Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1), a negative regulator of oligodendrocyte differentiation and myelination, is associated with Show more
Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1), a negative regulator of oligodendrocyte differentiation and myelination, is associated with cognitive function, and its expression is highly upregulated in Alzheimer's disease (AD) patients. Anti-LINGO-1 antibody treatment can effectively antagonize the negative regulatory effect of LINGO-1. In this study, we aim to assess the effect of anti-LINGO-1 antibody treatment on cognition and hippocampal oligodendrocytes in an AD transgenic animal model. First, 10-month-old male amyloid-β (Aβ) protein precursor (APP)/presenilin 1 (PS1) mice were administered anti-LINGO-1 antibody for 8 weeks. Then, learning and memory abilities were assessed with the Morris water maze (MWM) and Y-maze tests, and Aβ deposition and hippocampal oligodendrocytes were investigated by immunohistochemistry, immunofluorescence, and stereology. We found that anti-LINGO-1 antibody alleviated the deficits in spatial learning and memory abilities and working and reference memory abilities, decreased the density of LINGO-1 positive cells, decreased Aβ deposition, significantly increased the number of mature oligodendrocytes and the density of myelin, reversed the abnormal increases in the number of oligodendrocyte lineage cells and the densities of oligodendrocytes precursor cells in APP/PS1 mice. Our results provide evidence that LINGO-1 might be involved in the process of oligodendrocyte dysmaturity in the hippocampus of AD mice, and that antagonizing LINGO-1 can alleviate cognitive deficits in APP/PS1 mice and decrease Aβ deposition and promote oligodendrocyte differentiation and maturation in the hippocampus of these mice. Our findings suggest that changes in LINGO-1 and oligodendrocytes in the hippocampus play important roles in the pathogenesis of AD and that antagonizing LINGO-1 might be a potential therapeutic strategy for AD. Show less
Deregulated Wnt/β-catenin signaling is one of the main genetic alterations in human hepatocellular carcinoma (HCC). Comprehensive genomic analyses have revealed that gain-of-function mutation of CTNNB Show more
Deregulated Wnt/β-catenin signaling is one of the main genetic alterations in human hepatocellular carcinoma (HCC). Comprehensive genomic analyses have revealed that gain-of-function mutation of CTNNB1, which encodes β-catenin, and loss-of-function mutation of AXIN1 occur in approximately 35% of human HCC samples. Human HCCs with activation of the Wnt/β-catenin pathway demonstrate unique gene expression patterns and pathological features. Activated Wnt/β-catenin synergizes with multiple signaling cascades to drive HCC formation, and it functions through its downstream effectors. Therefore, strategies targeting Wnt/β-catenin have been pursued as possible therapeutics against HCC. Here, we review the genetic alterations and oncogenic roles of aberrant Wnt/β-catenin signaling during hepatocarcinogenesis. In addition, we discuss the implication of this pathway in HCC diagnosis, classification, and personalized treatment. Show less
Fat deposition is a complex economic trait regulated by polygenic genetic basis and environmental factors. Therefore, integrating multi-omics data to uncover its internal regulatory mechanism has attr Show more
Fat deposition is a complex economic trait regulated by polygenic genetic basis and environmental factors. Therefore, integrating multi-omics data to uncover its internal regulatory mechanism has attracted extensive attention. Here, we performed genomics and transcriptomics analysis to detect candidates affecting subcutaneous fat (SCF) deposition in beef cattle. The association of 770K SNPs with the backfat thickness captured nine significant SNPs within or near 11 genes. Additionally, 13 overlapping genes regarding fat deposition were determined via the analysis of differentially expressed genes and weighted gene co-expression network analysis (WGCNA). We then calculated the correlations of these genes with BFT and constructed their interaction network. Finally, seven biomarkers including ACACA, SCD, FASN, ACOX1, ELOVL5, HACD2, and HSD17B12 were screened. Notably, ACACA, identified by the integration of genomics and transcriptomics, was more likely to exert profound effects on SCF deposition. These findings provided novel insights into the regulation mechanism underlying bovine fat accumulation. Show less
Acute lung injury (ALI) represents a frequent sepsis-induced inflammatory disorder. Mesenchymal stromal cells (MSCs) elicit anti-inflammatory effects in sepsis. This study investigated the mechanism o Show more
Acute lung injury (ALI) represents a frequent sepsis-induced inflammatory disorder. Mesenchymal stromal cells (MSCs) elicit anti-inflammatory effects in sepsis. This study investigated the mechanism of exosomes from adipose-derived MSCs (ADMSCs) in sepsis-induced ALI. The IL-27r Show less
Acetylcholine (ACh) and norepinephrine (NE) are representative neurotransmitters of parasympathetic and sympathetic nerves, respectively, that antagonize each other to coregulate internal body functio Show more
Acetylcholine (ACh) and norepinephrine (NE) are representative neurotransmitters of parasympathetic and sympathetic nerves, respectively, that antagonize each other to coregulate internal body functions. This also includes the control of different kinds of hormone secretion from pancreatic islets. However, the molecular mechanisms have not been fully elucidated, and whether innervation in islets is abnormal in diabetes mellitus also remains unclear. Immunofluorescence colocalization and islet perfusion were performed and the results demonstrated that ACh/NE and their receptors were highly expressed in islet and rapidly regulated different hormones secretion. Phosphorylation is considered an important posttranslational modification in islet innervation and it was identified by quantitative proteomic and phosphoproteomic analyses in this study. The phosphorylated islet proteins were found involved in many biological and pathological processes, such as synaptic signalling transduction, calcium channel opening and insulin signalling pathway. Then, the kinases were predicted by motif analysis and further screened and verified by kinase-specific siRNAs in different islet cell lines (αTC1-6, Min6 and TGP52). After functional verification, Ksr2 and Pkacb were considered the key kinases of ACh and NE in insulin secretion, and Cadps, Mlxipl and Pdcd4 were the substrates of these kinases measured by immunofluorescence co-staining. Then, the decreased expression of receptors, kinases and substrates of ACh and NE were found in diabetic mice and the aberrant rhythm in insulin secretion could be improved by combined interventions on key receptors (M3 (pilocarpine) or α2a (guanfacine)) and kinases (Ksr2 or Pkacb). Abnormal innervation was closely associated with the degree of islet dysfunction in diabetic mice and the aberrant rhythm in insulin secretion could be ameliorated significantly after intervention with key receptors and kinases in the early stage of diabetes mellitus, which may provide a promising therapeutic strategy for diabetes mellitus in the future. Show less
S-adenosyl-l-homocysteine (SAH), an amino acid derivative, is a key intermediate metabolite in methionine metabolism, which is normally considered as a harmful by-product and hydrolyzed quickly once f Show more
S-adenosyl-l-homocysteine (SAH), an amino acid derivative, is a key intermediate metabolite in methionine metabolism, which is normally considered as a harmful by-product and hydrolyzed quickly once formed. AHCY (adenosylhomocysteinase) converts SAH into homocysteine and adenosine. There are two other members in the AHCY family, AHCYL1 (adenosylhomocysteinase like 1) and AHCYL2 (adenosylhomocysteinase like 2). Here we define AHCYL1 function as a SAH sensor to inhibit macroautophagy/autophagy through PIK3C3. The C terminus of AHCYL1 interacts with SAH specifically and the interaction with SAH promotes the binding of the N terminus to the catalytic domain of PIK3C3, resulting in inhibition of PIK3C3. More importantly, this observation was further validated 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
A new label-free method was developed for SERS detection of human apolipoprotein A4. Rolling circle amplification (RCA) was used, which could induce the production of AuNPs (poly adenine and adsorptio Show more
A new label-free method was developed for SERS detection of human apolipoprotein A4. Rolling circle amplification (RCA) was used, which could induce the production of AuNPs (poly adenine and adsorption gold nanoparticles). When there were two DNA labeled antibodies and target protein, MB1 (molecular beacon 1) was unfolded and the substrate was modified in the homogeneous solution, and the proximate complex was formed. The unfolded molecular beacon worked as a primer in the hybridization with the RCA template to start RCA, which could produce many long sequences of DNA containing amounts of adenines. The AuNPs were bound with the long-repeated adenine in the RCA product, causing accumulation of AuNPs on the surface of the electrode. It was indicated that the spectral characteristics of adenine at 736 cm Show less
Advanced glycation end products (AGEs) are stable products produced by the reaction of macromolecules such as proteins, lipids or nucleic acids with glucose or other reducing monosaccharides, which ca Show more
Advanced glycation end products (AGEs) are stable products produced by the reaction of macromolecules such as proteins, lipids or nucleic acids with glucose or other reducing monosaccharides, which can be identified by immunohistochemistry in the senile plaques and neurofibrillary tangles of Alzheimer's disease (AD) patients. Growing evidence suggests that AGEs are important risk factors for the development and progression of AD. 1,8-cineole (CIN) is a monoterpenoid compound which exists in many plant essential oils and has been proven to have neuroprotective activity, but its specific effect and molecular mechanisms are not clear. In this study, AGEs-induced neuronal injury and intracerebroventricular-AGE animals as the possible models for AD were employed to investigate the effects of CIN on AD pathology as well as the molecular mechanisms involved both in vivo and in vitro. Our study demonstrated that CIN could ameliorate tau phosphorylation by down-regulating the activity of GSK-3β and reducing Aβ production by inhibiting the activity of BACE-1 both in vivo and in vitro. It is suggested that CIN has certain therapeutic value in the treatment of AD. Show less
The Lauren classification of gastric tumors strongly correlates with prognosis. The purpose of this study was to explore the specific molecular mechanism of Lauren classification of gastric cancer and Show more
The Lauren classification of gastric tumors strongly correlates with prognosis. The purpose of this study was to explore the specific molecular mechanism of Lauren classification of gastric cancer and provide a possible theoretical basis for the treatment of gastric cancer. We standardized the gene expression data of five Gene Expression Omnibus gastric cancer databases and constructed a Weighted Co-expression Network Analysis (WGCNA) model based on clinicopathological information. The overall survival (OS) and disease-free survival (DFS) curves were extracted from the Cancer Genome Atlas (TCGA) and GSE62254 databases. Western blotting was used to measure protein expression in cells and tissues. Scratch and transwell experiments were used to test the migration ability of tumor cells. Immunohistochemistry was used to measure tissue protein expression in clinical tissue samples to correlate to survival data. The WGCNA model demonstrated that blue cyan was highly correlated with the Lauren classification of the tumor (r = 0.24, P = 7 × 10 LMOD1 is an oncogene associated with diffuse gastric cancer and can affect the occurrence and development of EMT by regulating the FAK-Akt/mTOR pathway. LMOD1 can therefore promote peritoneal metastasis of gastric cancer cells and can be used as a novel therapeutic target for gastric cancer. 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
Walnut kernel, a well-known TCM, is often used after being defatted in tradition. And defatted walnut powder extract (DWPE) has the actions of tonifying the liver and kidney, dissipating stagnation an Show more
Walnut kernel, a well-known TCM, is often used after being defatted in tradition. And defatted walnut powder extract (DWPE) has the actions of tonifying the liver and kidney, dissipating stagnation and removing blood stasis, which has the effect on non-alcoholic fatty liver disease (NAFLD). However, the effective components of DWPE in vivo were unclear and the multiple mechanisms of DWPE against NAFLD have not been explored. The studies were performed to screen the effective substances in vivo by identification of the metabolites of DWPE in rats and to seek the potential mechanisms of DWPE on NAFLD by construction of the network pharmacology based on metabolites and verification of the highly correlated pathway. To explore the effective substances in vivo, the metabolites of DWPE were identified in SD rats' bio-samples through UPLC-Q-Exactive Orbitrap MS. To analyze the mechanisms of DWPE on NAFLD, a Metabolite-Target-Disease network was established and the potential mechanisms were predicted. Then, highly correlated pathway was verified in animal and cells studies. A total of 52 metabolites of DWPE were identified in vivo, which were derived from gallic acid, ellagic acid (EA) and glansreginin A (Gla A). The possible metabolic pathways were phase Ⅰ (hydroxylation, hydrolyzation, etc) and phase Ⅱ metabolic reactions (methylation, sulfation and glucuronidation). Furthermore, in the network pharmacology, 54 core targets were enriched into pathways in cancer, nitrogen metabolism and other 9 pathways, which were essential pathways of DWPE against NAFLD. And the mechanism of nitrogen metabolism was verified in both of animal and cells studies. The results showed that DWPE could decline the concentration of ammonia and increase the expressions of carbonic anhydrase 2 (CA2) and carbamoylphosphate synthetase (CPS1) in nitrogen metabolism. Taken together, the study revealed the absorption components and their metabolic pathways and demonstrated the mechanism of nitrogen metabolism of DWPE on anti-NAFLD. Show less
As the most prevalent aboriginal group on Hainan Island located between South China and the mainland of Southeast Asia, the Li people are believed to preserve some unique genetic information due to th Show more
As the most prevalent aboriginal group on Hainan Island located between South China and the mainland of Southeast Asia, the Li people are believed to preserve some unique genetic information due to their isolated circumstances, although this has been largely uninvestigated. We performed the first whole-genome sequencing of 55 Hainan Li (HNL) individuals with high coverage (∼30-50×) to gain insight into their genetic history and potential adaptations. We identified the ancestry enriched in HNL (∼85%) is well preserved in present-day Tai-Kadai speakers residing in South China and North Vietnam, that is, Bai-Yue populations. A lack of admixture signature due to the geographical restriction exacerbated the bottleneck in the present-day HNL. The genetic divergence among Bai-Yue populations began ∼4,000-3,000 years ago when the proto-HNL underwent migration and the settling of Hainan Island. Finally, we identified signatures of positive selection in the HNL, some outstanding examples included FADS1 and FADS2 related to a diet rich in polyunsaturated fatty acids. In addition, we observed that malaria-driven selection had occurred in the HNL, with population-specific variants of malaria-related genes (e.g., CR1) present. Interestingly, HNL harbors a high prevalence of malaria leveraged gene variants related to hematopoietic function (e.g., CD3G) that may explain the high incidence of blood disorders such as B-cell lymphomas in the present-day HNL. The results have advanced our understanding of the genetic history of the Bai-Yue populations and have provided new insights into the adaptive scenarios of the Li people. Show less
Nausea is a discomforting sensation of gut malaise that remains a major clinical challenge. Several visceral poisons induce nausea through the area postrema, a sensory circumventricular organ that det Show more
Nausea is a discomforting sensation of gut malaise that remains a major clinical challenge. Several visceral poisons induce nausea through the area postrema, a sensory circumventricular organ that detects bloodborne factors. Here, we use genetic approaches based on an area postrema cell atlas to reveal inhibitory neurons that counteract nausea-associated poison responses. The gut hormone glucose insulinotropic peptide (GIP) activates area postrema inhibitory neurons that project locally and elicit inhibitory currents in nausea-promoting excitatory neurons through γ-aminobutyric acid (GABA) receptors. Moreover, GIP blocks behavioral responses to poisons in wild-type mice, with protection eliminated by targeted area postrema neuron ablation. These findings provide insights into the basic organization of nausea-associated brainstem circuits and reveal that area postrema inhibitory neurons are an effective pharmacological target for nausea intervention. Show less
Previous studies have shown that microtubule actin crosslinking factor 1 (MACF1) can regulate osteoblast proliferation and differentiation through non-coding RNA (ncRNA) in bone-forming osteoblasts. H Show more
Previous studies have shown that microtubule actin crosslinking factor 1 (MACF1) can regulate osteoblast proliferation and differentiation through non-coding RNA (ncRNA) in bone-forming osteoblasts. However, the role of MACF1 in targeting the competing endogenous RNA (ceRNA) network to regulate osteoblast differentiation remains poorly understood. Here, we profiled messenger RNA (mRNA), microRNA (miRNA), and long ncRNA (lncRNA) expression in MACF1 knockdown MC3TC‑E1 pre‑osteoblast cells. In total, 547 lncRNAs, 107 miRNAs, and 376 mRNAs were differentially expressed. Significantly altered lncRNAs, miRNAs, and mRNAs were primarily found on chromosome 2. A lncRNA-miRNA-mRNA network was constructed using a bioinformatics computational approach. The network indicated that mir-7063 and mir-7646 were the most potent ncRNA regulators and mef2c was the most potent target gene. Pathway enrichment analysis showed that the fluid shear stress and atherosclerosis, p53 signaling, and focal adhesion pathways were highly enriched and contributed to osteoblast proliferation. Importantly, the fluid shear stress and atherosclerosis pathway was co-regulated by lncRNAs and miRNAs. In this pathway, Dusp1 was regulated by AK079370, while Arhgef2 was regulated by mir-5101. Furthermore, Map3k5 was regulated by AK154638 and mir-466q simultaneously. AK003142 and mir-3082-5p as well as Ak141402 and mir-446 m-3p were identified as interacting pairs that regulate target genes. This study revealed the global expression profile of ceRNAs involved in the differentiation of MC3TC‑E1 osteoblasts induced by MACF1 deletion. These results indicate that loss of MACF1 activates a comprehensive ceRNA network to regulate osteoblast proliferation. Show less
Pulmonary fibrosis initiates a pneumonic cascade that leads to fibroblast dysfunction characterized by excess proliferation. Anoikis is a physiological process that ensures tissue development and home Show more
Pulmonary fibrosis initiates a pneumonic cascade that leads to fibroblast dysfunction characterized by excess proliferation. Anoikis is a physiological process that ensures tissue development and homeostasis. Researchers have not clearly determined whether disruption of anoikis is involved in pulmonary fibrosis. Here, we investigated the mechanism by which silica induces fibroblast activation via anoikis resistance and subsequent fibrosis. Anoikis of lung fibroblasts, alveolar epithelial cells and endothelial cells during the process of fibrosis was detected using CCK-8, western blot, cell count and flow cytometry (FCM) assays. Although the three cell types showed similar increases in proliferation, the expression of NTRK2, a marker of anoikis resistance, was upregulated specifically in fibroblasts, indicating the unique proliferation mechanism of fibroblasts in pulmonary fibrosis, which may be related to anoikis resistance. Furthermore, the CRISPR/Cas9 system was used to investigate the molecular mechanism of anoikis resistance; the SiO The current study revealed a specific pattern of fibroblast proliferation, and strategies targeting anoikis resistance may inhibit the pathological process of pulmonary fibrosis. This result provides a new approach for treating pulmonary fibrosis and new insights into the potential application of ZC3H4 in the development of novel therapeutic strategies for mitigating pulmonary fibrosis. Show less
Breast cancer has become the malignancy with the highest mortality rate in female patients worldwide. The limited efficacy of immunotherapy as a breast cancer treatment has fueled the development of r Show more
Breast cancer has become the malignancy with the highest mortality rate in female patients worldwide. The limited efficacy of immunotherapy as a breast cancer treatment has fueled the development of research on the tumor immune microenvironment. In this study, data on breast cancer patients were collected from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohorts. Differential gene expression analysis, univariate Cox regression analysis, and least absolute shrinkage and selection operator (LASSO) Cox regression analysis were performed to select overall survival (OS)-related, tumor tissue highly expressed, and immune- and inflammation-related genes. A tumor immune-inflammation signature (TIIS) consisting of 18 genes was finally screened out in the LASSO Cox regression model. Model performance was assessed by time-dependent receiver operating characteristic (ROC) curves. In addition, the CIBERSORT algorithm and abundant expression of immune checkpoints were utilized to clarify the correlation between the risk signature and immune landscape in breast cancer. Furthermore, the association of IL27 with the immune signature was analyzed in pan-cancer and the effect of IL27 on the migration of breast cancer cells was investigated since the regression coefficient of IL27 was the highest. A TIIS based on 18 genes was constructed The TIIS represents a promising prognostic tool for estimating OS in patients with breast cancer and is correlated with immune status. 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
Hyperbilirubinemia is a serious hazard to human health due to its neurotoxicity and lethality. So far, successful therapy for hyperbilirubinemia with fewer side effects is still lacking. In this study Show more
Hyperbilirubinemia is a serious hazard to human health due to its neurotoxicity and lethality. So far, successful therapy for hyperbilirubinemia with fewer side effects is still lacking. In this study, we aimed to clarify the effects of oridonin (Ori), an active diterpenoid extracted from Rabdosia rubescens, on hyperbilirubinemia and revealed the underlying molecular mechanism in vivo and in vitro. Here, we showed that liver X receptor alpha (LXRα) deletion eliminated the protective effect of Ori on phenylhydrazine hydrochloride-induced hyperbilirubinemia mice, indicating that LXRα acted as a key target for Ori treatment of hyperbilirubinemia. Ori significantly increased the expression of LXRα and UDP-glucuronosyltransferase 1A1 (UGT1A1) in the liver of wild-type (WT) mice, which were lost in LXRα Show less
Biofilm-immobilized continuous fermentation is a novel fermentation strategy that has been utilized in ethanol fermentation. Continuous fermentation contributes to the self-proliferation of Saccharomy Show more
Biofilm-immobilized continuous fermentation is a novel fermentation strategy that has been utilized in ethanol fermentation. Continuous fermentation contributes to the self-proliferation of Saccharomyces cerevisiae biofilms. Previously, we successfully described the cell cycle differences between biofilm-immobilized fermentation and calcium alginate-immobilized fermentation. In the present study, we investigated the relationship between biofilm formation and the cell cycle. We knocked down Show less
Runs of heterozygosity (ROHet) and homozygosity (ROH) harbor useful information related to traits of interest. There is a lack of investigating the effect of ROHet and ROH on reproductive success and Show more
Runs of heterozygosity (ROHet) and homozygosity (ROH) harbor useful information related to traits of interest. There is a lack of investigating the effect of ROHet and ROH on reproductive success and the loss of reproduction in mammals. Here, we detected and characterized the ROHet and ROH patterns in the genomes of Chinese indigenous pigs (i.e., Jinhua, Chun'an, Longyou Black, and Shengxian Spotted pigs), revealing the similar genetic characteristics of indigenous pigs. Later, we highlighted the underlying litter traits-related ROHet and ROH using association analysis with linear model in these four indigenous pig breeds. To pinpoint the promising candidate genes associated with litter traits, we further in-depth explore the selection patterns of other five pig breeds (i.e., Erhualian, Meishan, Minzhu, Rongchang, and Diqing pigs) with different levels of reproduction performance at the underlying litter traits-related ROHet and ROH using Show less
MicroRNAs (miRNAs) play an important role in the pathogenesis of atrial fibrillation (AF). Exosomal miRNAs may develop as promising biomarkers for AF. To explore significant exosomal miRNAs in AF, pla Show more
MicroRNAs (miRNAs) play an important role in the pathogenesis of atrial fibrillation (AF). Exosomal miRNAs may develop as promising biomarkers for AF. To explore significant exosomal miRNAs in AF, plasma exosomes were extracted from 3 patients with AF and 3 patients with sinus rhythm (SR), respectively. Differential expression of exosomal miRNAs were screened by high-throughput sequencing analysis and verified by qRT-PCR from 40 patients with AF and 40 patients with SR. The target genes prediction, biological function, and signaling pathways analysis were conducted by miRanda software, gene ontology (GO), and KEGG analysis. The results showed that there were 40 differently expressed exosomal miRNAs from AF patients compared with SR patients, of which 13 miRNAs were upregulated and 27 miRNAs were downregulated. qRT-PCR validation demonstrated that miR-124-3p, miR-378d, miR-2110, and miR-3180-3p were remarkably upregulated, while miR-223-5p, miR-574-3p, miR-125a-3p, and miR-1299 were downregulated. To explore the function of miR-124-3p associated with AF, plasma exosomes derived from AF patients were co-incubated with rat myocardial fibroblasts. The expression of miR-124-3p was upregulated in myocardial fibroblasts. The viability and proliferation of myocardial fibroblasts were elevated by transfecting with miR-124-3p overexpression plasmids using CCK8 and immunofluorescence-staining methods. AXIN1 was verified to be the target of miR-124-3p by luciferase assay in vitro. Expression of AXIN1 was reduced, while β-catenin, Collagen 1, and α-SMA were increased in myocardial fibroblasts with miR-124-3p overexpression. In conclusion, these findings suggested that circulating exosomal miRNAs may serve as novel biomarkers for AF, and miR-124-3p promotes fibroblast activation and proliferation through regulating WNT/β-catenin signaling pathway via AXIN1. Show less
Alzheimer's disease is a global public health problem and the most common form of dementia. Due to the failure of many single therapies targeting the two hallmarks, Aβ and Tau, and the multifactorial Show more
Alzheimer's disease is a global public health problem and the most common form of dementia. Due to the failure of many single therapies targeting the two hallmarks, Aβ and Tau, and the multifactorial etiology of AD, there is now more and more interest in nutraceutical agents with multiple effects such as Show less
Methionine or lysine has been reported to influence DNA methylation and fat metabolism, but their combined effects in N6-methyl-adenosine (m The results showed that the addition of RML in a LP diet te Show more
Methionine or lysine has been reported to influence DNA methylation and fat metabolism, but their combined effects in N6-methyl-adenosine (m The results showed that the addition of RML in a LP diet tended to lower the concentrations of plasma leptin (P = 0.07), triglyceride (P = 0.05), and non-esterified FA (P = 0.08). Feeding a LP diet increased the enzyme activity or mRNA expression of lipogenic enzymes and decreased lipolytic enzymes compared with the NP diet. This effect was reversed by supplementation of RML with a LP diet. The inclusion of RML in a LP diet affected the polyunsaturated fatty acids (PUFA), n-3 PUFA, and n-6 PUFA in the liver but not in the muscle, which might be linked with altered expression of FA desaturase-1 (FADS1) and acetyl-CoA carboxylase (ACC). A LP diet supplemented with RML increased (P < 0.05) total m Our findings showed that the inclusion of RML in a LP diet could alter fat deposition through modulations of lipogenesis and lipolysis in the liver and muscle. These changes in fat metabolism may be associated with the modification of m Show less
In this study, we evaluated the roles of heat-induced circEZH2 in the regulation of milk fat metabolism. CircEZH2 overexpression increased HC11 cell proliferation and decreased apoptosis. These change Show more
In this study, we evaluated the roles of heat-induced circEZH2 in the regulation of milk fat metabolism. CircEZH2 overexpression increased HC11 cell proliferation and decreased apoptosis. These changes were accompanied by increased expression of proliferation marker proteins (PCNA, Cyclin D, and Cyclin E) and the anti-apoptotic protein Bcl2, while expression of the pro-apoptotic proteins Bax and cleaved-caspase was reduced. SiRNA-mediated silencing of EZH2 in HC11 cells had the opposite effects. CircEZH2 overexpression promoted the uptake of a fluorescent fatty acid (Bodipy) as well as expression of the fatty acid transport-related protein CD36, lipolysis-related protein LPL, and unsaturated fatty acid metabolism-related proteins FADS1 and SCD1. Dual luciferase reporter assays verified the targeting relationship of the two ceRNA networks, circEZH2-miR378b-LPL and circEZH2-miR378b-CD36. This information provides further clarification of the role of circRNAs in milk fat regulation in addition to a theoretical basis for alleviating the effects of heat stress on milk production by dairy cows. Show less
Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder characterized by hyperammonaemia. The biochemical measurement of the intermediate metabolites is h Show more
Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder characterized by hyperammonaemia. The biochemical measurement of the intermediate metabolites is helpful for CPS1D diagnosis; it however cannot distinguish CPS1D from N-acetylglutamate synthetase deficiency. Therefore, next-generation sequencing (NGS) is often essential for the accurate diagnosis of CPS1D. NGS was performed to identify candidate gene variants of CPS1D in a Asian neonatal patient presented with poor feeding, reduced activity, tachypnea, lethargy, and convulsions. The potential pathogenicity of the identified variants was predicted by various types of bioinformatical analyses, including evolution conservation, domain and 3D structure simulations. Compound heterozygosity of CPS1D were identified. One was in exon 24 with a novel heterozygous missense variant c.2947C > T (p.P983S), and another was previously reported in exon 20 with c.2548C > T (p.R850C). Both variants were predicted to be deleterious. Conservation analysis and structural modeling showed that the two substituted amino acids were highly evolutionarily conserved, resulting in potential decreases of the binding pocket stability and the partial loss of enzyme activity. In this study, two pathogenic missense variants were identified with NGS, expanding the variants pectrum of the Show less
Lung cancer is one of the top causes of cancer-related death worldwide. Cellular senescence is a characteristic of cell cycle arrest that plays a role in carcinogenesis and immune microenvironment mod Show more
Lung cancer is one of the top causes of cancer-related death worldwide. Cellular senescence is a characteristic of cell cycle arrest that plays a role in carcinogenesis and immune microenvironment modulation. Despite this, the clinical and immune cell infiltration features of senescence in lung squamous cell carcinoma (LUSC) are unknown. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were used to get RNA-seq data and clinical information for LUSC. The least absolute shrinkage and selection operator (LASSO)-Cox regression, receiver operating characteristic (ROC), and Kaplan-Meier analysis were used to evaluate a risk model for predicting overall survival based on six differentially expressed genes. The tumor microenvironment (TME) and immunotherapy response were also studied. To discriminate LUSC into high- and low-risk subgroups, a risk model comprised of six cellular senescence-related genes (CDKN1A, CEBPB, MDH1, SIX1, SNAI1, and SOX5) was developed. The model could stratify patients into high-risk and low-risk groups, according to ROC and Kaplan-Meier analysis. In the TCGA-LUSC and GSE73403 cohorts, the high-risk group had a worse prognosis (P<0.05), and was associated with immune cell inactivation and being insensitive to immunotherapy in IMvigor210. We discovered a new LUSC classification based on six cellular senescence-related genes, which will aid in identifying patients who will benefit from anti-PD-1 treatment. Targeting senescence-related genes appears to be another option for improving clinical therapy for LUSC. Show less
Glucocorticoids, adrenal-derived steroid hormones, facilitate the physiological response to stress. High-density lipoproteins (HDL) are considered the primary source of cholesterol used for glucocorti Show more
Glucocorticoids, adrenal-derived steroid hormones, facilitate the physiological response to stress. High-density lipoproteins (HDL) are considered the primary source of cholesterol used for glucocorticoid synthesis in mice. Phospholipid transfer protein (PLTP) is a key player in HDL formation. In the current study we tested the hypothesis that HDL deficiency associated with genetic lack of PLTP negatively impacts the adrenal steroid function. We determined the glucocorticoid response to overnight food deprivation stress and the adrenal lipid and genetic phenotype of wild-type and PLTP knockout mice. Basal plasma corticosterone levels, adrenal weights, and adrenocortical neutral lipid stores were not different between wild-type and PLTP knockout mice. Strikingly, plasma corticosterone levels were also equally high in the two groups of mice under fasting conditions (two-way ANOVA genotype effect: P>0.05). However, compensatory mechanisms were active to overcome adrenal lipid depletion, since gene expression levels of cholesterol synthesis, acquisition and mobilization proteins were ~2-fold higher in PLTP knockout adrenals versus wild-type adrenals. In support of an overall similar glucocorticoid stress response, hepatic relative mRNA expression levels of the glucocorticoid receptor target/glucocorticoid-sensitive genes PEPCK, ANGPTL4, FGF21, TDO2 and HMGCS2 were also not different. We have shown that hypocholesterolemic PLTP knockout mice exhibit a normal glucocorticoid response to food deprivation. These novel data (1) highlight that the effect of HDL deficiency on adrenal glucocorticoid output in mice is model dependent and (2) imply that other (lipoprotein) cholesterol sources than HDL can also generate the pool utilized by adrenocortical cells to synthesize glucocorticoids. Show less
WWP2 is a HECT-type E3 ubiquitin ligase that regulates various physiological and pathological activities by binding to different substrates, but its role in atherosclerosis (AS) remains largely unknow Show more
WWP2 is a HECT-type E3 ubiquitin ligase that regulates various physiological and pathological activities by binding to different substrates, but its role in atherosclerosis (AS) remains largely unknown. The objective of the present study is to investigate the role and underlying molecular mechanisms of WWP2 in endothelial injury. We found that WWP2 expression is significantly decreased in Apolipoprotein E (ApoE) Show less