Acetylglutamine facilitates motor recovery and alleviates neuropathic pain after brachial plexus root avulsion in rats.

BACKGROUND: Brachial plexus root avulsion (BPRA), a disabling peripheral nerve injury, induces substantial motoneuron death, motor axon degeneration and denervation of biceps muscles, leading to the loss of upper limb motor function. Acetylglutamine (N-acetyl-L-glutamine, NAG) has been proven to exert neuroprotective and anti-inflammatory effects on various disorders of the nervous system. Thus, the present study mainly focused on the influence of NAG on motor and sensory recovery after BPRA in rats and the underlying mechanisms. METHODS: Male adult Sprague Dawley (SD) rats were subjected to BPRA and reimplantation surgery and subsequently treated with NAG or saline. Behavioral tests were conducted to evaluate motor function recovery and the mechanical pain threshold of the affected forelimb. The morphological appearance of the spinal cord, musculocutaneous nerve, and biceps brachii was assessed by histological staining. Quantitative real-time PCR (qRT‒PCR) was used to measure the mRNA levels of remyelination and regeneration indicators in myocutaneous nerves. The protein levels of inflammatory and pyroptotic indicators in the spinal cord anterior horn were measured using Western blotting. RESULTS: NAG significantly accelerated the recovery of motor function in the injured forelimbs, enhanced motoneuronal survival in the anterior horn of the spinal cord, inhibited the expression of proinflammatory cytokines and pyroptosis pathway factors, facilitated axonal remyelination in the myocutaneous nerve and alleviated atrophy of the biceps brachii. Additionally, NAG attenuated neuropathic pain following BPRA. CONCLUSION: NAG promotes functional motor recovery and alleviates neuropathic pain by enhancing motoneuronal survival and axonal remyelination and inhibiting the pyroptosis pathway after BPRA in rats, laying the foundation for the use of NAG as a novel treatment for BPRA.

Effects of combined treatment with ibandronate and pulsed electromagnetic field on ovariectomy-induced osteoporosis in rats.

Ibandronate (IBN) and pulsed electromagnetic field (PEMF) have each shown positive effects for treating osteoporosis, but no study has evaluated the relative effects of these treatments combined. This study investigated the effects of IBN + PEMF on bone turnover, mineral density, microarchitecture, and biomechanical properties in an ovariectomized (OVX) rat model of osteoporosis. Fifty 3-month-old rats were randomly apportioned to receive a sham-operation (n = 10), or ovariectomy (n = 40). The latter group was equally divided as the model (OVX control) or to receive IBN, PEMF, or IBN + PEMF. Beginning the day after surgery, the IBN and IBN + PEMF groups received weekly subcutaneous IBN; the PEMF and IBN + PEMF groups were given daily PEMF during the same 12 weeks. After 12 weeks of treatments, biochemical parameters, bone mineral density (BMD), microarchitecture parameters, biomechanical properties, and some metabolic modulators that are involved in bone resorption were compared. The L5 lumbar vertebral body BMDs of the IBN, PEMF, and IBN + PEMF groups were 121.6%, 119.5%, and 139.6%; maximum loads were 111.4%, 112.7%, and 121.9%; and energy to failure was 130.8%, 129.2%, and 154.9% of the OVX model, respectively. The IBN + PEMF group had significantly lower levels of serum tartrate-resistant acid phosphatase 5b, and greater improvement in BMD, bone microarchitecture, and strength of the lumbar spine compared with monotherapy groups. Results showed that IBN + PEMF had a more favorable effect on the lumbar spine in this osteoporosis model than did either monotherapy. Bioelectromagnetics. 38:31-40, 2017. © 2016 Wiley Periodicals, Inc.

Cognitive and neuropsychiatric impairment in cerebral radionecrosis patients after radiotherapy of nasopharyngeal carcinoma.

BACKGROUND: We sought to characterize the cognitive function and neuropsychiatric symptoms in cerebral radionecrosis (CRN) patients who have received conformal radiation for nasopharyngeal carcinoma. METHODS: A total of 40 patients treated with radiotherapy (RT) that developed CRN (RT + CRN), 40 patients treated with radiotherapy that did not have CRN (RT-No-CRN), and 36 newly diagnosed untreated nasopharyngeal carcinoma patients (No-RT) were recruited. The cognitive function and neuropsychiatric symptoms were evaluated with Montreal cognitive assessment (MoCA), the mini-mental state examination (MMSE), activity of daily living scale (ADL), neuropsychiatric inventory (NPI), Hamilton depression scale (HAMD) and Hamilton anxiety scale (HAMA). RESULTS: The RT + CRN group had the lowest mean MMSE, MoCA and ADL scores, while highest mean NPI, HAMD and HAMA scores among the three patient groups (P < 0.05). Thirty (75%) of the RT + CRN patients were deemed cognitively impaired by the MoCA compared with 9 (22.5%) by the MMSE (χ(2) = 22.064; P < 0.001). Eighty-two percents of subject in RT + CRN group experienced neuropsychiatric symptoms within the past 4 weeks. Irritability, anxiety, depression and agitation in the RT + CRN group were of the most significantly frequent among the 3 groups. CONCLUSIONS: The CRN patients generally have manifestations in cognitive and psychological impairment, which have their typical characteristics, and should be considered in CRN treatment and rehabilitation. The MoCA classifies more CRN patients as cognitively impaired than the MMSE, justifying further studies of the MoCA as an appropriate screen for CRN.

[Expression changes of Ang-1, Ang-2, Tie-2 and VEGF in co-culturing of endothelial cells and astrocytes after irradiation by X-ray and their significances].

OBJECTIVE: To explore the possible relationship between angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), Tie-2 and vascular endothelial growth factor (VEGF) and radiation brain injury (RBI) and detect the expressions of VEGF, Ang-1, Ang-2 and Tie-2 in co-cultured endothelial cells and astrocytes after an irradiation of X-ray. METHODS: Murine brain microvascular endothelial cells bEnd.3 and astrocytes were co-cultured in a Transwell culture plate and then exposed to X-ray at various doses (5, 10, 20 and 30 Gy) and cultured for 24 hours. The group without radiation acted as a control. Western blot was used to detect the expressions of VEGF, Ang-1, Ang-2 and Tie-2. RESULTS: As compared with the control group, the expression of VEGF increased in 5, 10, 20 and 30 Gy dose groups [(1.71 ± 0.11), (2.03 ± 0.05), (2.20 ± 0.06), (2.19 ± 0.08) vs (1.26 ± 0.10), P < 0.05]; the expression of Ang-1 decreased in 5, 10, 20 and 30 Gy dose groups [(2.27 ± 0.07), (2.28 ± 0.06), (2.01 ± 0.05), (1.54 ± 0.08) vs (2.46 ± 0.04), P < 0.05]; the expression of Tie-2 decreased in 5, 10, 20 and 30 Gy dose groups [(2.40 ± 0.10), (2.47 ± 0.06), (1.05 ± 0.09), (1.00 ± 0.08)vs(4.80 ± 0.07), P < 0.05]; the expression of Ang-2 increased in 5 Gy and 10 Gy dose groups [(2.10 ± 0.07), (2.43 ± 0.08)vs (1.69 ± 0.05), P < 0.05] while decreased in 20 Gy and 30 Gy dose groups [(1.12 ± 0.10), (1.21 ± 0.04)vs(1.69 ± 0.05), P < 0.05]. CONCLUSION: X-ray could differentially affect the expressions of VEGF, Ang-1, Ang-2 and Tie-2 in co-cultured endothelial cells and astrocytes. And the differential expressions of VEGF, Ang-1, Ang-2 and Tie-2 may be related with microvascular injury in RBI.

Mitochondrial calcium uptake 3 mitigates cerebral amyloid angiopathy-related neuronal death and glial inflammation by reducing mitochondrial dysfunction.

Cerebral amyloid angiopathy (CAA) is characterized by the cerebrovascular amyloid-ß (Aß) accumulation, and always accompanied by Alzheimer's disease (AD). Mitochondrial dysfunction-associated cellular events including cell death, inflammation and oxidative stress are implicated in the progression of CAA. Unfortunately, the molecular mechanisms revealing CAA pathogenesis are still obscure, thus requiring further studies. Mitochondrial calcium uptake 3 (MICU3), a regulator of the mitochondrial Ca2+ uniporter (MCU), mediates various biological functions, but its expression and influence on CAA are largely unknown. In the present study, we found that MICU3 expression was gradually declined in cortex and hippocampus of Tg-SwDI transgenic mice. Using stereotaxic operation with AAV9 encoding MICU3, we showed that AAV-MICU3 improved the behavioral performances and cerebral blood flow (CBF) in Tg-SwDI mice, along with markedly reduced Aß deposition through mediating Aß metabolism process. Importantly, we found that AAV-MICU3 remarkably improved neuronal death and mitigated glial activation and neuroinflammation in cortex and hippocampus of Tg-SwDI mice. Furthermore, excessive oxidative stress, mitochondrial impairment and dysfunction, decreased ATP and mitochondrial DNA (mtDNA) were detected in Tg-SwDI mice, while being considerably ameliorated upon MICU3 over-expression. More importantly, our in vitro experiments suggested that MICU3-attenuated neuronal death, activation of glial cells and oxidative stress were completely abrogated upon PTEN induced putative kinase 1 (PINK1) knockdown, indicating that PINK1 was required for MICU3 to perform its protective effects against CAA. Mechanistic experiment confirmed an interaction between MICU3 and PINK1. Together, these findings demonstrated that MICU3-PINK1 axis may serve as a key target for CAA treatment mainly through improving mitochondrial dysfunction.

Fruquintinib/HMPL-013 ameliorates cognitive impairments and pathology in a mouse model of cerebral amyloid angiopathy (CAA).

Cerebral amyloid angiopathy (CAA) is characterized by the cerebrovascular amyloid-ß (Aß) accumulation, and always accompanied by Alzheimer's disease (AD). The mechanisms revealing CAA pathogenesis are still unclear, and it is challenging to develop an efficient therapeutic strategy for its treatment. Vascular endothelial growth factor (VEGF) and its receptors including VEGFR-1,-2,-3 activation are involved in Aß processing, and modulate numerous cellular events associated with central nervous system (CNS) diseases. In the present study, we attempted to explore the regulatory function of fruquintinib (also named as HMPL-013), a highly selective inhibitor of VEGFR-1,-2,-3 tyrosine kinases, on CAA progression in Tg-SwDI mice. Here, we found that HMPL-013-rich diet consumption for 12 months significantly improved the behavioral performances and cerebral blood flow (CBF) of Tg-SwDI mice compared with the vehicle group. Importantly, HMPL-013 administration considerably reduced Aß1-40 and Aß1-42 burden in cortex and hippocampus of Tg-SwDI mice through regulating Aß metabolism process. Congo red staining confirmed Aß deposition in vessel walls, reflecting CAA formation, which was, however, strongly ameliorated after HMPL-013 treatment. Neuron death, aberrant glial activation and pro-inflammatory response in brain tissues of Tg-SwDI mice were dramatically alleviated after HMPL-013 consumption. More studies showed that the protective effects of HMPL-013 against CAA might be partially attributed to its regulation on the expression of genes associated with blood vasculature. Intriguingly, VEGF and phosphorylated VEGFR-1,-2 protein expression levels were remarkably decreased by HMPL-013 in cortex and hippocampus of Tg-SwDI mice, which were validated in HMPL-013-treated brain vascular endothelial cells (BVECs) under hypoxia. Finally, we found that VEGF-induced human umbilical vein endothelial cells (HUVEC) proliferation and tube formation were strongly abolished upon HMPL-013 exposure. Collectively, all these findings demonstrated that oral administration of HMPL-013 had therapeutic potential against CAA by reducing Aß deposition, inflammation and neuron death via suppressing VEGF/VEGFR-1,-2 signaling.

Treatment of radiation-induced brain injury with bisdemethoxycurcumin.

Radiation therapy is considered the most effective non-surgical treatment for brain tumors. However, there are no available treatments for radiation-induced brain injury. Bisdemethoxycurcumin (BDMC) is a demethoxy derivative of curcumin that has anti-proliferative, anti-inflammatory, and anti-oxidant properties. To determine whether BDMC has the potential to treat radiation-induced brain injury, in this study, we established a rat model of radiation-induced brain injury by administering a single 30-Gy vertical dose of irradiation to the whole brain, followed by intraperitoneal injection of 500 µL of a 100 mg/kg BDMC solution every day for 5 successive weeks. Our results showed that BDMC increased the body weight of rats with radiation-induced brain injury, improved learning and memory, attenuated brain edema, inhibited astrocyte activation, and reduced oxidative stress. These findings suggest that BDMC protects against radiation-induced brain injury.

High-frequency repetitive transcranial magnetic stimulation protects against cerebral ischemia/reperfusion injury in rats: Involving the mitigation of ferroptosis and inflammation.

BACKGROUND AND AIM: Repetitive transcranial magnetic stimulation (rTMS) has been found to attenuate cerebral ischemia/reperfusion (I/R) injury. However, its effects and mechanism of action have not yet been clarified. It has been reported that cerebral I/R injury is closely associated not only with ferroptosis but also with inflammation. Hence, the current study aimed to investigate whether high-frequency rTMS attenuates middle cerebral artery occlusion (MCAO)-induced cerebral I/R injury and further to elucidate the mediatory role of ferroptosis and inflammation. METHODS: The protective effects of rTMS on experimental cerebral I/R injury were investigated using transient MCAO model rats. Neurological scores and pathological changes of cerebral ischemic cortex were assessed to evaluate the effects of rTMS on cerebral I/R injury. The involvement of ferroptosis and that of inflammation were examined to investigate the mechanism underlying the effects of rTMS. RESULTS: High-frequency rTMS remarkably rescued the MCAO-induced neurological deficits and morphological damage. rTMS treatment also increased the mRNA and protein expression of glutathione-dependent peroxidase 4, decreased the mRNA and protein levels of acyl-CoA synthetase long-chain family member 4 and transferrin receptor in the cortex. Moreover, rTMS administration reduced the cerebrospinal fluid IL-1ß, IL-6, and TNF-α concentrations. CONCLUSION: These findings implicated that high-frequency rTMS alleviates MCAO-induced cerebral I/R injury, and the underlying mechanism could involve the inhibition of ferroptosis and inflammation. Our study identifies rTMS as a promising therapeutic agent for the treatment of cerebral I/R injury. Moreover, the mechanistic insights into ferroptosis and inflammation advance our understanding of it as a potential therapeutic target for diseases beyond cerebral ischemia stroke.

Itaconate alleviates ß2-microglobulin-induced cognitive impairment by enhancing the hippocampal amino-ß-carboxymuconate-semialdehyde-decarboxylase/picolinic acid pathway.

ß2-microglobulin (B2M) has been established to impair cognitive function. However, no treatment is currently available for B2M-induced cognitive dysfunction. Itaconate is a tricarboxylic acid (TCA) cycle intermediate that exerts neuroprotective effects in several neurological diseases. The amino-ß-carboxymuconate-semialdehyde-decarboxylase (ACMSD)/picolinic acid (PIC) pathway is a crucial neuroprotective branch in the kynurenine pathway (KP). The present study sought to investigate whether Itaconate attenuates B2M-induced cognitive impairment and examine the mediatory role of the hippocampal ACMSD/PIC pathway. We demonstrated that 4-Octyl Itaconate (OI, an itaconate derivative) significantly alleviated B2M-induced cognitive dysfunction and hippocampal neurogenesis impairment. OI treatment also increased the expression of ACMSD, elevated the concentration of PIC, and decreased the level of 3-HAA in the hippocampus of B2M-exposed rats. Furthermore, inhibition of ACMSD by TES-991 significantly abolished the protections of Itaconate against B2M-induced cognitive impairment and neurogenesis deficits. Exogenous PIC supplementation in hippocampus also improved cognitive performance and hippocampal neurogenesis in B2M-exposed rats. These findings demonstrated that Itaconate alleviates B2M-induced cognitive impairment by upregulation of the hippocampal ACMSD/PIC pathway. This is the first study to document Itaconate as a promising therapeutic agent to ameliorate cognitive impairment. Moreover, the mechanistic insights into the ACMSD/PIC pathway improve our understanding of it as a potential therapeutic target for neurological diseases beyond B2M-associated neurocognitive disorders.

Artemisinin Facilitates Motor Function Recovery by Enhancing Motoneuronal Survival and Axonal Remyelination in Rats Following Brachial Plexus Root Avulsion.

Artemisinin (ART), a well-known antimalarial medicine originally isolated from the plant Artemisia annua, exerts neuroprotective effects in the nervous system owing to an antioxidant effect. Here, we determined whether ART is capable of inhibiting the oxidative stress to enhance motoneuronal (MN) survival to promote motor function recovery of rats following brachial plexus root avulsion (BPRA) with reimplantation surgery. Rats following BPRA and reimplantation were subcutaneously injected with 500 µL of PBS or 16 mg/mL ART once daily for 7 days after surgery. Terzis grooming test (TGT), histochemical staining, real-time polymerase chain reaction, and Western blot were conducted to determine the recovery of motor function of the upper limb, the survival rate of MNs, the oxidative stress levels in the ventral horn of the spinal cord, the morphology of abnormal musculocutaneous nerve fibers, the remyelination of axons in musculocutaneous nerves, and the degree of bicep atrophy. ART significantly increased TGT score, improved the survival of MNs, inhibited the oxidative stress, ameliorated the abnormal morphology of fibers in the musculocutaneous nerve, promoted the remyelination of axons, and alleviated muscle atrophy. Take together, ART can improve the survival of MNs and axonal remyelination to promote the motor function recovery via inhibiting oxidative stress, suggesting that ART may represent a new approach to the therapy of spinal root avulsion.

BDMC protects AD in vitro via AMPK and SIRT1.

BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disorder without any satisfactory therapeutic approaches. AD is mainly characterized by the deposition of ß-amyloid protein (Aß) and extensive neuronal cell death. Curcumin, with anti-oxidative stress (OS) and cell apoptosis properties, plays essential roles in AD. However, whether bisdemethoxycurcumin (BDMC), a derivative of curcumin, can exert a neuroprotective effect in AD remains to be elucidated. METHODS: In this study, SK-N-SH cells were used to establish an in vitro model to investigate the effects of BDMC on the Aß1-42-induced neurotoxicity. SK-N-SH cells were pretreated with BDMC and with or without compound C and EX527 for 30 min after co-incubation with rotenone for 24 h. Subsequently, western blotting, cell viability assay and SOD and GSH activity measurement were performed. RESULTS: BDMC increased the cell survival, anti-OS ability, AMPK phosphorylation levels and SIRT1 in SK-N-SH cells treated with Aß1-42. However, after treatment with compound C, an AMPK inhibitor, and EX527, an SIRT1inhibitor, the neuroprotective roles of BDMC on SK-N-SH cells treated with Aß1-42 were inhibited. CONCLUSION: These results suggest that BDMC exerts a neuroprotective role on SK-N-SH cells in vitro via AMPK/SIRT1 signaling, laying the foundation for the application of BDMC in the treatment of neurodegenerative diseases related to AMPK/SIRT1 signaling.

Ionizing radiation modulates vascular endothelial growth factor expression through STAT3 signaling pathway in rat neonatal primary astrocyte cultures.

BACKGROUND AND PURPOSE: Radiation-induced brain injury (RBI) usually occurs six months to three years after irradiation, often shows cognitive dysfunction, epilepsy, and other neurological dysfunction. In severe cases, it can cause a wide range of cerebral edema, even herniation. It seriously threatens the survival of patients and their quality of life, and it becomes a key factor in limiting the radiation dose and lowering the therapeutic efficacy in recent years. Therefore, studying the pathogenesis of RBI and exploring new therapeutic targets are of great significance. METHODS: In our study, we observed the activation and secretory function in astrocytes as well as the intracellular signal transducer and activator of transcription 3 (STAT3) signal transduction pathway activation status after exposing different doses of X-ray irradiation by using MTT, Immunocytologic analysis, and Western blot analysis. Further, we used the same way to explore the role of vascular endothelial growth factor (VEGF) in signal transduction pathways playing in the activation of astrocytes after irradiating through the use of specificInhivascular endothelial growth factorbitors of STAT3. RESULTS: Ast can be directly activated, reactive hyperplasia and hypertrophy, the expression of the activation marker glial fibrillary acidic protein is increased, and the expression of vascular endothelial growth factor (VEGF) in the cells is increased, which may lead to RBI. After the addition of STAT3 pathway inhibitor, most of the Ast radiation activation was suppressed, and the expression of high-level expression of VEGF decreased after irradiation. CONCLUSION: Our findings demonstrated that X-ray irradiation directly induced the activation of astrocytes in a persistent manner and X-ray irradiation activated STAT3 signaling pathway. As the same time, we found that X-ray irradiation induced the activation of astrocytes and secretion cytokine. The STAT3 signaling pathway may participate in the pathogenesis of radiation-induced brain injury.

Bisdemethoxycurcumin exerts a cell-protective effect via JAK2/STAT3 signaling in a rotenone-induced Parkinson's disease model in vitro.

INTRODUCTION: Oxidative stress and cell apoptosis have both been suggested to be closely associated with the pathogenesis of Parkinson's disease (PD). Previously, bisdemethoxycurcumin (BDMC) has been shown to exhibit several desirable characteristics as a candidate neuroprotective agent, including antioxidant and anti-inflammatory activities in the nervous system. However, whether BDMC can exert cell-protective roles in an in vitro model of PD remains unknown. MATERIAL AND METHODS: SH-SY5Y cells were pretreated with BDMC, with or without AG490 and SI-201, for 30 min, followed by a co-incubation with rotenone for 24 h. Subsequently, a cell viability assay and western blotting was performed, and SOD and GSH activities were analyzed. RESULTS: The results revealed that the pretreatment with BDMC enhanced the cell survival, antioxidative stress capacity and the phosphorylation levels of JAK/STAT3 in SH-SY5Y cells treated with rotenone. However, following the incubation with AG490 and SI-201, inhibitors of the JAK/STAT3 signaling pathway, BDMC was unable to exert cell-protective roles in SH-SY5Y cells treated with rotenone. CONCLUSIONS: In conclusion, the results suggested that BDMC may exert a cell-protective role in SH-SY5Y cells in vitro via JAK2/STAT3 signaling, thus suggesting the possible application of BDMC for the treatment of neurodegenerative diseases related to JAK2/STAT3 signaling.

Berberine enhances L1 expression and axonal remyelination in rats after brachial plexus root avulsion.

BACKGROUND AND PURPOSE: Enhanced remyelination of the regenerated axons results in functional re-innervation and improved functional motor recovery after brachial plexus root avulsion (BPRA). The neural cell adhesion molecule L1 (L1CAM, L1) regulates myelination and promotes regeneration after acute injury in the nervous system. Berberine (BBR) can exert neuroprotective roles against the lesion. Herein, we investigated whether berberine (BBR) can affect the expression of L1 and enhance the axonal remyelination in rats following BPRA. METHODS: The surgical procedures were performed to build the rat brachial plexus avulsion and re-implantation model, and then, the rats were treated with BBR. After the rehabilitation for 12 weeks, the musculocutaneous nerves were collected for quantitative real-time PCR, Western blot analysis, and histochemical and immunofluorescence staining. RESULTS: We observed that, BBR treatment ameliorated the abnormal musculocutaneous nerve fibers morphology, up-regulated the L1 expression, increased the myelination-related genes, decreased the differentiated-associated genes, and up-regulated the phosphorylation of ERK. CONCLUSION: These results suggest that BBR may enhance L1 expression and promote axonal remyelination after spinal root avulsion.

Bisdemethoxycurcumin inhibits oxidative stress and antagonizes Alzheimer's disease by up-regulating SIRT1.

INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disease. It can lead to progressive cognitive impairment, memory loss, and behavioral alterations. So far, the exact cellular and molecular mechanisms underlying this disorder remain unclear. And there are no effective treatments to prevent, halt, or reverse AD. In recent years, Chinese traditional medicine has become a new force in the treatment of AD, and the typical representatives of natural herbal ingredients are curcumin and its derivatives. Bisdemethoxycurcumin (BDMC), which is a classical derivative of curcumin, was found to have neuroprotective effects against a cell model of Alzheimer's disease (AD) in our previous studies. This study investigated the intrinsic mechanism of BDMC against AD in animal models. METHODS: In this study, BDMC was injected into the lateral ventricles of normal C57BL/6 mice, APP/PS mice, and APP/PS mice treated with EX527 (the inhibitor of SIRT1). Y maze and Morris water maze were used to test the learning and memory ability of mice. Nissl staining was used to observe the morphological changes of neurons. Immunofluorescence staining was used to detect Aß deposition in mice. The activities of GSH and SOD were determined to observe the levels of oxidative stress in mice. And Western blot analyses were used to detect content of SIRT1 in mice. RESULTS: In the APP/PS mice, after BDMC intervention, their cognitive function improved, oxidative stress adjusted, the number of neurons increased, Aß deposition decreased, and the level of SIRT1 expression increased. However, when SIRT1 is inhibited, BDMC on the improvement in the learning and memory ability and the improvement on oxidative stress in APP/PS1 mice were reversed. CONCLUSION: Our findings demonstrated that in the AD mice, BDMC has antagonistic effect on AD. And an intermediate step in the antagonism effect is caused by SIRT1 upregulation, which leading to decreased oxidative stress. Based on these, we concluded that BDMC injection into the lateral ventricle can act against AD by upregulating SIRT1 to antioxidative stress.

Corticosterone induces neurotoxicity in PC12 cells via disrupting autophagy flux mediated by AMPK/mTOR signaling.

AIMS: Our previous study indicated that chronic stress caused autophagy impairment and subsequent neuron apoptosis in hippocampus. However, the mechanism underlying the stress-induced damage to neurons is unclear. In present work, we investigated whether stress-level glucocorticoids (GCs) GCs promoted PC12 cell damage via AMPK/mTOR signaling-mediated autophagy. METHODS: Chronic stress-induced PC12 cell injury model was built by treatment with high level corticosterone (CORT). Cell injury was evaluated by flow cytometry assay and transmission electron microscopy observation. RESULTS: Autophagy flux was measured based on the changes in LC3-II and P62 protein expressions, and the color alteration of mCherry-GFP-LC3-II transfection. Our results showed that CORT not only increased cell injury and apoptosis, but also dysregulated AMPK/mTOR signaling-mediated autophagy flux, as indicated by the upregulated expression of LC3-II and P62 proteins, and the lowered ration of autolysosomes to autophagosomes. Mechanistically, our results demonstrated that autophagy activation by AMPK activator metformin or mTOR inhibitor rapamycin obviously promotes cell survival and autophagy flux, improved mitochondrial ultrastructure, and reduced expression of Cyt-C and caspase-3 in CORT-induced PC12 cells. CONCLUSION: These results indicate that high CORT triggers PC12 cell damage through disrupting AMPK/mTOR-mediated autophagy flux. Targeting this signaling may be a promising approach to protect against high CORT and chronic stress-induced neuronal impairment.

Effects of Diet Based on IgG Elimination Combined with Probiotics on Migraine Plus Irritable Bowel Syndrome.

Several research studies have revealed that migraine has a solid link with gastrointestinal diseases especially irritable bowel syndrome (IBS). This study was carried out to investigate therapeutic potential of diet based on IgG elimination combined with probiotics on migraine plus irritable bowel syndrome. A total of 60 patients diagnosed with migraine plus IBS were recruited for the study. IgG antibodies against 266 food varieties were detected by ELISA. Then, the subjects were randomized into three groups for treatment of IgG elimination diet or probiotics or diet combined with probiotics. Migraine symptom, gut function score, medication use, and serum serotonin level were measured at baseline, 7 weeks, and 14 weeks. Improvement of migraine and gut symptom was achieved at a certain time point. Reduced use of over-the-counter- (OTC-) analgesics was seen in all groups. However, use of triptans did not show significant difference. An increased serum serotonin level was seen in subjects treated with elimination diet and elimination diet combined with probiotics. IgG elimination diet combined with probiotics may be beneficial to migraine plus IBS. It may provide new insight by understanding the intricate relationship between migraine and gastrointestinal diseases.

Wake-up stroke and sleep-disordered breathing: a meta-analysis of current studies.

Sleep-disordered breathing (SDB) is a frequent comorbidity in patients with wake-up stroke (WUS). It affects the occurrence of this disease through its interference of breathing changes and sleep quality. We aim to assess the performances of sleep-disordered breathing in WUS. A systematical search for the studies that investigated sleep-disordered breathing in WUS was done in PubMed, Web of Science, and Cochrane Library. Data were extracted by two independent investigators, and then analyzed using the Revman 5.0 software. A total of five studies with 591 patients were included in the meta-analysis. The pooling data of sleep parameters showed that patients with WUS had a higher AHI and ODI than those with non-WUS (NWUS) [AHI: SMD: 0.58 (0.05, 1.10), P = 0.03; ODI: SMD: 0.63 (0.06, 1.21), P = 0.03). In addition, an increased incidence of severe SAS is found in WUS (OR: 3.18; 95% CI 1.27, 7.93; P = 0.01). However, no differences were found in AI, ESS, and the number of sleep apnea syndrome (SAS) between the two groups (P > 0.05). Therefore, WUS patients intended to have a severe SDB status, affecting the respiratory effects. Early prevention and attention should be paid on potential stroke sufferers with SAS, especially those with severe SAS.

Telomerase: a target for therapeutic effects of curcumin and a curcumin derivative in Aß1-42 insult in vitro.

This study was designed to investigate whether telomerase was involved in the neuroprotective effect of curcumin and Cur1. Alzheimer's disease is a consequence of an imbalance between the generation and clearance of amyloid-beta peptide in the brain. In this study, we used Aß1-42 (10 µg/ml) to establish a damaged cell model, and curcumin and Cur1 were used in treatment groups. We measured cell survival and cell growth, intracellular oxidative stress and hTERT expression. After RNA interference, the effects of curcumin and Cur1 on cells were verified. Exposure to Aß1-42 resulted in significant oxidative stress and cell toxicity, and the expression of hTERT was significantly decreased. Curcumin and Cur1 both protected SK-N-SH cells from Aß1-42 and up-regulated the expression of hTERT. Furthermore, Cur1 demonstrated stronger protective effects than curcumin. However, when telomerase was inhibited by TERT siRNA, the neuroprotection by curcumin and Cur1 were ceased. Our study indicated that the neuroprotective effects of curcumin and Cur1 depend on telomerase, and thus telomerase may be a target for therapeutic effects of curcumin and Cur1.

[Prevalence of asymptomatic intracranial artery stenosis in middle-aged and elderly population in the community of Foshan city, Guangdong province: a cross-sectional study].

OBJECTIVE: To investigate the prevalence and risk factors of asymptomatic intracranial artery stenosis in middle-aged and elderly population in the community of Foshan city, Guangdong province. METHODS: Subjects from residential communities were chosen through Cluster sampling method. Physical data and history were collected. Serum fasting glucose, total cholesterol and triglycerides concentrations were tested with venous blood samples. Intracranial artery stenosis was diagnosed by transcranial Doppler (TCD). Data was analyzed by the software SPSS 18.0. RESULTS: 1405 subjects met the inclusive criteria, among which 163 (11.6%) were found one (7.4%) or more (4.2%) stenotic arteries, and the standardized rate was 10.3%. 9.89% of the SICA, and 3.05%, 2.29%, 1.59%, 1.38%, 0.89% of basilar artery, middle cerebral artery, anterior cerebral artery, vertebral artery, posterior cerebral artery were found stenotic respectively. Data from the age-stratified analysis showed that the prevalence in these above 70 (27.8%) was significantly higher than that under age 70 (7.5%) (P = 0.000). Single factor and logistic regression analysis demonstrated the history of diabetes mellitus and elevated systolic pressure present were significantly different between stenotic group and the non-stenotic group (P = 0.000, P = 0.000), which were the independent risk factors of asymptomatic stenosis of intracranial arteries (OR = 2.362, 95%CI: 1.194 - 4.674;OR = 1.024, 95%CI: 1.016 - 1.031). CONCLUSION: Comparatively high prevalence of asymptomatic intracranial artery stenosis in middle-aged and aged community population was found in the Southern part of China, especially among the age group above 70. History of diabetes and elevated systolic pressure seemed to be the independent risk factors of asymptomatic stenosis of intracranial arteries.