plasma, liver function indexes, and expression levels of ApoA5 were detected. HepG2 cells were treated with 0.1% DMSO (control group), 25 μmol/L olanzapine (low-dose group), 50 μmol/L olanzapine (medium-dose group), and 100 μmol/L olanzapine (high-dose group) for 24 h. HepG2 cells pretreated with 100 μmol/L olanzapine were transfected with siRNA and scrambled siRNA (negative control), respectively. We observed the changes in lipid droplets within liver tissues and cells using oil red O staining and fat deposition in liver tissues using HE staining. The mRNA and protein levels of ApoA5 were determined by real-time PCR and Western blotting, respectively. After intervention with 3 and 6 mg/(kg·d) olanzapine for 8 weeks, there was no significant difference in body weight among the 3 groups ( The short-term intervention of olanzapine does not significantly increase body weight of mice, but it can directly induce hypertriglyceridemia and NAFLD in mice. Olanzapine inhibits hepatic apoA5 secretion but does not affect hepatic apoA5 synthesis, resulting in the pathogenesis of NAFLD. Inhibition of apoA5 secretion plays a key role in the development of olanzapine-related NAFLD, which may serve as an intervention target for this disease. Show less
Mounting evidence has linked both obesity and metabolic disorders with dysbiosis of the gut microbiota. Dietary inulin is conducive to modulating this dysbiosis, and represents a potential means to im Show more
Mounting evidence has linked both obesity and metabolic disorders with dysbiosis of the gut microbiota. Dietary inulin is conducive to modulating this dysbiosis, and represents a potential means to improve disorders of glucose and lipid metabolism. However, the mechanisms underlying these improvements are largely unclear. Obese ob/ob mice were fed a standard chow, a low fiber diet (LFD) or a high fiber diet (HFD) for 4 weeks, and the body weight, fecal short chain fatty acids (SCFAs) level, and plasma and liver lipid profiles were analyzed. Oral glucose tolerance testing, and gut microbiota sequencing were also conducted. Dietary inulin improved the dysbiosis of the gut microbiota, attenuated the decrease in phylum Bacteroidetes, repressed the increase of phylum Firmicutes, and led to an increase in the ratio of Firmicutes/Bacteroidetes. At the family level, inulin promoted the expansion of SCFAs-producing Ruminococcaceae and Lachnospiraceae bacteria, which increased the fecal SCFAs concentrations. At the genus level, inulin increased the levels of Bacteroides and Bifidobacteria. Furthermore, our results revealed that there was enhanced expression of angiopoietin-like protein 4 (ANGPTL4), which might be induced by the higher production of SCFAs, and this may underlie the improvements in the disorders of glucose and lipid metabolism seen in mice with added dietary inulin. In conclusion, inulin may ameliorate metabolic disorders by remodeling the gut microbiota and increasing the production of SCFAs, which might be mediated by the ANGPTL4-related signaling pathway. Interventions targeting the gut microbiota warrant further investigation as a novel therapy for metabolic diseases. PRACTICAL APPLICATIONS: Mounting evidence has linked both obesity and metabolic disorders with dysbiosis of the gut microbiota. Dietary inulin is conducive to modulating this dysbiosis, and represents a potential means to improve disorders of glucose and lipid metabolism. However, the mechanisms underlying these improvements are largely unclear. In the present study, we investigated the effects of dietary fiber (inulin) on metabolic homeostasis using ob/ob mice. The results of our study demonstrate that inulin-induced remodeling of the gut microbiota resulted in increased production of short chain fatty acids (SCFAs), leading to the enhanced expression of angiopoietin-like protein 4 (ANGPTL4), which improved the glucose and lipid metabolism. Our results suggest that the gut microbiota, SCFAs and ANGPTL4 pathway at least partially mediate the beneficial effects of inulin on metabolic disorders in ob/ob mice. Show less
The migration of osteoblastic cells to bone formation surface is an essential step for bone development and growth. However, whether the migration capacity of osteoblastic cells is compromised during Show more
The migration of osteoblastic cells to bone formation surface is an essential step for bone development and growth. However, whether the migration capacity of osteoblastic cells is compromised during osteoporosis occurrence and how it contributes to bone formation reduction remain unexplored so far. In this work, we found, as a positive regulator of cell migration, microtubule actin crosslinking factor 1 (MACF1) enhanced osteoblastic cells migration. We also examined whether MACF1 could facilitate osteoblastic cells' migration to bone formation surface to promote bone formation through another cytoskeleton protein, microtubule associated protein 1 (MAP1B). Preosteoblast cell line MC3T3-E1 with different MACF1 level was used for in vitro and in vivo cell migration assay; Primary cortical bone derived mesenchymal stem cells (C-MSCs) from bone tissue of MACF1 conditional knock out (cKO) mice was used for in vitro cell migration assay. Cell migration ability in vitro was evaluated by wound healing assay and transwell assay and in vivo by bone marrow cavity injection. Small interfering RNA (siRNA) was used for knocking down Map1b in MC3T3-E1 cell. Lithium chloride (LiCl) and Wortmannin (Wort) were used for inhibiting/activating GSK3β pathway activity. Luciferase report assay was performed for detection of transcriptional activity of TCF7 for Map1b; Chromatin immunoprecipitation (ChIP) was engaged for the binding of TCF7 to Map1b promoter region. We found MACF1 enhanced MC3T3-E1 cell and C-MSCs migration in vitro through promoting microtubule (MT) stability and dynamics, and increased the injected MC3T3-E1 cell number on bone formation surface, which indicated a promoted bone formation. We further authenticated that MAP1B had a similar function to MACF1 and was regulated by MACF1 in osteogenic cell, and silencing map1b repressed MC3T3-E1 cell migration in vitro. Mechanistically, by adopting MC3T3-E1 cell with different MACF1 level or treated with LiCl/Wort, we discovered that MACF1 decreased the levels of 1265 threonine phosphorylated MAP1B (p[T1265] MAP1B) through inhibiting GSK3β activity. Additionally, total MAP1B mRNA expression level was upregulated by MACF1 through strengthening the binding of TCF7 to the map1b promoter sequence. Our study uncovered a novel role of MACF1 in bone formation and MAP1B regulation, which suggested that MACF1 could be a potential therapeutic target for osteoporosis. Show less
We aimed to explore and identify candidate protein biomarkers of cryoglobulinemia (CGE) in disease control patients with negative cryoglobulin (DC) or healthy controls (HCs). The tandem mass tag (TMT) Show more
We aimed to explore and identify candidate protein biomarkers of cryoglobulinemia (CGE) in disease control patients with negative cryoglobulin (DC) or healthy controls (HCs). The tandem mass tag (TMT)-labeled serum quantitative proteomics approach was used to identify differentially expressed proteins between the CGE and DC groups. Ingenuity pathway analysis was used for functional annotation of differentially expressed proteins. Biomarker candidates were validated in another cohort using the parallel reaction monitoring (PRM) method. Apolipoprotein A1 (APOA1), apolipoprotein CIII (APOC3), adiponectin, and proprotein convertase subtilisin/kexin type-9 (PCSK9), which represent key proteins involved in the cholesterol metabolism pathway, were further verified in an increased number of samples by enzyme-linked immunosorbent assay (ELISA). A total of 1004 proteins were identified, of which 109 proteins were differentially expressed between the CGE and DC groups. These differentially expressed proteins were primarily involved in hepatic fibrosis/hepatic stellate cell activation and immune/inflammation-related pathways. In the disease and biofunction analysis, these proteins were mainly associated with the adhesion of blood cells, leukocyte migration, cholesterol transport, and transport of lipids. Twelve candidate biomarkers were validated by PRM-based proteomics, and proteins involved in the cholesterol metabolism pathway were further verified. APOA1, APOC3, adiponectin and PCSK9 concentrations were increased in CGE patients compared with healthy controls (P=0.0123, 0.1136, 0.5760, and 0.0019, respectively). This report describes the first application of a TMT-PRM-ELISA workflow to identify and validate CGE-specific biomarkers in serum. APOA1 and PCSK9 have been confirmed to be increased in CGE patients, demonstrating that proteins involved in cholesterol metabolism are also implicated in the development of CGE. These findings contribute to pathogenesis research and biomarker discovery in CGE. Show less
Agouti-related protein (AgRP) is a neuropeptide synthesized by AgRP/NPY neurons and transcribed as 132 amino acids in humans and 142 amino acids (AgRP1) in Japanese seabass (
Minghui Bao, Haotong Li, Jianping Li · 2022 · Journal of cellular and molecular medicine · Blackwell Publishing · added 2026-04-24
Aldosterone-producing adenoma (APA) is a common cause of secondary hypertension. This study aimed to explore the lncRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) network to uncover molecular mecha Show more
Aldosterone-producing adenoma (APA) is a common cause of secondary hypertension. This study aimed to explore the lncRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) network to uncover molecular mechanism underlying APA. The mRNA and lncRNA expression data of APA and adjacent adrenal gland (AAG) from GSE60044, GSE64957 and GSE101894 were obtained from the Gene Expression Omnibus (GEO) database to analyse differentially expressed genes (DEGs) and lncRNAs (DElncs). Hub genes were identified by robust rank aggregation (RRA) and protein-protein interaction (PPI) network analysis. The miRcode and miRWalk network tools were used to construct the ceRNA network. 1526 upregulated and 1512 downregulated DEGs were identified, which are mainly enriched in extracellular matrix and Ca Show less
Jiaxin Li, Minhan Yi, Binbin Li+5 more · 2022 · Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · Springer · added 2026-04-24
Neurodegenerative genes are critical in neuronal loss in Parkinson's disease (PD). We performed a systematic meta-analysis including all the studies published on PD risk related to genes encoding enzy Show more
Neurodegenerative genes are critical in neuronal loss in Parkinson's disease (PD). We performed a systematic meta-analysis including all the studies published on PD risk related to genes encoding enzymes vital for dopamine metabolism and neuron survival. We included neurodegeneration-related genes which were divided into four groups according to their functions: main enzymes in dopamine metabolism, receptors and transporters for dopamine or other metabolites, neuroprotective factors for dopaminergic neurons, and genes associated with dopaminergic neurons survival reported in other neurological diseases. We collected original articles from PubMed, Embase, and Web of Science databases. Revman 5.3 software was used to analyze data. The allele model (AM) was used to test the effect size of the effect allele between the case group and the control group and secondary analysis using the dominant model (DM) and recessive model (RM) to analyze the contributions from heterozygote and homozygote to the allele risk. Odds ratio (OR) and 95% confidence interval (CI) were used to present the pooled results. We included 31 variants in 20 genes for the final pooled analysis. Consequently, SLC6A4/5-HTT HTTLPR, BDNF rs56164415, FGF20 rs1721100, PARK16 rs823128, rs823156, rs947211, APOE e2, A2M rs669, RIT2 rs12456492, MAPT intron 9 H1H2, and STH rs62063857 variants were statistically associated with PD risk while researched variants in COMT, DBH, MAO, DAT/SLC6A3, DRD2, GRIN2B, GSK3β, ATP13A2, LINGO1, PICALM, and GRN were not related to PD risk. Several variants from neurodegeneration-related genes are associated with PD risk, which may help deepen the understanding of PD pathogenesis and improve clinical treatment strategies. Show less
Airway epithelial cell (AEC) dysfunction has been proven to be involved in the pathogenesis of asthma, which may be induced by the use of dexamethasone (Dex). The altered expression of microRNAs (miRN Show more
Airway epithelial cell (AEC) dysfunction has been proven to be involved in the pathogenesis of asthma, which may be induced by the use of dexamethasone (Dex). The altered expression of microRNAs (miRNAs/miRs) has been found in asthma. However, the detailed mechanisms responsible for the effects of miR‑375 on Dex‑induced AEC dysfunction remain elusive. Thus, the present study aimed to elucidate these mechanisms. Following treatment with Dex for 0, 6, 12 and 24 h, AEC viability, migration, invasion and apoptosis were examined using Cell Counting Kit‑8 (CCK‑8), wound healing and Transwell assays, and flow cytometry, respectively. The expression levels of miR‑375, dual specificity phosphatase 6 (DUSP6) and apoptosis‑related proteins (Bcl‑2, Bax, cleaved caspase‑3) were measured using reverse transcription‑quantitative polymerase chain reaction and western blot analysis. The target genes and potential binding sites of miR‑375 and DUSP6 were predicted using TargetScan and confirmed using dual‑luciferase reporter assay. The viability, migration, invasion and apoptosis of Dex‑treated AECs were further assessed with or without miR‑375 and DUSP6. In the AECs (9HTE cells), Dex treatment suppressed cell viability and miR‑375 expression, whereas it promoted cell apoptosis and the expression of DUSP6, the target gene of miR‑375. The overexpression of miR‑375 reversed the effects of Dex treatment on miR‑375 expression, cell viability, migration and invasion, and apoptosis‑related protein expression; in turn, these effects were reversed by the overexpression of DUSP6, with the exception of miR‑375 expression. On the whole, the present study demonstrates that the overexpression of miR‑375 counteracts the effects of Dex treatment on AEC viability, migration, invasion and apoptosis by targeting DUSP6. Thus, it was suggested that the downregulated expression of miR‑375 may be a therapeutic target for AEC dysfunction. Show less
A series of 10-alkoxy-Anthryl-isoxazole-pyrrole-doubletails (RO-AIMs) were synthesized using a crown ether assisted nucleophilic aromatic substitution followed by a modified Schotten-Baumann reaction. Show more
A series of 10-alkoxy-Anthryl-isoxazole-pyrrole-doubletails (RO-AIMs) were synthesized using a crown ether assisted nucleophilic aromatic substitution followed by a modified Schotten-Baumann reaction. The novel RO-AIMs described here exhibit robust growth inhibition for the human SNB19 CNS glioblastoma cell line, and biphenyl analog 8c had activity in the nanomolar regime, which represents the most efficacious compound in the AIM series to date. Computational modeling for RO-AIMs binding in a ternary complex with c-myc quadruplex DNA and its helicase DHX36 is presented which represents our current working hypothesis. Show less
Glioma is one of the most common intracranial malignancies that plagues people around the world. Despite current improvements in treatment, the prognosis of glioma is often unsatisfactory. Necroptosis Show more
Glioma is one of the most common intracranial malignancies that plagues people around the world. Despite current improvements in treatment, the prognosis of glioma is often unsatisfactory. Necroptosis is a form of programmed cell death. As research progresses, the role of necroptosis in tumors has gradually attracted the attention of researchers. And lncRNA is regarded as a critical role in the development of cancer. Therefore, this study is aimed at establishing a prognostic model based on necroptosis-associated lncRNAs to accurately assess the prognosis and immune response of patients with glioma. The RNA sequences of glioma patients and normal brain samples were downloaded from The Cancer Genome Atlas (TCGA) and GTEx databases, respectively. The coexpression analysis was performed to identify the necroptosis-related lncRNAs. Then, we utilized LASSO analysis following univariate Cox analysis to construct a prognostic model. Subsequently, we applied the Kaplan-Meier curve, time-dependent receiver operating characteristics (ROC), and univariate and multivariate Cox regression analyses to assess the effectiveness of this model. And the functional enrichment analyses and immune-related analyses were employed to investigate the potential biological functions. A validation set was obtained from the Chinese Glioma Genome Atlas (CGGA) database. And qRT-PCR was employed to further validate the expression levels of selected necroptosis-associated lncRNAs. Seven necroptosis-related lncRNAs (FAM13A-AS1, JMJD1C-AS1, LBX2-AS1, ZBTB20-AS4, HAR1A, SNHG14, and LINC00900) were determined to construct a prognostic model. The area under the ROC curve (AUC) was 0.871, 0.901, and 0.911 at 1, 2, and 3 years, respectively. The risk score was shown to be an important independent predictor in both univariate and multivariate Cox regression analyses. Through functional enrichment analyses, we found that the differentially expressed genes (DEGs) were mainly enriched in protein binding and signaling-related biological functions and immune-associated pathways. In conclusion, we established and validated a novel necroptosis-related lncRNA signature, which could accurately predict the overall survival of glioma patients and serve as potential therapeutic targets. Show less
Lysoforte (LFT) plays a vital role in maintaining broilers' health and intestinal morphology. However, the mechanism behind the effects of LFT improving intestinal morphology and health is still uncle Show more
Lysoforte (LFT) plays a vital role in maintaining broilers' health and intestinal morphology. However, the mechanism behind the effects of LFT improving intestinal morphology and health is still unclear. Therefore, this study was implemented to explore the central genes linked to the regulatory effect of LFT. Seventy-five newly hatched Cobb 500 male broilers were randomly divided into three groups: control, LFT500, and LFT1000 groups, with 25 chicks per group. The control chicks were provided with the basal diet, and the birds in LFT500 and LFT1000 groups were offered the same basal diet with 500 g/ton and 1,000 g/ton LFT, respectively. GSE94622 dataset consisted of the control and two LFT-treated groups (LFT500 and LFT1000). Jejuna samples were obtained from Gene Expression Omnibus (GEO). Totally 106-344 DEGs were obtained by comparing LFT500 and LFT1000 vs. control and LFT1000 vs. LFT500. Gene ontology (GO) enrichment suggested that the DEGs are mainly related to the phosphatidylethanolamine biosynthetic process and neuron projection extension. KEGG analysis suggested the DEGs were enriched in AGE-RAGE, fatty acid elongation, ECM-receptor interaction (ECMRI), glycerophospholipid metabolism, focal adhesion, unsaturated fatty acids biosynthesis, and ABC transporters. Moreover, 29 genes, such as Show less
Endothelial dysfunction is common in diabetes. Apolipoprotein (apo) A-IV functions to antagonize inflammation and oxidative stress. The present study aimed to investigate the relationship between flow Show more
Endothelial dysfunction is common in diabetes. Apolipoprotein (apo) A-IV functions to antagonize inflammation and oxidative stress. The present study aimed to investigate the relationship between flow-mediated dilation (FMD) and serum apoA-IV level in type 2 diabetes mellitus (T2DM) patients. METHODS: A total of 84 T2DM patients with chest discomfort were enrolled in this study. Their baseline characteristics and clinical parameters were documented. Endothelial function of the participants was evaluated by examining FMD of brachial artery. The severity of coronary atherosclerosis was determined by quantitative coronary angiography. Serum apoA-IV levels were measured by ELISA. These diabetic patients were dichotomized into low FMD (n = 42) and high FMD (n = 42) groups. Serum apoA-IV levels were significantly higher in high FMD group than in low FMD group (29.96 ± 13.17 vs 17.69 ± 9.16 mg/dL, P < 0.001). Moreover, the patients were also categorized into three apoA-IV tertile groups. FMD was significantly different across three apoA-IV tertiles (P < 0.001). Serum apoA-IV levels were positively correlated to FMD (r = 0.469, P < 0.001). Logistic regression analysis was performed to determine risk factors for low FMD. apoA-IV levels together with the risk factor hsCRP remained significantly to be independent determinants of low FMD (P < 0.01). Linear regression analysis was performed, and apoA-IV levels together with total-to-HDL cholesterol ratio were independently correlated with FMD (P < 0.01). Serum apoA-IV levels are associated with FMD, suggesting that apoA-IV protects endothelial function in patients with T2DM. Show less
The tripartite motif (TRIM) family of E3 ubiquitin ligases is well known for its roles in antiviral restriction and innate immunity regulation, in addition to many other cellular pathways. In particul Show more
The tripartite motif (TRIM) family of E3 ubiquitin ligases is well known for its roles in antiviral restriction and innate immunity regulation, in addition to many other cellular pathways. In particular, TRIM25-mediated ubiquitination affects both carcinogenesis and antiviral response. While individual substrates have been identified for TRIM25, it remains unclear how it regulates diverse processes. Here we characterized a mutation, R54P, critical for TRIM25 catalytic activity, which we successfully utilized to "trap" substrates. We demonstrated that TRIM25 targets proteins implicated in stress granule formation (G3BP1/2), nonsense-mediated mRNA decay (UPF1), nucleoside synthesis (NME1), and mRNA translation and stability (PABPC4). The R54P mutation abolishes TRIM25 inhibition of alphaviruses independently of the host interferon response, suggesting that this antiviral effect is a direct consequence of ubiquitination. Consistent with that, we observed diminished antiviral activity upon knockdown of several TRIM25-R54P specific interactors including NME1 and PABPC4. Our findings highlight that multiple substrates mediate the cellular and antiviral activities of TRIM25, illustrating the multi-faceted role of this ubiquitination network in modulating diverse biological processes. Show less
Traditional Chinese herbal medicine draws more attention to explore an effective therapeutic strategy for Alzheimer's disease (AD). Shenqi Yizhi granule (SQYG), a Chinese herbal recipe, has been appli Show more
Traditional Chinese herbal medicine draws more attention to explore an effective therapeutic strategy for Alzheimer's disease (AD). Shenqi Yizhi granule (SQYG), a Chinese herbal recipe, has been applied to ameliorate cognitive impairment in mild-to-moderate AD patients. However, the overall molecular mechanism of SQYG in treating AD has not been clarified. This study aimed to investigate the molecular mechanism of SQYG on AD using an integration strategy of network pharmacology and molecular docking. The active compounds of SQYG and common targets between SQYG and AD were screened from databases. The herb-compound network, compound-target network, and protein-protein interaction network were constructed. The enrichment analysis of common targets and molecular docking were performed. 816 compounds and 307 common targets between SQYG and AD were screened. KEGG analysis revealed that common targets were mainly enriched in lipid metabolism, metal ion metabolism, IL-17 signaling pathway, GABA receptor signaling, and neuroactive ligand-receptor interaction. Molecular docking analysis showed high binding affinity between ginsenoside Rg1 and A The therapeutic mechanisms of SQYG on AD were associated with regulating lipid metabolism, metal ion metabolism, IL-17 signaling pathway, and GABA receptor signaling. Ginsenoside Rg1, tanshinone IIA, baicalin, astragaloside IV, and folic acid may play an important role in AD treatment. Show less
Nelumbo nucifera (N. nucifera), a kind of edible Chinese herbal, has been studied in treating hyperlipidemia. However, the hypolipidemic mechanism of N. nucifera remains unknown. Aims of this review: Show more
Nelumbo nucifera (N. nucifera), a kind of edible Chinese herbal, has been studied in treating hyperlipidemia. However, the hypolipidemic mechanism of N. nucifera remains unknown. Aims of this review: We aimed to screen the effective constituent of N. nucifera alkaloids and elucidated the potential mechanism for treating hyperlipidemia. A triple combination strategy of UHPLC-MS We comprehensively investigated the characterization of N. nucifera alkaloids by using UHPLC-LTQ-Orbitrap MS 35 compounds were identified from N. nucifera alkaloid extraction by UHPLC-LTQ-Orbitrap MS O-nornuciferine and N. nucifera alkaloids had exibited significant effects in hyperlipidemia. The candidate genes were LDLR, LPL and ANGPTL4, etc. It was most likely that they adjusted lipid metabolism by modulating expression levels of various key factors which were involved in bile secretion, glycerolipid metabolism, sphingolipid metabolism and PPAR signaling pathway, and so on. This study clarified the hypolipidemic mechanism of the alkaloids in N. nucifera, and laid a foundation for the subsequent development of clinical application and better quality of N. nucifera. Show less
MicroRNAs (miRNAs) are one type of noncoding RNAs that interfere with mRNA translation to downregulate gene expression, which results in posttranscriptional gene silencing. Over the past two decades, Show more
MicroRNAs (miRNAs) are one type of noncoding RNAs that interfere with mRNA translation to downregulate gene expression, which results in posttranscriptional gene silencing. Over the past two decades, miRNAs have been widely reported to impact the progression of malignant tumours by interfering with cancer initiation and progression; therefore, miRNAs represent potential new diagnostic and therapeutic tools. miR-650 is a newly identified miR, and increasing studies have demonstrated that miR-650 plays critical roles in cancer progression, such as mediating the Wnt signalling pathway/AXIN1 (axis inhibition protein 1) axis in hepatocellular carcinoma. Nevertheless, associations between the expression patterns and molecular mechanisms of miR-650 in cancer have not been comprehensively described. In this article, we review the existing evidence regarding the mechanisms by which miR-650 expression is altered and their relation to cancer. Moreover, the promising clinical application of miR-650 for diagnosis and treatment is highlighted. Show less
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide, with high incidence and mortality rates and low survival rates. However, the detailed molecular mechanism of ESCC Show more
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide, with high incidence and mortality rates and low survival rates. However, the detailed molecular mechanism of ESCC progression remains unclear. Here, we first showed significantly higher WNT5A and SNAIL expression in ESCC samples than in corresponding paracancerous samples. High WNT5A and SNAIL expression levels correlated positively with lymphatic metastasis and poor prognosis for patients with ESCC based on immunohistochemical (IHC) staining of 145 paired ESCC samples. Spearman's correlation analyses confirmed the strong positive correlation between WNT5A and SNAIL expression, and patients with ESCC presenting coexpression of WNT5A and SNAIL had the worst prognosis. Then, we verified that the upregulation of WNT5A promoted ESCC cell metastasis in vivo and in vitro, suggesting that WNT5A might be a promising therapeutic target for the prevention of ESCC. Furthermore, WNT5A overexpression induced the epithelial-mesenchymal transition via histone deacetylase 7 (HDAC7) upregulation, and HDAC7 silencing significantly reversed WNT5A-induced SNAIL upregulation and ESCC cell metastasis. In addition, we used HDAC7 inhibitors (SAHA and TMP269) to further confirm that HDAC7 participates in WNT5A-mediated carcinogenesis. Based on these results, HDAC7 is involved in WNT5A-mediated ESCC progression, and approaches targeting WNT5A and HDAC7 might be potential therapeutic strategies for ESCC. Show less
Cistanche deserticola Ma (cistanche) is a traditional herb with a wide range of therapeutic properties. However, no evidence of cistanche's effect on adipogenesis has been found. The effect of cistanc Show more
Cistanche deserticola Ma (cistanche) is a traditional herb with a wide range of therapeutic properties. However, no evidence of cistanche's effect on adipogenesis has been found. The effect of cistanche that promotes the adipogenesis of 3T3-L1 preadipocytes was proved by using MTT spectrophotometry, Nile Red staining, Oil Red O staining and transcriptome sequencing technology. The mRNA level of key transcription factors for adipogenesis such as PPAR, AP2 and LPL were examined by RT-PCR. The results showed that the intracellular lipid content in cistanche treated cells were notably increased when compared with the non-treated cells. Between the differentiation and cistanche treated groups, the expression of adipogenesis related genes such as grow hormone releasing hormone (Ghrp), BCL2/adenovirus E1B interacting protein 3 (Bnip3) and Gastric inhibitory polypeptide receptor (Gipr) were significantly increased. Our findings also verified that cistanche promoted adipogenesis, which was accompanied by up-regulated level of Bnip3 and PPAR. This study could uncover new signaling pathways involved in adipogenesis regulation. Show less
Chronic pain is defined as pain that persists typically for a period of over six months. Chronic pain is often accompanied by an anxiety disorder, and these two tend to exacerbate each other. This can Show more
Chronic pain is defined as pain that persists typically for a period of over six months. Chronic pain is often accompanied by an anxiety disorder, and these two tend to exacerbate each other. This can make the treatment of these conditions more difficult. Glucose-dependent insulinotropic polypeptide (GIP) is a member of the incretin hormone family and plays a critical role in glucose metabolism. Previous research has demonstrated the multiple roles of GIP in both physiological and pathological processes. In the central nervous system (CNS), studies of GIP are mainly focused on neurodegenerative diseases; hence, little is known about the functions of GIP in chronic pain and pain-related anxiety disorders. The chronic inflammatory pain model was established by hind paw injection with complete Freund's adjuvant (CFA) in C57BL/6 mice. GIP receptor (GIPR) agonist (D-Ala In the present study, we found that hind paw injection with CFA induced pain sensitization and anxiety-like behaviors in mice. The expression of GIPR in the ACC was significantly higher in CFA-injected mice. D-Ala GIPR activation was found to produce analgesic and anxiolytic effects, which were partially due to attenuation of neuroinflammation and inhibition of excitatory transmission in the ACC. GIPR may be a suitable target for treatment of chronic inflammatory pain and pain-related anxiety. Show less
Epigenetic alteration is a pivotal factor in tumor metastasis. PHD finger protein 13 (PHF13) is a recently identified epigenetic reader of H3K4me2/3 that functions as a transcriptional co-regulator. I Show more
Epigenetic alteration is a pivotal factor in tumor metastasis. PHD finger protein 13 (PHF13) is a recently identified epigenetic reader of H3K4me2/3 that functions as a transcriptional co-regulator. In this study, we demonstrate that PHF13 is required for pancreatic-cancer-cell growth and metastasis. Integrative analysis of transcriptome and epigenetic profiles provide further mechanistic insights into the epigenetic regulation of genes associated with cell metastasis during the epithelial-to-mesenchymal transition (EMT) induced by transforming growth factor β (TGFβ). Our data suggest PHF13 depletion impairs activation of TGFβ stimulated genes and correlates with a loss of active epigenetic marks (H3K4me3 and H3K27ac) at these genomic regions. These observations argue for a dependency of TGFβ target activation on PHF13. Furthermore, PHF13-dependent chromatin regions are enriched in broad H3K4me3 domains and super-enhancers, which control genes critical to cancer-cell migration and invasion, such as SNAI1 and SOX9. Overall, our data indicate a functional and mechanistic correlation between PHF13 and EMT. Show less
Guillain-Barré syndrome (GBS) is an acute inflammatory autoimmune and demyelinating disease of the peripheral nervous system. Currently, valid biomarkers are unavailable for the diagnosis of GBS. A co Show more
Guillain-Barré syndrome (GBS) is an acute inflammatory autoimmune and demyelinating disease of the peripheral nervous system. Currently, valid biomarkers are unavailable for the diagnosis of GBS. A comparative proteomics analysis was performed on the cerebrospinal fluid (CSF) from 10 patients with GBS and 10 patients with noninflammatory neurological disease (NND) using the tandem mass tags technique. The differentially expressed proteins were analyzed by bioinformatics, and then the candidate proteins were validated by the enzyme-linked immunosorbent assay method in another cohort containing 160 samples (paired CSF and plasma of 40 patients with GBS, CSF of 40 NND patients and plasma of 40 healthy individuals). In all, 298 proteins were successfully identified in the CSF samples, of which 97 differentially expressed proteins were identified in the GBS and NND groups. Three key molecules were identified as candidate molecules for further validation. The CSF levels of TGOLN2 and NCAM1 decreased in GBS patients compared with NND patients, whereas the CSF levels of APOC3 increased. The enzyme-linked immunosorbent assay results were consistent with our proteomics analysis. Interestingly, in the validation cohort, serum APOC3 levels in the GBS group were consistent with those in the CSF samples and significantly higher than those in the healthy control group. Our preliminary data suggest that the CSF protein expression profile of patients with GBS is different from that of patients with NND. Moreover, alterations of TGOLN2, NCAM1and APOC3 may be used as novel biomarkers for identifying patients with GBS. Show less
Thyroid carcinoma is the most prevalent endocrine cancer globally and the primary cause of cancer-related mortality. Epigenetic modifications are progressively being linked to metastasis. This study a Show more
Thyroid carcinoma is the most prevalent endocrine cancer globally and the primary cause of cancer-related mortality. Epigenetic modifications are progressively being linked to metastasis. This study aimed to examine whole-genome DNA methylation patterns and the gene expression profiles in thyroid cancer tissue samples using a MethylationEPIC BeadChip (850K), RNA sequencing, and a targeted bisulfite sequencing assay. The results of the Illumina Infinium human methylation kit (850K) analyses identified differentially methylated CpG locations (DMPs) and differentially methylated CpG regions (DMRs) encompassing nearly the entire genome with high resolution and depth. Gene ontology and KEGG pathway analyses revealed that the genes associated with DMRs belonged to various domain-specific ontologies, including cell adhesion, molecule binding, and proliferation. The RNA-Seq study found 1627 differentially expressed genes, 1174 of which that were up-regulated and 453 of which that were down-regulated. The targeted bisulfite sequencing assay revealed that CHST2, DPP4, DUSP6, ITGA2, SLC1A5, TIAM1, TNIK, and ABTB2 methylation levels were dramatically lowered in thyroid cancer patients when compared to the controls, but GALNTL6, HTR7, SPOCD1, and GRM5 methylation levels were significantly raised. Our study revealed that the whole-genome DNA methylation patterns and gene expression profiles in thyroid cancer shed new light on the tumorigenesis of thyroid cancer. Show less