Fasudil in Combination With Bone Marrow Stromal Cells (BMSCs) Attenuates Alzheimer\u27s Disease-Related Changes Through the Regulation of the Peripheral Immune System.

Alzheimer\u27s disease (AD) is a chronic progressive neurodegenerative disease. Its mechanism is still not clear. Majority of research focused on the central nervous system (CNS) changes, while few studies emphasize on peripheral immune system modulation. Our study aimed to investigate the regulation of the peripheral immune system and its relationship to the severity of the disease after treatment in an AD model of APPswe/PSEN1dE9 transgenic (APP/PS1 Tg) mice. APP/PS1 Tg mice (8 months old) were treated with the ROCK-II inhibitor 1-(5-isoquinolinesulfonyl)-homo-piperazine (Fasudil) (intraperitoneal (i.p.) injections, 25 mg/kg/day), bone marrow stromal cells (BMSCs; caudal vein injections, 1 × 1

Effects of sea-buckthorn leaves on performance and serum metabolic profiles in Altay lambs

In this study, the effects of sea-buckthorn (Hippophae rhamnoides L.) leaves (SL) on the biochemical parameters and metabolomic profiling in Altay lamb (Ovis aries) were observed. Sixty six-month-old male Altay lambs (body weight 28.0 ± 3.5 kg) were randomly assigned to four groups (n=15). The experimental groups were named as CON, 2.5%, 5.0% and 7.5%. The group CON, contained animals fed with a basal diet. Animals of the other groups were fed a treatment diet consisting of 2.5% (Group 2.5%), 5.0% (Group 5.0%) and 7.5% (Group 7.5%) SL. The experimental period lasted 56 days. The results showed that the average daily gain (ADG) and average daily feed intake (ADFI) increased with the increase in the levels of dietary SL. Dietary SL showed a direct relationship with total protein (TP), albumin, globulin and total cholesterol (TC) content of the experimental animals. However, an indirect relationship was observed between dietary SL and the concentration of urea nitrogen (UN). The concentrations of glucose, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) showed quadratic change. Additional changes occurred in the endogenous metabolites involving multiple pathways. The pathways were tricarboxylic acid (TCA) cycle, the metabolism of protein and amino acid and the metabolism of fatty acid and steroid. The changes in metabolites primarily revealed an increase in amino acids and carbohydrates and a decrease in lipid metabolites. These findings provide a comprehensive insight into the effects of the metabolic aspects of sea-buckthorn leaves on Altay lambs. In addition, the present research results provide a better understanding to the development and utilization of sea-buckthorn as a healthy additive for small ruminant production.Keywords: Hippophae rhamnoides L., lamb, metabolomics, growth performance, serum parameter

The Flare and Warp of the Young Stellar Disk traced with LAMOST DR5 OB-type stars

We present analysis of the spatial density structure for the outer disk from 8$-$14 \,kpc with the LAMOST DR5 13534 OB-type stars and observe similar flaring on north and south sides of the disk implying that the flaring structure is symmetrical about the Galactic plane, for which the scale height at different Galactocentric distance is from 0.14 to 0.5 \,kpc. By using the average slope to characterize the flaring strength we find that the thickness of the OB stellar disk is similar but flaring is slightly stronger compared to the thin disk as traced by red giant branch stars, possibly implying that secular evolution is not the main contributor to the flaring but perturbation scenarios such as interactions with passing dwarf galaxies should be more possible. When comparing the scale height of OB stellar disk of the north and south sides with the gas disk, the former one is slightly thicker than the later one by $\approx$ 33 and 9 \,pc, meaning that one could tentatively use young OB-type stars to trace the gas properties. Meanwhile, we unravel that the radial scale length of the young OB stellar disk is 1.17 $\pm$ 0.05 \,kpc, which is shorter than that of the gas disk, confirming that the gas disk is more extended than stellar disk. What is more, by considering the mid-plane displacements ($Z_{0}$) in our density model we find that almost all of $Z_{0}$ are within 100 \,pc with the increasing trend as Galactocentric distance increases.Comment: 14 pages and 8 figures, Accepted by APJ for publicatio

Therapeutic effect of Rho kinase inhibitor FSD-C10 in a mouse model of Alzheimer\u27s disease.

Fasudil, a Rho kinase (ROCK) inhibitor, effectively inhibits disease severity in a mouse model of Alzheimer\u27s disease (AD). However, given its significant limitations, including a relatively narrow safety window and poor oral bioavailability, Fasudil is not suitable for long-term use. Thus, screening for ROCK inhibitor(s) that are more efficient, safer, can be used orally and suitable for long-term use in the treatment of neurodegenerative disorders is required. The main purpose of the present study is to explore whether FSD-C10, a novel ROCK inhibitor, has therapeutic potential in amyloid precursor protein/presenilin-1 transgenic (APP/PS1 Tg) mice, and to determine possible mechanisms of its action. The results showed that FSD-C10 effectively improved learning and memory impairment, accompanied by reduced expression of amyloid-β1-42 (Aβ 1-42 ), Tau protein phosphorylation (P-tau) and β-site APP-cleaving enzyme in the hippocampus and cortex area of brain. In addition, FSD-C10 administration boosted the expression of synapse-associated proteins, such as postynaptic density protein 95, synaptophsin, α-amino 3-hydroxy-5-methyl-4-isoxa-zolep-propionate receptor and neurotrophic factors, e,g., brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. Taken together, our results demonstrate that FSD-C10 has therapeutic potential in the AD mouse model, possibly through inhibiting the formation of Aβ 1-42 and P-tau, and promoting the generation of synapse-associated proteins and neurotrophic factors

FSD-C10: A more promising novel ROCK inhibitor than Fasudil for treatment of CNS autoimmunity.

Rho-Rho kinase (Rho-ROCK) triggers an intracellular signalling cascade that regulates cell survival, death, adhesion, migration, neurite outgrowth and retraction and influences the generation and development of several neurological disorders. Although Fasudil, a ROCK inhibitor, effectively suppressed encephalomyelitis (EAE), certain side effects may limit its clinical use. A novel and efficient ROCK inhibitor, FSD-C10, has been explored. In the present study, we present chemical synthesis and structure of FSD-C10, as well as the relationship between compound concentration and ROCK inhibition. We compared the inhibitory efficiency of ROCKI and ROCK II, the cell cytotoxicity, neurite outgrowth and dendritic formation, neurotrophic factors and vasodilation between Fasudil and FSD-C10. The results demonstrated that FSD-C10, like Fasudil, induced neurite outgrowth of neurons and dendritic formation of BV-2 microglia and enhanced the production of neurotrophic factor brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3). However, the cell cytotoxicity and vasodilation of FSD-C10 were relatively small compared with Fasudil. Although Fasudil inhibited both ROCK I and ROCK II, FSD-C10 more selectively suppressed ROCK II, but not ROCK I, which may be related to vasodilation insensitivity and animal mortality. Thus, FSD-C10 may be a safer and more promising novel ROCK inhibitor than Fasudil for the treatment of several neurological disorders

Abnormal Global Brain Functional Connectivity in Primary Insomnia Patients: A Resting-State Functional MRI Study

Background: Resting-state functional magnetic resonance imaging (fMRI) studies have uncovered the disruptions of functional brain networks in primary insomnia (PI) patients. However, the etiology and pathogenesis underlying this disorder remains ambiguous, and the insomnia related symptoms are influenced by a complex network organization in the brain. The purpose of this study was to explore the abnormal intrinsic functional hubs in PI patients using a voxel-wise degree centrality (DC) analysis and seed-based functional connectivity (FC) approach.Methods: A total of 26 PI patients and 28 healthy controls were enrolled, and they underwent resting-state fMRI. Degree centrality was measured across the whole brain, and group differences in DC were compared. The peak points, which significantly altered DC between the two groups, were defined as the seed regions and were further used to calculate FC of the whole brain. Later, correlation analyses were performed between the changes in brain function and clinical features.Results: Primary insomnia patients showed DC values lower than healthy controls in the left inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) and showed a higher DC value in the right precuneus. The seed-based analyses demonstrated decreased FC between the left MTG and the left posterior cingulate cortex (PCC), and decreased FC was observed between the right precuneus and the right lateral occipital cortex. Reduced DC in the left IFG and decreased FC in the left PCC were positively correlated with the Pittsburgh sleep quality index and the insomnia severity index.Conclusions: This study revealed that PI patients exhibited abnormal intrinsic functional hubs in the left IFG, MTG, and the right precuneus, as well as abnormal seed-based FC in these hubs. These results contribute to better understanding of how brain function influences the symptoms of PI