Discovery and pharmacodynamic evaluation of the novel butene lactone derivative M355 against influenza A virus in vitro and in vivo.

A new series of butene lactone derivatives were designed according to an influenza neuraminidase target and their antiviral activities against H1N1 infection of Madin-Darby canine kidney cells were evaluated. Among them, a compound that was given the name M355 was identified as the most potent against H1N1 (EC50 = 14.7 µM) with low toxicity (CC50 = 538.13 µM). It also visibly reduced the virus-induced cytopathic effect. Time-of-addition analysis indicated that H1N1 was mostly suppressed by M355 at the late stage of its infectious cycle. M355 inhibited neuraminidase in a dose-dependent fashion to a similar extent as oseltamivir, which was also indicated by a computer modeling experiment. In a mouse model, lung lesions and virus load were reduced and the expression of nucleoprotein was moderated by M355. The enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction analyses revealed that the levels of interferon-γ, interferon regulatory factor-3, Toll-like receptor-3, tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and IL-8 were downregulated in the M355-treated groups, whereas the levels of IL-10 and IL-13 were upregulated. Similarly, IgG was found to be increased in infected mice plasma. These results demonstrate that M355 inhibit the expression of H1N1 in both cellular and animal models. Thus, M355 has the potential to be effective in the treatment of influenza A virus infection.

Screening and pharmacodynamic evaluation of the anti-respiratory syncytial virus activity of butene lactones in vitro and in vivo.

A series of butene lactones were synthesized and these compounds were tested for anti-respiratory syncytial virus (RSV) activity in vitro. Three compounds exhibited an antiviral effect, the highest of which was compound 6b3 with an effective concentration 50% of 6.35 µM. The effects of 6b3 were then evaluated in vivo and a significant reduction in the lung index caused by RSV was detected. Reduced inflammatory infiltration and necrosis of the lungs were revealed by histopathology and gross pathology. Activation of an early immune response by 6b3 was also observed by cytokine analysis via a real-time polymerase chain reaction. These results indicated that 6b3 has an anti-RSV effect both in vitro and in vivo, and is a possible candidate compound for the development of an anti-RSV drug in the future.

Higher serum VGF protein levels discriminate bipolar depression from major depressive disorder.

Misdiagnosis between major depressive disorder (MDD) and bipolar depression (BD) is quite common. Our previous study found significantly lower serum VGF (non-acronymic) in MDD patients. However, it is unclear whether same changes occur in BD patients. Therefore, we aimed to investigate the relationship between serum VGF levels in BD and MDD patients. General information, scores of 17-item Hamilton Depression Rating Scale (HDRS), and fasting blood samples of all participants including 30 MDD patients, 20 BD patients, and 30 healthy controls (HC) were collected. Serum VGF levels were measured by Enzyme-linked immunosorbent assay kits. Pearson correlation analysis was used to analyze correlations between serum VGF levels and clinical information. Receiver operating characteristic (ROC) curve and likelihood ratios (LRs) were used to analyze the differential potential of serum VGF. Serum VGF levels were significantly lower in MDD patients but higher in BD patients compared with HC (both PTukey < 0.01). No correlation was found between serum VGF levels and any data of subjects. The optimal cutoff for serum VGF in discriminating BD patients from MDD patients was ≥1093.85 pg/ml (AUC = 0.990, sensitivity of 95%, specificity of 100% and accuracy of 95%). LRs further confirmed the differential efficiency of serum VGF in distinguishing BD and MDD patients with +LR of infinity and -LR of 0. The results suggest that serum VGF level changed significantly in MDD and BD patients and serum VGF may be an indicator for differentiating BD patients from MDD patients.

A comparative study of anhedonia components between major depression and schizophrenia in Chinese populations.

BACKGROUND: Anhedonia is a prominent symptom of major depressive disorder (MDD) and schizophrenia. At present, it is believed that hedonic processing rather consists of the anticipatory and consummatory phase. The aim of this research is to explore the different anhedonia components in MDD and schizophrenia in Chinese populations. METHODS: A Chinese version of the Temporal Experience of Pleasure Scale (TEPS) was used to evaluate 176 MDD patients, 346 schizophrenia patients, and 268 healthy controls. Additionally, the 17-item Hamilton Depression Rating Scale (HAMD-17) was used for MDD patients, while the Positive and Negative Syndrome Scale (PANSS) was applied for schizophrenia. RESULTS: The scores of consummatory (TEPS-CON) and anticipatory pleasure (TEPS-ANT) in MDD and schizophrenia were both significantly lower than healthy controls (both P < 0.001). TEPS-CON and TEPS-ANT were negatively correlated with the score of HAMD-17, the duration of illness and admission times in MDD (P < 0.05 or 0.01). TEPS-CON was negatively related to PANSS total scores and negative symptoms (P < 0.05 or 0.01), but no significant correlation was found with duration of illness and admission times in schizophrenia (P > 0.05). There was no significant correlation between TEPS-ANT and any clinical variables (P > 0.05). CONCLUSIONS: The consummatory and anticipatory pleasures were both impaired in MDD and schizophrenia. Consummatory and anticipatory anhedonia can be considered as a "state" in MDD, but as a "trait" in schizophrenia.

Chemotherapeutics for Toxoplasma gondii: Molecular Biotargets, Binding Modes, and Structure-Activity Relationship Investigations.

Toxoplasmosis, an infectious zoonotic disease caused by the apicomplexan parasite Toxoplasma gondii (T. gondii), is a major worldwide health problem. However, there are currently no effective options (chemotherapeutic drugs or prophylactic vaccines) for treating chronic latent toxoplasmosis infection. Accordingly, seeking more effective and safer chemotherapeutics for combating this disease remains a long-term and challenging objective. In this paper, we summarize possible molecular biotargets, with an emphasis on those that are druggable and promising, including, without limitation, calcium-dependent protein kinase 1, bifunctional thymidylate synthase-dihydrofolate reductase, and farnesyl diphosphate synthase. Meanwhile, as important components of medicinal chemistry, the binding modes and structure-activity relationship profiles of the corresponding inhibitors were also illuminated. We anticipate that this information will be helpful for further identification of more effective chemotherapeutic interventions to prevent and treat zoonotic infections caused by T. gondii.

The Advances on the Protective Effects of Ginsenosides on Myocardial Ischemia and Ischemia-Reperfusion Injury.

Ginseng is a traditional medicine with a complex chemical composition, wide bioactivity and unique pharmacological action. Many studies have confirmed that ginsenosides are the active ingredients of ginseng, and ginsenosides have always been the focus of different researchers. With the development of modern separation and analysis technology, more than 150 kinds of ginsenosides have been isolated. The ginsenosides Rb1, Rb2, Rc, Rg1 and Re account for more than 80% of total ginsenosides, and other saponins, such as Rd, Rg3 and Rh2, which are minor constituents, accounting for only a small portion of the total amount. In recent years, ginsenosides have been found to possess strong pharmacological activities, such as antioxidation, clearing of oxygen free radicals, reducing calcium overload and anti-apoptosis. Ginsenosides play a protective role in ischemia-reperfusion injury. This paper reviews the protective effects of ginsenosides on myocardial ischemia and ischemiareperfusion injury.

Dysregulation of Long Non-coding RNAs and mRNAs in Plasma of Clear Cell Renal Cell Carcinoma Patients Using Microarray and Bioinformatic Analysis.

Objective: The roles of long non-coding RNAs (lncRNAs) in the diagnosis of clear cell renal cell carcinoma (ccRCC) are still not well-defined. We aimed to identify differentially expressed lncRNAs and mRNAs in plasma of ccRCC patients and health controls systematically. Methods: Expression profile of plasma lncRNAs and mRNAs in ccRCC patients and healthy controls was analyzed based on microarray assay. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway-based approaches were used to investigate biological function and signaling pathways mediated by the differentially expressed mRNAs. SOCS2-AS1 was selected for validation using Real-Time PCR. The differentially expressed lncRNAs and mRNAs were further compared with E-MTAB-1830 datasets using Venn and the NetworkAnalyst website. The GEPIA and ULCAN websites were utilized for the evaluation of the expression level of differentially expressed mRNA and their association with overall survival (OS). Results: A total of 3,664 differentially expressed lncRNAs were identified in the plasma of ccRCC patients, including 1,511 up-regulated and 2,153 down-regulated lncRNAs (fold change ≥2 and P < 0.05), respectively. There were 2,268 differentially expressed mRNAs, including 932 up-regulated mRNAs and 1,336 down-regulated mRNAs, respectively (fold change ≥2 and P < 0.05). Pathway analysis based on deregulated mRNAs was mainly involved in melanogenesis and Hippo signaling pathway (P < 0.05). In line with the lncRNA microarray findings, the SOCS2-AS1 was down-regulated in ccRCC plasma and tissues, as well as in cell lines. Compared with the E-MTAB-1830 gene expression profiles, we identified 18 lncRNAs and 87 mRNAs differently expressed in both plasma and neoplastic tissues of ccRCC. The expression of 10 mRNAs (EPB41L4B, CCND1, GGT1, CGNL1, CYSLTR1, PLAUR, UGT3A1, PROM2, MUC12, and PCK1) was correlated with the overall survival (OS) rate in ccRCC patients based on the GEPIA and ULCAN websites. Conclusions: We firstly reported differentially expressed lncRNAs in ccRCC patients and healthy controls systemically. Several differentially expressed lncRNAs and mRNAs were identified, which might serve as diagnostic or prognostic markers. The biological function of these lncRNAs and mRNAs should be further validated. Our study may contribute to the future treatment of ccRCC and provide novel insights into cancer biology.

Discovery and SAR Research for Antivirus Activity of Novel Butenolide on Influenza A Virus H1N1 In Vitro and In Vivo.

Influenza viruses (IV) cause substantial morbidity and mortality through routine seasonal spread and epidemics. A novel series of butenolides were discovered to be able to inhibit influenza H1N1 activity in vitro, and the SAR for anti-influenza activity was investigated. By optimization of the hit compound, compound 37 was obtained with an EC50 of 6.7 µM against influenza A virus H1N1 as an inhibitor of NA and with low cytotoxicity on MDCK cells. Also, it can inhibit the expression of the influenza A virus gene in the lung of SPF KM mice to show antivirus activity in vivo. These results suggested that compound 37 could inhibit the influenza A virus H1N1 via targeting NA.

[-2548G/A functional polymorphism in the promoter region of leptin gene and antipsychotic agent-induced weight gain in schizophrenic patients: a study of nuclear family-based association].

OBJECTIVE: To investigate whether there is association between the-2548G/A functional polymorphism in the promoter region of leptin gene and weight gain following antipsychotic agents (APS) acute treatment in schizophrenic patients. METHODS: Eight-four Chinese Han untreated schizophrenia patients in 70 nuclear families were recruited. The polymorphism of leptin gene was determined with PCR-RFLP technique. Body weight was measured in the patients on admission the and after 10 weeks treatment with risperidone or chlorpromazine. RESULTS: There was an average (8.00+/-6.13)% increases in baseline weight after the 10 week treatment. There were significant differences in the distribution of allele frequencies (chi2=4.031, P=0.045) between the patients with weight changed >or=7% and <7% subgroups. Family-based association analysis further confirmed the above significant finding by transmission disequilibrium test but not by quantitative trait transmission disequilibrium test. CONCLUSION: The finding confirms that the-2548G/A polymorphism in promoter region of leptin gene is associated with APS-induced weight gain.

The effect of chronic antipsychotic treatment on sexual behaviour, hormones and organ size in the male rat.

Antipsychotic drug-induced sexual dysfunction is an important and problematic side effect. We have investigated the effect of chronic antipsychotic treatment on sexual behaviour, sex hormones and genital organ size in the male rat. The following sexual functions were significantly impaired in both risperidone (2 mg/kg) and haloperidol (2 mg/kg) groups at 3 weeks: libido (assessed in mounting frequency and intromission), sexual arousability/motivation (in terms of latencies for mounting and intromission) and orgasm (in terms of latency for ejaculation). At 6 weeks, haloperidol also suppressed the 'hit ratio' (intromissions/mounts) as well as the above-mentioned parameters indicating erectile dysfunction. Risperidone had no significant effect on sexual function at 6 weeks. Compared with the control group, haloperidol and risperidone decreased the serum level of testosterone after 6 weeks but not after 3 weeks. The two drugs did not influence the serum level of leutenizing hormone (LH). At 3 weeks, the epididymis was significantly decreased below controls in both risperidone and haloperidol groups. At 6 weeks, the epididymis, seminal vesicle and prostate weights were significantly reduced in the haLoperidol group, but not in the risperidone group. The serum concentration of testosterone significantly correlated with sex organ weight, but not with sexual behaviours. These results suggest that sexual function, testosterone levels and genital tissue size in male rats were affected to different degrees by risperidone and haloperidol. These findings contribute to our understanding of antispsychotic drug-induced male sexual dysfunction.

Combined serum levels of multiple proteins in tPA-BDNF pathway may aid the diagnosis of five mental disorders.

Mental disorders are severe, disabling conditions with unknown etiology and are commonly misdiagnosed when clinical symptomology criteria are solely used. Our previous work indicated that combination of serum levels of multiple proteins in tissue plasminogen activator (tPA)-brain-derived neurotrophic factor (BDNF) pathway improved accuracy of diagnosis of major depressive disorder (MDD). Here, we measured serum levels of tPA, plasminogen activator inhibitor-1 (PAI-1), BDNF, precursor-BDNF (proBDNF), tropomyosin-related kinase B (TrkB) and neurotrophin receptor p75 (p75NTR) in patients with paranoid schizophrenia (SZ, n = 34), MDD (n = 30), bipolar mania (BM, n = 30), bipolar depression (BD, n = 22), panic disorder (PD, n = 30), and healthy controls (HCs, n = 30) by Enzyme-linked immunosorbent assay kits. We used receiver operating characteristic (ROC) curve to analyze diagnostic potential of these proteins. We found, compared with HCs, that serum tPA and proBDNF were lower in SZ, BM and BD; TrkB was lower in SZ and BD; and p75NTR was declined in SZ and BM. ROC analysis showed that combined serum level of tPA, PAI-1, BDNF, proBDNF, TrkB and p75NTR was better than any single protein in accuracy of diagnosis and differentiation, suggesting that the combination of multiple serum proteins levels in tPA-BDNF pathway may have a potential for a diagnostic panel in mental disorders.

Serum free Fatty acids and glucose metabolism, insulin resistance in schizophrenia with chronic antipsychotics.

BACKGROUND: Weight gain and type 2 diabetes mellitus (DM) are often linked to antipsychotics treatment. The aim of the study is to investigate serum free fatty acids (FFA) levels in schizophrenic patients who received long-term antipsychotics treatment, and to explore the associations between serum FFA and fasting blood glucose, and insulin resistance. METHODS: 308 inpatients with schizophrenia who met with the criteria of DSM-IV were recruited into this study, and were divided into four groups: control subjects, single obesity, impaired glucose tolerance (IGT) and type 2 DM according to different body mass index, fasting blood glucose level and 2-hour postprandial blood glucose. Serum FFA was measured with colorimetry. Serum insulin and leptin were measured with radioimmunoassay respectively. RESULTS: There was a significant elevation in serum FFA levels in schizophrenic patients who received long-term antipsychotics treatment, especially in single obesity, IGT, and DM groups. The elevated serum FFA was remarkably positive correlated with fasting blood glucose and insulin resistance. CONCLUSIONS: The study suggested the elevated serum FFA in schizophrenic patients with long-term antipsychotics treatment affected the blood glucose metabolism, may have played an important role in insulin resistance and type 2 DM, and was also an important trait of metabolic syndromes.

Modes of Antiviral Action of Chemical Portions and Constituents from Woad Root Extract against Influenza Virus A FM1.

Woad root has been used for the prevention of influenza for hundreds of years in many Asian countries. In this study, the antiviral modes of clemastanin B (CB), epigoitrin, phenylpropanoid portion (PEP), and the mixture of phenylpropanoids, alkaloids, and organic acid portions (PEP + ALK + OA) from wood root extract against influenza virus A FM1 were investigated. The results revealed that CB, epigoitrin, PEP, and PEP + ALK + OA exert their anti-influenza activity via inhibiting the virus multiplication, prophylaxis, and blocking the virus attachment. The primary mode of action of PEP and PEP + ALK + OA is the inhibition of virus replication. The inhibitory effect on virus attachment and multiplication is the main modes for epigoitrin. All the compounds or chemical portions from woad root extract tested in this study do not have direct virucidal activity. Our results provided the comprehensive analysis of the antiviral mechanism of wood root extract.

Altered regional brain function in the treatment-naive patients with somatic symptom disorder: a resting-state fMRI study.

INTRODUCTION: Somatic symptom disorder (SSD) is an illness that occurs over a long time and results in significant disruption in daily life. Clinically, SSD patients typically express complaints that involve a variety of organ systems. However, the neural mechanism of SSD remains poorly understood. METHODS: Using resting-state functional magnetic resonance imaging, we investigated the characteristics of the regional basal brain function during resting state in patients with SSD. Eleven treatment-naïve SSD patients and 12 age-matched healthy controls were recruited in this study. Between-group differences in regional homogeneity values were analyzed. RESULTS: Compared with the healthy control group, the SSD group showed significant increases in regional homogeneity values in the right medial prefrontal cortex, anterior cingulate cortex and supramarginal gyrus, and significant decreases in the bilateral middle occipital gyrus, superior occipital gyrus and right cuneus and left postcentral gyrus and cerebellum. Meanwhile, the regional homogeneity value of the right medial prefrontal cortex positively correlated with the total duration of SSD. CONCLUSIONS: The abnormal resting-state patterns in regional brain activity may contribute to understanding the mechanism of SSD.

[No association of -1438G/A polymorphism in promoter region of 5-HT2A receptor gene with antipsychotic agent-induced weight gain].

OBJECTIVE: To investigate whether the -1438G/A polymorphism in the promoter region of 5-HTR2A gene associates with the weight gain following antipsychotic agents (APS) acute treatment in schizophrenic patients. METHODS: Eighty-four Chinese Han patients with schizophrenia at the first onset were recruited from among 70 nuclear families. The polymorphism of 5-HTR2A gene was determined with PCR-RFLP technique. Body weight was measured in the patients on admission after 10 weeks of treatment with risperidone or chlorpromazine. RESULTS: There were no statistically significant differences in the distribution frequencies of genotype (chi2: 0.172, v1, P > 0.05) and allele (chi2: 0.121, v1, P > 0.05) of -1438G/A polymorphism of 5-HTR2A gene between subgroups (weight gain >or= 7% or < 7%). Likewise, there was no significant difference in weight gain between genotype groups. By means of transmission disequilibrium test and quantitative transmission disequilibrium test, no significant association between the -1438G/A polymorphism of 5-HTR2A gene and weight gain was observed. CONCLUSION: 5-HTR2A gene -1438G/A polymorphism was probably not associated with APS-induced weight gain in Chinese Han patients with schizophrenia in this study.

[Association of -2548G/A functional polymorphism in the promoter region of leptin gene with antipsychotic agent-induced weight gain].

OBJECTIVE: To investigate whether the -2548G/A functional polymorphism in promoter region of leptin gene influencing weight gain following antipsychotic agents (APS) acute treatment in schizophrenic patients. METHODS: 128 Chinese Han untreated patients with schizophrenia (male 61, female 67) with an age and gender matched health controls (n = 38) were recruited. The polymorphism of leptin gene was determined with PCR-RFLP technique. MRI determined abdominal body fat in 22 controls and 30 patients on admission and after 10 weeks treatment with risperidone or chlorpromazine. Body mass index (BMI) was measured on admission and every week subsequently (for patients). RESULTS: There were average increases in (6.2 +/- 5.7)% of baseline weight and in (38.5 +/- 42)% of baseline abdominal subcutaneous fat (SUB) and in (40.0 +/- 41.2)% of baseline intra-abdominal fat (IAF) 10 weeks after treatment. There were no significant differences in the distribution of allele and genotypes either between the patients and controls or between gender groups. It was found significantly increased weight gain in the patient with the -2548AA genotype (chi(2) = 7.529, df = 1, P = 0.006; OR = 1.941; 95% CI: 1.175 - 3.207); The genotypes had no influence on the baseline weight indicators both in patients and controls. However, as compared with the patients with G allele, the patients with AA genotype had significant increase in BMI (P = 0.003) and SUB (P = 0.009). CONCLUSION: The finding identify that the -2548G/A polymorphism in promoter region of leptin gene associated with APS-induced weight gain and abdominal fat deposition and distribution. -2548AA may be a genetic risk factor for the development of weight gain and body fat deposition in Chinese Han schizophrenic patients during APS acute treatment.

Voice recognition and altered connectivity in schizophrenic patients with auditory hallucinations.

Auditory verbal hallucination (AVH) is a pathological hallmark of schizophrenia; however, their neural basis is unclear. Voice identity is an important phenomenological feature of AVHs. Certain voice identity recognition deficits are specific to schizophrenic patients with AVHs. We tested our hypothesis that among schizophrenia patients with hallucination, dysfunctional voice identity recognition is associated with poor functional integration in the neural networks involved in the evaluation of voice identity. Using functional magnetic resonance imaging (fMRI) during a voice recognition task, we examined the modulation of neural network connectivity in 26 schizophrenic patients with or without AVHs, and 13 healthy controls. Our results showed that the schizophrenic patients with AVHs had altered frontotemporal connectivity compared to the schizophrenic patients without AVHs and healthy controls. The latter two groups did not show any differences in functional connectivity. In addition, the strength of frontotemporal connectivity was correlated with the accuracy of voice recognition. These findings provide preliminary evidence that impaired functional integration may contribute to the faulty appraisal of voice identity in schizophrenic patients with AVHs.