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Objectives: Our objective was to assess the efficacy of golimumab (GLM) in patients with poor prognostic factors (PPFs). Methods: This is a post hoc analysis of GO-FORTH Phase 2/3 study. Cluster analysis was used to determine a patient population with high-risk patterns based on seven PPFs suggested by the European Alliance of Associations for Rheumatology recommendations and limited physical function. Radiographic progression, disease activity, and physical function and associated factors were evaluated over 52 weeks. Results: Overall, 261 rheumatoid arthritis patients were classified into three clusters characterised by high disease activity, high C-reactive protein levels, and limited physical function at baseline. GLM showed suppression of progressive modified total sharp score and decreases in Disease Activity Score 28-joint counts with erythrocyte sedimentation rate and Health Assessment Questionnaire – Disease Index, in all the clusters. In Cluster C that showed almost all the PPF characteristics, a higher rate of change in modified total sharp score ≤0 was observed in GLM 100 mg group than in GLM 50 mg group (63.9% versus 46.5%). C-reactive protein concentration and physical limitation were associated with radiographic progression of Cluster C in GLM treatment. Conclusions: GLM was effective in rheumatoid arthritis patients in a subpopulation at high risk of PPF in GO-FORTH study. A dose of 100 mg may be more beneficial in preventing radiographic progression in this population. [ABSTRACT FROM AUTHOR]

Background and Purpose: Visceral hypersensitivity is responsible for pathogenesis of irritable bowel syndrome (IBS). Therefore, its prevention can help avoid abdominal pain and discomfort in IBS. To find candidate drugs for visceral hypersensitivity, we screened existing medicines for their ability to prevent visceral sensitivity induced by colorectal distension (CRD) in rats and identified chlorpromazine, a typical antipsychotic drug, as a candidate compound. In this study, we investigated the effect of chlorpromazine on visceral hypersensitivity.Experimental Approach: Visceral sensitivity (visceromotor response) was monitored by measuring the electrical activity of the abdominal external oblique muscle contraction in response to CRD using a barostat apparatus. Visceral hypersensitivity was induced by a colonic instillation of sodium butyrate or acetic acid in neonates.Key Results: Oral administration of chlorpromazine suppressed butyrate-induced visceral hypersensitivity to CRD. Interestingly, atypical antipsychotic drugs, quetiapine and risperidone, ameliorated butyrate-induced visceral hypersensitivity, whereas the typical antipsychotic drugs, haloperidol and sulpiride, did not. Pharmacological analysis using specific inhibitors showed that a selective 5-HT2A receptor antagonist, ketanserin, suppressed butyrate-induced visceral hypersensitivity, whereas a selective dopamine D2 receptor antagonist, L-741626, did not. Furthermore, the 5-HT2A receptor agonist AL-34662 stimulated visceral sensitivity to CRD in healthy control rats but not in butyrate-treated rats. These findings suggest that increased 5-HT levels in the colon contribute to the induction of visceral hypersensitivity.Conclusions and Implications: Our results indicate that chlorpromazine ameliorates visceral hypersensitivity and that the 5-HT2A receptor is a potential therapeutic target for treating abdominal pain and discomfort in IBS. [ABSTRACT FROM AUTHOR]

Origin recognition complex (ORC), a six-protein complex, is the most likely initiator of chromosomal DNA replication in eukaryotes. Throughout the cell cycle, ORC binds to chromatin at origins of DNA replication and functions as a ‘landing pad’ for the binding of other proteins, including Cdt1p, to form a prereplicative complex. In this study, we used yeast two-hybrid analysis to examine the interaction between Cdt1p and every ORC subunit. We observed potent interaction with Orc6p, and weaker interaction with Orc2p and Orc5p. Coimmunoprecipitation assay confirmed that Cdt1p interacted with Orc6p, as well as with Orc1p and Orc2p. We mapped the C-terminal region, and a middle region of Orc6p (amino acids residues 394–435, and 121–175, respectively), as important for interaction with Cdt1p. Cdt1p was purified to examine its direct interaction with ORC, and its effect on the activity of ORC. Glutathione- S-transferase pull-down analysis revealed that Cdt1p binds directly to ORC. Cdt1p neither bound to origin DNA and ATP nor affected ORC-binding to origin DNA and ATP. These results suggest that interaction of Cdt1p with ORC is involved in the formation of the prereplicative complex, rather than in regulation of the activity of ORC. [ABSTRACT FROM AUTHOR]

Origin recognition complex (ORC), a six-protein complex (Orc1p–6p), is the most likely initiator of chromosomal DNA replication in eukaryotes. Although ORC of Saccharomyces cerevisiae has been studied extensively from biochemical and genetic perspectives, its quaternary structure remains unknown. Previous studies suggested that ORC has functions other than DNA replication, such as gene silencing, but the molecular mechanisms of these functions have not been determined. In this study, we used yeast two-hybrid analysis to examine the interaction between ORC subunits and to search for ORC-binding proteins. As well as the known Orc4p–Orc5p interaction, we revealed strong interactions between Orc2p and Ord3p (2p–3p), Orc2p and Ord5p (2p–5p), Orc2p and Ord6p (2p–6p) and Orc3p and Ord6p (3p–6p) and weaker interactions between Orc1p and Ord4p (1p–4p), Orc3p and Ord4p (3p–4p), Orc2p and Ord3p (3p–5p) and Orc5p and Ord3p (5p–6p). These results suggest that 2p–3p–6p may form a core complex. Orc2p and Orc6p are phosphorylated in vivo, regulating initiation of DNA replication. However, replacing the phosphorylated amino acid residues with others that cannot be phosphorylated, or that mimic phosphorylation, did not affect subunit interactions. We also identified several proteins that interact with ORC subunits; Sir4p and Mad1p interact with Orc2p; Cac1p and Ykr077wp with Orc3p; Rrm3p and Swi6p with Orc5p; and Mih1p with Orc6p. We discuss roles of these interactions in functions of ORC. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder, with the characteristic symptoms of chronic abdominal pain and altered bowel habits (diarrhea, constipation, or both). IBS is a highly prevalent condition, which negatively affects quality of life and is a significant burden on global healthcare costs. Although many pharmacological medicines have been proposed to treat IBS, including those targeting receptors, channels, and chemical mediators related to visceral hypersensitivity, successful pharmacotherapy for the disease has not been established. Visceral hypersensitivity plays an important role in IBS pathogenesis. Immune activation is observed in diarrhea-predominant patients with IBS and contributes to the development of visceral hypersensitivity. Adenosine is a chemical mediator that regulates many physiological processes, including inflammation and nociception. Among its receptors, the adenosine A 2B receptor regulates intestinal secretion, motor function, and the immune response. We recently demonstrated that the adenosine A 2B receptor is involved in visceral hypersensitivity in animal models of IBS. In this review, we discuss the possibility of the adenosine A 2B receptor as a novel therapeutic target for IBS., Competing Interests: T.A. and M.T. belong to an endowed research division of LTT Bio-Pharma Co., Ltd. (Tokyo, Japan).

We previously reported that 2-fluoroloxoprofen has lower gastric ulcerogenic activity than loxoprofen, a nonsteroidal anti-inflammatory drug (NSAID) without selectivity for COX-2. We synthesized derivatives of 2-fluoroloxoprofen and studied their properties. Compared to 2-fluoroloxoprofen, one derivative, 11a, exhibited higher anti-inflammatory activity and an equivalent ulcerogenic effect. These results suggest that 11a could be therapeutically beneficial for use as an NSAID.