The epithelial-mesenchymal transition (EMT) is an important pathological process in the occurrence of pulmonary fibrosis. Changes in histone methylation modifications of key genes play an important ro Show more
The epithelial-mesenchymal transition (EMT) is an important pathological process in the occurrence of pulmonary fibrosis. Changes in histone methylation modifications of key genes play an important role in this process. As a histone methyltransferase, the regulatory mechanism and role of SET domain bifurcated 1 (SETDB1) in pulmonary fibrosis remain unclear. We found that SETDB1 inhibited EMT and that cells attenuated the expression of SETDB1 to relieve this inhibition during transforming growth factor-β (TGF-β)-induced EMT. Silencing SETDB1 expression significantly enhanced the mesenchymal phenotype induced by TGF-β and the expression and deposition of fibronectin and significantly reduced the expression of E-cadherin. The decrease in E-cadherin expression and the induction of EMT led to increased lipid reactive oxygen species (ROS) and ferrous ions, which induced ferroptosis. Chromatin immunoprecipitation (ChIP) results showed that SETDB1 regulates the expression of Snai1 by catalyzing the histone H3 lysine 9 trimethylation (H3K9me3) of Snai1, the main transcription factor that initiates the process of EMT, and thus, indirectly regulates E-cadherin. Surprisingly, when examining the effect of overexpressed SETDB1 on EMT, we found that overexpressed SETDB1 alleviated EMT and also caused ferroptosis. We suggest that the overexpression of SETDB1 partially reverses the mesenchymal phenotype to an epithelial state, while those cells that fail to reverse are depleted by ferroptosis. In conclusion, the histone methylase SETDB1 regulates Snai1 epigenetically, driving EMT gene reprogramming and ferroptosis in response to TGF-β. However, there are unexplored links between the epigenetic reprogramming and transcriptional processes that regulate EMT in a TGF-β-dependent manner. 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
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
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
In day-to-day life, we often must choose between pursuing familiar behaviors or adjusting behaviors when new strategies might be more fruitful. The dorsomedial striatum (DMS) is indispensable for arbi Show more
In day-to-day life, we often must choose between pursuing familiar behaviors or adjusting behaviors when new strategies might be more fruitful. The dorsomedial striatum (DMS) is indispensable for arbitrating between old and new action strategies. To uncover molecular mechanisms, we trained mice to generate nose poke responses for food, then uncoupled the predictive relationship between one action and its outcome. We then bred the mice that failed to rapidly modify responding. This breeding created offspring with the same tendencies, failing to inhibit behaviors that were not reinforced. These mice had less post-synaptic density protein 95 in the DMS. Also, densities of the melanocortin-4 receptor (MC4R), a high-affinity receptor for α-melanocyte-stimulating hormone, predicted individuals' response strategies. Specifically, high MC4R levels were associated with poor response inhibition. We next found that reducing Mc4r in the DMS in otherwise typical mice expedited response inhibition, allowing mice to modify behavior when rewards were unavailable or lost value. This process required inputs from the orbitofrontal cortex, a brain region canonically associated with response strategy switching. Thus, MC4R in the DMS appears to propel reward-seeking behavior, even when it is not fruitful, while moderating MC4R presence increases the capacity of mice to inhibit such behaviors. Show less
To investigate the 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
Endothelial dysfunction is common in diabetes. Apolipoprotein (apo) A-IV functions to antagonize inflammation and oxidative stress. The present study aimed to investigate the relationship between flow Show more
Endothelial dysfunction is common in diabetes. Apolipoprotein (apo) A-IV functions to antagonize inflammation and oxidative stress. The present study aimed to investigate the relationship between flow-mediated dilation (FMD) and serum apoA-IV level in type 2 diabetes mellitus (T2DM) patients. METHODS: A total of 84 T2DM patients with chest discomfort were enrolled in this study. Their baseline characteristics and clinical parameters were documented. Endothelial function of the participants was evaluated by examining FMD of brachial artery. The severity of coronary atherosclerosis was determined by quantitative coronary angiography. Serum apoA-IV levels were measured by ELISA. These diabetic patients were dichotomized into low FMD (n = 42) and high FMD (n = 42) groups. Serum apoA-IV levels were significantly higher in high FMD group than in low FMD group (29.96 ± 13.17 vs 17.69 ± 9.16 mg/dL, P < 0.001). Moreover, the patients were also categorized into three apoA-IV tertile groups. FMD was significantly different across three apoA-IV tertiles (P < 0.001). Serum apoA-IV levels were positively correlated to FMD (r = 0.469, P < 0.001). Logistic regression analysis was performed to determine risk factors for low FMD. apoA-IV levels together with the risk factor hsCRP remained significantly to be independent determinants of low FMD (P < 0.01). Linear regression analysis was performed, and apoA-IV levels together with total-to-HDL cholesterol ratio were independently correlated with FMD (P < 0.01). Serum apoA-IV levels are associated with FMD, suggesting that apoA-IV protects endothelial function in patients with T2DM. Show less
Airway epithelial cell (AEC) dysfunction has been proven to be involved in the pathogenesis of asthma, which may be induced by the use of dexamethasone (Dex). The altered expression of microRNAs (miRN Show more
Airway epithelial cell (AEC) dysfunction has been proven to be involved in the pathogenesis of asthma, which may be induced by the use of dexamethasone (Dex). The altered expression of microRNAs (miRNAs/miRs) has been found in asthma. However, the detailed mechanisms responsible for the effects of miR‑375 on Dex‑induced AEC dysfunction remain elusive. Thus, the present study aimed to elucidate these mechanisms. Following treatment with Dex for 0, 6, 12 and 24 h, AEC viability, migration, invasion and apoptosis were examined using Cell Counting Kit‑8 (CCK‑8), wound healing and Transwell assays, and flow cytometry, respectively. The expression levels of miR‑375, dual specificity phosphatase 6 (DUSP6) and apoptosis‑related proteins (Bcl‑2, Bax, cleaved caspase‑3) were measured using reverse transcription‑quantitative polymerase chain reaction and western blot analysis. The target genes and potential binding sites of miR‑375 and DUSP6 were predicted using TargetScan and confirmed using dual‑luciferase reporter assay. The viability, migration, invasion and apoptosis of Dex‑treated AECs were further assessed with or without miR‑375 and DUSP6. In the AECs (9HTE cells), Dex treatment suppressed cell viability and miR‑375 expression, whereas it promoted cell apoptosis and the expression of DUSP6, the target gene of miR‑375. The overexpression of miR‑375 reversed the effects of Dex treatment on miR‑375 expression, cell viability, migration and invasion, and apoptosis‑related protein expression; in turn, these effects were reversed by the overexpression of DUSP6, with the exception of miR‑375 expression. On the whole, the present study demonstrates that the overexpression of miR‑375 counteracts the effects of Dex treatment on AEC viability, migration, invasion and apoptosis by targeting DUSP6. Thus, it was suggested that the downregulated expression of miR‑375 may be a therapeutic target for AEC dysfunction. Show less
Zikuan Leng, Longyu Li, Xiang Zhou+6 more · 2022 · Medical science monitor : international medical journal of experimental and clinical research · added 2026-04-24
BACKGROUND Fundamental and clinical interest in mesenchymal stem cells (MSCs) has risen dramatically over the past 3 decades. The immunomodulatory and differentiation abilities are the main mechanisms Show more
BACKGROUND Fundamental and clinical interest in mesenchymal stem cells (MSCs) has risen dramatically over the past 3 decades. The immunomodulatory and differentiation abilities are the main mechanisms in vitro and in vivo. However, increasing evidence casts doubt on the stemness and immunogenicity of MSCs. MATERIAL AND METHODS We conducted a high-throughput 10x RNA sequencing and Smart-seq2 scRNA-seq analysis to reveal gene expression of Wharton jelly MSCs (WJ-MSCs) at a single-cell level. Multipotent differentiation, subpopulations, marker genes, human leucocyte antigen (HLA) gene expression, and cell cluster trajectory analysis were evaluated. RESULTS The WJ-MSCs had considerable heterogeneity between cells in terms of gene expression. They highly, partially, and hardly expressed genes related to mesodermal differentiation, endodermal differentiation, and ectodermal differentiation, respectively. Some cells seem to be bipotent or unipotent stem cells. Further, Monocle and cell cluster trajectory analysis demonstrated that 1 of the 3 divided clusters performed as stem cells, accounting for 12.6% of the population. The marker genes for a stem cell cluster were CRIM1, GLS, PLOD2, NEXN, ACTR2, FN1, MBNL1, LMOD1, COL3A1, NCL, SEC62, EPRS, COL5A2, COL8A1, and VCAN. In addition, the MSCs also highly, partially, and hardly expressed HLA-I antigen genes, HLA-II genes, and the HLA-G gene, respectively, indicating that MSCs probably have immunogenicity. A Kyoto Encyclopedia of Genes and Genomes pathway analysis of the 3 clusters demonstrated that they were mainly connected with viral infectious diseases, cancer, and endocrine and metabolic disorders. The most expressed transcription factors were zf-C2H2, HMG/HMGY, and Homeobox. CONCLUSIONS We found that only a subpopulation of WJ-MSCs are real stem cells and WJ-MSCs probably do not have immune privilege. Show less
The prognosis of human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer (MBC) remained unsatisfactory currently, more anti-HER2 agents are needed. Here we report a phase I s Show more
The prognosis of human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer (MBC) remained unsatisfactory currently, more anti-HER2 agents are needed. Here we report a phase I study that evaluated the safety, activity, and biomarkers of LZM005, a HER2 antibody, used as a monotherapy or in combination with trastuzumab plus docetaxel in patients with HER2-positive MBC. From October 2017 to December 2019, 34 patients received LZM005 (14 monotherapy, 20 combination therapy). No DLT was observed. The common adverse events (AEs) in phase Ia included diarrhea (21.4%), infusion reaction (21.4%), and hypertriglyceridemia (21.4%), while those in phase Ib were leukopenia (85.0%), neutropenia (75.0%), anemia (60.0%), diarrhea (60.0%), and rash/pruritus (50.0%). All AEs were manageable. In phase Ia, partial response (PR) was achieved in one case (1/14, overall response rate [ORR]: 7.1%); the disease control rate was 42.90% (6/14). In phase Ib, 11 patients (55.0%) achieved PR, and eight (40.0%) had stable disease. The ORR was 100% (6/6) in trastuzumab-naive and 35.7% (5/14) in trastuzumab-pretreated patients. Biomarker analysis showed that chromatin remodeling genes KMT2B and BRWD1 were associated with better progression-free survival. LZM005 is well tolerated and shows potent activity in patients with HER2-positive MBC. Show less
Liver cancer is the fifth most prevalent malignant tumor, while hepatocellular carcinoma represents the most prevalent subtype worldwide. Previous studies have associated the chromobox family, critica Show more
Liver cancer is the fifth most prevalent malignant tumor, while hepatocellular carcinoma represents the most prevalent subtype worldwide. Previous studies have associated the chromobox family, critical components of epigenetic regulatory complexes, with development of many malignancies owing to their role in inhibiting differentiation and promoting proliferation of cancer cells. However, little is known regarding their function in development and progression of hepatocellular carcinoma. In the present study, we analyzed differential expression, prognostic value, immune cell infiltration, and gene pathway enrichment of chromobox family in hepatocellular carcinoma patients. Next, we performed Pearson's correlation analysis to determine the relationships between chromobox family proteins with tumor-immune infiltration. Results revealed that high expression of CBX1, CBX2, CBX3, CBX6, and CBX8 was associated with poor survival rates of hepatocellular carcinoma patients. These five factors were used to build prognostic gene models using LASSO Cox regression analysis. Results indicated that high expression of CBX2 and CBX3 proteins was significantly associated with poor prognosis for hepatocellular carcinoma patients. The resulting nomogram revealed that CBX3 and T stages were significantly correlated with prognosis of hepatocellular carcinoma patients. Notably, predictive CBX3 was strongly correlated with immune cell infiltration. Furthermore, results from functional enrichment analysis revealed that CBX3 was mainly involved in regulation of methylation of Histone H3-K27. Collectively, these findings suggest that CBX3 could be a biomarker for predicting prognosis of hepatocellular carcinoma patients. Show less
Tubby-like protein 3 (TULP3) is a member of the tubby family, has been related to the development of nervous system by gene knockout researches. Nevertheless, the role of TULP3 in the gastric cancer i Show more
Tubby-like protein 3 (TULP3) is a member of the tubby family, has been related to the development of nervous system by gene knockout researches. Nevertheless, the role of TULP3 in the gastric cancer is not clear. Western blotting and real-time polymerase chain reaction (PCR) were employed for the quantitative detection of TULP3 expression in the gastric cancer and consecutive non-cancerous tissues, and gastric cancer cells. The roles of TULP3 in invasion, migration as well as proliferation of the gastric cancer cell in vivo and in vitro through utilizing colony formation, MTT, wound-healing, transwell and mouse xenograft model. Western blotting assay was implemented in order to clarify the potential molecular mechanisms. Furthermore, electron microscopy and western blot were evaluated TULP3 expression in gastric cancer patient extracted serum exosomes. TULP3 expression levels were remarkably upregulated in the gastric cancer tissues and cells. Subsequent functional assays demonstrated that TULP3 downregulation suppressed invasion, migration as well as the proliferation of the gastric cancer cell. Mechanism assays depicted that the PTEN/Akt/Snail signaling pathway can inhibit invasion, migration as well as the proliferation of the gastric cancer cell via TULP3 silencing. Finally, we found that the expression of TULP3 could be determined in the extracted serum exosomes. The expression of TULP3 in gastric cancer group was higher in comparison with normal group. Our results reveal that TULP3 might serve as a potential prognostic biomarker and therapeutic target for the treatment of gastric cancer. Show less
Differentiation blockade is a hallmark of acute myeloid leukemia (AML). A strategy to overcome such a blockade is a promising approach against the disease. The lack of understanding of the underlying Show more
Differentiation blockade is a hallmark of acute myeloid leukemia (AML). A strategy to overcome such a blockade is a promising approach against the disease. The lack of understanding of the underlying mechanisms hampers development of such strategies. Dysregulated ribonucleotide reductase (RNR) is considered a druggable target in proliferative cancers susceptible to deoxynucleoside triphosphate (dNTP) depletion. Herein, we report an unanticipated discovery that hyperactivating RNR enables differentiation and decreases leukemia cell growth. We integrate pharmacogenomics and metabolomics analyses to identify that pharmacologically (eg, nelarabine) or genetically upregulating RNR subunit M2 (RRM2) creates a dNTP pool imbalance and overcomes differentiation arrest. Moreover, R-loop-mediated DNA replication stress signaling is responsible for RRM2 activation by nelarabine treatment. Further aggravating dNTP imbalance by depleting the dNTP hydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) enhances ablation of leukemia stem cells by RRM2 hyperactivation. Mechanistically, excessive activation of extracellular signal-regulated kinase (ERK) signaling downstream of the imbalance contributes to cellular outcomes of RNR hyperactivation. A CRISPR screen identifies a synthetic lethal interaction between loss of DUSP6, an ERK-negative regulator, and nelarabine treatment. These data demonstrate that dNTP homeostasis governs leukemia maintenance, and a combination of DUSP inhibition and nelarabine represents a therapeutic strategy. Show less
Traditional Chinese herbal medicine draws more attention to explore an effective therapeutic strategy for Alzheimer's disease (AD). Shenqi Yizhi granule (SQYG), a Chinese herbal recipe, has been appli Show more
Traditional Chinese herbal medicine draws more attention to explore an effective therapeutic strategy for Alzheimer's disease (AD). Shenqi Yizhi granule (SQYG), a Chinese herbal recipe, has been applied to ameliorate cognitive impairment in mild-to-moderate AD patients. However, the overall molecular mechanism of SQYG in treating AD has not been clarified. This study aimed to investigate the molecular mechanism of SQYG on AD using an integration strategy of network pharmacology and molecular docking. The active compounds of SQYG and common targets between SQYG and AD were screened from databases. The herb-compound network, compound-target network, and protein-protein interaction network were constructed. The enrichment analysis of common targets and molecular docking were performed. 816 compounds and 307 common targets between SQYG and AD were screened. KEGG analysis revealed that common targets were mainly enriched in lipid metabolism, metal ion metabolism, IL-17 signaling pathway, GABA receptor signaling, and neuroactive ligand-receptor interaction. Molecular docking analysis showed high binding affinity between ginsenoside Rg1 and A The therapeutic mechanisms of SQYG on AD were associated with regulating lipid metabolism, metal ion metabolism, IL-17 signaling pathway, and GABA receptor signaling. Ginsenoside Rg1, tanshinone IIA, baicalin, astragaloside IV, and folic acid may play an important role in AD treatment. Show less
Nelumbo nucifera (N. nucifera), a kind of edible Chinese herbal, has been studied in treating hyperlipidemia. However, the hypolipidemic mechanism of N. nucifera remains unknown. Aims of this review: Show more
Nelumbo nucifera (N. nucifera), a kind of edible Chinese herbal, has been studied in treating hyperlipidemia. However, the hypolipidemic mechanism of N. nucifera remains unknown. Aims of this review: We aimed to screen the effective constituent of N. nucifera alkaloids and elucidated the potential mechanism for treating hyperlipidemia. A triple combination strategy of UHPLC-MS We comprehensively investigated the characterization of N. nucifera alkaloids by using UHPLC-LTQ-Orbitrap MS 35 compounds were identified from N. nucifera alkaloid extraction by UHPLC-LTQ-Orbitrap MS O-nornuciferine and N. nucifera alkaloids had exibited significant effects in hyperlipidemia. The candidate genes were LDLR, LPL and ANGPTL4, etc. It was most likely that they adjusted lipid metabolism by modulating expression levels of various key factors which were involved in bile secretion, glycerolipid metabolism, sphingolipid metabolism and PPAR signaling pathway, and so on. This study clarified the hypolipidemic mechanism of the alkaloids in N. nucifera, and laid a foundation for the subsequent development of clinical application and better quality of N. nucifera. Show less
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide, with high incidence and mortality rates and low survival rates. However, the detailed molecular mechanism of ESCC Show more
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide, with high incidence and mortality rates and low survival rates. However, the detailed molecular mechanism of ESCC progression remains unclear. Here, we first showed significantly higher WNT5A and SNAIL expression in ESCC samples than in corresponding paracancerous samples. High WNT5A and SNAIL expression levels correlated positively with lymphatic metastasis and poor prognosis for patients with ESCC based on immunohistochemical (IHC) staining of 145 paired ESCC samples. Spearman's correlation analyses confirmed the strong positive correlation between WNT5A and SNAIL expression, and patients with ESCC presenting coexpression of WNT5A and SNAIL had the worst prognosis. Then, we verified that the upregulation of WNT5A promoted ESCC cell metastasis in vivo and in vitro, suggesting that WNT5A might be a promising therapeutic target for the prevention of ESCC. Furthermore, WNT5A overexpression induced the epithelial-mesenchymal transition via histone deacetylase 7 (HDAC7) upregulation, and HDAC7 silencing significantly reversed WNT5A-induced SNAIL upregulation and ESCC cell metastasis. In addition, we used HDAC7 inhibitors (SAHA and TMP269) to further confirm that HDAC7 participates in WNT5A-mediated carcinogenesis. Based on these results, HDAC7 is involved in WNT5A-mediated ESCC progression, and approaches targeting WNT5A and HDAC7 might be potential therapeutic strategies for ESCC. Show less
Epigenetic alteration is a pivotal factor in tumor metastasis. PHD finger protein 13 (PHF13) is a recently identified epigenetic reader of H3K4me2/3 that functions as a transcriptional co-regulator. I Show more
Epigenetic alteration is a pivotal factor in tumor metastasis. PHD finger protein 13 (PHF13) is a recently identified epigenetic reader of H3K4me2/3 that functions as a transcriptional co-regulator. In this study, we demonstrate that PHF13 is required for pancreatic-cancer-cell growth and metastasis. Integrative analysis of transcriptome and epigenetic profiles provide further mechanistic insights into the epigenetic regulation of genes associated with cell metastasis during the epithelial-to-mesenchymal transition (EMT) induced by transforming growth factor β (TGFβ). Our data suggest PHF13 depletion impairs activation of TGFβ stimulated genes and correlates with a loss of active epigenetic marks (H3K4me3 and H3K27ac) at these genomic regions. These observations argue for a dependency of TGFβ target activation on PHF13. Furthermore, PHF13-dependent chromatin regions are enriched in broad H3K4me3 domains and super-enhancers, which control genes critical to cancer-cell migration and invasion, such as SNAI1 and SOX9. Overall, our data indicate a functional and mechanistic correlation between PHF13 and EMT. Show less
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
Pancreatic cancer (PC) is a lethal type of cancer for which effective therapies are limited. Long non‑coding RNAs (lncRNAs) represent a critical type of regulator category, mediating the tumorigenesis Show more
Pancreatic cancer (PC) is a lethal type of cancer for which effective therapies are limited. Long non‑coding RNAs (lncRNAs) represent a critical type of regulator category, mediating the tumorigenesis and development of various tumor types, including PC. However, the expression patterns and functions of numerous lncRNAs in PC remain poorly understood. In the present study, linc01614 was identified as a PC‑related lncRNA. linc01614 was notably upregulated in PC tissues and cell lines and was associated with the poor disease‑free survival of patients with PC according to the analysis of The Cancer Genome Atlas‑derived datasets. Functionally, linc01614 knockdown suppressed PC cell proliferation, migration and invasion Show less
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
The ubiquitin-proteasome system is an essential regulator of Acf7, which serves as a key effector for the maintenance of the EMT program and migration. However, the precise mechanism for the deubiquit Show more
The ubiquitin-proteasome system is an essential regulator of Acf7, which serves as a key effector for the maintenance of the EMT program and migration. However, the precise mechanism for the deubiquitination of Acf7 is still not fully understood. Using a proteomic approach, we identified ubiquitin-specific peptidase 14 (USP14) as an Acf7-associated deubiquitinase. Our findings show that there was an interaction between USP14 and Acf7. The expression of USP14 and Acf7 were elevated in lung cancer tissues compared to adjacent normal cells. Employing the overexpression of USP14 and the Show less
Nasal-type natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy with poor survival outcomes that is relatively resistant to chemotherapy. N6-Methyladenosine (m6A) modification, the most Show more
Nasal-type natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy with poor survival outcomes that is relatively resistant to chemotherapy. N6-Methyladenosine (m6A) modification, the most prevalent modification of eukaryotic messenger RNA, is involved in the progression of various tumors. However, it is unclear whether it has a physiological role in NKTCL development. To address this question, we probed its function and molecular mechanisms in NKTCL. Initially, we demonstrated that Wilms' tumor 1-associated protein (WTAP), a major RNA N6-adenosine methyltransferase, was obviously upregulated in human NKTCL cell lines (YTS and SNK-6 cells), compared with normal NK cells. Functionally, depletion of WTAP noticeably repressed proliferation and facilitated apoptosis in YTS and SNK-6 cells. Moreover, intervention of WTAP evidently prohibited NKTCL cell chemotherapy resistance to cisplatin, as reflected by a lower inhibition of cell viability and decreased expression of drug resistance-associated protein expression MRP-1 and P-gp in YTS and SNK-6 cells. With regard to the mechanism, we revealed that WTAP enhanced dual-specificity phosphatases 6 (DUSP6) expression by increasing m6A levels of DUSP6 mRNA transcript, leading to oncogenic functions in NKTCL. Interestingly, WTAP contributed to the progression and chemotherapy sensitivity of NKTCL by stabilizing DUSP6 mRNA in an m6A-dependent manner. Taken together, these findings uncovered a critical function for WTAP-guided m6A methylation and identified DUSP6 as an important target of m6A modification in the regulation of chemotherapy resistance in NKTCL oncogenesis. This study highlights WTAP as a potential therapeutic target of NKTCL treatment. Show less
Carbamoyl phosphate synthetase 1 (CPS1), which is the antigen for the hepatocyte paraffin 1 antibody, exhibits focal immunoreactivity in adenocarcinoma from the gastrointestinal tract, but its express Show more
Carbamoyl phosphate synthetase 1 (CPS1), which is the antigen for the hepatocyte paraffin 1 antibody, exhibits focal immunoreactivity in adenocarcinoma from the gastrointestinal tract, but its expression profiles and roles in gastric cancer (GC) remain largely unknown. The present study aimed to determine the expression pattern and prognostic value of CPS1 in Correa's cascade using tissues from 32 patients with chronic atrophic gastritis with intestinal metaplasia (IM), 62 patients with low- or high-grade intraepithelial neoplasia (IN) and 401 patients with GC. The expression of CPS1 was diffuse and strongly positive in 32 cases (100%) of IM of the glandular epithelium, and gradually downregulated in Correa's cascade, with a strongly positive ratio of 21 (70%) in low-grade IN and 4 (12.5%) in high-grade IN. The levels of CPS1 expression were significantly higher in diffuse-type GC, with 37 (26%) cases strongly positive for CPS1, compared with 14 (8%) in intestinal-type and 11 (13%) cases in mixed-type GC. In intestinal-type GC, CPS1 expression was completely lost in 107 (62%) of cases, which was associated with an advanced Tumor-Node-Metastasis stage (P=0.031) and depth of invasion (P=0.037). Kaplan-Meier analysis suggested that low CPS1 expression levels were independently associated with a short overall survival (OS) time in the three types of GC (P<0.001 in intestinal-type, P=0.003 in diffuse-type and P=0.018 in mixed-type GC). Furthermore, low levels of CPS1 mRNA and high methylation levels in the CPS1 promoter were associated with a short OS time in patients with GC. These results suggested that the expression of CPS1 was progressively downregulated in Correa's cascade, and that CPS1 may serve as a prognostic marker for patients with GC, regardless of tumor type. Show less
Chemoresistance is a severe clinical challenge in breast cancer. Hypoxia and cancer stem cells (CSCs) contribute to the paclitaxel (PTX) resistance, but the molecular mechanisms are still elusive. Mic Show more
Chemoresistance is a severe clinical challenge in breast cancer. Hypoxia and cancer stem cells (CSCs) contribute to the paclitaxel (PTX) resistance, but the molecular mechanisms are still elusive. MicorRNAs (miRNA) have been considered a promising therapeutic strategy in various cancers. Here, we identified the crucial function of miR-526b-3p in regulating PTX resistance and CSC properties. Our data demonstrated that miR-526b-3p mimic repressed the cell viability of breast cancer cells. The counts of Edu-positive cells were reduced by miR-526b-3p in breast cancer cells. Meanwhile, the apoptosis of breast cancer cells was induced by miR-526b-3p. Tumorigenicity analysis in the nude mice confirmed that miR-526b-3p attenuated the breast cancer cell growth Show less
Drug resistance is one of the major challenges for treatment of hepatocellular carcinoma (HCC) with sorafenib. Our present study found that sorafenib resistant (SR) HCC cells showed epithelial-mesench Show more
Drug resistance is one of the major challenges for treatment of hepatocellular carcinoma (HCC) with sorafenib. Our present study found that sorafenib resistant (SR) HCC cells showed epithelial-mesenchymal transition (EMT) characteristics with the downregulation of epithelial marker and upregulation of mesenchymal makers. The expression of Snail, a core factor of EMT, was increased in HCC/SR cells, while knockdown of Snail can restore sorafenib sensitivity and EMT potential of HCC/SR cells. Further, the upregulation of protein stability was responsible for the upregulation of Snail in HCC/SR cells. ATM and CSN2, which can stabilize Snail protein, were increased in HCC/SR cells. Knockdown of ATM and CSN2 can suppress the expression of Snail and increase sorafenib sensitivity of HCC/SR cells. It indicated that targeted inhibition of Snail might be helpful to overcome sorafenib resistance of HCC patients. Show less
Danhong injection (DHI) is a Chinese medical injection applied to the clinical treatment of cardiovascular diseases that has anti-inflammatory, antiplatelet aggregation and antithrombotic effects. Thi Show more
Danhong injection (DHI) is a Chinese medical injection applied to the clinical treatment of cardiovascular diseases that has anti-inflammatory, antiplatelet aggregation and antithrombotic effects. This study aimed to explore the effects of DHI on dyslipidemia and cholesterol metabolism in high-fat diet-fed rats. Sprague Dawley (SD) rats were randomly divided into six groups: normal group (Normal); hyperlipidemia model group (Model); DHI-treated groups at doses of 1.0 mL/kg, 2.0 mL/kg, 4.0 mL/kg; and simvastatin positive control group (2.0 mg/kg). The hypolipidemic effects of DHI were evaluated by measuring serum lipid levels, hepatic function and oxidative stress, respectively. And pathological changes in liver tissues were determined using hematoxylin-eosin (H&E) and oil red O staining. Moreover, the mRNA and protein expression levels of cholesterol metabolism related genes were detected by real-time PCR (RT-PCR) and Western blot. Compared with the Model group, DHI treatment markedly decreased the liver index and improved the pathological morphology of liver tissues. DHI treatment dose-dependently decreased the levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), malondialdehyde (MDA), and free fatty acids (FFA) in serum or liver tissues (P < 0.01 or P < 0.05), and increased the high-density lipoprotein cholesterol (HDL-C) and tripeptide glutathione (GSH) (P < 0.01 or P < 0.05). The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were increased in the DHI-treated groups (P < 0.01 or P < 0.05), while the alanine transaminase (ALT) and aspartate transaminase (AST) were decreased (P < 0.01 or P < 0.05). Furthermore, the expression levels of LDL receptor (LDLR), cholesterol 7-α-hydroxylase (CYP7A1), liver X receptor α (LXRα), and peroxisome proliferator-activated receptor α (PPARα) were dose-dependently upregulated in the DHI-treated groups, whereas the expression of sterol regulatory element-binding protein-2 (SREBP-2) was downregulated. Our study demonstrated that DHI markedly ameliorated hyperlipidemia rats by regulating serum lipid levels, inhibiting hepatic lipid accumulation and steatosis, improving hepatic dysfunction, and reducing oxidative stress. The potential mechanism was also tentatively investigated and may be related to the promotion of bile acid synthesis via activation of the PPARα-LXRα-CYP7A1 pathway. Therefore, DHI could be regarded as a potential hypolipidemic drug for the treatment of hyperlipidemia. Show less
AKI is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is available for AKI. RNA interference (RNAi) provides a new and potent method for Show more
AKI is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is available for AKI. RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this issue. We engineered red blood cell-derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs to treat experimental AKI in a mouse model after renal ischemia/reperfusion (I/R) injury and unilateral ureteral obstruction (UUO). Phage display identified peptides that bind to the kidney injury molecule-1 (Kim-1). RNA-sequencing (RNA-seq) characterized the transcriptome of ischemic kidney to explore potential therapeutic targets. REVs targeted with Kim-1-binding LTH peptide (REV A red blood cell-derived extracellular vesicle platform targeted Kim-1 in acutely injured mouse kidney and delivered siRNAs for transcription factors Show less
Metabolic reprogramming plays an important role in tumorigenesis. However, the metabolic types of different tumors are diverse and lack in-depth study. Here, through analysis of big databases and clin Show more
Metabolic reprogramming plays an important role in tumorigenesis. However, the metabolic types of different tumors are diverse and lack in-depth study. Here, through analysis of big databases and clinical samples, we identified a carbamoyl phosphate synthetase 1 (CPS1)-deficient hepatocellular carcinoma (HCC) subtype, explored tumorigenesis mechanism of this HCC subtype, and aimed to investigate metabolic reprogramming as a target for HCC prevention. A pan-cancer study involving differentially expressed metabolic genes of 7,764 tumor samples in 16 cancer types provided by The Cancer Genome Atlas (TCGA) demonstrated that urea cycle (UC) was liver-specific and was down-regulated in HCC. A large-scale gene expression data analysis including 2,596 HCC cases in 7 HCC cohorts from Database of HCC Expression Atlas and 17,444 HCC cases from in-house hepatectomy cohort identified a specific CPS1-deficent HCC subtype with poor clinical prognosis. In vitro and in vivo validation confirmed the crucial role of CPS1 in HCC. Liquid chromatography-mass spectrometry assay and Seahorse analysis revealed that UC disorder (UCD) led to the deceleration of the tricarboxylic acid cycle, whereas excess ammonia caused by CPS1 deficiency activated fatty acid oxidation (FAO) through phosphorylated adenosine monophosphate-activated protein kinase. Mechanistically, FAO provided sufficient ATP for cell proliferation and enhanced chemoresistance of HCC cells by activating forkhead box protein M1. Subcutaneous xenograft tumor models and patient-derived organoids were employed to identify that blocking FAO by etomoxir may provide therapeutic benefit to HCC patients with CPS1 deficiency. In conclusion, our results prove a direct link between UCD and cancer stemness in HCC, define a CPS1-deficient HCC subtype through big-data mining, and provide insights for therapeutics for this type of HCC through targeting FAO. Show less