Tumor Microenvironment-Activated Theranostics Nanozymes for Fluorescence Imaging and Enhanced Chemo-Chemodynamic Therapy of Tumors.

Chemodynamic therapy (CDT) is widely explored for tumor-specific therapy by converting endogenous H2O2 to lethal ·OH to destroy cancer cells. However, ·OH scavenging by glutathione (GSH) and insufficient intratumoral H2O2 levels seriously hinder the application of CDT. Herein, we reported the fabrication of copper ion-doped ZIF-8 loaded with gold nanozymes and doxorubicin hydrochloride (DOX) for the chemotherapy and CDT synergistic treatment of tumors with the assistance of tumor microenvironment (TME)-activated fluorescence imaging. The Cu2+-doped ZIF-8 shell was gradually degraded to release DOX and gold nanoclusters responding to the acidic TME. The fluorescence signal of the tumor region was acquired after the quenched fluorescence of the gold nanoclusters by Cu2+ and DOX by aggregation-induced quenching was turned on because of the interaction of GSH with Cu2+ and the release of free DOX. The Cu2+ ions could deplete the GSH via redox reactions and the generated Cu+ could convert internal H2O2 to ·OH for tumor CDT. The chemotherapeutic effect of DOX was strengthened through drug efflux inhibition and drug sensitivity increase due to the consumption of GSH and ·OH burst. Moreover, DOX could raise the level of H2O2 and augment the effect of CDT. In addition, the fluorescent gold nanoclusters not only served as a peroxidase to convert H2O2 to ·OH but also employed as an oxidase to consume GSH, resulting in the amplification of chemotherapy and CDT. This work presents an approach to construct tumor microenvironment-activated theranostic probes without external stimuli and to achieve the tumor elimination through cascade reactions and synergistic treatment.

A new indole alkaloid with anti-inflammatory from the branches of Nauclea officinalis.

A new indole alkaloid, 17-oxo-19-(Z)-naucline, and six known alkaloids 2-7 were isolated from the branches of Nauclea officinalis. The structure of the new compound 1 was characterised mainly by analysing its physical data including IR, 1 D, 2 D NMR, and HR-ESI-MS. Other compounds were identified by comparisons their data with those reported in the literature. Compound1, 4, 5, 6, 7 showed in vitro anti-inflammatory activity decrease the LPS-stimulated production of nitric oxide in RAW264.7 cell, while all compounds exhibited weak cytotoxicity against human tumour cell lines (LOVO, A549 and HepG2).

Gender differences in the prevalence of diabetes mellitus in chronic hospitalized patients with schizophrenia on long-term antipsychotics.

Gender-specific relationships between diabetes mellitus (DM) and schizophrenia have previously received little systematic study. The results showed that the overall DM prevalence was 20% with rates of 17% (58/343) in males and 27% (46/172) in females (p<0.01). Furthermore, increased body mass index (BMI), abdominal obesity and antipsychotic types were predictors of diabetes in these chronic schizophrenic patients.

Nicotine dependence and serum BDNF levels in male patients with schizophrenia.

OBJECTIVE: Schizophrenia is associated with a significantly high prevalence of smoking. Upregulation of neurotrophins by nicotine is well established. Accumulating evidence shows that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. The purposes of this study were to compare BDNF levels in smokers to nonsmokers with schizophrenia and examine the association between BDNF levels and psychopathological symptoms. MATERIALS AND METHODS: Serum BDNF levels were measured in 139 male inpatients with DSM-IV schizophrenia: 102 smokers and 37 nonsmokers. Symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). RESULTS: The positive PANSS symptoms were lower in smokers than in nonsmokers, while the negative symptoms were lower in those who smoked more cigarettes. BDNF levels were significantly higher in smokers than in nonsmokers (p < 0.05). Higher BDNF levels correlated with fewer negative symptoms and with smoking more cigarettes. CONCLUSION: The fewer positive symptoms in smokers and fewer negative symptoms in those who smoked more cigarettes may be associated with nicotine-induced upregulation of BDNF.

Increased serum S100B in never-medicated and medicated schizophrenic patients.

S100B is a calcium-binding protein, which is produced primarily by glial cells. It modulates the proliferation and differentiation of neurons and glia by affecting protective and apoptotic mechanisms. Recently, several studies have shown increased serum S100B levels in patients with schizophrenia, suggesting that S100B might be relevant to the pathophysiology of schizophrenia. S100B levels were assessed using ELISA in the serum of 80 never-medicated early-stage and 82 medicated chronic schizophrenia patients and 97 healthy controls subjects. The psychopathology of schizophrenia was assessed by the Positive and Negative Syndrome Scale (PANSS). Our results showed significantly increased serum S100B levels in both never-medicated and medicated patients compared to normal controls (both p<0.0001). S100B in never-medicated patients was also markedly increased, compared with medicated patients (p<0.0001). S100B changes observed were irrespective of neuroleptic medication, gender, age, and smoking. Increased S100B levels in the early stage of schizophrenia suggest that glial cell activation or structural damage may be part of a neurodegenerative process in schizophrenia. The lower S100B levels in chronic than early-stage patients further suggest that antipsychotic treatment may reduce this neurodegeneration.

Increased S100B serum levels in schizophrenic patients with tardive dyskinesia: association with dyskinetic movements.

Several studies show that calcium-binding protein S100B is increased in schizophrenia and may be involved in the pathogenesis of tardive dyskinesia (TD). We therefore compared serum S100B levels in normal controls (n=60), schizophrenic patients with (n=32) and without TD (n=50). Assessments included the abnormal involuntary movement scale (AIMS) and the positive and negative syndrome scale (PANSS). Serum S100B levels were measured by enzyme-linked immunosorbent assay (ELISA). The results indicated that patients with TD had higher serum S100B levels than normals and those without TD. Serum S100B levels were positively correlated with AIMS scores in patients with TD. These data suggest that increased S100B levels may be related to neuro-degeneration, associated with TD pathophysiology.

Association between monoamine oxidase (MAO)-A gene variants and schizophrenia in a Chinese population.

Monoamine oxidase (MAO) A is a critical enzyme in the catabolism of dopamine. Dysfunction of dopaminergic systems has been implicated in the pathophysiology of schizophrenia, suggesting that MAOA gene variation might be associated with the disorder. MAOA gene variation was compared between 234 Chinese schizophrenic patients and 121 healthy controls. Three polymorphic markers of the MAOA gene were analyzed using PCR techniques: two MAOA restriction fragment length polymorphisms (RFLP), -941G/T and -1460C/T, and the variable number tandem repeats (VNTR) in the promoter region. Linkage disequilibrium and haplotype analyses were performed with Bonferroni correction for multiple testing. In single marker analyses the 941T allele was significantly associated with schizophrenia in men (p=0.01). Haplotype analyses revealed a significant overall difference (p=0.03) between schizophrenia and control men, with higher frequencies of haplotypes containing the major allele (T) of -941T/G and the short allele (3 repeats) of the VNTR polymorphisms. No significant associations were detected for females using single markers or haplotypes. These findings suggest that genetic variants in MAOA may play a role in susceptibility to schizophrenia in Chinese men.

The novel oxidative stress marker thioredoxin is increased in first-episode schizophrenic patients.

Excessive free radical production leading to oxidative stress may be involved in the pathophysiology of schizophrenia. Oxidative stress increases serum thioredoxin (TRX), a redox-regulating protein with antioxidant activity recognized as an oxidative-stress marker. The aim of this study was to assess the clinical significance of serum TRX levels in various stages of schizophrenia. Serum TRX levels were determined using ELISA from 60 never-medicated first-episode and 66 medicated chronic schizophrenia patients and 66 healthy control subjects matched for age and gender. The psychopathology of schizophrenia was assessed by the Positive and Negative Syndrome Scale (PANSS). Our results showed that group comparison between first-episode and chronic patients and control groups revealed significantly increased serum TRX only in first-episode patients. Increased levels of TRX in patients experiencing an acute stage schizophrenic episode was also significantly higher compared to chronic schizophrenic patients on antipsychotic medication. Serum TRX was also positively correlated with positive symptoms of schizophrenia. Our results suggest oxidative stress occurs in an acute stage of schizophrenic episode and may have an important role in pathogenesis and symptomology of schizophrenia. Lower TRX levels in chronic patients treated with antipsychotics may have implications for treatment outcome.

Gender differences in the prevalence, risk and clinical correlates of tardive dyskinesia in Chinese schizophrenia.

OBJECTIVE: Despite extensive use of antipsychotic drug treatment, few studies address the prevalence of tardive dyskinesia (TD) in homogeneous ethnic groups such as the Chinese. This study examined gender-specific relationships between TD and symptom levels in schizophrenia among Han Chinese, which have previously received little systematic study. MATERIALS AND METHODS: Five hundred and twenty-two inpatients with schizophrenia receiving long-term treatment with antipsychotics were evaluated with the AIMS. The patient's psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS). Demographic and clinical data were collected from a detailed questionnaire and medical records. RESULTS: The overall TD prevalence was 33.7% with rates of 39.2% (138/352) in males and 22.4% (38/170) in females (chi (2) = 14.6, df = 1, p < 0.0001; adjust odds ratio 2.06; CI, 1.32-3.16). The AIMS score in patients with TD was lower in females than males (5.3 +/- 3.9 vs 6.7 +/- 3.7, t = 2.52, p < 0.01) after adjustment for the significant covariates. TD was associated with the negative symptoms on the PANSS in both genders, and with age, PANSS total and positive symptoms in men, not women. CONCLUSION: Our present findings suggest that there are gender differences in the prevalence, risk, and clinical correlates of TD in schizophrenia. Although this study is limited by cross-sectional designs, the magnitude of these gender-specific differences is substantial and deservers further prospective study.

Superoxide dismutase and cytokines in chronic patients with schizophrenia: association with psychopathology and response to antipsychotics.

OBJECTIVE: Both schizophrenia and oxidative stress have been associated with immune system abnormalities in interleukin-2 and -6 (IL-2; IL-6) and increases in superoxide dismutase (SOD) activity. These abnormalities may improve during antipsychotic drug treatment that reduces symptoms in schizophrenic patients. MATERIALS AND METHODS: Subjects included 30 healthy controls (HC) and 78 schizophrenic (SCH) in-patients who were randomly assigned to 12 weeks of double-blind treatment with risperidone 6 mg/day or haloperidol 20 mg/day. Ratings using the Positive and Negative Syndrome Scale (PANSS) were correlated with blood SOD and serum IL-2 levels. RESULTS: SCH patients who were medication-free for 2 weeks had greater SOD, IL-2, and IL-6 levels than HC. At baseline, these SOD elevations were associated with higher PANSS total scores and the IL-2 elevations with lower PANSS positive symptom scores. The SOD and IL-2 levels in the SCH were also positively correlated. After treatment, PANSS positive symptoms and both SOD and IL-2 showed a significant decrease, but IL-6 showed no change. The SOD and IL-2 reductions were correlated with the reductions in PANSS total score, and SOD reductions also correlated with positive subscore reductions. Females showed these associations more strongly than males. CONCLUSION: Our results suggest that the dysregulation in the cytokine system and oxidative stress in patients with schizophrenia is implicated in clinical symptoms and is improved at least partially with antipsychotic treatment. The stronger associations in females deserve further study and confirmation.

Lower serum cytokine levels in smokers than nonsmokers with chronic schizophrenia on long-term treatment with antipsychotics.

OBJECTIVE: Schizophrenia is associated with various abnormalities in the immune system. Suppression of inflammatory cytokines by cigarette smoke is well-established. The purpose of this study was to determine any differences in cytokine profiles in smokers and nonsmokers with schizophrenia and whether there were any relationships among altered cytokine profiles and psychopathological symptoms. MATERIALS AND METHODS: Serum interleukin (IL)-2, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha levels were measured in 96 male inpatients with DSM-IV schizophrenia: 66 smokers and 30 nonsmokers. Symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). RESULTS: The positive PANSS symptoms were lower in smokers than nonsmokers, while the negative symptoms were lower in those who smoked more cigarettes. Cytokine levels were positively correlated: IL-2 level with IL-6 and IL-6 with both IL-8 and TNF-alpha. Both IL-2 and IL-6, but not IL-8 or TNF-alpha, were significantly lower in smokers than nonsmokers (p < 0.002; p < 0.01). Lower IL-2 levels correlated with fewer negative symptoms and with smoking more cigarettes. CONCLUSIONS: The fewer positive symptoms in smokers and fewer negative symptoms in those who smoked more cigarettes may be associated with nicotine-induced suppression of some inflammatory cytokines.

Association between interleukin-3 receptor alpha polymorphism and schizophrenia in the Chinese population.

Schizophrenia has been observed to be associated with various abnormalities in cytokines and cytokine receptors. Three very recent reports showed the evidence that the IL3 gene, colony stimulating factor 2 receptor alpha (CSF2RA), beta (CSF2RB) and IL-3 receptor alpha (IL3RA), the IL-specific receptor subunits for CSF2 and IL3, respectively, are associated with schizophrenia. To examine the association of the IL3RA polymorphism (rs6603272) with schizophrenia in a Chinese population, 310 physically healthy patients with schizophrenia were compared with 330 age-, sex- matched normal controls. Statistically significant differences were observed in both allelic and genotypic frequencies of the rs6603272 polymorphism (Allele, chi2=6.24, d.f.=1, p=0.013, odds ratio (OR)=1.35, 95% CI 1.07-1.71; Genotype, chi2=6.85, d.f.=2, p=0.033). Our results indicate a small but significant contribution of the IL3RA polymorphism to susceptibility to schizophrenia, suggesting that the IL3 pathway may be involved in schizophrenia.

BDNF levels and genotype are associated with antipsychotic-induced weight gain in patients with chronic schizophrenia.

Recent evidence suggests that centrally released brain-derived neurotrophic factor (BDNF) modulates eating behavior and metabolism that is responsible for body weight fluctuation. BDNF also may play an important role in the therapeutic action of antipsychotic medications. We investigated whether the Val66Met polymorphism of the BDNF gene affected weight gain after long-term antipsychotic treatment in schizophrenia. The polymorphism was genotyped in 196 Chinese patients with schizophrenia on long-term antipsychotic medication. Serum BDNF was measured in all patients and 50 normal controls. Mean body mass index (BMI) change was evaluated retrospectively by means of clinical records. The results showed that there was a significant relationship between the three BDNF Val/Met genotypes and mean BMI gain, with genotype having a strong effect on BMI gain in male but not female patients. BDNF levels were significantly lower in patients than normal controls, and negatively correlated with BMI gain in female but not male patients. Our results suggest that variation in the BDNF gene may be a risk factor for weight gain in male patients with schizophrenia on long-term antipsychotic treatment, and decreased BDNF levels may be associated with weight gain in females.

Disrupted antioxidant enzyme activity and elevated lipid peroxidation products in schizophrenic patients with tardive dyskinesia.

BACKGROUND: Free radical-mediated pathology has been implicated in the development of tardive dyskinesia (TD). Antioxidant defense system alterations and increased lipid peroxidation have been postulated as a possible mechanism for neuronal damage associated with TD. However, the relationship between antioxidant enzymes, lipid peroxidation products, and the severity of TD symptoms has not been determined within a single patient group. METHOD: Plasma levels of malondialdehyde (MDA), a marker of lipid peroxidation, superoxide dismutase, glutathione peroxidase, and catalase were examined in 80 patients with schizophrenia (DSM-IV criteria) and TD (Schooler-Kane criteria) and 45 schizophrenia patients without TD. Results were compared to those of 50 age-, sex-, and smoking status-matched controls. Tardive dyskinesia severity was assessed using the Abnormal Involuntary Movement Scale, and patient psychopathology was assessed using the Positive and Negative Syndrome Scale. RESULTS: Patients with TD had lower plasma superoxide dismutase, glutathione peroxidase, and catalase levels but higher MDA levels than those without TD. In the patients with TD, MDA levels were positively correlated with Abnormal Involuntary Movement Scale total score and with Positive and Negative Syndrome Scale negative subscore. Superoxide dismutase and catalase activities were inversely correlated with MDA levels. CONCLUSIONS: Our data support the hypothesis that oxidative stress is involved in the patho-physiology of TD. These data also suggest a relationship between oxidative stress and the severity of dyskinesia in TD patients. Increased lipid peroxidation may likely be a result of decreased endogenous antioxidant enzyme activities in TD.

Association of functional catechol O-methyl transferase (COMT) Val108Met polymorphism with smoking severity and age of smoking initiation in Chinese male smokers.

RATIONALE: Catechol-O-methyltransferase (COMT) is an enzyme involved in the degradation and inactivation of the neurotransmitter dopamine, which is important in mediating drug reward such as nicotine in tobacco smoke. Different COMT alleles encode enzyme whose activity varies from three- to fourfold that may affect dopamine levels and alter subjective effects of nicotine. Recent evidence also suggests that a COMT polymorphism may be especially important in determining an individual's predisposition to developing nicotine dependence. SUBJECTS AND METHODS: We studied the COMT Val108Met polymorphism in a male population of 203 current smokers, 66 former smokers, and 102 non-smokers. The age-adjusted odds ratios were estimated by multiple logistic regression models. RESULTS: The results showed no significant association of the COMT Val108Met with initiation, persistent smoking, or smoking cessation. However, current smokers with the Met allele had significantly higher Fagerstrom Test for Nicotine Dependence scores (7.5 +/- 2.1 vs 6.8 +/- 1.8, p = 0.018) and started smoking significantly earlier (18.4 +/- 4.9 vs 20.1 +/- 5.9 years, p = 0.036). CONCLUSIONS: These results suggest that the COMT Val108Met polymorphism may not influence smoking status in a Chinese male population but may influence the age at which smoking started and smoking severity among smokers. However, the findings must be regarded as preliminary because of the relatively small sample size and marginal associations and should be replicated in a larger cohort.

Nicotine dependence, symptoms and oxidative stress in male patients with schizophrenia.

The high rate of smoking in schizophrenia may reflect patients' attempts to reduce the side effects of antipsychotic medications, and one mechanism for this reduction may be a reduction in oxidative stress and free radical-mediated brain damage that may contribute to schizophrenic symptoms and to complications of its treatment. Symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS), side effects were assessed with the Simpson and Angus Rating Scale (SAS), and malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were measured in plasma. All of these measures were compared in 130 male inpatients with DSM-IV schizophrenia: 104 smokers and 26 non-smokers. The results showed that the positive PANSS symptoms were lower in smokers than non-smokers (14.5 vs 17.5), while the negative symptoms were lower in those who smoked more cigarettes (r=-0.23). The SAS showed no differences. The CAT activity was correlated with both GSH-Px and SOD activities. Of the three enzymes only the CAT activity was significantly higher in smokers than non-smokers (2.9 vs 1.6 U/ml), but greater SOD activity correlated more cigarettes smoked (r=0.24). Consistent with some protection against oxidative stress, MDA also was significantly lower in smokers than non-smokers (9.2 vs 14.4 nmol/ml). The fewer positive symptoms in smokers and fewer negative symptoms in those who smoked more cigarettes may be a selection bias, but appears to be associated with decreased oxidative stress and lipid peroxidation in schizophrenics who smoke tobacco.