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
Single nucleotide polymorphisms that affect RNA modification (RNAm-SNPs) may have functional roles in coronary artery disease (CAD). The aim of this study was to identify RNAm-SNPs in CAD susceptibili Show more
Single nucleotide polymorphisms that affect RNA modification (RNAm-SNPs) may have functional roles in coronary artery disease (CAD). The aim of this study was to identify RNAm-SNPs in CAD susceptibility loci and highlight potential risk factors. CAD-associated RNAm-SNPs were identified in the CARDIoGRAMplusC4D and UK Biobank genome-wide association studies. Gene expression and circulating protein levels affected by the RNAm-SNPs were identified by QTL analyses. Cell experiments and Mendelian randomization (MR) methods were applied to test whether the gene expression levels were associated with CAD. We identified 81 RNAm-SNPs that were associated with CAD or acute myocardial infarction (AMI), including m The present study identified RNAm-SNPs in CAD susceptibility genes, gene expression and circulating proteins as risk factors for CAD and suggested that RNA modification may play a role in the pathogenesis of CAD. 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
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
Metabolomics genome wide association study (GWAS) help outline the genetic contribution to human metabolism. However, studies to date have focused on relatively healthy, population-based samples of Wh Show more
Metabolomics genome wide association study (GWAS) help outline the genetic contribution to human metabolism. However, studies to date have focused on relatively healthy, population-based samples of White individuals. Here, we conducted a GWAS of 537 blood metabolites measured in the Chronic Renal Insufficiency Cohort (CRIC) Study, with separate analyses in 822 White and 687 Black study participants. Trans-ethnic meta-analysis was then applied to improve fine-mapping of potential causal variants. Mean estimated glomerular filtration rate was 44.4 and 41.5 mL/min/1.73m Show less
Recent studies have revealed the close correlation between microRNAs (miRs) and Parkinson's disease (PD). Here, we aimed to investigate the neuroprotective effect of miR-124 in a PD mouse model. MiR-1 Show more
Recent studies have revealed the close correlation between microRNAs (miRs) and Parkinson's disease (PD). Here, we aimed to investigate the neuroprotective effect of miR-124 in a PD mouse model. MiR-124 expression in human plasma was detected by qRT-PCR. PD mouse model was established by stereotactic injection of 6-hydroxydopmine. Lentivirus were used to deliver and overexpress miR-124 and Axin1 into the substantia nigra. Multiple behavioral tests and oxidative stress assays were carried out to access the protective effect of miR-124 against PD. Western blot and luciferase assay were conducted to dissect the underlying molecular mechanisms. MiR-124 expression was decreased in PD patients. Overexpression of miR-124 in PD mice could improve motor defects, ameliorate dopaminergic neurons loss, and reduce oxidative stress. Mechanistically, miR-124 targeted Axin1 directly, and then attenuated PD progression via suppressing Axin1 and activating the Wnt/β-catenin pathways in PD mice. MiR-124 is an important neuroprotective factor, which suppresses Axin1 and activates Wnt/β-catenin signaling pathways in PD mice. Show less
Pancreatic cancer (PC) is a highly devastating neoplasm due to its irrepressible characteristics and propensity to override the available treatment strategies. Rapid prevalence and enormous severity o Show more
Pancreatic cancer (PC) is a highly devastating neoplasm due to its irrepressible characteristics and propensity to override the available treatment strategies. Rapid prevalence and enormous severity of this cancer urgently demand the exploration of novel approaches for the development of effective therapeutic measures. Metabolic derangement is one of the hallmarks of cancers which restructures mitochondrial activities and biological pathways. Apart from their bioenergetic and biosynthetic functions, mitochondria are also implicated in a myriad of cellular functions including proliferation, differentiation, apoptosis, senescence, homeostasis, and other cell regulatory mechanisms. It has been noted that PC, like other types of cancers, exploits these activities in favor of tumor growth and survival by inducing mitochondrial dysfunctions such as mitochondrial-DNA mutation, metabolic enzyme modification, ROS generation, mitophagy, evasion of apoptosis, and mitochondrial biogenesis. During pancreatic carcinogenesis, a large number of onco-factors including Bcl-2 family proteins, NF-κB, HIFs, NRF2, NOX, MFNs, DRP1, DUSP6, Cyp-D, PARKIN, and others are dysregulated, resulting into reprogramming of metabolic pathways and cellular kinetics. Hence, targeted interventions in these metabolic derangements may present some effective anticancer approaches. The current review gives an insight into various mitochondrial disorders and their targetable molecules in PC which may provide certain novel opportunities in the pursuit of therapeutic development. Furthermore, we have also discussed certain treatment perspectives in PC based on specific mitochondrial activities. Show less
Fatty acid composition contributes greatly to the nutritional value of meat, and breeds/strains are important factors affecting the composition of fatty acid. Recently, few studies have focused on the Show more
Fatty acid composition contributes greatly to the nutritional value of meat, and breeds/strains are important factors affecting the composition of fatty acid. Recently, few studies have focused on the fatty acid composition in breast muscle of different duck breeds. Therefore, the objective of the present study was to compare the fatty acid composition and lipid metabolism-related genes expression in breast muscle of Jianchang duck (J), Cherry Verry duck (CV) and 3 crossbred strains (BH1, BH2 and MC♂ × (BGF2♂ × GF2♀)♀ (MBG)). Our results showed that the breast muscle of J had the highest contents of C22:1(n-9) but the lowest ratios of Ʃ-omega 6 (Ʃn-6)/Ʃ-omega 3 (Ʃn-3), Ʃ-mono-unsaturated fatty acid (ƩMUFA)/Ʃ-saturated fatty acid (ƩSFA) and Ʃ-polyunsaturated fatty acid (ƩPUFA)/ƩSFA. The ƩPUFA/ƩSFA ratio was higher in breast muscle of MBG than in that of BH2 and CV, and the contents of C22:1(n-9), ƩMUFA and ƩPUFA were higher in BH1 than in BH2 and CV. Furthermore, the mRNA levels of SCD1, FADS2, ELOVL2, and ELOVL5 were significantly higher in MBG (P < 0.05), while those of FASD1 and ACACA were significantly higher in BH1 than in BH2 and CV (P < 0.05). Principal component analysis showed that fatty acids variation exhibited extensive positive loading on principal components (PCs). Correlation analysis showed that PC1 and PC3 of BH1, as well as PC1 of MBG were correlated with the mRNA levels of ACACA and FABP3, respectively. Thus, it could be concluded that the breast muscles of MBG and BH1 have better fatty acid composition, which was closely related to the increased expression levels of SCD1, FADS2, ELOVL2, and ELOVL5 genes in MBG but FADS1 and ACACA in BH1. Moreover, these results also showed that crossbreeding could optimize the composition of fatty acid in breast muscle of ducks. Show less
Increasing evidence shows that autophagy impairment is involved in the pathogenesis and progression of neurodegenerative diseases including Parkinson's disease (PD). We previously identified a natural Show more
Increasing evidence shows that autophagy impairment is involved in the pathogenesis and progression of neurodegenerative diseases including Parkinson's disease (PD). We previously identified a natural alkaloid named corynoxine B (Cory B) as a neuronal autophagy inducer. However, its brain permeability is relatively low, which hinders its potential use in treating PD. Thus we synthesized various derivatives of Cory B to find more potent autophagy inducers with improved brain bioavailability. In this study, we evaluated the autophagy-enhancing effect of CB6 derivative and its neuroprotective action against PD in vitro and in vivo. We showed that CB6 (5-40 μM) dose-dependently accelerated autophagy flux in cultured N2a neural cells through activating the PIK3C3 complex and promoting PI3P production. In MPP Show less
Salivary adenoid cystic carcinoma (SACC) is a malignant tumor, which is characterized by a higher incidence of distant metastasis. The aim of this study was to investigate the role and mechanism of pr Show more
Salivary adenoid cystic carcinoma (SACC) is a malignant tumor, which is characterized by a higher incidence of distant metastasis. The aim of this study was to investigate the role and mechanism of protein kinase D1 (PKD1) in regulating the epithelial-mesenchymal transition (EMT) and promotes the metastasis in SACC. We analyzed the expression of PKD1 in 40 SACC patients and different metastatic potential cell lines. Then, we investigated whether the migration and growth of SACC were regulated by PKD1 using shRNA interference or inhibition of kinase active in vitro cell. Moreover, the mechanism by which PKD1 regulates the stability of Snail protein was determined. Finally, nude mice were used to testify the function of PKD1 via tail vein injection. PKD1 was correlated with metastasis and poor prognosis of SACC patients. PKD1 inhibition attenuated proliferation, migration, invasion, and EMT of SACC cells. Conversely, kinase active PKD1 could induce EMT and promoted cell migration in human HSG cell. Furthermore, downregulation of PKD1 regulated Snail via phosphorylation at Ser-11 on Snail protein and promotion of proteasome-mediated degradation, and reduced lung metastasis in vivo. Our results suggest that PKD1 induces the EMT and promotes the metastasis, which illustrate that PKD1 may be a potential prognostic biomarker and serve as a potential therapeutic target for SACC patients. Show less
Dihydrotanshinone (DIH) is an extract of Salvia miltiorrhiza Bunge. It has been reported that DIH could regulate NF-κB signaling pathway. The aim of this study was to investigate whether DIH could pro Show more
Dihydrotanshinone (DIH) is an extract of Salvia miltiorrhiza Bunge. It has been reported that DIH could regulate NF-κB signaling pathway. The aim of this study was to investigate whether DIH could protect mice from lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. In this study, sixty mice were randomly divided into five groups, one group as blank control group, the second group as LPS control group, and the last three groups were pre-injected with different doses of DIH and then inhaled LPS for experimental comparison. After 12 h of LPS treatment, the wet-dry ratio, histopathlogical changes, and myeloperoxidase (MPO) activity of lungs were measured. In addition, ELISA kits were used to measure the levels of TNF-α and IL-1β inflammatory cytokines in bronchoalveolar lavage fluids (BALF), and western blot analysis was used to measure the activity of NF-κB signaling pathway. The results demonstrated that DIH could effectively reduce pulmonary edema, MPO activity, and improve the lung histopathlogical changes. Furthermore, DIH suppressed the levels of inflammatory cytokines in BALF, such as TNF-α and IL-1β. In addition, DIH could also downregulate the activity of NF-κB signaling pathway. We also found that DIH dose-dependently increased the expression of LXRα. In addition, DIH could inhibit LPS-induced IL-8 production and NF-κB activation in A549 cells. And the inhibitory effects were reversed by LXRα inhibitor geranylgeranyl pyrophosphate (GGPP). Therefore, we speculate that DIH regulates LPS-induced ALI in mice by increasing LXRα expression, which subsequently inhibiting NF-κB signaling pathway. Show less
Cardiomyopathies are a heterogeneous group of diseases predominantly affecting the heart muscle and often lead to progressive heart failure-related disability or cardiovascular death. Hypertrophic car Show more
Cardiomyopathies are a heterogeneous group of diseases predominantly affecting the heart muscle and often lead to progressive heart failure-related disability or cardiovascular death. Hypertrophic cardiomyopathy (HCM) is a cardiac muscle disorder mostly caused by the mutations in genes encoding cardiac sarcomere. Germ-line mutations in Show less
Post-translational modifications (PTMs) are a covalent processing process of proteins after translation. Proteins are capable of playing their roles only after being modified, so as to maintain the no Show more
Post-translational modifications (PTMs) are a covalent processing process of proteins after translation. Proteins are capable of playing their roles only after being modified, so as to maintain the normal physiological function of cells. As a key modification of protein post-translational modification, ubiquitination is an essential element, which forms an enzyme-linked reaction through ubiquitin-activating enzyme, ubiquitin binding enzyme, and ubiquitin ligase, aiming to regulate the expression level and function of cellular proteins. Nedd4 family is the largest group of ubiquitin ligases, including 9 members, such as Nedd4-1, Nedd4L (Nedd4-2), WWP1, WWP2, ITCH, etc. They could bind to substrate proteins through their WW domain and play a dominant role in the ubiquitination process, and then participate in various pathophysiological processes of cardiovascular diseases (such as hypertension, myocardial hypertrophy, heart failure, etc.). At present, the role of Nedd4L in the cardiovascular field is not fully understood. This review aims to summarize the progress and mechanism of Nedd4L in cardiovascular diseases, and provide potential perspective for the clinical treatment or prevention of related cardiovascular diseases by targeting Nedd4L. Show less
Lung adenocarcinoma (LUAD) is one of the main causes of cancer-related mortality, with a strong tendency to metastasize early. Transforming growth factor-β (TGF-β) signaling is a powerful regulator to Show more
Lung adenocarcinoma (LUAD) is one of the main causes of cancer-related mortality, with a strong tendency to metastasize early. Transforming growth factor-β (TGF-β) signaling is a powerful regulator to promote metastasis of LUAD. Here, we screened long non-coding RNAs (lncRNAs) responsive to TGF-β and highly expressed in LUAD cells, and finally obtained our master molecular LINC00152. We proved that the TGF-β promoted transcription of LINC00152 through the classical TGF-β/SMAD3 signaling pathway and maintained its stability through the RNA-binding protein HuR. Moreover, LINC00152 increased ZEB1, SNAI1 and SNAI2 expression via increasing the interactions of HuR and these transcription factors, ultimately promoting epithelial-mesenchymal transition of LUAD cell and enhancing LUAD metastasis in vivo. These data provided evidence that LINC00152 induced by TGF-β promotes metastasis depending HuR in lung adenocarcinoma. Designing targeting LINC00152 and HuR inhibitors may therefore be an effective therapeutic strategy for LUAD treatment. Show less
Osteoarthritis (OA) is a degenerative joint disease that acts as a major cause of early disability in the old population. However, the molecular mechanisms of autophagy in osteoclasts involved in OA r Show more
Osteoarthritis (OA) is a degenerative joint disease that acts as a major cause of early disability in the old population. However, the molecular mechanisms of autophagy in osteoclasts involved in OA remain unclear. The gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) repository. The NCBI GEO2R and ScanGEO analysis tool were used to identify differentially expressed genes (DEGs). The protein-protein interaction (PPI) network was predicted by the STRING website and visualized with Cytoscape software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were performed to enrich GO terms and signaling pathways using Metascape database. To predict LC3-interacting region (LIR) motif among these DEGs, the iLIR database was selected to assess specific short linear sequences. To obtain potential upstream miRNA targets of these DEGs, the mRNA-miRNA interaction networks were predicted by miRWalk database. The knee OA model was performed in mice, and autophagy related mRNAs of osteoclasts were identified. Experimental specimens were further verified with histopathological staining. Our results reveal that the role of autophagy in osteoclasts could be a regulatory mechanism in OA and that these autophagy-related genes might be targets for the intervention of OA disease. Show less
Childhood overweight and obesity (OW/OB) is a worldwide public health problem, and its genetic risks remain unclear. To investigate risks of OW/OB associated with genetic variances in We conducted a c Show more
Childhood overweight and obesity (OW/OB) is a worldwide public health problem, and its genetic risks remain unclear. To investigate risks of OW/OB associated with genetic variances in We conducted a case-control study with 734 infants included at delivery and followed up to 12-month old. The classification and regression tree analysis were used to generate the structure of the gene-gene interactions, while the unconditional multivariate logistic regression models were applied to analyze the single SNP, gene-gene interactions, and cumulative effects of the genotypes on OW/OB, adjusted for potential confounders. There were 219 (29.84%) OW/OB infants. Rs543874 G allele and rs11030104 AA genotype increased the risk of OW/OB in 12-month-old infants ( Rs543874, rs11030104, and rs11191580 were associated with OW/OB in 12-month-old Chinese infants, and the three SNPs together with rs10913469 and rs11165675 had a combined effect on OW/OB. Show less
The most hostile form of urologic cancer, clear cell renal cell carcinoma (ccRCC), has a high fatality rate and poor prognosis due to tumor metastasis at initial presentation. The complex process driv Show more
The most hostile form of urologic cancer, clear cell renal cell carcinoma (ccRCC), has a high fatality rate and poor prognosis due to tumor metastasis at initial presentation. The complex process driving ccRCC metastasis is still unknown, though. In this study, we demonstrate that Spindle and kinetochore-associated protein 1 (SKA1) expression is significantly upregulated in ccRCC tissues and associated with aggressive clinicopathologic characteristics. Functionally, SKA1 knockdown on ccRCC cells reduced cancer cell motility both Show less
Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease often caused by sarcomeric gene mutations. MYBPC3 is one of the most common genes associated with HCM. In this study, we ge Show more
Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease often caused by sarcomeric gene mutations. MYBPC3 is one of the most common genes associated with HCM. In this study, we generated a human induced pluripotent stem cell line ZZUNEUi028-A from a 19-year-old male HCM patient with c. 1504C → T in MYBPC3 gene using non-integrative Sendai viral reprogramming technology. This cell line expresses pluripotency markers, exhibits a normal male karyotype (46, XY) and can differentiate into all three germ layers in vitro. ZZUNEUi028-A can serve as a cell disease model in the understanding of HCM pathogenesis. 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
Malignant meningiomas often show invasive growth that makes complete tumor resection challenging, and they are more prone to recur after radical resection. Invasive meningioma associated transcript 1 Show more
Malignant meningiomas often show invasive growth that makes complete tumor resection challenging, and they are more prone to recur after radical resection. Invasive meningioma associated transcript 1 (IMAT1) is a long noncoding RNA located on Show less
Oxidative stress-associated endothelial damage is the initiation factor of cardiovascular disease, and protein posttranslational modifications play critical roles in this process. Bcl-2-associated ath Show more
Oxidative stress-associated endothelial damage is the initiation factor of cardiovascular disease, and protein posttranslational modifications play critical roles in this process. Bcl-2-associated athanogene 3 (BAG3) is a molecular chaperone regulator of the BAG family, which interacts with various proteins and influences cell survival by activating multiple pathways. BAG3 undergoes posttranslational modifications; however, research evaluating BAG3 acetylation and its regulatory mechanism is lacking. In addition, the interacting protein and regulatory mechanism of BAG3 in oxidative stress-associated endothelial damage remain unclear. Here, key molecular interactions and protein modifications of BAG3 were identified in oxidative stress-associated endothelial damage. Endothelial-specific BAG3 knockout in the mouse model starkly enhances oxidative stress-associated endothelial damage and vascular remodeling, while BAG3 overexpression in mice significantly relieves this process. Mechanistically, poly(ADP-ribose) polymerase 1 (PARP1), causing oxidative stress, was identified as a novel physiological substrate of BAG3. Indeed, BAG3 binds to PARP1's BRCT domain to promote its ubiquitination (K249 residue) by enhancing the E3 ubiquitin ligase WWP2, which leads to proteasome-induced PARP1 degradation. Furthermore, we surprisingly found that BAG3 represents a new substrate of the acetyltransferase CREB-binding protein (CBP) and the deacetylase Sirtuin 2 (SIRT2) under physiological conditions. CBP/SIRT2 interacted with BAG3 and acetylated/deacetylated BAG3's K431 residue. Finally, deacetylated BAG3 promoted the ubiquitination of PARP1. This work reveals a novel regulatory system, with deacetylation-dependent regulation of BAG3 promoting PARP1 ubiquitination and degradation via enhancing WWP2, which is one possible mechanism to decrease vulnerability of oxidative stress in endothelial cells. Show less
Two-pore domain potassium channels (K2P) are a large family of "background" channels that allow outward "leak" of potassium ions. The NALCN/UNC80/UNC79 complex is a non-selective channel that allows i Show more
Two-pore domain potassium channels (K2P) are a large family of "background" channels that allow outward "leak" of potassium ions. The NALCN/UNC80/UNC79 complex is a non-selective channel that allows inward flow of sodium and other cations. It is unclear how K2Ps and NALCN differentially modulate animal behavior. Here, we found that loss of function (lf) in the K2P gene twk-40 suppressed the reduced body curvatures of C. elegans NALCN(lf) mutants. twk-40(lf) caused a deep body curvature and extended backward locomotion, and these phenotypes appeared to be associated with neuron-specific expression of twk-40 and distinct twk-40 transcript isoforms. To survey the functions of other less studied K2P channels, we examined loss-of-function mutants of 13 additional twk genes expressed in the motor circuit and detected defective body curvature and/or locomotion in mutants of twk-2, twk-17, twk-30, twk-48, unc-58, and the previously reported twk-7. We generated presumptive gain-of-function (gf) mutations in twk-40, twk-2, twk-7, and unc-58 and found that they caused paralysis. Further analyses detected variable genetic interactions between twk-40 and other twk genes, an interdependence between twk-40 and twk-2, and opposite behavioral effects between NALCN and twk-2, twk-7, or unc-58. Finally, we found that the hydrophobicity/hydrophilicity property of TWK-40 residue 159 could affect the channel activity. Together, our study identified twk-40 as a novel modulator of the motor behavior, uncovered potential behavioral effects of five other K2P genes and suggests that NALCN and some K2Ps can oppositely affect C. elegans behavior. 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
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
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
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
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