Commensal Enterococcus faecalis W5 ameliorates hyperuricemia and maintains the epithelial barrier in a hyperuricemia mouse model.

OBJECTIVE: The intestine is responsible for approximately one-third of uric acid (UA) excretion. The effect of commensal Enterococcus faecalis (E. faecalis), one of the most colonized bacteria in the gut, on UA excretion in the intestine remains to be investigated. The aim of this study was to evaluate the effect of commensal E. faecalis on UA metabolism and gut microbiota. METHODS: The 16S rRNA gene sequencing was used to examine the species of Enterococcus in mouse fecal content. E. faecalis strain was isolated from mouse feces and identified to be E. faecalis W5. The hyperuricemia (HUA) animal model was established with yeast-rich forage and 250 mg·kg-1 ·day-1 potassium oxonate. Oral administration of E. faecalis W5 was given for 20 days, serving as the Efa group. RESULTS: Disrupted intestinal barrier, activated proinflammatory response and low UA excretion in the intestine were found in HUA mice. After E. faecalis W5 treatment, the gut barrier was restored and serum UA level was decreased. Additionally, fecal and intestinal UA levels were elevated, intestinal urate transporter ABCG2 and purine metabolism were upregulated. Moreover, short-chain fatty acid levels were increased, and intestinal inflammation was ameliorated. CONCLUSIONS: Commensal E. faecalis W5 ameliorated HUA through reversing the impaired gut barrier, promoting intestinal UA secretion by regulating ABCG2 expression, and decreasing intestinal UA synthesis by regulating purine metabolism. The results may provide the potential for developing treatments for HUA through the intestine.

The Impact of Preoperative Sarcopenia on Survival Prognosis in Patients Receiving Neoadjuvant Therapy for Esophageal Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Sarcopenia is a poor prognostic factor in patients with esophageal cancer (EC). It can be aggravated by neoadjuvant therapy (NAT) that improves the prognosis of patients with EC. Until now, the impact of preoperative sarcopenia on survival prognosis in patients receiving NAT for EC remains unclear. METHODS: We systematically researched relevant studies in the PubMed, EMBASE, Web of Science, the Cochrane Library databases up to March 8, 2020. Prevalence of sarcopenia before and after NAT, overall survival (OS) and disease-free survival (DFS) were collected for analysis. Finally, eleven cohort studies were included. RESULTS: Pooled analysis indicated that preoperative sarcopenia was negatively associated with OS. (HR = 1.290; 95% CI [1.078-1.543]; P = 0.005; I 2 = 0.0%) and DFS (HR = 1.554; 95% CI [1.177-2.052]; P = 0.002; I 2 = 0.0%) in the patients with EC receiving NAT. The prevalence of sarcopenia increased by 15.4% following NAT (95%CI [12.9%-17.9%]). Further subgroup analysis indicated that sarcopenia diagnosed following NAT (HR = 1.359; 95% CI [1.036-1.739]; P = 0.015; I 2 = 6.9%) and age >65 years (HR = 1.381; 95% CI [1.090- 1.749]; P = 0.007; I 2 = 0.0%) were the independent risk factors for decreased OS. CONCLUSIONS: Clinicians should strengthen the screening of preoperative sarcopenia in patients of EC both receiving NAT and older than 65 years and give active nutritional support to improve the prognosis of patients. SYSTEMATIC REVIEW REGISTRATION: International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY), identifier INPLASY202050057.

Application of endoscopic submucosal dissection in duodenal space-occupying lesions.

BACKGROUND: Endoscopic submucosal dissection (ESD) has been advocated by digestive endoscopists because of its comparable therapeutic effect to surgery, reduced trauma, faster recovery, and fewer complications. However, ESD for lesions of the duodenum is more challenging than those occurring at other levels of the gastrointestinal tract due to the thin intestinal wall of the duodenum, narrow intestinal space, rich peripheral blood flow, proximity to vital organs, and high risks of critical adverse events including intraoperative and delayed bleeding and perforation. Because of the low prevalence of the disease and the high risks of severe adverse events, successful ESD for lesions of the duodenum has rarely been reported in recent years. AIM: To investigate the efficacy and safety of ESD in the treatment of duodenal space-occupying lesions. METHODS: Clinical data of 24 cases of duodenal lesions treated by ESD at the Digestive Endoscopy Center of the Affiliated Hospital of Qingdao University from January 2016 to December 2019 were retrospectively analyzed. RESULTS: All of the 24 cases from 23 patients underwent ESD treatment for duodenal space-occupying lesions under general anesthesia, including 15 male and 8 female patients, with a mean age of 58.5 (32.0-74.0) years. There were 12 lesions (50%) in the duodenal bulb, 9 (37.5%) in the descending part, and 3 (12.5%) in the ball-descending junction. The mean diameter of the lesion was 12.75 (range, 11-22) mm. Thirteen lesions originated from the mucosa, of which 4 were low-grade intraepithelial neoplasia, 3 were hyperplastic polyps, 2 were chronic mucositis, 2 were adenomatous hyperplasia, 1 was high-grade intraepithelial neoplasia, and 1 was tubular adenoma. Eleven lesions were in the submucosa, including 5 neuroendocrine neoplasms, 2 cases of ectopic pancreas, 1 stromal tumor, 1 leiomyoma, 1 submucosal duodenal adenoma, and 1 case of submucosal lymph follicular hyperplasia. The intraoperative perforation rate was 20.8% (5/24), including 4 submucosal protuberant lesions and 1 depressed lesion. The mean length of hospital stay was 5.7 (range, 3-10) d, and the average follow-up time was 25.8 (range, 3.0-50.0) mo. No residual disease or recurrence was found in all patients, and no complications, such as infection and stenosis, were found during the follow-up period. CONCLUSION: ESD is safe and effective in the treatment of duodenal lesions; however, the endoscopists should pay more attention to the preoperative preparation, intraoperative skills, and postoperative treatment.

Interdisciplinarity research based on NSFC-sponsored projects: A case study of mathematics in Chinese universities.

We investigate the interdisciplinarity of mathematics based on an analysis of projects sponsored by the NSFC (National Natural Science Foundation of China). The motivation of this study lies in obtaining an efficient method to quantify the research interdisciplinarities, revealing the research interdisciplinarity patterns of mathematics discipline, giving insights for mathematics scholars to improve their research, and providing empirical supports for policy making. Our data set includes 6147 NSFC-sponsored projects implemented by 3225 mathematics professors in 177 Chinese universities with established mathematics departments. We propose the weighted-mean DIRD (diversity of individual research disciplines) to quantify interdisciplinarity. In addition, we introduce the matrix computation method, discover several properties of such a matrix, and make the computation cost significantly lower than the bitwise computation method. Finally, we develop an automatic DIRD computing system. The results indicate that mathematics professors at top normal universities in China exhibit strong interdisciplinarity; mathematics professors are most likely to conduct interdisciplinary research involving information science (research department), computer science (research area), computer application technology (research field), and power system bifurcation and chaos (research direction).

Effects of Late Evening Snack on Cirrhotic Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Energetic effects of late evening snack (LES) on cirrhotic patients were reported recently, but there was no quantitative analysis. In this meta-analysis, we reviewed and quantified the effects of LES on energy metabolism and substrate oxidation in the patients with cirrhosis, which will be of benefit for liver cirrhosis nutritional therapy. METHODS: A systematic search was conducted in PubMed, Embase, Web of Science, Elsevier, China National Knowledge Infrastructure, and Wanfang Database for relevant trials published until July 2017. These studies statistically were combined and analyzed by RevMan 5.3. RESULTS: Fourteen trials comprising 478 cases were eligible for analysis. The results showed that the respiratory quotient value (MD = 11.09) and carbohydrate oxidation value (MD = 0.05) significantly elevated with one week or with up to three weeks of LES treatment in cirrhotic patients (P < 0.05). Meanwhile, the levels of serum albumin (MD = 2.98) and cholinesterase (SMD = 1.09) were increased with LES administration for three weeks or that lasting twelve weeks (P < 0.05). However, there was no significant improvement for the levels of alanine aminotransferase (ALT) (P = 0.53), aspartate aminotransferase (AST) (P = 0.96), and total bilirubin (TB) (P = 0.32). CONCLUSIONS: LES could improve the energy malnutrition state of cirrhotic patients. However, it may have little effect on reducing liver parenchymal injury indexes such as serum aminotransferase.

Cucurbitacin B and SCH772984 exhibit synergistic anti-pancreatic cancer activities by suppressing EGFR, PI3K/Akt/mTOR, STAT3 and ERK signaling.

Cucurbitacin B (CuB) is a natural tetracyclic triterpene product and displays antitumor activity across a wide array of cancers. In this study, we explored the anti-pancreatic cancer activity of CuB alone and in combination with SCH772984, an ERK inhibitor, in vitro and in vivo. CuB inhibited proliferation of pancreatic cancer cells by arresting them in the G2/M cell cycle phase. This was associated with inhibition of EGFR expression and activity and downstream signaling, including PI3K/Akt/mTOR and STAT3. Interestingly, ERK activity was markedly enhanced by activating AMPK signaling after 12 h of CuB treatment. SCH772984 potentiates the cytotoxic effect of CuB on pancreatic cancer cells through complementary inhibition of EGFR, PI3K/Akt/mTOR, STAT3 and ERK signaling, followed by an increase in the pro-apoptotic protein Bim and a decrease in the anti-apoptotic proteins Mcl-1, Bcl-2, Bcl-xl and survivin. Furthermore, combined therapy with CuB and SCH772984 resulted in highly significant growth inhibition of pancreatic cancer xenografts. These results may provide a basis for further development of combining CuB and ERK inhibitors to treat pancreatic cancer.

A Novel WASP Gene Mutation in a Chinese Boy with Wiskott-Aldrich Syndrome.

Wiskott-Aldrich syndrome (WAS) is a rare inherited X-linked recessive immunodeficiency disease characterized by eczema, thrombocytopenia, immune deficiency, and bloody diarrhea and is caused by WASP gene mutations. This study reports a case of WAS with a novel mutation. A newborn Chinese infant was admitted to the hospital because of intermittent bloody stools, recurrent infections, and persistent thrombocytopenia. Genetic analysis of the coding sequences and flanking splice sites of the WASP gene showed a novel WASP gene deletion mutation (1144delA) at exon 10. Family history showed that both his mother and aunt had a heterozygous genotype of the WASP gene. The infant died at the age of 4 months due to persistent thrombocytopenia and severe pneumonia. A novel WASP gene deletion (1144delA) at exon 10 was identified in a Chinese infant with WAS. This base deletion results in a frame-shift mutation of the gene for an early stop codon at amino acid 444.

Analysis of mitochondrial haplogroups associated with TTR Val30Ala familial amyloidotic polyneuropathy in Chinese patients.

Extracellular deposition of abnormal transthyretin (TTR) amyloid fibrils leads to familial amyloidotic polyneuropathy (FAP), an inherited autsomal dominant disease. A large number of protein variants, each caused by a different point mutation in the TTR gene have been identified, including TTR Val30Ala. Since the age of onset, organ involvement, and disease progression are highly variable in FAP, even among individuals with the same TTR genetic variation. it is likely that other genetic and environmental factors influence FAP disease phenotype. One study has found a relationship between mitochondrial haplogroups and age of onset of FAP. In this study, we wondered whether certain mitochondrial haplogroups were associated with the cases of TTR Val30Ala FAP in a Chinese population. Mitochondrial haplogroup analysis was performed on a group of patients and their relatives and on a group of healthy controls. All FAP probands were unrelated in their maternal lineages. The chi-squared test for independence found no difference in mitochondrial haplogroup distribution between FAP and control groups. This is the first study reporting frequency and distribution of different haplogroups in FAP in a Chinese population. Although the study group was small, TTR Val30Ala FAP in China seems unrelated to mitochondrial haplogroup.

Clinical and histopathological features of familial amyloidotic polyneuropathy with transthyretin Val30Ala in a Chinese family.

Familial amyloidotic polyneuropathy (FAP) is characterized by extracellular deposition of amyloid fibrils caused by a point mutation in the transthyretin (TTR) gene. TTR amyloidosis is linked to a vast number of mutations with varying phenotype and tissue distribution. Several Chinese kindred with FAP type 1 have been reported in Beijing, Hong Kong, Taiwan, and elsewhere. Here, histopathological features and TTR gene polymorphism were analyzed by using autopsy and blood specimens from a Chinese proband of a family with FAP. This proband is a 34-year old man with FAP type 1 who developed motor, sensory and autonomic impairments with neuropathy, gastrointestinal dysfunction, and orthostatic hypotension. Genetic findings of TTR revealed a T to C transition in codon 30 causing the mutation TTR Ala30. This patient died of respiratory and circulatory failure 7 years after onset. Autopsy showed heavy amyloid deposition in the peripheral nerves, liver, testes, thyroid, pancreas and muscles. There was moderate deposition in the heart, kidneys, bladder, gastrointestinal tract, tongue, lung, blood vessels, and gall bladder. The spleen showed only slight deposition, and none was observed in the central nervous system. TTR amyloidosis was confirmed by immunochemical staining with a specific TTR antibody. These results indicate that the distribution of amyloid deposition, (i.e., heavy in the liver, testes and slight in the spleen), is a characteristic feature and reflects the severity of FAP with TTR Val30Ala.

[Impact of cytochrome P450 CYP2C9 variant allele CYP2C9 * 3 on the pharmacokinetics of glibenclamide and lornoxicam in Chinese subjects].

AIM: To investigate the impact of CYP2C9 * 3 on the pharmacokinetics of glibenclamide and lornoxicam. METHODS: CYP2C9 * 3 was measured in 83 non-related Chinese subjects by PCR-RFLP. The pharmacokinetics of lornoxicam and glibenclamide were investigated in 18 subjects (7 with CYP2C9 * 1/* 3 genotype and 11 with * 1/* 1 genotype). Glibenclamide and lornoxicam in plasma were determined by the sensitive liquid chromatography-tandem mass spectrometry, separately. RESULTS: After a single oral dose of 2.5 mg glibenclamide, C(max) was (70.0 +/- 11.5) microg x L(-1) in CYP2C9 * 1/ * 3 subjects and (51.9 +/- 12.3) microg x L(-1) in * 1/ *1 subjects. AUC(0-infinity) were (435 +/- 47) vs (287 +/- 95) microg x h x L(-1) (in * 1/ * 3 vs * 1/ *1 subjects), and CL/F were (96 +/- 9.3) vs (160 +/- 51) mL x min(-1), respectively. Statistic analysis results indicated that glibenclamide AUC(0-infinity) was significantly higher (1.5-fold) and subsequently CL/F was significantly lower (40%) in CYP2C9 * 1/ * 3 subjects than those in * 1/ * 1 subjects (P < 0.01). After a single oral dose of 8 mg lornoxicam, C(max) was (1.54 +/- 0.24) mg x L(-1) in CYP2C9 * 1/ * 3 subjects and (1.19 +/- 0.37) mg x L(-1) in * 1/ * 1 subjects. AUC(o-infinity were (14.9 +/- 2.2) vs (6.92 +/- 1.48) mg x h x L(-1) (in * 1/ *3 vs * 1/ * 1 subjects), and CL/F were (9.1 +/- 1.2) vs (20.1 +/- 4.6) mL x min(-1), respectively. Statistic analysis results indicated that lornoxicam AUC(0-infinity) was significantly higher (2. 2-fold) and subsequently CL/F was significantly lower (55% ) in CYP2C9 * 1/ * 3 subjects than those in * 1/ * 1 subjects (P < 0.001). CONCLUSION: CYP2C9 * 3 greatly affects both the pharmacokinetic profiles of glibenclamide and lornoxicam. The elimination of these drugs significantly decreased in subjects with CYP2C9 * 1/ * 3 genotype, especially lornoxicam.

A possible signal transduction pathway for cyclin D2 expression by a pectic polysaccharide from the roots of bupleurum falcatum L. in murine B cell.

Bupleuran 2IIc, a pectic polysaccharide isolated from the roots of bupleurum falcatum L., was previously characterized as a T-cell-independent B cell mitogen. This study focuses on elucidating the mechanism by which bupleuran 2IIc induces cyclin D2 production for inducing mitogenesis in murine B cells. Bupleuran 2IIc was digested with endo-alpha-(1-->4)-D-polygalacturonase and the resulting bupleuran 2IIc/PG-1 ("ramified" region) strongly stimulated cyclin D2 expression. When murine B cells were stimulated with bupleuran 2IIc/PG-1, phosphorylation of tyrosine residues of a number of proteins was observed. Cyclin D2 expression by bupleuran 2IIc/PG-1 was inhibited by the tyrosine kinase inhibitors, genistein and herbimycin A, and the Src family tyrosine kinase inhibitor, PP2, suggesting a possible role for tyrosine kinases. The stimulation by bupleuran 2IIc/PG-1 of cyclin D2 expression was significantly decreased by inhibitors, PI 3-kinase (LY294002 and Wortmannin), PLCgamma (U73122), PKC (H-7), receptor-operated calcium entry inhibitor (SK&F 96365), and calcineurin (FK506). Both PD98059 and U0126, highly selective inhibitors of MEK1 and MEK1/2, respectively, did not strongly suppress the expression of cyclin D2 after stimulation by bupleuran 2IIc/PG-1. The results suggest that (1) bupleuran 2IIc/PG-1 is the active site for induction of cyclin D2 by bupleuran 2IIc, (2) the expression of the cyclin D2 gene by bupleuran 2IIc/PG-1 may be mediated via the activation of PI 3-kinase and PLCgamma followed by activation of PKC and calcium mobilization, and (3) the ERK1/2 cascade is not a central signaling pathway for bupleuran 2IIc/PG-1-induced cyclin D2 expression.

Induction of cell cycle regulatory proteins by murine B cell proliferating pectic polysaccharide from the roots of Bupleurum falcatum L.

Bupleuran 2IIc, a pectic polysaccharide isolated from the roots of Bupleurum falcatum L., was characterized as a T-cell-independent B cell mitogen, that activates, proliferates and differentiates B cells in vivo and in vitro (Immunology 97 (1999) 540). Studies were focused on elucidating the mechanism by which bupleuran 2IIc causes proliferation of B cells and expression of cell cycle regulatory proteins. B cells showed slower rates of entry into the S and G2/M phases of the cell cycle when stimulated with bupleuran 2IIc versus anti-IgM. However, the Stimulation Index continued up to two times longer with bupleuran 2IIc over anti-IgM. Although both bupleuran 2IIc and anti-IgM induced similar expressions of cell cycle regulatory proteins, cyclins D2, A, and B1, in B cells, those cells stimulated with bupleuran 2IIc appeared to sustain expressions of these protein for longer periods of time. Stimulation of B cells with bupleuran 2IIc induced phosphorylation of retinoblastoma protein, pRB, an important gene product regulating the restriction point, R, which is responsible for the transition from the G0/G1 to the S phases of the cell cycle. The results of this study demonstrate that both bupleuran 2IIc and anti-IgM interact with B cells, thus, leading to expressions of cell cycle regulatory proteins. However, the respective modes of binding and proximity of interactions with the B cell membrane may differ.