High Expression of PKM2 Was Associated with the Poor Prognosis of Acute Leukemia.

PURPOSE: To explore the clinical significance of plasma pyruvate kinase M2 (PKM2) in assessing the incidence and prognosis of acute leukemia. METHODS: Plasma samples from 56 acute myeloid leukemia (AML) patients, 40 acute lymphoblastic leukemia (ALL) patients, and 66 plasma samples from healthy individuals were collected. The level of plasma PKM2 was detected by enzyme-linked immunosorbent assay. The clinical significance of PKM2 in acute leukemia was assessed by analyzing receiver operating characteristic and survival curves. RESULTS: The plasma levels of PKM2 in AML or ALL patients were significantly higher than those in healthy individuals, respectively. PKM2 can be used as a potential diagnostic index with the AUC of 0.827 for AML and 0.837 for ALL. The level of plasma PKM2 in ALL patients with a BCR/ABL-positive genotype was significantly higher than that in patients with a BCR/ABL-negative genotype (p<0.05). The event-free survival and the overall survival of acute leukemia patients with higher PKM2 expression was worse than those with lower PKM2 expression. CONCLUSION: This study showed that higher levels of PKM2 was negatively correlated with the prognosis of acute leukemia. Therefore, PKM2 can be used as a potential index to assess the incidence and prognosis of acute leukemia.

Neuroprotective effects of vitamin D and 17ß-estradiol against ovariectomy-induced neuroinflammation and depressive-like state: Role of the AMPK/NF-κB pathway.

Estrogen replacement therapy (ERT) has been proven to relieve menopausal-related mental disorders including depression in postmenopausal women. However, the unsafety of ERT hinders its clinical use. In this study, we would evaluate whether vitamin D (VD), a hormone with optimal safety profile, could relieve the depressive-like symptom in ovariectomized (OVX) rats. Furthermore, we would determine whether vitamin D and 17ß-estradiol (E2) exert neurological function through their immunomodulatory effect in OVX rats. Middle-aged female SD rats were randomly divided into four groups, namely, control (SHAM), OVX, OVX + VD, and OVX + E2. Vitamin D (calcitriol, 100 ng/kg) and 17ß-estradiol (30 µg/kg) had been daily gavaged in the OVX + VD and OVX + E2 group, respectively. After 10-week administration, vitamin D and 17ß-estradiol both showed anti-depressive-like activity in the OVX rats. Using the method of immunofluorescent staining and western blot, vitamin D and 17ß-estradiol were demonstrated to upregulate each other's receptors, including VDR, ERα, and ERß in the hippocampus of OVX rats. Additionally, the upregulation of VDR, calbindin-D28k, and calbindin-D9k suggested that the vitamin D signaling system was amplified by vitamin D and 17ß-estradiol. Vitamin D and 17ß-estradiol showed neuroprotective effects by decreasing OVX-induced apoptosis and neuronal damage, regulating the AMPK/NF-κB signaling pathway, and reducing the proinflammatory cytokines (IL-1ß, IL-6, and TNFα), as well as iNOS and COX-2 in the hippocampus of OVX rats. Collectively, the present study demonstrated that vitamin D and 17ß-estradiol could upregulate each other's receptors and regulate the AMPK/NF-κB pathway to relieve the OVX-induced depressive-like state. The results could stimulate translational research towards the vitamin D potential for prevention or treatment of menopause-related depression.

Exercise improves depressive symptoms by increasing the number of excitatory synapses in the hippocampus of CUS-Induced depression model rats.

Exercise has been considered for the treatment of depression, but the mechanism by which exercise improves depression is still unclear. To clarify the mechanism, rats were randomly divided into the control, chronic unpredictable stress (CUS)/standard and CUS/running groups. The rats in the CUS/running group ran for four weeks. In this study, a sucrose preference test (SPT) was used to evaluate the depression-like symptoms in the rats, and western blot, immunohistochemical and stereological analyses were performed to study the expression of synaptic-related proteins in the hippocampus and the changes in excitatory synapses in each sub-region. The results show that sucrose preference in the CUS/standard group was significantly lower than that in the control group, but in the CUS/running group, sucrose preference was higher than that in the CUS/standard group. Surprisingly, there was no difference in the synaptic-related proteins in the hippocampus among groups. The CUS/standard group exhibited fewer spinophilin+ (Sp+) dendritic spines representing excitatory synapses in CA1, CA3 and dentate gyrus (DG) of the hippocampus than the control group, whereas the CUS/running group exhibited significantly more Sp+ dendritic spines in these regions than the CUS/standard group, indicating that excitatory synapses were reduced in depressed rats and that running exercises could reverse this change. We hypothesize that the changes in the number of excitatory synapses better reflect the changes in depressive symptoms than the level of synaptic proteins and that the effect of exercise on excitatory synapses in the sub-regions of the hippocampus may be an important structural indicator of the improvement of depressive symptoms.

Quantitative study of the capillaries within the white matter of the Tg2576 mouse model of Alzheimer's disease.

INTRODUCTION: To quantitatively investigate the capillaries within the white matter of Tg2576 Alzheimer's disease (AD) transgenic mice during the early stage. METHODS: In the current study, 10-month-old male Tg2576 AD mice were used as the early-stage AD group and age-matched nontransgenic littermate mice were used as the wild-type group. Then, the Morris water maze was used to examine the spatial learning and memory abilities of the mice in both groups, and unbiased stereological methods were used to accurately quantify the volume of white matter and the parameters of the capillaries within the white matter, such as the total length, total volume, and total surface area of capillaries. RESULTS: The Morris water maze performance of the Tg2576 group was worse than that of the wild-type group, while the white matter volume did not significantly differ between the wild-type group and the Tg2576 group. The total length, total volume, and total surface area of the capillaries within the white matter of the Tg2576 group were significantly decreased compared to those of the wild-type group. CONCLUSIONS: The current study provide structural basis for understanding the pathological changes of the early stage of AD and cognitive decline in AD might be associated with changes in the white matter capillaries. Capillaries within the white matter might, thus, serve as a valid target for the prevention and treatment of early-stage AD.

Changes in white matter and the effects of fluoxetine on such changes in the CUS rat model of depression.

OBJECTIVE: To explore the pathogenesis of depression and the possible mechanism of the effects of selective serotonin reuptake inhibitors (SSRIs) on the myelinated fibers and myelin sheaths in the white matter during the antidepressant action of fluoxetine. METHODS: In this study, Sprague Dawley (SD) rats were divided into a Control group, a group treated with CUS and no drugs (CUS/Standard group) and a group treated with CUS and fluoxetine (CUS/FLX group). The CUS/FLX group was treated with fluoxetine at dose of 5 mg/kg for 21 days. The white matter volume, the myelinated fiber parameters and the myelin sheath volume in the white matter were calculated from transmission electron microscope images through unbiased stereological methods. RESULTS: The total volume and total length of myelinated fibers;and mean volume of white matter of the CUS/Standard group were significantly decreased compared to values from the control group (p = 0.025, p = 0.007, p = 0.000), whereas no significant differences in these stereological parameters were found between the CUS/Standard and CUS/FLX groups (p > 0.05). CONCLUSIONS: Fluoxetine successfully treated depression-like behavior but had no effects on the white matter or its component myelinated fibers in the CUS rat model of depression.

Sex Differences in the White Matter and Myelinated Fibers of APP/PS1 Mice and the Effects of Running Exercise on the Sex Differences of AD Mice.

Previous studies have suggested that changes in the white matter might play an important role in the pathogenic processes of Alzheimer's disease (AD). However, no study has investigated sex differences in these changes. Previous studies found that running exercise could delay both the decline in spatial learning and memory abilities as well as the changes in the white matter during early AD in male mice. However, whether exercise also has an effect on the changes in the white matter in female AD mice remains unknown. To address these questions, 6- and 10-month-old male and female APP/PS1 double transgenic AD mice were used. The 6-month-old male and female APP/PS1 double transgenic AD mice underwent a 4-month running exercise regime. The white matter volume and parameters of the myelinated fibers in the white matter of the 10-month-old exercised and non-exercised male and female AD mice were investigated using electron microscopy and stereological methods. There were no significant differences in the mean escape latencies between the male and female AD mice in the non-exercised groups, but after 4 months of treadmill exercise, the mean escape latencies of the female exercised AD mice had significantly shortened compared with those of the male exercised AD mice. The total white matter volume and most of the parameters of the myelinated fibers of the white matter in the female AD mice were significantly lower than those of the male AD mice. The total length of the myelinated fibers with diameters ranging from 0.6 to 0.7 µm, the axonal diameter of the myelinated fibers and the g-ratio of the myelinated fibers in the white matter of the exercised female AD mice were significantly increased compared with those of the non-exercised female AD mice. There were sex-specific differences in the white matter and myelinated fibers of white matter in the AD mice. Running exercise more effectively delayed the decline in spatial learning and memory abilities and delayed the changes in the myelinated fibers of the white matter in female transgenic mice with early AD than in male transgenic mice.

Effect of running exercise on the number of the neurons in the hippocampus of young transgenic APP/PS1 mice.

To investigate the effect of running exercise on the number of the neurons in the hippocampus of young APP/PS1 mice, twenty 6-month-old male APP/ PS1 transgenic mice were randomly divided into the APP/PS1 control (AD control) group and the APP/PS1 running (AD running) group (10 mice per group), and ten wild-type mice of the littermate were regarded as the wild-type (WT) group. The AD running mice ran on motorized treadmill machiene for 4 months, while the WT mice and AD control mice were housed in standard condition without running. Then, Morris water maze tests (MWM) were used to assess the special learning and memory abilities of mice in three groups. The stereological methods were used to quantitatively evaluate the volume of the hippocampus, CA1/2, CA3 and the dentate gyrus (DG) and count the number of the neurons in CA1/2, CA3 and DG. We found that 4-month running effectively shortened the escape latency of young APP/PS1 control mice in MWM. More importantly, 4-month running effectively increased the volumes of the hippocampus, CA1/2, CA3 and DG and increased the number of neurons in CA1/2, CA3 and DG in young APP/PS1 mice. The present results suggested that 4-month running has significant beneficial effects on the spatial learning and memory capacities of young APP/PS1 mice and could delay the progress of atrophy of hippocampus and the neuron death in CA1/2, CA3 and DG in young APP/PS1 mice.

Effects of exercise on capillaries in the white matter of transgenic AD mice.

Previous studies have shown that exercise can prevent white matter atrophy in APP/PS1 transgenic Alzheimer's disease (AD) mice. However, the mechanism of this protective effect remains unknown. To further understand this issue, we investigated the effects of exercise on the blood supply of white matter in transgenic AD mice. Six-month-old male APP/PS1 mice were randomly divided into a control group and a running group, and age-matched non-transgenic littermates were used as a wild-type control group. Mice in the running group ran on a treadmill at low intensity for four months. Then, spatial learning and memory abilities, white matter and white matter capillaries were examined in all mice. The 10-month-old AD mice exhibited deficits in cognitive function, and 4 months of exercise improved these deficits. The white matter volume and the total length, total volume and total surface area of the white matter capillaries were decreased in the 10-month-old AD mice, and 4 months of exercise dramatically delayed the changes in these parameters in the AD mice. Our results demonstrate that even low-intensity running exercise can improve spatial learning and memory abilities, delay white matter atrophy and protect white matter capillaries in early-stage AD mice. Protecting capillaries might be an important structural basis for the exercise-induced protection of the structural integrity of white matter in AD.

White matter atrophy and myelinated fiber disruption in a rat model of depression.

Brain imaging and postmortem studies have indicated that white matter abnormalities may contribute to the pathology and pathogenesis of depression. However, until now, no study has quantitatively investigated white matter changes in depression in rats. The current study used the chronic unpredictable stress (CUS) model of depression. Body weight and sucrose preference test (SPT) scores were assessed weekly. Upon successfully establishing the CUS animal model, all animals were tested using the SPT and the open field test (OFT). Then, transmission electron microscopy and unbiased stereological methods were used to investigate white matter changes in the rats. Compared with the control group, the body weight and sucrose preference of the CUS rats were significantly decreased (p < .001, p < .001, respectively). In the OFT, the total time spent and the total distance traveled in the inner area by the CUS rats were significantly lower than those of the control group (p = .002, p = .001, respectively). The stereological results revealed that white matter volume, the total volume, and the total length and mean diameter of myelinated fibers in the white matter of the CUS rats were significantly decreased compared to the control rats (p = .042, p = .038, p = .035, p = .019, respectively). The results of this study suggested that white matter atrophy and disruption of myelinated fibers in the white matter may contribute to the pathophysiology underlying depression, which might provide new targets for the development of novel therapeutic interventions for depression.

Running exercise protects the capillaries in white matter in a rat model of depression.

Running has been shown to improve depressive symptoms when used as an adjunct to medication. However, the mechanisms underlying the antidepressant effects of running are not fully understood. Changes of capillaries in white matter have been discovered in clinical patients and depression model rats. Considering the important part of white matter in depression, running may cause capillary structural changes in white matter. Chronic unpredictable stress (CUS) rats were provided with a 4-week running exercise (from the fifth week to the eighth week) for 20 minutes each day for 5 consecutive days each week. Anhedonia was measured by a behavior test. Furthermore, capillary changes were investigated in the control group, the CUS/Standard group, and the CUS/Running group using stereological methods. The 4-week running increased sucrose consumption significantly in the CUS/Running group and had significant effects on the total volume, total length, and total surface area of the capillaries in the white matter of depression rats. These results demonstrated that exercise-induced protection of the capillaries in white matter might be one of the structural bases for the exercise-induced treatment of depression. It might provide important parameters for further study of the vascular mechanisms of depression and a new research direction for the development of clinical antidepressant means. J. Comp. Neurol. 524:3577-3586, 2016. © 2016 Wiley Periodicals, Inc.