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.

Enhancement Mechanism of Fish-Scale Surface Texture on Flow Switching and Mixing Efficiency in Microfluidic Chips.

Surface textures have a significant influence on surface-functional properties, which provide an alternative solution to create an accurate control of microfluidics flow. This paper studies the modulation ability of fish-scale surface textures on microfluidics flowing behavior on the ground of the early research on vibration machining-induced surface wettability variation. A microfluidic directional flow function is proposed by modifying the wall of the microchannel at the T-junction with different surface textures. The retention force caused by the surface tension difference between the two outlets in the T-junction is studied. In order to investigate the influence of fish-scale textures on the performance of the directional flowing valve and micromixer, T-shaped and Y-shaped microfluidic chips were fabricated. The experimental results indicated that with the aid of the fish-scale surface textures generated by vibration-assisted micromilling, directional liquid flow can be achieved at a specific input pressure range and the mixing efficiency of microfluidics can be improved dramatically.

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.

Investigation on the Micro Cutting Mechanism and Surface Topography Generation in Ultraprecision Diamond Turning.

Revealing forming mechanism of workpiece surface topography plays an important role in improving ultraprecision turning. In this paper, the forming mechanism of the turning workpiece surface topography is analyzed and verified by the theoretical simulation and experiment respectively. First, the factors directly related to the turning process are analyzed, and a volumetric error model is built and discussed, which considered geometric errors, tool geometry, spindle vibrations, feed rate, cut depth, and feed system position change. The vibration mechanism and laws of the spindle system under multi-field coupling is analyzed, and the effect of the spindle axial vibration on the turning surface topography is studied. In addition, influence of coupled vibrations on the turning surface texture is analyzed, and an equivalent machining model is constructed to identify crucial geometric errors of the workpiece surface topography. Finally, a homemade ultraprecision machine tool system is built and used for turning the workpiece surface, and the tested results of the surface topography demonstrate Ra is better, 10 nm and Rv is better, 20 nm. The end face of the workpiece forms periodically fluctuating wave and ripple patterns, and the comparison between theoretical analysis and experimental detection of the surface topography is verified.

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.

Cytoskeleton stiffness regulates cellular senescence and innate immune response in Hutchinson-Gilford Progeria Syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is caused by the accumulation of mutant prelamin A (progerin) in the nuclear lamina, resulting in increased nuclear stiffness and abnormal nuclear architecture. Nuclear mechanics are tightly coupled to cytoskeletal mechanics via lamin A/C. However, the role of cytoskeletal/nuclear mechanical properties in mediating cellular senescence and the relationship between cytoskeletal stiffness, nuclear abnormalities, and senescent phenotypes remain largely unknown. Here, using muscle-derived mesenchymal stromal/stem cells (MSCs) from the Zmpste24-/- (Z24-/- ) mouse (a model for HGPS) and human HGPS fibroblasts, we investigated the mechanical mechanism of progerin-induced cellular senescence, involving the role and interaction of mechanical sensors RhoA and Sun1/2 in regulating F-actin cytoskeleton stiffness, nuclear blebbing, micronuclei formation, and the innate immune response. We observed that increased cytoskeletal stiffness and RhoA activation in progeria cells were directly coupled with increased nuclear blebbing, Sun2 expression, and micronuclei-induced cGAS-Sting activation, part of the innate immune response. Expression of constitutively active RhoA promoted, while the inhibition of RhoA/ROCK reduced cytoskeletal stiffness, Sun2 expression, the innate immune response, and cellular senescence. Silencing of Sun2 expression by siRNA also repressed RhoA activation, cytoskeletal stiffness and cellular senescence. Treatment of Zmpste24-/- mice with a RhoA inhibitor repressed cellular senescence and improved muscle regeneration. These results reveal novel mechanical roles and correlation of cytoskeletal/nuclear stiffness, RhoA, Sun2, and the innate immune response in promoting aging and cellular senescence in HGPS progeria.

Investigation on the Tool Wear Suppression Mechanism in Non-Resonant Vibration-Assisted Micro Milling.

Excessive tool wear during hard and brittle material processing severely influences cutting performance. As one of the advanced machining technologies, vibration-assisted micro milling adds high-frequency small amplitude vibration on a micro milling tool or workpiece to improve cutting performance, especially for hard and brittle materials. In this paper, the tool wear suppression mechanism in non-resonant vibration-assisted micro milling is studied by using both finite element simulation and experiment methods. A finite element model of vibration-assisted micro milling using ABAQUS is developed based on the Johnson cook material and damage models. The tool-workpiece separation conditions are studied by considering the tool tip trajectories. The machining experiments are carried out on Ti-6Al-4V with a coated micro milling tool (fine-grain tungsten carbide substrate with ZrO2-BaCrO4 (ZB) coating) under different vibration frequencies (high, medium, and low) and cutting states (tool-workpiece separation or non-separation). The results show that tool wear can be reduced effectively in vibration-assisted micro milling due to different wear suppression mechanisms. The relationship between tool wear and cutting performance is studied, and the results indicate that besides tool wear reduction, better surface finish, lower burrs, and smaller chips can also be obtained as vibration assistance is added.

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.

Ultrastructure Characteristics of Different Chinese Medicine Syndromes of Helicobacter pylori-Correlated Gastric Diseases.

OBJECTIVE: To explore the ultrastructure characteristics of patients with dampness-heat of Pi (Spleen)-Wei (Stomach) syndrome (DHPW) and Pi-qi deficiency syndrome (PQD), both of which are Helicobacter pylori (Hp)-correlated gastric diseases (HPCG), and implicate a helpful hint for the clinical microcosmic syndrome differentiation. METHODS: Fourteen gastric mucosa samples from 6 chronic gastritis (CG) and 6 active peptic ulcer (including 8 DHPW, 4 PQD) as well as 2 healthy volunteers were collected and tested for Hp infection. The ultrastructure of gastric mucosa was observed under the transmission electron microscope (TEM). RESULTS: Among 14 gastric mucosa samples, 8 of them were Hp positive (6 DHPW and 2 PQD), which were all accordance with the results screened by supermicro-pathological method. Under TEM, the normal gastric mucosa, with tidy microvilli and abundant in mucus granules, mitochondria and rough endoplasmic reticulum distributed evenly, and with smooth nucleus membrane. But in those specimens of DHPW with Hp infection, microvilli were presented with burr shape. Especially, those samples from dampness-heat syndrome with predominant heat type (DHSH) patients were more obvious, with microvilli damaged, mitochondria concentrated and distributed in disorder, secretory tubule extended. In dampness-heat syndrome with predominant dampness type (DHSD) patients, mucus granules aggregated obviously, mitochondria swelled and blurred, and rough endoplasmic reticulum crowded. For 2 samples of DHPW without Hp infection, their microvilli were intact, with mitochondria increased and gathered but well-distributed, and secretory tubule extended mildly. In 2 PQD patients with Hp positive, the specimens of microvilli were sparse, and their mucus granules and mitochondria were decreased, with fractured crests and vacuole, secretory tubules extension to nucleus membrane, and rough endoplasmic reticulum extension in a pool-like way, and nucleus condensed. The 2 samples from PQD patients without Hp infection were characterized with intact microvilli, decreased mitochondria, fractured crest and extended rough endoplasmic reticulum in a pool-like way. CONCLUSION: It's obviously different in ultrastructure of DHPW and PQD patients under TEM, which may give a helpful hint for the microcosmic syndrome differentiation of HPCG.

Renal Subcapsular Transplantation of 2'-Deoxyguanosine-Treated Murine Embryonic Thymus in Nude Mice.

The thymus is an important central immune organ, which plays an essential role in the development and differentiation of T cells. Thymus transplantation is an important method for investigating thymic epithelial cell function and T cells maturation in vivo. Here we will describe the experimental methods used within our laboratory to transplant 2'-deoxyguanosine (to deplete donor's lymphocytes) treated embryonic thymus into the renal capsule of an athymic nude mouse. This method is both simple and efficient and does not require special skills or devices. The results obtained via this simple method showed that transplanted thymus can effectively support the recipient's T cells production. Additionally, several key points with regards to the protocol will be further elucidated.

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.

MUC1 and MUC5AC Acting on Helicobacter pylori-Related Deficiency and Solid Syndrome of Spleen and Stomach.

To investigate the relationship of MUC1, MUC5AC, and the syndrome of spleen and stomach, 109 subjects (34 peptic ulcer (PU), 62 chronic gastritis (CG), and 13 healthy volunteers (CON)) were included. All the subjects included were surveyed with questionnaire to classify them into damp-heat syndrome of spleen and stomach (DHSS), spleen-qi deficiency syndrome (SQD), and CON, examined by gastric endoscope, and biopsied. Rapid urease and methylene blue staining (MBS) were performed on every subject to diagnose for Helicobacter pylori (Hp) infection, and both were defined as Hp-positive. Hematoxylin and eosin (HE) staining was performed on every specimen to explore the histomorphology, inflammatory degree, and inflammatory activity of different groups; then Elivision™ plus kit was used to test the expression of MUC1 and MUC5AC. All the results of digital images were reviewed by two experts blindly. The inflammatory degree with Hp infection was higher than those uninfected or CON, but no significant difference was found between DHSS and SQD. And the expressions of MUC5AC with positive Hp was higher than those with negative Hp or CON regardless of the deficiency and solid syndrome of spleen-stomach but not for MUC1. We speculate that the deficiency and solid syndrome of spleen-stomach is a condition like Tai Ji symbol of dynamic equilibrium, showing the higher expression of MUC5AC but no change of MUC1 in the circumstance of Hp infection.

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.

Digoxin-induced anemia among patients with atrial fibrillation and heart failure: clinical data analysis and drug-gene interaction network.

Digoxin is widely used to treat various heart conditions. In order to clarify the association between digoxin and anemia adverse reaction, we inspected case reports submitted to the FDA Adverse Event Reporting System (FAERS) between January 2004 and December 2015. These reports involved 75618 atrial fibrillation patients and 15699 heart failure patients. Compared to other therapies, digoxin treatment was significantly more likely to be concurrent with anemia adverse reaction among both atrial fibrillation patients (pooled OR = 1.38, 95% CI 1.14-1.68, P-value = 0.001) and heart failure patients (pooled OR =1.50, 95% CI 1.33-1.59-, P =4.27×10-5). We further explored previously published evidences and found 821 human genes directly or indirectly interacting with digoxin. Functional analysis indicated that these genes were significantly enriched in the biological processes of iron transport, which are closely related to iron deficiency anemia. Taken together, our retrospective analysis demonstrated the significant association between digoxin treatment and anemia adverse reaction, which should be seriously considered in clinical practice. Functional enrichment analysis on digoxin-related genes warranted subsequent research on the underlying toxicological mechanisms.