Oxidation of 5-methoxy-N,N-diisopropyltryptamine in rat liver microsomes and recombinant cytochrome P450 enzymes

The oxidative metabolism of 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), a tryptamine-type designer drug, was studied using rat liver microsomal fractions and recombinant cytochrome P450 (CYP) enzymes. 5-MeO-DIPT was biotransformed mainly into a side-chain N-deisopropylated metabolite and partially into an aromatic ring O-demethylated metabolite in liver microsomal fractions from untreated rats of both sexes. This metabolic profile is different from our previous findings in human liver microsomal fractions, in which the aromatic ring O-demethylation was the major pathway whereas the side-chain N-deisopropylation was minor [Narimatsu S, Yonemoto R, Saito K, Takaya K, Kumamoto T, Ishikawa T, et al. Oxidative metabolism of 5-methoxy-N,N-diisopropyltryptamine (Foxy) by human liver microsomes and recombinant cytochrome P450 enzymes. Biochem Pharmacol 2006;71:1377-85]. Kinetic and inhibition studies indicated that the side-chain N-dealkylation is mediated by CYP2C11 and CYP3A2, whereas the aromatic ring O-demethylation is mediated by CYP2D2 and CYP2C6 in untreated male rats. Pretreatment of male rats with beta-naphthoflavone (BNF) produced an aromatic ring 6-hydroxylated metabolite. Recombinant rat and human CYP1A1 efficiently catalyzed 5-MeO-DIPT 6-hydroxylation under the conditions used. These results provide valuable information on the metabolic fate of 5-MeO-DIPT in rats that can be used in the toxicological study of this designer drug.     

Pericardio-peritoneal drainage using a subcostal approach

A 56-year-old man admitted to our hospital for cardiac tamponade due to dilated cardiomyopathy did not respond to treatment by usual medical means or surgery. Pericardio-peritoneal drainage was conducted using a subcostal approach. Seven months later, the patient remains well and free of signs of pericardial tamponade. This method has proved to be safe and effective in patients with persistent massive pericardial effusion.     

Successfully treated descending necrotizing mediastinitis through mediansternotomy using a pedicled omental flap.

A 21-year-old man with an oropharyngeal abscess admitted to our institution was initially treated with systemic antibiotics but was referred to our department when his condition rapidly deteriorated. His respiratory insufficiency required circulatory support. A computed tomographic scan showed a parapharyngeal abscess descending into the mediastinum with multiple right-side capsulized empyema and pericardial effusion. We conducted emergency surgery through a mediansternotomy using a pedicled omental flap. Postoperative clinical and radiologic assessment showed a normal chest X-ray and primary wound healing without sternal dehiscence. Mediansternotomy using a pedicled omental flap offers excellent exposure for a complete one-stage operation with debridement of all affected tissues of the subauricular region, the mediastinum, and both pleural cavities. We conclude that this method yields good results for patients with acute widespread descending necrotizing mediastinitis.     

Preliminary Experience of Endovascular Embolization Using N-Butyl Cyanoacrylate for Hemoptysis due to Infectious Pulmonary Artery Pseudoaneurysms via Systemic Arterial Approach

We report 5 patients with hemoptysis due to infectious pulmonary artery pseudoaneurysm (PAP) treated with endovascular embolization using N-butyl cyanoacrylate (NBCA) injected via bronchial and nonbronchial systemic arterial approaches. Infectious diseases included inactive tuberculosis (n = 3), nontuberculous mycobacteriosis (n = 1), and chronic infection of unknown origin (n = 1). Seven PAPs were detected on selective systemic angiography, and injection of NBCA was performed. Disappearance of all PAPs was confirmed on systemic arteriography after the intervention. In all patients, hemoptysis was stopped without major complications, and it did not recur during the follow-up period (mean, 351 d; range, 285–427 d).     

Prognostic value of volumetric FDG PET/CT parameters in patients with oral tongue squamous cell carcinoma who were treated by superselective intra-arterial chemoradiotherapy

Purpose

This study aimed to evaluate the predictive and prognostic value of FDG PET/CT-based volumetric parameters in patients with oral tongue squamous cell carcinoma (OTSCC) treated by superselective intra-arterial chemoradiotherapy (IA-CRT).

Methods

We conducted a retrospective study including 33 patients with biopsy-proven OTSCC between May 2007 and February 2016. All of the patients were treated by IA-CRT. Pretreatment SUV_max and metabolic tumor volume (MTV) of the primary tumor were measured. The SUV thresholds of 2.5 and 5.0 were used. Progression-free survival (PFS) and overall survival (OS) were chosen as endpoints to evaluate prognosis. Univariate and multivariate analyses were performed to assess the potential independent effect of FDG PET/CT parameters.

Results

The median follow-up for surviving patients was 40.7 months (range 6.0–107.5 months). In univariate and multivariate analyses, SUV_max and MTV (5.0) were independent prognostic factors for PFS. In univariate analysis, SUV_max failed to predict OS. MTV (5.0) was a significant prognostic factor for OS, but multivariate analysis failed to show statistical independence because it could not exclude the possibility of an artifact due to N stage.

Conclusions

FDG PET/CT-based volumetric parameters may be significant prognostic markers for survival of patients with OTSCC who are treated by IA-CRT.

     

FFA3 Activation Stimulates Duodenal Bicarbonate Secretion and Prevents NSAID-Induced Enteropathy via the GLP-2 Pathway in Rats

Background

Therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enteropathy in humans and experimental animals, a cause of considerable morbidity. Unlike foregut NSAID-associated mucosal lesions, most treatments for this condition are of little efficacy. We propose that the endogenously released intestinotrophic hormone glucagon-like peptide-2 (GLP-2) prevents the development of NSAID-induced enteropathy. Since the short-chain fatty acid receptor FFA3 is expressed on enteroendocrine L cells and on enteric nerves in the gastrointestinal tract, we further hypothesized that activation of FFA3 on L cells protects the mucosa from injury via GLP-2 release with enhanced duodenal HCO₃ ^? secretion. We thus investigated the effects of synthetic selective FFA3 agonists with consequent GLP-2 release on NSAID-induced enteropathy.

Methods

We measured duodenal HCO₃ ^? secretion in isoflurane-anesthetized rats in a duodenal loop perfused with the selective FFA3 agonists MQC or AR420626 (AR) while measuring released GLP-2 in the portal vein (PV). Intestinal injury was produced by indomethacin (IND, 10 mg/kg, sc) with or without MQC (1–10 mg/kg, ig) or AR (0.01–0.1 mg/kg, ig or ip) treatment.

Results

Luminal perfusion with MQC or AR (0.1–10 µM) dose-dependently augmented duodenal HCO₃ ^? secretion accompanied by increased GLP-2 concentrations in the PV. The effect of FFA3 agonists was inhibited by co-perfusion of the selective FFA3 antagonist CF3-MQC (30 µM). AR-induced augmented HCO₃ ^? secretion was reduced by iv injection of the GLP-2 receptor antagonist GLP-2(3-33) (3 nmol/kg), or by pretreatment with the cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor CFTR_inh-172 (1 mg/kg, ip). IND-induced small intestinal ulcers were dose-dependently inhibited by intragastric administration of MQC or AR. GLP-2(3-33) (1 mg/kg, ip) or CF3-MQC (1 mg/kg, ig) reversed AR-associated reduction in IND-induced enteropathy. In contrast, ip injection of AR had no effect on enteropathy.

Conclusion

These results suggest that luminal FFA3 activation enhances mucosal defenses and prevents NSAID-induced enteropathy via the GLP-2 pathway. The selective FFA3 agonist may be a potential therapeutic candidate for NSAID-induced enteropathy.

     

Association between the expression of core 3 synthase and survival outcomes of patients with cholangiocarcinoma

Cholangiocarcinoma (CCA) is a highly aggressive and metastatic type of malignant carcinoma that is associated with high mortality rates and is difficult to detect at early stages. Core 3 structure is a mucin-type O-glycans synthesized by β1,3-N-acetylglucosaminyltransferase 6 (core 3 synthase), which plays an important role in the digestive system, in particular gastrointestinal goblet cells. It has been reported that core 3 synthase-expressing cells show lower migratory and invasive rates, and lower metastatic activity. A immunohistochemical study also showed that this enzyme was expressed in normal epithelial cells of the colon, but completely disappeared in colorectal cancer cells. The present study aimed to identify biomarkers that could be used to predict the prognosis of patients with CCA. Pathological specimens of 185 CCA tissues were immunohistochemically stained with two antibodies, G8-144 and MECA-79, which recognize core 3 synthase and 6-sulfated N-acetyllactosamine on the extended core-1 O-glycans, respectively. The association between G8-144 or MECA-79 positivity and patient prognosis was statistically analyzed. Positive expression of G8-144 was associated with improved prognosis in patients with distal CCA (dCCA). Patients with dCCA positive for G8-144 showed lower mortality rates than those with negative expression. However, the positive expression of MECA-79 was associated with CCA progression and metastasis, indicating that it is a poor prognostic marker for CCA. In conclusion, as both antibodies resulted in mirror-image staining, the involvement of G8-144 and MECA-79 in O-glycan synthesis could be considered as potential favorable and unfavorable biomarkers, respectively, for CCA prognosis.     

Lectin microarray analysis of pluripotent and multipotent stem cells

Stem cells have a capability to self-renew and differentiate into multiple types of cells; specific markers are available to identify particular stem cells for developmental biology research. In this study, we aimed to define the status of somatic stem cells and the pluripotency of human embryonic stem (hES) and induced pluripotent stem (iPS) cells using a novel molecular methodology, lectin microarray analysis. Our lectin microarray analysis successfully categorized murine somatic stem cells into the appropriate groups of differentiation potency. We then classified hES and iPS cells by the same approach. Undifferentiated hES cells were clearly distinguished from differentiated hES cells after embryoid formation. The pair-wise comparison means based on 'false discovery rate' revealed that three lectins -Euonymus europaeus lectin (EEL), Maackia amurensis lectin (MAL) and Phaseolus vulgaris leucoagglutinin [PHA(L)]- generated maximal values to define undifferentiated and differentiated hES cells. Furthermore, to define a pluripotent stem cell state, we generated a discriminant for the undifferentiated state with pluripotency. The discriminant function based on lectin reactivities was highly accurate for judgment of stem cell pluripotency. These results suggest that glycomic analysis of stem cells leads to a novel comprehensive approach for quality control in cell-based therapy and regenerative medicine.