The SMAD2/miR-4256/HDAC5/p16INK4a signaling axis contributes to gastric cancer progression.

The dysregulation of exosomal microRNAs (miRNAs) plays a crucial role in the development and progression of cancer. This study investigated the role of a newly identified serum exosomal miRNA miR-4256 in gastric cancer (GC) and the underlying mechanisms. The differentially expressed miRNAs were firstly identified in serum exosomes of GC patients and healthy individuals using next-generation sequencing and bioinformatics. Next, the expression of serum exosomal miR-4256 was analyzed in GC cells and GC tissues, and the role of miR-4256 in GC was investigated by in vitro and in vivo experiments. Then, the effect of miR-4256 on its downstream target genes HDAC5/p16INK4a was studied in GC cells, and the underlying mechanisms were evaluated using dual luciferase reporter assay and Chromatin Immunoprecipitation (ChIP). Additionally, the role of the miR-4256/HDAC5/p16INK4a axis in GC was studied using in vitro and in vivo experiments. Finally, the upstream regulators SMAD2/p300 that regulate miR-4256 expression and their role in GC were explored using in vitro experiments. miR-4256 was the most significantly upregulated miRNA and was overexpressed in GC cell lines and GC tissues; in vitro and in vivo results showed that miR-4256 promoted GC growth and progression. Mechanistically, miR-4256 enhanced HDAC5 expression by targeting the promoter of the HDAC5 gene in GC cells, and then restrained the expression of p16INK4a through the epigenetic modulation of HDAC5 at the p16INK4a promoter. Furthermore, miR-4256 overexpression was positively regulated by the SMAD2/p300 complex in GC cells. Our data indicate that miR-4256 functions as an oncogene in GC via the SMAD2/miR-4256/HDAC5/p16INK4a axis, which participates in GC progression and provides novel therapeutic and prognostic biomarkers for GC.

Hepatic DKK1-driven steatosis is CD36 dependent.

Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide; about 25% of NAFLD silently progress into steatohepatitis, in which some of them may develop into fibrosis, cirrhosis and liver failure. However, few drugs are available for NAFLD, partly because of an incomplete understanding of its pathogenic mechanisms. Here, using in vivo and in vitro gain- and loss-of-function approaches, we identified up-regulated DKK1 plays a pivotal role in high-fat diet-induced NAFLD and its progression. Mechanistic analysis reveals that DKK1 enhances the capacity of hepatocytes to uptake fatty acids through the ERK-PPARγ-CD36 axis. Moreover, DKK1 increased insulin resistance by activating the JNK signaling, which in turn exacerbates disorders of hepatic lipid metabolism. Our finding suggests that DKK1 may be a potential therapeutic and diagnosis candidate for NAFLD and metabolic disorder progression.

A Freshwater Fish-Based Diet Alleviates Liver Steatosis by Modulating Gut Microbiota and Metabolites: A Clinical Randomized Controlled Trial in Chinese Participants With Nonalcoholic Fatty Liver Disease.

INTRODUCTION: We aimed to assess the effects of 2 isoenergetic intervention diets (a freshwater fish-based diet [F group] or freshwater fish-based and red meat-based diets alternately [F/M group]) on liver steatosis and their relationship with intestinal flora in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: In this open-label, 84-day randomized controlled trial, 34 NAFLD patients with hepatic steatosis ≥10% were randomly assigned to the F group or F/M group in a 1:1 ratio using a computer-generated random number allocation by a researcher not involved in the study. Liver fat content and gut microbiota and its metabolites were measured. RESULTS: At the end of intervention, the absolute reduction of hepatic steatosis was significantly greater in the F group than in the F/M group (-4.89% vs -1.83%, P = 0.032). Of the 16 secondary clinical outcomes, the improvement in 7 in the F group was greater compared with the F/M group, including alanine aminotransferase and gamma-glutamyl transferase. Furthermore, dietary freshwater fish and red meat consumption alternately did not exacerbate NAFLD. Moreover, changes in the enrichment of Faecalibacterium, short-chain fatty acids, and unconjugated bile acids and the depletion of Prevotella 9 and conjugated bile acids in the F group were significantly greater compared with the F/M group. DISCUSSION: Higher intake of freshwater fish may be beneficial to NAFLD by regulating gut microbiota and its metabolites, whereas intake of a similar total of animal protein and fat from the alternating freshwater fish and red meat may not be harmful for NAFLD in the dietary management of patients with NAFLD.

Differential Effects of Dietary White Meat and Red Meat on NAFLD Progression by Modulating Gut Microbiota and Metabolites in Rats.

Objective: To assess the effects of dietary white meat (grass carp and chicken) and red meat (pork and beef) on metabolic parameters, including the intestinal microbiota and its metabolites (SCFAs and bile acids) in NAFLD rats induced by high-fat diet. Methods: NAFLD rats were randomly assigned to five groups: NAFLD group, grass carp group, chicken group, pork group, and beef group (10 rats in each group), and these rats were fed for 8 weeks using the high-fat diet, grass carp-based diet, chicken-based diet, pork-based diet, and beef-based diet, respectively. At the end of the intervention, NAFLD-related metabolic indexes, intestinal flora, and its metabolites were measured. Results: The grass carp-based diet significantly improved hepatic pathological changes and glycolipid metabolism, and the chicken-based diet only partially improved the metabolic parameters. However, NAFLD progression was observed in the pork group and the beef group. What is more, the white meat-based diet-mediated changes in the enrichment of beneficial bacteria (such as Lactobacillus or Akkermansia), SCFAs, and unconjugated BAs (such as UDCA) and the depletion of pathogenic bacteria (such as Bilophila and Prevotella_9) and conjugated BAs were observed, while the red meat-based diet-induced changes in the enrichment of pathogenic bacteria (Prevotella_9 or Lachnospiraceae_UCG-010) and conjugated BAs and the depletion of SCFAs and unconjugated BAs were found. Conclusion: The dietary white meat and red meat modulating gut microbiota and its metabolites may favor and aggravate NAFLD in rats, respectively.

Repulsive Guidance Molecule b Deficiency Induces Gut Microbiota Dysbiosis and Increases the Susceptibility to Intestinal Inflammation in Mice.

Imbalance of gut microbiota can induce or aggravate intestinal inflammation. To enhance our understanding of the molecular mechanisms of gut microbiota and inflammatory bowel disease (IBD), we studied the role of repulsive guidance molecule b (RGMb) in gut microbiota and colitis in mice. We generated Rgmb knockout mice and inducible Rgmb knockout mice and induced colitis using dextran sulfate sodium (DSS) in these mice. 16S ribosomal RNA (rRNA) high-throughput sequencing was performed to acquire the gut microbiota composition and abundance. We found that Rgmb deficiency significantly altered the diversity of gut microbiota and also induced dysbiosis. In sharp contrast to the balanced distribution of various bacteria in control mice, Prevotellaceae was almost exhausted in Rgmb-deficient mice under both basal and inflammatory conditions. Correlation analysis indicated that Prevotellaceae was negatively associated with inflammation in Rgmb-deficient mice with colitis. Similar results were obtained at the early inflammatory stage of colitis associated colon cancer (CAC). Taken together, our results reveal that Rgmb deficiency leads to dysbiosis of predominant gut microbiota under basal and inflammatory conditions. Rgmb-deficiency-mediated Prevotellaceae loss may render mice more susceptible to intestinal inflammation. Therefore, RGMb may be a novel potential target for reconstruction of the gut microbiota for the treatment of IBD.

MiR-483-5p promotes IGF-II transcription and is associated with poor prognosis of hepatocellular carcinoma.

The human insulin-like growth factor-II (IGF-II) gene transcribes four mRNAs (P1 mRNA-P4 mRNA), and P3 mRNA overexpression contributes to hepatocarcinogenesis. IGF-II-derived miR-483-5p is implicated in the development of cancers. Here, we investigated the involvement of miR-483-5p in P3 mRNA overexpression regulation and its role in hepatocellular carcinoma. Our results showed that miR-483-5p up-regulated P3 mRNA transcription by targeting the 5'-untranslated region (5'UTR) of P3 mRNA in hepatocellular carcinoma. The mechanism was involved in recruiting of an argonaute 1(Ago1)-argonaute 2 (Ago2) complex to the P3 mRNA 5'UTR and the P3 promoter of IGF-II gene by miR-483-5p, accompanied by increased enrichment of RNA polymerase II and activating histone marks histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 27 acetylation (H3K27ac), and histone 4 lysine 5/8/12/16 acetylation (H4Kac) at the P3 promoter. High miR-483-5p expression was an independent predictor for shorter survival of HCC patients. The findings suggest that miR-483-5p promotes P3 mRNA transcription by recruiting the Ago1-Ago2 complex to the P3 mRNA 5'UTR and is associated with poor prognosis of HCC. Our results display a potential new model for miRNAs to up-regulate gene expression.

Acute abrin poisoning treated with continuous renal replacement therapy and hemoperfusion successfully: A case report.

RATIONALE: Abrin is a highly toxic protein obtained from the seeds of Abrus precatorius, but poisoning due to ingestion of A precatorius is extremely rare in China. PATIENT CONCERNS: A 16-year-old girl, perfectly healthy before, was admitted to the department of gastroenterology owing to intentional ingestion of 10 crushed A precatorius seeds, with multiple episodes of somnolent and anxious mental status, vomiting, abdominal pain, diarrhea, hematochezia, and hematuria. DIAGNOSIS: Acute abrin poisoning. INTERVENTIONS: We immediately took effective measures including gastric lavage, purgation, gastric acid suppression by proton pump inhibitor (PPI), liver protection, hemostasis, blood volume and electrolytes resuscitation, continuous renal replacement therapy (CRRT), and hemoperfusion (HP). OUTCOMES: Her unwell mental status was improved to the point at which she became conscious and relaxed. The symptoms of vomiting, abdominal pain, diarrhea, hematochezia, and hematuria disappeared gradually. The girl eventually made an excellent recovery with no complications at her 3-month follow-up. LESSONS: The combination of CRRT and HP is an efficient measure in the treatment of abrin poisoning for which there is no specific antidote. This is the first reported case of an abrin poisoning patient successfully treated by CRRT plus HP. Our experience will be useful to other physicians in managing patients of acute abrin poisoning in the future.

Matrix Metalloproteinase-9 -1562C/T Gene Polymorphism Is Associated with Diabetic Nephropathy.

To investigate the association between the metalloproteinase-9 (MMP9) -1562C/T polymorphism and diabetic nephropathy (DN) in Han Chinese, the patients with type 2 diabetes were collected and divided into the non-DN (NDN) and DN groups; controls were recruited. Genotype and allele frequencies were assessed using polymerase chain reaction and restriction fragment length polymorphism. Results showed that SBP, DBP, HbA1c, UAER, Cr, BUN, TG, and TC were higher in the DN group compared with the control and NDN groups. SBP, HbA1c, and TC in DN patients with the TT and CT genotypes were lower than in those with CC. Compared with controls, the frequency of the T allele in the DN group was significantly lower. The MMP9 -1562C allele, SBP, Cr, BUN, TG, and TC were independent risk factors for DN. All of the above suggested that the MMP9 -1562C/T polymorphism was associated with DN in Han Chinese.

Percutaneous Microwave Ablation in the Spleen for Treatment of Hypersplenism in Cirrhosis Patients.

AIM: The aim of this study was to estimate the feasibility and therapeutic effectiveness of percutaneous microwave ablation in the treatment of hypersplenism in cirrhosis. METHODS: Forty-one cirrhosis patients with hypersplenism were treated with ultrasonography-guided percutaneous microwave ablation between February 2007 and August 2011. Peripheral blood cell counts, portal vein diameter, splenic vein diameter, and blood flow of splenic vein were evaluated before and after the operation, and complications of the treatment were also investigated. All patients were followed up for 24 months. RESULTS: The levels of platelets and white blood cells were increased, while the splenic vein diameter narrowed gradually after the therapy and 24 months later. Moreover, patients received percutaneous microwave ablation had much lower splenic venous flow velocity. The portal vein diameter did not change significantly 6 months after the treatment, although it narrowed gradually within 3 months after the treatment. Furthermore, no complications such as uncontrollable bleeding, splenic abscess, spleen rupture, and damage in surrounding organ happened after the therapy. CONCLUSIONS: Graded percutaneous microwave ablation, as a minimally invasive therapy, could damage the spleen, increase the levels of platelets and white blood cells, and reduce portal hypertension effectively without serious complications. Percutaneous microwave ablation is an effective, safe, and feasible method for cirrhosis patients with hypersplenism.

Quantification of the erythrocyte deformability using atomic force microscopy: correlation study of the erythrocyte deformability with atomic force microscopy and hemorheology.

Atomic force microscope (AFM) is a powerful and prospective tool in the studies of the cellular deformability within a single cell. However, the reliability of using AFM in estimating the cellular average deformability was suspected. Hemorheology, one of common clinical examinations, can assess the deformability of erythrocytes. In order to validate the reliability in estimating the cellular deformability with AFM, the correlation was studied between the stiffness of the erythrocyte membrane with AFM and the deformation index with the hemorheology test. Blood samples were taken from 5 diabetes mellitus patients and 5 healthy non-obese people. The erythrocyte deformability was detected by AFM and the hemorheology test, respectively. Excellent correlation (r=0.907, p=0.000<0.01) was found between the average erythrocyte stiffness with AFM and the deformation index obtained from the hemorheology test. Besides, it was found that the average stiffness and the deformation index of diabetes mellitus patients were significantly higher than those of healthy non-obese people (p=0.007 and p=0.003). The result was consistent with the impairment of erythrocytes form diabetes mellitus patients. Therefore, it is the first time that the quantification relation of the erythrocyte deformability was investigated with AFM and the hemorheology test, and the feasible and reliable were validated that AFM is used to investigate the mechanical properties of different living cells qualitatively and quantitatively.

Femoral neuropathy after pelvic surgery.

Postoperative femoral neuropathy is an uncommon complication occurring after pelvic surgery. Inappropriate stretching and prolonged compression of the nerve are 2 major mechanisms of the neuropathy. Here we report 2 cases of femoral neuropathy immediately following pelvic surgery. Both cases had neither previous vascular nor peripheral nerve disease. They suffered from weakness of left hip flexion and knee extension and sensory impairment over the left lower limb after surgery. Electromyography and nerve conduction studies confirmed left femoral neuropathy. Both of the patients received physical therapy and had nearly total neurological recovery within 3 months. We report this unusual complication that followed major pelvic surgery and also review the literature and discuss the possible etiology for prevention of this injury.