Effects of involuntary treadmill running in combination with swimming on adult neurogenesis in an Alzheimer's mouse model.

Physical exercise plays a role on the prevention and treatment of Alzheimer's disease (AD), but the exercise mode and the mechanism for these positive effects is still ambiguous. Here, we investigated the effect of an aerobic interval exercise, running in combination with swimming, on behavioral dysfunction and associated adult neurogenesis in a mouse model of AD. We demonstrate that 4 weeks of the exercise could ameliorate Aß42 oligomer-induced cognitive impairment in mice utilizing Morris water maze tests. Additionally, the exercised Aß42 oligomer-induced mice exhibited a significant reduction of anxiety- and depression-like behaviors compared to the sedentary Aß42 oligomer-induced mice utilizing an Elevated zero maze and a Tail suspension test. Moreover, by utilizing 5'-bromodeoxyuridine (BrdU) as an exogenous cell tracer, we found that the exercised Aß42 oligomer-induced mice displayed a significant increase in newborn cells (BrdU+ cells), which differentiated into a majority of neurons (BrdU+ DCX+ cells or BrdU+NeuN+ cells) and a few of astrocytes (BrdU+GFAP+ cells). Likewise, the exercised Aß42 oligomer-induced mice also displayed the higher levels of NeuN, PSD95, synaptophysin, Bcl-2 and lower level of GFAP protein. Furthermore, alteration of serum metabolites in transgenic AD mice between the exercised and sedentary group were significantly associated with lipid metabolism, amino acid metabolism, and neurotransmitters. These findings suggest that combined aerobic interval exercise-mediated metabolites and proteins contributed to improving adult neurogenesis and behavioral performance after AD pathology, which might provide a promising therapeutic strategy for AD.

Effects of Involuntary and Voluntary Exercise in Combination with Acousto-Optic Stimulation on Adult Neurogenesis in an Alzheimer's Mouse Model.

Single-factor intervention, such as physical exercise and auditory and visual stimulation, plays a positive role on the prevention and treatment of Alzheimer's disease (AD); however, the therapeutic effects of single-factor intervention are limited. The beneficial effects of these multifactor combinations on AD and its molecular mechanism have yet to be elucidated. Here, we investigated the effect of multifactor intervention, voluntary wheel exercise, and involuntary treadmill running in combination with acousto-optic stimulation, on adult neurogenesis and behavioral phenotypes in a mouse model of AD. We found that 4 weeks of multifactor intervention can significantly increase the production of newborn cells (BrdU+ cells) and immature neurons (DCX+ cells) in the hippocampus and lateral ventricle of Aß oligomer-induced mice. Importantly, the multifactor intervention could promote BrdU+ cells to differentiate into neurons (BrdU+ DCX+ cells or BrdU+ NeuN+ cells) and astrocytes (BrdU+GFAP+ cells) in the hippocampus and ameliorate Aß oligomer-induced cognitive impairment and anxiety- and depression-like behaviors in mice evaluated by novel object recognition, Morris water maze tests, elevated zero maze, forced swimming test, and tail suspension test, respectively. Moreover, multifactor intervention could lead to an increase in the protein levels of PSD-95, SYP, DCX, NeuN, GFAP, Bcl-2, BDNF, TrkB, and pSer473-Akt and a decrease in the protein levels of BAX and caspase-9 in the hippocampal lysates of Aß oligomer-induced mice. Furthermore, sequencing analysis of serum metabolites revealed that aberrantly expressed metabolites modulated by multifactor intervention were highly enriched in the biological process associated with keeping neurons functioning and neurobehavioral function. Additionally, the intervention-mediated serum metabolites mainly participated in glutamate metabolism, glucose metabolism, and the tricarboxylic acid cycle in mice. Our findings suggest the potential of multifactor intervention as a non-invasive therapeutic strategy for AD to anti-Aß oligomer neurotoxicity.

Inhibitory effects of oxymatrine on hepatic stellate cells activation through TGF-ß/miR-195/Smad signaling pathway.

BACKGROUND: Oxymatrine (OM), a quinolizidine alkaloid extracted from a herb Sophorae Flavescentis Radix, has been used to treat liver fibrotic diseases. However, the mechanism of its anti-fibrosis effects is still unclear. TGF-ß/Smad signaling and miR-195 have been proved to paly an important role in hepatic stellate cells (HSCs) activation and liver fibrosis. In this study, we investigated whether OM could inhibit HSCs activation through TGF-ß1/miR-195/Smads signaling or not. METHODS: First, the effects of OM on HSC-T6 in different concentrations and time points were tested by MTT assay. We choose three appropriate concentrations of OM as treatment concentrations in following experiment. By Quantitative Real-time PCR and Western Blot, then we investigated the effect of OM on miR-195, Smad7 and α-SMA's expressions to prove the correlation between OM and the TGF-ß1/miR-195/Smads signaling. Last, miR-195 mimic and INF-γ were used to investigate the relation between miR-195 and OM in HSC activation. RESULTS: Our results showed that the proliferation of HSC was significantly inhibited when OM concentration was higher than 200 µg/mL after 24 h, 100 µg/mL after 48 h and 10 µg/mL after 72 h. The IC50 of OM after 24, 48 and 72 h were 539, 454, 387 µg/mL respectively. OM could down-regulate miR-195 and α-SMA (P < 0.01), while up-regulate Smad7 (P < 0.05). In HSC-T6 cells transfected with miR-195 mimic and pretreated with OM, miR-195 and α-SMA were up-regulated (P < 0.05), and Smad7 was down-regulated (P < 0.05) . CONCLUSIONS: Given these results, OM could inhibit TGF-ß1 induced activation of HSC-T6 proliferation in a dose-dependent and time-dependent manner to some extent. We proved that OM inhibited HSC activation through down-regulating the expression of miR-195 and up-regulating Smad7.

MicroRNA-195 Activates Hepatic Stellate Cells In Vitro by Targeting Smad7.

BACKGROUND AND AIM: Aberrant activation of the TGF-ß1/Smad pathway contributes to the activation of hepatic stellate cells (HSCs). MicroRNA-195 has been shown to regulate the activation of HSCs. The aim of this study was to investigate the role of miRNA-195 in HSCs activation. METHODS: A liver fibrotic rat model induced by diethylnitrosamine was established. Dual luciferase reporter assays were performed to verify that Smad7 was the target of miRNA-195. The expression levels of miR-195, Smad7, and α-SMA in HSC-T6 transfected, respectively, with miR-195 mimic, inhibitor, or control were measured by qRT-PCR. The protein expression of Smad7 was detected by Western blot analysis. RESULTS: Enhanced miR-195 and decreased Smad7 were observed in diethylnitrosamine-induced liver fibrotic rats (P < 0.05). Dual luciferase reporter assays showed that the miR-195 mimic significantly suppressed the luciferase activity of a reporter plasmid carrying the binding site of miR-195 on the 3'UTR of Smad7 (P < 0.05). The miR-195 mimics activated HSCs, further elevated miR-195 and α-SMA (P < 0.01), and reduced the Smad7 level (P < 0.05). The miR-195 inhibitors blocked the activation of HSCs, reduced the expression of miR-195 and α-SMA (P < 0.01), and upregulated the expression of Smad7 (P < 0.05). CONCLUSION: Collectively, we demonstrated that miRNA-195 activated HSCs by targeting Smad7.

A meta-analysis comparing the efficacy of entecavir and tenofovir for the treatment of chronic hepatitis B infection.

The efficacy of entecavir and tenofovir in patients with chronic hepatitis B virus (HBV) is inconsistent. To address this issue, we conducted a meta-analysis based on a current review of the literature addressing the efficacy and safety of entecavir and tenofovir. Electronic databases were searched through June 2014 for relevant clinical trials. We included 2 randomized controlled trials, 2 prospective cohort studies, and 7 case-control studies that included 1,656 patients. In the entecavir group, 842 of 992 were nucleos(t)ide-naïve chronic HBV patients, and in the tenofovir group 481 of 664 were nucleos(t)ide-naïve. The virological response to tenofovir was superior to entecavir (RR: 0.82; 95%CI: 0.72-0.93), especially in nucleos(t)ide-naïve chronic HBV patients at 48 weeks (RR: 0.78; 95%CI: 0.65-0.92). Additionally, there was no difference between entecavir and tenofovir for virological response at 24 weeks (RR: 0.87, 95%CI: 0.71-1.05). The alanine aminotransferase normalization rate, serological response, and adverse event rate were also not significantly different between entecavir and tenofovir at 24 or 48 weeks after treatment. These results suggest that tenofovir is a better choice to treat chronic HBV patients than entecavir as it is better able to suppress HBV viral load and has a similar safety profile.

catena-Poly[[silver(I)-µ-[N-(4-pyridyl-meth-yl)pyridine-4-carboxamide-κN:N']] nitrate monohydrate].

The title coordination polymer, {[Ag(C(12)H(11)N(3)O)]NO(3)·H(2)O}(n), has a polycationic chain motif in which the Ag atom is bridged by the heterocyclic ligand; the Ag atom shows linear coordination. If the two long Ag⋯O(nitrate) inter-actions [2.794 (6) and 2.867 (5) Å] are regarded as bonds, the compound adopts a three-dimensional network structure. The water mol-ecule consolidates the network structure by forming hydrogen bonds, one to the polycationic chain and one to the nitrate anion.

catena-Poly[[silver(I)-µ-N-(3-pyridyl-meth-yl)pyridine-4-carboxamide] nitrate monohydrate].

In the title compound, {[Ag(C(12)H(11)N(3)O)]NO(3)·H(2)O}(n), the Ag atom is coordinated by two N atoms from the heterocyclic ligand, giving a linear polycationic chain. Two long Ag⋯O(nitrate) inter-actions [2.667 (3) and 2.840 (3) Å] result in a three-dimensional network. The water mol-ecule consolidates the network structure by forming hydrogen bonds, one to the polycationic chain and one to the nitrate anion.