Cycloastragenol: A Novel Senolytic Agent That Induces Senescent Cell Apoptosis and Restores Physical Function in TBI-Aged Mice.

Accumulating evidence indicates that the increased burden of senescent cells (SCs) in aged organisms plays an important role in many age-associated diseases. The pharmacological elimination of SCs with "senolytics" has been emerging as a new therapy for age-related diseases and extending the healthy lifespan. In the present study, we identified that cycloastragenol (CAG), a secondary metabolite isolated from Astragalus membrananceus, delays age-related symptoms in mice through its senolytic activity against SCs. By screening a series of compounds, we found that CAG selectively kills SCs by inducing SCs apoptosis and that this process is associated with the inhibition of Bcl-2 antiapoptotic family proteins and the PI3K/AKT/mTOR pathway. In addition, CAG treatment also suppressed the development of the senescence-associated secretory phenotype (SASP) in SCs, thereby inhibiting cell migration mediated by the SASP. Furthermore, the administration of CAG for 2 weeks to mice with irradiation-induced aging alleviated the burden of SCs and improved the animals' age-related physical dysfunction. Overall, our studies demonstrate that CAG is a novel senolytic agent with in vivo activity that has the potential to be used in the treatment of age-related diseases.

Synchronization of Non-linear Oscillators for Neurobiologically Inspired Control on a Bionic Parallel Waist of Legged Robot.

Synchronization of coupled non-linear oscillators inspired by a central pattern generator (CPG) can control the bionic robot and promote the coordination and diversity of locomotion. However, for a robot with a strong mutual coupled structure, such neurobiological control is still missing. In this contribution, we present a σ-Hopf harmonic oscillator with decoupled parameters to expand the solution space of the locomotion of the robot. Unlike the synchronization of original Hopf oscillators, which has been fully discussed, the asymmetric factor of σ-Hopf oscillator causes a deformation in oscillation waveform. Using the non-linear synchronization theory, we construct the transition state model of the synchronization process to analyze the asymmetrical distortion, period change and duty ratio inconsistency. Then a variable coupling strength is introduced to eliminate the waveform deformation and maintain the fast convergence rate. Finally, the approach is used for the locomotion control of a bionic parallel waist of legged robot, which is a highly coupled system. The effectiveness of the approach in both independent and synthesis behavior of four typical motion patterns are validated. The result proves the importance of controllability of the oscillation waveform and the instantaneous state of the synchronization, which benefits the transition and transformation of the locomotion and makes the coupling motion more flexible.

The protective effect of cycloastragenol on aging mouse circadian rhythmic disorder induced by d-galactose.

Aging process in mammals is associated with a decline in amplitude and a long period of circadian behaviors which are regulated by a central circadian regulator in the suprachiasmatic nucleus (SCN) and local oscillators in peripheral tissues. It is unclear whether enhancing clock function can retard aging. Using fibroblasts expressing per2::lucSV and senescent cells, we revealed cycloastragenol (CAG), a natural aglycone derivative from astragaloside IV, as a clock amplitude enhancing small molecule. CAG could activate telomerase to antiaging, but no reports focused on its effects on circadian rhythm disorders in aging mice. Here we analyze the potential effects of CAG on d-galactose-induced aging mice on the circadian behavior and expression of clock genes. For this purpose, CAG (20 mg/kg orally), was administered daily to d-galactose (150 mg/kg, subcutaneous) mice model of aging for 6 weeks. An actogram analysis of free-running activity of these mice showed that CAG significantly enhances the locomotor activity. We further found that CAG increase expressions of per2 and bmal1 genes in liver and kidney of aging mouse. Furthermore, CAG enhanced clock protein BMAL1 and PER2 levels in aging mouse liver and SCN. Our results indicated that the CAG could restore the behavior of circadian rhythm in aging mice induced by d-galactose. These data of present study suggested that CAG could be used as a novel therapeutic strategy for the treatment of age-related circadian rhythm disruption.

Image Fusion: A Novel Approach in Gamma Knife Surgery Treating Trigeminal Neuralgia.

OBJECTIVE: Finding accurate locations for radiosurgical targets in trigeminal neuralgia (TN) remains challenging. This study provides a novel approach of image fusion used in locating radiosurgical targets for gamma knife surgery (GKS) in the treatment of TN. METHODS: Magnetic resonance imaging (MRI) scans were performed before frame fixation, and computed tomography (CT) scans were performed following frame fixation. Fusion of the CT and MRI images was performed to locate the treatment target. The therapeutic effects were evaluated following GKS. RESULTS: The CT image ensures precise imaging for defining the fiducial localizers. Multi-modality medical imaging allows the trigeminal nerve (CN V) to be distinguished from the adjacent corresponding vessels. Thus, image fusion makes isocenter positioning more accurate. Significant changes in the frequency, intensity, and length of pain attacks following GKS were achieved. CONCLUSION: Diagnostic MRI co-registered with stereotactic CT can be used for accurate target location. The therapeutic effects of image fusion for GKS treatment of TN are satisfactory.

Effects of hydrochloric acid washing on the microstructure and pyrolysis bio-oil components of sweet sorghum bagasse.

Acid washing is an alternative and promising approach for biomass to produce high-quality bio-oil. The hydrochloric acid washing pretreatment of sweet sorghum bagasse was performed in this study. The effects of acid washing on the ultrastructure of sweet sorghum bagasse were investigated using scanning electron microscope and Fourier transform infrared, and the effects on pyrolysis using thermogravimetric analyzer and a fast pyrolysis device. The results indicated acid treatment obviously changed the surface morphology of the cell walls of sweet sorghum bagasse, effectively removed most metals from sweet sorghum bagasse, and increased the volatiles and bio-oil yields. The results showed that bio-oil produced from pretreated sweet sorghum bagasse contained less components categories, lower contents of phenols, aldehydes, furans and alcohols, while much higher contents of d-allose and ketones than that from the original sample. Hydrochloric acid-washing pretreatment of sweet sorghum bagasse can increase the contents of some high-value chemicals in bio-oil.

Casein glycomacropeptide hydrolysates inhibit PGE2 production and COX2 expression in LPS-stimulated RAW 264.7 macrophage cells via Akt mediated NF-κB and MAPK pathways.

A casein glycomacropeptide hydrolysate (GMPH) was found to possess inhibitory activity against lipopolysaccharide (LPS)-induced inflammatory response in our previous study. In the current study, the inhibitory effect and the underlying molecular mechanism of GMPH on inflammatory response in LPS-stimulated RAW264.7 macrophages were further investigated. Results showed that GMPH significantly suppressed LPS-induced intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) production. GMPH reduced the production of prostaglandin E2 (PEG2) and the expression of cyclooxygenase-2 (COX-2) and cytosolic phospholipase A2 (cPLA2) in LPS-stimulated macrophages. GMPH also attenuated LPS-induced phosphorylation of MAPK (c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38) and protein kinase B (Akt). Furthermore, GMPH inhibited nuclear transcription factor kappa-B (NF-κB) activation by suppressing the nuclear translocation of NF-κB p65, which was markedly reversed by LY294002, an Akt inhibitor. These results demonstrated that GMPH exerts anti-inflammatory functions through the inactivation of MAPK and Akt in LPS-stimulated RAW264.7 macrophages, therefore may hold potential to ameliorate inflammation-related metabolic disorders.

Sea cucumber peptides exert anti-inflammatory activity through suppressing NF-κB and MAPK and inducing HO-1 in RAW264.7 macrophages.

The anti-inflammatory effect of sea cucumber peptides (SCP) in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages was tested. SCP significantly reduced LPS-induced nitric oxide release by inhibiting the inducible nitric oxide synthase mRNA expression without affecting the cell viability. The mRNA expression of LPS-induced inflammatory cytokines including tumour necrosis factor-α, interleukin (IL)-1ß and IL-6 was suppressed. SCP inhibited LPS-induced degradation of the inhibitor of κBα (IκBα) and nuclear transposition of NF-κB p65, resulting in decreased NF-κB transactivation. Moreover, SCP suppressed the LPS-induced phosphorylation of JNK, ERK and p38. In addition, the expression of heme oxygenase (HO)-1 in macrophages was up-regulated by SCP in a dose-dependent manner. The inhibition effect of SCP on the mRNA expression of LPS-induced inflammatory cytokines was partially reversed by co-treatment with a HO-1 inhibitor. The SCP with anti-inflammatory activity was made up of low-molecular-weight peptides rich in glycine, glutamic acid and aspartic acid. Collectively, these results demonstrate that SCP exerts anti-inflammatory function through inhibiting NF-κB and MAPK activation and inducing HO-1 expression in macrophages.

Endotoxin-Binding Peptides Derived from Casein Glycomacropeptide Inhibit Lipopolysaccharide-Stimulated Inflammatory Responses via Blockade of NF-κB activation in macrophages.

Systemic low-grade inflammation and increased circulating lipopolysaccharide (LPS) contribute to metabolic dysfunction. The inhibitory effects and underlying molecular mechanisms of casein glycomacropeptide (GMP) hydrolysate on the inflammatory response of LPS-stimulated macrophages were investigated. Results showed that the inhibitory effect of GMP hydrolysates obtained with papain on nitric oxide (NO) production were obviously higher than that of GMP hydrolysates obtained with pepsin, alcalase and trypsin (p < 0.05), and the hydrolysate obtained with papain for 1 h hydrolysis (GHP) exhibited the highest inhibitory effect. Compared with native GMP, GHP markedly inhibited LPS-induced NO production in a dose-dependent manner with decreased mRNA level of inducible nitric oxide synthase (iNOS). GHP blocked toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway activation, accompanied by downregulation of LPS-triggered significant upregulation of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß gene expression. Furthermore, GHP could neutralize LPS not only by direct binding to LPS, but also by inhibiting the engagement of LPS with the TLR4/MD2 complex, making it a potential LPS inhibitor. In conclusion, these findings suggest that GHP negatively regulates TLR4-mediated inflammatory response in LPS-stimulated RAW264.7 cells, and therefore may hold potential to ameliorate inflammation-related issues.