iridoids and Weight-Gain

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by motor neurons degeneration and muscular atrophy. There is no effective SMA treatment. Loganin is a botanical candidate with anti-inflammatory, anti-oxidant, glucose-lowering and anti-diabetic nephropathy activities. The aim of this study is to investigate the potential protective effects of loganin on SMA using two cellular models, SMN-deficient NSC34 cells and SMA patient fibroblasts, and an animal disease model, SMAΔ7 mice. In SMN-deficient NSC34 cells, loganin increased cell viability, neurite length, and expressions of SMN, Gemin2, SMN-Gemin2 complex, p-Akt, p-GSK-3β, p-CREB, BDNF and Bcl-2. However, both AG1024 (IGF-1 R antagonist) and IGF-1 R siRNA attenuated the protective effects of loganin on SMN level and cell viability in SMN-deficient NSC34 cells. In SMA patient fibroblasts, loganin up-regulated levels of SMN, FL-SMN2, and Gemins, increased numbers of SMN-containing nuclear gems, modulated splicing factors, and up-regulated p-Akt. Furthermore, in the brain, spinal cord and gastrocnemius muscle of SMAΔ7 mice, loganin up-regulated the expressions of SMN and p-Akt. Results from righting reflex and hind-limb suspension tests indicated loganin improved muscle strength of SMAΔ7 mice; moreover, loganin activated Akt/mTOR signal and inhibited atrogin-1/MuRF-1 signal in gastrocnemius muscle of SMAΔ7 mice. Loganin also increased body weight, but the average lifespan of loganin (20mg/kg/day)-treated SMA mice was 16.80±0.73 days, while saline-treated SMA mice was 10.91±0.96 days. In conclusion, the present results demonstrate that loganin provides benefits to SMA therapeutics via improving SMN restoration, muscle strength and body weight. IGF-1 plays an important role in loganin neuroprotection. Loganin can be therefore a valuable complementary candidate for treatment of neuromuscular diseases via regulation of muscle protein synthesis and neuroprotection.

Topics: Animals; Apoptosis; Cell Line; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Fibroblasts; Genetic Predisposition to Disease; Humans; Insulin-Like Growth Factor I; Iridoids; Mice; Mice, Transgenic; Motor Activity; Motor Neurons; Muscle Proteins; Muscle Strength; Muscle, Skeletal; Muscular Atrophy, Spinal; Mutation; Nerve Degeneration; Neuroprotective Agents; Phenotype; Phosphorylation; Protein Biosynthesis; Proto-Oncogene Proteins c-akt; RNA Interference; Signal Transduction; SKP Cullin F-Box Protein Ligases; Survival of Motor Neuron 1 Protein; Time Factors; TOR Serine-Threonine Kinases; Transfection; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Weight Gain

The aim of the present study was to investigate the antiobesity effect of oleuropein on high-fat diet (HFD) induced body weight gain and visceral adiposity in mice, and to explore the underlying mechanisms involved.. C57BL/6N mice were fed with a normal diet, HFD (40% fat of total energy), and HFD-supplemented with 0.03% oleuropein for 10 wk. Oleuropein significantly reduced HFD-induced body weight gain and visceral adiposity. Oleuropein also significantly reversed the HFD-induced elevations of adipogenic related gene expression involved in WNT10b- and galanin-mediated signalings in adipose tissue of mice. Consistent with in vivo findings, oleuropein dose-dependently suppressed lipid accumulation in 3T3-L1 cells during preadipocyte differentiation. Additionally, exposure of the 3T3-L1 preadipocytes to oleuropein resulted in a marked attenuation of the secreted frizzled-related protein 2 (WNT inhibitor) or galnon (galanin receptor agonist) induced cellular lipid accumulation.. This study demonstrated the oleuropein-reduced body weight gain and visceral adiposity in HFD-fed mice. The protective effect of oleuropein against HFD-induced adiposity in mice appeared to be mediated through the upregulation of genes involved in WNT10b-mediated signaling and downregulation of genes involved in galanin-mediated signaling cascades.

Topics: 3T3-L1 Cells; Adiposity; Animals; Cell Differentiation; Diet, High-Fat; Dose-Response Relationship, Drug; Galanin; Gene Expression Regulation; Hyperlipidemias; Iridoid Glucosides; Iridoids; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Obese; Signal Transduction; Weight Gain; Wnt Proteins

Connective tissue growth factor (CTGF) plays a pathogenic role in diabetic nephropathy (DN). Loganin, an iridoid glucoside compound was isolated from Cornus officinalis Sieb. et Zucc. This study was conducted to investigate the efficacy of loganin on DN and to elucidate the potential mechanism. High glucose (HG) stimulated cultured human renal proximal tubular epithelial cells (HK-2) analyzed CTGF expression by Western blotting and investigated whether extracellular signal-regulated kinase (ERK) signaling pathway was involved. Streptozotocin (STZ)-induced experimental DN, randomized to receive intragastric (i.g.) of loganin. Renal tissue, blood and urine samples were collected to determine and analyze. In vitro study, loganin reduced CTGF excretion in HG-induced HK-2 cells through the ERK signaling pathway. In vivo study, I.g. of loganin 5 mg/kg or 10 mg/kg significantly ameliorated renal function and increased body weight. Meanwhile, loganin reduced renal CTGF expression by immunohistochemical staining, reduced serum levels of CTGF. Besides, there were no significant differences in blood sugar levels between the loganin groups compared to the STZ-treated group. Furthermore, loganin ameliorated renal pathology. These results suggested that loganin exerts an early renal protective role to DN. Inhibition of CTGF may be a potential target in DN therapy, which highlights the possibility of using loganin to treat DN.

Topics: Animals; Blood Glucose; Cell Line; Cell Proliferation; Connective Tissue Growth Factor; Cornus; Cystatin C; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Epithelial Cells; Glucose; Humans; Immunohistochemistry; Iridoids; Kidney; Male; MAP Kinase Signaling System; Rats; Rats, Sprague-Dawley; Weight Gain