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Objective To investigate the associations of mitochondrial DNA (mtDNA) genetic variants with SLE susceptibility, glucocorticoid (GC) efficacy and prognosis. Methods Our study was done in two stages. First, we performed whole mitochondrial genome sequencing in 100 patients and 100 controls to initially screen potential mtDNA variants associated with disease and GC efficacy. Then, we validated the results in an independent set of samples. In total, 605 SLE patients and 604 normal controls were included in our two-stage study. A two-stage efficacy study was conducted in 512 patients treated with GCs for 12 weeks. We also explored the association between mtDNA variants and SLE prognosis. Results In the combined sample, four mtDNA variants (A4833G, T5108C, G14569A, CA514-515-) were associated with SLE susceptibility (all PBH Conclusion We identified novel mtDNA genetic variants that were associated with SLE susceptibility, GC efficacy, and prognosis. Interactions between mtDNA variants and environmental factors were related to SLE risk and GC efficacy. Our findings provide important information for future understanding of the occurrence and development of SLE.

Background The undergraduate program of psychiatry has been widely established in recent years to improve the education and recruitment of psychiatrists in China. We aim to investigate the career choice of medical students majoring in psychiatry in China and the influential factors. Method This multicenter study was conducted in 26 medical schools in China from May to October of 2019. Participants included 4610 medical students majoring in psychiatry and 3857 medical students majoring in clinical medicine. Multivariable logistic regression was used to investigate the influential factors of students’ choices of psychiatry at matriculation and as a career. Results 44.08% of psychiatry majored students gave psychiatry as a first choice at matriculation, and 56.67% of them would choose psychiatry as a career, which was in sharp contrast to the proportion of clinical medicine majored students who would choose psychiatry as a career (0.69%). Personal interest (59.61%), suggestions from family members (27.96%), and experiencing mental problems (23.19%) were main reasons for choosing psychiatry major at matriculation. Personal interest (odds ratio [OR] = 2.12, 95% confidence interval [CI] = 1.87–2.40), experiencing a psychiatry clerkship (OR = 1.99, 95% CI = 1.28–3.08), being female (OR = 1.50, 95% CI = 1.30–1.68), experiencing mental problems (OR = 1.33, 95% CI = 1.28–1.56), and suggestions from family members (OR = 1.25, 95% CI = 1.08–1.46) correlated positively with students’ choice of psychiatry as career. Students who lacked psychiatry knowledge (OR = 0.49, 95% CI = 0.29–0.85) or chose psychiatry because of lower admission scores (OR = 0.80, 95% CI = 0.63–0.97) were less likely to choose psychiatry as a career. Conclusion More than half of psychiatry majored medical school students planned to choose psychiatry as their career, whereas very few students in the clinic medicine major would make this choice. Increasing students’ interest in psychiatry, strengthening psychiatry clerkships, and popularizing psychiatric knowledge are modifiable factors to increase the psychiatry career intention. The extent to which medical students’ attitudes toward psychiatry can be changed through medical school education and greater exposure to psychiatry will need further investigation.

Background Systemic lupus erythematosus is a heterogeneous autoimmune disease characterized by multi‐system injuries and overproduction of autoantibodies. There are many genetic studies on SLE, but no report has considered the relationship between cytoplasmic dynein and SLE susceptibility. Objectives Our study intends to investigate whether DYNC1H1 gene SNP/CNV is related to SLE susceptibility, GCs efficacy, HRQOL, anxiety, and depression in Chinese SLE patients. Methods A total of 502 cases and 544 healthy controls were recruited into the case‐control study, and 472 subjects from the case group were followed up for 12 weeks to evaluate GCs efficacy, HRQOL, anxiety, and depression. Multiplex SNaPshot technique was applied to genotype the seven SNPs of DYNC1H1, and AccuCopyTM method was conducted to quantify the copy number of DYNC1H1. Anxiety and depression were evaluated using HAMA and HAMD‐24 scales, respectively. The SF‐36 scale was used to assess HRQOL. Results The significant association between SNP rs1190606 and SLE susceptibility was displayed in the dominant model (PBH = 0.004) as well as its allele model (PBH = 0.004). We also found that SNP rs2273440 was related to photosensitization symptom in SLE patients (PBH = 0.032). In the follow‐up study, SNP rs11160668 was connected with the improvement of BP in male patients (PBH = 0.011). However, no association of DYNC1H1 gene with GCs efficacy, anxiety, and depression was found. No CNV in DYNC1H1 was detected. Conclusions The study suggests that DYNC1H1 gene polymorphisms may have an effect on SLE susceptibility and BP improvement of HRQOL in Chinese SLE patients., In allele analysis, the frequency of allele G of rs1190606 in SLE patients was significantly higher than that in controls (39.14% vs 31.89%; P = 5.30×10‐4, PBH = 0.004). In genetic polymorphism analysis, rs1190606 was associated with the susceptibility of SLE (dominant model: Padj = 5.75×10‐4, PBH = 0.004).

Analogues of vertebrate natriuretic peptides (NPs) present in plants, termed plant natriuretic peptides (PNPs), comprise a novel class of hormones that systemically affect salt and water balance and responses to plant pathogens. Several lines of evidence indicate that Arabidopsis thaliana PNP (AtPNP-A) affects cellular redox homeostasis, which is also typical for the signaling of its vertebrate analogues, but the molecular mechanism(s) of this effect remains elusive. Here we report identification of catalase 2 (CAT2), an antioxidant enzyme, as an interactor of AtPNP-A. The full-length AtPNP-A recombinant protein and the biologically active fragment of AtPNP-A bind specifically to CAT2 in surface plasmon resonance (SPR) analyses, while a biologically inactive scrambled peptide does not. In vivo bimolecular fluorescence complementation (BiFC) showed that CAT2 interacts with AtPNP-A in chloroplasts. Furthermore, CAT2 activity is lower in homozygous atpnp-a knockdown compared with wild type plants, and atpnp-a knockdown plants phenocopy CAT2-deficient plants in their sensitivity to elevated H2O2, which is consistent with a direct modulatory effect of the PNP on the activity of CAT2 and hence H2O2 homeostasis. Our work underlines the critical role of AtPNP-A in modulating the activity of CAT2 and highlights a mechanism of fine-tuning plant responses to adverse conditions by PNPs.

With the purpose of identifying novel selective κ opioid receptor (KOR) antagonists as potential antidepressants from nepenthone analogues, starting from N -nor- N -cyclopropylmethyl-nepenthone (SLL-020ACP), a highly selective and potent KOR agonist, a series of 7 β -methyl-nepenthone analogues was conceived, synthesized and assayed on opioid receptors based on the concept of hybridization. According to the pharmacological results, the functional reversal observed in orvinol analogues by introduction of 7 β -methyl substituent could not be reproduced in nepenthone analogues. Alternatively, introduction of 7 β -methyl substituent was associated with substantial loss of both subtype selectivity and potency but not efficacy for nepenthone analogues, which was not found in 7 β -methyl orvinol analogues. Surprisingly, SLL-603, a 7 β -methyl analogue of SLL-020ACP, was identified to be a KOR full agonist. The possible molecular mechanism for the heterogeneity in activity cliff was also investigated. In conclusion, 7 β -methyl substituent was a structural locus associated with activity cliff and demonstrated as a pharmacological heterogeneity between nepenthone and orvinol analogues that warrants further investigations.

This study aimed to analyze how restorative care is implemented in long-term care facilities and factors associated with resident outcomes in Taiwan. A one-group pre-test and post-test design was adopted in 24 long-term care facilities by collecting a sample of 310 participants at the baseline and 210 at six months. Participants were residents aged 65 or over, and were being constrained, used diapers, or were bedridden, or a combination of these. Their physical and mental functions were measured using Activities of Daily Living (ADLs), Instrumental Activities of Daily Living (IADLs), Mini-Mental State Examination (MMSE), Geriatric Depression Scale-15 (GDS-15), and EuroQol-5D (EQ-5D). Mean differences in the outcomes were analyzed, and mixed effect models were used to examine influencing factors. The results showed that most of the participants had good family support. However, participants with better family support were more likely to drop out. Improvements were found in the residents&rsquo, outcomes on physical function, depression and quality of life. Social support was a significant influencing factor on most of the outcomes. In conclusion, restorative care was found to have positive effects on residents&rsquo, physical function and helped maintain mental function. Sufficient support and communication between participants, families, and staff in facilities are key factors leading to positive outcomes.

This analysis of clinical data from systemic lupus erythematosus (SLE) patients with chylothorax and/or chylous ascites was conducted to guide further clinical work.From June 2008 to June 2019, 15 SLE patients (14 females and 1 male) with chylothorax and/or chylous ascites were hospitalized at the Beijing Shijitan Hospital. Sixty SLE patients without chylothorax and chylous ascites were randomly selected as controls. Patients', clinical data was investigated.The mean age of onset of chylothorax and/or chylous ascites in patients with SLE was 35.7 ± 3.7 years (range, 15-69 years). The mean disease duration of chylothorax and/or chylous ascites in patients with SLE was 13.7 ± 3.4 months (range, 1-48 months). Patients with chylothorax and/or chylous ascites were always diagnosed at later stages of SLE compared with the controls. Among cases, glomerulonephritis and hematologic system involvement were the most common complications. Anti-Sjogren's syndrome antigen A antibody was positive in 7 cases (46.7%). Among cases, direct lymphangiography was performed in 13 patients, indicating thoracic duct outlet obstruction or a poor backflow at the terminal of the thoracic duct. Subsequently, 13 patients were treated with corticosteroids, combined with immunosuppressants in 11 patients and thoracic duct surgery in 6 patients. Eleven patients were followed up for 0.5 to 7.0 years. One patient died of infection. Eight patients (53.3%) achieved remission.Chylothorax and/or chylous ascites are rare complications of SLE. An early diagnosis and timely initiation of glucocorticoids, immunosuppressants, and surgery are critical to relieve symptoms and to improve prognosis.

Dezocine is becoming dominated in China market for relieving moderate to severe pain. It is believed that Dezocine’s clinical efficacy and little chance to provoke adverse events during the therapeutic process are mainly attributed to its partial agonist activity at the μ opioid receptor. In the present work, we comprehensively studied the pharmacological characterization of Dezocine and identified that the analgesic effect of Dezocine was a result of action at both the κ and μ opioid receptors. We firstly found that Dezocine displayed preferential binding to μ opioid receptor over κ and δ opioid receptors. Dezocine, on its own, weakly stimulated G protein activation in cells expressing κ and μ receptors, but in the presence of full κ agonist U50,488 H and μ agonist DAMGO, Dezocine inhibited U50,488H- and DAMGO-mediated G protein activation, indicating that Dezocine was a κ partial agonist and μ partial agonist. Then the in intro results were verified by in vivo studies in mice. We observed that Dezocine-produced antinociception was significantly inhibited by κ antagonist nor-BNI and μ antagonist β-FNA pretreatment, indicating that Dezocine-mediated antinociception was via both the κ and μ opioid receptors. When co-administrating of Dezocine with U50,488 H or morphine, Dezocine was capable of inhibiting U50,488H- or morphine-induced antinociception. Finally, κ receptor activation-associated side effect sedation was investigated. We found that Dezocine displayed limited sedative effect with a ceiling effecting at a moderate dose. Thus, our work led to a better understanding of the analgesic mechanism of action of Dezocine in vivo.

Background and purpose β-Arrestins function as signal transducers linking GPCRs to ERK1/2 signalling either by scaffolding members of ERK1/2s cascades or by transactivating receptor tyrosine kinases through Src-mediated release of transactivating factor. Recruitment of β-arrestins to the activated GPCRs is required for ERK1/2 activation. Our previous studies showed that δ receptors activate ERK1/2 through a β-arrestin-dependent mechanism without inducing β-arrestin binding to the δ receptors. However, the precise mechanisms involved remain to be established. Experimental approach ERK1/2 activation by δ receptor ligands was assessed using HEK293 cells in vitro and male Sprague Dawley rats in vivo. Immunoprecipitation, immunoblotting, siRNA transfection, intracerebroventricular injection and immunohistochemistry were used to elucidate the underlying mechanism. Key results We identified a new signalling pathway in which recruitment of β-arrestin2 to the EGFR rather than δ receptor was required for its role in δ receptor-mediated ERK1/2 activation in response to H-Tyr-Tic-Phe-Phe-OH (TIPP) or morphine stimulation. Stimulation of the δ receptor with ligands leads to the phosphorylation of PKCδ, which acts upstream of EGFR transactivation and is needed for the release of the EGFR-activating factor, whereas β-arrestin2 was found to act downstream of the EGFR transactivation. Moreover, we demonstrated that coupling of the PKCδ/EGFR/β-arrestin2 transactivation pathway to δ receptor-mediated ERK1/2 activation was ligand-specific and the Ser(363) of δ receptors was crucial for ligand-specific implementation of this ERK1/2 activation pathway. Conclusions and implications The δ receptor-mediated activation of ERK1/2 is via ligand-specific transactivation of EGFR. This study adds new insights into the mechanism by which δ receptors activate ERK1/2.

Background We previously reported that a methanol extract of Glycyrrhizae radix (MEGR) blocked methamphetamine-induced locomotor sensitization and conditioned place preference in rats. In the present study, the effects of MEGR on repeated nicotine-induced locomotor sensitization and enhanced extracellular dopamine (DA) release in the nucleus accumbens (Nacc) were evaluated. Methods Male Sprague–Dawley rats received repeated administrations of nicotine (0.4 mg/kg, subcutaneous) or saline twice a day for 7 d and were challenged with nicotine 4 d after the last daily dosing. During the 4-d withdrawal period, the rats were treated once a day with MEGR (60 or 180 mg/kg/d). Extracellular DA levels were measured by in vivo microdialysis, the malondialdehyde levels and the activities of superoxide dismutase and catalase in the Nacc were biochemically evaluated, and the expression of antioxidant proteins was confirmed by Western blot assays. All data were assessed with analysis of variance tests followed by post-hoc comparison tests and p values

Sjogren syndrome (SS) is characterized by dysfunction of the exocrine glands, particularly the salivary and lacrimal glands. Thus, labial salivary gland biopsy is useful method for diagnosing SS. The aim of the present study was to investigate the microRNA (miRNA or miR) profile of labial salivary glands obtained from SS patients and to examine the correlation of miR-181a and -16 levels with the pathological grade in SS. miRNA expression in labial salivary gland tissues was profiled in 3 female patients with primary SS and 3 female patients with non-SS sicca syndrome using microarray analysis. In addition, a literature search and miRNA target gene prediction were performed to collect miRNAs involved in SS pathogenesis. Subsequent to integrating all database results, miR-181a and -16 were identified to be associated with the Ro/SS-associated antigen A and La/SS-associated antigen B during SS pathogenesis. Therefore, these miRNAs were selected for further verification in labial salivary gland tissues of 28 patients with SS and 18 non-SS sicca syndrome control individuals by quantitative reverse transcription-quantitative polymerase chain reaction. Compared with the control group, 76 miRNAs were upregulated and 51 were downregulated in the labial salivary gland of SS patients according to microarray results. In particular, miR-181a and -16 expression levels in the labial salivary gland of SS patients were decreased in comparison with those in the controls. Furthermore, the decreased expression levels of these miRNAs were associated with the labial salivary pathological focus scores. In conclusion, the present study examined the miRNA profiles in the labial salivary glands of SS patients and detected decreased miR-181a and -16 expression levels compared with the control individuals. Finally, the decreased levels of miR-181a and -16 were associated with the salivary gland pathological focus scores, suggesting that miR-181a and -16 may serve a role in the pathogenesis of SS.

This paper used computer to simulate thinking modes of human brain, to establish an artificial intelligence expert system for diagnosis and treatment of child AD/HD based on artificial neural network. The diagnosis system involves expert knowledge database, artificial neural network and the relational database. The clinical data were obtained from 10 epidemiological and outpatient department, and 1125 valid data were harvested for the system compilation. The diagnosis of 627 cases adopting the man-machine double-blind controlled trial, the Kappa value was 0.98 (P < 0.001). The research can help junior clinicians to learn abundant clinical experiences of senior child psychiatrists, and can help children of AD/HD throughout the country.

The finite element analysis method was adopted to simulate the masonry wall strengthened with steel strips and was verified by comparing with test results. The influence rules of two factors including the cross sectional area of steel strips and vertical compression were investigated. The results show that, as for unreinforced masonry wall, the relationship of the shear capacity of unreinforced masonry wall and the vertical compressive strain is linear under lateral load; the speed of stiffness degeneration is accelerated after the peak point of the curves, but decrease with the increasing of lateral displacement. As for masonry wall strengthened with steel strips, the shear capacity increases significantly, and shows nonlinear relationship with the cross section area of the steel strips and vertical compression; ductility is improved. Finally, a computational formula of shear capacity based on a lot of parametric analysis is proposed to calculate the sectional dimension of steel strips, and it provides theoretical foundation for establishing thorough design method of masonry wall strengthened with steel strips.

Background Activation of epidermal growth factor receptor (EGFR) plays an important role in angiotensin II (Ang II)–induced cardiac hypertrophy, but little is known about the underlying mechanism that results in EGFR activation. In this study, we aimed to confirm the important role of nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) in Ang II–induced EGFR activation and subsequent cardiac hypertrophy by upregulating expression of a disintegrin and metalloproteinase (MMP)-17 (ADAM17). Methods Small interference RNA (siRNA) was adopted to knock down ADAM17 or Nox4 expression. Nox4 plasmid was used to construct cardiomyocytes with Nox4 overexpression. Results Nox4 and ADAM17 increased in an abdominal artery coarctation-induced model of myocardial hypertrophy. In vitro studies showed that Nox4 was required in Ang II–induced EGFR activation and subsequent myocardial hypertrophy. Nox4 siRNA and Nox4 overexpression demonstrated that Nox4 controlled the transcription and translation of ADAM17. Furthermore, we observed that the ratio of phosphor-EGFR (p-EGFR) to EGFR was significantly reduced by ADAM17 siRNA in hypertrophic cardiomyocytes. Enzyme-linked immunosorbent assay studies revealed that Nox4 and ADAM17 mediated the release of mature heparin-binding EGF-like growth factor (HB-EGF), which played a critical role in the Ang II–induced EGFR activation. Moreover, the results of reactive oxygen species (ROS) scavenging by N-acetyl cysteine (NAC) indicated that ROS were required in the Nox4-mediated upregulation of ADAM17 expression. Conclusions In summary, Nox4 is required in Ang II–induced EGFR activation and subsequent cardiac hypertrophy; it increased the expression of ADAM17, which induced the release of mature HB-EGF. ROS were also required in the Nox4-mediated upregulation of ADAM17 expression.

The cellular uptake and localization of photosensitizer-loaded nanoparticles have significant impact on photodynamic therapy (PDT) efficacy due to short lifetime and limited action radius of singlet oxygen. Herein, we develop poly(ethylene glycol) (PEG)- and polyethylenimine (PEI)-functionalized zinc(II) phthalocyanine (ZnPc)-loaded mesoporous silica nanoparticles (MSNs), which are able to distribute in the cytosol by endolysosomal escape. In this photosensitizer-carrier system (PEG-PEI-MSNs/ZnPc), ZnPc is a PDT agent; MSNs are the nanocarrier for encapsulating ZnPc; PEI facilitates endosomal escape; and PEG enhances biocompatibility. The as-synthesized PEG-PEI-MSNs/ZnPc have a high escape efficiency from the lysosome to the cytosol due to the "proton sponge" effect of PEI. Compared with the ZnPc-loaded MSNs, the phototoxicity of the PEG-PEI-MSNs/ZnPc is greatly enhanced in vitro. By measuring the mitochondrial membrane potential, a significant loss of >80% Δψm after treatment with PEG-PEI-MSNs/ZnPc-PDT is observed. It is further demonstrated that the ultra-efficient passive tumor targeting and excellent PDT efficacy are achieved in tumor-bearing mice upon intravenous injection of PEG-PEI-MSNs/ZnPc and the followed light exposure. We present here a strategy for enhancement of PDT efficacy by endolysosomal escape and highlight the promise of using multifunctional MSNs for cancer therapy.

Apolipoprotein E (apoE) is one of the major transporters of cholesterol in the body and is essential for maintaining various neural functions in the brain. Given that hypercholesterolemia is a risk factor in Alzheimer's disease (AD), it has been suggested that altered cholesterol metabolism may be involved in the development of the pathogenesis, including neural degeneration, commonly observed in AD patients. Neurotrophic factors and their receptors, which are known to regulate various neural functions, are also known to be altered in various neurodegenerative diseases. We therefore hypothesized that cholesterol metabolism may itself influence the neurotrophin system within the brain. We decided to investigate this possibility by modulating the amount of dietary cholesterol given to apoE-knockout (apoE-KO) and wild-type (WT) mice, and examining the mRNA expression of various neurotrophin ligands and receptors in their hippocampal formations. Groups of eight-week-old apoE-KO and WT mice were fed a diet containing either "high" (HCD) or "normal" (ND) levels of cholesterol for a period of 12 weeks. We found that high dietary cholesterol intake elevated BDNF mRNA expression in both apoE-KO and WT mice and TrkB mRNA expression in apoE-KO animals. On the other hand, NGF and TrkA mRNA levels remained unchanged irrespective of both diet and mouse type. These findings indicate that altered cholesterol metabolism induced by HCD ingestion combined with apoE deficiency can elicit a differential response in the various neurotrophin ligand/receptor systems in the mouse hippocampus. Whether such changes can lead to neural degeneration, and the mechanisms that may be involved in this, awaits further research.

Aim: To investigate the effects of ATPM-ET ((-)-3-N-Ethylaminothiazolo (5,4-b)-N-cyclopropylmethylmorphinan hydrochloride) on physical dependence and behavioral sensitization to morphine in mice. Methods: The pharmacological profile of ATPM-ET was characterized using competitive binding and GTPγS binding assays. We then examined the antinociceptive effects of ATPM-ET in the hot plate test. Morphine dependence assay and behavioral sensitization assay were used to determine the effect of ATPM-ET on physical dependence and behavior sensitization to morphine in mice. Results: The binding assay indicated that ATPM-ET ATPM-ET exhibited a high affinity to both κ- and µ-opioid receptors with K i values of 0.15 nmol/L and 4.7 nmol/L, respectively, indicating it was a full κ-opioid receptor agonist and a partial μ-opioid receptor agonist. In the hot plate test, ATPM-ET produced a dose-dependent antinociceptive effect, with an ED50 value of 2.68 (2.34-3.07) mg/kg. Administration of ATPM-ET (1 and 2 mg/kg, sc) prior to naloxone (3.0 mg/kg, sc) injection significantly inhibited withdrawal jumping of mice. In addition, ATPM-ET (1 and 2 mg/kg, sc) also showed a trend toward decreasing morphine withdrawal-induced weight loss. ATPM-ET (1.5 and 3 mg/kg, sc) 15 min before the morphine challenge significantly inhibited the morphine-induced behavior sensitiza- tion (P

Background Antiviral drug-resistant HBV mutants under a variety of treatment protocols are complex and only partly understood. Here, a population-based cross-sectional study was performed to analyse the profile of resistance mutations in distinct evolutionary pathways refractory to different nucleoside/nucleotide analogues (NAs). Methods Serum samples of 199 chronic hepatitis B patients undergoing NA treatment from five hospitals in four northern cities of China were obtained between January 2007 and July 2009. The genotypic resistance of HBV in these samples was characterized. The full-length HBV reverse transcriptase region was amplified, sequenced and analysed with particular focus on the following NA-resistant changes: rtL80, rtI169, rtV173, rtL180, rtA181, rtT184, rtA194, rtS202, rtM204, rtN236 and rtM250. Results Among 199 HBV isolates, 30 (15.08%) and 169 (84.92%) were genotypes B and C, respectively, and 65 (32.66%) harboured NA-resistant mutations. The prevalence of mutations at rtM204 was 34.33% in 134 patients who had received or who had been exposed to lamivudine-based therapy. Five cases of rtN236 mutations were detected exclusively among 75 patients receiving adefovir-dipivoxil-based therapies. A total of 19 cases of multidrug resistance rtA181 mutations were observed in those with lamivudine-, adefovir-dipivoxil- or telbivudine-based treatment (186 cases), but not in those undergoing entecavir treatment (13 cases). Mutations were not found at rtI169, rtT184, rtA194 or rtS202. rtM204 mutations (27 rtM204I, 15 rtM204V and 5 rtM204I/V cases) were detected at the highest frequency among 65 mutants (72.30% [47/65]) and found to display 16 combination mutation patterns, in which rtM204I and rtM204V were significantly associated with rtL80I/V and rtL180M, respectively ( PConclusions One-third of the studied population harboured NA-resistant HBV with complicated mutation patterns. Monitoring HBV genotypic resistance mutation markers and patterns is therefore shown to be beneficial for optimizing antiviral therapies and for avoiding clinical deterioration.

Atrial natriuretic peptide (ANP) has an important role in maintaining the homeostasis of body fluids and blood pressure and also in preventing cardiac hypertrophy and initiating the process of apoptosis. An immunoreactive analog of ANP was discovered in plants over a decade ago and termed plant natriuretic peptide (PNP). PNP is a small protein that contains sequence and structural similarity to ANP within a predicted protruding psi (psi) loop. Since application of ANP or PNP stimulates similar functional effects in plants, it is conceivable that PNP may have effects on mammalian cells. In this report, we show that purified recombinant PNP induces apoptosis in a dose dependent and cell type specific manner. Rat cardiac myoblasts (H9c2 cells) were more susceptible to the apoptotic promoting effects of PNP and ANP than HEK-293T cells where PNP had a protective effect at lower concentrations. Similarly rat thoracic myoblasts (A-10) were less responsive to both PNP and ANP than the H9c2 cells. Since PNP is mimicking the effect of ANP in this instance, PNP may prove to be a useful lead molecule for developing novel therapeutic natriuretic peptides.

To examine the relationship between the RAVE (relative activity versus endocytosis) values of opiate agonists and their dependence liability by studying several potent analgesics with special profiles in the development of physical and psychological dependence.The effects of (-)-cis-(3R,4S,2'R) ohmefentanyl (F9202), (+)-cis-(3R,4S,2'S) ohmefentanyl (F9204), dihydroetorphine (DHE) and morphine on [(35)S]GTP gamma S binding, forskolin-stimulated cAMP accumulation, and receptor internalization were studied in CHO cells stably expressing HA-tagged mu-opioid receptors (CHO-HA-MOR). cAMP overshoot in response to the withdrawal of these compound treatments was also tested.All four agonists exhibited the same rank order of activity in stimulation of [(35)S]GTP gamma S binding, inhibition of adenylyl cyclase (AC) and induction of receptor internalization: DHEF9204F9202morphine. Based on these findings and the previous in vivo analgesic data obtained from our and other laboratories, the RAVE values of the four agonists were calculated. The rank order of RAVE values was morphineF9202F9204DHE. For the induction of cAMP overshoot, the rank order was F9202or=morphineF9204or=DHE.Taken in combination with previous findings of these compounds' liability to develop dependence, the present study suggests that the agonist with the highest RAVE value seems to have a relatively greater liability to develop psychological dependence relative to the agonist with the lowest RAVE value. However, the RAVE values of these agonists are not correlated with their probability of developing physical dependence or inducing cAMP overshoot, a cellular hallmark of dependence.

Si 4+ and B 3+ were doped into the spinel block of blue-emitting BaMgAl 10 O 17 :Eu 2+ phosphor. Their photoluminescence, such as emission characteristic and thermal stability, were investigated under ultraviolet (UV) and vacuum ultraviolet (VUV) excitation. The results showed that proper quantities of Si 4+ or B 3+ doping could obviously improve the emission intensity. However, the thermal stability of Si 4+ or B 3+ doped phosphors was worse than that of undoped samples. Based on lattice defect theory, the mechanisms of these interesting phenomena were discussed and explained, which revealed that the thermal degradation of BaMgAl 10 O 17 :Eu 2+ had great correlation with the lattice environment.

Single phase of Gd0.9Eu0.1Al3(BO3)(4) and Gd0.9Eu0.1Al3(BO3)(4):Re3+ (Re =Y, Sc and Bi) powder samples was prepared by the solid-state reaction and their luminescence properties were investigated under ultraviolet and vacuum ultraviolet excitation. Under 254 nm excitation, the emission intensity of Eu3+ increased after Y3+, SC3+ or Bi3+ replacing part Gd3+ of Gd0.9Eu0.1Al3(BO3)(4). Under 147 nm excitation, when substituting part Gd3+ With Sc3+ or Bi3+, the emission intensity of Eu3+ decreased, but increased after doping appropriate Y3+ and the maximum emission intensity was obtained at the concentration of x=0.6 in Gd0.9-xYxEu0.1Al3(BO3)(4). Compared with the red commercial phosphor (Y,Gd)BO3:Eu3+, the optimum phosphor Gd0.3Y0.6Eu0.1Al3(BO3)(4) exhibited about 92% the integrated emission intensity with chromaticity coordinates of (0.66, 0.33) under 147 nm excitation. (C) 2008 Elsevier B.V. All rights reserved.

ATPM [(-)-3-amino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride] was found to have mixed kappa- and mu-opioid activity and identified to act as a full kappa-agonist and a partial mu-agonist by in vitro binding assays. The present study was undertaken to characterize its in vivo effects on morphine antinociceptive tolerance in mice and heroin self-administration in rats. ATPM was demonstrated to yield more potent antinociceptive effects than (-)U50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide). It was further found that the antinociceptive effects of ATPM were mediated by kappa- and mu-, but not delta-opioid, receptors. In addition to its agonist profile on the mu-receptor, ATPM also acted as a mu-antagonist, as measured by its inhibition of morphine-induced antinociception. It is more important that ATPM had a greater ratio of the ED(50) value of sedation to that of antinociception than (-)U50,488 (11.8 versus 3.7), indicative of a less sedative effect than (-)U50,488H. In addition, ATPM showed less potential to develop antinociceptive tolerance relative to (-)U50,488H and morphine. Moreover, it dose-dependently inhibited morphine-induced antinociceptive tolerance. Furthermore, it was found that chronic treatment of rats for 8 consecutive days with ATPM (0.5 mg/kg s.c.) produced sustained decreases in heroin self-administration. (-)U50,488H (2 mg/kg s.c.) also produced similar inhibitory effect. Taken together, our findings demonstrated that ATPM, a novel mixed kappa-agonist and mu-agonist/-antagonist, could inhibit morphine-induced antinociceptive tolerance, with less potential to develop tolerance and reduce heroin self-administration with less sedative effect. kappa-Agonists with some mu-activity appear to offer some advantages over selective kappa-agonists for the treatment of heroin abuse.

Interactions between gastrointestinal signals are a part of integrated systems regulating food intake (FI). We investigated whether cholecystokinin (CCK)-8 and urocortin systems potentiate each other to inhibit FI and gastric emptying (GE) in fasted mice. Urocortin 1 and urocortin 2 (1 μg/kg) were injected ip alone or with CCK (3 μg/kg) in lean, diet-induced obese (DIO) or corticotropin-releasing factor receptor-2 (CRF2)-deficient mice. Gastric vagal afferent activity was recorded from a rat stomach-vagus in vitro preparation. When injected separately, urocortin 1, urocortin 2, or CCK did not modify the 4-h cumulative FI in lean mice. However, CCK plus urocortin 1 or CCK plus urocortin 2 decreased significantly the 4-h FI by 39 and 27%, respectively, compared with the vehicle + vehicle group in lean mice but not in DIO mice. Likewise, CCK-urocortin-1 delayed GE in lean but not DIO mice, whereas either peptide injected alone at the same dose had no effect. CCK-urocortin 2 suppression of FI was observed in wild-type but not CRF2-deficient mice. Gastric vagal afferent activity was increased by intragastric artery injection of urocortin 2 after CCK at a subthreshold dose, and the response was reversed by devazepide. These data establish a peripheral synergistic interaction between CCK and urocortin 1 or urocortin 2 to suppress FI and GE through CRF2 receptor in lean mice that may involve CCK modulation of gastric vagal afferent responsiveness to urocortin 2. Such synergy is lost in DIO mice, suggesting a resistance to the satiety signaling that may contribute to maintain obesity.

Single phase of Ba1−xZnxGd0.75Tb0.25B9O16 and BaGd0.75−xCexTb0.25B9O16 (0 ≤ x ≤ 0.125) was prepared by the solid-state reaction. Under 254 nm excitation, Zn2+ impaired the emission of Tb3+; Ce3+ sensitized the luminescence of Tb3+ ascribing to the energy transfer of Ce3+ → Tb3+ and/or Ce3+ → Gd3+ → Tb3+ occurring, and the optimum emission was observed at x = 0.05 in BaGd0.75−xCexTb0.25B9O16. Under 147 nm excitation, Zn2+ sensitized the emission of Tb3+ and the optimum emission was obtained at x = 0.075 in Ba1−xZnxGd0.75Tb0.25B9O16, which could be due to the fact that the energy absorption relating to Zn2+ occurred and the absorbed energy was transferred to Tb3+ finally; Ce3+ depressed the luminescence of Tb3+, which could be attributed to the fact that Ce3+ has no absorption in vacuum ultraviolet region and the role of Gd3+ was weakened. Compared with BaGd0.75Tb0.25B9O16 and the commercial phosphor Zn2SiO4:Mn2+, the optimum phosphor Ba0.925Zn0.075Gd0.75Tb0.25B9O16 exhibited about 127% and 51% integrated emission intensity respectively and the shorter decay time of about 2.822 ms under 147 nm excitation.

A novel series of 1-(pyrrolidin-1-ylmethyl)-2-[(3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinoline derivatives maj-3a-maj-3u were synthesized and evaluated in vitro for their binding affinity at κ-opioid receptors. Maj-3c displayed the highest affinity for κ-opioid receptors (Ki = 0.033 nM) among all the compounds evaluated. Furthermore, all four stereoisomers of compound 3c were prepared, and (1S,18S)-3c was identified as the most potent (Ki = 0.0059 nM) κ-opioid receptor agonist among the four stereoisomers. Maj-3c produced significant antinociception (ED50 = 0.000406 mg kg(-1)) compared to U-50,488H and original BRL 52580 in the acetic acid writhing assay, but its strong sedative effect (ED50 = 0.000568 mg kg(-1)) observed in the mouse rotation test reduced its druggability. To minimize the central nervous system side effects, a series of hydroxyl-containing analogs of maj-3c were synthesized, and maj-11a was found to be a potent κ-opioid receptor agonist (Ki = 35.13 nM). More importantly, the dose for the sedative effect (ED50 = 9.29 mg kg(-1)) of maj-11a was significantly higher than its analgesic dose (ED50 = 0.392 mg kg(-1)), which made it a promising peripheral analgesic candidate compound with weak sedative side effects.

Aim: To characterize the pharmacological profiles of a novel κ-opioid receptor agonist MB-1C-OH. Methods: [ 3 H]diprenorphine binding and [ 35 S]GTPγS binding assays were performed to determine the agonistic properties of MB-1C-OH. Hot plate, tail flick, acetic acid-induced writhing, and formalin tests were conducted in mice to evaluate the antinociceptive actions. Forced swimming and rotarod tests of mice were used to assess the sedation and depression actions. Results: In [ 3 H]diprenorphine binding assay, MB-1C-OH did not bind to μ- and δ-opioid receptors at the concentration of 100 μmol/L, but showed a high affinity for κ-opioid receptor ( K i =35 nmol/L). In [ 35 S]GTPγS binding assay, the compound had an E max of 98% and an EC 50 of 16.7 nmol/L for κ-opioid receptor. Subcutaneous injection of MB-1C-OH had no effects in both hot plate and tail flick tests, but produced potent antinociception in the acetic acid-induced writhing test (ED 50 =0.39 mg/kg), which was antagonized by pretreatment with a selective κ-opioid receptor antagonist Nor-BNI. In the formalin test, subcutaneous injection of MB-1C-OH did not affect the flinching behavior in the first phase, but significantly inhibited that in the second phase (ED 50 =0.87 mg/kg). In addition, the sedation or depression actions of MB-1C-OH were about 3-fold weaker than those of the classical κ agonist (–)U50,488H. Conclusion: MB-1C-OH is a novel κ-opioid receptor agonist that produces potent antinociception causing less sedation and depression.

Obestatin is a new peptide for which anorexigenic effects were recently reported in mice. We investigate whether peripheral injection of obestatin or co-injection with cholecystokinin (CCK) can modulate food intake, gastric motor function (intragastric pressure and emptying) and gastric vagal afferent activity in rodents. Obestatin (30, 100 and 300 microg/kg, i.p.) did not influence cumulative food intake for the 2h post-injection in rats or mice nor gastric emptying in rats. In rats, obestatin (300 microg/kg) did not modify CCK (1 microg/kg, i.p.)-induced significant decrease in food intake (36.6%) and gastric emptying (31.0%). Furthermore, while rats injected with CCK (0.3 microg/kg, i.v.) displayed gastric relaxation, no change in gastric intraluminal pressure was elicited by obestatin (300 microg/kg, i.v.) pre- or post-CCK administration. In in vitro rat gastric vagal afferent preparations, 20 units that had non-significant changes in basal activity after obestatin at 30 microg responded to CCK at 10 ng by a 182% increase. These data show that obestatin neither influences cumulative food intake, gastric motility or vagal afferent activity nor CCK-induced satiety signaling.

A bioactive fraction (GLPG) was extracted and purified from the mycelia of Ganoderma lucidumby EtOH precipitation and DEAEcellulose column chromatography. GLPG was a proteoglycan and had a carbohydrate:protein ratio of 10.4:1. Its antiviral activities against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) were investigated by the cytopathic effect (CPE) inhibition assay in cell culture. This kind of polysaccharide inhibited the development of the cytopathic effect in dose-dependent manner in HSV-infected cells, moreover did not show any cytotoxic effects on cells even when a concentration was as high as 2000g/ml. In order to study the possible mode of action of the antiviral activity of GLPG, cells were treated with GLPG before, during and after infection, and the viral titers in the supernatant of cell culture 48 h post-infection were tested by TCID50 assay. The antiviral effects in pre-treated and treated during virus infection with GLPG were more remarkable than the treatment of post-infection. Although the precise mechanism has yet to be defined, our work suggested that GLPG inhibits viral replication by interfering with the early events of viral adsorption and entry into target cells. Thus, this proteoglycan seems to be a potential candidate for anti-HSV agents. © 2004 Elsevier Ireland Ltd. All rights reserved.

We previously reported that the κ agonists with mixed μ activity could attenuate heroin self-administration with less potential to develop tolerance. The present study further investigated the effects of (-)-3-N-Ethylamino-thiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride (ATPM-ET), a κ agonist and μ agonist/antagonist, on the acquisition and reinstatement of morphine-induced conditioned place preference (CPP), heroin self-administration and heroin-primed reinstatement of drug-seeking behavior. We found that ATPM-ET produced a longer duration of potent antinociceptive effects with less side effect of sedation. More importantly, ATPM-ET attenuated the acquisition of morphine-induced CPP, without affecting the reinstatement of morphine CPP. Furthermore, ATPM-ET significantly inhibited heroin self-administration and the reinstatement of heroin primed drug-seeking behavior. Taken together, ATPM-ET, a novel κ agonist and μ agonist/antagonist may have utility for the treatment of drug dependence.

The structure and antioxidant activity of a polysaccharide from mycelia fermentation of Hirsutella sinensis were analyzed. The natural active component water-soluble polysaccharides was isolated from mycelia, and three polysaccharide fractions HSP-1, HSP-2, and HSP-3 were purified with chromatography and the structures were identified. The structural characteristics determination with a combination of chemical and instrumental analysis methods showed that the mainly component HSP-1 was about 1.7×104 Da, and composed of glucose, mannose and galactose at a molar ratio of 4.5:1.0:1.4. Further researches revealed that HSP-1 was a branched polysaccharide possessing a backbone of (1→4)-α-D-glucose residues (~70%), (1→4)-α-D-mannose residues (~15%) and (1→4)-α-D-galactose residues (~15%). The branches were at the (1,2,4,6→)-α-D-glucose residues (~8%) of the backbone, mainly composed of (1→4)-α-D-glucose residues, (1→4)-α-D-galcatose residues, (1→4)-α-D-mannose residues, and terminated with α-D-galactose residues. The in vitro antioxidant assay proved HSP-1 possessed the hydroxyl radical-scavenging activity with an IC50 value of 0.834 mg/mL.

To prevent the blood-borne interference and reflex actions via neighboring organs and the central nervous system, the study was conducted in an in vitro isolated stomach-gastric vagus nerve preparation obtained from overnight-fasted, urethan-anesthetized rats. Afferent unit action potentials were recorded from the gastric branch of the vagus nerve. The left gastric artery was catheterized for intra-arterial injection. In vitro we found that 1) 55/70 gastric vagal afferents (GVAs) were polymodal, responding to CCK-8 and mechanical stimuli, 13 were mechanoreceptive, and 2 were CCK-responsive; 2) sequential or randomized intra-arterial injections of CCK-8 (0.1–200 pmol) dose-dependently increased firing rate and reached the peak rate at 100 pmol; 3) the action was suppressed by CCK-A (Devazepide) but not by CCK-B (L-365,260) receptor antagonist; 4) neither antagonist blocked the mechanosensitivity of GVA fibers. These results are consistent with corresponding in vivo well-documented findings. Histological data indicate that the layered structure of the stomach wall was preserved in vitro for 6–8 h. Based on these results, it seems reasonable to use the in vitro preparation for conducting a study that is usually difficult to be performed in vivo. For instance, because there was no blood supply in vitro, the composition of the interstitial fluid, i.e., the ambient nerve terminals, can be better controlled and influenced by intra-arterial injection of a defined solution. Here we report that acutely changing the ambient CCK level by a conditioning stimulus (a preceding intra-arterial injection of increasing doses of CCK-8) reduced the CCK sensitivity of GVA terminals to a subsequent test stimulus (a constant dose of CCK-8 intra-arterial injection).

The single phase of Gd 0.95 Eu 0.05 Ba 3 B 9 O 18 and Gd 0.95 Tb 0.05 Ba 3 B 9 O 18 was prepared by the solid-state reaction. Their photoluminescence properties were investigated under ultraviolet and vacuum ultraviolet excitation. The results indicated that the charge transfer excitation band of Eu 3+ and 4f 8 → 4f 7 5d 1 transitions of Tb 3+ dominated the excitation spectra of Gd 0.95 Eu 0.05 Ba 3 B 9 O 18 and Gd 0.95 Tb 0.05 Ba 3 B 9 O 18 in ultraviolet region, respectively. The broad band of the host lattice absorption with maximum at about 165 nm was observed in vacuum ultraviolet region, which could consist of the absorptions of BO 3 groups and Ba–O groups. Under 254 and 147 nm excitation, Gd 0.95 Eu 0.05 Ba 3 B 9 O 18 and Gd 0.95 Tb 0.05 Ba 3 B 9 O 18 showed red and green emission peaking at about 592 and 541 nm, respectively.

BaMgAl10O17:Eu2+ doped with 0–6% additional Mg2+ were synthesized by co-precipitation method. Their photoluminescence and thermal stability were investigated under ultraviolet (UV) and vacuum ultraviolet (VUV) excitation. The additional Mg2+-doped samples exhibited stronger emission intensity and better thermal stability than the sample without additional Mg2+ under 254 or 147 nm excitation. After thermal degradation, the 4% additional Mg2+-doped sample had the highest emission intensity which was 12.7% and 16.6% stronger than that of the sample without additional Mg2+ under 254 and 147 nm excitation, respectively. Moreover, the improvement mechanisms on emission intensity and thermal stability were discussed.

The effect of short-term lower esophageal distension on intragastric pressure (IGP) and the related neural pathways involved were investigated in urethane-anesthetized rats in which enteric nervous system connections were interrupted by ligations of the pylorus and the gastroesophageal junction while keeping the gastric vagus nerve trunks intact. Under these conditions, lower esophageal distension with a bolus of 0.2 to 0.5 ml saline in 0.1 ml step increments, raised the inside esophagus balloon pressure from 1.89 +/- 0.17 to 4.21 +/- 0.13 cm H2O and reduced IGP from -0.42 +/- 0.08 to -0.77 +/- 0.12 cm H2O, respectively. Bilateral cervical vagotomy partly blocked the gastric relaxation induced by 0.5 ml esophageal distension from -0.77 +/- 0.12 to -0.34 +/- 0.02 cm H2O; in contrast, a further bilateral splanchnectomy partly rebounded the effect of 0.5 ml esophageal distension from -0.34 +/- 0.02 to -0.46 +/- 0.05 cm H2O. These results suggest that the enteric nervous system may not play a prominent role in acute esophageal distension induced-gastric relaxation. However, more than 50% of this effect is central nervous system mediated (via the long vago-vagal reflex). The other 40% can be maintained without central and enteric nervous systems involvement, probably via a proposed gastric vagal afferent-esophageal collateral reflex.

Actin rearrangements are induced in the dorsal hippocampus after conditioned morphine withdrawal, and involved in the formation of conditioned place aversion. In the present study, we investigated the mechanisms underlying the actin rearrangements in rat dorsal hippocampus induced by conditioned morphine withdrawal. The RhoA-ROCK pathway inhibitor Y27632 (8.56 μg/1 μL per side) or the Rac1 inhibitor NSC23766 (25 μg/1 μL per side) was microinjected into the dorsal hippocampus of rats. Conditioned place aversion (CPA) induced by naloxone-precipitated morphine withdrawal was assessed. Crude synaptosomal fraction of hippocampus was prepared, and the amount of F-actin and G-actin was measured with an Actin Polymerization Assay Kit. Conditioned morphine withdrawal significantly increased actin polymerization in the dorsal hippocampus at 1 h following the naloxone injection. Preconditioning with microinjection of Y27632, but not NSC23766, attenuated CPA, and blocked the increase in actin polymerization in the dorsal hippocampus. Our results suggest that the small GTPase RhoA, but not Rac1, in the dorsal hippocampus is responsible for CPA formation, mainly through its regulation of actin rearrangements.

Transcriptional coactivator PPARγ coactivator-1α (PGC-1α) and corepressor receptor-interacting protein 140 (RIP140) are opposing-functional regulators in maintaining energy balance of most metabolic tissues and cells. However, the relative contributions of both factors to energy metabolism in cardiomyocytes remain largely unknown. Herein, we reported that the relative protein levels of RIP140/PGC-1α were up-regulated in the failing hearts after chronic myocardial infarction (MI), and correlated negatively with the energy state index phosphocreatine (PCr)/ATP ratios. Real-time PCR analysis revealed that mRNA expressions of estrogen related receptor α (ERRα), peroxisome proliferate activated receptor α and β (PPARα, PPARβ), nuclear respiratory factor 1 (NRF1) and their target genes were repressed by RIP140 and induced by PGC-1α in a dose dependent manner in neonatal rat cardiomyocytes. We also observed that overexpression of RIP140 through adenovirus delivery can abrogate the PGC-1α-mediated induction of mitochondrial membrane potential elevation and mitochondrial biogenesis, and activate both autophagy and apoptosis pathways. We conclude that RIP140 and PGC-1α exert antagonistic role in regulating cardiac energy state and mitochondrial biogenesis.

Distinct opioid receptor agonists have been proved to induce differential patterns of ERK activation, but the underlying mechanisms remain unclear. Here, we report that Ser363 in the δ-opioid receptor (δOR) determines the different abilities of the δOR agonists DPDPE and TIPP to activate ERK by G-protein- or β-arrestin-dependent pathways. Although both DPDPE and TIPP activated ERK1/2, they showed different temporal, spatial and desensitization patterns of ERK activation. We show that that DPDPE employed G protein as the primary mediator to activate the ERK cascade in an Src-dependent manner, whereas TIPP mainly adopted a β-arrestin1/2-mediated pathway. Moreover, we found that DPDPE gained the capacity to adopt the β-arrestin1/2-mediated pathway upon Ser363 mutation, accompanied by the same pattern of ERK activation as that induced by TIPP. Additionally, we found that TIPP- but not DPDPE-activated ERK could phosphorylate G-protein-coupled receptor kinase-2 and β-arrestin1. However, such functional differences of ERK disappeared with the mutation of Ser363. Therefore, the present study reveals a crucial role for Ser363 in agonist-specific regulation of ERK activation patterns and functions.

The kappa-opioid receptor (KOR), a member of the opioid receptor family, is widely expressed in the central nervous system and peripheral tissues. Substantial evidence has shown that activation of KOR by agonists and endogenous opioid peptides in vivo may produce a strong analgesic effect that is free from the abuse potential and the adverse side effects of mu-opioid receptor (MOR) agonists, such as morphine. In addition, activation of the KOR has also been shown to exert an inverse effect on morphine-induced adverse actions, such as tolerance, reward, and impairment of learning and memory. Therefore, the KOR has received much attention in the effort to develop alternative analgesics to MOR agonists and agents for the treatment of drug addiction. However, KOR agonists also produce several severe undesirable side effects such as dysphoria, water diuresis, salivation, emesis, and sedation in nonhuman primates, which may limit the clinical utility of KOR agonists for pain and drug abuse treatment. This article will review the role of KOR activation in mediating antinociception and addiction. The possible therapeutic application of kappa-agonists in the treatment of pain and drug addiction is also discussed.

Cryptotanshinone (CTS), a major constituent extracted from the medicinal herb Salvia miltiorrhiza Bunge, has well-documented antioxidative and anti-inflammatory effects. In the present study, the pharmacological effects and underlying molecular mechanisms of CTS on lipopolysaccharide (LPS)-induced inflammatory responses were investigated. By enzyme-linked immunosorbent assay, we observed that CTS reduced significantly the production of proinflammatory mediators (tumor necrosis factor-α and interleukin-6) induced by LPS in murine macrophage-like RAW264.7 cells. Mechanistically, CTS inhibited markedly the phosphorylation of mitogen-activated protein kinases (MAPKs), including ERK1/2, p38MAPK, and JNK, which are crucially involved in regulation of proinflammatory mediator secretion. Moreover, immunofluorescence and western blot analysis indicated that CTS abolished completely LPS-triggered nuclear factor-κB (NF-κB) activation. Taken together, these data implied that NF-κB and MAPKs might be the potential molecular targets for clarifying the protective effects of CTS on LPS-induced inflammatory cytokine production in macrophages.

Zinc blende, sphericity, monodisperse, high luminescence ZnSe quantum dots (QDs) were synthesized by a one-step mild hydrothermal route with Zn and Se dissolved in aqueous NaOH as the source material. The structure and the morphology of the sample were examined by X-ray diffraction (XRD) and transmission electron microscopy (TEM). The results indicated that the products were cubic blende ZnSe ranging from 3.2 to 4.5 nm in size. TEM images showed that the QDs have very good dispersibility and distribution. The characteristic features of the absorption and photoluminescence spectra of ZnSe quantum dots were studied at room temperature. Compared with the bulk ZnSe, the absorption edges and luminescent peaks of ZnSe QDs were blue shifted to higher energies due to the quantum confinement effect. Photoluminescence at ultraviolet excitation showed the strong emission at 390 nm related to the higher excitonic states. ZnSe QDs exhibiting photoluminescence line widths as narrow as 40-60 nm. Meanwhile, we simply explored the theoretical mechanism of luminescence in ZnSe QDs and analogized the relation of various point defect concentrations of ZnSe.

Full-length hepatitis B virus (HBV) reverse transcriptase (RT) sequences were amplified and sequenced among 192 nucleos(t)ide analogue (NA)-naive Chinese patients with chronic hepatitis B. Deduced amino acids (AAs) at 42 previously reported potential NA resistance (NAr) mutation positions in RT region were analyzed. Patients were found with either B-genotype (28.65%) or C-genotype (71.35%) infections. Rt53, rt91, rt124, rt134, rt221, rt224, rt238 and rt256 were identified as B- and C-genotype-dependent polymorphic AA positions. AA substitutions at 11 classical NAr mutation positions, i.e. rt80, rt169, rt173, rt180, rt181, rt184, rt194, rt202, rt204, rt236 and rt250, were not detected. However, potential NAr mutations were found in 30.73% (59/192) isolates, which involved 18 positions including rt53, rt207, rt229, rt238 and rt256, etc. The concomitant AA changes of HBsAg occurred in 16.67% (32/192) isolates including sG145R mutation. One-third of mutation positions were located in functional RT domains (e.g. rt207 and rt233), A-B interdomains (overlapping HBsAg 'a' determinant and showing most concomitant immune-associated mutations) and non-A-B interdomains (e.g. rt191 and rt213), respectively. Genotypes B and C each showed several preferred positions to mutate. These results might provide insights into understanding the evolution and selection basis of NAr HBV strains under antiviral therapy.

Natriuretic peptides (NP) were first identified in animals where they play a role in the regulation of salt and water balance. This regulation is partly mediated by intracellular changes in cyclic GMP (cGMP). NP immunoanalogues occur in many plants and have been isolated, with two NP encoding genes characterised in Arabidopsis thaliana L. (AtPNP-A and AtPNP-B). Part of AtPNP-A contains the region with homology to human atrial (A)NP. We report here on the effects of recombinant AtPNP-A and smaller synthetic peptides within the ANP-homologous region with a view to identifying the biologically active domain of the molecule. Furthermore, we investigated interactions between AtPNP-A and the hormone, abscisic acid (ABA). ABA does not significantly affect Arabidopsis mesophyll protoplast volume regulation, whereas AtPNP-A and synthetic peptides promote water uptake into the protoplasts causing swelling. This effect is promoted by the membrane permeable cGMP analogue, 8-Br-cGMP, and inhibited by guanylate cyclase inhibitors indicating that increases in cGMP are an essential component of the plant natriuretic peptides (PNP) signalling cascade. ABA does not induce cGMP transients and does not affect AtPNP-A dependent cGMP increases, hence the two regulators differ in their second messenger signatures. Interestingly, AtPNP-A significantly delays and reduces the extent of ABA stimulated stomatal closure that is also based on cell volume regulation. We conclude that a complex interplay between observed PNP effects (stomatal opening and protoplast swelling) and ABA is likely to be cell type specific.

In vitro gastric vagal afferents' (GVAs) unit activities were recorded from the ventral GVA nerve strands in rats. The responsiveness of 16 GVA terminals to close intra-arterial injection of vehicle (0.1 ml), leptin (350 pmol), and cholecystokinin (CCK)-8 (10 pmol) was analyzed to generate a spike count-versus-time histogram. Data of 5-min spike counts before and after each treatment were normalized by dividing the latter by the former. A quotient (Q) > 1 indicates an excitatory effect, Q < 1 indicates an inhibitory effect, and Q close to 1 indicates no effect. Two types of GVA terminals were identified. Type 1 (n = 8) responded to leptin with Q > 1; CCK-8 pretreatment did not consistently alter leptin sensitivity. In contrast, Type 2 (n = 8) responded to leptin with Q < 1 or close to 1, and CCK-8 pretreatment increased the leptin sensitivity so that the terminals responded to subsequent leptin with Q > 1. These data suggest that Type 1 and Type 2 GVA terminals may provide afferent neural signals, which, in turn, will be involved in body weight and food intake control systems, respectively.

The membrane potential (E(m)) was used as an indicator to evaluate the effect of stem cell factor (SCF) on the membrane integrity of peritoneal mast cells (PMCs). PMCs were harvested from the peritoneal lavage of Sprague-Dawley rats, purified more than 95% and cultured with or without the presence of SCF (2 x 10(-8) M). E(m) values were measured with conventional intracellular recording techniques. Results from day 1 to day 4 in culture were compared. Significant differences in average E(m) (aE(m)) (P < 0.01, analysis of variance) were seen on days 3 and 4 (means +/- SE in millivolts): -67.4 +/- 8.0 and -59.4 +/- 4.8 with SCF vs. -24.8 +/- 7.9 and -7.6 +/- 3.9 without SCF, respectively. Moreover, after culture with SCF for > 1 wk, the aE(m) values of purified PMCs had a tendency to reach plateau values similar to that of unpurified PMCs on day 1 (at -20 mV). The morphological appearances of PMCs can be correlated with the results of aE(m) measurements. PMCs with a smooth spherical shape and highly refractive appearance, and better tolerance to electrode impalement, showed E(m) with greater negative values and lesser fluctuations. These results indicate that SCF can maintain the membrane properties and viability of purified PMCs in a long-term culture.

Xin-Hua Tian,1,2 Zhi-Gang Wang,1,2 Han Meng,1,2 Yu-Hua Wang,2 Wei Feng,2 Feng Wei,2 Zhi-Chun Huang,2 Xiao-Ning Lin,2 Lei Ren3,41Xiehe Clinical College of Medicine, Fujian Medical University, Fuzhou, 2Department of Neurosurgery, Zhongshan Hospital, 3Research Center of Biomedical Engineering, Department of Biomaterials, College of Materials, 4State Key Laboratory for Physical Chemistry of Solid Surfaces, Xiamen University, Xiamen, People's Republic of ChinaBackground: Gene transfer using a nanoparticle vector is a promising new approach for the safe delivery of therapeutic genes in human disease. The Tat peptide-decorated gelatin-siloxane (Tat-GS) nanoparticle has been demonstrated to be biocompatible as a vector, and to have enhanced gene transfection efficiency compared with the commercial reagent. This study investigated whether intracisternal administration of Tat-GS nanoparticles carrying the calcitonin gene-related peptide (CGRP) gene can attenuate cerebral vasospasm and improve neurological outcomes in a rat model of subarachnoid hemorrhage.Method: A series of gelatin-siloxane nanoparticles with controlled size and surface charge was synthesized by a two-step sol-gel process, and then modified with the Tat peptide. The efficiency of Tat-GS nanoparticle-mediated gene transfer of pLXSN-CGRP was investigated in vitro using brain capillary endothelial cells and in vivo using a double-hemorrhage rat model. For in vivo analysis, we delivered Tat-GS nanoparticles encapsulating pLXSN-CGRP intracisternally using a double-hemorrhage rat model.Results: In vitro, Tat-GS nanoparticles encapsulating pLXSN-CGRP showed 1.71 times higher sustained CGRP expression in endothelial cells than gelatin-siloxane nanoparticles encapsulating pLXSN-CGRP, and 6.92 times higher CGRP expression than naked pLXSN-CGRP. However, there were no significant differences in pLXSN-CGRP entrapment efficiency and cellular uptake between the Tat-GS nanoparticles and gelatin-siloxane nanoparticles. On day 7 of the in vivo experiment, the data indicated better neurological outcomes and reduced vasospasm in the subarachnoid hemorrhage group that received Tat-GS nanoparticles encapsulating pLXSN-CGRP than in the group receiving Tat-GS nanoparticles encapsulating pLXSN alone because of enhanced vasodilatory CGRP expression in cerebrospinal fluid.Conclusion: Overexpression of CGRP attenuated vasospasm and improved neurological outcomes in an experimental rat model of subarachnoid hemorrhage. Tat-GS nanoparticle-mediated CGRP gene delivery could be an innovative strategy for treatment of cerebral vasospasm after subarachnoid hemorrhage.Keywords: gene transfer, nanoparticles, calcitonin gene-related peptide, cerebral vasospasmCorrigendum for this paper has been published