The autoimmune response induced by α-synuclein peptides drives neuronal cell death and glial cell activation.

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with the loss of dopaminergic neurons and neuroinflammation. Recent studies have identified a role of T cells in the pathogenesis of PD. Additionally, these studies suggested that α-synuclein (α-Syn) is related to abnormal T-cell responses and may act as an epitope and trigger autoimmune T-cell responses. However, it is unclear whether the α-Syn-mediated autoimmune response occurs and whether it is related to neuronal cell death and glial cell activation. In this study, we investigated the autoimmune T-cell response induced by α-Syn peptides and evaluated the neurotoxic effect of the α-Syn peptide-mediated autoimmune response. The immunization of mice with α-Syn peptides resulted in enhanced autoimmune responses, such as the peptide recall response, polarization toward Th1/Th17 cells, and regulatory T cell imbalance. Furthermore, the α-Syn autoimmune response led to the death of primary neurons cocultured with splenocytes. Treatment with conditioned media from α-Syn peptide-immunized splenocytes induced microglia and toxic A1-type astrocyte activation. Taken together, our results provide evidence of the potential role of the α-Syn-initiated autoimmune response and its contribution to neuronal cell death and glial cell activation.

A Novel Tactile Sensing System Utilizing Magnetorheological Structures for Dynamic Contraction and Relaxation Motions.

It is well known that the rheological properties of magnetorheological (MR) material change under a magnetic field. So far, most works on MR materials have been oriented toward actuating characteristics instead of sensing functions. In this work, to realize dynamic tactile motion, a spherical MR structure was designed as a sensor, incorporating a magnetic circuit core to provide maximum dynamic motion. After manufacturing a prototype (sample), a sinusoidal magnetic field of varying exciting frequency and magnitude was applied to the sample, and the dynamic contraction and relaxation motion depending on the exciting magnetic field was observed. Among the test results, when 10% deformation occurred, the instantaneous force generated was from 2.8 N to 8.8 N, and the force when relaxed was from 1.2 N to 3.5 N. It is also shown that the repulsive force within this range can be implemented using an acceptable input current. The special tactile sensing structure proposed in this work can be used as a sensor to measure the field-dependent viscoelastic properties of human tissues such as stomach, liver, and overall body. In addition, it could be usefully applied to robot surgery, because it can mimic the dynamic motions of various human organs under various surgical conditions.

Changes in aquaporins expression due to acute water restriction in naturally aging mice

Aquaporins (AQPs) are water channels in the cell membrane that regulate osmosis in response to rapid changes in intracellular and extracellular fluid concentration caused by extrinsic factors. While there are so many studies on the association of AQPs with muscular atrophy, sarcopenia, and Duchenne muscular dystrophy (DMD), the expression of AQP has not been verified in naturally aging mice or humans. Notably, due to the characteristics of AQPs, the difference in function cannot be evaluated without extrinsic factors such as acute water restriction. The purpose of this study was to investigate the changes in AQPs expression and function due to natural aging under acute water restriction conditions in aging mice. The expression of AQP4 was shown to decrease with aging similar to previous studies. However, for the first time, this study results confirmed that AQP1 expression increased in aging mice. In addition, the expression of Aqp1 decreased in the acute water restricted group compared to the control group after acute water restriction in aging mice. These results suggest that although the expression of AQP1 increases with aging, its function is reduced. We also confirmed that overexpression of Aqp1 can inhibit myotube differentiation and that knockdown can promote myotube differentiation through in vitro experiments. In conclusion, based on our results, we suggest that the AQP1 is an important factor in sarcopenia caused by natural aging accompanied by chronic dehydration. (AU)

Changes in aquaporins expression due to acute water restriction in naturally aging mice.

Aquaporins (AQPs) are water channels in the cell membrane that regulate osmosis in response to rapid changes in intracellular and extracellular fluid concentration caused by extrinsic factors. While there are so many studies on the association of AQPs with muscular atrophy, sarcopenia, and Duchenne muscular dystrophy (DMD), the expression of AQP has not been verified in naturally aging mice or humans. Notably, due to the characteristics of AQPs, the difference in function cannot be evaluated without extrinsic factors such as acute water restriction. The purpose of this study was to investigate the changes in AQPs expression and function due to natural aging under acute water restriction conditions in aging mice. The expression of AQP4 was shown to decrease with aging similar to previous studies. However, for the first time, this study results confirmed that AQP1 expression increased in aging mice. In addition, the expression of Aqp1 decreased in the acute water restricted group compared to the control group after acute water restriction in aging mice. These results suggest that although the expression of AQP1 increases with aging, its function is reduced. We also confirmed that overexpression of Aqp1 can inhibit myotube differentiation and that knockdown can promote myotube differentiation through in vitro experiments. In conclusion, based on our results, we suggest that the AQP1 is an important factor in sarcopenia caused by natural aging accompanied by chronic dehydration.

Effects of lifelong spontaneous exercise on skeletal muscle and angiogenesis in super-aged mice.

There has been an increasing awareness of sarcopenia, which is characterized by a concomitant decrease in skeletal muscle mass and quality due to aging. Resistance exercise is considered more effective than aerobic exercise in terms of therapeutic exercise. To confirm the effect of long-term aerobic exercise in preventing sarcopenia, we evaluated the skeletal muscle mass, quality, and angiogenic capacity of super-aged mice that had undergone lifelong spontaneous exercise (LSE) through various experiments. Our findings show that LSE could maintain skeletal muscle mass, quality, and fitness levels in super-aged mice. In addition, ex vivo experiments showed that the angiogenic capacity was maintained at a high level. However, these results were not consistent with the related changes in the expression of genes and/or proteins involved in protein synthesis or angiogenesis. Based on the results of previous studies, it seems certain that the expression at the molecular level does not represent the phenotypes of skeletal muscle and angiogenesis. This is because aging and long-term exercise are variables that can affect both protein synthesis and the expression patterns of angiogenesis-related genes and proteins. Therefore, in aging and exercise-related research, various physical fitness and angiogenesis variables and phenotypes should be analyzed. In conclusion, LSE appears to maintain the potential of angiogenesis and slow the aging process to maintain skeletal muscle mass and quality. Aerobic exercise may thus be effective for the prevention of sarcopenia.

PEGylation improves the therapeutic potential of dimerized translationally controlled tumor protein blocking peptide in ovalbumin-induced mouse model of airway inflammation.

Dimerized translationally controlled tumor protein (dTCTP) initiates a variety of allergic responses in mouse models and that dTCTP-binding peptide 2 (dTBP2) attenuates the allergic inflammation by targeting dTCTP. However, the usefulness of peptide-based drugs is often limited due to their short half-lives, rapid degradation, and high levels of clearance after systemic administration. In this study, we chemically conjugated dTBP2 with 10 kDa polyethylene glycol (PEG) to improve its therapeutic potential. N-terminal mono-PEGylated dTBP2 (PEG-dTBP2) was characterized by in vitro bioactivity assay, pharmacokinetics study, and in vivo efficacy. When compared to the unmodified dTBP2, PEG-dTBP2 reduced proinflammatory cytokine IL-8 secretion in human bronchial cells by 10 to 15% and increased plasma half-life by approximately 2.5-fold in mice. This study specifically demonstrated that PEG-dTBP2 shows higher inhibitory action against ovalbumin (OVA)-induced airway inflammation in mice compared to dTBP2. Importantly, PEG-dTBP2, when administered once at 1 mg/kg, significantly reduced the migration of inflammatory cells and the levels of cytokines in the bronchoalveolar lavage fluids as well as OVA-specific IgE levels in serum. In addition, the degree of goblet cell hyperplasia and mucus secretion were significantly attenuated in the PEG-dTBP2 group compared with the control group. These results suggest that PEG-dTBP2 can be considered a potential candidate drug for regulating allergic inflammation.

Comparative analysis of the association between various serum vitamin D biomarkers and sarcopenia.

BACKGROUND: Vitamin D status is associated with muscle strength and maintenance of muscle fibers. However, which serum vitamin D biomarker better reflects sarcopenia remains unclear. The aim of this study was to investigate associations between various serum vitamin D biomarkers (total 25-hydroxy vitamin D [25(OH)D], bioavailable 25(OH)D, 24,25-dihydroxyvitamin D [24,25(OH)2 D], and vitamin D metabolite ratio [VMR]) and sarcopenia. METHODS: The data for 83 hip fracture patients were finally included in the analysis. Sarcopenia was defined according to the Asia Working Group for Sarcopenia (AWGS) criteria. Measurements of 24,25(OH)2 D and 25(OH)D were made using solid-phase extraction (SPE) and subsequent liquid chromatography-tandem mass spectrometry (LC-MS/MS). Vitamin D binding protein (VDBP) concentration was measured using an enzyme-linked immunosorbent assay. The VMR was calculated by dividing serum 24,25(OH)2 D by serum 25(OH)D and then multiplying by 100. Based on total 25(OH)D, VDBP, and albumin concentrations, bioavailable 25(OH)D concentrations were calculated using the equations from the other previous studies. RESULTS: Bioavailable 25(OH)D levels were significantly (p = 0.030) decreased in the sarcopenia group compared with the non-sarcopenia group. Results of ROC analysis for the diagnosis of sarcopenia using serum level of bioavailable of 25(OH)D revealed that the cutoff point for bioavailable 25(OH)D was 1.70 ng/ml (AUC = 0.649, p < 0.001). In the group with a bioavailable 25(OH)D less than 1.70 ng/ml, the incidence of sarcopenia increased by 3.3 times (odds ratio: 3.33, p = 0.013). CONCLUSION: We demonstrated that bioavailable 25(OH)D was associated with sarcopenia among the various serum vitamin D biomarkers. Bioavailable vitamin D might be helpful for assessing the risk of sarcopenia.

Clinical utility of cerebrospinal fluid vitamin D-binding protein as a novel biomarker for the diagnosis of viral and bacterial CNS infections.

BACKGROUND: Rapid and accurate diagnosis of central nervous system (CNS) infections is important, and laboratory tests help diagnose CNS infections. Even when the patient has symptoms, laboratory tests often do not reveal any specific findings. The potential of vitamin D-binding protein (VDBP) to be used as a biomarker for viral and bacterial CNS infections was studied. METHODS: A total of 302 subjects with suspected CNS infection who underwent lumbar puncture were included. Clinical and laboratory data were collected retrospectively. VDBP levels were measured in the cerebrospinal fluid (CSF) samples. Genotyping for the GC gene encoding VDBP was also performed. VDBP levels were analyzed and compared by CNS infection, pathogen, CSF opening pressure, and GC genotype. RESULTS: A CNS infection group (n = 90) and a non-CNS infection group (n = 212) were studied. In terms of its receiver operating characteristic, CSF VDBP showed an area under the curve of 0.726 for the diagnosis of CNS infection. CSF VDBP levels were significantly different between the CNS infection and non-infection groups. The CNS infection group with enterovirus showed a statistically lower distribution of CSF VDBP levels than the other virus groups. The group with CSF opening pressure > 25 cmH2O showed higher CSF VDBP levels than the other groups. There was no significant difference in GC gene allele distribution between the CNS infection and non-infection groups. CONCLUSIONS: CSF VDBP levels were increased in patients with CNS infection. The CSF VDBP showed potential as a new biomarker for viral and bacterial CNS infections.

Resveratrol can enhance osteogenic differentiation and mitochondrial biogenesis from human periosteum-derived mesenchymal stem cells.

BACKGROUND: Osteoporosis is a metabolic bone disorder that leads to low bone mass and microstructural deterioration of bone tissue and increases bone fractures. Resveratrol, a natural polyphenol compound, has pleiotropic effects including anti-oxidative, anti-aging, and anti-cancer effects. Resveratrol also has roles in increasing osteogenesis and in upregulating mitochondrial biogenesis of bone marrow-derived mesenchymal stem cells (BM-MSCs). However, it is still unclear that resveratrol can enhance osteogenic differentiation or mitochondrial biogenesis of periosteum-derived MSCs (PO-MSCs), which play key roles in bone tissue maintenance and fracture healing. Thus, in order to test a possible preventive or therapeutic effect of resveratrol on osteoporosis, this study investigated the effects of resveratrol treatments on osteogenic differentiation and mitochondrial biogenesis of PO-MSCs. METHODS: The optimal doses of resveratrol treatment on PO-MSCs were determined by cell proliferation and viability assays. Osteogenic differentiation of PO-MSCs under resveratrol treatment was assessed by alkaline phosphatase activities (ALP, an early biomarker of osteogenesis) as well as by extracellular calcium deposit levels (a late biomarker). Mitochondrial biogenesis during osteogenic differentiation of PO-MSCs was measured by quantifying both mitochondrial mass and mitochondrial DNA (mtDNA) contents. RESULTS: Resveratrol treatments above 10 µM seem to have negative effects on cell proliferation and viability of PO-MSCs. Resveratrol treatment (at 5 µM) on PO-MSCs during osteogenic differentiation increased both ALP activities and calcium deposits compared to untreated control groups, demonstrating an enhancing effect of resveratrol on osteogenesis. In addition, resveratrol treatment (at 5 µM) during osteogenic differentiation of PO-MSCs increased both mitochondrial mass and mtDNA copy numbers, indicating that resveratrol can bolster mitochondrial biogenesis in the process of PO-MSC osteogenic differentiation. CONCLUSION: Taken together, the findings of this study describe the roles of resveratrol in promoting osteogenesis and mitochondrial biogenesis of human PO-MSCs suggesting a possible application of resveratrol as a supplement for osteoporosis and/or osteoporotic fractures.

Involvement of mitochondrial biogenesis during the differentiation of human periosteum-derived mesenchymal stem cells into adipocytes, chondrocytes and osteocytes.

Due to a rapidly expanding aging population, the incidence of age-related or degenerative diseases has increased, and efforts to handle the issue with regenerative medicine via adult stem cells have become more important. And it is now clear that the mitochondrial energy metabolism is important for stem cell differentiation. When stem cells commit to differentiate, glycolytic metabolism is being shifted to mitochondrial oxidative phosphorylation (OXPHOS) to meet an increased cellular energy demand required for differentiated cells. However, the nature of cellular metabolisms during the differentiation process of periosteum-derived mesenchymal stem cells (POMSC) is still unclear. In the present study, we investigated mitochondrial biogenesis during the adipogenic, chondrogenic, and osteogenic differentiation of POMSCs. Both mitochondrial DNA (mtDNA) contents and mitochondrial proteins (VDAC and mitochondrial OXPHOS complex subunits) were increased during all of these mesenchymal lineage differentiations of POMSCs. Interestingly, glycolytic metabolism is reduced as POMSCs undergo osteogenic differentiation. Furthermore, reducing mtDNA contents by ethidium bromide treatments prevents osteogenic differentiation of POMSCs. In conclusion, these results indicate that mitochondrial biogenesis and OXPHOS metabolism play important roles in the differentiation of POMCS and suggest that pharmaceutical modulation of mitochondrial biogenesis and/or function can be a novel regulation for POMSC differentiation and regenerative medicine.