A Mechanism for microRNA Arm Switching Regulated by Uridylation.

Strand selection is a critical step in microRNA (miRNA) biogenesis. Although the dominant strand may change depending on cellular contexts, the molecular mechanism and physiological significance of such alternative strand selection (or "arm switching") remain elusive. Here we find miR-324 to be one of the strongly regulated miRNAs by arm switching and identify the terminal uridylyl transferases TUT4 and TUT7 to be the key regulators. Uridylation of pre-miR-324 by TUT4/7 re-positions DICER on the pre-miRNA and shifts the cleavage site. This alternative processing produces a duplex with a different terminus from which the 3' strand (3p) is selected instead of the 5' strand (5p). In glioblastoma, the TUT4/7 and 3p levels are upregulated, whereas the 5p level is reduced. Manipulation of the strand ratio is sufficient to impair glioblastoma cell proliferation. This study uncovers a role of uridylation as a molecular switch in alternative strand selection and implicates its therapeutic potential.

Etomoxir, a carnitine palmitoyltransferase 1 inhibitor, combined with temozolomide reduces stemness and invasiveness in patient-derived glioblastoma tumorspheres.

INTRODUCTION: The importance of fatty acid oxidation (FAO) in the bioenergetics of glioblastoma (GBM) is being realized. Etomoxir (ETO), a carnitine palmitoyltransferase 1 (CPT1) inhibitor exerts cytotoxic effects in GBM, which involve interrupting the FAO pathway. We hypothesized that FAO inhibition could affect the outcomes of current standard temozolomide (TMZ) chemotherapy against GBM. METHODS: The FAO-related gene expression was compared between GBM and the tumor-free cortex. Using four different GBM tumorspheres (TSs), the effects of ETO and/or TMZ was analyzed on cell viability, tricarboxylate (TCA) cycle intermediates and adenosine triphosphate (ATP) production to assess metabolic changes. Alterations in tumor stemness, invasiveness, and associated transcriptional changes were also measured. Mouse orthotopic xenograft model was used to elucidate the combinatory effect of TMZ and ETO. RESULTS: GBM tissues exhibited overexpression of FAO-related genes, especially CPT1A, compared to the tumor-free cortex. The combined use of ETO and TMZ further inhibited TCA cycle and ATP production than single uses. This combination treatment showed superior suppression effects compared to treatment with individual agents on the viability, stemness, and invasiveness of GBM TSs, as well as better downregulation of FAO-related gene expression. The results of in vivo study showed prolonged survival outcomes in the combination treatment group. CONCLUSION: ETO, an FAO inhibitor, causes a lethal energy reduction in the GBM TSs. When used in combination with TMZ, ETO effectively reduces GBM cell stemness and invasiveness and further improves survival. These results suggest a potential novel treatment option for GBM.

Dual inhibition of CPT1A and G6PD suppresses glioblastoma tumorspheres.

PURPOSE: Limited treatment options are currently available for glioblastoma (GBM), an extremely lethal type of brain cancer. For a variety of tumor types, bioenergetic deprivation through inhibition of cancer-specific metabolic pathways has proven to be an effective therapeutic strategy. Here, we evaluated the therapeutic effects and underlying mechanisms of dual inhibition of carnitine palmitoyltransferase 1A (CPT1A) and glucose-6-phosphate dehydrogenase (G6PD) critical for fatty acid oxidation (FAO) and the pentose phosphate pathway (PPP), respectively, against GBM tumorspheres (TSs). METHODS: Therapeutic efficacy against GBM TSs was determined by assessing cell viability, neurosphere formation, and 3D invasion. Liquid chromatography-mass spectrometry (LC-MS) and RNA sequencing were employed for metabolite and gene expression profiling, respectively. Anticancer efficacy in vivo was examined using an orthotopic xenograft model. RESULTS: CPT1A and G6PD were highly expressed in GBM tumor tissues. Notably, siRNA-mediated knockdown of both genes led to reduced viability, ATP levels, and expression of genes associated with stemness and invasiveness. Similar results were obtained upon combined treatment with etomoxir and dehydroepiandrosterone (DHEA). Transcriptome analyses further confirmed these results. Data from LC-MS analysis showed that this treatment regimen induced a considerable reduction in the levels of metabolites associated with the TCA cycle and PPP. Additionally, the combination of etomoxir and DHEA inhibited tumor growth and extended survival in orthotopic xenograft model mice. CONCLUSION: Our collective findings support the utility of dual suppression of CPT1A and G6PD with selective inhibitors, etomoxir and DHEA, as an efficacious therapeutic approach for GBM.

Obesity-induced TRB3 negatively regulates Brown adipose tissue function in mice.

Brown adipose tissue (BAT) and stimulating adaptive thermogenesis have been implicated as anti-obese and anti-diabetic tissues due to their ability to dissipate energy as heat by the expression of UCP1. We have recently demonstrated that TRB3 impairs differentiation of brown preadipocytes via inhibiting insulin signaling. However, the roles of the protein in BAT function and thermogenesis in vivo have not yet been established. For this study we tested the hypothesis that TRB3 mediates obesity- and diabetes-induced impairments in BAT differentiation and function, and that inhibition of TRB3 improves BAT function. TRB3 expression was increased in BAT from high-fat fed mice and ob/ob mice, which was associated with decreased UCP1 expression. Incubation of brown adipocytes with palmitate increased TRB3 expression and decreased UCP1. Knockout of TRB3 in mice displayed higher UCP1 expression in BAT and cold resistance. Incubation of brown adipocytes with ER stressors increased TRB3 but decreased UCP1 and ER stress markers were elevated in BAT from high-fat fed mice and ob/ob mice. Finally, high-fat feeding in TRB3KO mice were protected from obesity-induced glucose intolerance and displayed cold resistance and higher expression of BAT-specific markers. These data demonstrate that high-fat feeding and obesity increase TRB3 in BAT, resulting in impaired tissue function.

TRB3 regulates skeletal muscle mass in food deprivation-induced atrophy.

Tribbles 3 (TRB3) is a pseudokinase that has been found in multiple tissues in response to various stress stimuli, such as nutrient deprivation and endoplasmic reticulum (ER) stress. We recently found that TRB3 has the potential to regulate skeletal muscle mass at the basal state. However, it has not yet been explored whether TRB3 regulates skeletal muscle mass under atrophic conditions. Here, we report that food deprivation for 48 h in mice significantly reduces muscle mass by ∼15% and increases TRB3 expression, which is associated with increased ER stress. Interestingly, inhibition of ER stress in C2C12 myotubes reduces food deprivation-induced expression of TRB3 and muscle-specific E3-ubiquitin ligases. In further in vivo experiments, muscle-specific TRB3 transgenic mice increase food deprivation-induced muscle atrophy compared with wild-type (WT) littermates presumably by the increased proteolysis. On the other hand, TRB3 knockout mice ameliorate food deprivation-induced atrophy compared with WT littermates by preserving a higher protein synthesis rate. These results indicate that TRB3 plays a pivotal role in skeletal muscle mass regulation under food deprivation-induced muscle atrophy and TRB3 could be a pharmaceutical target to prevent skeletal muscle atrophy.-Choi, R. H., McConahay, A., Silvestre, J. G., Moriscot, A. S., Carson, J. A., Koh, H.-J. TRB3 regulates skeletal muscle mass in food deprivation-induced atrophy.

Adipose tissue-specific knockout of AMPKα1/α2 results in normal AICAR tolerance and glucose metabolism.

AMP-activated protein kinase (AMPK) is a member of Ser/Thr kinases that has been shown to regulate energy balance. Although recent studies have demonstrated the function of AMPK in adipose tissue using different fat-specific AMPK knockout mouse models, the results were somewhat inconsistent. For this study, we tested the hypothesis that AMPK in adipose tissue regulates whole body glucose metabolism. To determine the role of adipose tissue AMPK in vivo, we generated fat-specific AMPKα1/α2 knockout mice (AMPKFKO) using the Cre-loxP system. Body weights of AMPKFKO mice were not different between 8 and 27 weeks of age. Furthermore, tissue weights (liver, kidney, muscle, heart and white and brown adipose tissue) were similar to wild type littermates and DEXA scan analysis revealed no differences in percentages of body fat and lean mass. Knockout of AMPKα1/α2 in adipose tissue abolished basal and AICAR-stimulated phosphorylation of AMPK and Acetyl-CoA Carboxylase, a downstream of AMPK. Despite of the ablation of AICAR-stimulated AMPK phosphorylation, the blood glucose-lowering effect of AICAR injection (i.p.) was normal in AMPKFKO mice. In addition, AMPKFKO displayed normal fasting blood glucose concentration, glucose tolerance, insulin tolerance, and insulin signaling, indicating normal whole body glucose metabolism. These data demonstrate that adipose tissue AMPK plays a minimum role in whole body glucose metabolism on a chow diet.

Tribbles 3 regulates protein turnover in mouse skeletal muscle.

Skeletal muscle atrophy is associated with a disruption in protein turnover involving increased protein degradation and suppressed protein synthesis. Although it has been well studied that the IGF-1/PI3K/Akt pathway plays an essential role in the regulation of the protein turnover, molecule(s) that triggers the change in protein turnover still remains to be elucidated. TRB3 has been shown to inhibit Akt through direct binding. In this study, we hypothesized that TRB3 in mouse skeletal muscle negatively regulates protein turnover via the disruption of Akt and its downstream molecules. Muscle-specific TRB3 transgenic (TRB3TG) mice had decreased muscle mass and fiber size, resulting in impaired muscle function. We also found that protein synthesis rate and signaling molecules, mTOR and S6K1, were significantly reduced in TRB3TG mice, whereas the protein breakdown pathway was significantly activated. In contrast, TRB3 knockout mice showed increased muscle mass and had an increase in protein synthesis rate, but decreases in FoxOs, atrogin-1, and MuRF-1. These findings indicate that TRB3 regulates protein synthesis and breakdown via the Akt/mTOR/FoxO pathways.

Tribbles 3 inhibits brown adipocyte differentiation and function by suppressing insulin signaling.

Recent studies have demonstrated that adult humans have substantial amounts of functioning brown adipose tissue (BAT). Since BAT has been implicated as an anti-obese and anti-diabetic tissue, it is important to understand the signaling molecules that regulate BAT function. There has been a link between insulin signaling and BAT metabolism as deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function. Tribbles 3 (TRB3) is a pseudo kinase that has been shown to regulate metabolism and insulin signaling in multiple tissues but the role of TRB3 in BAT has not been studied. In this study, we found that TRB3 expression was present in BAT and overexpression of TRB3 in brown preadipocytes impaired differentiation and decreased expression of BAT markers. Furthermore, TRB3 overexpression resulted in significantly lower oxygen consumption rates for basal and proton leakage, indicating decreased BAT activity. Based on previous studies showing that deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function, we assessed insulin signaling in brown preadipocytes and BAT in vivo. Overexpression of TRB3 in cells impaired insulin-stimulated IRS1 and Akt phosphorylation, whereas TRB3KO mice displayed improved IRS1 and Akt phosphorylation. Finally, deletion of IRS1 abolished the function of TRB3 to regulate BAT differentiation and metabolism. These data demonstrate that TRB3 inhibits insulin signaling in BAT, resulting in impaired differentiation and function.

Health benefit of fucosterol from marine algae: a review.

Seaweeds belong to a group of marine plants known as algae, which are consumed as sea vegetables in several Asian countries. Recent studies have focused on the biological and pharmacological activities of seaweeds and their highly bioactive secondary metabolites because of their potential in the development of new pharmaceutical agents. Although several varieties of bioactive novel compounds such as phlorotannins, diterpenes and polysaccharides from seaweeds have already been well scrutinized, fucosterol as a phytosterol still needs to reinvent itself. Fucosterol (24-ethylidene cholesterol) is a sterol that can be isolated from algae, seaweed and diatoms. Fucosterol exhibits various biological therapeutics, including anticancer, antidiabetic, antioxidant, hepatoprotective, antihyperlipidemic, antifungal, antihistaminic, anticholinergic, antiadipogenic, antiphotodamaging, anti-osteoporotic, blood cholesterol reducing, blood vessel thrombosis preventive and butyrylcholinesterase inhibitory activities. In this review, we address some potential approaches for arbitrating novel fucosterol biologics in the medical field, focusing on the selection of personalized drug candidates and highlighting the challenges and opportunities regarding medical breakthroughs. We also highlight recent advances made in the design of this novel compound, as the significant health benefits from using these optimized applications apply to the nutraceutical and pharmaceutical fields.

Acyanotic tetralogy of Fallot in a Persian cat.

An 8-year-old, intact male Persian cat was presented with a prominent heart murmur, exercise intolerance, anorexia, and periodontitis. There was no cyanosis and no laboratory evidence for systemic hypoxemia. Echocardiography showed a dextropositioned aorta, moderate pulmonic stenosis (maximal velocity 4.06 m/s), ventricular septal defect, and right ventricular hypertrophy. The shunt direction was predominantly left-to-right in systole and minimally right-to-left in diastole. The cat was diagnosed with acyanotic (pink) tetralogy of Fallot and was managed medically with atenolol.

Tétralogie de Fallot acyanotique chez un chat Persan. Un chat Persan mâle intact âgé de 8 ans a été présenté avec un souffle cardiaque évident, une intolérance à l'effort, de l'anorexie et une parodontite. Il n'y avait pas de cyanose ni de résultats de laboratoire indiquant l'hypoxémie systémique. L'échocardiographie a montré une aorte en dextroposition, une sténose pulmonaire modérée (vélocité maximale de 4,06 m/s), une malformation septale ventriculaire et une hypertrophie ventriculaire droite. La direction du shunt était principalement de gauche à droite en systole et minimalement de droite à gauche en diastole. Un diagnostic de tétralogie de Fallot acyanotique (rose) a été posé et a été géré médicalement à l'aide d'aténolol.(Traduit par Isabelle Vallières).

L-Alanylglutamine inhibits signaling proteins that activate protein degradation, but does not affect proteins that activate protein synthesis after an acute resistance exercise.

Sustamine™ (SUS) is a dipeptide composed of alanine and glutamine (AlaGln). Glutamine has been suggested to increase muscle protein accretion; however, the underlying molecular mechanisms of glutamine on muscle protein metabolism following resistance exercise have not been fully addressed. In the present study, 2-month-old rats climbed a ladder 10 times with a weight equal to 75 % of their body mass attached at the tail. Rats were then orally administered one of four solutions: placebo (PLA-glycine = 0.52 g/kg), whey protein (WP = 0.4 g/kg), low dose of SUS (LSUS = 0.1 g/kg), or high dose of SUS (HSUS = 0.5 g/kg). An additional group of sedentary (SED) rats was intubated with glycine (0.52 g/kg) at the same time as the ladder-climbing rats. Blood samples were collected immediately after exercise and at either 20 or 40 min after recovery. The flexor hallucis longus (FHL), a muscle used for climbing, was excised at 20 or 40 min post exercise and analyzed for proteins regulating protein synthesis and degradation. All supplements elevated the phosphorylation of FOXO3A above SED at 20 min post exercise, but only the SUS supplements significantly reduced the phosphorylation of AMPK and NF-kB p65. SUS supplements had no effect on mTOR signaling, but WP supplementation yielded a greater phosphorylation of mTOR, p70S6k, and rpS6 compared with PLA at 20 min post exercise. However, by 40 min post exercise, phosphorylation of mTOR and rpS6 in PLA had risen to levels not different than WP. These results suggest that SUS blocks the activation of intracellular signals for MPB, whereas WP accelerates mRNA translation.

Cardiopulmonary and anesthetic effects of the combination of butorphanol, midazolam and alfaxalone in Beagle dogs.

OBJECTIVE: To evaluate the physiological variables, arterial blood gas values, induction of anesthesia quality, and recovery quality using the combination of butorphanol, midazolam and alfaxalone in dogs. ANIMALS: Ten healthy adult Beagle dogs weighing 8.3 ± 3.1 kg. METHODS: Rectal temperature (T), pulse rate (PR), respiratory rate (f(R)), mean arterial pressure (MAP), and arterial blood gases were measured and recorded prior to intravenous (IV) administration of butorphanol, prior to administration of both midazolam and alfaxalone IV 10 minutes later, then every 5 minutes for 20 minutes. M-mode echocardiographic left ventricular (LV) indices were measured before and 5 minutes after administration of alfaxalone. Qualitative scores for induction of anesthesia and recovery were allocated, duration of anesthesia and recovery were calculated, and adverse events were recorded. RESULTS: Scores for induction and recovery quality were excellent. No significant adverse events were observed. Mean ± SD time from induction to extubation and to standing (full recovery) was 29 ± 6 and 36 ± 8 minutes, respectively. There were statistically significant changes in PR, f(R) and MAP after drug administration. Transient hypercarbia developed after alfaxalone injection. The echocardiographic LV indices were reduced after alfaxalone injection, although those changes were not statistically significant. CONCLUSIONS AND CLINICAL RELEVANCE: The combination of butorphanol, midazolam and alfaxalone provided excellent quality of induction of anesthesia and exerted minimal cardiopulmonary effects in healthy dogs.

Rutin Stimulates Adipocyte Differentiation and Adiponectin Secretion in 3T3-L1 Adipocytes.

Rutin is aflavonoid, which is found in many plants. It has been shown to reduce blood glucose and increase insulin levels in diabetic rats. In the present study, the authors aimed to elucidate the molecular basis for the observed antidiabetic activity using murine 3T3-L1 preadipocyte cultures. The treatment of differentiating 3T3-L1 cells with rutin at concentrations of 3, 10, 30 and 100 µM significantly increased lipid accumulation and mRNA expression of transcription factors, such as peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein alpha, and adipocyte fatty acid-binding protein. Furthermore, rutin at concentrations of 10, 30 and 100 µM increased adiponectin mRNA expression together with stimulating the secretion of adiponectin in differentiating 3T3-L1 cells. These results indicate that the stimulatory effect of rutin on adipocyte differentiation likely occurs through up-regulation of adipogenic transcription factors and downstream adipocyte-specific gene expression. Such effects of rutin on adiponectin secretion and adipocyte activity may account for, at least in part, the antidiabetic effects of consumption of food containing rutin.

Umbelliferone increases the expression of adipocyte-specific genes in 3T3-L1 adipocyte.

Umbelliferone (UMB), a natural product of coumarin family, has been shown to reduce blood glucose and to improve lipid profiles in streptozotocin (STZ)-induced diabetic rats. Our objective was to examine the effect of UMB on adipogenesis by investigating its stimulatory effect on lipid accumulation and mRNA expression of adipogenic transcription factors and adipocyte-specific genes in 3 T3-L1 preadipocyte culture. An Oil Red O staining was used to monitor lipid accumulation, and we found that UMB treatment at concentration range of 10-100 µM significantly increased lipid accumulation of differentiating 3 T3-L1 cells. At the molecular level of adipogenesis, we examined the mRNA expression of adipogenic transcription factors, peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein α, and sterol regulatory element-binding protein 1c. Those transcription factors were increased by UMB at 10-100 µM. Interestingly, UMB also stimulated the mRNA expression of adipocyte-specific genes, adipocyte fatty acid-binding protein, lipoprotein lipase, fatty acid synthase, fatty acid translocase, and adiponectin. Our findings indicate that the stimulatory effect of UMB on adipocyte differentiation likely occurs through up-regulation of adipogenic transcription factors and downstream adipocyte-specific gene expression.

Skeletal muscle PGC-1α remodels mitochondrial phospholipidome but does not alter energy efficiency for ATP synthesis.

Background: Exercise training is thought to improve the mitochondrial energy efficiency of skeletal muscle. Some studies suggest exercise training increases the efficiency for ATP synthesis by oxidative phosphorylation (OXPHOS), but the molecular mechanisms are unclear. We have previously shown that exercise remodels the lipid composition of mitochondrial membranes, and some of these changes could contribute to improved OXPHOS efficiency (ATP produced by O2 consumed or P/O). Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional co-activator that coordinately regulates exercise-induced adaptations including mitochondria. We hypothesized that increased PGC-1α activity is sufficient to remodel mitochondrial membrane lipids and promote energy efficiency. Methods: Mice with skeletal muscle-specific overexpression of PGC-1α (MCK-PGC-1α) and their wildtype littermates were used for this study. Lipid mass spectrometry and quantitative PCR were used to assess muscle mitochondrial lipid composition and their biosynthesis pathway. The abundance of OXPHOS enzymes was determined by western blot assay. High-resolution respirometry and fluorometry analysis were used to characterize mitochondrial bioenergetics (ATP production, O2 consumption, and P/O) for permeabilized fibers and isolated mitochondria. Results: Lipidomic analyses of skeletal muscle mitochondria from wildtype and MCK-PGC-1α mice revealed that PGC-1α increases the concentrations of cone-shaped lipids such as phosphatidylethanolamine (PE), cardiolipin (CL), and lysophospholipids, while decreases the concentrations of phosphatidylcholine (PC), phosphatidylinositol (PI) and phosphatidic acid (PA). However, while PGC-1α overexpression increased the abundance of OXPHOS enzymes in skeletal muscle and the rate of O2 consumption (JO2), P/O values were unaffected with PGC-1α in permeabilized fibers or isolated mitochondria. Conclusions: Collectively, overexpression of PGC-1α promotes the biosynthesis of mitochondrial PE and CL but neither PGC-1α nor the mitochondrial membrane lipid remodeling induced in MCK-PGC-1α mice is sufficient to increase the efficiency for mitochondrial ATP synthesis. These findings suggest that exercise training may increase OXPHOS efficiency by a PGC-1α-independent mechanism, and question the hypothesis that mitochondrial lipids directly affect OXPHOS enzymes to improve efficiency for ATP synthesis.

Designed synthesis of well-defined Pd@Pt core-shell nanoparticles with controlled shell thickness as efficient oxygen reduction electrocatalysts.

Improving the electrocatalytic activity and durability of Pt-based catalysts with low Pt content toward the oxygen reduction reaction (ORR) is one of the main challenges in advancing the performance of polymer electrolyte membrane fuel cells (PEMFCs). Herein, a designed synthesis of well-defined Pd@Pt core-shell nanoparticles (NPs) with a controlled Pt shell thickness of 0.4-1.2 nm by a facile wet chemical method and their electrocatalytic performances for ORR as a function of shell thickness are reported. Pd@Pt NPs with predetermined structural parameters were prepared by in situ heteroepitaxial growth of Pt on as-synthesized 6 nm Pd NPs without any sacrificial layers and intermediate workup processes, and thus the synthetic procedure for the production of Pd@Pt NPs with well-defined sizes and shell thicknesses is greatly simplified. The Pt shell thickness could be precisely controlled by adjusting the molar ratio of Pt to Pd. The ORR performance of the Pd@Pt NPs strongly depended on the thickness of their Pt shells. The Pd@Pt NPs with 0.94 nm Pt shells exhibited enhanced specific activity and higher durability compared to other Pd@Pt NPs and commercial Pt/C catalysts. Testing Pd@Pt NPs with 0.94 nm Pt shells in a membrane electrode assembly revealed a single-cell performance comparable with that of the Pt/C catalyst despite their lower Pt content, that is the present NP catalysts can facilitate low-cost and high-efficient applications of PEMFCs.

Blockade of CCL2/CCR2 signalling ameliorates diabetic nephropathy in db/db mice.

BACKGROUND: CCL2/C-C chemokine receptor 2 (CCR2) signalling is suggested to play a significant role in various kidney diseases including diabetic nephropathy. We investigated the renoprotective effect of a CCR2 antagonist, RS102895, on the development of diabetic nephropathy in a type 2 diabetic mouse model. METHODS: Six-week-old diabetic db/db and non-diabetic db/m mice were fed either normal chow or chow mixed with 2 mg/kg/day of RS102895 for 9 weeks. We investigated the effects of CCR2 antagonism on blood glucose, blood pressure, albuminuria and the structure and ultrastructure of the kidney. RESULTS: Diabetes-induced albuminuria was significantly improved after CCR2 antagonist treatment, and glucose intolerance was improved in the RS102895-treated diabetic mice. RS102895 did not affect blood pressure, body weight or kidney weight. Mesangial expansion, glomerular basement membrane thickening and increased desmin staining in the diabetic kidney were significantly improved after RS102895 treatment. The up-regulation of vascular endothelial growth factor mRNA expression and the down-regulation of nephrin mRNA expression were markedly improved in the kidneys of RS102895-treated diabetic mice. Increased renal CD68 and arginase II and urinary malondialdehyde in diabetes were effectively attenuated by RS102895 treatment. CONCLUSION: Blockade of CCL2/CCR2 signalling by RS102895 ameliorates diabetic nephropathy not only by improving blood glucose levels but also by preventing CCL2/CCR2 signalling from altering renal nephrin and VEGF expressions through blocking macrophage infiltration, inflammation and oxidative stress in type 2 diabetic mice.

New crystal structure: synthesis and characterization of hexagonal wurtzite MnO.

Most transition metal oxides have a cubic rocksalt crystal structure, but ZnO and CoO are the only stable transition metal oxides known to possess a hexagonal structure. Unprecedented hexagonal wurtzite MnO has been prepared by thermal decomposition of Mn(acac)(2) on a carbon template. Structural characterization has been carried out by TEM, SAED, and a Rietveld analysis using XRD. The experimental and theoretical magnetic results indicate magnetic ordering of the hexagonal wurtzite MnO. Density functional calculations have been performed in order to understand the electronic and piezoelectric properties of the newly synthesized hexagonal wurtzite MnO.

Peroxisome proliferator-activated receptor-δ activation ameliorates albuminuria by preventing nephrin loss and restoring podocyte integrity in type 2 diabetes.

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)-δ is a ligand-activated transcription factor in regulating gene expression and is believed to play an important role in various kidney diseases including diabetic nephropathy. This study investigated the efficacy of GW610742, a highly specific agonist for PPAR-δ, for the treatment of diabetic nephropathy. METHODS: Type 2 diabetic Otsuka Long-Evans Tokushima Fatty rats were randomized into an untreated diabetic group (n = 9) and a GW610742-treated diabetic group (n= 9). The GW610742 was administered (10 mg/kg/day) orally for 11 weeks. Long-Evans Tokushima Otsuka rats (n = 9) were used as a non-diabetic control. RESULTS: Albuminuria was markedly increased and renal PPAR-δ expression was decreased in diabetes. Diabetic albuminuria and renal injury markers, such as glomerular basement membrane thickening, decreased number of slit pores between podocyte foot processes, decreased nephrin expression, increased desmin expression and increased CCL2 expression, were significantly reversed through the treatment with GW610742. PPAR-δ agonist GW610742 markedly increased nephrin expression in cultured podocytes. Nephrin mRNA expression was markedly decreased in response to high glucose in cultured podocytes and effectively prevented by GW610742. CONCLUSIONS: PPAR-δ activation by GW610742 ameliorates albuminuria by preventing diabetes-induced nephrin loss and restoring podocyte integrity, implying that GW610742 may be a potential therapeutic agent for diabetic nephropathy.

Sesquiterpenes and other constituents from Dendranthema zawadskii var. latilobum.

Six new germacranolides, zawadskinolides A-F (1-6), and a new eudesmane glucoside, chrysantiloboside (7) were isolated from the aerial parts of Dendranthema zawadskii var. latilobum, along with thirteen known constituents. Their structures were elucidated by means of spectroscopic evidence. Bioassay showed that flavonoids such as apigenin (9), (-)-eriodictyol (10) and nepetin (12), as well as the sesquiterpene lactone, zawadskinolide F (6), inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells with IC50 values of 66.15, 132.55, 35.44, and 91.32 µM, respectively.