Broad transcriptional response of the human esophageal epithelium to proton pump inhibitors.

BACKGROUND: Proton pump inhibitors (PPIs) have been recognized as a primary treatment of eosinophilic esophagitis (EoE), an allergic inflammatory disease of the esophageal mucosa. The mechanisms underlying esophageal epithelial responses to PPIs remain poorly understood. OBJECTIVE: We hypothesized that PPIs can counteract IL-13-mediated esophageal epithelial responses that are germane for EoE pathogenesis. METHODS: Transcriptional responses of human esophageal cells to IL-13 and the PPIs omeprazole and esomeprazole were assessed by RT-PCR and RNA sequencing. Cytokine secretion was measured by multiplex analysis and ELISA. RESULTS: Human esophageal epithelial cells robustly responded to PPI stimulation by inducing a set of 479 core genes common between omeprazole and esomeprazole treatments. The transcriptional response to PPIs was partially mediated through the aryl hydrocarbon receptor signaling pathway, as the aryl hydrocarbon receptor antagonist GNF-351 modified approximately 200 genes, particularly those enriched in metabolic processes and regulation of cell death. PPI treatment reversed approximately 20% of the IL-13 transcriptome. Functional analysis of the PPI-responsive, upregulated genes revealed enrichment in metabolic and oxidation processes, and the unfolded protein response. In contrast, downregulated genes were overrepresented in functional terms related to cell division and cytoskeletal organization, which were also enriched for the genes in the EoE transcriptome reversed by PPIs. Furthermore, PPI treatment decreased the IL-13-induced proliferative response of esophageal epithelial cells. CONCLUSIONS: These results demonstrate broad effects of PPIs on esophageal epithelium, including their ability to curtail transcriptomic processes involved in cellular proliferation and IL-13-induced responses, and they highlight the importance of AHR signaling in mediating these responses.

[A Case of Congenital Tufting Enteropathy with EpCAM Gene Complex Heterozygous Mutation (c.491+1G>A; c.352_353ins CACC)].

The patient, a one-month-old male infant, was admitted for "recurrent diarrhea for 20 + days and vomiting for 4 days". On the 8th day after birth, the patient began to develop recurrent refractory diarrhea, accompanied by abdominal distension, vomiting, dehydration, acidosis, and malnutrition. There were many cases of malignant tumors of the digestive system in the patient's family. Genetic testing identified compound heterozygous mutations (c.491+1G>A; c.352_353ins CACC) in epithelial cell adhesion molecule (EpCAM) gene and the patient was hence diagnosed with congenital tufting enteropathy. The patient was given partial parenteral nutrition support. The patient's diarrheal symptom was improved, but it was difficult to increase the amount of formula because any increase in the amount of formula for the patient would inevitably result in abdominal distention and vomiting. The patient experienced repeated fever in the later period of hospitalization and was eventually discharged from the hospital with the family's signed consent. He still had diarrhea and vomiting after leaving the hospital. Four weeks after discharge, the patient lost about 1 kg of weight and eventually died.

Paternal origin of Tungusic-speaking populations: Insights from the updated phylogenetic tree of Y-chromosome haplogroup C2a-M86.

OBJECTIVES: Haplogroup C2a-M48 is the predominant paternal lineage of Tungusic-speaking populations, one of the largest population groups in Siberia. Up until now, the origins and dispersal of Tungusic-speaking populations have remained unclear. In this study, the demographic history of Tungusic-speaking populations was explored using the phylogenetic analysis of haplogroup C2a-M86, the major subbranch of C2a-M48. MATERIALS AND METHODS: In total, 18 newly generated Y chromosome sequences from C2a-M48 males and 20 previously available Y-chromosome sequences from this haplogroup were analyzed. A highly revised phylogenetic tree of haplogroup C2a-M86 with age estimates was reconstructed. Frequencies of this lineage in the literature were collected and a comprehensive analysis of this lineage in 13 022 individuals from 245 populations in Eurasia was performed. RESULTS: The distribution map of C2a-M48 indicated the most probable area of origin and diffusion route of this paternal lineage in North Eurasia. Most C2a-M86 samples from Tungusic-speaking populations belonged to the sublineage C2a-F5484, which emerged about 3300 years ago. We identified six unique sublineages corresponding to the Manchu, Evenks, Evens, Oroqen, and Daurpopulations; these sublineages diverged gradually over the past 1900 years. Notably, we observed a clear north-south dichotomous structure for sublineages derived from C2a-F5484, consistent with the internal north-south divergence of Tungusic languages and ethnic groups. CONCLUSIONS: We identified the important founding paternal haplogroup, C2a-F5484, for Tungusic-speaking populations as well as numerous unique subgroups of this haplogroup. We propose that the timeframe for the divergence of C2a-F5484 corresponds with the early differentiation of ancestral Tungusic-speaking populations.

Phylogenetic analysis of the Y-chromosome haplogroup C2b-F1067, a dominant paternal lineage in Eastern Eurasia.

Human Y-chromosome haplogroup C2b-F1067 is one of the dominant paternal lineages of populations in Eastern Eurasia. In order to explore the origin, diversification, and expansion of this haplogroup, we generated 206 new Y-chromosome sequences from C2b-F1067 males and coanalyzed 220 Y-chromosome sequences of this haplogroup. BEAST software was used to reconstruct a revised phylogenetic tree of haplogroup C2b-F1067 with age estimates. The revised phylogeny of C2b-F1067 included 155 sublineages, 1986 non-private variants, and >6000 private variants. The age estimation suggested that the initial splitting of C2b-F1067 happened at about 32.8 thousand years ago (kya) and the major sublineages of this haplgroup experienced continuous expansion in the most recent 10,000 years. We identified numerous sublineages that were nearly specific for Korean, Mongolian, Chinese, and other ethnic minorities in China. In particular, we evaluated the candidate-specific lineage for the Dayan Khan family and the Confucius family, the descendants of the ruling family of the Chinese Shang dynasty. These findings suggest that ancient populations with varied C2b-F1067 sublineages played an important role during the formation of most modern populations in Eastern Eurasia, and thus eventually became the founding paternal lineages of these populations.

Reduced thiamine binding is a novel mechanism for TPK deficiency disorder.

Thiamine pyrophosphokinase (TPK) converts thiamine (vitamin B1) into thiamine pyrophosphate (TPP), an essential cofactor for many important enzymes. TPK1 mutations lead to a rare disorder: episodic encephalopathy type thiamine metabolism dysfunction. Yet, the molecular mechanism of the disease is not entirely clear. Here we report an individual case of episodic encephalopathy, with familial history carrying a novel homozygous TPK1 mutation (p.L28S). The L28S mutation leads to reduced enzymatic activity, both in vitro and in vivo, without impairing thiamine binding and protein stability. Thiamine supplementation averted encephalopathic episodes and restored the patient's developmental progression. Biochemical characterization of reported TPK1 missense mutations suggested reduced thiamine binding as a new disease mechanism. Importantly, many disease mutants are directly or indirectly involved in thiamine binding. Thus, our study provided a novel rationale for thiamine supplementation, so far the major therapeutic intervention in TPK deficiency.

[The Extract from Punica Granatum (Pomegranate) Leaves Promotes Apoptosis and Impairs Metastasis in Prostate Cancer Cells].

OBJECTIVE: To investigate the effects of pomegranate leaves extract(PLE)on proliferation,apoptosis and metastasis of prostate cancer cells. METHODS: The proliferation of TRAMP-C1,DU145,PC3 prostate cancer cells treated with different concentrations of PLE (final mass concentrations were 12.5,25,50,100, 200 µg/mL,respectively) for different time (24,48,72 h) was detected by MTT assay. Colony formation assay was performed to verify the long-term effects of PLE on the proliferation of DU145 and PC3 cells.After being treated with PLE for 48 h,Hoechst-33258 staining was used to observe the changes in the nucleus,the cell apoptotic rate was detected by flow cytometry,and wound-healing migration assay was perform to test the change of migration. RESULTS: In comparison with the control group,PLE in the range of 12.5-200 µg/mL had a certain inhibitory effect on the proliferation of TRAMP-C1,DU145 and PC3 cells ( P<0.05).In the range of 6.25-100 µg/mL,the number of colony formation of DU145 and PC3 was significantly reduced( P<0.01).After PLE treated for 48 h, the apoptotic features of nuclear fragmentation and the formation apoptotic body was observed in PC3. With the increase of concentration,the apoptotic rate increased gradually ( P<0.05),and the ability of cells to migrate to the scratch area was significantly weaker than the control group ( P<0.01). CONCLUSION: PLE has effect on proliferation,apoptosis and metastasis of prostate cancer cells.

[Clinical features of Enterococcus faecium meningitis in children].

OBJECTIVE: To summarize the clinical features of Enterococcus faecium meningitis in children. METHODS: The clinical data of nine children with Enterococcus faecium meningitis were analyzed. RESULTS: In all the nine children, Enterococcus faecium was isolated from blood, cerebrospinal fluid, or peripherally inserted central catheters; 6 (67%) patients were neonates, 2 (22%) patients were younger than 6 months, and 1 (11%) patient was three years and four months of age. In those patients, 56% had high-risk factors before onset, which included intestinal infection, resettlement of drainage tube after surgery for hydrocephalus, skull fracture, perinatal maternal infection history, and catheter-related infection. The main symptoms were fever and poor response. In those patients, 22% had seizures; no child had meningeal irritation sign or disturbance of consciousness. The white blood cell count and level of C-reactive protein were normal or increased; the nucleated cell count in cerebrospinal fluid was normal or mildly elevated; the protein level was substantially elevated; the glucose level was decreased. The drug sensitivity test showed that bacteria were all sensitive to vancomycin and the vancomycin treatment was effective. Only one child had the complication of hydrocephalus. CONCLUSIONS: Enterococcus faecium meningitis occurs mainly in neonates and infants. The patients have atypical clinical features. A high proportion of patients with Enterococcus faecium meningitis have high-risk factors. Enterococcus faecium is sensitive to vancomycin.

[Clinical Feature in Infants of Breast Feeding Allergy and Its Possible Relation with Gastrointestinal Peptide Change in Breast Milk].

OBJECTIVES: To investigate clinical features in infants of breast milk allergy(BMA), and the possible relationship with the changes of somatostatin (SST) and motilin (MTL) in breast milk. METHODS: Twenty three cases of pure breast feeding infants with allergic gastroenteritis were collected, while another 23 normal infants with pure breast feeding were enrolled as normal controls. Samples of infant stools and breast milk were collected for the measurement of SST and MTL levels detected by by radioimmunity. RESULTS: The levels of SST and MTL in stool samples (pg/mg) were 32.6±8.9, 2.3±3.7 in BMA group and 56.2±12.7, 21.6±4.7 in normal control group, respectively. Those in breast milk (pg/mg) were 236.7±28.9, 159.4±36.7 in BMA group and 412.6±36.7, 216.8±59.7 in normal control group, respectively. All the differences were statistically significant ( P<0.05). In BMA infants, the clinical features were 91.3% (20/23) of diarrhea, 86.9% (21/23) of vomiting, 69.6% (16/23) of hematochezia, 95.7% (22/23) of C-reactive protein (CRP) increasing, 87.0% (20/23) of occult blood in stools, 73.9% (17/23) of neutrophil increasing, 39.1% (9/23) of WBC in stools. CONCLUSIONS: For those infants of breast feeding with persisting and repeated gastrointestinal symptoms, allergy for breast milk should be considered. Deficiency of SST and MTL in breast milk may be a possible cause for food allergy.

[Effect of ingested immunoglobulin on sIgA expression in pediatric rotavirus enteritis].

OBJECTIVE: To identify the effects of ingested anti-rotavirus immunoglobulin on enteric expressions of SIgA in pediatric rotavirus enteritis. METHODS: In this randomized, placebo controlled clinic trial, 100 patients of pediatric rotavirus enteritis who simultaneously received fluid replacement as basic therapy, were randomly divided into control and immunoglobulin treated groups. The patients in experimental group were given "ingested antirotavirus IgY". Stool sample was collected at day 1, 3, 5, 7, 9 and 11, the level of fecal SIgA was quantifies by radioimmunoassay kit, and fecal rotavirus shedding was detected by double-sandwich ELISA. RESULTS: The frequency of diarrhea in immunoglobulin group was obviously less than that in control group (P<0.05). The mean course of diarrhea was (4.5 +/- 0.92) d in immunoglobulin group, and (5.8 +/- 1.68) d in control group (P=0.015). The fecal SIgA level in immunoglobulin group was higher than that in control group(P<0.05). The doubling time of SIgA level was the 3rd d in immunoglobulin group, and the 5th d in control group. The fecal rotavirus shedding in immunoglobulin group was obviously lower than that in control group (P < 0.05). CONCLUSION: Ingested anti-rotavirus immunoglobulin could promote the expression of enteric SIgA to remove rotavirus, achieving the benefit to release diarrhea in pediatric rotavirus enteritis.

[The Expressions of Somatostatin and Cycloxygenase-2 in Chronic Hepatitis, Hepatic Cirrhosis, Precancerous Lesion and Hepatocellular Carcinoma].

OBJECTIVE: To investigate the expression difference of somatostatin (SST) , SST receptors (SSTR) and COX-2 in chronic hepatitis, hepatic cirrhosis, precancerous lesion and hepatocellular Carcinoma, and explore the relationship between portal hypertension and SST/SSTR expressions. METHODS: A series of human liver tissues were obtained from surgery, including normal liver 4 cases, chronic hepatitis 14 cases, hepatic cirrhosis 40 cases, precancerous lesion 40 cases and HCC tissues 40 cases. Peripheral bloods were collected from 20 patients before and after the operation of transjugular intrahepatic portosystemic shunt (TIPS). SSTR 1-5 subtypes in hepatic tissues were detected by immunohistochemical study and RT-PCR. Levels of SST and COX-2 were quantified by radioimmunoassay and Western blot. RESULTS: 90% of precancerosis expressed high levels of SSTR 2, 5 subtypes, and SSTR mainly distributed surrounding portal vein. At lest 60%o of HCC expressed SSTR 2, 5 subtypes, and there were positive correlations between levels of SSTR 1-5 and SST. Levels of SST in peripheral blood of cirrhotic patients significantly increased after TIPS(P<0. 05). Levels of COX-2 were highest in cirrhosis (about 90%), and decreased in precancerosis (about 80%) and HCC tissues. CONCLUSIONS: Precancerosis or early stage of HCC may be the optimum time for synergetic medication of SST analogue and COX-2 inhibitor.

Synthesis and biological evaluation of novel benzamide derivatives as potent smoothened antagonists.

A series of novel benzamide derivatives were prepared and evaluated using cell-based measurements. Among these compounds, 10f significantly inhibited Hedgehog signaling and showed equivalent or more potency than GDC-0449 in different tests. Furthermore, compound 10f potently inhibited the proliferation of Daoy, a medulloblastoma cell line that is reported to be resistant to GDC-0449, which indicated a promising prospect in the treatment of Hedgehog signaling pathway related cancer in clinical trial.

A BINOL-based ratiometric fluorescent sensor for Zn2+ and in situ generated ensemble for selective recognition of histidine in aqueous solution.

A novel BINOL-based ratiometric fluorescent sensor (R2) is presented, which can selectively respond to Zn(2+) over Cd(2+) and other metal ions with fluorescence enhancement in aqueous solution. The R2 was successfully applied in the imaging of Zn(2+) in living cells. Additionally, the in situ generated R2-Zn(II) ensemble could further serve as a probe to distinguish histidine from other amino acids via a displacement mode.

Dianthracene-cyclen conjugate: the first equal-equivalent responding fluorescent chemosensor for Pb2+ in aqueous solution.

A dianthracene-cyclen conjugate was synthesized via 'click' chemistry, which could serve as an equal-equivalent responding chemosensor for Pb(2+) in aqueous solution. Moreover, it could be successfully applied in the detection of Pb(2+) in living cells and fetal calf serum.

[Therapeutic effect of probiotics and oral IgY as supplementary drugs in the treatment of pediatric rotavirus enteritis: a comparative study].

OBJECTIVE: To compare the therapeutic effect of probiotics and oral immunoglobulin on pediatric rotavirus enteritis. METHODS: A randomized, controlled trial was conducted in 150 children with rotavirus enteritis who were randomly divided into control, probiotic and immunoglobulin groups (n=50 each). In addition to basic treatment, the control group was given placebo, the probiotic group was given live combined bifidobacterium and lactobacillus tablets, and the immunoglobulin group was orally given anti-rotavirus egg yolk immunoglobulin (IgY). Clinical symptoms such as stool frequency and stool properties were recorded every day. Fresh stool samples were collected on days 1, 3, 5, 7, 9 and 11 of treatment. Intestinal flora imbalance was detected and divided into three degrees by microscopic examination of stool. Fecal SIgA level and fecal rotavirus shedding were measured by radioimmunoassay and double-antibody sandwich ELISA respectively. RESULTS: Compared with the control group, the probiotic group had reduced intestinal flora imbalance, decreased stool frequency, and reduced incidence of secondary intestinal bacterial infection after 3 days of treatment (P<0.05). There was no significant difference in disease course between the probiotic and control groups. Compared with the control group, the immunoglobulin group had a significantly increased fecal SIgA level after 1 day of treatment (P<0.05), significantly decreased frequency of diarrhea and fecal rotavirus shedding after 3 days of treatment (P<0.05), and a significantly shorter disease course (4.5±1.0 vs 5.8±1.7 days; P<0.05). CONCLUSIONS: For children with rotavirus enteritis, probiotics can reduce intestinal flora imbalance and prevent secondary intestinal bacterial infection, but probiotics take a long time to relieve clinical symptoms and cannot shorten the course of disease. Oral immunoglobulin takes effect quickly and can rapidly eliminate rotavirus, promote the production of SIgA, and shorten the course of disease.

(2-Anilino-4-methyl-thia-zol-5-yl)(4-chloro-phen-yl)methanone.

The title compound, C(17)H(13)ClN(2)OS, crystallizes with three independent mol-ecules (A, B and C) in the asymmetric unit which differ slightly in their conformations. In mol-ecule A, the thiazole ring makes dihedral angles of 27.44 (14) and 66.05 (6)° with the phenyl and chloro-benzene rings. In mol-ecule B, the respective angles are 29.09 (10) and 47.63 (9)°, while values of 25.67 (11) and 51.01 (7)° are observed in mol-ecule C. In the crystal, N-H⋯N and N-H⋯O hydrogen bonds generate a three-dimensional network structure.

Global attitudes on and the status of enteral nutrition therapy for pediatric inflammatory bowel disease.

Enteral nutrition (EN) is a diet-remission therapy for inflammatory bowel disease (IBD) that plays a more important role in children than adults. EN includes exclusive enteral nutrition (EEN), partial enteral nutrition (PEN), and maintenance enteral nutrition (MEN). However, EEN remains an unstandardized treatment for pediatric IBD. The types and methods of EN differ around the world. The current study reviewed the EN literature on children with IBD. A total of 12 survey studies were identified that analyzed the current state of EN use, including clinical opinions, implementation methods, treatment course, EEN formula, IBD classification, progress, dietary reintroduction, and patient feedback. The findings revealed that EEN has a strong effect on mild to moderate Crohn's disease (CD). The usage rates of this treatment in different sites were ileum/colon (Paris classification L3) > ileum (L1) > upper digestive tract (L4) > colon (L2) > perianal disease (P) > ulcerative colitis (UC) > extraintestinal lesions. The polymeric formula was the most used EN formulation. New EN diets include a CD exclusion diet (CDED), a specific carbohydrate diet (SCD), and a CD treatment-with-eating (CD-TREAT) diet. Children with IBD responded similarly to EEN administered orally or using a feeding tube. Most guidelines recommended 6-8 weeks of EEN treatment to induce remission. Many clinicians preferred to combine drug medications during EEN and recommended that MEN accounts for at least 25-35% of daily caloric intake. EN remains an unstandardized therapy that requires teamwork across disciplines.

Discovery of highly potent and selective 7-ethyl-10-hydroxycamptothecin-glucose conjugates as potential anti-colorectal cancer agents.

7-Ethyl-10-hydroxycamptothecin (SN38), a highly potent metabolite of irinotecan, has an anticancer efficacy 100-1000 folds more than irinotecan in vitro. However, the clinical application of SN38 has been limited due to the very narrow therapeutic window and poor water solubility. Herein, we report the SN38-glucose conjugates (Glu-SN38) that can target cancer cells due to their selective uptake via glucose transporters, which are overexpressed in most cancers. The in vitro antiproliferative activities against human cancer cell lines and normal cells of Glu-SN38 were investigated. One of the conjugates named 5b showed high potency and selectivity against human colorectal cancer cell line HCT116. Furthermore, 5b remarkably inhibited the growth of HCT116 in vivo. These results suggested that 5b could be a promising drug candidate for treating colorectal cancer.

Action Mechanism Underlying Improvement Effect of Fuzi Lizhong Decoction on Nonalcoholic Fatty Liver Disease: A Study Based on Network Pharmacology and Molecular Docking.

OBJECTIVE: This study aimed to decipher the bioactive compounds and potential mechanism of traditional Chinese medicine (TCM) formula Fuzi Lizhong Decoction (FLD) for nonalcoholic fatty liver disease (NAFLD) treatment via an integrative network pharmacology approach. METHODS: The candidate compounds of FLD and its relative targets were obtained from the TCMSP and PharmMapper web server, and the intersection genes for NAFLD were discerned using OMIM, GeneCards, and DisGeNET. Then, the PPI and component-target-pathway networks were constructed. Moreover, GO enrichment and KEGG pathway analysis were performed to investigate the potential signaling pathways associated with FLD's effect on NAFLD. Eventually, molecular docking simulation was carried out to validate the binding affinity between potential core components and key targets. RESULTS: A total of 143 candidate active compounds and 129 relative drug targets were obtained, in which 61 targets were overlapped with NAFLD. The PPI network analysis identified ALB, MAPK1, CASP3, MARK8, and AR as key targets, mainly focusing on cellular response to organic cyclic compound, steroid metabolic process, and response to steroid hormone in the biological processes. The KEGG pathway analysis demonstrated that 16 signaling pathways were closely correlated with FLD's effect on NALFD with cancer pathways, Th17 cell differentiation, and IL-17 signaling pathways as the most significant ones. In addition, the molecular docking analysis revealed that the core active compounds of FLD, such as 3'-methoxyglabridin, chrysanthemaxanthin, and Gancaonin H, had a high binding activity with such key targets as ALB, MAPK1, and CASP3. CONCLUSIONS: This study suggested that FLD exerted its effect on NAFLD via modulating multitargets with multicompounds through multipathways. It also demonstrated that the network pharmacology-based approach might provide insights for understanding the interrelationship between complex diseases and interventions of the TCM formula.

Synthesis and biological evaluation of novel acenaphthene derivatives as potential antitumor agents.

Twelve novel acenaphthene derivatives have been synthesized. The structures of all compounds were confirmed by ¹H-NMR, MS and elemental analysis. Their antitumor activities were evaluated in six human solid tumor cell lines, namely non-small cell lung cancer (H460), human colon adenocarcinoma (SW480), human breast cancer cell (MDA-MB-468 and SKRB-3), human melanoma cell (A375) and human pancreatic cancer (BxPC-3). Among them, compound 3c shows the best antitumor activity against SKRB-3 cell line, as high as the positive control adriamycin.