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ABSTRACT: The relationship between learning/memory performance and long-term potentiation (LTP) induction is ambiguous. Although a large body of data supports a strong correspondence between learning/memory performance and LTP, many studies have also provided evidence to the contrary. In this study, we found that 2-month-old senescence-accelerated mice/prone 8 (SAMP8 mice) displayed both impaired performance in a Morris water maze and enhanced LTP compared to senescence-accelerated mice/resistance 1 (SAMR1). BALB/c mice challenged with Complete Freund's adjuvant (CFA) performed better in the shuttle-box test but displayed impaired LTP compared to intact animals. It is interesting that BALB/c mice challenged with incomplete Freund's adjuvant (IFA) performed better than intact animals, with no LTP impairment. Cytokine analysis showed no significant differences between the IL-6, IL-10 or TNF-α content in the intact hippocampal tissues of either the SAMR1 and SAMP8 mice or the immune challenged BALB/c and intact animals. Further analysis demonstrated that the increase in cytokine content was higher in the hippocampal tissues used for LTP recording in the SAMR1 and CFA-challenged animals compared to the SAMP8 and intact BALB/c mice. A correlation analysis demonstrated that pro-inflammatory cytokines (IL-6 and TNF-α) displayed a negative correlation with LTP, while an anti-inflammatory cytokine (IL-10) displayed a positive correlation with LTP. These results suggest that pro-inflammatory cytokines induced by LTP manipulation in experiments (e.g., via tissue injury caused by electrode insertion) may be one of the factors contributing to the observed lack of correspondence between memory/learning ability and LTP.
Neuroscience 11/2012; · 3.38 Impact Factor
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ABSTRACT: INTRODUCTION: Naturally occurring CD4+CD25+ regulatory T (Treg) cells are central to the maintenance of peripheral tolerance. Impaired activity and/or a lower frequency of these cells lead to systemic lupus erythematosus (SLE). Manipulating the number or activity of Treg cells is to be a promising strategy in treating it and other autoimmune diseases. We have examined the effects of Y27, a novel derivative of 4-hydroxyquinoline-3-formamide, on SLE-like symptoms in MRL/lpr autoimmune mice and BDF1 hybrid mice. Whether the beneficial effect of Y27 involves modulation of CD4+CD25+ Treg cells has also been investigated. METHODS: Female MRL/lpr mice that spontaneously develop lupus were treated orally by gavage with Y27 for 10 weeks, starting at 10 weeks of age. BDF1 mice developed a chronic graft-versus-host disease (GVHD) by two weekly intravenous injections of parental female DBA/2 splenic lymphocytes, characterized by immunocomplex-mediated glomerulonephritis resembling SLE. Y27 was administered to chronic GVHD mice for 12 weeks. Nephritic symptoms were monitored and the percentage of CD4+CD25+FoxP3+ Treg peripheral blood leukocyte was detected with mouse regulatory T cell staining kit by flowcytometry. Purified CD4+CD25+ Tregs were assessed for immune suppressive activity using the mixed lymphocyte reaction. RESULTS: The life-span of MRL/lpr mice treated with Y27 for 10 weeks was significantly prolonged, proteinuria and renal lesion severity were ameliorated, and blood urea nitrogen, triglyceride and serum anti-double-stranded DNA antibodies were decreased. Similar results were found in chronic GVHD mice. Administration of Y27 had little impact on percentage of the peripheral blood lymphocyte CD4+CD25+Foxp3+ Treg cells in both groups of mice. In contrast, the suppressive capacity of CD4+CD25+ Treg cells in splenocytes was markedly augmented in Y27-treated mice ex vivo. CONCLUSIONS: Experimental evidence of the protect effects of Y27 against autoimmune nephritis has been shown. The mechanism may involve enhancement of the suppressive capacity of CD4+CD25+ Treg cells.
Arthritis research & therapy 11/2012; 14(6):R235. · 4.27 Impact Factor
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ABSTRACT: Hemiasterlin is a tripeptide with highly alkylated unnatural amino acids. It acts as a potent tumor cell growth inhibitor.
From the comparison of the N-terminal between hemiasterlin and its analogues, a further modification was conducted on this
position for a SAR study. Some unnatural amino acids with aryl or ureido groups were introduced into the N-terminal of hemiasterlin
analogues to improve their hydrophobicity/hydrophilicity. Here 14 hemiasterlin analogues were synthesized. And their activities
against tumor cell lines were evaluated. Discussions on SAR preliminarily indicated that no matter whether the N-terminals
come from the aryl or alkyl units, sufficient steric bulk, lipophilicity and methylation of the N-terminal should be crucial
factors to the cytotoxic activity.
International Journal of Peptide Research and Therapeutics 04/2012; 15(3):187-194. · 0.99 Impact Factor
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ABSTRACT: Liuwei Dihuang decoction (LW) is a typical traditional Chinese medicine (TCM) prescription and consists of six herbs including Rehmannia glutinosa Libosch. (family: Scrophulariaceae), Cornus officinalis Sieb. (family: Cornaceae), Dioscorea opposite Thunb. (family: Dioscoreaceae), Alisma orientale (G. Samuelsson) Juz (family: Alismataceae), Poria cocos (Schw.)Wolf (family: Polyporaceae) and Paeonia suffruticosa Andrews (family: Paeoniaceae). It has long been used clinically in treatment of many kinds of diseases with the sign of Yin insufficiency of kidney.
Our previous pharmacological studies demonstrated that LW possesses effect of ameliorating the decline of the learning and memory in senescence accelerated mouse/prone 8 (SAMP8), but the mechanism has not been well established. LW-containing serum (LWCS) is used in the current study to elucidate the possible mechanisms.
6-month-old SAMP8 was used in this study to investigate the effect of LWCS on the induction of long-term potentiation (LTP). Primary cultured hippocampal neurons were used in this study to investigate the effects of LWCS on [Ca(2+)](i), I(Ca) and N-Methyl-d-aspartate (NMDA)-evoked currents. [Ca(2+)](i) was imaged using Fluo-3 and whole-cell patch recordings were applied to study the I(Ca) and NMDA-evoked currents.
We find that LWCS facilitates the induction of LTP in hippocampal slices of 6-month-old SAMP8. In primary cultured hippocampal neurons, LWCS increases intracellular [Ca(2+)](i), the I(Ca) is suppressed by LWCS, and NMDA-evoked currents are promoted.
These results indicate that LW improves the synaptic plasticity by inhibiting voltage-dependent calciumchannels (VDCCs) and promoting the function of NMDA receptors. This improvement might be one of the mechanisms contributing to cognitive improvement effect of LW.
Journal of ethnopharmacology 03/2012; 140(2):384-90. · 2.32 Impact Factor
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ABSTRACT: In this study, we investigated the performance of BALB/c mice in Morris water maze task under two different illumination (bright and dim light) conditions. The results show that BALB/c mice could not complete the Morris water maze task under bright light (BLC), but performed very well under dim light (DLC). Animals that swam under BLC had a higher serum corticosterone level than those under DLC. Animals pretrained under DLC had a lower serum corticosterone level than those directly exposed to BLC. Our results also show that animals under BLC had a higher level of thigmotaxis (a behavioral anxiety measure during testing) than under DLC. Correlation analysis shows that corticosterone and thigmotaxis levels have a positive correlation with escape latency, indicating that corticosterone and thigmotaxis levels have a negative correlation with learning/memory performance. These results suggest that BALB/c mice have the ability to learn a spatial task; under BLC, they performed poorly owing to a high level of thigmotaxis.
Behavioural brain research 09/2011; 226(1):26-31. · 3.22 Impact Factor
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ABSTRACT: In this work, metabonomic methods utilizing (1)H NMR spectroscopy and multivariate statistical technique have been applied to investigate the metabolic profiles of SAM. The serum metabolome of senescence-prone 8 (SAMP8), a murine model of age-related learning and memory deficits and Alzheimer's disease (AD), was compared with that of control, senescence-resistant 1 (SAMR1), which shows normal aging process. Serum samples were collected for study from both male and female 12-month-old SAMP8 and age matched SAMR1 ( n = 5). (1)H NMR spectra of serum were analyzed by pattern recognition using principal components analysis. The results showed that the serum metabolic patterns of SAMP8 and SAMR1 were significantly different due to strains and genders. Subtle differences in the endogenous metabolite profiles in serum between SAMP8 and SAMR1 were observed. The most important metabolite responsible for the strain separation was lack of inosine, which meant the protective function of anti-inflammation, immunomodulation and neuroprotection might be attenuated in SAMP8. Other differential metabolites observed between strains included decreased glucose, PUFA, choline, phosphocholine, HDL, LDL, D-3-hydoxybutyrate, citrate and pyruvate and increased lactate, SFA, alanine, methionine, glutamine and VLDL in serum of SAMP8 compared with those of SAMR1, suggesting perturbed glucose and lipid metabolisms in SAMP8. Besides the differences observed between the strains, an impact of gender on metabolism was also found. The females exhibited larger metabolic deviations than males and these gender differences in SAMP8 were much larger than in SAMR1. Higher levels of VLDL, lactate and amino acids and lower levels of HDL, LDL and unsaturated lipids were detected in female than in male SAMP8. These facts indicated that the metabolism disequilibrium in female and male SAMP8 was different and this may partly explain that females were more prone to AD than males. The results of this work may provide valuable clues to the understanding of the mechanisms of the senile impairment and the pathological changes of AD, as well as show the potential power of the combination of the NMR technique and the pattern recognition method for the analysis of the biochemical changes of certain pathophysiologic conditions.
Journal of Proteome Research 09/2008; 7(9):3678-86. · 5.11 Impact Factor
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Jiankun Qie,
Jinbo Ma,
Liangyou Wang,
Xiaoyu Xu,
Jianquan Zheng,
Sijian Dong,
Jianwei Xie,
Huixian Sun, Wenxia Zhou,
Chunhui Qi,
Xiunan Zhao,
Yongxiang Zhang,
Keliang Liu
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ABSTRACT: Site-specific mono-PEGylations were performed in different conformational regions of Thymosin alpha 1 (T alpha 1) by introducing one cysteine residue into the chosen site and coupling with thiol-specific mPEG-MAL reagent. Results demonstrated that PEGylated sites and regions influenced the conformations and pharmacokinetic profiles of the peptide greatly with following order: alpha-helix, beta-turn, random coil and terminals, but little on the immunoactivity.
Drug metabolism letters. 09/2007; 1(3):232-40.
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Jiankun Qie,,
Jinbo Ma,,
Liangyou Wang,,
Xiaoyu Xu,,
Jianquan Zheng,,
Sijian Dong,,
Jianwei Xie,,
Huixian Sun,, Wenxia Zhou,,
Chunhui Qi,,
Xiunan Zhao,,
Yongxiang Zhang,,
Keliang Liu,
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ABSTRACT: Site-specific mono-PEGylations were performed in different conformational regions of Thymosin alpha 1 (Tα1) by introducing one cysteine residue into the chosen site and coupling with thiol-specific mPEG-MAL reagent. Results demonstrated that PEGylated sites and regions influenced the conformations and pharmacokinetic profiles of the peptide greatly with following order: α-helix, β-turn, random coil and terminals, but little on the immunoactivity.
Drug Metabolism Letters 07/2007; 1(3):232-340.
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ABSTRACT: LXT-101 is a newly developed GnRH (gonadotropin-releasing hormone) analogue. In this study, the in vivo pharmacological profile in intact male rats and binding characters of LXT-101 were illustrated, and regulation of mRNA of hormone receptors related to the pituitary-gonadal axis during and after administration was observed to reveal its molecular mechanism of potent effect and reversibility. After single subcutaneous injections, LXT-101 produced a dose- and time-dependent suppression of serum testosterone level. Multiple administrations and osmotic pump implantation revealed that the time of onset and dose needed to maintain the effect of chemical castration decreased as the frequency of injection increased and gave direct proof that depot formulation could significantly improve the duration of antagonist delivery and pharmacological activities compared to the injectable formulation. And LXT-101 showed excellent character of regulating the pituitary-gonadal axis quickly and reversibly. Competitive binding assay showed that LXT-101 could specifically bind a pituitary GnRH receptor with high affinity. These results indicated that LXT-101 is fit for sustained-release formulation and it might possibly be developed as an ideal candidate for treating sex hormone-sensitive tumors and other disorders.
Regulatory Peptides 10/2006; 136(1-3):122-9. · 2.11 Impact Factor
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ABSTRACT: The effect of Liuwei Dihuang decoction (LW), a traditional Chinese medicine (TCM) prescription, on voltage-dependent currents and synaptic transmission were investigated in cultured hippocampal neurons of rat by whole-cell patch clamp recording technique. After application with serum from LW-treated rats, termed LW-containing serum (LWCS) for 48 h, the amplitude of delay rectifying K+ current (IK) and voltage-gated Ca2+ current (ICa) decreased. While the frequency of spontaneous excitatory post-synaptic current (sEPSC) and miniature excitatory post-synaptic current (mEPSC) increased significantly. Yet the amplitude of voltage-depended Na+ current (INa) and transient outward K+ current (IA), membrane capacitance and resistance remained unchanged. The results indicated that LWCS possessed the effect of modulating or improving neuronal and synaptic function, which possibly contribute to the cognition enhancing effect of LW.
Journal of Ethnopharmacology 07/2006; 106(2):166-72. · 3.01 Impact Factor
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ABSTRACT: Whole-cell currents in cultured hippocampal neurons were recorded to investigate the effects of SO-3, a new O-superfamily conopeptide derived from Conus striatus, on voltage-sensitive channels. SO-3 had no effect on voltage-sensitive sodium currents, delayed rectifier potassium currents, and transient outward potassium currents. Similar to the selective N-type calcium channel blocker omega-conotoxin MVIIA (MVIIA), SO-3 could concentration-dependently inhibit the high voltage-activated (HVA) calcium currents (I(Ca)). MVIIA(3 microM), 10 microM nimodipine, and 0.5 microM omega-agatoxin IVA (Aga) could selectively block the N-, L-, and P/Q-type I(Ca), which contributed approximately 32, approximately 38, and approximately 21% of the HVA currents in hippocampal neurons, respectively. About 31% of the total HVA currents were inhibited by 3 microM SO-3. SO-3 (3 microM) and 3 microM MVIIA inhibited the overlapping components of HVA currents, whereas no overlapping component was inhibited by 3 microM SO-3 and 10 microM nimodipine, or by 3 microM SO-3 and 0.5 microM Aga. Also, 3 microM SO-3 had no effect on R-type currents. SO-3 had less inhibitory effects on non-N-type HVA currents than MVIIA at higher concentrations (30 and 100 microM). The inhibitory effects of SO-3 and MVIIA on HVA currents were almost fully reversible. However, the recovery from block by MVIIA was more rapid than recovery from block by SO-3. It is concluded that SO-3 is a new omega-conotoxin selectively targeting N-type voltage-sensitive calcium channels. Considering the significance of N-type calcium channels for pain transduction, SO-3 may have therapeutic potential as a novel analgesic agent.
British Journal of Pharmacology 08/2005; 145(6):728-39. · 4.41 Impact Factor
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ABSTRACT: The molecular and cellular mechanisms underlying the cognitive deficiency of senescence-accelerated mouse prone/8 (SAMP8) have been attributed to many pathological changes in neurons. Recently, increasing evidence has shown that astrocytes, by mean of d-serine, involve in the process of synaptic transmission. Here we reported that the long-term potentiation (LTP) in CA1 area of hippocampal slices prepared from 2-, 6- and 12-month-old SAMP8 significantly decreased with age. Meanwhile, the LTP in the slices of 6- and 12-month-old mice markedly decreased below that of the age-matched normal strain SAMR1. Supplement with exogenous d-serine, a main product of astrocytes and a coagonist at the "glycin-binding" site of N-methyl-d-aspartate (NMDA) receptors, not only directly enhanced the deficient LTP but also rescued the abolished LTP by d-amino acid oxidase (DAAO) in slices from 12-month-old SAMP8. This ameliorative effect of d-serine was inhibited by either AP-V or 5,7-dichlorokynurenic acid (DCKA). These results suggest that absence of d-serine or dysfunction of the astrocytes possibly was one of mechanisms underlying the decrease of NMDA receptor-dependent LTP and cognition in aged SAMP8.
Neuroscience Letters 05/2005; 379(1):7-12. · 2.11 Impact Factor
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ABSTRACT: Estrogen receptor (ER) has two subtypes, ERα and ERβ. In this study, age-related changes of hippocampal gene expressions of ERα and ERβ were examined in senescence-accelerated mouse (SAM) with real-time reverse transcription-polymerase chain reaction (RT-PCR) technique, in an attempt to explore the relationship between estrogen receptor expression and age-related deficit of learning and memory in SAM. The results showed that the hippocampal ERα gene expressed constantly at the ages from 3 to 15 months in both SAMR1 and SAMP8. But the change of hippocampal ERβ gene expression was different from ERα gene during the aging process. In SAMR1, the expression of ERβ gene kept at a relatively high level at the ages from 3 to 12 months, and decreased significantly at the age of 15 months. In SAMP8, the expression of ERβ gene kept at a higher level at the ages of 3 and 6 months, and gradually decreased with advancing age, and reached the lowest level at the age of 15 months in both genders. The expression of ERβ gene decreased earlier in SAMP8 compared with SAMR1 during the aging process. These results suggested that the early decline of the expression of ERβ gene, but not ERα gene in the hippocampus of SAMP8 contribute to their age-related deterioration of learning and memory function.
International Congress Series.
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ABSTRACT: Senescence-accelerated mouse (SAM) have been used as animal models in the studies of senescence and age-associated disorders for many years. The typical feature of SAM-prone8 (SAMP8), a substrain of SAM, is the development of early onset of learning and memory deficit during its aging process, while SAM-resistant1 (SAMR1) shows normal aging process. To study the synaptic mechanism underlying the cognitive deterioration of SAMP8, whole-cell recording technique was used to compare the synaptic function of cultured SAMP8 hippocampal neurons with that of SAMR1 in our experiments. Paired-pulse depression (PPD), a simple form of use-dependent synaptic plasticity, is measured in autapse in response to paired stimulation. Those autapses in tests possessed the compatible evoked EPSC in amplitude. However, the degree of PPD in cultured hippocampal neurons of SAMP8 was far larger and the time constant of the autapse recovery from PPD was longer than those of SAMR1. In addition, mEPSC recorded in autapse were lower in frequency in SAMP8 compared with that of SAMR1, but with the similar amplitude, suggesting that presynaptic mechanism was involved. These results suggested that the synaptic plasticity of hippocampal neurons of SAMP8 is deficient compared to that of SAMR1, which may be caused by some kind of presynaptic functional disorders.
International Congress Series.
