The Natural Protoalkaloid Methyl-2-Amino-3-Methoxybenzoate (MAM) Alleviates Positive as well as Cognitive Symptoms in Rat and Mouse Schizophrenia Models.

The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present for the first time a preclinical exploration of the effects of the promising natural atypical antipsychotic Methyl-2-Amino-3- Methoxybenzoate (MAM), a brain-penetrable protoalkaloid from the seed of the plant Nigella damascena. Using animal models related to hyperdopaminergic activity, namely the pharmacogenetic apomorphine (D2/D1 receptor agonist)-susceptible (APO-SUS) rat model and pharmacologically induced mouse and rat models of schizophrenia, we found that MAM reduced gnawing stereotypy and climbing behaviours induced by dopaminergic agents. This predicts antipsychotic activity. In line, MAM antagonized apomorphine-induced c-Fos and NPAS4 mRNA levels in post-mortem brain nucleus accumbens and dorsolateral striatum of APO-SUS rats. Furthermore, phencyclidine (PCP, an NMDA receptor antagonist) and 2,5-Dimethoxy-4-iodoamphetamine (DOI, a 5HT2A/2C receptor agonist) induced prepulse inhibition deficits, reflecting the positive symptoms of schizophrenia, which were rescued by treatment with MAM and atypical antipsychotics alike. Post-mortem brain immunostaining revealed that MAM blocked the strong activation of both PCP- and DOI-induced c-Fos immunoreactivity in a number of cortical areas. Finally, during a 28-day subchronic treatment regime, MAM did not induce weight gain, hyperglycemia, hyperlipidemia or hepato- and nephrotoxic effects, side effects known to be induced by atypical antipsychotics. MAM also did not show any cataleptic effects. In conclusion, its brain penetrability, the apparent absence of preclinical side effects, and its ability to antagonize positive and cognitive symptoms associated with schizophrenia make MAM an exciting new antipsychotic drug that deserves clinical testing.

The Novel Lipid-Lowering Drug D-47 Ameliorates Hepatic Steatosis and Promotes Brown/Beige-Like Change of White Adipose Tissue in db/db Mice.

D-47 is a newly developed solid dispersion of the arginine salt of (S)-(+)-4-[1-(4-tert-butylphenyl)-2-oxo-pyrrolidin-4-yl]methoxybenzoic acid (S-2E), which inhibits sterol and fatty acid synthesis. D-47 was recently shown to lower the serum level and hepatic content of both triglyceride and cholesterol in a rabbit model of familial hypercholesterolemia. We here investigated the effects of D-47 on dyslipidemia and hepatic steatosis in comparison with those of bezafibrate in the db/db mouse model of obesity. Treatment of db/db mice with D-47 or bezafibrate for 14 days lowered the serum triglyceride concentration without affecting that of cholesterol. D-47, but not bezafibrate, almost completely eliminated lipid droplets in hepatocytes and markedly lowered the triglyceride content of the liver in these mice. The two agents induced similar changes in the hepatic expression of genes including those related to ß-oxidation or fatty acid synthesis. D-47 however significantly reduced the mass of white adipose tissue and up-regulated the expression of genes related to energy expenditure, mitochondrial function, fatty acid oxidation or lipolysis in this tissue, indicating that D-47 induced the brown/beige adipocyte-like change in white adipose tissue, whereas bezafibrate had no such effects. Treatment of 3T3-L1 adipocytes with D-47 provoked the expression of genes related to mitochondrial function, fatty acid oxidation or lipolysis. Our data have thus shown that D-47 ameliorated hypertriglyceridemia and hepatic steatosis in an animal model of obesity, and they suggest that this latter effect might be mediated through the change of adipose tissue characteristics.

Ameliorating effects of D-47, a newly developed compound, on lipid metabolism in an animal model of familial hypercholesterolemia (WHHLMI rabbits).

Improvements induced in lipid metabolism in the liver by D-47, a newly developed compound, were examined herein. WHHLMI rabbits, an animal model of hypercholesterolemia and coronary atherosclerosis, was fed D-47-supplemented chow for 5 weeks at a dose of 30mg/kg. Lipid concentration were assayed using enzymatic methods. Plasma lipoproteins were fractionated with an ultracentrifuge. mRNA expression was analyzed with real-time PCR. Lipidome analyses of lipoproteins were performed using supercritical fluid chromatography mass spectrometry. In the D-47-treated group, serum lipid levels decreased by 23% for total cholesterol and by 40% for triglycerides. These reductions were mainly attributed to decreases in the VLDL fraction. Compared with the control, in the D-47 group, lipid contents in the liver were decreased by 22% in cholesterol and by 69% in triglycerides, and fat accumulation was decreased by 57% in pericardial fat and by 17% in mesenteric fat. In lipidome analyses of VLDL fraction, lysophosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylethanolamine plasmalogen, sphingomyelin, and ceramide were decreased by the D-47 treatment. mRNA expression in the liver was 51% lower for FAS and 24% lower for MTP, but 5.9- and 5.1-fold higher for CYP7A1 and CPT-1, respectively, in the D-47 group than in the control. mRNA expression was 72%, 64%, and 36% higher for LPL, CTP-1, and PPARγ, respectively, in mesenteric fat in the D-47 group. D-47 is a potent lipid-lowering compound that uses a different mechanism of action from that of statins. It has potential as a compound in the treatment of steatohepatitis and metabolic syndrome.

Materials for retrograde filling in root canal therapy.

BACKGROUND: Root canal therapy is a sequence of treatments involving root canal cleaning, shaping, decontamination and obturation. It is conventionally performed through a hole drilled into the crown of the affected tooth, namely orthograde root canal therapy. For teeth that cannot be treated with orthograde root canal therapy, or for which it has failed, retrograde root filling, which seals the root canal from the root apex, is a good alternative. Many materials, such as amalgam, zinc oxide eugenol and mineral trioxide aggregate (MTA), are generally used. Since none meets all the criteria an ideal material should possess, selecting the most efficacious material is of utmost importance. OBJECTIVES: To determine the effects of different materials used for retrograde filling in children and adults for whom retrograde filling is necessary in order to save the tooth. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 13 September 2016); the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 13 September 2016); MEDLINE Ovid (1946 to 13 September 2016); Embase Ovid (1980 to 13 September 2016); LILACS BIREME Virtual Health Library (1982 to 13 September 2016); and OpenSIGLE (1980 to 2005). ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. We also searched Chinese BioMedical Literature Database (in Chinese, 1978 to 20 September 2016); VIP (in Chinese, 1989 to 20 September 2016); China National Knowledge Infrastructure (in Chinese, 1994 to 20 September 2016); and Sciencepaper Online (in Chinese, to 20 September 2016). No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) only that compared different retrograde filling materials, with reported success rate that was assessed by clinical or radiological methods for which the follow-up period was at least 12 months. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently and in duplicate. Original trial authors were contacted for any missing information. Two review authors independently carried out risk of bias assessments for each eligible study following Cochrane methodological guidelines. MAIN RESULTS: We included six studies (916 participants with 988 teeth) reported in English. All the studies had high risk of bias. The six studies examined five different comparisons, including MTA versus intermediate restorative material (IRM), MTA versus super ethoxybenzoic acid cement (Super-EBA), Super-EBA versus IRM, dentine-bonded resin composite versus glass ionomer cement and glass ionomer cement versus amalgam. There was therefore little pooling of data and very little evidence for each comparison.There is weak evidence of little or no difference between MTA and IRM at the first year of follow-up (risk ratio (RR) 1.09; 95% confidence interval (CI): 0.97 to 1.22; 222 teeth; quality of evidence: low). Insufficient evidence of a difference between MTA and IRM on success rate at the second year of follow-up (RR 1.06; 95% CI: 0.89 to 1.25; 86 teeth, 86 participants; quality of evidence: very low). All the other outcomes were based on a single study. There is insufficient evidence of any difference between MTA and Super-EBA at the one-year follow-up (RR 1.03; 95% CI: 0.96 to 1.10; 192 teeth, 192 participants; quality of evidence: very low), and only weak evidence indicating there might be a small increase in success rate at the one-year follow-up in favour of IRM compared to Super-EBA (RR 0.90; 95% CI: 0.80 to 1.01; 194 teeth; quality of evidence: very low). There was also insufficient and weak evidence to show that dentine-bonded resin composite might be a better choice for increasing retrograde filling success rate compared to glass ionomer cement at the one-year follow-up (RR 2.39; 95% CI: 1.60 to 3.59; 122 teeth, 122 participants; quality of evidence: very low). And there was insufficient evidence of a difference between glass ionomer cement and amalgam at both the one-year (RR 0.98; 95% CI: 0.86 to 1.12; 105 teeth; quality of evidence: very low) and five-year follow-ups (RR 1.00; 95% CI: 0.84 to 1.20; 82 teeth; quality of evidence: very low).None of these studies reported an adverse event. AUTHORS' CONCLUSIONS: Based on the present limited evidence, there is insufficient evidence to draw any conclusion as to the benefits of any one material over another. We conclude that more high-quality RCTs are required.

A Randomized Controlled Study of Mineral Trioxide Aggregate and Super Ethoxybenzoic Acid as Root-end Filling Materials in Endodontic Microsurgery: Long-term Outcomes.

INTRODUCTION: The purpose of the present study was to evaluate the long-term clinical outcome of endodontic microsurgery when mineral trioxide aggregate (MTA) and super ethoxybenzoic acid (Super EBA; Harry J. Bosworth, Skokie, IL) were used as root-end filling materials. Additionally, this study aimed to compare the clinical outcome of endodontic microsurgery at the 1-year follow-up with that at the 4-year follow-up. METHODS: Two hundred sixty teeth were randomly assigned to either the MTA or Super EBA group in equal numbers using the minimization method. Endodontic microsurgery was performed according to the Yonsei protocol. The previous study of 192 teeth examined at the 1-year follow-up revealed a success rate of 95.6% for MTA and 93.1% for Super EBA. Patients were recalled 4 years after surgery, and treated teeth were classified as successes or failures with Molven's criteria. The Pearson chi-square test and the McNemar test were conducted to analyze and compare the success rates. RESULTS: A total of 182 teeth were examined at the 4-year follow-up. The success rate was 91.6% for MTA and 89.9% for Super EBA. Statistical analysis of the success rate did not show any significant difference between the 2 materials (P = .8). The overall success rate at the 4-year follow-up was 89.5%, which was slightly lower compared with 94.3% at the 1-year follow-up. However, there was no significant difference between the follow-up periods (P = .063). CONCLUSIONS: This study identified no significant difference in the 4-year success rates of MTA and Super EBA as root-end filling materials in endodontic microsurgery. Additionally, compared with short-term outcomes, long-term follow-up outcomes were not significantly different.