ObjectivesThere is a critical need to develop effective treatments for diabetic neuropathy. This study determined if a selective mGluR2/3 receptor agonist prevented or treated experimental diabetic peripheral neuropathy (DPN) through glutamate recycling and improved mitochondrial function.MethodsAdult male streptozotocin treated Sprague‐Dawley rats with features of type 1 diabetes mellitus (T1DM) or Low Capacity Running (LCR) rats with insulin resistance or glucose intolerance were treated with 3 or 10 mg/kg/day LY379268. Neuropathy end points included mechanical allodynia, nerve conduction velocities (NCV), and intraepidermal nerve fiber density (IENFD). Markers of oxidative stress, antioxidant response, glutamate recycling pathways, and mitochondrial oxidative phosphorylation (OXPHOS) associated proteins were measured in dorsal root ganglia (DRG).ResultsIn diabetic rats, NCV and IENFD were decreased. Diabetic rats treated with an mGluR2/3 agonist did not develop neuropathy despite remaining diabetic. Diabetic DRG showed increased levels of oxidized proteins, decreased levels of glutathione, decreased levels of mitochondrial DNA (mtDNA) and OXPHOS proteins. In addition, there was a 20‐fold increase in levels of glial fibrillary acidic protein (GFAP) and the levels of glutamine synthetase and glutamate transporter proteins were decreased. When treated with a specific mGluR2/3 agonist, levels of glutathione, GFAP and oxidized proteins were normalized and levels of superoxide dismutase 2 (SOD2), SIRT1, PGC‐1α, TFAM, glutamate transporter proteins, and glutamine synthetase were increased in DRG neurons.InterpretationActivation of glutamate recycling pathways protects diabetic DRG and this is associated with activation of the SIRT1‐PGC‐1α–TFAM axis and preservation of mitochondrial OXPHOS function.

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The prophylactic granisetron-dexamethasone combination was more effective than granisetron alone in the prevention of post-operative emesis during the first 24 h after anaesthesia in children undergoing middle ear surgery.

BackgroundThe high‐fat, low carbohydrate ketogenic diet (KD) is a proven therapy for patients with medically refractory epilepsy. The metabolic changes induced by the KD mimics the physiological alteration of fasting and calorie restriction – wherein ketone levels are elevated (ketosis). Both the KD and its metabolic substrates are involved in modulating anti‐seizure effects, but the molecular target of these beneficial effects have yet to be fully elucidated. One potential molecular explanation links the mammalian target of rapamycin (mTOR) signaling pathway. Disruptions in the mTOR pathway may explain in part susceptibility to and pathogenesis of epilepsy. The primary purpose of this study was to investigate the role of metabolic changes in mTOR signaling pathway in the Kcna1‐null mouse model of epilepsy and whether its mechanistic effects are linearly correlated with ketosis.MethodsSpontaneously epileptic Kcna1‐null (KO) mice were generated using heterozygous breeding pairs. At P21‐ 23, mice were treated with the KD and either standard diet (SD) or SD with subcutaneous administration of BHB through osmotic mini‐pumps for 2–3 weeks. Blood from tail clippings were used to measure BHB and glucose levels. EEG electrodes were implanted through parasaggital burr holes in either wild type (WT) mice or KO mice around P28. Following a 3‐day recovery period, seizure activity was assessed over 72 continuous hours. After over 2 weeks of treatment, hippocampal lysates were collected from: (1) SD‐fed WT; (2) SD‐fed KO; (3) KD‐fed WT; (4) KD‐fed KO; (5) saline‐treated WT; (6) saline‐treated KO; (7) BHB‐treated WT; and (8) BHB–treated KO mice. Samples were probed with antibodies against upstream modulators of mTOR, either phosphorylated ‐ or total –AMPK, and downstream effectors of mTOR, phospho‐ or total ‐ S6, as well as a downstream effectors of AMPK, either glial fibrillary acidic protein (GFAP) or Tubulin. Total RNA obtained from hippocampus or whole brain using TRIzol was reverse transcribed into cDNA by RT‐PCR and then the single‐stranded cDNA was amplified by PCR with primers for GFAP and β‐actin.ResultsUsing western blot analysis, mTOR signaling was significantly increased in KO mice accompanied with spontaneous epileptic discharge, and levels of upstream pAMPK were decreased in these animals compared to control and KD‐fed KO mice. KO mice showed a significant enhancement in the downstream markers pS6 and p4EBP1, whereas this effect was strongly suppressed by the KD treatment. KD treatment led to a reduction in pS6 in kainic acid (KA)‐treated control mice. KA resulted in a gradual increase of GFAP. In contrast, at 24 hours post KA injection, KD‐fed mice exhibited a significant decrease in expression level of GFAP.ConclusionCollectively, either the KD or ketone not only reduces the severity of seizures in two different mouse models, but also attenuates mTOR signaling pathways. Further, our finding that phospho‐S6 is reduced by KD treatment suggests a mechanistic link between mTOR inhibition and decreases in astrogliosis, both mechanisms that could contribute to the anti‐seizure and neuroprotective effects of the KD. The results provide evidence for the functional protective link between the KD and its primary metabolic substrate, β‐hydroxybutyrate, in spontaneously epileptic Kcna1‐null mice. Finally, the therapeutic effects of BHB and the KD may be in part inhibitory action of glial cell activation through modulation of mTOR signaling pathway Effects of the ketogenic diet on seizure‐evoked upregulation of mTOR signaling pathways in the hippocampus of Kcna1‐null mice. (A & D)

The essential oil of ARTEMISIA NILAGIRICA was analysed by capillary gas chromatography, IR, (1)H-NMR, and GC-MS. The main constituents of the oil are camphor, beta-eudesmol, 1,8-cineole, borneol, artemisia alcohol, camphene, alpha-gurjunene, P-cymene, terpinene-4-ol and alpha-pinene.

Rice, a staple food worldwide, contains varying amount of nutrients in different grain tissues. The underlying molecular mechanism of such distinct nutrient partitioning remains poorly-investigated. Here, an optimized rapid Laser Capture Microdissection (LCM) approach was used to individually collect pericarp, aleurone, embryo and endosperm from 10 Days After Fertilization (DAF) old grains. Subsequent RNA-Seq analysis in these tissues have identified 7760 differentially expressed genes (DEGs). Analysis of promoter sequences of tissue specific genes identified many known and novel cis-elements important for grain filling and seed development. Using identified DEGs, comprehensive spatial gene expression pathways were built for spatial accumulation of starch, proteins, lipids and iron. The extensive transcriptomic analysis has provided many novel insights about nutrient partitioning mechanisms, for instance, it reveals a gradient in Seed Storage Protein accumulation across the analysed four tissue-types. It further reveals that partitioning of various minerals, such as iron, is most likely regulated through transcriptional control of their transporters. In addition, the extensive analysis of this study is presented as an interactive online tool (https://biogeek.shinyapps.io/DEGs/) that provides a much-needed resource for future functional genomics studies aimed to improve grain quality and seed development.

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