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A new gold(i) self-relay catalysis consisting of a 3,3-rearrangement, Nazarov cyclization and Michael addition cascade of 1,3-enyne acetates with aurones and their derived azadienes is reported, producing functionalized cyclopentenones.

Edaravone (Eda) is a free radical scavenger used in clinical trials for the treatment of ischemic stroke and amyotrophic lateral sclerosis. However, how Eda exerts its neuroprotective effects remains to be elucidated. We investigated the neuroprotective effects of Eda in cultured hippocampal neurons and in a mouse model of AlCl3/D-galactose-induced cognitive impairment. Eda protected hippocampal neurons by eliminating H2O2 or glutamate-induced toxicity, leading to decreased cell viability and neurite shortening. Consistently, Eda restored impaired levels of BDNF, FGF2 and their associated signaling axes (including TrkB, p-Akt and Bcl-2) to attenuate neuronal death. In a mouse model of chemically-induced cognitive impairment, Eda restored the levels of BDNF, FGF2 and TrkB/Akt signaling axis to attenuate neuronal apoptosis, thereby ameliorating cognitive impairment. Meanwhile, the pro-inflammation was eliminated due to the restoration of pro-inflammatory factors such as TNF-α, IL-6, IL-1β, and NOS2. In summary, Eda is an effective drug for protecting neurons from neurotoxic injury. BDNF, FGF2, and their regulated pathways may be potential therapeutic targets for neuroprotection.

A new photocatalytic three-component annulation of 2-alkynylaryldiazonium tetrafluoroborates with γ-hydroxyl terminal alkynes and sodium metabisulfite is reported using fac-Ir(ppy)3 as the photocatalyst for the first time and used to produce a series of (Z)-thiochromene 1,1-dioxides bearing an exocyclic double bond with moderate to good yields in a highly stereoselective manner. A wide variety of easily available substrates with substituent diversity could successfully participate in this photocatalysis with good functional group tolerance.

New tunable catalytic [2+2] cycloaddition/silane-mediated conjugate transfer reductions of yne-allenones have been developed, by which substituent-diverse cyclobutarenes with generally good yields were selectively synthesized by adjusting Fe-H and Cu-H catalytic systems. Use of the Fe-H system triggers 1,6-conjugate reduction to dihydrocyclobuta[a]naphthalen-4-ols whereas the Cu-H complex enables 1,4-conjugate reduction to cyclobuta[a]naphthalen-4(2H)-ones.

2,3,5,4'-Tetrahydroxystilbene-2-O-β-d-glucoside (THSG) is the major active ingredient in Plygonum multiflorum that displays a great deal of health-benefits including anti-oxidation, anti-hyperlipidemia, anti-cancer, anti-inflammation and neuroprotection. However, it is unclear whether THSG exerts neuroprotective functions by regulating neurotrophic factors and their associated signaling pathways. In this study, hippocampal neurons were challenged with staurosporine (STS) to establish a neural damage model. We found that STS-induced cytotoxicity introduced significant morphological collapse and initiating cell apoptosis, along with the down regulation of BDNF and TrkB/Akt signaling axis. In contrast, neurons pretreated with THSG showed resistance to STS-induced toxicity and maintained cell survival. THSG rescued STS induced dysfunctions of BDNF and its associated TrkB/Akt signaling, and restored the expression of Bcl-2 and Caspase-3. However, inhibition of TrkB activity by K252a or Akt signaling by LY294002 abolished the neuroprotective effects of THSG. Therefore, BDNF and TrkB/Akt signaling axis is a promise target for THSG mediated neuroprotective functions.

Ginsenoside Rg1 is the main active ingredient of Panax ginseng with the activity of neuroprotective, antioxidant and strengthening the immune system. Therefore, we hypothesized that Rg1 may afford anti-aging effects although the mechanism remains to be elucidated. In this study, chemically induced aging mice were established by consecutive administration of D-galactose and AlCl3. We found that Rg1 effectively ameliorates spatial learning and memory deficits in aging mice demonstrated by their improved performance in step down avoidance tests and Morris water maze experiments. Rg1 restored aging-induced decline of FGF2 and BDNF, reactivated TrkB/Akt signaling pathways in the hippocampus and prefrontal cortex to inhibit apoptosis, for the expression of anti-apoptotic protein Bcl-2 and apoptosis promoting enzyme cleaved-Caspase3 were antagonistically restored. Therefore, these results established the anti-aging effects of Rg1, and FGF2, BDNF and associated signaling pathways might be promising targets. Our data may provide a new avenue to the pharmacological research and diet therapeutic role of ethnic products such as Rg1 in anti-aging and aging associated diseases.

Astrocytes are the major glia cells in the central nervous system (CNS). Increasing evidence indicates that more than to be safe-guard and supporting cells for neurons, astrocytes play a broad spectrum of neuroprotective and pathological functions. Thus, they are compelling models to decipher mechanistic insights of glia cells to CNS insults and for the development of drugs. Edaravone is a free radical scavenger with the capacity to eliminate hydroxyl radicals and lipid peroxides. In this study, we examined the neuroprotective effects of edaravone in rat astrocytes challenged by hydrogen peroxide (H2O2) or bacterial lipopolysaccharides (LPS), respectively. We discovered that edaravone attenuated H2O2-induced oxidative stress by reactivating the Akt signaling axis and antagonistically restoring the expression of apoptosis associated regulators such as Bcl-2 and Caspase-3. Consistently, inhibition of Akt signaling by LY294002 attenuated the anti-oxidative activity of edaravone. In addition, edaravone mitigated LPS-induced morphological changes in astrocytes and alleviated the inflammatory activation and expression of TNF-α, IL-1β, IL-6 and NOS2. In summary, our data suggested that edavarone effectively protects astrocytes from oxidative stress or infectious insults, which may pave a new avenue for its application in preclinical research and human disease therapeutics.

An effective chiral GAP methodology for preparing α-aminomethyl enaminones through a (R)-CSA-catalyzed asymmetric aza-Baylis-Hillman reaction is reported. Excellent yields and high diastereoselectivity could be obtained under mild conditions and convenient GAP techniques. The confirmations of the absolute configuration of N-phosphonyl imine and chiral enaminone by X-ray diffraction provides an explicit explanation of the chirality mechanism for GAP chemistry.

We previously demonstrated the antioxidant activity of Coeloglossum viride var. bracteatum extract (CE) in rat cortical neurons and in mice with chemically induced cognitive impairment. In this work, we established a staurosporine (STS)-induced toxicity model to decipher the neuroprotective mechanisms of CE. We found that CE protected cell viability and neurite integrity in STS-induced toxicity by restoring the levels of FGF2 and its associated PI3K/Akt signaling axis. LY294002, a pan-inhibitor of PI3K, antagonized the activity of CE, although its-mediated restoration of FGF2 was unaffected. In addition, CE restored levels of Bcl-2/Caspase-3, PKCα/CaM pathway, and Dnmt3a and Dnmt3b, two methyltransferases that contribute to de novo DNA methylation. The Dnmts inhibitor 5-azacytidine impaired CE-mediated restoration of Dnmt3 or CaM, as well as the transition of DNA methylation status on the Dnmt3 promoter. These results reveal potential mechanisms that could facilitate the study and application of CE as a neuroprotective agent., CE; Dnmt3a; Dnmt3b; FGF2; PI3K/Akt; Staurosporine

OBJECTIVE Gisenoside Rg1 is a potent neuroprotectant in ginseng. The aim of this study was to investigate the elimination effect of Rg1 on cadmium (Cd)-induced neurotoxicity. MATERIALS AND METHODS A cumulative Cd exposure mouse model was established. Also, the toxicity of Cd and the protective effect of Rg1 were examined in vitro using cultured neurons and microglia. RESULTS We found that Cd-intoxicated mice exhibited significant injury in the liver, kidney, small intestine, and testis, along with cognitive impairment. Antioxidant enzymes such as SOD, GSH-Px and CAT were reduced in the blood and brain, and correspondingly, the lipid peroxidation product MDA was elevated. In the brain, astrocytes and microglia were activated, characterized by an increase in inflammatory factors such as TNF-α, IL-1β and IL-6, as well as their protein markers GFAP and IBA1. However, Rg1 eliminated Cd-induced toxicity and restored oxidative stress and inflammatory responses, correspondingly restoring the behavioral performance of the animals. Meanwhile, the BDNF-TrkB/Akt and Notch/HES-1 signaling axes were involved in the Rg1-mediated elimination of Cd-induced toxicity. CONCLUSION Rg1 is a promising agent for the elimination of Cd-induced toxicity.

The neurotoxicity caused by cadmium (Cd) is well known in humans and experimental animals. However, there is no effective treatment for its toxicity. In this study, we established Cd toxicity models in cultured cells or mice to investigate the detoxification effect of edaravone (Eda). We found that Eda protected GL261 cells from Cd toxicity and prevented the loss of cell viability. In Cd-exposed mice, liver, kidney and testicular damage, as well as cognitive dysfunction were observed. Oxidative stress and inflammatory responses, such as decreased SOD and CAT, increased LDH and MDA, and abnormal changes in the inflammatory factors TNF-α, IL-1β, IL-6 and IL-10 were detected in serum and brain tissue. Eda protected mice from Cd-induced toxicity and abrogated oxidative stress and inflammatory responses. Also, Eda prevented inflammatory activation of microglia and astrocytes and was accompanied by restoration of the neuronal marker protein MAP2, indicating restoration of neuronal function. In addition, the BDNF-TrkB/Akt and Notch/HES-1 signaling axes were involved in the response of Eda to the elimination of Cd toxicity. In conclusion, Eda does contribute to the clearance of Cd-induced toxicity.

CE exerted neuroprotective effects against a range of oxidative stress and amyloid toxicity in neurons. Here, we investigated the anti-aging effects of CE in chemically-induced aging mice established by consecutive administration of D-galactose combined with AlCl3. Behavior analysis verified that CE significantly ameliorates learning and memory deficit of aging mice. CE treatment evoked the hippocampus expression of neurotrophins BDNF and FGF2, reactivated PI3K/Akt signaling pathway and rescued the decline of anti-apoptotic protein Bcl-2, but abolished the elevation of active Caspase-3. Meanwhile, the expression of inflammatory factors including TNF-α, IL-6, NOS2 and IL-1β was decreased. Collectively, we established the neuroprotective role of CE that ameliorates chemically-induced cognitive deficit through up regulation of BDNF and FGF2, reactivating the PI3K/Akt signaling pathway and sequestering neuroinflammation. Our work will assist in the development of functional food and medicine for clinical trials of anti-aging and dementia.

Apple (Malus pumila Mill.) leaves contain many antioxidant polyphenols that have received considerable attention due to their potential prevention of various chronic human diseases. The present study aimed to provide a comprehensive evaluation of polyphenols in apple leaves. The petroleum ether, ethyl acetate, and 75% ethanol extracts of apple leaves were assessed for their total phenolic and flavonoid contents and antioxidant activities. Among the three extracts, the 75% ethanol extract contained the highest phenolic (56.74 mg/g) and flavonoid (37.56 mg/g) contents and had the highest antioxidant activity (EC50 value 50.96 mg/L) by 2, 2-diphenyl-1-picrylhydrazyl assay. According to high performance liquid chromatography profiling and high-speed countercurrent chromatography separation, the 75% ethanol extract contained five major polyphenols phloridzin (P, 66.1 mg/g), isoquercitrin (IQ, 8.4 mg/g), quercetin 3-O-xyloside (9.5 mg/g), quercetin 3-O-arabinoside (10.7 mg/g), and quercetin 3-O-rhamnoside (28.5 mg/g). Additionally, the five separated polyphenols were investigated for their antioxidant activities and protective effects against hydrogen peroxide-induced oxidative stress in rat hippocampal neurons in vitro. The results showed that all the five polyphenols had antioxidant activities like the synthetic antioxidants butylated hydroxytoluene (BHT) and tert-butylhydroquinone (TBHQ) and IQ had the highest antioxidant activity (EC50 value 2.92 mg/L) among them. The IQ combination with P or with BHT had significant synergism in antioxidant activity at the ratios from 25:1 to 1:25 (w/w) and the strongest synergism at the ratio of 1:1. The IQ showed significant neuroprotective effect at the concentrations of 0.5–1.0 mg/L, while P and BHT had no neuroprotective effect and TBHQ had neurotoxic effect at high concentrations (0.5–5.0 mg/L). These results indicated that apple leaves could be exploited as a cheap and abundant resource of antioxidants and their utilization could be very attractive for pharmaceutical, food, and cosmetic industries.

Parkinson's disease is the second most common neurodegenerative disease. Researchers have shown that oxidative stress and apoptosis play an important role in the Parkinson's disease process. Isoquercitrin (quercetin-3-O-β-d-glucopyranoside) is a natural flavonol compound and one of the main active ingredients of agricultural waste apple pomace. Increasing evidence indicates that this compound possesses anti-oxidation, anti-aging, and anti-inflammation properties. In this study, isoquercitrin was purified from apple pomace by high-speed countercurrent chromatography and its neuroprotective effect on Parkinson's disease was investigated in MPTP-induced acute mouse models. It was found that isoquercitrin ameliorated the animal behaviors against MPTP-induced neurotoxicity, mitigated the loss of dopamine neurons induced by MPTP, increased tyrosine hydroxylase and dopamine transporter expression, reduced the pro-apoptotic signaling molecule bax expression and inhibited MPTP-triggered oxidative stress. Our results demonstrated that isoquercitrin has protective effects on the MPTP subacute model mouse, which might be partially mediated through the actions of anti-oxidation and anti-apoptosis. Isoquercitrin might be a new promising protective drug for the improvement of Parkinson's disease.

Semen Cuscutae, called Tu-si-zi in Chinese, is a kind of dried mature seed in the Convolvulaceae family. It mainly distributes in China, Korea, Pakistan, Vietnam, India and Thailand. It is used as a kidney-tonifying drug for treatment of aging related diseases such as osteoporosis in traditional Chinese medicine. However, the exact mechanisms on bone resorption are poorly studied.The aim of this study was to investigate the potential effect of Semen Cuscutae on ovariectomy (OVX)-induced osteoporosis in mice and clarify the exact mechanisms by which Semen Cuscutae exert the anti-osteoporosis effect.Qualitative and quantitative analyses of Semen Cuscutae were performed by UPLC-Q-TOF-MS and HPLC-MS/MS, respectively. Changes in bone mineral density (BMD) induced by OVX in mice were measured by dual-energy X-ray absorptiometry and micro-computed tomography (μCT). Tartrate-resistant acid phosphatase (TRAP) staining as well as hematoxylin and eosin (HE) staining were used to observe bone microarchitectural changes. ELISA kits were used to assess the therapeutic effects of Semen Cuscutae on the serum levels of osteoprotegerin (OPG), tartrate-resistant acid phosphatase 5b (TRACP-5b), and receptor activator of nuclear factor-κB (RANKL). The effect of Semen Cuscutae on primary cell viability was assessed using CCK-8 and anti-tartrate phosphatase assays. TRAP staining and actin ring staining were used to observe the effect of Semen Cuscutae on osteoclast differentiation. Western blotting was used to measure the effects of Semen Cuscutae on expressions of NFATC1, c-Src kinase, and c-fos.Results from UPLC-Q-TOF-MS showed that the main components of Semen Cuscutae were flavonoid compounds that included quercitrin, quercetin, hyperoside, caffeic acid, rutin, chlorogenic acid, luteolin, apigenin, kaempferol, isoquercetin, cryptochlorogenic acid, isorhamnetin-3-O-glucoside, and astragalin. After the Semen Cuscutae extract was orally administered to OVX mice, bone density increased (P 0.01) and bone microstructure was significantly improved (P 0.01 or 0.05). Additionally, Semen Cuscutae exhibited a significant descending effect in the levels of serum TRACP-5b and RANKL, while there was a significant increase in OPG in the Semen Cuscutae group compared with the OVX group, especially at high doses. Moreover, we found that increasing of c-fos, c-Src kinase, and NFATC1 protein expressions were reversed by Semen Cuscutae in vitro and in vivo.Our results showed that Semen Cuscutae exhibited anti-osteoporosis effects through the c-fos/c-Src kinase/NFATC1 signaling pathway.

Tea polyphenols (TP) are the major ingredients in tea beverages that display health-benefits including anti-oxidation, anti-inflammation, anti-aging, attenuating blood pressure and deflating. In this study, we investigated the neuroprotective effects of TP to attenuate staurosporine (STS)-induced cytotoxicity. Rat hippocampal neurons were isolated, cultured and incubated with STS to induce neurite collapse and apoptosis, however, the medication of TP eliminated these adverse effects and maintained the morphology of neurons. STS decreased the expression of pro-BDNF, downregulated the TrkB/Akt/Bcl-2 signaling axis and promoted the activation of Erk1/2 and caspase-3. In contrast, TP rescued the expression of pro-BDNF and antagonistically restored the biochemistry of aforementioned signaling effectors. Consistently, the activity of TP can be attenuated by the inhibition of TrkB or Akt by small chemicals K252a and LY294002. Therefore, BDNF-TrkB and Akt signaling axis is essential for TP-mediated neuroprotective effects. In summary, TP showed beneficial effects to protect neurons from exogenous insults such as STS-induced neural cytotoxicity and cell death.

Ethnopharmacological relevance Tibetan ginseng named Wangla (tuber of Coeloglossum viride var. bracteatum) is a traditional tonic that has Yang-strengthening and qi-enhancing, tranquilizing, intelligence-enhancing and longevity-enhancing properties. It has been used to treat impotence, spermatorrhea, anemia and insomnia. Therefore, its characteristic components and neuronal modulating effects were studied. Aim of the study: To investigate the elimination of Aβ-induced toxicity by CE and to elucidate the molecular mechanisms involving BDNF, FGF2, and their related signaling axis, and the RIP1-driven inflammatory pathway. Materials and methods We established Aβ-induced toxicity models in cultured neurons and ICR mice, respectively. MWM and fear conditioning tests were performed for behavioral analysis of cognitive functions in mice. Western blot was used to investigate the levels of BDNF, FGF2, and their downstream effector TrkB/Akt/Bcl-2, as well as the RIP1-driven RIP1/RIP3/MLKL pathway. Immunofluorescence assay is used to examine the status of glial cells. Results CE abrogated Aβ toxicity and inhibited apoptosis in cultured neurons, mainly by regulating the BDNF, FGF2, and TrkB/Akt signaling pathways as well as RIP1-driven inflammation and necroptosis. Similarly, mice injected intracerebrally with Aβ exhibited cognitive deficits and had elevated oxidative stress and inflammatory factors detected in their serum and brain. However, CE-treated mice showed recovery of cognitive abilities and quelled levels of oxidative stress and inflammatory factors. Moreover, Aβ toxicity led to a reduction in BDNF, FGF2, and related signaling regulators in the hippocampus and prefrontal cortex, accompanied by activation of RIP1-driven inflammatory signaling pathways, and a reduction in TBK1 and Bcl-2. However, CE restored the levels of BDNF, FGF2, and TrkB/Akt signaling pathway, while inhibiting RIP1-induced RIP1/RIP3/MLKL pathway, thereby antagonizing apoptosis and maintaining neuronal activity. Conclusions CE effectively eliminated the toxicity of Aβ in cultured neurons and mouse models, which holds promise for drug development.

// Yan Zhang 1 , Meng Che 1 , Jing Yuan 1 , Yun Yu 1 , Chang Cao 1 , Xiao-Yan Qin 1 and Yong Cheng 1 1 Center on Translational Neuroscience, College of Life and Environmental Sciences, Minzu University of China, Beijing 100081, China Correspondence to: Yong Cheng, email: yongcheng@muc.edu.cn Keywords: cytokine, inflammation, Down syndrome, meta-analysis, systematic review Received: July 26, 2017 Accepted: September 03, 2017 Published: September 19, 2017 ABSTRACT Evidence suggests that immune system alterations in Down syndrome (DS) may be early events that drive neuropathological and cognitive changes of Alzheimer’s disease. The primary objective of this meta-analysis was to investigate whether there is an abnormal cytokine profile in DS patients when compared with healthy control (HC) subjects. A systematic search of Pubmed and Web of Science identified 19 studies with 957 DS patients and 541 HC subjects for this meta-analysis. Random effects meta-analysis demonstrated that patients with DS had significantly increased circulating tumor necrosis factor-α (Hedges’ g = 1.045, 95% confidence interval (CI) = 0.192 to 1.898, p = 0.016), interleukin (IL)-1β (Hedges’ g = 0.696, 95% confidence CI = 0.149 to 1.242, p = 0.013), interferon-γ (Hedges’ g = 0.978, 95% CI = 0.417 to 1.539, p = 0.001) and neopterin (Hedges’ g = 0.815, 95% CI = 0.423 to 1.207, p < 0.001) levels compared to HC subjects. No significant differences were found between patients with DS and controls for concentrations of IL-4, IL-6, IL8 and IL-10. In addition, most of the cytokine data in this meta-analysis were from children with DS and HC, and subgroup analysis showed that children with DS had elevated tumor necrosis factor-α, IL-1β and interferon-γ levels when compared with controls. Taken together, these results demonstrated that patients (children) with DS are accompanied by increased circulating cytokine tumor necrosis factor-α, IL-1β and interferon-γ levels, strengthening the clinical evidence that patients (children) with DS are accompanied by an abnormal inflammatory response.

Since discovery in 1982, carboxypeptidase E (CPE) has been shown to be involved in the biosynthesis of a wide range of neuropeptides and peptide hormones in endocrine tissues, and in the nervous system. This protein is produced from pro-CPE and exists in soluble and membrane forms. Membrane CPE mediates the targeting of prohormones to the regulated secretory pathway, while soluble CPE acts as an exopeptidase and cleaves C-terminal basic residues from peptide intermediates to generate bioactive peptides. CPE also participates in protein internalization, vesicle transport and regulation of signaling pathways. Therefore, in two types of CPE mutant mice, Cpefat/Cpefat and Cpe knockout, loss of normal CPE leads to a lot of disorders, including diabetes, hyperproinsulinemia, low bone mineral density and deficits in learning and memory. In addition, the potential roles of CPE and ΔN-CPE, an N-terminal truncated form, in tumorigenesis and diagnosis were also addressed. Herein, we focus on dissecting the pathophysiological roles of CPE in the endocrine and nervous systems, and related diseases.

The major bioactive ingredient THSG of Polygonum multiflorum is well established for its anti-oxidation, anti-aging and anti-inflammation properties. Increasing evidence supports the capacity of THSG to ameliorate the biochemistry of neurotrophins and their downstream signaling axis in mouse models to attenuate neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In this study, the neuroprotective effects of THSG were studied in vitro and in vivo. In cultured mesencephalic dopamine neurons and SH-SY5Y cell line, it was found that THSG protected the integrity of the cell body and neurite branching from MPP+-induced toxicity by restoring the expression of FGF2 and BDNF and their downstream signaling pathways to inhibit apoptosis and promote cell survival. The inhibition of Akt signaling by LY294002 or TrkB activity by K252a eliminated the neuroprotective effects of THSG. In the MPTP-induced mouse models of Parkinson's disease, THSG ameliorated the animal behaviors against MPTP-induced neurotoxicity, which was demonstrated by the pole test and the tail suspension test. Biochemical and immunohistochemical analysis verified the THSG-mediated restoration of the FGF2-Akt and BDNF-TrkB signaling axis in the substantia nigra and corpus striatum and the recovery of dopaminergic neurons. These results establish the neuroprotective effects of THSG in vitro and in vivo and unravel the underlying mechanism against toxin-induced neural atrophy, providing a new avenue for the use and pharmacological research of edible medicine for anti-neurodegenerative diseases.

New radical-triggered three-component bicyclization cascades of 2-alkynyl aryldiazonium tetrafluoroborates with a sulfur dioxide surrogate DABCO·(SO2)2 and internal alkynes such as haloalkynes and ynones have been reported for the first time, leading to 49 examples of polycyclic sulfones with moderate to good yields and high levels of regioselectivity. This transformation initiated by an in situ generated arylsulfonyl radical proceeds efficiently under mild and neutral redox conditions, which provide an easy and metal-free pathway toward the formation of a range of richly decorated indeno[1,2-c]thiochromene 5,5-dioxides.

A new Mannich-type reaction of aryl propiolaldehydes with benzofuran-3(2H)-one and cyclic secondary amines was established, enabling a completely stereoselective protocol to access a series of unreported δ-amino-α,β,γ,δ-unsaturated cycloketones in generally good yields. This approach could tolerate various cyclic secondary amines including four-, five-, six-membered and bicyclic rings with water as a major by-product.

The occurrence of depressive disorder has long been attributed to changes in monoamines, with the focus of drug treatment strategies being to change the effectiveness of monoamines. However, the success achieved by changing these processes is limited and further stimulates the exploration of alternative mechanisms and treatments. Fibroblast growth factor 2 (FGF-2), which occurs in a high-molecular weight (HMW) and low-molecular weight (LMW) form, is a potent developmental modulator and nervous system regulator that has been suggested to play an important role in various psychiatric disorders. In this study, we investigated the antidepressant effects of HMW and LMW FGF-2 on depression induced by chronic stress. Both peripheral LMW and HMW FGF-2 attenuated the depression-like behaviors in chronic unpredictable mild stress (CUMS) mice to a similar extent, as determined by the forced swimming, tail suspension, and sucrose preference tests. We then showed that CUMS-induced oxidative stresses in mice were inhibited by FGF-2 treatments both in central and peripheral. We also showed that both forms of FGF-2 increased the phosphorylation of ERK and AKT, increased Bcl-2 expression and inhibited caspase-3 activation in CUMS mice. Interestingly, HMW FGF-2 enhanced the activity of the brain-derived neurotrophic factor (BDNF) to a greater extent than did LMW FGF-2 in the hippocampus. Taken together, these results suggest that depressive symptoms can be relieved by administering different forms of FGF-2 peripherally in a CUMS-induced depression model through a similar antidepressant signaling pathway, therefore suggesting a potential clinical use for FGF-2 as a treatment for depression.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with poorly understood etiology. Increasing evidence suggest that inflammation may play a critical role in the pathogenesis of ALS. Several studies have demonstrated altered levels of blood cytokines in ALS, but results were inconsistent. Therefore, we did a systematic review of studies comparing blood inflammatory cytokines between ALS patients and control subjects, and quantitatively combined the clinical data with a meta-analysis. The systematic review of Pubmed and Web of Science identified 25 studies encompassing 812 ALS patients and 639 control subjects. Random-effects meta-analysis demonstrated that blood tumor necrosis factor-α (TNF; Hedges’ g = 0.655; p = 0.001), TNF receptor 1 (Hedges’ g = 0.741; p

The excessive release and accumulation of glutamate in the brain is known to be associated with excitotoxicity. CE, an extract derived from the plant Coeloglossum viride var. Bracteatum, exerted neuroprotective effects against amyloid toxicity and oxidative stress in cortical neurons. The aims of this study are to examine whether CE also attenuates glutamate neurotoxicity in rat primary cultured cortical neurons and to determine the effect of CE in vivo. According to the results of MTT, LDH release, and TUNEL assays, the CE treatment significantly reduced glutamate-induced neurotoxicity in a dose-dependent manner. Moreover, the protective effects of CE were blocked by an Akt inhibitor, LY294002, suggesting that the PI3K/Akt signalling pathway is involved in the neuroprotective effects of CE. In addition, CE might regulate the PKC-GluA2 axis to prevent neuronal apoptosis. CE also protected against dopaminergic neuronal loss in a mouse model of MPTP-induced PD. Based on our results, CE exerted neuroprotective effects both in vitro and in vivo, thus providing a potential therapeutic target for the treatment or prevention of neurodegeneration.

Marine microorganisms, particularly marine-derived fungi, have been recognized as a potential source of structurally novel and biologically potent metabolites that have become significant chemical entities for drug discovery [1]. Recently, a growing number of fungi derived from marine invertebrates have been reported to produce novel bioactive secondary metabolites [2]. However, chemical studies on fungi derived from zoanthids are relatively rare [3–6]. As part of our ongoing investigation on natural bioactive products from marine fungi in the South China Sea, a zoanthid-derived fungus, authenticated as Trichoderma sp. TA26-28, attracted our attention because the EtOAc extract of the fungal fermentation broth exhibited significant antibacterial activity against a panel of pathogenic bacteria. Chemical investigation of the extract led to the isolation of eight known compounds, including three anthraquinones 1–3, one xanthone 4, one epoxy-lactone 5, and three cerebrosides 6–8. We report herein the fermentation, isolation, structure elucidation, and biological activity of these metabolites. Fungus Material. The fungal strain Trichoderma sp. (TA26-28) was isolated from a piece of fresh tissue from the inner part of the zoanthid Palythoa haddoni (GX-WZ-20100026), collected from the Weizhou coral reef in the South China Sea in April 2010. The fungus was identified as a Trichoderma sp. based on sequence analysis of the internal transcribed spacer, and its sequence data had been submitted to GenBank, accession number JF819149. The strain was deposited at the Key Laboratory of Marine Drugs, the Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, P. R. China. Culture Conditions. Starter cultures were maintained on GPY medium (glucose 20 g, peptone 10 g, yeast extract 10 g, agar 20 g in 1 L artificial seawater). Plugs of agar supporting mycelia growth were cut and transferred aseptically to a 250 mL Erlenmeyer flask containing 100 mL of liquid medium (composition of medium: 200 g/L cooked and sliced potatoes, 20 g/L glucose in 1 L artificial seawater). The flask was incubated at 27 C on a rotary shaker for one week. The mycelium was aseptically transferred to 1 L Erlenmeyer flasks containing culture liquid (400 mL). The flasks were then incubated at 27 C without shaking for 4 weeks.

The present study explored the effect of 2,3,5,4′-tetrahydroxystilbene-2-O-β- d -glucoside (THSG) on the staurosporine (STS)-induced toxicity in cultured rat hippocampal neurons. The results showed that administration of 200 μM of THSG significantly protected against 0.3 μM of STS-induced apoptosis in cultured rat hippocampal neurons tested by methyl thiazolyl tetrazolium (MTT) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assays. Furthermore, when the Akt signaling pathway was blocked by LY294002, an inhibitor of Phosphatidyl Inositol 3-kinase (PI3K), the protective effects of THSG against STS-induced neurotoxicity were abrogated. We further examined the involvement of PI3K/Akt signaling pathway in THSG protection against STS-induced cytotoxicity on cultured neurons and found that administration of THSG significantly inhibited the STS-induced decreases in the content of phosphorylated AKt (p-Akt). Moreover, we found that THSG rescued the down-regulation of B cell lymphoma/lewkmia-2 (Bcl 2 ) and pro-caspase-3 (pro-Csp3) caused by STS in the neurons. These results indicate that THSG protect the cultured rat hippocampal neurons against STS-induced cytotoxicity and the PI3K/Akt signaling and mitochondrial apoptotic pathways are involved in the THSG-induced protective effects.

The ethylene cracking furnace tube is one of the most important components of an ethylene cracking furnace. Carburization of furnace tube is one of the most important causes which lead the tube to fail. In this paper, the model that describes diffusion of carbon and the precipitation of carbides was established based on Fick’ law and equilibrium constant method. The finite difference method was adopted to simulate the distribution of carbon concentration. By applying the model, the distribution of carbon concentration along thickness in HP-Nb tubes was predicted for the different service times. According to the temperature distribution of furnace tube, obtained by the analysis of heat transfer, the thermal stresses of the furnace tube with various carburization extents were analyzed by using the finite element code ABAQUS for the actual heating process of an ethylene cracking furnace. The analysis results show that the maximum circumferential thermal stress exists near the inner wall of the carburized tube, which usually causes cracking of the carburized tube along the longitudinal direction.

Recently the neuronal toxicity of intracellular amyloid beta (iAbeta) in Alzheimer's disease is attracting more and more attention. The present study explored the effects of curcumin on the iAbeta-induced toxicity in primary cultured rat prefrontal cortical neurons. The cell viability of primary cultured prefrontal cortical neurons decreased significantly after virus driven transfection of Abeta from 1 day to 7 days. Interestingly, administration of 1 microM, 10 microM or 20 microM of curcumin significantly inhibited the iAbeta-induced toxicity in primary cultured rat prefrontal cortical neurons tested by MTT and LDH release assays. We further studied the involvements of apoptotic or neuroprotective pathway proteins in curcumin protection against iAbeta-induced cytotoxicity in primary cultured rat prefrontal cortical neurons. The results demonstrated that the contents of activated caspase-3 increased significantly by iAbeta, while curcumin significantly inhibited the iAbeta-induced increases of activated caspase-3 tested by Western blot. And the contents of p-AKT decreased significantly after iAbeta treatment, while administration of curcumin significantly inhibited the iAbeta-induced decreases in the contents of p-AKT. The results suggest that curcumin may play a protective effect in primary cultured rat prefrontal cortical neurons against iAbeta-induced cytotoxicity, and both AKT and caspase-3 are involved in the curcumin-induced protective effects.

The present study explored the effect of curcumin against amyloid beta (Abeta)-induced toxicity on cultured rat primary prefrontal cortical neurons. The results showed that administration of 10 microM of curcumin induced significantly protection against 20 microM of Abeta(25-35)-induced toxicity on the cultured rat primary prefrontal cortical neurons tested by MTT and TUNEL assays. We further examined the involvements of the apoptotic or anti-apoptotic proteins in curcumin protection against Abeta(25-35)-induced cytotoxicity on cultured neurons and found that the content of apoptotic protein caspase-3 was increased and the content of anti-apoptotic factor Bcl2 was decreased significantly after Abeta(25-35) treatments, while administration of curcumin significantly inhibited the Abeta(25-35)-induced increases in the content of caspase-3 and inhibited the Abeta(25-35)-induced decreases in the content of Bcl2 tested by Western blot. The results suggest that curcumin protects cultured rat primary prefrontal cortical neurons against Abeta-induced cytotoxicity, and both Bcl2 and caspase-3 are involved in the curcumin-induced protective effects.

The hydroxylapatite nanostructures with different morphologies have been synthesized by a facile solution approach. The samples were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM) technologies, and Fourier transforms infrared spectroscopy (FT-IR). The control mechanism of the hydroxylapatite with various morphologies nanostructures was investigated. Some practical experimental conclusions could be obtained, which were expected to have potential values in crystal engineering research and practical applications.

The present study explored the neuroprotective effect ofCoeloglossum viridevar. bracteatum extract (CE) against oxidative stress in rat cortical neurons. The results demonstrated that administration of CE inhibited hydrogen peroxide-induced neurotoxicity tested by MTT, LDH release, and TUNEL assays. We further found that CE inhibited the activation of caspase-3 (Csp3) induced by hydrogen peroxide. Moreover, CE was found to reverse the hydrogen peroxide-induced downregulation of active AKT and Bcl-2. We then showed that the neuroprotective effect of CE was blocked by adding the AKT inhibitor, Ly294002. Thus, our data strongly indicated that CE played a neuroprotective role against oxidative stress-induced neurotoxicity.

Curcumin is extracted from the turmeric plant (Curcuma longa Linn.) and is widely used as a food additive and traditional medicine. The present study investigated the activity of curcumin against staurosporine (STS) toxicity in cell culture.Rat hippocampal neurons in primary culture were exposed to STS (20 μmol/L) and treated with curcumin (20 μmol/L). Cell viability was tested by MTT assay and reactive oxygen species (ROS) were measured using the MitoSOX™ red mitochondrial superoxide indicator. Western blot was used to assess changes in the levels of caspase-3 (Csp3), heat shock protein 70 (Hsp70) and Akt.The results showed that curcumin protects against STS-induced cytotoxicity in rat hippocampal neurons. Csp3, Hsp70, Akt and ROS activation may be involved in this protection.Curcumin could be a potential drug for combination with STS in cancer treatment to reduce the unwanted cytotoxicity of STS.

To explore the effects of curcumin (CMN) on hepatic injury induced by acetaminophen (APAP) in vivo.Male mice were randomly divided into three groups: group I (control) mice received the equivalent volumes of phosphate-buffered saline (PBS) intraperitoneally (ip); Group II [APAP + carboxymethylcellulose (CMC)] mice received 1% CMC (vehicle) 2 h before APAP injection; Group III (APAP + CMN) mice received curcumin (10 or 20 mg/kg, ip) 2 h before before or after APAP challenge. In Groups II and III, APAP was dissolved in pyrogen-free PBS and injected at a single dose of 300 mg/kg. CMN was dissolved in 1% CMC. Mice were sacrificed 16 h after the APAP injection to determine alanine aminotransferase (ALT) levels in serum and malondialdehyde (MDA) accumulation, superoxide dismutase (SOD) activity and hepatocyte apoptosis in liver tissues.Both pre- and post-treatment with curcumin resulted in a significant decrease in serum ALT compared with APAP treatment group (10 mg/kg: 801.46 ± 661.34 U/L; 20 mg/kg: 99.68 ± 86.48 U/L vs 5406.80 ± 1785.75 U/L, P0.001, respectively). The incidence of liver necrosis was significantly lowered in CMN treated animals. MDA contents were significantly reduced in 20 mg/kg CMN pretreatment group, but increased in APAP treated group (10.96 ± 0.87 nmol/mg protein vs 16.03 ± 2.58 nmol/mg protein, P0.05). The decrease of SOD activity in APAP treatment group and the increase of SOD in 20 mg/kg CMN pretreatment group were also detected (24.54 ± 4.95 U/mg protein vs 50.21 ± 1.93 U/mg protein, P0.05). Furthermore, CMN treatment efficiently protected against APAP-induced apoptosis via increasing Bcl-2/Bax ratio.CMN has significant therapeutic potential in both APAP-induced hepatotoxicity and other types of liver diseases.