Utilization of nitrogen, sulfur co-doped porous carbon micron spheres as bifunctional electrocatalysts for electrochemical detection of cadmium, lead and mercury ions and oxygen evolution reaction.

The development of high-performance bifunctional electrocatalysts for oxygen evolution reaction and heavy metal ion (HMI) detection is significant and challenging. Here, a novel nitrogen, sulfur co-doped porous carbon sphere bifunctional catalyst was designed and fabricated by hydrothermal followed by carbonization using starch as carbon source and thiourea as nitrogen, sulfur source for HMI detection and oxygen evolution reactions. Under the synergistic effect of pore structure, active sites and nitrogen, sulfur functional groups, C-S0.75-HT-C800 demonstrated excellent HMI detection performance and oxygen evolution reaction activity. Under optimized conditions, the detection limits (LODs) of C-S0.75-HT-C800 sensor were 3.90, 3.86 and 4.91 nM for Cd2+, Pb2+ and Hg2+ when detected individually; and the sensitivities were 13.12, 19.50 and 21.19 µA/µM. The sensor also obtained high recoveries of Cd2+, Hg2+ and Pb2+ in river water samples. During the oxygen evolution reaction, a Tafel slope of 70.1 mV/dec and a low overpotential of 277 mV were obtained for C-S0.75-HT-C800 electrocatalyst with a current density of 10 mA/cm2 in basic electrolyte. This research offers a neoteric and simple strategy in the design as well as fabrication of bifunctional carbon-based electrocatalysts.

Compound porcine cerebroside and ganglioside injection attenuates cerebral ischemia-reperfusion injury in rats by targeting multiple cellular processes.

BACKGROUND: Compound porcine cerebroside and ganglioside injection (CPCGI) is a neurotrophic drug used clinically to treat certain functional disorders of brain. Despite its extensive usage throughout China, the exact mechanistic targets of CPCGI are unknown. This study was carried out to investigate the protective effect of CPCGI against ischemic neuronal damage in rats with middle cerebral artery occlusion (MCAO) reperfusion injury and to investigate the neuroprotective mechanisms of CPCGI. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were subjected to MCAO surgery for 2 hours followed by reperfusion. The rats were administered CPCGI once a day for 14 days after reperfusion, and behavioral tests were performed 1, 3, 7, and 14 days post MCAO. Hematoxylin-eosin staining was used to measure infarct volume, and immunohistochemical analysis was performed to determine the number of NeuN-positive neurons in the ischemic cortex penumbra. Finally, the relative expression levels of proteins associated with apoptosis (Bcl-2, Bax, and GADD45α), synaptic function (Synaptophysin, SNAP25, Syntaxin, and Complexin-1/2), and mitochondrial function (KIFC2 and UCP3) were determined by Western blot. RESULTS: CPCGI treatment reduced infarct size, decreased neurological deficit scores, and accelerated the recovery of somatosensory function 14 days after MCAO. In addition, CPCGI reduced the loss of NeuN-positive cells in the ischemic cortex penumbra. In the ischemic cortex, CPCGI treatment decreased GADD45α expression, increased the Bcl-2/Bax ratio, augmented Synaptophysin, SNAP25, and Complexin-1/2 expression, and increased the expression of KIFC2 and UCP3 compared with sham rats 14 days after MCAO reperfusion injury. CONCLUSION: CPCGI displays neuroprotective properties in rats subjected to MCAO injury by inhibiting apoptosis and improving synaptic and mitochondrial function.

Effect of Chinese herbal compound Naofucong () on the inflammatory process induced by high glucose in BV-2 cells.

OBJECTIVE: To determine the effect of medicated serum of Chinese herbal compound Naofucong (, NFC) on the microglia BV-2 cells viability and the transcription and expression of interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) in microglia BV-2 cells to further explore the mechanisms underlying the protective effect of NFC on inflammatory process induced by high glucose. METHODS: The microglia BV-2 cells incubated in vitro were divided into different groups: the control group (25 mmol/L glucose), the model group (75 mmol/L glucose), high glucose media containing different dose medicated serum of NFC. After being cultured for 24 h, changes in IL-6 and TNF-α were measured by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. The expression of surface marker CD11b of activated microglia was measured by confocal laser scanning microscope and Western blot. Nuclear factor-κB (NF-κB) p-p65 expression was analyzed by Western blot. RESULTS: The model group obviously increased the expression of microglial surface marker CD11b and NF-κB p-p65 (all P<0.01), induced a signifificant up-regulation of release and the mRNA expression of IL-6 and TNF-α (P<0.01 or P<0.05). The medicated serum of NFC could obviously down-regulate the transcription and expression of surface marker CD11 b and NF-κB p-p65 (all P<0.01), and inhibit the mRNA and protein expression (P<0.01 or P<0.05) of inflflammatory cytokines, such as IL-6 and TNF-α, in microglia BV-2 cells cultured with high glucose for 24 h. CONCLUSIONS: The inhibition of microglial activation and IL-6 and TNF-α expression induced by high glucose may at least partly explain NFC therapeutic effects on diabetes-associated cognitive decline diseases. Its underlying mechanism could probably be related to the inhibition of NFC on NF-κB phosphorylation.

M2 Macrophage Transplantation Ameliorates Cognitive Dysfunction in Amyloid-ß-Treated Rats Through Regulation of Microglial Polarization.

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly population. Neuroinflammation induced by amyloid-ß (Aß) aggregation is considered to be the critical factor underlying AD pathological mechanisms. Alternatively activated (M2) macrophages/microglia have been reported to have neuroprotective effects in neurodegenerative disease. In this study, we characterized the neuroprotective effects of M2 macrophage transplantation in AD model rats and investigated the underlying mechanisms. Intracerebroventricular injection of Aß1 - 42 to rats was used to model AD and resulted in cognitive impairment, neuronal damage, and inflammatory changes in the brain microenvironment. We observed an increased interferon regulatory factor (IRF) 5/IRF4 ratio, resulting in greater production of classically activated (M1) versus M2 microglia. M2 macrophage transplantation attenuated inflammation in the brain, reversed Aß1 - 42-induced changes in the IRF4-IRF5 ratio, drove endogenous microglial polarization toward the M2 phenotype, and ameliorated cognitive impairment. Nerve growth factor (NGF) treatment reduced the IRF5/IRF4 ratio and induced primary microglial polarization to the M2 phenotype in vitro; these effects were prevented by tyrosine Kinase Receptor A (TrkA) inhibition. M2 macrophage transplantation restored the balance of IRF4-IRF5 by affecting the expression of NGF and inflammatory cytokines in the brains of AD model rats. This drove microglial polarization to the M2 phenotype, promoted termination of neuroinflammation, and resulted in improved cognitive abilities.

MicroRNA-31 inhibits lung adenocarcinoma stem-like cells via down-regulation of MET-PI3K-Akt signaling pathway.

Accumulated evidences suggested that microRNAs (miRs) play an important role in non-small cell lung cancer (NSCLC). However, how miRs perform their functions in lung adenocarcinoma cancer stem cells (CSCs) remains unknown. Notably, most studies pay more attention to the effects of miRNAs on the metastasis traits whereas the growth activities of CSCs are rather undervalued. In our report, using A549CD133+cells, we examined the inhibitory effects and the underlying mechanisms of microRNA-31 (miR-31) on the growth of lung adenocarcinoma CSC-like cells. Initially, we determined the level of miR-31 in A549 and A549CD133+ cells. Over-expression of miR-31 was found in A549CD133+ cells by microarray and real-time quantitative PCR (RTqPCR) assays. Experiments in multiple NSCLC cell lines in vitro and A549CD133+ cells xenograft models in vivo confirmed that down regulation of miR-31 resulted in increase of A549CD133+ cells growth, whereas overexpression of miR-31 led to the inhibition of adenocarcinoma cell proliferation. Also, MET proto-oncogene has been determined to be a direct target of miR-31 by dual luciferase report, RT-qPCR and western blot analysis. Down regulation of MET inhibited viability of A549CD133+ cells. The levels of PI3Kinase, Akt and p-Akt as well as downstream proteins were consequently decreased. These results suggest that miR-31 might inhibit the growth of lung adenocarcinoma cancer stem-like cells via down regulation of the MET-PI3K-Akt signaling pathway.

Enhanced in vivo antitumor efficacy of dual-functional peptide-modified docetaxel nanoparticles through tumor targeting and Hsp90 inhibition.

Although conventional anticancer drugs exhibit excellent efficacy, serious adverse effects and/or even toxicity have occurred due to their nonselectivity. Moreover, active targeting approaches have not consistently led to successful outcomes. Ligands that simultaneously possess targeting capability and exert a strong influence on intracellular signaling cascades may be expected to improve the therapeutic efficacy of active targeting nanoparticulate carriers. In this study, we screened a targeting peptide, LPLTPLP, which specifically bound to non-small cell lung cancer (NSCLC) specimens in vitro. Surprisingly, this peptide inhibited the expression of Hsp90 and induced apoptosis by preventing autophagy in A549 cells treated with docetaxel. The results suggested that this peptide might be used as a promising dual-functional ligand for cancer treatment. Based on these findings, we designed and developed a novel active targeting delivery system by modifying docetaxel nanoparticles (DNP) with the dual-functional ligand LPLTPLP. We consistently demonstrated that the cellular uptake of nanoparticles (NPs) was significantly enhanced in vitro. Furthermore, the targeting NPs exhibited significantly improved antitumor efficacy and biodistribution compared with nontargeting nanodrug and free docetaxel. These findings demonstrate the feasibility of dual-functional NPs for efficient anticancer therapy.

Neuroprotective effects of Aceglutamide on motor function in a rat model of cerebral ischemia and reperfusion.

PURPOSE: To investigate the effect and underlying mechanism of Aceglutamide on motor dysfunction in rats after cerebral ischemia-reperfusion. METHODS: Adult male Sprague-Dawley rats were subjected to 2 h transient middle cerebral artery occlusion (MCAO). Aceglutamide or vehicle was intraperitoneally given to rats at 24 h after reperfusion and lasted for 14 days. Subsequently functional recovery was assessed and number of tyrosine hydroxylase (TH)-positive neurons in substantia nigra (SN) was analyzed. Tumor necrosis factor receptor-associated factor 1(TRAF1), P-Akt and Bcl-2/Bax were determined in mesencephalic tissue by Western blot method. PC12 cells and primary cultured mesencephalic neurons were employed to further investigate the mechanism of Aceglutamide. RESULTS: Aceglutamide treatment improved behavioral functions, reduced the infarction volume, and elevated the number of TH-positive neurons in the SN. Moreover, Aceglutamide significantly attenuated neuronal apoptosis in the SN. Meanwhile Aceglutamide treatment significantly inhibited the expression of TRAF1 and up-regulated the expression of P-Akt and Bcl-2/Bax ratio both in vitro and in vivo. CONCLUSIONS: Aceglutamide ameliorated motor dysfunction and delayed neuronal death in the SN after ischemia, which involved the inhibition of pro-apoptotic factor TRAF1 and activation of Akt/Bcl-2 signaling pathway. These data provided experimental information for applying Aceglutamide to ischemic stroke treatment.

Targeting docetaxel-PLA nanoparticles simultaneously inhibit tumor growth and liver metastases of small cell lung cancer.

Small cell lung cancer (SCLC) is one of the most malignant cancers in the world and 5-year survival rate has not been significantly improved with conventional chemotherapy. Targeting treatment may be a promising alternative to enhance the antitumor efficacy. Present study was aimed at establishing a targeting nanodrug delivery system for SCLC therapy. A targeting peptide (AHSGMYP, named AP), screened in H446 cells by phage display technology, was conjugated to the docetaxel (DTX) encapsulated polylactic acid nanoparticles (DN) to prepare the targeting DTX nanoparticles (AP-DN). Cell cytotoxicity, cellular uptake, therapeutic efficacy and biodistribution of AP-DN were investigated in vitro and in vivo experiment. The mean particle size of AP-DN was 260 nm with encapsulation efficiency >94% and a sustained release profile. Cytotoxicity of AP-DN against H446 cell was superior to that of DTX and DN. AP-DN exhibited excellent antitumor efficacy and particularly effectively inhibited the liver metastases with better tolerance. Results of cellular uptake and biodistribution indicated that the excellent antitumor efficacy of AP-DN was attributed to both the increased accumulation of drug and cellular uptake. To our knowledge, this is the first report on establishing SCLC targeting delivery system which offers a potential therapeutic alterative for SCLC therapy.

Antagomir-1290 suppresses CD133⁺ cells in non-small cell lung cancer by targeting fyn-related Src family tyrosine kinase.

Cancer stem-like cells (CSLCs) are involved in cancer initiation, development, and metastasis, and microRNAs (miRNAs) play pivotal roles in regulating CSLCs. miRNA-based therapeutic strategy associated with CSLCs might promise potential new therapeutic approaches. In the present study, we found that miR-1290 was increased in CD133(+) cells. Antagomir-1290 significantly suppressed tumor volume and weight initiated by CD133(+) cells in vivo. Furthermore, antagomir-1290 significantly inhibited the proliferation, clonogenicity, invasion, and migration of CD133(+) cells by targeting fyn-related Src family tyrosine kinase. These findings provide insights into the clinical prospect of miR-1290-based therapies for non-small cell lung cancer.

Neuroprotective effects of 5-(4-hydroxy-3-dimethoxybenzylidene)-thiazolidinone in MPTP induced Parkinsonism model in mice.

Parkinson's disease (PD) is a neurological disorder characterized by degeneration of nigrostriatal dopaminergic (DAergic) system. Present treatment targeting to DAergic system solely ameliorated the symptoms but failed to retard the DAergic neuron degeneration, therefore new therapeutic methods aiming at preventing or delaying the neurodegenerative process are urgently needed. In the present study, we found that 5-(4-hydroxy-3-dimethoxybenzylidene)-2-thioxo-4-thiazolidinone (RD-1), a compound derived from rhodanine, protected DAergicneurons from neurotoxicity of MPTP/MPP(+). Firstly, RD-1 significantly improved the locomotor ability in the MPTP mice model, and elevated the tyrosine hydroxylase (TH) positive cell numbers in substantianigra pars compacta (SNpc) and the integrated optical density (IOD) of TH-positive nerve fibers in striatum respectively. Since mitochondrial dysfunction plays an important role in pathogenesis of PD, thereby we investigated the molecular mechanisms of RD-1 against MPTP/MPP(+) neurotoxicity, focusing on its effects on the mitochondrial dysfunction. Immunoblotting analysis showed that RD-1 significantly elevated the Parkin and Miro2 expression levels in acute MPTP treated mice, and improved mitochondrial membrane potential and ATP synthesis in MPP(+)-treated Neuro-2a cells. Moreover, RD-1attenuated impaired mitochondrial transport and vesicle release dysfunction evoked by MPP(+) cytotoxicity in cultured primary mesencephalic neurons. Taken together, these results indicate that improving the mitochondrial dysfunction may be a good choice to delay the neurodegenerative progression commonly associated with PD.

Active targeting docetaxel-PLA nanoparticles eradicate circulating lung cancer stem-like cells and inhibit liver metastasis.

Lung cancer is the major cause of cancer related lethality worldwide, and metastasis to distant organs is the pivotal cause of death for the vast majority of lung cancer patients. Accumulated evidence indicates that lung cancer stem-like cells (CSLCs) play important roles in metastagenesis, and these circulating CSLCs may be important targets to inhibit the subsequent metastasis. The present study was aimed at establishing CSLC-targeting polylactic acid (PLA) encapsulated docetaxel nanoparticles for antimetastatic therapy. Cyclic binding peptides were screened on CSLCs in vitro and the peptide CVKTPAQSC exhibiting high specific binding ability to pulmonary adenocarcinoma tissue was subsequently conjugated to the nanoparticles loaded with docetaxel (NDTX). Antimetastatic effect of CSLC-targeting nanoparticles loaded with docetaxel (TNDTX) was evaluated in a nude mouse model of liver metastasis. Results showed that, in the absence of targeting peptide, NDTX hardly exhibited any antimetastatic effect. However, TNDTX treatment significantly decreased the metastatic tumor area in the nude mouse liver. Histopathological and serological results also confirmed the antimetastatic efficacy of TNDTX. To our knowledge, this is the first report on establishing a CSLC-based strategy for lung cancer metastatic treatment, and we hope this will offer a potential therapeutic approach for management of metastatic lung cancer.

Phytoestrogen α-zearalanol ameliorates memory impairment and neuronal DNA oxidation in ovariectomized mice.

OBJECTIVE: The aim of this study was to evaluate the effect of a novel phytoestrogen, α-Zearalanol, on Alzheimer's disease-related memory impairment and neuronal oxidation in ovariectomized mice. METHODS: Female C57/BL6 mice were ovariectomized or received sham operations and treatment with equivalent doses of 17ß-estradiol or α-Zearalanol for 8 weeks. Their spatial learning and memory were analyzed using the Morris water maze test. The antioxidant enzyme activities and reactive oxygen species generation, neuronal DNA oxidation, and MutT homolog 1 expression in the hippocampus were measured. RESULTS: Treatment with 17ß-estradiol or α-Zearalanol significantly improved spatial learning and memory performance in ovariectomized mice. In addition, 17ß-estradiol and α-Zearalanol attenuated the decrease in antioxidant enzyme activities and increased reactive oxygen species production in ovariectomized mice. The findings indicated a significant elevation in hippocampi neuronal DNA oxidation and reduction in MutT homolog 1 expression in estrogen-deficient mice, but supplementation with 17ß-estradiol or α-Zearalanol efficaciously ameliorated this situation. CONCLUSION: These results demonstrate that α-Zearalanol is potentially beneficial for improving memory impairments and neuronal oxidation damage in a manner similar to that of 17ß-estradiol. Therefore, the compound may be a potential therapeutic agent that can ameliorate neurodegenerative disorders related to estrogen deficiency.

Phytoestrogen -zearalanol ameliorates memory impairment and neuronal DNA oxidation in ovariectomized mice

OBJECTIVE: The aim of this study was to evaluate the effect of a novel phytoestrogen, α-Zearalanol, on Alzheimer's disease-related memory impairment and neuronal oxidation in ovariectomized mice. METHODS: Female C57/BL6 mice were ovariectomized or received sham operations and treatment with equivalent doses of 17β-estradiol or α-Zearalanol for 8 weeks. Their spatial learning and memory were analyzed using the Morris water maze test. The antioxidant enzyme activities and reactive oxygen species generation, neuronal DNA oxidation, and MutT homolog 1 expression in the hippocampus were measured. RESULTS: Treatment with 17β-estradiol or α-Zearalanol significantly improved spatial learning and memory performance in ovariectomized mice. In addition, 17β-estradiol and α-Zearalanol attenuated the decrease in antioxidant enzyme activities and increased reactive oxygen species production in ovariectomized mice. The findings indicated a significant elevation in hippocampi neuronal DNA oxidation and reduction in MutT homolog 1 expression in estrogen-deficient mice, but supplementation with 17β-estradiol or α-Zearalanol efficaciously ameliorated this situation. CONCLUSION: These results demonstrate that α-Zearalanol is potentially beneficial for improving memory impairments and neuronal oxidation damage in a manner similar to that of 17β-estradiol. Therefore, the compound may be a potential therapeutic agent that can ameliorate neurodegenerative disorders related to estrogen deficiency. .

Propofol may protect PC12 cells from ß-amyloid25₋35 induced apoptosis through the GSK-3ß signaling pathway.

BACKGROUND: There are two major pathological hallmarks of Alzheimer's disease. One is the progressive accumulation of beta-amyloid (Aß) in the form of senile plaques; the other is hyperphosphorylated tau, causing neuronal apoptosis. Some inhalation anesthetics, such as isoflurane and desflurane, have been suggested to induce Aß accumulation and cause AD-like neuropathogenesis. Whether intravenous anesthetics have similar effects is still unclear. We therefore set out to determine the relationship between propofol and AD-like pathogenesis. METHODS: PC12 cells were cultured in serum-free medium for 12 hours prior to drug treatment. Various concentrations from 5 µmol/L to 80 µmol/L of aggregated Aß25-35 were added to determine a proper concentration for further study. After exposure to 10 µmol/L Aß25-35 alone or with 20 µmol/L propofol for 6 hours, PC12 cell viability was determined by MTT assay. Western blotting and immunocytochemical staining were performed to observe the protein expression of the Bcl-2 family, tau phosphorylation at different sites, and tau protein kinases and phosphatases. RESULTS: Aß25-35 induced a decrease in PC12 cell viability in a dose-dependent manner. Exposure to 10 µmol/L Aß25-35 for 6 hours resulted in the mild cell survival, accompanied by a decline in Bcl-2, and an increase in phosphorylation of GSK-3ß and tau at different sites. Compared with the Aß25-35 group, cells treated with propofol alone showed no significant difference, while cells co-incubated with propofol and Aß25-35 showed a significantly higher survival rate (P < 0.01 or P < 0.05). Tau phosphorylation at Ser396, Ser404 and Thr231 and the level of GSK-3ß in PC12 cells increased after exposure to 10 µmol/L Aß25-35. Co-incubation with propofol attenuated cellular apoptosis by inhibiting tau phosphorylation. CONCLUSIONS: These data indicate that propofol may protect PC12 cells from Aß25-35-induced apoptosis and tau hyperphosphorylation through the GSK-3ß pathway, therefore it may be a safer anesthesia for AD and elderly patients.

Involvement of heat shock protein 70 in the DNA protective effect from estrogen.

As an endogenous cytoprotective factor, the protection of estrogen and heat shock protein-70 (Hsp70) on DNA has been documented, respectively, but the functional interaction between estrogen and Hsp70 on DNA damage repair is largely unknown. We therefore investigated the relation between estrogen and Hsp70 in terms of DNA protection in in vitro. The findings showed a significant reduction in cell survival and elevation in oxidative stress while cells were exposed to amyloid ß (Aß25-35) peptide, but preincubation of the cells with 17ß-estradiol (17ß-E2) ameliorated this situation. In addition, 17ß-E2 alleviated oxidized DNA damage induced by Aß and elevated the expression of Hsp70. However, the beneficial properties of 17ß-E2 on reducing DNA damage were attenuated when Hsp70 gene was silenced accordingly. These results indicate that Hsp70 plays a role in DNA protection mediated by estrogen, and the DNA protection may be involved in Alzheimer's disease preventive effect from estrogen.

Aggravation effect of isoflurane on Aß(25-35)-induced apoptosis and tau hyperphosphorylation in PC12 cells.

Some anesthetics have been suggested to induce Alzheimer's disease (AD) neuro-pathogenesis. Increasing evidence indicates that hyperphosphorylated tau plays a key role in the pathogenic events that occur in AD. Isoflurane has been shown to induce apoptosis, which leads to accumulation of amyloid-ß (Aß). We set out to investigate whether isoflurane can induce apoptosis by increasing hyperphosphorylated tau in Aß25-35-induced cells and the underlying mechanism. Cultured rat pheochromocytoma cells (PC12) were exposed to 20 mM Aß25-35 alone or with 2% isoflurane for 6 h. The cell viability was determined by MTT assay, and the apoptosis rate was detected by flowcytometry. Western blotting and immunocytochemical staining were performed to observe the protein expression of Bcl-2 family, tau phosphorylation of different sites, tau protein kinases and phosphatases. Additionally, lithium chloride was administered to all above groups to investigate the changes of apoptosis rate and protein expression. The apoptosis rate was significantly increased in Aß25-35 group compared with the others groups, which was accompanied by bcl-2 decline, and the phosphorylation of glycogen synthase kinase-3ß (GSK-3ß) and tau of two sites increased. LiCl attenuated the cellular apoptosis by inhibition the level of tau phosphorylation. Isoflurane upregulated the level of phosphorylated GSK-3ß, which phosphorylate tau at different sites, and aggravated the apoptotic rate of the Aß25-35-induced PC12 cells. It indicated that isoflurane-induced tau phosphorylation might play a role in the AD-like development.

The neuroprotective effects of phytoestrogen α-zearalanol on ß-amyloid-induced toxicity in differentiated PC-12 cells.

Although favorable effects of estrogen replacement therapy on Alzheimer's disease on postmenopausal women have been recognized, an associated increased incidence of uterine and breast tumors has jeopardized the clinical use of estrogen. Phytoestrogen α-zearalanol (α-ZAL) is a reductive product of the Gibberella zeae metabolite and abundant in plants and vegetables, which has been shown to protect cell injury with low side-effects on uterine and breast. This study was designed to evaluate the neuroprotective effects of α-ZAL, on the cultured differentiated PC-12 cells, while 17ß-estradiol (17ß-E2) has been used as an estrogen positive control. Following a 24 h exposure of the cells to amyloid ß-peptide fragment 25-35 (Aß25₋35), a significant reduction in cell survival and activities of total superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), as well as increased of malondialdehyde (MDA) were observed. However, preincubation of the cells with α-ZAL or 17ß-E2 prior to Aß25₋35 exposure elevated the cell survival and SOD and GSH-Px activities, and decreased the level of MDA. In addition, Aß25₋35 caused a significant cell apoptosis and increased apoptotic rate, accompanied by decreasing of bcl-2 expression and increasing bax, caspase-3 expression, pretreatment of the cells with α-ZAL or 17ß-E2 ameliorated these changes induced by Aß25₋35. Taken together, these data indicated that the phytoestrogen α-ZAL may effectively antagonize Aß25₋35-induced cell toxicity by attenuating oxidative stress and apoptotic cell death, in a manner similar to 17ß-E2. Our results suggested that α-ZAL can be used as a potential substitute of 17ß-E2 in postmenopausal women for Alzheimer's disease prevention.

Analgesic effect of gabapentin in a rat model for chronic constrictive injury.

BACKGROUND: Gabapentin has been widely and successfully used in the clinic for many neuropathic pain syndromes since last decade, however its analgesic mechanisms are still elusive. Our study was to investigate whether Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) contributes to the analgesic effect of gabapentin on a chronic constriction injury (CCI) model. METHODS: Gabapentin (2%, 100 mg/kg) or saline (0.5 ml/100 g) was injected intraperitoneally 15 minutes prior to surgery and then every 12 hours from postoperative day 0 - 4 to all rats in control, sham and CCI groups. The analgesic effect of gabapentin was assessed by measuring mechanical allodynia and thermal hyperalgesia of rats. Expression and activation of CaMKII were quantified by reverse-transcriptional polymerase chain reaction and Western blotting. RESULTS: The analgesic effect of gabapentin on mechanical allodynia and thermal hyperalgesia was significant in the CCI model, with maximal reduction reached on postoperative day 8. Gabapentin decreased the expression of the total CaMKII and phosphorylated CaMKII in CCI rats. CONCLUSION: The analgesic effect of gabapentin on CCI rats may be related to the decreased expression and phosphorylation of CaMKII in the spinal cord.

Protective effects of octacosanol on 6-hydroxydopamine-induced Parkinsonism in rats via regulation of ProNGF and NGF signaling.

AIM: To investigate the protective effects of octacosanol in 6-hydroxydopamine-induced Parkinsonian rats and find whether octacosanol has effects on pro nerve growth factor (pro-NGF), NGF and the downstream effector proteins. METHODS: Behavioral tests, enzymatic assay, tyrosine hydroxylase immunohistochemistry, TUNEL and Western blot were used to investigate the effects of octacosanol in this rat model of PD. RESULTS: Oral administration of octacosanol (35-70 mg/kg, po for 14 d) significantly improved the behavioral impairments in rats induced by 6-OHDA and dose-dependently preserved the free radical scavenging capability of the striatum. Octacosanol treatment also effectively ameliorated morphological appearances of TH-positive neuronal cells in nigrostriatal systems and decreased the apoptotic cells induced by 6-OHDA in striatum. In addition, octacosanol strikingly blocked the 6-OHDA-induced increased expression of proNGF-p75NTR-sortilin death signaling complex and its downstream effector proteins. Meantime, octacosanol prevented the decreased levels of NGF, its receptors TrkA and p-Akt which together mediated the cell survival pathway. CONCLUSION: The findings implicated that the anti-parkinsonism effects afforded by octacosanol might be mediated by its neuro-microenvironment improving potency through retrieving the ratios of proNGF:NGF and the respective receptors p75NTR:TrkA in vivo. Due to its excellent tolerability and non-toxicity, octacosanol may be a promising agent for PD treatment.

Effects of hormone replacement therapy on magnetic resonance imaging of brain parenchyma hyperintensities in postmenopausal women.

AIM: To apply 3.0 magnetic resonance imaging (MRI) to study the effects of long-term, low dose hormone replacement therapy (HRT) on the brain parenchyma of postmenopausal women. METHODS: A total of 155 postmenopausal healthy female medical staff members from Peking Union Medical College Hospital were enrolled. The HRT group was composed of 71 subjects who had been given a low dose of HRT for over 4 years, while 84 women who had never been given HRT were enrolled in the control group. The Mini-Mental State Examination (MMSE) was used to evaluate mental state, and an Enzyme-Linked ImmunoSorbent Assay (ELISA) was used to detect plasma levels of sex hormones. In addition, all participants were subjected to an MRI, including axial T2 weighted imaging (T2WI), fluid-attenuated inversion recovery (FLAIR), T1 weighted imaging (T1WI, oblique coronal, vertical to the hippocampus, slice thickness 3 mm without gaps), and a 3D image of the whole brain. RESULTS: The ELISA showed that the plasma level of estradiol in the HRT group was significantly higher than that in the control group (P<0.05). No differences were observed in the MMSE between the two groups. In participants older than 70 years of age, the number of deep white matter hyperintensities (DWMHs) in the control group was significantly higher than that in the HRT group (P=0.0013); however, in other age subgroups, no statistical differences were observed. Finally, no significant difference in periventricular hyperintensity (PVH) between the two groups was observed. CONCLUSION: We found that a high plasma level of estradiol in postmenopausal women receiving long-term HRT was correlated with the survival of brain parenchyma.Acta Pharmacologica Sinica (2009) 30: 1065-1070; doi: 10.1038/aps.2009.81.