Chiral Brønsted Acid-Catalyzed Asymmetric Reaction via Vinylidene ortho-Quinone Methides.

Vinylidene ortho-quinone methides (VQMs) have been proven to be versatile and crucial intermediates in the catalytic asymmetric reaction in last decade, and thus have drawn considerable concentrations on account of the practical application in the construction of enantiomerically pure functional organic molecules. However, in comparison to the well established chiral Brønsted base-catalyzed asymmetric reaction via VQMs, chiral Brønsted acid-catalyzed reaction is rarely studied and there is no systematic summary to date. In this review, we summarize the recent advances in the chiral Brønsted acid-catalyzed asymmetric reaction via VQMs according to three types of reactions: a) intermolecular asymmetric nucleophilic addition to VQMs; b) intermolecular asymmetric cycloaddition of VQMs; c) intramolecular asymmetric cyclization of VQMs. Finally, we put forward the remained challenges and opportunities for potential breakthroughs in this area.

[Expression of Peroxiredoxin-6 Gene in Patients with Acute Myeloid Leukemia and Its Clinical Significance].

OBJECTIVE: To study the expression of Peroxiredoxin-6 (Prdx6) gene in elderly patients with acute myeloid leukemia (AML) and its clinical significance. METHODS: The expression level of Prdx6 in bone marrow cells of 33 cases of AML, 8 cases of CML and 11 cases of other blood diseases was detected by PCR. The correlation of the abnormal expression of Prdx6 with patient age and blood routine parameters was further analyzed. RESULTS: the expression level of Prdx6 in elderly patients with AML (≥60 years) was significantly lower than that in younger patients (＜60 years) (P＜0.05); the expression level of Prdx6 in low WBC (≤1×109/L) group was lower than that in medium WBC (1-10×109/L) group or high WBC (＞10×109/L) group (P＜0.05); the proportion of WBC count (≤1×109/L) in elderly patients with AML reached 38.5%, which was significantly higher than that in younger patients (5%) (P＜0.05); the overall survival (OS) rate of elderly patients was lower than that of younger patients (P＜0.05). CONCLUSION: The expression of Prdx6 in elderly patients with AML is low, moreover, it relates with low value of WBC in peripheral blood, suggesting that it may be one of poor prognostic factors for the elderly patients with AML.

[Toll-like Receptor Agonists in Radiation Protection].

Ionizing radiation causes the massive apoptosis of human tissue cells,leading to dysfunction of the gastrointestinal tract and hematopoietic system.Thus,high-efficiency,low-toxicity radiation protection drugs are urgently needed.Toll-like receptor agonists have been developed based on the anti-apoptotic mechanism of tumor cells in recent years,which exert their radioprotective effects by activating downstream pathways,mainly nuclear factor-κB.Here we elucidate several agonists of Toll-like receptors involved in radiation protection,with an attempt to inform the research and development of new radiation protection agents.

Transplantation of bone marrow mesenchymal stem cells promotes learning and memory functional recovery and reduces hippocampal damage in rats with alcohol-associated dementia.

BACKGROUND: Chronic ethanol exposure leads to permanent damage to the central nervous system and produces cognitive deficits such as learning and memory impairment. The present study was designed to explore the therapeutic effect of bone marrow mesenchymal stem cells (BMMSCs) on a rat model of alcohol-associated dementia (AAD). METHODS: Bone marrow mesenchymal stem cells were prelabeled with 4',6-diamidino-2-phenylindole and directly transplanted into the hippocampus of AAD rats, an important site of alcohol effects that lead to cognitive deficits. The therapeutic effect of BMMSCs was evaluated by observing Morris water maze behavior, hippocampus morphology, and neuronal apoptosis. Still, the activities of antioxidant enzymes including total superoxide dismutase and glutathione peroxidase in rat hippocampus were measured, and the expression of brain-derived neurotrophic factor in rat hippocampus was also detected by the method of immunohistochemistry. RESULTS: Transplantation of BMMSCs directly into the hippocampus significantly improved the learning and memory function of AAD rats and prevented alcohol-induced hippocampal damages. Moreover, BMMSC transplantation inhibited neuron cell apoptosis and increased the activity of total superoxide dismutase in the hippocampus. Moreover, transplantation of BMMSCs improved the protein level of brain-derived neurotrophic factor in the hippocampus in parallel with behavioral and histologic recovery for AAD rats. CONCLUSIONS: The findings indicate that the functional benefit observed in the BMMSC-grafted AAD rats is caused by the reduction of oxidative damage and the production of trophic factors by BMMSCs. Bone marrow mesenchymal stem-cell transplantation may be a useful and feasible method for clinical treatment of alcohol-induced brain injuries.

Hydrogen sulfide inhibits opioid withdrawal-induced pain sensitization in rats by down-regulation of spinal calcitonin gene-related peptide expression in the spine.

Hyperalgesia often occurs in opioid-induced withdrawal syndrome. In the present study, we found that three hourly injections of DAMGO (a µ-opioid receptor agonist) followed by naloxone administration at the fourth hour significantly decreased rat paw nociceptive threshold, indicating the induction of withdrawal hyperalgesia. Application of NaHS (a hydrogen sulfide donor) together with each injection of DAMGO attenuated naloxone-precipitated withdrawal hyperalgesia. RT-PCR and Western blot analysis showed that NaHS significantly reversed the gene and protein expression of up-regulated spinal calcitonin gene-related peptide (CGRP) in naloxone-treated animals. NaHS also inhibited naloxone-induced cAMP rebound and cAMP response element-binding protein (CREB) phosphorylation in rat spinal cord. In SH-SY5Y neuronal cells, NaHS inhibited forskolin-stimulated cAMP production and adenylate cyclase (AC) activity. Moreover, NaHS pre-treatment suppressed naloxone-stimulated activation of protein kinase C (PKC) α, Raf-1, and extracellular signal-regulated kinase (ERK) 1/2 in rat spinal cord. Our data suggest that H2S prevents the development of opioid withdrawal-induced hyperalgesia via suppression of synthesis of CGRP in spine through inhibition of AC/cAMP and PKC/Raf-1/ERK pathways.

Chronic morphine treatment induces over-expression of HSP70 in mice striatum related with abnormal ubiquitin-proteasome degradation.

BACKGROUND: It has been shown that opioid dependence-related neuronal plasticity may rely not only on protein synthesis, but also on protein degradation, mainly mediated by ubiquitin-proteasome system (UPS). The aim of the present study was to determine the effect of morphine on the regulation of protein degradation in the brain and to determine which proteins are involved in the underlying mechanism. METHODS: Mice were given chronic morphine administration and the state of morphine dependence was confirmed by induction of naloxone-precipitated withdrawal jumping. The level of ubiquitinated proteins in the striatum and spinal cord of morphine-dependent mice was detected by Western blotting. One of the abnormal-ubiquitinated proteins in mice striatum was identified by electrospray ionization quadrupole time-of-flight tandem mass spectrometry and the result was further confirmed by Western blotting and immunofluorescence method. RESULTS: We found that the expression of some ubiquitinated proteins was clearly decreased in the striatum of morphine-depnendent mice, but not in the spinal cord. And we identified a ubiquitinated protein (>79 kDa) decreased in the striatum as heat shock cognate 70 protein, one member of the 70 kDa family of heat shock proteins (HSP70). Moreover, we confirmed the level of HSP70 protein was significantly increased in mice striatum. CONCLUSIONS: These data strongly suggest morphine-induced HSP70 overexpression in the striatum is closely related with its abnormal degradation by UPS and it seems to be an important mechanism associated with morphine dependence.

Hydrogen sulfide attenuates opioid dependence by suppression of adenylate cyclase/cAMP pathway.

AIMS: The best-established mechanism of opioid dependence is the up-regulation of adenylate cyclase (AC)/cAMP pathway, which was reported to be negatively regulated by hydrogen sulfide (H2S), a novel endogenous neuromodulator. The present study was, therefore, designed to determine whether H2S is able to attenuate the development of opioid dependence via down-regulating AC/cAMP pathway. RESULTS: We demonstrated that application of sodium hydrosulphide (NaHS) and GYY4137, two donors of H2S, significantly alleviated naloxone-induced robust withdrawal jumping (the most sensitive and reliable index of opioid physical dependence) in morphine-treated mice. Repeated treatment with NaHS inhibited the up-regulated protein expression of AC in the striatum of morphine-dependent mice. Furthermore, NaHS also attenuated morphine/naloxone-elevated mRNA levels of AC isoform 1 and 8, production of cAMP, and phosphorylation of cAMP response element-binding protein (CREB) in mice striatum. These effects were mimicked by the application of exogenous H2S or over-expression of cystathione-ß-synthase, an H2S -producing enzyme, in SH-SY5Y neuronal cells on treatment with [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-Enkephalin, a selective µ-opioid receptor agonist. Blockade of extracellular-regulated protein kinase 1/2 (ERK1/2) with its specific inhibitor attenuated naloxone-induced CREB phosphorylation. Pretreatment with NaHS or stimulation of endogenous H2S production also significantly suppressed opioid withdrawal-induced ERK1/2 activation in mice striatum or SH-SY5Y cells. INNOVATION: H2S treatment is important in prevention of the development of opioid dependence via suppression of cAMP pathway in both animal and cellular models. CONCLUSION: Our data suggest a potential role of H2S in attenuating the development of opioid dependence, and the underlying mechanism is closely related to the inhibition of AC/cAMP pathway.

Effects of chronic morphine treatment on protein expression in rat dorsal root ganglia.

The initial aim of this study was to identify protein changes in the dorsal root ganglia (DRG) associated with long-term morphine treatment. We carried out a differential proteomics analysis on samples from the DRG of control and morphine-dependent rats (5-40 mg/kg, subcutaneously, twice daily for 28 days) after 4 days of morphine withdrawal. Proteins showing a statistically significant variation between the two groups were selected for identification by mass spectrometric analysis. Twelve proteins were unambiguously identified, with the majority being enzymes involved in energy metabolism and protein degradation, signaling and cytoskeletal proteins. Aldolase C and proteasome subunit alpha type 3 (PRC8 or alpha7) were further examined by Western blot analysis in the DRG, prefrontal cortex, nucleus accumbens, striatum, hippocampus, ventral tegmental area and locus coeruleus. In addition, expression of PRC8 in the nucleus accumbens tissue after spontaneous or naloxone-precipitated withdrawal was determined using immunohistochemical staining. Our results indicate that the expression levels of aldolase C and PRC8 proteins were altered in a time- and region-specific manner, and suggest that they could be implicated in the molecular changes underlying adaptations of neurons observed with chronic morphine treatment.

Chronic morphine administration induces over-expression of aldolase C with reduction of CREB phosphorylation in the mouse hippocampus.

In recent studies, alterations in the activity and expression of metabolic enzymes, such as those involved in glycolysis, have been detected in morphine-dependent patients and animals. Increasing evidence demonstrates that the hippocampus is an important brain region associated with morphine dependence, but the molecular events occurring in the hippocampus following chronic exposure to morphine are poorly understood. Aldolase C is the brain-specific isoform of fructose-1, 6-bisphosphate aldolase which is a glycolytic enzyme catalyzing reactions in the glycolytic, gluconeogenic, and fructose metabolic pathways. Using Western blot and immunofluorescence assays, we found the expression of aldolase C was markedly increased in the mouse hippocampus following chronic morphine treatment. Naloxone pretreatment before morphine administration suppressed withdrawal jumping, weight loss, and overexpression of aldolase C. CREB is a transcription factor regulated through phosphorylation on Ser133, which is known to play a key role in the mechanism of morphine dependence. When detecting the expression of phosphorylated CREB (p-CREB) in the mouse hippocampus using Western blot and immunohistochemistry, we found CREB phosphorylation was clearly decreased following chronic morphine treatment. Interestingly, laser-confocal microscopy showed that overexpression of aldolase C in mouse hippocampal neurons was concomitant with the decreased immunoreactivity of p-CREB. The results suggest potential links between the morphine-induced alteration of aldolase C and the regulation of CREB phosphorylation, a possible mechanism of morphine dependence.

1-Hydroxymethyl-1-methylethan-aminium chloride.

The asymmetric unit of the title compound, C(4)H(12)NO(+)·Cl(-), contains two independent ion pairs. Weak intra-molecular C-H⋯O and N-H⋯O hydrogen bonds result in the formation of three five-membered rings, which have envelope conformations. The crystal structure contains intermolecular O-H⋯Cl, N-H⋯O, N-H⋯Cl and O-H⋯O hydrogen bonds.

2-Methyl-7-nitro-2,3-dihydro-1-benzofuran.

The dihydro-furan ring of the title compound, C(9)H(9)NO(3), adopts an envelope conformation. The nitro group is twisted slightly away from the attached benzene ring [dihedral angle = 21.9 (1)°].

[Hydroquinone inhibits NF-kappaB expression in human bone marrow stromal cells in vitro].

This study was aimed to investigate whether hydroquinone (HQ) can inhibit NF-kappaB expression activated by phorbol myristate acetate (PMA), and to explore the relationship between the mechanism and the hematology toxicity of benzene tentatively. The human bone marrow stromal cells (BMSC) were harvested by in vitro culture and their change of morphology were observed. The activity and protein expression of NF-kappaB p65 extracted from those BMSC were measured with immunohistochemistry and TransAM P65 kit. The results showed that in cells exposed to HQ, P65 transferred from cell nucleus to cytoplasma around cell nucleus and its concentration lowered by immunohistochemistry. And TransAM P65 kit assay revealed that HQ effects at different concentrations were distinctive at respective time. The detected parameters in 100 micromol/L HQ group were significantly different from control group after exposure for 72 hours. But the parameters at different time in micromol/L HQ group were not obviously different. It is concluded that hydroquinone can inhibit NF-kappaB activated by PMA in BMSCs culture. This kind of inhibitory action correlated with the concentration of HQ and exposure time.