Triterpenoids with neurotrophic activity from Ganoderma lucidum

A new triterpenoid, 4,4,14α-trimethyl-5α-chol-7,9(11)-dien-3-oxo-24-oic acid (1), together with seven known triterpenoids, were isolated from the dried fruiting bodies of Ganoderma lucidum. Their structures were elucidated by extensive spectroscopic analyses. Bioassay results revealed that compounds 1 and methyl ganoderic acid B (5) had nerve growth factor-like neuronal survival-promoting effects, whereas compounds 1, and 4-7 showed brain-derived neurotrophic factor-like neuronal survival-promoting activities.     

BDNF promotes EGF-induced proliferation and migration of human fetal neural stem/progenitor cells via the PI3K/Akt pathway

Neurogenesis is a complex process, which contributes to the ability of the adult brain to function normally and adapt to diseases. Epidermal growth factor (EGF) is known to play an important role in neurogenesis; however, the underlying mechanism is still unclear. Here, we hypothesized that brain-derived neurotrophic factor (BDNF) can enhance the effect of EGF on neurogenesis. Using in vitro cell culture of aborted human fetal brain tissues, we investigated proliferation and migration of neural stem/progenitor cells (NSPCs) after treatment with EGF and different concentrations of BDNF. EGF stimulated proliferation and migration of NSPCs, and this effect was significantly enhanced by co-incubation with BDNF. In the NSPCs treated with 50 ng/mL BDNF, BrdU incorporation was significantly increased (from 7.91% to 17.07%), as compared with that in the control. Moreover, the number of migrating cells was at least 2-fold higher than that in the control. Furthermore, phosphorylation of Akt-1 was increased by BDNF treatment, as well. By contrast, the enhancing effect of BDNF on EGF-induced proliferation and migration of NSPCs were abolished by an inhibitor of PI3K, LY294002. These findings suggest that BDNF promotes EGF-induced proliferation and migration of NSPC through the PI3K/Akt pathway, providing significant insights into not only the mechanism underlying EGF-induced neurogenesis but also potential neuronal replacement strategies to treat brain damage.     

A facile preparation of 4-(1-Acetyl-4(1H)-pyridylidene)-2-oxazohn-5-ones

4-(1-Acetyl-4(1H)-pyridylidene)-2-oxazolin-5-ones were prepared by the reaction of acylglycines with pyridine and acetic anhydride under oxygen. Acidic and alkaline hydrolysis of 2-oxazolin-5-ones provided oxazole derivatives, pyridine derivatives, and carboxylic acids.     

The antidepressant effect of 4-hydroxybenzyl alcohol 2-naphthoate through monoaminergic,GABAergic system and BDNF signaling pathway

Abstract

Gastrodigenin, also known as 4-hydroxybenzyl alcohol (HBA), is one of the main components of Gastrodia elata, which is a perfect lead compound of natural products. In order to get new active compounds, we modified the structure of HBA through esterification with carboxylic acid, and got a series of derivatives in which 4-hydroxybenzyl alcohol 2-naphthoate (NHBA) showed stronger antidepressant activity than HBA. In this paper, we firstly evaluated the antidepressant activity of NHBA by tail suspension test (TST) and forced swimming test (FST). Then, we carried out the biochemical assay and western blot to determine its mechanism. The results displayed that NHBA could increase the content of serotonin, dopamine, norepinephrine, γ-aminobutyric acid, brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) in mice brain. It suggested that NHBA exhibited an antidepressant-like effect through monoaminergic system, GABAergic system and BDNF/TrkB signaling pathways.     

Synthesis and transformations of derivatives of 2-aryl-5-(3,5-dimethyl-1H-pyrazol-1-yl)-1,3-oxazole-4-carboxylic acid

On the basis of methyl esters of 2-aryl-5-hydrazino-1,3-oxazole-4-carboxylic acids the earlier unknown methyl esters of 2-aryl-5-(3,5-dimethyl-1H-pyrazol-1-yl)-1,3-oxazole-4-carboxylic acids as well as their functional derivatives were synthesized. The latter were used for further transformations, in particular, for introducing the residues of highly basic aliphatic amines into the 5 position of oxazole, and the oxazol-2-yl moiety into the 4 position of the oxazole ring.     

Growth factor-expressing human neural progenitor cell grafts protect motor neurons but do not ameliorate motor performance and survival in ALS mice

Neural progenitor cells (NPs) have shown several promising benefits for the treatment of neurological disorders. To evaluate the therapeutic potential of human neural progenitor cells (hNPs) in amyotrophic lateral sclerosis (ALS), we transplanted hNPs or growth factor (GF)-expressing hNPs into the central nervous system (CNS) of mutant Cu/Zn superoxide dismutase (SOD1^G93A) transgenic mice. The hNPs were engineered to express brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), VEGF, neurotrophin-3 (NT-3), or glial cell-derived neurotrophic factor (GDNF), respectively, by adenoviral vector and GDNF by lentiviral vector before transplantation. Donor-derived cells engrafted and migrated into the spinal cord or brain of ALS mice and differentiated into neurons, oligodendrocytes, or glutamate transporter-1 (GLT1)-expressing astrocytes while some cells retained immature markers. Transplantation of GDNF- or IGF-1-expressing hNPs attenuated the loss of motor neurons and induced trophic changes in motor neurons of the spinal cord. However, improvement in motor performance and extension of lifespan were not observed in all hNP transplantation groups compared to vehicle-injected controls. Moreover, the lifespan of GDNF-expressing hNP recipient mice by lentiviral vector was shortened compared to controls, which was largely due to the decreased survival times of female animals. These results imply that although implanted hNPs differentiate into GLT1-expressing astrocytes and secrete GFs, which maintain dying motor neurons, inadequate trophic support could be harmful and there is sexual dimorphism in response to GDNF delivery in ALS mice. Therefore, additional therapeutic approaches may be required for full functional recovery.     

Pimprinols A–C,from the terrestrial actinomycete,Streptomyces sp.

A Streptomyces sp. Lv3-13, isolated from the rhizosphere soil of the plant Mespilus germanica, has yielded three new pimprinine derivatives, named pimprinols A–C (1–3) and the unknown (2-aminophenyl)(2-ethyloxazol-5-yl) methanone (4) along with the known compounds 2-ethyl oxazole pimprinine and 2-propyl oxazole pimprinine. The structures of the compounds were elucidated based on spectroscopic methods including UV, HR-ESIMS and 1D, 2D NMR data. Compounds 1–4 were screened for antimicrobial and cytotoxic activities.     

A Convenient Synthesis of 2-Arylnaphtho[1,2-d]oxazole Derivatives Promoted by Triethylamine

A variety of 2-arylnaphtho[ 1,2-d]oxazole derivatives were efficiently synthesized in moderate to high yields by the reaction of aromatic aldehydes with 1-amino-2-naphthol derivatives in the presence of triethylamine in refluxing ethanol in air. Seven new 2-arylnaphtho[1,2-d]oxazole derivatives were obtained and characterized by the spectral data and elemental analysis. In addition, the X-ray crystal structures of 2-[4-（N,N-dimethylamino）phenyl]naphtho[ 1,2-d] oxzole （3d） and 1, 1＇-bis（naphtho[ 1,2-d]oxazol-2-yl）ferrocene （3n） have been determined.     

Detection of ATP-binding to growth factors

It was shown in previous work that the interaction of growth factors (GFs) with adenosine triphosphate (ATP) is essential for their neuroprotective effect. Here we investigated the nature of the association of human basic fibroblast growth factor (bFGF), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) with ATP. It was demonstrated that this interaction involves the formation of non-covalent ATP-GF complexes that are labile at low pH and that could be selectively purified and subjected to electrospray and MALDI-TOF mass spectrometry. The results obtained with these techniques indicated that the stability of the complexes is high. Main features of the procedure used here are: (1) reversed-phase purification of nucleotide-protein non-covalent complexes, (2) their detection with MALDI-TOF-MS using acid-free matrix, and/or (3) their measurement with ESI-MS using soft desolvation conditions. The methodology was successful in providing proof for the presence of various nucleotide-GF complexes. It was extended to other nucleotide-binding proteins (ribonuclease A) as well as proteins that do not exhibit nucleotide binding (lysozyme) as positive and negative control, respectively. Thus, the method demonstrated its general use for the investigation of a wide range of proteins interacting with nucleotides as long as their complexes are sufficiently stable to accommodate the experimental conditions.     

Reaction of 2-acylamino-3,3-dichloroacrylonitriles with 2-aminothiophenol

Reactions of 2-acylamino-3,3-dichloroacrylonitriles with 2-aminothiophenol in the presence of triethylamine was shown to lead to 2-aryl-3,3-bis(2-aminophenylsulfanyl)acrylonitrile, which suffered a transformation into 5-amino-4-(benzothiazol-2-yl)oxazole derivatives at heating without solvent. The formation of the same compounds from these reagents proceeded in one step in the presence of N,N-dimethylaniline. The presence of primary amino groups in the derivatives of 5-aminooxazole was confirmed by acylation and further transformation, which was used also for indroduction of various biophoric sites in 5 position of the oxazole ring.     

新型α1受体拮抗剂先导化合物的寻找(I): 5-氯-2-(4-(芳氧烷基)哌嗪-1-基)苯并噁唑类化合物的设计、合成及生物活性研究

为寻找用于治疗良性前列腺增生的新型α1受体拮抗剂, 以本研究组发现的2-[(4-(2-(2-氯苯氧基)乙基)哌嗪-1-基)甲基]-5-甲基苯并噁唑(wb5c)为先导化合物, 结合已构建的α1-AR拮抗剂药效团模型, 通过骨架改造, 设计出以苯并噁唑-2-基哌嗪为母核的目标物, 然后以5-氯-2-氨基酚和取代苯酚为原料, 经缩合、卤代、氨化、Williamson醚合成、取代等反应共合成11个新目标化合物, 结构经ESI-MS, 1H NMR, IR及HRMS确证. 初步药理活性实验表明, 目标物具有中等强度α1受体拮抗活性, 符合我们提出的三元素药效团模型. 5-氯-2-[4-(芳氧烷基)哌嗪-1-基]类化合物是一类新的具有潜在开发价值的α1受体拮抗剂.     

Synthesis, singlet oxygen photogeneration and DNA photocleavage of porphyrins with nitrogen heterocycle tails

Eight novel compounds were prepared by reaction of 5-(bromo- propoxyphenyl)-10,15,20-triphenylporphyrin with oxazole thiols, 1,3,4-oxadiazole thiols and 1,3,4-thiadiazole thiols, and their structures confirmed by UV-vis, IR, 1H-NMR, MS and elemental analysis. The assessment of indirectly measured 1O(2) production rates against 5,10,15,20-tetraphenyl porphyrin (H(2)TPP) were described and the relative singlet oxygen production yields were：porphyrin 5 > porphyrins 1, 3, 4, 6-8, H(2)TPP > porphyrin 2. Porphyrin 4 and porphyrin 7 showed substantial photocleavage activities toward DNA, with over 75% cleavage observed at 40 μM. It suggested that these those porphyrins with nitrogen heterocycle tails are potential photosensitive agents.     

Neuroprotection signaling pathway of nerve growth factor and brain-derived neurotrophic factor against staurosporine induced apoptosis in hippocampal H19-7 cells

Neurotrophins protect neurons against excitotoxicity; however the signaling mechanisms for this protection remain to be fully elucidated. Here we report that activation of the phosphatidyl inositol 3 kinase (PI3K)/Akt pathway is critical for protection of hippocampal cells from staurosporine (STS) induced apoptosis, characterized by nuclear condensation and activation of the caspase cascade. Both nerve growth factor (NGF) and brain-derived growth factor (BDNF) prevent STS-induced apoptotic morphology and caspase-3 activity by upregulating phosphorylation of the tropomyosin receptor kinase (Trk) receptor. Inhibition of Trk receptor by K252a altered the neuroprotective effect of both NGF and BDNF whereas inhibition of the p75 neurotrophin receptor (p75NTR) had no effect. Impairment of the PI3K/Akt pathway or overexpression of dominant negative (DN)-Akt abolished the protective effect of both neurotrophins, while active Akt prevented cell death. Moreover, knockdown of Akt by si-RNA was able to block the survival effect of both NGF and BDNF. Thus, the survival action of NGF and BDNF against STS-induced neurotoxicity was mediated by the activation of PI3K/Akt signaling through the Trk receptor.     

Chronic mild stress decreases survival, but not proliferation, of new-born cells in adult rat hippocampus

New-born cells continue to proliferate and survive to become mature granule cells in adult rat hippocampus. Although this process, known as neurogenesis, is inhibited by acute stress, it is not clear whether chronic stress affects neurogenesis. To determine whether chronic mild stress (CMS) influences neurogenesis in the adult rat hippocampus, male Sprague-Dawley rats were exposed to CMS and administered bromodeoxyuridine (BrdU) before or after CMS to observe the survival/differentiation or proliferation of new-born cells, respectively. In addition, we measured brain-derived neurotrophic factor (BDNF) mRNA in the granule cell layer (GCL) of the hippocampus, because BDNF is known to play an important role in the survival of new-born cells. CMS significantly decreased the survival of new-born cells in the GCL, but did not influence the proliferation or differentiation of new-born cells. CMS did not affect the proliferation and survival of new-born cells in the hilus. In addition, CMS did not change BDNF mRNA levels in the GCL. These results demonstrate that CMS reduces the survival of new-born cells but not of their proliferation, suggesting that repeated mild stress could influence a part of neurogenesis, but not the whole part of neurogenesis. These results raise the possibility that the survival of new-born cells may be suppressed in the presence of normal BDNF mRNA levels in GCL.     

Copper,BDNF and Its N‐terminal Domain: Inorganic Features and Biological Perspectives

Brain‐derived neurotrophic factor (BDNF) is a neurotrophin that influences development, maintenance, survival, and synaptic plasticity of central and peripheral nervous systems. Altered BDNF signaling is involved in several neurodegenerative disorders including Alzheimer’s disease. Metal ions may influence the BDNF activity and it is well known that the alteration of Cu²⁺ homeostasis is a prominent factor in the development of neurological pathologies. The N‐terminal domain of BDNF represents the recognition site of its specific receptor TrkB, and metal ions interaction with this protein domain may influence the protein/receptor interaction. In spite of this, no data inherent the interaction of BDNF with Cu²⁺ ions has been reported up to now. Cu²⁺ complexes of the peptide fragment BDNF(1–12) encompassing the sequence 1–12 of N‐terminal domain of human BDNF protein were characterized by means of potentiometry, spectroscopic methods (UV/Vis, CD, EPR), parallel tempering simulations and DFT‐geometry optimizations. Coordination features of the acetylated form, Ac‐BDNF(1–12), were also characterized to understand the involvement of the terminal amino group. Whereas, an analogous peptide, BDNF(1–12)D3N, in which the aspartate residue was substituted by an asparagine, was synthesized to provide evidence on the possible role of carboxylate group in Cu²⁺ coordination. The results demonstrated that the amino group is involved in metal binding and the metal coordination environment of the predominant complex species at physiological pH consisted of one amino group, two amide nitrogen atoms, and one carboxylate group. Noteworthy, a strong decrease of the proliferative activity of both BDNF(1–12) and the whole protein on a SHSY5Y neuroblastoma cell line was found after treatment in the presence of Cu²⁺. The effect of metal addition is opposite to that observed for the analogous fragment of nerve growth factor (NGF) protein, highlighting the role of specific domains, and suggesting that Cu²⁺ may drive different pathways for the BDNF and NGF in physiological as well as pathological conditions.     

Derivatives of 5-(Dimethylamino)-4-tosyl-1,3-oxazole-2-carbaldehyde and Its Analogs

Treatment of N-(2,2,2-trichloro-1-tosylethyl)dichloroacetamide with excess dimethylamine, piperidine, or morpholine gave substituted aminals of the oxazole series, whose facile acid hydrolysis provided 5-(dimethylamino)-4-tosyl-1,3-oxazol-2-carbaldehyde and its analogs having the piperidino and morpholino group in the 5 position of the oxazole ring. The resulting aldehydes and their aminals were condensed with phenylhydrazine, thiosemicarbazide, N-alkylrhodanines, and 1,3-dimethylbarbituric acid to obtain 2,5-disubstituted derivatives of 4-tosyl-1,3-oxazole.__________Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 6, 2005, pp. 1002–1006.Original Russian Text Copyright © 2005 by Vyzhdak, Danielova, Kiselev, Drach.     

3D-ASL灌注成像与静息态功能MRI在癫痫诊断及鉴别中的价值

选取123例癫痫患者作为研究组,同期69例健康体检者作为对照组,均行三维动脉自旋标记技术(3D-ASL)灌注成像与静息态功能MRI(rs-FMRI)检查,研究二者在癫痫病诊断及鉴别中的价值.结果发现,研究组全面发作脑血流量(CBF)、低频振幅(ALFF)＜部分发作和对照组,全面发作血清脑源性神经细胞营养因子(BDNF)...     

The Protection of Lactic Acid Bacteria Fermented-Mango Peel against Neuronal Damage Induced by Amyloid-Beta

Mango peels are usually discarded as waste; however, they contain phytochemicals and could provide functional properties to food and promote human health. This study aimed to determine the optimal lactic acid bacteria for fermentation of mango peel and evaluate the effect of mango peel on neuronal protection in Neuron-2A cells against amyloid beta (Aβ) treatment (50 μM). Mango peel can be fermented by different lactic acid bacteria species. Lactobacillus acidophilus (BCRC14079)-fermented mango peel produced the highest concentration of lactic acid bacteria (exceeding 10⁸ CFU/mL). Mango peel and fermented mango peel extracts upregulated brain-derived neurotrophic factor (BDNF) expression for 1.74-fold in Neuron-2A cells. Furthermore, mango peel fermented products attenuated oxidative stress in Aβ-treated neural cells by 27%. Extracts of L. acidophilus (BCRC14079)-fermented mango peel treatment decreased Aβ accumulation and attenuated the increase of subG1 caused by Aβ induction in Neuron-2A cells. In conclusion, L. acidophilus (BCRC14079)-fermented mango peel acts as a novel neuronal protective product by inhibiting oxidative stress and increasing BDNF expression in neural cells.     

New easy approach to the synthesis of 2,5-disubstituted and 2,4,5-trisubstituted 1,3-oxazoles. The reaction of 1-(methylthio)acetone with nitriles

The reaction of 1-(methylthio)acetone with different nitriles in the presence of triflic anhydride led to the one-pot formation of 2-substituted 5-methyl-4-methylthio-1,3-oxazoles in good yield. 1,2- and 1,4-Bisozaxolyl-substituted benzenes were obtained when the reaction was carried out using aromatic dinitriles. The methylthio group at the C4 position of the oxazole ring was easily removed with Raney nickel to form 2-substituted 5-methyl-1,3-oxazoles in good yields. 4-Methylsulfonyl derivatives were prepared by the oxidation of the MeS group with m-CPBA. The proposed mechanism for the formation of oxazoles involves an unstable 1-(methylthio)-2-oxopropyl triflate, which was detected from the low-temperature NMR spectra.     

2-phenyl-4-bis(methylthio)methyleneoxazol-5-one: versatile template for diversity oriented synthesis of heterocycles

4-Bis(methylthio)methylene-2-phenyloxazol-5-one (1) has been shown to be a versatile template for the synthesis of novel heterocyclic scaffolds. The key protocol involves nucleophilic ring opening of 1 with various primary aliphatic, aromatic amines and diamines to give open-chain amide adducts which are transformed into 4-bis(methylthio)methylene-2-phenyl-1-alkyl/arylimidazol-5-(4H)-ones (5) in good yields in the presence of anhydrous NaOAc/AcOH. Similarly, the amide adducts 4h-i from 3,4-dimethoxyphenylethylamine and tryptamine undergo interesting rearrangement in the presence of POCl(3) to furnish 1-(2-phenyl-5-methylthio-4-thiazolyl)dihydroisoquinoline and β-carboline derivatives 8-9 in good yields. The amide adduct 14 from o-phenylenediamine on exposure to refluxing acetic acid or in the presence of Ag(2)CO(3) affords substituted 3H-1,5-benzodiazepinone, 2-(5-methylthio-2-phenyl-4-oxazolyl)-1H-benzimidazole and trisubstituted oxazole (15-17), whereas the bis-adduct from ethylenediamine yields ethylene bridge tethered bis-imidazole 23 and bis-oxazole 24 under similar reaction conditions. Probable mechanisms for the formation of various products have been suggested.