Current Issue : July - September Volume : 2017 Issue Number : 3 Articles : 6 Articles
Background: Mitochondrial dysfunction is associated with obesity and various obesity-associated pathological\nconditions including glucose intolerance. 5-Aminolevulinic acid (ALA), a precursor of heme metabolites, is a natural\namino acid synthesized in the mitochondria, and various types of cytochromes containing heme contribute to aerobic\nenergy metabolism. Thus, ALA might have beneficial effects on the reduction of adiposity and improvement of glucose\ntolerance through its promotion of heme synthesis. In the present study, we investigated the effects of ALA combined\nwith sodium ferrous citrate (SFC) on obesity and glucose intolerance in diet-induced obese mice.\nMethods: We used 20-weeks-old male C57BL/6J diet-induced obesity (DIO) mice that had been fed high-fat diet from\n4th week or wild-type C57BL/6J mice. The DIO mice were orally administered ALA combined with SFC (ALA/SFC) for\n6 weeks. At the 4th and 5th week during ALA/SFC administration, mice were fasted for 5 h and overnight, respectively\nand used for oral glucose tolerance test. After the ALA/SFC administration, the plasma glucose levels, weight of white\nadipose tissue, and expression levels of mitochondrial oxidative phosphorylation (OXPHOS) complexes were examined.\nFurthermore, the effects of ALA/SFC on lipid content and glucose uptake were examined in vitro.\nResults: Oral administration of ALA/SFC for 6 weeks reduced the body weight by about 10% and the weight of white\nadipose tissues in these animals. In vitro, ALA/SFC reduced lipid content in mouse 3T3-L1 adipocytes in a\ndose dependent manner, and enhanced glucose uptake in 3T3-L1 adipocytes by 70ââ?¬â??90% and rat L6 myoblasts by 30% at\n6 h. Additionally, oral administration of ALA/SFC reduced plasma glucose levels and improved glucose tolerance in DIO\nmice. Furthermore, ALA/SFC enhanced the expression of OXPHOS complexes III, IV, and V by 40ââ?¬â??70% in white adipose\ntissues of DIO mice, improving mitochondrial function.\nConclusions: Our findings indicate that ALA/SFC is effective in the reduction of adiposity and improvement of glucose\ntolerance, and that the induction of mitochondrial OXPHOS complex III, IV, and V by ALA/SFC might be an essential\ncomponent of the molecular mechanisms underlying these effects. ALA/SFC might be a useful supplement for obesity\nand obesity-related metabolic disease such as type 2 diabetes mellitus....
Glycogen synthase kinase 3 (GSK-3) is a ubiquitously expressed and evolutionarily conserved serine threonine protein kinase. GSK-3 Kinase in addition to its regulation of glycogen metabolism, plays important role in a various cellular reaction. These include cell growth and differentiation, apoptosis, embryonic development, insulin response and in neurological response as in Alzheimer disease and protein synthesis. Glycogen synthase kinase-3 (GSK3) consists of highly homologous α- and β-isoforms, phosphorylates and thereby inactivates glycogen synthase (GS), resulting in reduced glycogenesis. GSK-3 may represent an important therapeutic target for insulin resistance. GSK-3b that plays a critical role CNS function via the proteins tau and b-catenin and in cancer via angiogenesis, apoptosis and tumorigenesis. Inhibitors of GSK-3 are being proposed as potential therapies for disorders such as bipolar mood disorders (lithium and valproic acid are GSK-3 inhibitors), Alzheimer’s disease (in which GSK-3 is believed to play a key role in formation of the neurofibrillary tangles and amyloid plaques) and stroke. A few GSK-3b inhibitors have been now advanced to Phases I and II of clinical trials. GSK-3 Kinase gave the impression of being prominent target for various disease and can be utilized to develop novel drug therapy....
Hyperfunction of brain 5-hydroxytryptamine2C (5-HT2C) receptor is suggested to be involved in anxiety as evidenced by fact that a putative 5-HT2C receptor agonist 1-(m-chlorophenyl)-piperazine (m-CPP) causes anxiety in humans. Agomelatine with its 5-HT2C antagonistic properties, represents a new concept for treatment of anxiety. The anxiolytic potential of agomelatine (10, 30, 100 mg/kg, p.o.) was evaluated and compared with diazepam (1 mg/kg, i.p.) using elevated plus maze (EPM), light dark apparatus (LDA), Hole board apparatus (HBA), open field apparatus (OFA), marble burying test (MBT) and social interaction test (SI). In addition, anxiolytic potential of agomelatine (10, 30 mg/kg, p.o.) was also evaluated by using m-CPP (1 mg/kg, i.p.) in all above models, m-CPP (7 mg/kg, i.p.) induced hypolocomotion and m-CPP (5 mg/kg, i.p.) induced hypophagia. In EPM, LDA, HBA, OFA, MBT and SI agomelatine significantly (p<0.05) increased time spent in open arm, entries in open arm, time spent in light zone, light dark transitions, number of head dips, duration of head dips, number of squares traversed, number of marbles buried and time spent in social interaction respectively. Agomelatine significantly (p<0.05) inhibited the hypolocomotion and hypophagia induced by m-CPP. Our results suggest that agomelatine, a 5-HT2C receptor antagonist may have therapeutic potential for treatment of anxiety....
Our group has earlier demonstrated that three enzymes sensitive to peptidase\ninhibitors (PIs), amastatin (A)-, captopril (C)-, and phosphoramidon (P),\nplayed an important role in inactivation of enkephalins at the spinal level.\nDynorphin-converting enzyme (DCE) hydrolyzes dynorphin (Dyn) A (1-17)\nor Dyn A (1-13) mainly at the Arg6-Arg7 bond. Dynorphin A and its derived\npeptides interact with opioid and glutamate receptors at their N- and C-terminals,\nrespectively. The purpose of the present study was to evaluate the antinociceptive\npotency and toxicity of intrathecal administered Dyn A (1-17),\nDyn A (1-13), or Dyn A (1-6) under pretreatment with ACP and/or the DCE\ninhibitor p-hydroxymercuribenzoate (PHMB). The effect of these PIs on Dyn\nA (1-17)-induced inhibition of electrically-evoked contractions in mouse vas\ndeferens was also investigated. The inhibitory potency of Dyn A (1-17) on\nelectrically-evoked contractions in mouse vas deferens under pretreatment\nwith ACP was higher than that with AC, AP, or CP. Pretreatment with ACP\naugmented Dyn A (1-17) or (1-13)-induced antinociception by approximately\n50- or 30-fold with no sign of allodynia when administered intrathecally at\nlow doses. Pretreatment with ACP and PHMB induced neuropathy. These\nfindings showed that intrathecal administration of low-dose Dyn A (1-17) or\nDynA (1-13) increased antinociception under pretreatment with ACP, but\nwithout signs of allodynia in rat....
Caffeine is a promising drug for the management of neurodegenerative diseases such as\nParkinson�s disease (PD), demonstrating neuroprotective properties that have been attributed to its\ninteraction with the basal ganglia adenosine A2A receptor (A2AR). However, the doses needed\nto exert these neuroprotective effects may be too high. Thus, it is important to design novel\napproaches that selectively deliver this natural compound to the desired target. Docosahexaenoic\nacid (DHA) is the major omega-3 fatty acid in the brain and can act as a specific carrier of caffeine.\nFurthermore, DHA displays properties that may lead to its use as a neuroprotective agent. In the\npresent study, we constructed a novel bivalent ligand covalently linking caffeine and DHA and\nassessed its pharmacological activity and safety profile in a simple cellular model. Interestingly,\nthe new bivalent ligand presented higher potency as an A2AR inverse agonist than caffeine alone.\nWe also determined the range of concentrations inducing toxicity both in a heterologous system and\nin primary striatal cultures. The novel strategy presented here of attaching DHA to caffeine may\nenable increased effects of the drug at desired sites, which could be of interest for the treatment of PD....
Background: Triptolide (TP), an active constituent of Tripterygium wilfordii, possesses numerous pharmacological\nactivities. However, its effects on cytochrome P450 enzymes (CYP450s) in rats remain unexplored.\nMethods: In this study, the effects of triptolide on the six main CYP450 isoforms (1A2, 2C9, 2C19, 2D6, 2E1, and 3A)\nwere investigated both in vivo and in vitro. We monitored the body weight, survival proportions, liver index,\nchanges in pathology, and biochemical index upon TP administration, in vivo. Using a cocktail probe of CYP450\nisoform-specific substrates and their metabolites, we then carried out in vitro enzymatic studies in liver microsomal\nincubation systems via ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS).\nFinally, we verified our results at the messenger ribonucleic acid (mRNA) and protein level through quantitative\nreal-time polymerase chain reaction (RT-qPCR), western blotting, and immunohistochemical detection.\nResults: The in vivo toxicity study confirmed that Sprague-Dawley (SD) rats exhibited dose-dependent\nhepatotoxicity after intragastric administration of TP [200, 400, and 600 �¼g/(kg.day)] for 28 days. In case of the\nCYP450 isoforms 3A, 2C9, 2C19, and 2E1, the in vitro metabolic study demonstrated a decrease in the substrate\nmetabolic rate, metabolite production rate, and Vmax, with an increase in the Km value, compared with that\nobserved in the control group. Additionally, a TP dose-dependent decrease in the mRNA levels was observed in the\nfour major isoforms of CYP3A subfamily (3A1/3A23, 3A2, 3A9, and 3A62) and CYP2C9. A similar effect was also\nobserved with respect to the protein levels of CYP2C19 and CYP2E1.\nConclusions: This study suggests that TP can cause hepatotoxicity by reducing the substrate affinity, activity, and\nexpression at the transcriptional and protein levels of the CYP450 isoforms 3A, 2C9, 2C19, and 2E1. TP also has the\npotential to cause pharmacokinetic drug interactions when co-administered with drugs metabolized by these four\nisoforms. However, further clinical studies are needed to evaluate the significance of this interaction....
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