Development of a high-throughput screening system targeting the protein-protein interactions between PRL and CNNM.

Phosphatase of regenerating liver (PRL) is an oncogenic protein that promotes tumor progression by directly binding to cyclin M (CNNM) membrane proteins and inhibiting their Mg efflux activity. In this study, we have developed a high-throughput screening system to detect the interactions between PRL and CNNM proteins based on homogenous time-resolved fluorescence resonance energy transfer (HTR-FRET, HTRF). We optimized the tag sequences attached to the recombinant proteins of the CNNM4 CBS domains and PRL3 lacking the carboxyl terminal CAAX motif, and successfully detected the interaction by observing the FRET signal in the mixture of the tagged proteins and fluorophore-conjugated antibodies.

-Schistosomal activity and ADMET properties of 1,2,5-oxadiazinane-containing compound synthesized by visible-light photoredox catalysis.

The incorporation of saturated nitrogen-containing heterocycle 1,2,5-oxadiazinane into small molecules represents a compelling avenue in drug discovery due to its unexplored behavior within biological systems and incomplete protocols for synthesis. In this study, we present 1,2,5-oxadiazinane, an innovative heterocyclic bioisostere of piperizin-2-one and novel chemotype of the -schistosomal drug praziquantel (PZQ), which has been the only clinical drug available for three decades. PZQ is associated with significant drawbacks, including poor solubility, a bitter taste, and low metabolic stability.

Synthesis and biochemical characterization of naphthoquinone derivatives targeting bacterial histidine kinases.

Waldiomycin is an inhibitor of histidine kinases (HKs). Although most HK inhibitors target the ATP-binding region, waldiomycin binds to the intracellular dimerization domain (DHp domain) with its naphthoquinone moiety presumed to interact with the conserved H-box region. To further develop inhibitors targeting the H-box, various 2-aminonaphthoquinones with cyclic, aliphatic, or aromatic amino groups and naphtho [2,3-d] isoxazole-4,9-diones were synthesized.

Tetracyclines enhance antitumor T-cell immunity via the Zap70 signaling pathway.

Background: Cancer immunotherapy including immune checkpoint inhibitors is only effective for a limited population of patients with cancer. Therefore, the development of novel cancer immunotherapy is anticipated. In preliminary studies, we demonstrated that tetracyclines enhanced T-cell responses.

Risk factors for rebleeding in gastroduodenal ulcers.

Background: Rebleeding after hemostasis of the gastroduodenal ulcer (GDU) is one of the indicators associated with death among GDU patients. However, there are few studies on risk score that contribute to rebleeding after endoscopic hemostasis of bleeding peptic ulcers.

Aims: The aim of this study was to identify factors associated with rebleeding, including patient factors, after endoscopic hemostasis of bleeding gastroduodenal ulcers and to stratify the risk of rebleeding.

Synthesis and Biological Evaluation of Simplified Ansellone Analogues with Lipophilic Side Chains as HIV Latency-Reversing Agents.

Structurally simplified analogues of ansellone A, in which the decalin skeleton is replaced with a lipophilic chain, were prepared and their HIV latency-reversing activities biologically evaluated. In particular, two analogues bearing ether and alkenyl side chains, respectively, showed comparable activities to that of ansellone A. Each of the simplified compounds was easily synthesized using Prins cyclisation chemistry.

Design and synthesis of 4-acetoxypentanamide derivatives of spliceostatin A and their biological evaluation towards prostate cancer treatment.

We designed and synthesized novel 4-acetoxypentanamide derivatives of spliceostatin A, whose 4-acetoxypentenamide moiety is reduced (7), isomerized (8), or substituted with methyl at the α-position (9). The results of biological evaluation against AR-V7 and the docking analysis of each derivative suggest that the geometry of the 4-acetoxypentenamide moiety of spliceostatin A is important for its biological activity.

Restoration of Cardiac Myosin Light Chain Kinase Ameliorates Systolic Dysfunction by Reducing Superrelaxed Myosin.

Background: Cardiac-specific myosin light chain kinase (cMLCK), encoded by , regulates cardiac contractility through phosphorylation of ventricular myosin regulatory light chain. However, the pathophysiological and therapeutic implications of cMLCK in human heart failure remain unclear. We aimed to investigate whether cMLCK dysregulation causes cardiac dysfunction and whether the restoration of cMLCK could be a novel myotropic therapy for systolic heart failure.

Design, Synthesis, and Monoamine Oxidase B Selective Inhibitory Activity of -Arylated Heliamine Analogues.

Monoamine oxidase B (MAO-B) metabolizes monoamines such as dopamine regarding neural transmission and controls its level in the mammalian's brain. When MAO-B metabolizes dopamine abnormally, normal neurotransmission does not occur, and central nervous system disorders such as Parkinson's disease may develop. Although several MAO inhibitors have been developed, most of them have no selectivity between monoamine oxidase A (MAO-A) and MAO-B, or they work irreversibly against the enzyme.

Scoring system for predicting the prognosis of elderly gastric cancer patients after endoscopic submucosal dissection.

Objectives: Comprehensive assessments of the long-term outcomes of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in the elderly are unavailable. We aimed to create a scoring system to predict the long-term prognosis after ESD for EGC among patients aged ≥75 years.

Methods: We conducted retrospective studies of two cohorts: a single-center cohort (2006-2011) for developing the scoring system, and a multicenter cohort for validating the developed system (2012-2016).

Modified N score is helpful for identifying patients who need endoscopic intervention among those with black stools without hematemesis.

Objectives: Although black stools are one of the signs of upper gastrointestinal bleeding, not all patients without hematemesis need endoscopic intervention. There is no apparent indicator to select who needs treatment thus far. The aim of this study was to establish a novel score that predicts the need for endoscopic intervention in patients with black stools without hematemesis.

[Gastric metastasis of breast cancer treated as stage IV gastric cancer for 13 years: a case report].

A 52-year-old woman had a surgical history of breast cancer. A follow-up blood test showed that the level of carcinoembryonic antigen was elevated. Esophagogastroduodenoscopy revealed a Borrmann type IV tumor in the stomach, and biopsy revealed poorly differentiated adenocarcinoma with signet ring cells.

Effect of weight change and lifestyle modifications on the development or remission of nonalcoholic fatty liver disease: sex-specific analysis.

The effects of changes in various lifestyle habits on nonalcoholic fatty liver disease (NAFLD) have not been well elucidated. We aimed to clarify how weight change and lifestyle modifications were associated with the development or remission of NAFLD. In this longitudinal cohort study, we reviewed the periodic health checkup data of 1,421 subjects with no causes of liver disease besides NAFLD who had received at least two health checkups between 2009 and 2018.

A case of mucinous cystic neoplasm of the pancreas misdiagnosed as a pancreatic pseudocyst at the initial exam and resected after a 2-year follow-up.

A 44-year-old woman was referred to our hospital because of a cystic lesion in the pancreatic body that was found by computed tomography (CT) as a result of a screening for impaired liver function after the patient presented with a high fever in 2011. Trans-abdominal ultrasonography (US) revealed a 33-mm unilocular cyst within the pancreatic body and a 5-mm hypoechoic mass in the pancreatic neck. Contrast-enhanced CT showed a slight enhancement around the cyst and a mild dilation of the main pancreatic duct, but neither septum nor nodule was detected inside.

Importance of appropriate pharmaceutical management in pregnant women with ulcerative colitis.

Background: Ulcerative colitis (UC) often occurs in women of childbearing age. Compared to Western countries, however, few studies have investigated the impact of UC on the progress of pregnancy in Asian populations.

Methods: We retrospectively examined 91 pregnancies in 64 patients with UC experienced at our hospital and related institutions from 1991 to 2011, focusing on the relationship between the progression of UC during pregnancy, progress of the pregnancy itself, and the treatment of UC.

[A case of type 2 autoimmune pancreatitis associated with Crohn disease].

A 45-year-old woman visited our hospital due to upper left quadrant pain and melena. Colonoscopy revealed longitudinal ulcers in the transverse colon. The endoscopic findings and pathological examination of a biopsy specimen led to diagnosis of Crohn disease, and mesalazine was administered.

New class of corticotropin-releasing factor (CRF) antagonists: small peptides having high binding affinity for CRF receptor.

The discovery of small and potent peptide antagonists of the corticotropin-releasing factor (CRF) receptor is described. Through the structure-activity relationship studies of 12-amino acid peptide corresponding to the C-terminal residues of astressin, we assumed that a particular surface of the alpha-helix was important for binding to the receptor. The small peptide containing d-Ala31 and cyclohexylalanine38 on that surface was as potent as astressin in binding to the CRF receptor and showed significant ACTH suppression when administered to rats.

4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as selective cyclooxygenase-2 inhibitors: enhancement of the selectivity by introduction of a fluorine atom and identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522(1).

A series of 4-(4-cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamide derivatives were synthesized and evaluated for their abilities to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) enzymes. In this series, substituent effects at the ortho position to the sulfonamide group on the phenyl ring were examined. Most substituents reduced or lost both COX-2 and COX-1 activities.

4-Aryl/cycloalkyl-5-phenyloxazole derivatives as selective COX-2 inhibitors.

A series of 4-aryl/cycloalkyl-5-phenyloxazole derivatives was synthesized and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1). These compounds were found to be potent and selective COX-2 inhibitors.