Effects of Sultopride and Sulpiride on Serum Prolactin Level in Schizophrenia.

Sultopride or sulpiride was administered to 26 schizophrenic patients. In the male patients, there was a significant correlation between serum concentrations of sultopride and sulpiride and prolactin response. In the female patients, there was no significant correlation between them. In sultopride treatment, prolaction response was suggested to be predictive of a good therapeutic response

A Serine Palmitoyltransferase Inhibitor Blocks Hepatitis C Virus Replication in Human Hepatocytes

Background & AimsHost cell lipid rafts form a scaffold required for replication of hepatitis C virus (HCV). Serine palmitoyltransferases (SPTs) produce sphingolipids, which are essential components of the lipid rafts that associate with HCV nonstructural proteins. Prevention of the de novo synthesis of sphingolipids by an SPT inhibitor disrupts the HCV replication complex and thereby inhibits HCV replication. We investigated the ability of the SPT inhibitor NA808 to prevent HCV replication in cells and mice.MethodsWe tested the ability of NA808 to inhibit SPT’s enzymatic activity in FLR3-1 replicon cells. We used a replicon system to select for HCV variants that became resistant to NA808 at concentrations 4- to 6-fold the 50% inhibitory concentration, after 14 rounds of cell passage. We assessed the ability of NA808 or telaprevir to inhibit replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in mice with humanized livers (transplanted with human hepatocytes). NA808 was injected intravenously, with or without pegylated interferon alfa-2a and HCV polymerase and/or protease inhibitors.ResultsNA808 prevented HCV replication via noncompetitive inhibition of SPT; no resistance mutations developed. NA808 prevented replication of all HCV genotypes tested in mice with humanized livers. Intravenous NA808 significantly reduced viral load in the mice and had synergistic effects with pegylated interferon alfa-2a and HCV polymerase and protease inhibitors.ConclusionsThe SPT inhibitor NA808 prevents replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in cultured hepatocytes and in mice with humanized livers. It might be developed for treatment of HCV infection or used in combination with pegylated interferon alfa-2a or HCV polymerase or protease inhibitors

Establishment of infectious HCV virion-producing cells with newly designed full-genome replicon RNA

Hepatitis C virus (HCV) replicon systems enable in-depth analysis of the life cycle of HCV. However, the previously reported full-genome replicon system is unable to produce authentic virions. On the basis of these results, we constructed newly designed full-genomic replicon RNA, which is composed of the intact 5′-terminal-half RNA extending to the NS2 region flanked by an extra selection marker gene. Huh-7 cells harboring this full-genomic RNA proliferated well under G418 selection and secreted virion-like particles into the supernatant. These particles, which were round and 50 nm in diameter when analyzed by electron microscopy, had a buoyant density of 1.08 g/mL that shifted to 1.19 g/mL after NP-40 treatment; these figures match the putative densities of intact virions and nucleocapsids without envelope. The particles also showed infectivity in a colony-forming assay. This system may offer another option for investigating the life cycle of HCV

Novel oral SPT inhibitor CH5169356 inhibits hepatic stellate cell activation and ameliorates hepatic fibrosis in mouse models of non‐alcoholic steatohepatitis (NASH)

Abstract Ceramide is a central molecule of sphingolipid metabolism and is involved in the development of non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH). It has already been reported that the inhibition of serine palmitoyltransferase (SPT), the rate‐limiting enzyme in the sphingolipid biosynthetic pathway, has an inhibitory effect on hepatic lipidosis, but its effect on severe hepatic fibrosis is not clear. In this study, we examined whether a SPT inhibitor could suppress the activation of hepatic stellate cells (HSC) and ameliorate the progression of NASH. Effects on sphingolipid metabolism and HSC activation marker genes by NA808, a SPT inhibitor, were evaluated in an immortalized HSC cell line (E14C12). NA808 decreased sphingolipid synthesis and the expression of α‐smooth muscle actin (α‐SMA) and collagen 1A1 mRNA in HSC. We identified a novel oral SPT inhibitor, CH5169356, which is a prodrug of NA808. CH5169356 was administered in the Ath+HF model, a NASH mouse model with liver fibrosis induced by atherogenic and high‐fat content diets. CH5169356 showed a significant decrease in the expression of α‐SMA and collagen 1A1 mRNA in the liver and an inhibition of liver fibrosis progression. CH5169356 was also evaluated in a Stelic animal model (STAM), a NASH mouse model induced through a different mechanism than that of the Ath+HF model, and showed a significant anti‐fibrotic effect. In conclusion, CH5169356 could inhibit the progression of hepatic fibrosis in the pathogenesis of NASH by suppressing HSC activation, suggesting that CH5169356 would be a potential oral NASH therapeutic agent

An interferon-like small chemical compound CDM-3008 suppresses hepatitis B virus through induction of interferon-stimulated genes

B型肝炎ウイルス抑制物質の作用機序解明 --新規抗B型肝炎治療薬の開発へ期待--. 京都大学プレスリリース. 2019-06-13.Oral administration of nucleotide analogues and injection of interferon-α (IFNα) are used to achieve immediate suppression in replication of hepatitis B virus (HBV). Nucleotide analogs and IFNα inhibit viral polymerase activity and cause long-term eradication of the virus at least in part through removing covalently closed circular DNA (cccDNA) via induction of the APOBEC3 deaminases family of molecules, respectively. This study aimed to explore whether the orally administrable low molecular weight agent CDM-3008 (RO8191), which mimics IFNα through the binding to IFNα/β receptor 2 (IFNAR2) and the activation of the JAK/STAT pathway, can suppress HBV replication and reduce cccDNA levels. In primary cultured human hepatocytes, HBV DNA levels were decreased after CDM-3008-treatment in a dose-dependent manner with a half-maximal inhibitory concentration (IC50) value of 0.1 μM, and this was accompanied by significant reductions in cellular cccDNA levels, both HBeAg and HBsAg levels in the cell culture medium. Using a microarray we comprehensively analyzed and compared changes in gene (mRNA) expression in CDM-3008- and IFNα-treated primary cultured human hepatocytes. As reported previously, CDM-3008 mimicked the induction of genes that participate in the interferon signaling pathway. OAS1 and ISG20 mRNA expression was similarly enhanced by both CDM-3008 and IFNα. Thus, CDM-3008 could suppress pgRNA expression to show anti-HBV activity. APOBEC3F and 3G mRNA expression was also induced by CDM-3008 and IFNα treatments, suggesting that cccDNA could be degraded through induced APOBEC3 family proteins. We identified the genes whose expression was specifically enhanced in CDM-3008-treated cells compared to IFNα-treated cells. The expression of SOCS1, SOCS2, SOCS3, and CISH, which inhibit STAT activation, was enhanced in CDM-3008-treated cells suggesting that a feedback inhibition of the JAK/STAT pathway was enhanced in CDM-3008-treated cells compared to IFNα-treated cells. In addition, CDM-3008 showed an additive effect with a clinically-used nucleoside entecavir on inhibition of HBV replication. In summary, CDM-3008 showed anti-HBV activity through activation of the JAK/STAT pathway, inducing the expression of interferon-stimulated genes (ISGs), with greater feedback inhibition than IFNα

Effects of Sultopride and Sulpiride on Serum Prolactin Level in Schizophrenia.

Sultopride or sulpiride was administered to 26 schizophrenic patients. In the male patients, there was a significant correlation between serum concentrations of sultopride and sulpiride and prolactin response. In the female patients, there was no significant correlation between them. In sultopride treatment, prolaction response was suggested to be predictive of a good therapeutic response.identifier:奈良医学雑誌 Vol.46 No.6 p.592-598identifier:04695550identifier:13450069identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/2992identifier:奈良医学雑誌, 46(6): 592-59

Subclinical Elevation of Plasma C-Reactive Protein and Illusions/Hallucinations in Subjects with Parkinson’s Disease: Case–control Study

<div><p>Background</p><p>Though infections are associated with psychotic symptoms, whether or not subclinical inflammation is associated with hallucinations is not known in Parkinson’s disease (PD).</p><p>Purpose</p><p>To investigate the association of illusions/hallucinations and plasma CRP levels in PD patients without symptomatic infections.</p><p>Methods</p><p>PD patients not diagnosed as having infections were assessed for illusions and hallucinations using the Parkinson Psychosis Questionnaire (PPQ). It comprises four-domain questions: PPQ-A for sleep problems, PPQ-B for hallucinations/illusions, PPQ-C for delusions, and PPQ-D for disorientation. Assigning patients with ≥1 points in the PPQ-B score to be cases and others as controls, the association of hallucinations/illusions and clinical features (age, sex, duration of PD, Unified Parkinson’s Disease Rating Scale part 3 (UPDRS-3), Mini-Mental State Examination (MMSE) score, sleep disturbance (PPQ-A score) as well as daily doses of L-Dopa, dopamine agonists, amantadine, and selegiline) were analyzed using a case–control design.</p><p>Results</p><p>A total of 111 patients were examined and plasma CRP levels were <0.1–6.0 mg/L. Hallucinations or illusions were detected in 28 (25.2%). There were significant differences in age, UPDRS-3 score, MMSE score, PPQ-A, daily doses of L-Dopa and dopamine agonists and plasma CRP levels between cases and controls. A multivariate logistic regression model revealed that UPDRS-3 scores and plasma CRP levels were significantly associated with hallucinations/illusions with an adjusted odds ratio of 1.96 (95% confidence interval (CI) 1.20–3.20) per 10 points and 1.57 (95% confidence interval 1.13–2.16) per two-fold, respectively. Dividing patients into thirds by CRP levels (≤0.2, 0.3–0.6, ≥0.7 mg/L), the prevalence of hallucinations/illusions was 13.2%, 21.6%, and 41.7%, in the bottom-, middle-, and top-thirds, respectively (for trend p = 0.012).</p><p>Conclusions</p><p>Subclinical elevation of plasma CRP levels was associated with hallucinations or illusions after adjustment for motor disability, suggesting that subclinical elevations of CRP levels might be an independent risk for hallucinations/illusions.</p></div