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.

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.

[-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.

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.

[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.