Single-Cell Rna Sequencing Deconvolutes the in Vivo Heterogeneity of Human Bone Marrow-Derived Mesenchymal Stem Cells

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent stromal cells that have a critical role in the maintenance of skeletal tissues such as bone, cartilage, and the fat in bone marrow. In addition to providing microenvironmental support for hematopoietic processes, BM-MSCs can differentiate into various mesodermal lineages including osteoblast/osteocyte, chondrocyte, and adipocyte that are crucial for bone metabolism. While BM-MSCs have high cell-to-cell heterogeneity in gene expression, the cell subtypes that contribute to this heterogeneity in vivo in humans have not been characterized. To investigate the transcriptional diversity of BM-MSCs, we applied single-cell RNA sequencing (scRNA-seq) on freshly isolated CD271+ BM-derived mononuclear cells (BM-MNCs) from two human subjects. We successfully identified LEPRhi CD45low BM-MSCs within the CD271+ BM-MNC population, and further codified the BM-MSCs into distinct subpopulations corresponding to the osteogenic, chondrogenic, and adipogenic differentiation trajectories, as well as terminal-stage quiescent cells. Biological functional annotations of the transcriptomes suggest that osteoblast precursors induce angiogenesis coupled with osteogenesis, and chondrocyte precursors have the potential to differentiate into myocytes. We also discovered transcripts for several clusters of differentiation (CD) markers that were either highly expressed (e.g., CD167b, CD91, CD130 and CD118) or absent (e.g., CD74, CD217, CD148 and CD68) in BM-MSCs, representing potential novel markers for human BM-MSC purification. This study is the first systematic in vivo dissection of human BM-MSCs cell subtypes at the single-cell resolution, revealing an insight into the extent of their cellular heterogeneity and roles in maintaining bone homeostasis

Sanguinarine Attenuates Neuropathic Pain in a Rat Model of Chronic Constriction Injury

Objective. There is still no effective treatment of neuropathic pain. Sanguinarine is a natural plant medicine with anti-inflammatory effects, but its effect on neuropathic pain remains unclear. This study was aimed at investigating the potential of sanguinarine to attenuate neuropathic pain. Methods. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Rats were randomly divided into several groups: sham, CCI, CCI+SG (1.00 mg/kg), CCI+SG (2.50 mg/kg), and CCI+SG (6.25 mg/kg). SG was injected intraperitoneally from the day of surgery every three days. The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were recorded before surgery and on days 1, 3, 7, and 14 after surgery. The microglia in the spinal dorsal horn were examined by immunofluorescence. p38 MAPK expression in the spinal dorsal horn was detected by PCR and Western blot analysis. Cytokine levels in the spinal dorsal horn were measured by ELISA. Results. MWT and TWL were significantly reduced in the CCI group, but sanguinarine recovered MWT and TWL in the CCI group. In addition, sanguinarine inhibited the activation of microglia and decreased the expression of p-p38 and TNF-α, IL-1β, and IL-6 in the spinal dorsal horn of the CCI group in a dose-dependent manner. Conclusions. Our results suggest that sanguinarine can attenuate neuropathic pain via inhibiting the activation of microglia and the activation of the p38 MAPK signaling pathway

Microstructure and properties of a new high density alloy

A new high density alloy NiW750 was developed, which was based on the faced-center cubic solid solution structure and aging strengthening mechanism. Microstructure of the alloy was observed by SEM and TEM. The material characteristics under dynamic compressing loading were investigated by using the split Hopkinson pressure bar test. The comparison among the NiW750, ultra high strength steel G50 and tungsten 93WNiFe was also conducted.The results show that the NiW750 high density alloy has the best comprehensive properties among three materials. After aging at 750℃/5h,the tensile strength of NiW750 can achieve up to 1746MPa,while the impact toughness (akU) can achieve 113J/cm2. Under the condition of dynamic loading, the material shows strain rate hardening effect obviously as its dynamic flow stress can reach about 2250MPa. The adiabatic shear bands are formed within specimens in the direction of 45° to the central axis with a bandwidth of 80-150μm at the strain rate of about 5500s-1 and a wide transition zone, so as to avoid the premature emergence of the shear fracture

Curcumin Attenuates Beta-Amyloid-Induced Neuroinflammation via Activation of Peroxisome Proliferator-Activated Receptor-Gamma Function in a Rat Model of Alzheimer's Disease

Neuroinflammation is known to have a pivotal role in the pathogenesis of Alzheimer’s disease (AD), and curcumin has been reported to have therapeutical effects on AD because of its anti-inflammatory effects. Curcumin is not only a potent PPARγ agonist, but also has neuroprotective effects on cerebral ischemic injury. However, whether PPARγ activated by curcumin is responsible for the anti-neuroinflammation and neuroprotection on AD remains unclear, and needs to be further investigated. Here, using both APP/PS1 transgenic mice and beta-amyloid-induced neuroinflammation in mixed neuronal/glial cultures, we showed that curcumin significantly alleviated spatial memory deficits in APP/PS1 mice and promoted cholinergic neuronal function in vivo and in vitro. Curcumin also reduced the activation of microglia and astrocytes, as well as cytokine production and inhibited nuclear factor kappa B (NF-κB) signaling pathway, suggesting the beneficial effects of curcumin on AD are attributable to the suppression of neuroinflammation. Attenuation of these beneficial effects occurred when co-administrated with PPARγ antagonist GW9662 or silence of PPARγ gene expression, indicating that PPARγ might be involved in anti-inflammatory effects. Circular dichroism and co-immunoprecipitation analysis showed that curcumin directly bound to PPARγ and increased the transcriptional activity and protein levels of PPARγ. Taking together, these data suggested that PPARγ might be a potential target of curcumin, acting to alleviate neuroinflammation and improve neuronal function in AD

Cyanidin suppresses amyloid beta-induced neurotoxicity by inhibiting reactive oxygen species-mediated DNA damage and apoptosis in PC12 cells

Amyloid beta (Aß)-induced oxidative stress is a major pathologic hallmark of Alzheimer′s disease. Cyanidin, a natural flavonoid compound, is neuroprotective against oxidative damage-mediated degeneration. However, its molecular mechanism remains unclear. Here, we investigated the effects of cyanidin pretreatment against Aß-induced neurotoxicity in PC12 cells, and explored the underlying mechanisms. Cyanidin pretreatment significantly attenuated Aß-induced cell mortality and morphological changes in PC12 cells. Mechanistically, cyanidin effectively blocked apoptosis induced by Aß, by restoring the mitochondrial membrane potential via upregulation of Bcl-2 protein expression. Moreover, cyanidin markedly protected PC12 cells from Aß-induced DNA damage by blocking reactive oxide species and superoxide accumulation. These results provide evidence that cyanidin suppresses Aß-induced cytotoxicity, by preventing oxidative damage mediated by reactive oxide species, which in turn inhibits mitochondrial apoptosis. Our study demonstrates the therapeutic potential of cyanidin in the prevention of oxidative stress-mediated Aß neurotoxicity