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
Epithelial ovarian cancer (EOC) is a fatal gynecological malignancy. This study explored the mechanism of TAZ in regulating drug sensitivity of cisplatin (DDP-)-resistant EOC cells through the ANGPTL4 Show more
Epithelial ovarian cancer (EOC) is a fatal gynecological malignancy. This study explored the mechanism of TAZ in regulating drug sensitivity of cisplatin (DDP-)-resistant EOC cells through the ANGPTL4/SOX2 axis. The A2780/DDP cells were prepared by stepwise progressive concentration method. The drug resistance and TAZ expression in EOC cells were determined. Drug sensitivity was measured after TAZ overexpression in A2780 cells and TAZ downregulation in A2780/DDP cells, respectively. The effects of TAZ knockdown on apoptosis rate, stemness, and cancer stem cell (CSC) marker (CD44, OCT4, and ALDH1A) levels in A2780/DDP and DDP-treated A2780/DDP cells were assessed. The binding of TAZ and ANGPTL4 was verified using ChIP-qPCR, and ANGPTL4 and SOX2 levels were determined. The effects of different combined treatments of TAZ, ANGPTL4, and SOX2 on drug sensitivity of A2780/DDP cells and DDP-treated A2780/DDP cells were evaluated. TAZ was upregulated in drug-resistant EOC cells. TAZ knockdown significantly increased the drug sensitivity of A2780/DDP cells, while TAZ overexpression markedly decreased the drug sensitivity of A2780 cells. TAZ silencing promoted apoptosis of drug-resistant EOC cells and inhibited cell stemness. TAZ targeted ANGPTL4 and TAZ silencing enhanced drug sensitivity of A2780/DDP cells by inhibiting ANGPTL4. ANGPTL4 overexpression elevated SOX2 expression, and SOX2 downregulation reduced the drug resistance and promoted the apoptosis of A2780/DDP cells. TAZ regulates DDP sensitivity of drug-resistant EOC cells via the ANGPTL4/SOX2 axis. Show less
Macroautophagy/autophagy is a highly conserved process in eukaryotic cells. It plays a critical role in cellular homeostasis by delivering cytoplasmic cargos to lysosomes for selective degradation. OP Show more
Macroautophagy/autophagy is a highly conserved process in eukaryotic cells. It plays a critical role in cellular homeostasis by delivering cytoplasmic cargos to lysosomes for selective degradation. OPTN (optineurin), a well-recognized autophagy receptor, has received considerable attention due to its multiple roles in the autophagic process. OPTN is associated with many human disorders that are closely related to autophagy, such as rheumatoid arthritis, osteoporosis, and nephropathy. Here, we review the function of OPTN as an autophagy receptor at different stages of autophagy, focusing on cargo recognition, autophagosome formation, autophagosome maturation, and lysosomal quality control. OPTN tends to be protective in most autophagy associated diseases, though the molecular mechanism of OPTN regulation in these diseases is not well understood. A comprehensive review of the function of OPTN in autophagy provides valuable insight into the pathogenesis of human diseases related to OPTN and facilitates the discovery of potential key regulators and novel therapeutic targets for disease intervention in patients with autophagic diseases. Show less
To explore the diagnosis value of inflammatory markers and cytokines in neonatal sepsis. In this retrospective analysis, 90 cases of neonatal sepsis admitted to our hospital from April 2019 to April 2 Show more
To explore the diagnosis value of inflammatory markers and cytokines in neonatal sepsis. In this retrospective analysis, 90 cases of neonatal sepsis admitted to our hospital from April 2019 to April 2021 were included in the observation group, and 70 healthy neonates who received routine physical examinations in our hospital during the same period were recruited as the control group. Comparison and analysis of inflammatory markers and cytokines levels between the two groups were performed on days 1, 3, and 7 after the onset. Flow cytometry was used to measure the white blood cells (WBCs) and percentage of neutrophils (N%), immunoturbidimetry was used to determine C-reactive protein (CRP), immunochromatographic analysis was used to determine procalcitonin (PCT) in plasma, and the enzyme-linked immunosorbent assay was used to determine interleukin-27 (IL-27), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor- Compared with healthy controls, neonatal sepsis resulted in significantly higher levels of WBC, N%, PCT, and CRP on days 1, 3, and 7 after onset. The levels of WBC, N%, and PCT were continuously decreased from day 1 to day 7, while the levels of CRP were increased on day 1 and day 3 but declined on day 7 ( Neonatal sepsis was associated with fluctuating levels of WBC, N%, PCT, CRP, IL-27, IL-6, IL-10, and TNF- Show less
While multiple transcription factors (TFs) have been recognized to drive epithelial-mesenchymal transition (EMT) in cancer, their interdependence and context-dependent functions are poorly understood. Show more
While multiple transcription factors (TFs) have been recognized to drive epithelial-mesenchymal transition (EMT) in cancer, their interdependence and context-dependent functions are poorly understood. In this study, we show that FOXQ1 and SNAI1 act as independent TFs within the EMT program with a shared ability to upregulate common EMT TFs without reciprocally impacting the expression of one another. Despite this independence, human mammary epithelial cells (HMLE) with ectopic expression of either FOXQ1 or SNAI1 share a common gene set that is enriched for a DDR2 coexpression signature. Further analysis identified DDR2 as the most upregulated receptor tyrosine kinase and a shared downstream effector of FOXQ1 and SNAI1 in triple-negative breast cancer (TNBC) cell lines. Alteration of DDR2 expression in either FOXQ1 or SNAI1 driven EMT models or in TNBC cells resulted in a profound change of cell motility without significantly impacting EMT marker expression, cell morphology, or the stem cell population. Lastly, we demonstrated that knockdown of DDR2 in the FOXQ1-driven EMT model and TNBC cell line significantly altered the global metabolic profile, including glutamine-glutamate and Aspartic acid recycling. 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
Brachial plexus avulsion (BPA) is a devastating traumatic peripheral nerve injury complicated with paralysis of the upper extremity. We previously reported that leucine-rich repeat and immunoglobulin- Show more
Brachial plexus avulsion (BPA) is a devastating traumatic peripheral nerve injury complicated with paralysis of the upper extremity. We previously reported that leucine-rich repeat and immunoglobulin-like domain-containing NOGO receptor-interacting protein 1 (LINGO-1) has a potent role in inhibiting neuron survival and axonal regeneration after the central nervous system (CNS) damage and miR-615 is a potential microRNA (miRNA) negatively regulated LINGO-1. However, the effect of miR-615 in BPA remains to be elucidated. Accumulating evidence indicates that pluronic F-127 (PF-127) hydrogel could serve as a promising vehicle for miRNA encapsulation. Thus, to further explore the potential role of hydrogel-miR-615 in BPA-reimplantation, the present study established the BPA rat model and injected miR-615 agomir encapsulated by PF-127 hydrogel into the reimplantation site using a microsyringe. In this study, results indicated that hydrogel-miR-615 agomir effectively alleviated motoneuron loss by LINGO-1 inhibition, promoted musculocutaneous nerve regeneration and myelination, reduced astrocytes activation, promoted angiogenesis and attenuated peripheral amyotrophy, leading to improved motor functional rehabilitation of the upper extremity. In conclusion, our findings demonstrate that miR-615-loaded PF-127 hydrogel may represent a novel therapeutic strategy for BPA treatment. Show less
Arctigenin (Arc) is a phenylpropanoid dibenzylbutyrolactone lignan in Arctium lappa L, which has been widely applied as a traditional Chinese herbal medicine for treating inflammation. In the present Show more
Arctigenin (Arc) is a phenylpropanoid dibenzylbutyrolactone lignan in Arctium lappa L, which has been widely applied as a traditional Chinese herbal medicine for treating inflammation. In the present study, we explored the neuroprotective effect and the potential mechanisms of arctigenin against LPS-evoked neuroinflammation, neurodegeneration, and memory impairments in the mice hippocampus. Daily administration of arctigenin (50 mg/kg per day, i.g.) for 28 days revealed noticeable improvements in spatial learning and memory deficits after exposure to LPS treatment. Arctigenin prevented LPS-induced neuronal/synaptic injury and inhibited the increases in Abeta (Aβ) generation and the levels of amyloid precursor protein (APP) and β-site amyloid precursor protein cleavage enzyme 1 (BACE1). Moreover, arctigenin treatment also suppressed glial activation and reduced the production of proinflammatory cytokines. In LPS-treated BV-2 microglial cells and mice, activation of the TLR4 mediated NF-κB signaling pathway was significantly suppressed by arctigenin administration. Mechanistically, arctigenin reduced the LPS-induced interaction of adiponectin receptor 1 (AdipoR1) with TLR4 and its coreceptor CD14 and inhibited the TLR4-mediated downstream inflammatory response. The outcomes of the current study indicate that arctigenin mitigates LPS-induced apoptotic neurodegeneration, amyloidogenesis and neuroinflammation as well as cognitive impairments, and suggest that arctigenin may be a potential therapeutic candidate for neuroinflammation/neurodegeneration-related diseases. Show less
To explore the functions of Chordin-like 2, which is encoded by The fetal RPE cells (fRPE) was obtained from aborted fetus which obeyed medical ethics. Real-time quantitative polymerase chain reaction Show more
To explore the functions of Chordin-like 2, which is encoded by The fetal RPE cells (fRPE) was obtained from aborted fetus which obeyed medical ethics. Real-time quantitative polymerase chain reaction was used to measure expression quantity of In normal RPE cells, BMP pathway can be activated in a correct temporal order, otherwise, the cells have incorrect differentiation orientation. And Chordin-like 2 plays a role in dynamic regulation of BMP pathway and it also regulates the differentiation of RPE cells. Therefore, this research enlightens a new direction to inhibit EMT and promote cell redifferentiation after injury. Show less
Early diagnosis and prognosis evaluation are of great significance to hepatitis E virus (HEV)-related acute liver failure (HEV-ALF) patients. We collected serum samples from 200 health controls (HCs), Show more
Early diagnosis and prognosis evaluation are of great significance to hepatitis E virus (HEV)-related acute liver failure (HEV-ALF) patients. We collected serum samples from 200 health controls (HCs), 200 patients with acute hepatitis E (AHE), and 200 HEV-ALF patients to evaluate serum exosome-derived carbamoyl phosphate synthase 1 (CPS1) levels and determine its diagnostic and prognostic value. The exosome-derived CPS1 levels in the HEV-ALF group were significantly higher than those in the AHE and HCs groups. The AUC of exosome-derived CPS1 to predict the occurrence of HEV-ALF was 0.850 (0.811-0.883). Both logistical regression and orthogonal partial least squares discriminant analysis (OPLS-DA) showed that exosome-derived CPS1 is an independent risk factor for HEV-ALF. The exosome-derived CPS1 levels were positively correlated with organ failure and the outcomes in HEV-ALF patients. The exosome-derived CPS1 levels in the worsening group were significantly higher than those in the fluctuating and the improving groups. The AUC of serum exosome-derived CPS1 to predict 30-day mortality was 0.829 (0.770-0.879), which was significantly greater than that of the Child-Pugh, KCH, and MELD models. The level of serum exosome-derived CPS1 might serve as a promising diagnostic and prognostic biomarker for HEV-ALF patients, which may provide better guidance for the diagnosis, prognosis, and treatment of HEV-ALF patients. Show less
Background Ischemic stroke is likely caused by interactions of multiple genes and environmental determinants. However, large-scale sequencing studies to discern functional genetic variants and their i Show more
Background Ischemic stroke is likely caused by interactions of multiple genes and environmental determinants. However, large-scale sequencing studies to discern functional genetic variants and their interactions with clinical and lifestyle risk factors on ischemic stroke are limited. Methods and Results We sequenced functional regions of 740 previously identified genes associated with atherosclerotic disease among 999 ischemic stroke cases and 1001 controls of Chinese ancestry. Multiple logistic regression models were used to examine the associations between variants and ischemic stroke and test interactions between variants and clinical and lifestyle risk factors. Functional variants achieving suggestive significance were replicated in an independent sample of 4724 ischemic stroke cases and 5029 controls. Driven by variant main effects, each minor allele of the correlated rs174535, rs174545, and rs3834458 variants at Show less
β-Secretase (BACE1) is the vital enzyme in the pathogenic processes of Alzheimer's disease (AD). However, the development of a powerful tool with sensitivity for BACE1 determination in vivo is a chall Show more
β-Secretase (BACE1) is the vital enzyme in the pathogenic processes of Alzheimer's disease (AD). However, the development of a powerful tool with sensitivity for BACE1 determination in vivo is a challenge. A novel NIR fluorescent probe HBAE was synthetized from 2-hydroxy-3-methylbenzaldehyde and 2-amino-benzenethiol by 5 steps. The fluorescence mechanism in the ESIPT systems of HBAE probe was insighted with time-dependent density functional theory (TD-DFT) at the TDPBE0 level with the def2-TZVP approach. The corresponding docking between HBAE and BACE1 (PDB: 5I3Y) was performed through the ducking method by DOCK6.8. Then the BBB permeability of HBAE is verified by transwell orifice plate. 22-month-old male AD-model (5XFAD) mice and age-matched wild-type mice were employed to observe the brain kinetics by intravenous injection. Finally, Immunohistochemistry was performed on the AD brain section to reveal the levels of BACE1 in hippocampus and cortex areas and other regions in AD mice through the brain tissue slices by HBAE. The NIR fluorescent probe HBAE was successfully applied in imaging BACE1 in AD model mice. The capability of HBAE in reflecting different level of BACE1 was performed by the specific imaging of the hippocampus region. We reported the first ESIPT near-infrared fluorescence probe HBAE for monitoring endogenous BACE1 in the AD live model mice, thus offering a versatile chemical tool for visualizing in the pathological processes of AD live brains. Remarkably, high resolution images showed the localization of red fluorescence stains in hippocampus of the AD brain. This study provides a promising way for functional insights from protein BACE1 in vivo. Show less
Average backfat thickness (BFT) is a critical complex trait in pig and an important indicator for fat deposition and lean rate. Usually, genome-wide association study (GWAS) was used to discover quant Show more
Average backfat thickness (BFT) is a critical complex trait in pig and an important indicator for fat deposition and lean rate. Usually, genome-wide association study (GWAS) was used to discover quantitative trait loci (QTLs) of BFT in a single population. However, the power of GWAS is limited by sample size in a single population. Alternatively, meta-analysis of GWAS (metaGWAS) is an attractive method to increase the statistical power by integrating data from multiple breeds and populations. The aim of this study is to identify shared genetic characterization of BFT across breeds in pigs via metaGWAS. RESULTS: In this study, we performed metaGWAS on BFT using 15,353 pigs (5,143 Duroc, 7,275 Yorkshire, and 2,935 Landrace) from 19 populations. We detected 40 genome-wide significant SNPs (Bonferroni corrected P < 0.05) and defined five breed-shared QTLs in across-breed metaGWAS. Markers within the five QTL regions explained 7 ~ 9% additive genetic variance and showed strong heritability enrichment. Furthermore, by integrating information from multiple bioinformatics databases, we annotated 46 candidate genes located in the five QTLs. Among them, three important (MC4R, PPARD, and SLC27A1) and seven suggestive candidate genes (PHLPP1, NUDT3, ILRUN, RELCH, KCNQ5, ITPR3, and U3) were identified. QTLs and candidate genes underlying BFT across breeds were identified via metaGWAS from multiple populations. Our findings contribute to the understanding of the genetic architecture of BFT and the regulating mechanism underlying fat deposition in pigs. 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
The most common pathological subtype of renal carcinoma is RCC, and its development is closely related to immune infiltration. In our study, we investigated the relationship between zinc finger protei Show more
The most common pathological subtype of renal carcinoma is RCC, and its development is closely related to immune infiltration. In our study, we investigated the relationship between zinc finger protein 668 and the prognostic risk, clinical characteristics, overall survival and related pathways. We analyzed the association between ZNF668 and immune cell infiltration through the TIMER database. The results showed that the expression of ZNF668 in RCC was higher than that in normal tissues (P < 0.001). The high expression of ZNF668 is clinically relevant, such as tumor stage (P = 0.001) and TNM classification (T: P = 7.37 e-04; N: P = 0.008; M: P < 0.001). Survival analysis showed that patients with high ZNF668 expression had a significantly poor prognosis (P = 0.023). Univariate analysis showed a significant decrease in overall survival in RCC patients with high ZNF668 expression (P = 0.023). Immuno-cell infiltration showed a significant decrease in CD4+ T cell and dendritic cell infiltration in RCC patients with high expression of ZNF668. GO/KEGG analysis showed that multiple pathways were differentially enriched in the high expression pathway of ZNF668, such as complement activation, and estrogen signaling pathway. In conclusion, high ZNF668 expression is a predictor in RCC. Show less
Depolarized mitochondria can be degraded via mitophagy, a selective form of autophagy. The RAB GTPase RAB7A was recently shown to play a key role in this process. RAB7A regulates late endocytic traffi Show more
Depolarized mitochondria can be degraded via mitophagy, a selective form of autophagy. The RAB GTPase RAB7A was recently shown to play a key role in this process. RAB7A regulates late endocytic trafficking under normal growth conditions but is translocated to the mitochondrial surface following depolarization. However, how RAB7A activity is regulated during mitophagy is not understood. Here, using a proximity-dependent biotinylation approach (miniTurbo), we identified C5orf51 as a specific interactor of GDP-locked RAB7A. C5orf51 also interacts with the RAB7A guanine nucleotide exchange factor (GEF) complex members MON1 and CCZ1. In the absence of C5orf51, localization of RAB7A on depolarized mitochondria is compromised and the protein is degraded by the proteasome. Furthermore, depletion of C5orf51 also inhibited ATG9A recruitment to depolarized mitochondria. Together, these results indicate that C5orf51 is a positive regulator of RAB7A in its shuttling between late endosomes and mitochondria to enable mitophagy. Show less
Diabetes is a serious disease that could greatly increase the risk of cardiovascular complications, whereas the underlying pathology of DN is still unknown. GPRC5B is a member of the RAIG subfamily of Show more
Diabetes is a serious disease that could greatly increase the risk of cardiovascular complications, whereas the underlying pathology of DN is still unknown. GPRC5B is a member of the RAIG subfamily of type 3 (family C) GPCR, and its role in DN is still unclear. To unveil the role of GPRC5B in diabetic nephropathy (DN) progression and investigate the potential signaling pathway. Podocytes were stimulated with high glucose and expression of GPRC5B was analyzed by qPCR and western blot. Then the level of GPRC5B was depleted by siRNA transfection and inflammatory cytokine level was monitored by ELISA assay. The ECM depostion and the activation of NF-κB pathway were detected by Immunoblot. We investigated the possible role of GPRC5B in the pathology of diabetic nephropathy. We found GPRC5B was highly expressed in high glocuse (HG) induced podocytes. The depletion of GPRC5B inhibited HG induced cell inflammation. In addition, the ablation of GPRC5B suppressed the HG induced ECM deposition. We further found GPRC5B could alleviate the inflammation and extracellular matrix deposition of HG-induced podocytes through NF-κB pathway. We therefore thought GPRC5B could serve as a promising target for the treatment of diabetic nephropathy. G-protein-coupled receptors. 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 (
To investigate the potential contribution of appetite regulation and modulation of gut microbiota to the ameliorated effects of apple polyphenols extracts (APE) on high carbohydrate diet (HCD)-induced Show more
To investigate the potential contribution of appetite regulation and modulation of gut microbiota to the ameliorated effects of apple polyphenols extracts (APE) on high carbohydrate diet (HCD)-induced body weight (BW) gain, we conducted this study. One hundred C57BL/6 male mice were randomly divided into seven groups and fed with the following diets for 12 weeks: chow diet (CON), HCD (HCD), high fructose and sucrose diet (HSCD), and HCD and HSCD with 125 or 500 mg/kg·day APE gavage. Compared to the CON group, the BW of mice in the HCD and HSCD groups increased significantly. HSCD induced a more significant weight gain in the white adipose tissue (WAT) and liver than HCD, accompanied by severe impairment of glucose tolerance and a larger diameter of adipocytes. On the other hand, by decreasing food intake, APE significantly reduced BW Show less
Common genetic factors likely contribute to multiple psychiatric diseases including mood and substance use disorders. Certain stable, heritable traits reflecting temperament, termed externalizing or i Show more
Common genetic factors likely contribute to multiple psychiatric diseases including mood and substance use disorders. Certain stable, heritable traits reflecting temperament, termed externalizing or internalizing, play a large role in modulating vulnerability to these disorders. To model these heritable tendencies, we selectively bred rats for high and low exploration in a novel environment [bred High Responders (bHR) vs. Low Responders (bLR)]. To identify genes underlying the response to selection, we phenotyped and genotyped 538 rats from an F 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
To detect whether Danlou Tablet (DLT) regulates the hypoxia-induced factor (HIF)-1α-angiopoietin-like 4 (Angptl4) mRNA signaling pathway and explore the role of DLT in treating chronic intermittent hy Show more
To detect whether Danlou Tablet (DLT) regulates the hypoxia-induced factor (HIF)-1α-angiopoietin-like 4 (Angptl4) mRNA signaling pathway and explore the role of DLT in treating chronic intermittent hypoxia (CIH)-induced dyslipidemia and arteriosclerosis. The mature adipocytes were obtained from 3T3-L1 cell culturation and allocated into 8 groups including control groups (Groups 1 and 5, 0.1 mL of cell culture grade water); DLT groups (Groups 2 and 6, 0.1 mL of 1,000 µg/mL DLT submicron powder solution); dimethyloxalylglycine (DMOG) groups (Groups 3 and 7, DMOG and 0.1 mL of cell culture grade water); DMOG plus DLT groups (Groups 4 and 8, DMOG and 0.1 mL of 1,000 µg/mL DLT submicron powder solution). Groups 1-4 used mature adipocytes and groups 5-8 used HIF-1 α-siRNA lentivirus-transfected mature adipocytes. After 24-h treatment, real-time polymerase chain reaction and Western blot were employed to determine the mRNA and protein expression levels of HIF-1 α and Angptl4. In animal experiments, the CIH model in ApoE Angptl4 expression was dependent on HIF-1 α, with a reduction in mRNA expression and no response in protein level to DMOG or DLT treatment in relation to siHIF-1 α -transfected cells. DLT inhibited HIF-1 α and Angptl4 mRNA expression (P<0.05 or P<0.01) and reduced HIF-1 α and Angptl4 protein expressions with DMOG in mature adipocytes (all P<0.01), as the effect on HIF-1 α protein also existed in the presence of siHIF-1 α (P<0.01). ApoE DLT had positive effects in improving dyslipidemia and arteriosclerosis by inhibiting Angptl4 protein level through HIF-1 α-Angptl4 mRNA signaling pathway. Show less
Metastasis is the leading cause of death in patients with colorectal cancer (CRC). The 5-year survival rate of CRC patients in whom the cancer has spread to distant sites is 13.5%. The most common sit Show more
Metastasis is the leading cause of death in patients with colorectal cancer (CRC). The 5-year survival rate of CRC patients in whom the cancer has spread to distant sites is 13.5%. The most common sites of CRC metastasis are liver and lung. The principal therapies for CRC metastatic disease are surgery, but its benefits are limited. This study aimed to reveal the regulatory mechanism of berberine on secondary homing of CRC cells to form metastatic focus. This was more valuable than the previous direct study of the migration and metastasis characteristics of CRC cells. In this study, we used the functional enrichment analysis of differentially expressed genes after berberine treatment and investigated co-expression modules related with CRC metastasis by WGCNA. PPI and survival analyses of significant modules were also conducted. The biological functions of berberine in CRC lung and liver metastasis were investigated by a series of in vitro and in vivo experiments: MTT, colony formation and mouse tail vein injection. And we scanned through the entire extracellular domain of HEY2 protein for autodocking analysis with berberine. We found the differentially expressed genes (DEGs) after berberine treatment were related with cancer progression and metastasis related pathways. Through WGCNA analysis, four cancer progression and metastasis related modules were detected. After PPI and survival analysis, we identified and validated HEY2 as a hub gene, high expression and poor survival at the metastatic stage. Functionally, berberine inhibited the survival, invasion and migration of CRC cells in vitro and in vivo. Mechanistically, berberine treatment down-regulated the expression of HEY2, metastasis related protein E-cadherin, β-catenin and Cyclin D1 during Mesenchymal epithelial transformation (MET). Berberine and HEY2 showed a significant interaction, and berberine binded to HEY2 protein at the residue HIS-99 interface with a hydrogen-bond distance of 1.9A. We revealed that berberine could significantly inhibit the expression of hub gene HEY2 and metastasis related proteins E-cadherin and β-catenin and Cyclin D1 during MET in CRC lung and liver metastases. In total, HEY2 was a promising candidate biomarker for prognosis and molecular characteristics in CRC metastasis. 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
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
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
Histone deacetylases (HDACs) are entwined with the pathogenesis of various cancers and potentially serve as promising therapeutic targets. Herein, we intend to explore the potential role of HDAC1 inhi Show more
Histone deacetylases (HDACs) are entwined with the pathogenesis of various cancers and potentially serve as promising therapeutic targets. Herein, we intend to explore the potential role of HDAC1 inhibitor (JSL-1) in the tumorigenesis and metastasis of cholangiocarcinoma (CC) and to highlight the molecular basis of its function. As shown by bioinformatics analysis and immunohistochemical detection, high HDAC1 expression was witnessed in CC tissues relative to matched controls from patients with cholecystitis. The molecular network that HDAC1 silencing reduced the enrichment of HDAC1 and Snail on the TPX2 promoter was identified using immunoprecipitation and chromatin immunoprecipitation assays. Both short hairpin RNA (shRNA)-mediated knockdown of HDAC1 and JSL-1 treatment exhibited anti-proliferative, anti-migration and anti-invasion effects on CC cells through downregulation of TPX2. The in vivo xenograft model was developed in nude mice. Consistently, the anti-tumorigenic and anti-metastatic properties of shRNA against HDAC1 and HDAC1 inhibitor were validated in the in vivo settings. Taken together, our data supported the notion that HDAC1 inhibitor retards the initiation and development of CC via mediating the TPX2/Snail axis, highlighting the anti-tumor molecular network functioned in CC. Show less