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Chiral amine-squaramide is a kind of effective hydrogen bond donor bifunctional catalyst to promote many asymmetric transformations. In this paper, novel chiral tertiary amine-squaramide derived from the natural product of the stevioside was developed and applied into the asymmetric Michael addition of acetylacetone to nitroolefins. This asymmetric reaction performed well, and a series of enantiomerically enriched compounds were obtained in high yields (up to 96%) with excellent enantioselectivities (up to 99% ee).

The convenient preparation of N2-unprotected five-membered cyclic guanidines was achieved through a cascade [3 + 2] cycloaddition between organo-cyanamides and α-haloamides under mild conditions in good to excellent yields (up to 99%). The corresponding cyclic guanidines could be easily transformed into hydantoins via hydrolysis.

New bifunctional primary amine-squaramides catalyzed asymmetric Michael addition reaction of α,α-disubstituted aldehydes to maleimides has been developed. This organocatalytic asymmetric reaction provides easy access to functionalized succinimides with a broad substrate scope. Both enantiomers of desired succinimide derivatives were obtained in good to excellent yields (up to 98%) with excellent enantioselectivities (up to >99% ee).

The covalently cross-linked chitosan-poly(ethylene glycol)1540 derivatives have been developed as a controlled release system with potential for the delivery of protein drug. The swelling characteristics of the hydrogels based on these derivatives as the function of different PEG content and the release profiles of a model protein (bovine serum albumin, BSA) from the hydrogels were evaluated in simulated gastric fluid with or without enzyme in order to simulate the gastrointestinal tract conditions. The derivatives cross-linked with difunctional PEG1540-dialdehyde via reductive amination can swell in alkaline pH and remain insoluble in acidic medium. The cumulative release amount of BSA was relatively low in the initial 2h and increased significantly at pH 7.4 with intestinal lysozyme for additional 12h. The results proved that the release-and-hold behavior of the cross-linked CS-PEG1540H-CS hydrogel provided a swell and intestinal enzyme controlled release carrier system, which is suitable for oral protein drug delivery.

Chiral primary amine–squaramides have not been extensively studied to date in the field of organocatalysis. In this paper, novel chiral squaramides derived from natural product stevioside were developed. Both enantiomers of a series of γ-nitroaldehydes were generated by using these squaramide catalysts for the Michael addition reaction of isobutyraldehyde to nitroolefins. This asymmetric reaction proceeded well to afford the desired products in high yields (up to 98%) with high to excellent enantioselectivities (up to 99% ee).

Amyloid β-peptide (Aβ) has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer's disease (AD). Humanin (HN) is a secretory peptide that inhibits the neurotoxicity of Aβ. However, the mechanism(s) by which HN exerts its neuroprotection against Aβ-induced AD-like pathological changes and memory deficits are yet to be completely defined. In the present study, we provided evidence that treatment of rats with HN increases the number of dendritic branches and the density of dendritic spines, and upregulates pre- and post-synaptic protein levels; these effects lead to enhanced long-term potentiation and amelioration of the memory deficits induced by Aβ(1-42). HN also attenuated Aβ(1-42)-induced tau hyperphosphorylation, apparently by inhibiting the phosphorylation of Tyr307 on the inhibitory protein phosphatase-2A (PP2A) catalytic subunit and thereby activating PP2A. HN also inhibited apoptosis and reduced the oxidative stress induced by Aβ(1-42). These findings provide novel mechanisms of action for the ability of HN to protect against Aβ(1-42)-induced AD-like pathological changes and memory deficits.

Chitosan has previously been exploited as a scaffold in tissue engineering processes. To avoid infection, chitosan must be sterilized prior to contact with bodily fluids or blood. Previous research has shown that autoclaved chitosan solution lead to decreased molecular weight, dynamic viscosity, and rate of gelling. We prepared a thermosensitive chitosan hydrogel using autoclaved chitosan powder (121 °C, 10 min) and β-glycerophosphate (chitosan-PA/GP) and compared the physicochemical properties and biocompatibility in vitro with autoclaved chitosan solution/GP hydrogel. The chitosan-PA/GP hydrogel had a shortened gelation time, higher viscosity, increased water absorption, appropriate degradation time, porous structure, and no obvious cytotoxicity on human periodontal ligament cells. Scanning electron microscopy demonstrated that the cells exhibited a normal morphology. The chitosan-PA/GP hydrogel promoted periodontal tissue regeneration in dog class III furcation defects. The chitosan-PA/GP thermosensitive hydrogel displayed suitable physicochemical properties and biocompatibilities and represents a promising candidate as an injectable tissue engineering scaffold.

A doubly stereocontrolled organocatalytic asymmetric Michael addition to the synthesis of substituted succinimides is described. Starting from aldehydes and maleimides, both enantiomers of the succinimides could be obtained in high to excellent yields (up to 98%) and enantioselectivities (up to 99%) when one of the two special chiral diterpene-derived bifunctional thioureas was individually used as a catalyst. Moreover, these catalysts can be efficiently used in large-scale catalytic synthesis with the same level of yield and enantioselectivity. Chirality 00:000–000, 2014. © 2014 Wiley Periodicals, Inc.

Patients with diabetes in the aging population are at high risk of Alzheimer's disease (AD), and reduction of sirtuin 1 (SIRT1) activity occurs simultaneously with the accumulation of hyperphosphorylated tau in the AD-affected brain. It is not clear, however, whether SIRT1 is a suitable molecular target for the treatment of AD. Here, we employed a rat model of brain insulin resistance with intracerebroventricular injection of streptozotocin (ICV-STZ; 3 mg/kg, twice with an interval of 48 h). The ICV-STZ-treated rats were administrated with resveratrol (RSV; SIRT1-specific activator) or a vehicle via intraperitoneal injection for 8 weeks (30 mg/kg, once per day). In ICV-STZ-treated rats, the levels of phosphorylated tau and phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) at the hippocampi were increased significantly, whereas SIRT1 activity was decreased without change of its expression level. The capacity of spatial memory was also significantly lower in ICV-STZ-treated rats compared with age-matched control. RSV, a specific activator of SIRT1, which reversed the ICV-STZ-induced decrease in SIRT1 activity, increases in ERK1/2 phosphorylation, tau phosphorylation, and impairment of cognitive capability in rats. In conclusion, SIRT1 protects hippocampus neurons from tau hyperphosphorylation and prevents cognitive impairment induced by ICV-STZ brain insulin resistance with decreased hippocampus ERK1/2 activity.

Hyperphosphorylated tau aggregated into neurofibrillary tangles is a hallmark lesion of Alzheimer's disease (AD) and is linked to synaptic and cognitive impairments. In animal models, cold water stress (CWS) can cause cognitive disorder and tau hyperphosphorylation. Capsaicin (CAP), a specific TRPV1 agonist, is neuroprotective against stress-induced impairment, but the detailed mechanisms are still elusive. Here, we investigated whether CAP mitigates CWS-induced cognitive and AD-like pathological alterations in rats. The animals were administered CAP (10 mg/kg in 0.2 ml, 0.1% ethanol) or a control (0.2 ml normal saline, 0.1% ethanol) by intragastric infusion 1 h before CWS treatment. Our results showed that CAP significantly attenuated CWS-induced spatial memory impairment and suppression of PP-DG long-term potentiation; CAP abolished CWS-induced dendritic regression and enhanced several memory-associated proteins decreased by CWS, such as synapsin I and PSD93; CAP also prevented CWS-induced tau hyperphosphorylation by abolishing inhibition of protein phosphatase 2A. Taken together, this study demonstrated that activation of TRPV1 can mitigate CWS-induced AD-like neuropathological alterations and cognitive impairment and may be a promising target for therapeutic intervention in AD.

The investigation on the structures, stabilities, and magnetism ofNimAln(m=1–3,n=1–9) clusters has been made by using first principles. We found some new ground-state structures which had not been found before. These mixed species prefer to adopt three-dimensional (3D) structures starting from four atoms. All the ground-state structures for the Ni-Al clusters are different from those of the corresponding pure Al clusters with the same number of atoms except for three atoms. The Mulliken population analysis shows that some charges transfer from the Al atoms to the Ni atoms.NiAln(n = odd number) cations, Ni2Al6neutral, Ni2Al1and Ni3Al cations and anions, and Ni3Al5anion have the magnetic moments of 2 μB. The magnetic moments of NiAl4and NiAl6cluster neutrals and cations are 2 μBand 3 μB, respectively. All the other cluster neutrals and ions do not have any nontrivial magnetic moments. The 3d electrons in Ni atoms are mainly responsible for the magnetism of the mixed Ni-Al clusters.

Chiral isosteviol-derived tertiary amine-thiourea was proven to be effective in catalyzing the asymmetric conjugate addition between α-substituted cyanoacetate and maleimides. Diverse succinimides bearing vicinal quaternary-tertiary stereocenters were obtained in excellent yields, excellent diastereoselectivities, and with good to high enantioselectivities. This catalytic system can be used efficiently in large-scale reactions with the yields and stereoselectivities being maintained at the same level.

A novel class of chiral bifunctional thioureas bearing a chiral lipophilic beyerane scaffold and a tertiary amino group was designed and prepared. The thioureas were proven to be effective for catalyzing the doubly stereocontrolled asymmetric Michael addition between acetylacetone and nitroolefins. The corresponding adducts were obtained in high yields (up to 95%) and with good to excellent enantioselectivities (up to 97%). In addition, the reaction of tert -butyl acetoacetate and trans -β-nitrostyrene also proceeded smoothly with good enantioselectivity.

A novel class of chiral multifunctional thioureas bearing a chiral lipophilic beyerane scaffold and a primary amino group were designed and prepared. The thioureas were proven to be effective for catalyzing the asymmetric Michael addition between isobutyraldehyde and maleimides with only 0.5 mol % catalyst loading, and exhibited double asymmetric induction. Both of the catalysts afforded the corresponding adduct with high to excellent yields (up to 98%) and excellent enantioselectivities (up to 99%). Furthermore, this catalytic system can be used efficiently in large-scale reactions with the yields and enantioselectivities being maintained at the same level.

A novel class of chiral amphiphilic bifunctional thioureas based on a beyerane scaffold and each containing a primary amino group were designed and synthesized from the readily available natural product isosteviol. The thioureas were shown to be effective for catalyzing asymmetric Michael additions between isobutyraldehyde and nitroalkenes. The chiral thiourea 1a furnished S enantiomers, whereas 1b afforded R enantiomers, both with high yields (up to 92 %) and high to excellent enantioselectivities (up to 98 %). Furthermore, the reactions proceeded smoothly both in organic solvents and in water under mild conditions.

A series of new polymer-supported palladium complexes with C,N-ligands (1a–e and 2a–c) were easily synthesized. The synthesized catalysts could be applied as efficient heterogeneous catalysts for the Heck coupling reaction (turnover frequency up to 12 600 h−1). Additionally, the catalysts could be recovered by a simple filtration progress and could be reused for at least five times with a slow progressive decrease in activity. Copyright © 2010 John Wiley & Sons, Ltd.

We have examined, by immunocytochemical methods and nociceptive behavior assessment in rats, whether astrocytes in the parabrachial nucleus (PBN) are involved in the regulation of traumatic occlusion. The expression of glial fibrillary acidic protein (GFAP) in PBN of ipsilateral and contralateral sides was up-regulated 4 h after occlusal changes in molars, reached peak levels at 24 h, and was then gradually down-regulated. PBN astrocytes activated by traumatic occlusion were found to have enlarged cell bodies and thickened processes within 8 h. An inhibitor of glia metabolism (FCA, fluorocitrate) reduced astrocyte activation and significantly attenuated the development of pain hypersensitivity in this model. The results suggested that the GFAP-immunoreactive astrocytes in PBN within the bridge of Varolius were activated by traumatic occlusion, and that they were involved in the transmission and modulation of nociceptive information in the central nervous system. However, although astrocytes in PBN are thus probably involved in causing post-occlusal hyperalgesia, we have not been able to exclude that astrocytes at other locations also contribute to this effect.

Recent developments of biotechnology have produced a great variety of protein and bioactive drugs. For these drugs to be used therapeutically, suitable drug delivery systems have become increasingly essential. Dextran-derived biomaterials have been considered to be compatible matrices for protein and bioactive drugs because of their hydrophilic properties and ability to control drug dissolution and permeability. A novel class of dextran-glycidylmethacrylate (Dex-GMA)/poly(ethylene glycol) (PEG) microspheres were designed and synthesized by polymerization of Dex-GMA emulsified in an aqueous PEG solution. Dex-GMA was prepared by substituting the hydroxyl groups in Dex by GMA. The drug loading and in vitro drug release was evaluated by routine procedure and the biological activity of BMP-loaded microspheres was studied by experimental cytology methods. Recombinant human bone morphogenetic protein-2 (rhBMP-2) were entrapped in dextran-derived microspheres quantitatively and with full preservation of their biological activity. In vitro release kinetics indicated that dextran-derived microspheres could retain rhBMP-2 in a variable manner depending on the preparation and degradation of the microspheres. The release profiles of rhBMP-2 from microspheres as a function of time showed that rhBMP-2 releasing kinetics in vitro fitted to first-order and Higuchi equations. The release profile in vitro was in accord with two phases kinetics law and more than 60% drug were released during 20 days. Cytology studies showed rhBMP-2 microspheres have good biological effects on cultured periodontal ligament cells, and could achieve a longer action time than concentration of rhBMP-2 solution. These properties make those microspheres interesting osteo-conductive BMP carriers, allowing to decrease the amount of implanted factor required for tissue regeneration.

A novel 99mTc nitrido xanthate complex 99mTcN(IPEXT)2 (IPEXT: isopentyl xanthate) has been synthesized by the reduction of 99mTcO4− into [99mTcN]2+ with stannous chloride in the presence of succinic dihydrazide and propylenediamine tetraacetic acid, followed by the addition of the corresponding xanthate ligand. The radiochemical purity of the complex was over 90% as measured by thin layer chromatography (TLC). No decomposition of the complex at room temperature was observed over a period of 6 hours. Its partition coefficient indicated that it was a lipophilic complex. The electrophoresis results showed the complex was neutral. Biodistribution in mice showed that the 99mTcN(IPEXT)2 complex accumulated in the heart with high uptake. The heart uptake (%IDg) was 8.00% at 5-minute post-injection, but the heart/lung, heart/liver and heart/blood ratios were not high, thereby, restricting the use of the complex as a good myocardial imaging agent.

Enantiopure isosteviol-derived tertiary amine-thiourea (THI) is proven to be effective in catalyzing the asymmetric conjugate addition between α-substituted cyanoacetates (I) and maleimides (II).

The activity of protein phosptase-2A (PP2A) is significantly decreased in the brains of Alzheimer's disease (AD) patients, but the upstream effectors for regulating PP2A activity are not fully understood. Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) is a key enzyme involved in energy metabolism and its gene expression level is reduced in AD brain specimens. Whether Nmnat2 can activate PP2A deserves to be explored. Here, we first measured the level of Nmnat2, Tyr307-phosphorylation of PP2A, and tau phosphorylation in Tg2576 mice. We observed that the mRNA and protein levels of Nmnat2 were significantly decreased with a simultaneous elevation of p-Tyr307-PP2A and tau phosphorylation in Tg2576 mice. Further studies in HEK293 cells with stable expression of human tau441 (HEK293/tau) demonstrated that simultaneous inhibition of PP2A by okadaic acid abolished the Nmnat2-induced tau dephosphorylation. Moreover, we further demonstrated that overexpression of Nmnat2 could activate PP2A with attenuation of tau phosphorylation, whereas downregulation of Nmnat2 by shRNA inhibited PP2A with tau hyperphosphorylation at multiple AD-associated sites. Our data provide the first evidence that Nmnat2 affects tau phosphorylation by regulating PP2A activity, suggesting that Nmnat2 may serve as a potential target in arresting AD-like tau pathologies.

The retinoblastoma protein, Rb, is detected in extracts of monkey CV-1 cells complexed with Pur alpha, a sequence-specific single-stranded DNA-binding protein implicated in control of gene transcription and DNA replication. These complexes can be immunoextracted from cell lysates using monoclonal antibodies to either Pur alpha or Rb. The Pur alpha-Rb complexes contain a form of Pur alpha with extensive post-synthetic modification, as demonstrated following expression of Pur alpha cDNA fused to a 9-amino acid epitope tag. Human Pur alpha, expressed as a glutathione S-transferase fusion protein, specifically binds to the hypophosphorylated form of Rb with an affinity as high as that of SV40 large T-antigen. In the absence of DNA, glutathione S-transferase-Pur alpha binds to p56RB, an NH2-terminal-truncated Rb protein purified from Escherichia coli, containing the T-antigen binding domain, to form multimeric complexes. The single-stranded DNA Pur alpha recognition element disrupts these complexes. Conversely, high concentrations of p56RB prevent Pur alpha binding to DNA. Through use of a series of deletion mutants, the DNA binding activity of Pur alpha is localized to a series of modular amino acid repeats. Rb binding involves a Pur alpha region with limited homology to the Rb-binding region of SV40 large T-antigen. Binding of Pur alpha to p56RB, the COOH-terminal portion of Rb, is inhibited by a synthetic peptide containing the T-antigen Rb-binding motif.

Purα (PurA) is a sequence-specific single-stranded-DNA-binding protein implicated in control of both DNA replication and transcription. We have localized the Purα gene (PURA) to human chromosome band 5q31 by fluorescence in situ hybridization with a 16-kb genomic probe together with hybridization of a cDNA probe to blots of DNA from human-hamster cell lines containing individual human chromosomes. Sequences with homology to the PURA locus are also present at 6ql4. The 5q31 locus is frequently deleted in myelogenous leukemias and other cancers.

Hyperhomocysteinemia (Hhcy) may induce memory deficits with β-amyloid (Aβ) accumulation and tau hyperphosphorylation. Simultaneous supplement of folate and vitamin B12 partially restored the plasma homocysteine level and attenuated tau hyperphosphorylation, Aβ accumulation and memory impairments induced by Hhcy. However, folate and vitamin B12 treatment have no effects on Hhcy which has the methylenetetrahydrofolate reductase genotype mutation. In this study, we investigated the effects of simultaneous supplement of betaine on Alzheimer-like pathological changes and memory deficits in hyperhomocysteinemic rats after a 2-week induction by vena caudalis injection of homocysteine (Hcy). We found that supplementation of betaine could ameliorate the Hcy-induced memory deficits, enhance long-term potentiation (LTP) and increase dendritic branches numbers and the density of the dendritic spines, with up-regulation of NR1, NR2A, synaptotagmin, synaptophysin, and phosphorylated synapsin I protein levels. Supplementation of betaine also attenuated the Hcy-induced tau hyperphosphorylation at multiple AD-related sites through activation protein phosphatase-2A (PP2A) with decreased inhibitory demethylated PP2A(C) at Leu309 and phosphorylated PP2A(C) at Tyr307. In addition, supplementation of betaine also decreased Aβ production with decreased presenilin-1 protein levels. Our data suggest that betaine could be a promising candidate for arresting Hcy-induced AD-like pathological changes and memory deficits.

The new chiral thiourea TUC bearing a chiral lipophilic beyerane scaffold and a primary amino group, catalyzes the asymmetric Michael addition between aliphatic aldehydes and different maleimides (I) with only 0.5 mol % loading.

The novel organocatalyst (I) is effective in the reaction of isobutyraldehyde (III) with nitroalkenes to afford the (S)-products (V).

New polymer-supported palladium complexes with C,N-ligands are easily synthesized and applied efficiently for the Heck reaction of iodobenzene and butylacrylate with high turnover frequencies up to 12 600.

Localized delivery of growth factors has significant potential as a future therapeutic strategy in tissue engineering and regenerative medicine. A nanoparticle vehicle was created and evaluated in this study with the intent to deliver growth factors for periodontal regeneration. Novel composite nanoparticles based on glycidyl methacrylate derivatized dextrans (Dex-GMA) and gelatin were fabricated by a facile method without using any organic solvents. The configurations of the resultant nanoparticles were evaluated by transmission electron microscopy, scanning electron microscopy, and atomic force microscope. Their surfaces were characterized by zeta-potential measurements, after which their properties including swelling, degradation, drug release, and cytotoxicity were also investigated using in vitro models. The particle size of Dex-GMA/gelatin nanoparticles (DG-NPs) ranged from 20 to 100 nm and showed a mono-disperse size distribution (mean diameter 53.7 nm) and a strongly negative surface zeta potential (−20 mV). The DG-NPs were characterized by good swelling and degradation properties in media including dextranase. The in vitro drug release studies showed that the efficient bone morphogenetic protein (BMP) release from DG-NPs was maintained for more than 12 d under degradation conditions, where more than 90% of the loaded BMP was released. No any relevant cell damage caused by DG-NPs was found in the cytotoxicity tests for a period of 24 h. These combined results demonstrate that DG-NPs fulfill the basic prerequisites for growth factor delivery. With further in vivo studies, those nanoparticles may offer a promising vehicle for the delivery of active drugs to the periodontium.