Coptisine-mediated downregulation of E2F7 induces G2/M phase arrest in hepatocellular carcinoma cells through inhibition of E2F4/NFYA/NFYB transcription factors.

Coptisine (COP) has been shown to exhibit a wide range of anticancer properties, including in hepatocellular carcinoma (HCC). Nevertheless, the precise mechanism of COP in the treatment of HCC remains elusive. This study aims to investigate the potential mechanism of action of COP against HCC. By evaluating the anti-HCC activity of COP in different HCC cells lines and in xenografted nude mice, it was found that COP inhibited HCC in vitro and in vivo. Through RNA-Seq analysis, E2F7 was identified as a potential target of COP against HCC, as well as the cell cycle as a possible pathway. The overexpression of E2F7 and the inhibition of CHK1 demonstrated that COP inhibits the activity of HCC and induces G2/M phase arrest of HCC cells by down-regulating E2F7 and influencing the CHK1/CDC25A pathway. Finally, the promoter fragmentation experiments and chromatin immunoprecipitation revealed that COP down-regulated E2F7 by inhibiting the E2F4/NFYA/NFYB transcription factors. In conclusion, our study demonstrated that COP downregulates E2F7 by affecting key transcription factors, thereby inducing cell cycle arrest and inhibits HCC cell growth. This provides further evidence of the efficacy of COP in the treatment of tumors.

Yiwei Xiaoyu granules for treatment of chronic atrophic gastritis with deficiency syndrome of the spleen and stomach.

BACKGROUND: The Correa sequence, initiated by Helicobacter pylori (H. pylori), commonly progresses to gastric cancer through the stage of chronic atrophic gastritis (CAG). Although eradication of H. pylori only reduces the risk of gastric cancer, it does not eliminate the risk for neoplastic progression. Yiwei Xiaoyu granules (YWXY) are a commonly used composite preparation in Chinese clinics. However, the pursuit of excellence in clinical trials and the establishment of standardized animal experiments are still needed to contribute to full understanding and application of traditional Chinese medicine in the treatment of CAG. AIM: To demonstrate the effectiveness of YWXY in patients with CAG and spleen-stomach deficiency syndrome (DSSS), by alleviating histological scores, improving response rates for pathological lesions, and achieving clinical efficacy in relieving DSSS symptoms. METHODS: We designed a double-blind, randomized, controlled trial. The study enrolled seventy-two H. pylori-negative patients (mean age, 52.3 years; 38 men) who were randomly allocated to either the treatment group or control group in a 1:1 ratio, and treated with 15 g YWXY or 0.36 g Weifuchun (WFC) tablet combined with the respective dummy for 24 wk. The pre-randomization phase resulted in the exclusion of 72 patients: 50 participants did not meet the inclusion criteria, 12 participants declined to participate, and 10 participants were excluded for various other reasons. Seven visits were conducted during the study, and histopathological examination with target endoscopic biopsy of narrow-band imaging was requested before the first and seventh visits. We also evaluated endoscopic performance scores, total symptom scores, serum pepsinogen and gastrin-17. RESULTS: Six patients did not complete the trial procedures. Treatment with YWXY improved the Operative Link on Gastric Intestinal Metaplasia Assessment (OLGIM) stage, compared with WFC (P < 0.05). YWXY provided better relief from symptoms of DSSS and better improvement in serum gastric function, compared with WFC (P < 0.05). CONCLUSION: YWXY compared with WFC significantly reduced the risk of mild or moderate atrophic disease, according to OLGIM stage, significantly relieved symptoms of DSSS, and improved serum gastric function.

IL-33 Accelerates Chronic Atrophic Gastritis through AMPK-ULK1 Axis Mediated Autolysosomal Degradation of GKN1.

Chronic atrophic gastritis (CAG) is a complex disease characterized by atrophy and inflammation in gastric mucosal tissue, especially with high expression of interleukins. However, the interaction and mechanisms between interleukins and gastric mucosal epithelial cells in CAG remain largely elusive. Here, we elucidate that IL-33 stands out as the predominant inflammatory factor in CAG, and its expression is induced by H. pylori and MNNG through the ROS-STAT3 signaling pathway. Furthermore, our findings reveal that the IL-33/ST2 axis is intricately involved in the progression of CAG. Utilizing phosphoproteomics mass spectrometry, we demonstrate that IL-33 enhances autophagy in gastric epithelial cells through the phosphorylation of AMPK-ULK1 axis. Notably, inhibiting autophagy alleviates CAG severity, while augmentation of autophagy exacerbates the disease. Additionally, ROS scavenging emerges as a promising strategy to ameliorate CAG by reducing IL-33 expression and inhibiting autophagy. Intriguingly, IL-33 stimulation promotes GKN1 degradation through the autolysosomal pathway. Clinically, the combined measurement of IL-33 and GKN1 in serum shows potential as diagnostic markers. Our findings unveil an IL-33-AMPK-ULK1 regulatory mechanism governing GKN1 protein stability in CAG, presenting potential therapeutic targets for its treatment.

Integrating transcriptomics and network pharmacology to reveal the mechanisms of total Rhizoma Coptidis alkaloids against nonalcoholic steatohepatitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Non-alcoholic steatohepatitis (NASH) has emerged as a major cause of cirrhosis and hepatocellular carcinoma, posing a significant threat to public health. Rhizoma Coptidis, a traditional Chinese medicinal herb has been shown to have significant curative effects on liver diseases. Total Rhizoma Coptidis Alkaloids (TRCA) is a primarily alkaloid mixture extracted from Rhizoma Coptidis, and its constituents are widely accepted to have hepatoprotective effects. AIM OF THE STUDY: This work aimed to investigate the efficacy and potential mechanisms of TRCA in ameliorating NASH through both in vitro experiments and in vivo mouse models. MATERIALS AND METHODS: The study employed a mice model induced by a high-fat diet (HFD) to evaluate the effectiveness and pharmacological mechanisms of TRCA in alleviating NASH. Transcriptomic sequencing and network pharmacology were used to explore the possible targets and mechanisms of TRCA to ameliorate NASH. Further validation was performed in free fatty acid (FFA)-induced human hepatocytes (LO2) and human hepatocellular carcinoma cells (HepG2). RESULTS: TRCA effectively ameliorated the main features of NASH such as lipid accumulation, hepatitis and hepatic fibrosis in the liver tissue of mice induced by HFD, as well as improved glucose tolerance and insulin resistance in mice. Combined with transcriptomic and network pharmacological analyses, 68 core targets associated with the improvement of NASH by TRCA were obtained. According to the KEGG results, the core targets were significantly enriched in the PI3K-AKT signaling pathway whereas TRCA ameliorated the aberrant down-regulation of the PI3K-AKT signaling pathway induced by HFD. Furthermore, the five highest-ranked genes were obtained by PPI network analysis. Moreover, our findings suggest that TRCA may impede the progression of HFD-induced NASH by regulating the expression of PPARG, MMP9, ALB, CCL2, and EGFR. CONCLUSIONS: TRCA can ameliorate HFD-induced liver injury by modulating aberrant downregulation of the PI3K-AKT signaling pathway. Key proteins such as PPARG, MMP9, ALB, CCL2, and EGFR may be critical targets for TRCA to ameliorate NASH. This finding supports using Rhizoma Coptidis, a well-known herbal medicine, as a potential therapeutic agent for NASH.

Abnormal activation of the Wnt3a/ß-catenin signaling pathway promotes the expression of T-box transcription factor 3(TBX3) and the epithelial-mesenchymal transition pathway to mediate the occurrence of adenomyosis.

BACKGROUND: T-box transcription factor 3(TBX3) is a transcription factor that can regulate cell proliferation, apoptosis, invasion, and migration in different tumor cells; however, its role in adenomyosis (ADM) has not been previously studied. Some of ADM's pathophysiological characteristics are similar to those of malignant tumors (e.g., abnormal proliferation, migration, and invasion). METHODS AND RESULTS: We hypothesized that TBX3 might have a role in ADM. We used tamoxifen-induced Institute of Cancer research (ICR) mice to establish ADM disease model. The study procedure included western blotting and immunohistochemistry to analyze protein levels; additionally, we used intraperitoneal injection of Wnt/ß-catenin pathway inhibitor XAV-939 to study the relationship between TBX3 and Wnt/ß-catenin pathway as well as Anti-proliferation cell nuclear antigen( PCNA) and TUNEL to detect cell proliferation and apoptosis, respectively. TBX3 overexpression and epithelial-to-mesenchymal transition (EMT) in ADM mice was found to be associated with activation of the Wnt3a/ß-catenin pathway. Treatment with XAV-939 in ADM mice led to the inhibition of both TBX3 and EMT; moreover, abnormal cell proliferation was suppressed, the depth of invasion of endometrium cells was limited. Thus, the use of XAV-939 effectively inhibited further invasion of endometrial cells. CONCLUSION: These findings suggest that TBX3 may play an important role in the development of ADM. The expression of TBX3 in ADM was regulated by the Wnt3a/ß-catenin pathway. The activation of the Wnt3a/ß-catenin pathway in ADM promoted TBX3 expression and induced the occurrence of EMT, thus promoting cell proliferation and inhibiting apoptosis, ultimately accelerating the development of ADM. The study provides a reference for the diagnosis of ADM.

The Inactivation of Hippo Signaling Pathway Promotes the Development of Adenomyosis by Regulating EMT, Proliferation, and Apoptosis of Cells.

Adenomyosis is a benign gynecological disease. The pathogenesis of adenomyosis is still unclear. The Hippo signaling pathway is highly conserved in vivo and associated with endometriosis and various cancers. Our objective was to study the expression of Hippo signaling pathway-related proteins in the uterus of mice with and without adenomyosis. We also sought to determine the relationship between the Hippo signaling pathway and cell migration, invasion, proliferation, and apoptosis in adenomyosis. The inactivation of Hippo signaling pathway and abnormal expression of EMT-related proteins were observed in mice with adenomyosis. In vitro, the YAP inhibitor verteporfin can inhibit the proliferation and migration of Ishikawa cells and promote apoptosis, while inhibiting the EMT process. In addition, intraperitoneal injection of verteporfin inhibits EMT process and proliferation and promotes apoptosis of cells in the uterus of adenomyosis mice. It suggests that the Hippo signaling pathway participates in the EMT, proliferation, and apoptosis of cells in adenomyosis. In conclusion, these results suggest that Hippo signaling pathway may be involved in the development of adenomyosis by regulating EMT, proliferation, and apoptosis of cells, which provide a potential target for the treatment of adenomyosis.

Preventive and inhibitive effects of Yiwei Xiaoyu granules on the development and progression of spasmolytic polypeptide-expressing metaplasia lesions.

BACKGROUND: Spasmolytic polypeptide-expressing metaplasia (SPEM) is a potential preneoplastic lesion. AIM: To elucidate the microRNA (miR)-7-mediated preventive and inhibitive effects of Yiwei Xiaoyu granules (YWXY) in SPEM lesions. METHODS: Gastric mucosa biopsies were collected from chronic atrophic gastritis patients and healthy people with signed informed consent. YWXY was administered to the mice with induced SPEM by tamoxifen, and the gastric mucosa was harvested on the tenth day of the experiment. Then immunohistochemistry and immunofluorescence were performed to validate the SPEM, lesions and the potential mechanism was investigated. RNA transcripts were detected with reverse transcription-quantitative polymerase chain reaction. RESULTS: The expression of miR-7 was downregulated in the SPEM lesions, and expression of trefoil factor 2 (TFF2) and clusterin was high in the human gastric mucosa. In vivo experiments showed that YWXY could inhibit the cell proliferation in the tamoxifen-induced SPEM lesions by regulating Ki67. Simultaneously, YWXY could restore the expression of miR-7 by regulating TFF2 by detection with immunofluorescence but not with reverse transcription-quantitative polymerase chain reaction, indicating its potential mechanism of targeting miR-7 by mediating TFF2. The expression of vascular endothelial growth factor-ß and gastric intrinsic factor was restored within 3 d of YWXY administration for the SPEM lesions, speculating that the possible mechanism of YWXY is to inhibit the development and progression of SPEM by regulating vascular endothelial growth factor-ß and gastric intrinsic factor. CONCLUSION: miR-7 downregulation is an early event in SPEM through regulation of TFF2 in human gastric mucosa. YWXY is able to inhibit the cell proliferation and restore the expression of miR-7 by mediating TFF2 in the SPEM mouse model.

Aberrant RhoA activation in macrophages increases senescence-associated secretory phenotypes and ectopic calcification in muscular dystrophic mice.

Duchenne Muscular Dystrophy (DMD) patients often suffer from both muscle wasting and osteoporosis. Our previous studies have revealed reduced regeneration potential in skeletal muscle and bone, concomitant with ectopic calcification of soft tissues in double knockout (dKO, dystrophin-/-; utrophin-/-) mice, a severe murine model for DMD. We found significant involvement of RhoA/ROCK (Rho-Associated Protein Kinase) signaling in mediating ectopic calcification of muscles in dKO mice. However, the cellular identity of these RhoA+ cells, and the role that RhoA plays in the chronic inflammation-associated pathologies has not been elucidated. Here, we report that CD68+ macrophages are highly prevalent at the sites of ectopic calcification of dKO mice, and that these macrophages highly express RhoA. Macrophages from dKO mice feature a shift towards a more pro-inflammatory M1 polarization and an increased expression of various senescence-associated secretory phenotype (SASP) factors that was reduced with the RhoA/ROCK inhibitor Y-27632. Further, systemic inhibition of RhoA activity in dKO mice led to reduced number of RhoA+/CD68+ cells, as well as a reduction in fibrosis and ectopic calcification. Together, these data revealed that RhoA signaling may be a key regulator of imbalanced mineralization in the dystrophic musculoskeletal system and consequently a therapeutic target for the treatment of DMD or other related muscle dystrophies.

Two Bariatric Surgical Procedures Differentially Alter the Intestinal Microbiota in Obesity Patients.

AIMS: To explore the intestinal microbiota composition affected by the two most widely used procedures of bariatric surgery, laparoscopic sleeve gastrectomy (LSG) and laparoscopic roux-en-Y gastric bypass (LRYGB), in Chinese obesity patients. METHODS: Stool samples were collected from the obese patients before (n = 87) and with follow-up after the surgery (n = 53). After DNA extraction, 16S rDNA (V3 + V4 regions) sequencing was completed on Illumina HiSeq 2500 sequencing platform. The samples were analyzed base on four groups, pre-LSG (n = 54), pre-LRYGB (n = 33), post-LSG (n = 33), and post-LRYGB (n = 20). The linear mixed models were used to analyze the alteration of intestinal microbiota before and after the surgeries of LSG or LRYGB. Student's t test and χ2 test were used for analysis of independent groups; Metastats analysis was used to compare the relative abundance of bacteria, and Pearson correlation and Spearman correlation analysis were used to test the correlation between indicated groups. RESULTS: 87 patients were included and 53 (60.92%) of them completed the follow-up (9.60 ± 3.92 months). Body mass index (BMI) decreased from 37.84 ± 6.16 kg/m2 to 26.22 ± 4.33 kg/m2 after LSG and from 45.75 ± 14.26 kg/m2 to 33.15 ± 10.99 kg/m2 after LRYGB. The relative abundance of 5 phyla and 42 genera were altered after the surgery in the cohort. Although no alteration of Firmicutes was observed at phylum level, 54.76% of the altered genera belong to phylum Firmicutes. Both LSG and LRYGB procedures increased the richness and evenness of intestinal microbiota in obese patients after the surgery. Particularly, 33 genera altered after LSG and 19 genera altered after LRYGB, in which 11 genera were common alterations in both procedures. CONCLUSION: Both LSG and LRYGB altered the composition of intestinal microbiota in Chinese obesity patients, and particularly increased the richness and evenness of microbiota. Genera belonging to phylum Firmicutes were the most altered bacteria by bariatric surgery. The procedure of LSG resulted in much more pronounced alteration of the intestinal microbiota abundance than that observed in LRYGB. While different genera were altered after LSG and LRYGB procedures, 10 genera were the common altered genera in both procedures. Bacteria altered after LSG and LRYGB were functionally associated with BMI, and with relieving of the metabolic syndromes.

Appendix Bleeding with Painless Bloody Diarrhea: A Case Report and Literature Review.

Appendix bleeding is an uncommon clinical phenomenon. In this article, we reported a case of appendix bleeding with painless bloody diarrhea. With the analysis of clinical features, clinical examination, experimental test and literature review, we diagnosed that the appendix bleeding might be caused by granulomatous appendicitis. This successfully cured case might be a reference for later diagnosis and treatment of appendix bleeding with painless bloody diarrhea.

Haploinsufficiency of Insm1 Impairs Postnatal Baseline ß-Cell Mass.

Baseline ß-cell mass is established during the early postnatal period when ß-cells expand. In this study, we show that heterozygous ablation of Insm1 decreases baseline ß-cell mass and subsequently impairs glucose tolerance. When exposed to a high-fat diet or on an ob/ob background, glucose intolerance was more severe in Insm1+/lacZ mice compared with Insm1+/+ mice, although no further decrease in the ß-cell mass was detected. In islets of early postnatal Insm1+/lacZ mice, the cell cycle was prolonged in ß-cells due to downregulation of the cell cycle gene Ccnd1 Although Insm1 had a low affinity for the Ccnd1 promoter compared with other binding sites, binding affinity was strongly dependent on Insm1 levels. We observed dramatically decreased binding of Insm1 to the Ccnd1 promoter after downregulation of Insm1 expression. Furthermore, downregulation of Ccnd1 resulted in a prolonged cell cycle, and overexpression of Ccnd1 rescued cell cycle abnormalities observed in Insm1-deficient ß-cells. We conclude that decreases in Insm1 interfere with ß-cell specification during the early postnatal period and impair glucose homeostasis during metabolic stress in adults. Insm1 levels are therefore a factor that can influence the development of diabetes.

Effects of Yangzheng Sanjie Decoction-containing serum mediated by microRNA-7 on cell proliferation and apoptosis in gastric cancer.

Gastric cancer (GC) is one of the most common types of cancer and a leading cause of cancer-associated mortality. MicroRNAs (miRNAs/miRs) are demonstrated to function as oncomiRs or tumor-suppressor-miRs in GC. miR-7 has been identified to be a tumor suppressor of GC by targeting epidermal growth factor receptor (EGFR). In our previous study, Yangzheng Sanjie Decoction (YZSJD), a traditional Chinese formula, was identified to be effective in alleviating the symptoms and even postponing turnover of precancerous lesions. To elucidate the mechanism of YZSJD, the present study evaluated the effects of YZSJD of the GC MKN-45 cell line and investigated the underlying molecular mechanisms using YZSJD-containing serum (YCS). The expression of miR-7 in GC, normal and adjacent tissue samples was examined. The results demonstrated that YCS inhibited proliferation by inducing cell cycle arrest at the S phase, and significantly induced apoptosis compared with the control group. miR-7 was significantly downregulated in GC tissues compared with the matched ones. Using reverse transcription-quantitative polymerase chain reaction and western blot analysis, the expression of miR-7 was inversely associated with EGFR. This indicates that YCS inhibits proliferation and induces apoptosis of GC cells mediated by miR-7 targeting EGFR, which may be one of the mechanisms whereby YZSJD exerts its effects on GC.

Yangzheng Sanjie decoction regulates proliferation and apoptosis of gastric cancer cells by enhancing let-7a expression.

AIM: To explore the let-7a-mediated anti-cancer effect of Yangzheng Sanjie decoction (YZSJD) in gastric cancer (GC) cells. METHODS: YZSJD-containing serum (YCS) was prepared using traditional Chinese medicine serum pharmacology methods. After YCS treatment, cell proliferation and apoptosis were assessed by cell counting kit-8 assay and flow cytometry, respectively, and miRNA expression profiles were determined using qPCR arrays. Let-7a expression was examined by in situ hybridization in GC tissues and by qPCR in GC cells. c-Myc protein expression was detected by immunohistochemistry in GC tissues, and by Western blot in cell lines. RESULTS: YZSJD significantly inhibited proliferation and induced apoptosis in AGS and HS-746T GC cells. After treatment with YCS, the miRNA expression profiles were altered and the reduced let-7a levels in both cell lines were up-regulated, accompanied by a decrease in c-Myc expression. Moreover, decreased let-7a expression and increased c-Myc expression were observed during the progression of gastric mucosa cancerization. CONCLUSION: YZSJD inhibits proliferation and induces apoptosis of GC cells by restoring the aberrant expression of let-7a and c-Myc.

Whole Genome Sequence Identified a Rare Homozygous Pathogenic Mutation of the DSG2 Gene in a Familial Arrhythmogenic Cardiomyopathy Involving Both Ventricles.

BACKGROUND: This study was designed to identify the pathogenic mutation in a Chinese family with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) using whole genome sequencing (WGS). METHODS AND RESULTS: Probands II:1 and II:2 underwent routine examinations for diagnosis. Genomic DNA was extracted from the peripheral blood of family members and analyzed using WGS. A total of 60,285 single-nucleotide polymorphisms (SNP) and 13,918 insertions/deletions (InDel) occurring in the exonic regions of genes and predisposing to cardiomyopathies and arrhythmias were identified. When filtered using the 1000 Genomes Project (2014 version), NHLBI ESP6500, and ExAC databases, 12 missense SNP and 2 InDel in exonic regions remained, the allele frequencies of which were <0.01 or unknown. The potentially pathogenic mutations that occurred in the genes DSG2, PKP4, PRKAG2, FOXD4, CTTN, and DMD, which were identified by SIFT or PolyPhen-2 software as "damaging," were validated using Sanger sequencing. Probands II:1 and II:2 shared an extremely rare homozygous mutation in the DSG2 (p.F531C) gene, which was also demonstrated using intersection analysis of WGS data from probands II:1 and II:2. Electron microscopy and histological staining of myocardial biopsies showed widened and destroyed intercalated discs, and interrupted, atrophic, and disarranged myocardial fibers, and hyperplastic interstitial fibers, collagen fibers, and adipocytes were infiltrated and invaded. CONCLUSIONS: A homozygous mutation of DSG2 p.F531C was identified as the pathogenic mutation in patients with ARVC/D involving both ventricles, as a result of widened and impaired intercalated discs, interrupted myocardial fibers, and abnormally hyperplastic interstitial fibers, collagen fibers, and adipocytes.

Interleukin-12 and interferon-γ acting on damp-heat of spleen- stomach syndrome triggered by Helicobacter pylori.

OBJECTIVE: To investigate the expression of and interleukin-12 (IL-12) and interferon-γ (IFN-γ) in relation to the pathology of damp-heat of spleen-stomach syndrome (DHSS) induced by Helicobacter pylori (H. pylori) infection. METHODS: In total, 114 individual gastric mucosal specimens including 83 DHSS, 19 spleen-qi deficiency syndrome (SQD) and 12 from healthy volunteers (CON) were collected by gastroscopy. To explore the relationship between the two syndromes and H. pylori infection, individual samples were tested using rapid urease and methylene blue tests. Hematoxylin and eosin stained sections were examined to grade for the degree of inflammation and inflammatory activity, and expression of IL-12 and IFN-γ was investigated by immunohistochemistry. RESULTS: Statistically significant differences in the degree of inflammation and inflammatory activity were observed between the groups of specimens: DHSS, SQD and CON (P < 0.05). Additionally, greater intestinal metaplasia (IM) and dysplasia were observed in the DHSS group, especially those with H. pylori infection. Expression of both IFN-γ; and IL-12 was higher in DHSS samples infected with H. pylori than in uninfected samples and in the CON (P < 0.05) but not in the SQD (P > 0.05) groups. Intriguingly, in gastric specimens exhibiting IM and dysplasia, IL-12 translocated from the nucleus into the cytoplasm. CONCLUSION: Our findings suggest that IL-12 and IFN-γ are involved in DHSS pathology, but not in SQD, acting as healthy-Qi. DHSS is not just the consequence of those two cytokines but results from the cross-talk between a number of cytokines and/or other proteins, which may warrant further investigation in DHSS patients infected with H. pylori.

Role of microRNA-7 in digestive system malignancy.

There are several malignancies of the digestive system (including gastric, pancreatic and colorectal cancers, and hepatocellular carcinoma), which are the most common types of cancer and a major cause of death worldwide. MicroRNA (miR)-7 is abundant in the pancreas, playing an important role in pancreatic development and endocrine function. Expression of miR-7 is downregulated in digestive system malignancies compared with normal tissue. Although there are contrasting results for miR-7 expression, almost all research reveals that miR-7 is a tumor suppressor, by targeting various genes in specific pathways. Moreover, miR-7 can target different genes simultaneously in different malignancies of the digestive system. By acting on many cytokines, miR-7 is also involved in many gastrointestinal inflammatory diseases as a significant carcinogenic factor. Consequently, miR-7 might be a biomarker or therapeutic target gene in digestive system malignancies.

Changes of Virtual Planar QRS and T Vectors Derived from Holter in the Populations with and without Diabetes Mellitus.

AIMS: Research related to type 2 diabetes mellitus (DM) and parameters of electrocardiography (ECG) was limited. Patients with and without DM (NDM) were randomly enrolled in a study to exploit the influence of DM on planar QRS and T vectors derived from the Virtual Holter process. METHODS: A total of 216 (NDM) and 127 DM patients were consecutively and randomly recruited. We selected a 1-minute length of ECG, which was scheduled for analysis at 4 AM. After a series of calculating algorisms, we received the virtual planar vector parameters. RESULTS: Patients with DM were elderly (65.61 ± 12.08 vs 59.41 ± 16.86 years, P < 0.001); higher morbidity of hypertension (76.38% vs 58.14%, P < 0.001) and coronary artery disease (44.09% vs 32.41%, P = 0.03); thicker interventricular septum (10.92 ± 1.77 vs 10.08 ± 1.96 mm, P < 0.001) and left ventricular posterior wall (9.84 ± 1.38 vs 9.39 ± 1.66 mm, P = 0.03); higher lipid levels and average heart rate (66.67 ± 12.04 vs 61.87 ± 13.36 bpm, P < 0.01); higher angle of horizontal QRS vector (HQRSA, -2.87 ± 48.48 vs -19.00 ± 40.18 degrees, P < 0.01); lower maximal magnitude of horizontal T vector (HTV, 2.33 ± 1.47 vs 2.88 ± 1.89 mm, P = 0.01) and maximal magnitude of right side T vector (2.77 ± 1.55 vs 3.27 ± 1.92 mm, P = 0.03), and no difference in angle of frontal QRS-T vector (FQRSTA, 32.77 ± 54.20 vs 28.39 ± 52.87 degrees, P = 0.74) compared with patients having NDM. After adjusting for confounding factors, DM was significantly effective on FQRSTA (regression coefficient -40.0, 95%CI -66.4 to -13.6, P < 0.01), HQRSA (regression coefficient 22.6, 95%CI 2.5 to 42.8, P = 0.03), and HTV (regression coefficient 0.9, 95%CI 0.2 to 1.7, P = 0.01). Confounding factors included: sex, 2-hour postprandial blood glucose, smoking, triglyceride, apolipoprotein A, creatinine, left ventricular ejection fraction, and average heart rate. CONCLUSIONS: The risk factors of DM and lipid metabolism abnormality particularly apolipoprotein A significantly modified parameters of virtual planar QRS and T vector, including frontal QRS-T angle.

Sp1 and c-Myc modulate drug resistance of leukemia stem cells by regulating survivin expression through the ERK-MSK MAPK signaling pathway.

BACKGROUND: Acute myeloid leukemia (AML) is initiated and maintained by a subset of self-renewing leukemia stem cells (LSCs), which contribute to the progression, recurrence and therapeutic resistance of leukemia. However, the mechanisms underlying the maintenance of LSCs drug resistance have not been fully defined. In this study, we attempted to elucidate the mechanisms of LSCs drug resistance. METHODS: We performed reverse phase protein arrays to analyze the expression of anti-apoptotic proteins in the LSC-enriched leukemia cell line KG-1a. Immuno-blotting, cell viability and clinical AML samples were evaluated to verify the micro-assay results. The characteristics and transcriptional regulation of survivin were analyzed with the relative luciferase reporter assay, mutant constructs, chromatin immuno-precipitation (ChIP), quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR), and western blotting. The levels of Sp1, c-Myc, phospho-extracellular signal-regulated kinase (p-ERK), phospho-mitogen and stress-activated protein kinase (p-MSK) were investigated in paired CD34+ and CD34- AML patient samples. RESULTS: Survivin was highly over-expressed in CD34 + CD38- KG-1a cells and paired CD34+ AML patients compared with their differentiated counterparts. Functionally, survivin contributes to the drug resistance of LSCs, and Sp1 and c-Myc concurrently regulate levels of survivin transcription. Clinically, Sp1 and c-Myc were significantly up-regulated and positively correlated with survivin in CD34+ AML patients. Moreover, Sp1 and c-Myc were further activated by the ERK/MSK mitogen-activated protein kinase (MAPK) signaling pathway, modulating survivin levels. CONCLUSION: Our findings demonstrated that ERK/MSK/Sp1/c-Myc axis functioned as a critical regulator of survivin expression in LSCs, offering a potential new therapeutic strategy for LSCs therapy.