Guilu Erxian Jiao enhances protein synthesis, glucose homeostasis, mitochondrial biogenesis and slow-twitch fibers in the skeletal muscle.

Guilu Erxian Jiao (GEJ) is a commonly used nutritional supplement due to its rich content of amino acids. It is also a traditional herbal medicine for improving degenerative joint. This study aimed to investigate the effect and mechanism of GEJ water extract (GEJ-WE) on skeletal muscle in C2C12 myotubes and C57BL/6J mice. Analysis of GEJ-WE were performed by high-performance liquid chromatography fingerprinting with chemical standards. Protein expression, mRNA level, glycogen content, mitochondria activity and ATP level were evaluated by western blots, real-time PCR, PAS staining, MTT and ATP bioluminescence assay, respectively. Skeletal muscle strength was evaluated by grip strength. Skeletal muscle volume, mass and fiber types were evaluated by micro computed tomography, histological analysis and immunofluorescence staining, respectively. Motor function was evaluated by rotarod performance and locomotor activity. In C2C12 myotubes, GEJ-WE significantly enhanced myogenic differentiation and myotube growth, protein synthesis signaling IGF-1/IGF-1R/IRS-1/Akt, Glut4 translocation, glycogen content, mitochondrial biogenesis signaling PGC-1α/NRF1/TFAM, mitochondrial activity and ATP production. However, IGF-1R antagonist AG1024 and PI3K inhibitor wortmannin reduced GEJ-WE-induced protein expression of MyHC, p-Akt, p-mTOR and p-GSK-3ß, Glut4 translocation and glycogen content. In C57BL/6J mice, GEJ-WE not only upregulated protein synthesis and mitochondrial biogenesis signaling, but it also increased muscle volume, relative muscle weight, cross-sectional area of myofibers, glycogen content and transition of fast-to-slow type fibers of skeletal muscles. Moreover, GEJ-WE enhanced grip strength and motor activity of mice. In conclusion, the upregulation of protein synthesis, myogenic differentiation, glucose homeostasis, mitochondrial biogenesis and slow-twitch fibers contributes to the mechanisms of GEJ-WE on the enhancement of skeletal muscle mass and motor function.

Hyperbaric Oxygen Therapy Improves Parkinson's Disease by Promoting Mitochondrial Biogenesis via the SIRT-1/PGC-1α Pathway.

Hyperbaric oxygen therapy (HBOT) has been suggested as a potential adjunctive therapy for Parkinson's disease (PD). PD is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The aim of this study was to investigate the protective mechanisms of HBOT on neurons and motor function in a 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and 1-methyl-4-phenylpyridinium (MPP+)-mediated neurotoxicity in SH-SY5Y cells on the potential protective capability. In vivo: male C57BL/6 mice were randomly divided into three groups: control, MPTP group and MPTP+HBOT group. The MPTP-treated mice were intraperitoneally received MPTP (20 mg/kg) four times at 2 h intervals within a day. The day after MPTP treatment, MPTP+HBOT mice were exposed to hyperbaric oxygen at 2.5 atmosphere absolute (ATA) with 100% oxygen for 1 h once daily for 7 consecutive days. In vitro: retinoic acid (RA)-differentiated SH-SY5Y cells were treated with MPP+ for 1 h followed by hyperbaric oxygen at 2.5 ATA with 100% oxygen for 1 h. The results showed that MPTP induced a significant loss in tyrosine hydroxylase (TH)-positive neurons in the SNpc of mice. HBOT treatment significantly increased the number of TH-positive neurons, with enhanced neurotrophic factor BDNF, decreased apoptotic signaling and attenuated inflammatory mediators in the midbrain of MPTP-treated mice. In addition, MPTP treatment decreased the locomotor activity and grip strength of mice, and these effects were shown to improve after HBOT treatment. Furthermore, MPTP decreased mitochondrial biogenesis signaling (SIRT-1, PGC-1α and TFAM), as well as mitochondrial marker VDAC expression, while HBOT treatment was shown to upregulate protein expression. In cell experiments, MPP+ reduced neurite length, while HBOT treatment attenuated neurite retraction. Conclusions: the effects of HBOT in MPTP-treated mice might come from promoting mitochondrial biogenesis, decreasing apoptotic signaling and attenuating inflammatory mediators in the midbrain, suggesting its potential benefits in PD treatment.

Protective effects of Liuwei dihuang water extracts on diabetic muscle atrophy.

BACKGROUND: Liuwei dihuang (LWDH), a widely used traditional Chinese herbal medicine, has been noticed for its potential on the improvement of diabetic complications including diabetic nephropathy and diabetic encephalopathy. However, whether LWDH can improve the effects of diabetic skeletal muscle atrophy has not yet been reported. PURPOSE: The present study aimed to investigate the protective effects and mechanisms of the water extract of Liuwei dihuang (LWDH-WE) on skeletal muscle in cellular and animal models of diabetic muscle atrophy. STUDY DESIGN: The muscle protective effects of LWDH-WE on diabetic muscle atrophy and weakness were examined in methylglyoxal (MG)-treated C2C12 myotubes and streptozotocin (STZ)-treated C57BL/6 mice, respectively. METHODS: C2C12 myoblasts were differentiated by differentiation medium to form myotube structures. C2C12 myotubes were pre-treated with LWDH-WE 1 h before MG treatment. Diabetic mice were induced by single intraperitoneal injection of STZ (150 mg/kg) in C57BL/6 mice. Cell viability was determined by MTT and LDH assays. Protein expressions were detected by western blots. Morphological changes of cells were observed by an inverted microscope. Mitochondria membrane potential and reactive oxygen species (ROS) production were measured by flow cytometry. Muscle strength was evaluated by measuring grip strength of mice. RESULTS: In C2C12 myotubes, LWDH-WE attenuated MG-induced cellular death and oxidative damage accompanied with improving mitochondrial membrane potential, inhibiting NADPH oxidase (Nox) activation, and ROS production. Moreover, LWDH-WE could attenuate MG-induced atrophy of C2C12 myotubes accompanied with regulating protein synthesis (IGF-1R, Akt, mTOR) and protein degradation (FoxO3a, atrogin-1, MuRF-1) signals. In STZ-induced diabetic mice, LWDH-WE improved body weight and skeletal muscle mass of mice. LWDH-WE also enhanced muscle strength of STZ-induced diabetic mice. Furthermore, LWDH-WE enhanced the improvement of insulin on gastrocnemius muscle mass and grip strength in STZ-treated mice. CONCLUSION: LWDH-WE possesses skeletal muscle protection via reducing oxidative damage and regulating protein synthesis and degradation pathways in MG-induced atrophy of C2C12 myotubes. We also reveal the novel protection of LWDH-WE against STZ-induced reduction of muscle mass and muscle strength in mice.

The novel protective effects of loganin against 1-methyl-4-phenylpyridinium-induced neurotoxicity: Enhancement of neurotrophic signaling, activation of IGF-1R/GLP-1R, and inhibition of RhoA/ROCK pathway.

Loganin, a major iridoid glycoside obtained from fruits of Cornus officinalis, possesses anti-inflammatory, antitumor, antidiabetic, and osteoporosis prevention effects. Loganin has been linked to neuroprotection in several models of neurodegeneration, including Parkinson's disease (PD). However, mechanisms underlying the neuroprotective effects of loganin are still mostly unknown. Here, we demonstrated the protective effects of loganin against PD mimetic toxin 1-methyl-4-phenylpyridinium (MPP+ ) and the important roles of insulin-like growth factor 1 receptor (IGF-1R) and glucagon-like peptide 1 receptor (GLP-1R) in the neuroprotective mechanisms of loganin. In primary mesencephalic neuronal cultures treated with or without MPP+ , loganin up-regulated expressions of neurotrophic signals including IGF-1R, GLP-1R, p-Akt, BDNF, and tyrosine hydroxylase. Loganin protected against MPP+ -induced apoptosis by up-regulating antiapoptotic protein and down-regulating proapoptotic protein. Moreover, loganin attenuated MPP+ -induced neurite damage via up-regulation of GAP43 and down-regulation of membrane-RhoA/ROCK2/p-LIMK/p-cofilin. Loganin also attenuated MPP+ -induced reactive oxygen species (ROS) production. However, both AG1024, an IGF-1R antagonist, and exendin 9-39, a GLP-1R antagonist, attenuated the protective effects of loganin on MPP+ -induced cytotoxicity, apoptosis, neurite length decrease, and ROS production. Our results suggest that loganin attenuates MPP+ -induced apoptotic death, neurite damage, and oxidative stress through enhancement of neurotrophic signaling, activation of IGF-1R/GLP-1R, and inhibition of RhoA/ROCK pathway, providing the evidence that loganin possesses novel neuroprotective effects.

Electronic microscopy evidence for mitochondria as targets for Cd/Se/Te-based quantum dot 705 toxicity in vivo.

The safety of quantum dots (QDs) 705 was evaluated in this study. Mice were treated with QD705 (intravenous) at a single dose of (40 pmol) for 4, 12, 16, and 24 weeks. Effects of QD705 on kidneys were examined. While there was a lack of histopathology, reduction in renal functions was detected at 16 weeks. Electron microscopic examination revealed alterations in proximal convoluted tubule (PCT) cell mitochondria at even much earlier time, including disorientation and reduction of mitochondrial number (early change), mitochondrial swelling, and later compensatory mitochondrial hypertrophy (enlargement mitochondria: giant mitochondria with hyperplastic inner cristae) as well as mitochondrial hyperplasia (increase in mitochondrial biogenesis and numbers) were observed. Such changes probably represent compensatory attempts of the mitochondria for functional loss or reduction of mitochondria in QD705 treated animals. Moreover, degeneration of mitochondria (myelin-figure and cytoplasmic membranous body formation) and degradation of cytoplasmic materials (isolated cytoplasmic pockets of degenerated materials and focal cytoplasmic degradation) also occurred in later time points (16-24 weeks). Such mitochondrial changes were not identical with those induced by pure cadmium. Taken together, we suggest that mitochondria appeared to be the target of QD705 toxicity and specific mitochondrial markers may be useful parameters for toxicity assessments of QDs or other metal-based nanomaterials.

Cd/Se/Te-based quantum dot 705 modulated redox homeostasis with hepatotoxicity in mice.

The objective of this study was to investigate whether quantum dot 705 (QD705) disrupts the cellular antioxidant systems leading to hepatotoxicity in mice. Mice were intravenously injected with QD705 and then sacrificed at week 12 or 16. Homeostasis of antioxidant-related metals, antioxidant activities, induction of oxidative stress, and toxicity in the liver were investigated. Although no histopathological change was observed, a time- and dose-dependent increase in metallothionein expression and reduction in liver function was noticed. Increased copper, zinc, and selenium levels and enhancements of the trace metal-corresponding transporters were noted at week 12. At week 16, a decline of selenium from its elevated level at week 12 was observed, which was accompanied by changes in glutathione peroxidase activity as well as in redox status. A significant reduction in superoxide dismutase activity was observed at 16 weeks. Furthermore, a corresponding elevation of heme oxygenase-1 expression, 8-oxo-7,8-dihydro-2'-deoxyguanosine, interleukin-6 and tumor necrosis factor-alpha suggested the presence of oxidative stress, oxidative DNA damage and inflammation.