Effectiveness and mechanism of the Chinese medicine Weiren Xiaoyou formula in improving palmoplantar warts.

Background: Palmoplantar warts (PWs) are a usual skin disease associated with human papillomavirus (HPV) that can affect patients' quality of life. The traditional Chinese medicine (TCM) Weiren Xiaoyou formula (WRXYF) is a relatively gentle and effective therapy that has achieved good therapeutic effects in clinical practice, but its mechanism has not yet been studied. Methods: A meta-analysis was carried out to identify the potential advantages of topical TCM for PW treatment. Clinical cases suggested that WRXYF was an effective therapeutic agent against PWs. Network pharmacology was utilized to predict potential targets for the main bioactive compound, tanshinone IIA (Tan IIA), in WRXYF. High-performance liquid chromatography with electrospray mass spectrometry (HPLC/ESI-MS) was applied to detect major components. The bioactivity of Tan IIA against PWs was then validated with quantitative polymerase chain reaction (q-PCR), fluorescence in situ hybridization (FISH), electron microscopy and Western blotting. Results: A meta-analysis was conducted on 10 randomized clinical trials (RCTs) involving 2260 participants suggested that topical TCM could more effectively treat PWs than conventional medications. Network pharmacology identified Tan IIA as a candidate agent from 17 major compounds assessed by HPLC/ESI-MS because of its stable binding with 10 PW targets. HPV2, HPV27, and HPV57 were the main infectious strains in tissues obtained from PW patients and in HPV-infected HaCaT cells. Tan IIA treatment effectively destroyed viral particles and reduced the viral copy numbers of the three HPV subtypes. The results shown that Tan IIA has the ability to halt the cell cycle of HPV-infected HaCaT cells specifically in the G0/G1 phase. A total of 6 cell cycle-related proteins were regulated after Tan IIA treatment, demonstrating the role of Tan IIA in inhibiting the cell cycle. Conclusion: Tan IIA, the primary bioactive constituent in WRXYF, enhances PWs by halting the cell cycle in the G0/G1 phase via modulation of the p53 signaling pathway.

Automated Digital Interventions and Smoking Cessation: Systematic Review and Meta-analysis Relating Efficiency to a Psychological Theory of Intervention Perspective.

BACKGROUND: Smoking remains a highly significant preventable global public health problem. In this context, digital interventions offer great advantages in terms of a lack of biological side effects, possibility of automatic delivery, and consequent human resource savings relative to traditional interventions. Such interventions have been studied in randomized controlled trials (RCTs) but have not been systematically reviewed with the inclusion of text-based and multiplatform-based interventions. In addition, this area has not been evaluated from the perspective of the psychological theoretical basis of intervention. OBJECTIVE: The aim of this paper is to assess the efficiency of digital interventions in RCT studies of smoking cessation and to evaluate the effectiveness of the strategies used for digital interventions. METHODS: An electronic search of RCTs was conducted using PubMed, Embase, and the Cochrane Library by June 30, 2021. Eligible studies had to compare automated digital intervention (ADI) to the use of a self-help guideline or no intervention. Participants were current smokers (aged 16 years or older). As the main outcome, abstinence after endpoint was extracted from the studies. Systematic review and meta-analysis were conducted to assess the efficiency of ADIs. Metaregressions were conducted to assess the relationship between intervention theory and effectiveness. RESULTS: A total of 19 trials (15,472 participants) were included in the analysis. The overall abstinence rate (95% CI) at the endpoint was 17.8% (17.0-18.7). The overall risk ratio of the intervention group compared to the controls at the endpoint was 17.8% (17.0-18.7). Cochrane risk-of-bias tool for randomized trials (ROB 2) suggested that most of the studies had a low risk of bias (56.3%). Psychological theory-related constructs or predictors, which refer to other theory-based concepts (rather than only behavioral theory) such as craving or anxiety, are associated with effectiveness. CONCLUSIONS: This study found that ADI had a clear positive effect compared to self-help guidelines or to no intervention, and effectiveness was associated with theory-related constructs or predictors. ADIs should be promoted by policy makers and clinical practitioners to address the huge gap between the need for smoking cessation and availability of traditional treatment resources. Possible increases in ADI efficiency may be achieved by optimally integrating psychotherapeutic theories and techniques. TRIAL REGISTRATION: PROSPERO CRD42021256593; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=256593.

Phellopterin cream exerts an anti-inflammatory effect that facilitates diabetes-associated cutaneous wound healing via SIRT1.

BACKGROUND: Diabetic ulcers, which are characterized by chronic nonhealing wounds with a long-lasting inflammatory state, are a typical symptom in individuals with diabetes, and there is still no effective treatment for these lesions. Angelica dahurica plays a critical role in inflammatory diseases. Among numerous monomeric compounds, phellopterin has been shown to have anti-inflammatory properties. PURPOSE: To research the bioactive constituents in Angelica dahurica and their mechanism of action in treating diabetic ulcers. STUDY DESIGN: Chemical research of Angelica dahurica led to the identification of a new coumarin, dahuricoumarin A (1), along with seven known compounds (2 - 8). All compounds were tested for anti-inflammatory activity, and phellopterin, compound (3), significantly decreased the expression of intercellular cell adhesion molecule-1 (ICAM-1), a representative indicator of inflammation. Phellopterin can also increase SIRT1 protein, a key target for inflammation. In our research, we confirmed the anti-inflammatory effects of phellopterin on diabetic ulcers and explored the underlying mechanism of action. METHODS: The expression of IFN-γ, SIRT1, and ICAM-1 in human diabetic ulcer tissues was studied using immunohistochemistry. Streptozotocin was used to induce a diabetic model in C57BL/6J mice, and ulcers were surgically introduced. After phellopterin treatment, the skin lesions of diabetic mice were observed over a period of time. The protein and mRNA expression levels of SIRT1 and ICAM-1 were measured using H&E, qRT-PCR and immunohistochemical staining. A HaCaT cell inflammatory model was induced by IFN-γ. Using a lentiviral packaging technique, MTT assay, and Western blotting, the effect of phellopterin on the proliferation of HaCaT cells and the expression of ICAM-1 was evaluated under normal and SIRT1 knockdown conditions. RESULTS: High levels of ICAM-1 and IFN-γ were identified, but low levels of SIRT1 were found in human diabetic ulcer tissues, and phellopterin showed therapeutic benefits in the healing process by attenuating chronic inflammation and promoting re-epithelialization, along with SIRT1 upregulation and ICAM-1 downregulation. However, inhibiting SIRT1 reversed its proliferative and anti-inflammatory effects. CONCLUSION: In vitro and in vivo, phellopterin exerts anti-inflammatory and proliferative effects that promote diabetic wound healing, and the potential mechanism depends on SIRT1.

Rhein promotes the proliferation of keratinocytes by targeting oestrogen receptors for skin ulcer treatment.

BACKGROUND: The Sheng-ji Hua-yu (SJHY) formula is a quite effective Traditional Chinese Medicines (TCM) in the treatment of delayed diabetic wounds. Previous research has shown that the SJHY formula has significant anti-inflammatory and wound-healing effects, but the precise mechanism remains unknown. The purpose of this study was to evaluate the effects of rhein, a compound extracted from SJHY formula, in keratinocytes and to investigate the underlying mechanisms. METHODS: Microscale thermophoresis (MST) technology was used to confirm that rhein binds directly to oestrogen receptors (ERs). Rhein was then used to treat keratinocytes in vitro. Cell cycle and proliferation analysis, Real-time polymerase chain reaction (RT-PCR) and Western-blot were conducted. RESULTS: Rhein increased the proportion of cells in the S phase of the cell cycle and promoted keratinocyte proliferation. ICI 182,780, an ER inhibitor, was also used to treat keratinocytes. The expression of c-myc mRNA and protein induced by rhein was antagonized by ICI 182,780, indicating that this induction is ER dependent. Intervention with ICI 182,780 had no effect on the upregulation of FosB and JunD, indicating that activator protein 1 (AP-1) members (FosB and JunD) are involved in rhein-induced c-myc mRNA and protein expression but does not require the ER. CONCLUSION: The present study found that rhein stimulates keratinocyte proliferation by activating the oestrogen signalling pathway via the oestrogen receptor, which induces the expression of c-myc in collaboration with FosB and JunD, thereby accelerating the process of re-epithelialization.

Therapeutic effects of the extract of Sancao Formula, a Chinese herbal compound, on imiquimod-induced psoriasis via cysteine-rich protein 61.

OBJECTIVE: Psoriasis is a common chronic inflammatory skin disease that is prone to recurrence, and the proinflammatory factor, cysteine-rich protein 61 (Cyr61), is important in its pathophysiology. Long-term clinical practice has shown that Sancao Formula (SC), a Chinese herbal compound, is effective in the treatment of psoriasis, but the precise mechanism remains unknown. In this study, we investigate the mechanism by which SC extract alleviates imiquimod (IMQ)-induced psoriasis. METHODS: The expression of Cyr61 in psoriatic lesions and normal healthy skin was detected using immunohistochemical analysis to investigate the biological role of Cyr61 in models of psoriatic inflammation. A psoriatic mouse model was established by topical application of IMQ, and the effect of topical application of SC extract was evaluated using the psoriasis area and severity index (PASI) score, hematoxylin-eosin staining, and histopathological features of the skin. Next, a HaCaT cell inflammation model was established using interferon-γ (IFN-γ), and the effect of SC extract on the mRNA and protein levels of Cyr61 and intercellular cell adhesion molecule-1 (ICAM-1) was confirmed using Western blot and quantitative real-time polymerase chain reaction analyses. RESULTS: Immunohistochemical staining showed that the expression of Cyr61 in psoriatic lesions was higher than that in normal skin samples (78.26% vs 41.18%, P < 0.05), and the number of Cyr61-positive cells in psoriatic lesions was also significantly higher than in normal skin (18.66 ± 2.51 vs 4.33 ± 1.52, P < 0.05). Treatment in mice with IMQ-induced psoriasis showed that SC extract could significantly improve the inflammatory phenotype, PASI score (10.875 ± 0.744 vs 3.875 ± 0.582, P < 0.05), and pathological features compared with those in IMQ model group; SC treatment was also associated with decreased levels of Cyr61 and ICAM-1. In the IFN-γ-induced inflammatory cell model, the mRNA and protein levels of Cyr61 and ICAM-1 were upregulated, while the SC extract downregulated the levels of Cyr61 and ICAM-1. CONCLUSION: The results provide a theoretical basis for the involvement of Cyr61 in the pathogenesis of psoriasis, and suggest that SC should be used to target Cyr61 for the prevention of psoriasis recurrence.

Functional Connectivity of Nucleus Accumbens and Medial Prefrontal Cortex With Other Brain Regions During Early-Abstinence Is Associated With Alcohol Dependence and Relapse: A Resting-Functional Magnetic Resonance Imaging Study.

Background: Alcohol dependence (AD) is a chronic recurrent brain disease that causes a heavy disease burden worldwide, partly due to high relapse rates after detoxification. Verified biomarkers are not available for AD and its relapse, although the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) may play important roles in the mechanism of addiction. This study investigated AD- and relapse-associated functional connectivity (FC) of the NAc and mPFC with other brain regions during early abstinence. Methods: Sixty-eight hospitalized early-abstinence AD male patients and 68 age- and education-matched healthy controls (HCs) underwent resting-functional magnetic resonance imaging (r-fMRI). Using the NAc and mPFC as seeds, we calculated changes in FC between the seeds and other brain regions. Over a follow-up period of 6 months, patients were measured with the Alcohol Use Disorder Identification Test (AUDIT) scale to identify relapse outcomes (AUDIT ≥ 8). Results: Thirty-five (52.24%) of the AD patients relapsed during the follow-up period. AD displayed lower FC of the left fusiform, bilateral temporal superior and right postcentral regions with the NAc and lower FC of the right temporal inferior, bilateral temporal superior, and left cingulate anterior regions with the mPFC compared to controls. Among these FC changes, lower FC between the NAc and left fusiform, lower FC between the mPFC and left cingulate anterior cortex, and smoking status were independently associated with AD. Subjects in relapse exhibited lower FC of the right cingulate anterior cortex with NAc and of the left calcarine sulcus with mPFC compared to non-relapsed subjects; both of these reductions in FC independently predicted relapse. Additionally, FC between the mPFC and right frontal superior gyrus, as well as years of education, independently predicted relapse severity. Conclusion: This study found that values of FC between selected seeds (i.e., the NAc and the mPFC) and some other reward- and/or impulse-control-related brain regions were associated with AD and relapse; these FC values could be potential biomarkers of AD or for prediction of relapse. These findings may help to guide further research on the neurobiology of AD and other addictive disorders.

CtBP1 transactivates RAD51 and confers cisplatin resistance to breast cancer cells.

Overexpression of RAD51 is found in many cancers including breast cancer and is associated with poor survival. Compared with normal cells, RAD51 promoter is hyperactive in cancer cells indicating that RAD51 is transcriptionally activated. However, little is known about the mechanisms and factors involved in RAD51 transcription regulation. Transcription corepressor, C-terminal binding protein 1 (CtBP1), is an oncogene repressing a panel of tumor suppressors transcription, which contributes to cancer progression. In this study, immunohistochemistry (IHC) revealed that RAD51 expression was positively correlated with CtBP1 expression in breast cancer patient tissues; short hairpin RNA-mediated CtBP1 depletion, chromatin immunoprecipitation, and dual-luciferase reporter assays showed that CtBP1 activated RAD51 transcription in breast cancer cells. Depletion of CtBP1 increased breast cancer cells' sensitivity to cisplatin and, in turn, expression of exogenous RAD51 in the CtBP1-depleted breast cancer cells increased resistance to cisplatin. The results demonstrated that CtBP1 conferred breast cancer cells resistance to cisplatin through transcriptional activation of RAD51.

Protocatechuic Aldehyde Represses Proliferation and Migration of Breast Cancer Cells through Targeting C-terminal Binding Protein 1.

PURPOSE: C-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor that is overexpressed in many cancers. CtBP1 transcriptionally represses a broad array of tumor suppressors, which promotes cancer cell proliferation, migration, invasion, and resistance to apoptosis. Recent studies have demonstrated that CtBP1 is a potential target for cancer therapy. This study was designed to screen for compounds that potentially target CtBP1. METHODS: Using a structure-based virtual screening for CtBP1 inhibitors, we found protocatechuic aldehyde (PA), a natural compound found in the root of a traditional Chinese herb, Salvia miltiorrhiza, that directly binds to CtBP1. Microscale thermophoresis assay was performed to determine whether PA and CtBP1 directly bind to each other. Further, clustered regularly interspaced short palindromic repeats associated Cas9 nuclease-mediated CtBP1 knockout in breast cancer cells was used to validate the CtBP1 targeting specificity of PA. RESULTS: Functional studies showed that PA repressed the proliferation and migration of breast cancer cells. Furthermore, PA elevated the expression of the downstream targets of CtBP1, p21 and E-cadherin, and decreased CtBP1 binding affinity for the promoter regions of p21 and E-cadherin in breast cancer cells. However, PA did not affect the expression of p21 and E-cadherin in the CtBP1 knockout breast cancer cells. In addition, the CtBP1 knockout breast cancer cells showed resistance to PA-induced repression of proliferation and migration. CONCLUSION: Our findings demonstrated that PA directly bound to CtBP1 and inhibited the growth and migration of breast cancer cells through CtBP1 inhibition. Structural modifications of PA are further required to enhance its binding affinity and selectivity for CtBP1.

GABAergic Abnormalities Associated with Sensorimotor Cortico-striatal Community Structural Deficits in ErbB4 Knockout Mice and First-Episode Treatment-Naïve Patients with Schizophrenia.

The current study was designed to explore how disruption of specific molecular circuits in the cerebral cortex may cause sensorimotor cortico-striatal community structure deficits in both a mouse model and patients with schizophrenia. We used prepulse inhibition (PPI) and brain structural and diffusion MRI scans in 23 mice with conditional ErbB4 knockout in parvalbumin interneurons and 27 matched controls. Quantitative real-time PCR was used to assess the differential levels of GABA-related transcripts in brain regions. Concurrently, we measured structural and diffusion MRI and the cumulative contribution of risk alleles in the GABA pathway genes in first-episode treatment-naïve schizophrenic patients (n = 117) and in age- and sex-matched healthy controls (n = 86). We present the first evidence of gray and white matter impairment of right sensorimotor cortico-striatal networks and reproduced the sensorimotor gating deficit in a mouse model of schizophrenia. Significant correlations between gray matter volumes (GMVs) in the somatosensory cortex and PPI as well as glutamate decarboxylase 1 mRNA expression were found in controls but not in knockout mice. Furthermore, these findings were confirmed in a human sample in which we found significantly decreased gray and white matter in sensorimotor cortico-striatal networks in schizophrenic patients. The psychiatric risk alleles of the GABA pathway also displayed a significant negative correlation with the GMVs of the somatosensory cortex in patients. Our study identified that ErbB4 ablation in parvalbumin interneurons induced GABAergic dysregulation, providing valuable mechanistic insights into the sensorimotor cortico-striatal community structure deficits associated with schizophrenia.

The level of IL-6 was associated with sleep disturbances in patients with major depressive disorder.

Purpose: Major depression disorder (MDD) was associated with inflammatory processes, but association results of inflammatory syndrome and MDD were inconsistent. To provide more evidence, we measured the plasma levels of IL-1ß, IL-6, interferon (INT)-α2, INT-γ, and tumor necrosis factor (TNF)-α in patients having MDD and explored correlations between the five proinflammatory cytokines and specific depressive symptoms. Patients and methods: Plasma concentrations of IL-1ß, IL-6, INT-α2, INT-γ, and TNF-α were measured using ELISA for 44 MDD patients and 54 healthy controls. Patients with MDD were assessed on the 17-item Hamilton Depression Rating Scale (HAMD-17), and a total score and five syndrome scores were acquired. Results: IL-6 levels in depressed patients were significantly elevated than in healthy controls, but no significant differences were observed in the levels of INF-α2, INF-γ, IL-1ß, or TNF-α. In addition, correlation analysis revealed that sleep disturbances positively correlated with IL-6. Although there was no significant difference between the two groups in the levels of INF-α2, a significant positive correlation between IFN-α2 and retardation was observed. Conclusion: Elevated IL-6 levels were observed in MDD patients and IL-6 may correlate with sleep disturbances.

Antipsychotics and risk of natural death in patients with schizophrenia.

Background: Research on antipsychotics and early mortality in schizophrenia has arisen from Western countries and results show that mortality from natural causes is obviously increased in schizophrenia. China, differs largely from Western countries in health and social welfare systems, and Asian patients are more susceptible to side-effects and might require less antipsychotics than their Western counterparts. We, therefore, investigated the association between antipsychotic use and increased mortality from natural causes among patients with schizophrenia in China. Methods: We conducted a population-based nested case-control study using patients' hardcopy archives obtained from the Severe Mental Health Disorder Systems of Chengdu between January 1, 2006 and December 31, 2013. We identified all schizophrenic patients aged 18-65 years who died of natural causes in 2013 (N=157), and their age- and gender-matched controls (N=444). Results: Antipsychotic use was more frequent in controls than in cases (59.9% vs 32.5%). Risk of death decreased significantly in those receiving antipsychotic monotherapy (adjusted odds ratio=0.27, 95% CI=0.16-0.46) and antipsychotic polypharmacy (adjusted odds ratio=0.29, 95% CI=0.12-0.70) than antipsychotic-free patients. Compared with monotherapy, antipsychotic-free treatment was associated with prominently increased mortality (adjusted odds ratio=3.64, 95% CI=2.18-6.08). When stratified by age and gender, the results remained unchanged. Conclusion: Antipsychotic monotherapy significantly decreased mortality from natural causes in schizophrenic patients while antipsychotic polypharmacy did not contribute to the excess mortality and deserves further clarification. We need to improve the physical health of schizophrenic patients and promote health education among community mental health staff and primary caregivers.

The 6-item Kessler psychological distress scale to survey serious mental illness among Chinese undergraduates: Psychometric properties and prevalence estimate.

OBJECTIVE: To evaluate the psychometric properties of the 6-item Kessler psychological distress scale (K6) in screening for serious mental illness (SMI) among undergraduates in a major comprehensive university in China. METHOD: The K6 was self-completed by 8289 randomly sampled participants. A group of them (n=222) were re-assessed using K6 and interviewed using the Chinese version of Composite International Diagnostic Interview 3.1 (CIDI-3.1). RESULTS: The test-retest reliability of the K6 scale was 0.79, the Cronbach's alpha was 0.84, and its area under the receiver operating curve (AUC) for diagnosing CIDI-3.1 SMI was 0.85 (95% CI=0.80-0.90). For the optimal cut-off of K6 (12/13), the sensitivity (SEN), specificity (SPE), positive predictive value (PPV), negative predictive value (NPV), and classification accuracy (AC) were 0.83, 0.79, 0.60, 0.93, and 0.80, respectively. The 12-month prevalence of SMI was estimated as 3.97% using this optimal cut-off. Binary logistic regression analysis (including gender, ethnicity, grade, number of siblings and family residency location) showed that only family residency location in rural areas compared to urban areas was significantly associated with more SMI. CONCLUSIONS: This study documented the value of using the K6 for detecting SMI in Chinese undergraduate populations and supported its cross-cultural reliability and validity.

Anti-N-methyl-d-aspartate receptor encephalitis in a patient with a 7-year history of being diagnosed as schizophrenia: complexities in diagnosis and treatment.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a form of autoimmune encephalitis associated with antibodies against the NR1 subunits of NMDARs. Although new-onset acute prominent psychotic syndromes in patients with NMDAR encephalitis have been well documented, there is a lack of case studies on differential diagnosis and treatment of anti-NMDAR encephalitis after a long-term diagnostic history of functional psychotic disorders. The present study reports an unusual case of anti-NMDAR encephalitis. The patient had been diagnosed with schizophrenia 7 years earlier, and was currently hospitalized for acute-onset psychiatric symptoms. The diagnosis became unclear when the initial psychosis was confounded with considerations of other neurotoxicities (such as neuroleptic malignant syndrome). Finally, identification of specific immunoglobulin G NR1 autoantibodies in the cerebrospinal fluid and greater effectiveness of immunotherapy over antipsychotics alone (which has been well documented in anti-NMDAR encephalitis) indicated the diagnosis of anti-NMDAR encephalitis in this case. Based on the available evidence, however, the relationship between the newly diagnosed anti-NMDAR encephalitis and the seemingly clear, long-term history of schizophrenia in the preceding 7 years is uncertain. This case report illustrates that psychiatrists should consider anti-NMDAR encephalitis and order tests for specific immunoglobulin G NR1 autoantibodies in patients presenting with disorientation, disturbance of consciousness, cognitive deficit, dyskinesia, autonomic disturbance, or rapid deterioration, even with a seemingly clear history of a psychiatric disorder and no specific findings on routine neuroimaging, electroencephalography, or cerebrospinal fluid tests in the early stage of the illness.

Micheliolide derivative DMAMCL inhibits glioma cell growth in vitro and in vivo.

BACKGROUND: There is no highly effective chemotherapy for malignant gliomas to date. We found that dimethylaminomicheliolide (DMAMCL), a selective inhibitor of acute myeloid leukemia (AML) stem/progenitor cells, inhibited the growth of glioma cells. METHODS: The distribution of DMAMCL in brain was analyzed by an ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS) system. The anti-tumor evaluations of DMAMCL in vitro were performed by MTT, FACS and RT-PCR. In vivo, the mixture of C6 cells and matrigel was injected into caudatum, and the anti-tumor activity of DMAMCL was evaluated by tumor growth and rat survival. The toxicity of DMAMCL was evaluated by body weight, daily food intake, hematological or serum biochemical analyses, and histological appearance of tissues. RESULTS: The IC50 values of DMAMCL against the C6 and U-87MG cell lines in vitro were 27.18 ± 1.89 µM and 20.58 ± 1.61 µM, respectively. DAMMCL down-regulated the anti-apoptosis gene Bcl-2 and increased apoptosis in C6 and U-87MG cells in a dose-dependent manner. In a C6 rat tumor model, daily administration of DMAMCL for 21 days reduced the burden of C6 tumors by 60% to 88% compared to controls, and more than doubled the mean lifespan of tumor-bearing rats. Distribution analysis showed that the DMAMCL concentration was higher in the brain than in plasma. Evaluations for toxicity revealed that oral administration of DMAMCL at 200 or 300 mg/kg once a day for 21 days did not result in toxicity. CONCLUSIONS: These results suggest that DMAMCL is highly promising for the treatment of glioma.

Optimization of 4-(N-cycloamino)phenylquinazolines as a novel class of tubulin-polymerization inhibitors targeting the colchicine site.

The 6-methoxy-1,2,3,4-tetrahydroquinoline moiety in prior leads 2-chloro- and 2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)quinazoline (1a and 1b) was modified to produce 4-(N-cycloamino)quinazolines (4a-c and 5a-m). The new compounds were evaluated in cytotoxicity and tubulin inhibition assays, resulting in the discovery of new tubulin-polymerization inhibitors. 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin- 2(1H)-one (5f), the most potent compound, exhibited high in vitro cytotoxic activity (GI50 1.9-3.2 nM), significant potency against tubulin assembly (IC50 0.77 µM), and substantial inhibition of colchicine binding (99% at 5 µM). In mechanism studies, 5f caused cell arrest in G2/M phase, disrupted microtubule formation, and competed mostly at the colchicine site on tubulin. Compound 5f and N-methylated analogue 5g were evaluated in nude mouse MCF7 xenograft models to validate their antitumor activity. Compound 5g displayed significant in vivo activity (tumor inhibitory rate 51%) at a dose of 4 mg/kg without obvious toxicity, whereas 5f unexpectedly resulted in toxicity and death at the same dose.

Performance of the 6-item Kessler scale for measuring serious mental illness in Hong Kong.

BACKGROUND: The 6-item Kessler scale (K6) promises to be a valuable epidemiological tool for assessing serious mental illness (SMI) in communities with limited resources for psychiatric research and treatment. Its performance in Chinese community has not been studied with reference to clinically assessed SMI. METHOD: From a representative telephone-based population survey (n = 3014) that administered the K6, 153 participants were readministered the K6 and, on the same day, interviewed face-to-face by clinicians using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition, Axis I Disorder. Predictive indicators such as McNemar χ(2), area under receiver operating characteristic curve and stratum-specific likelihood ratios were used to investigate the concordance between the K6 and clinical status of SMI, individual-level predicted probabilities of having SMI, and the weighted prevalence of SMI in the community. RESULT: The K6 exhibited high internal consistency and test-retest reliability. Factor analysis revealed 2 correlating components composed of depression and anxiety. Matching of K6 caseness and SMI status showed that at the cutoff of 12/13, the area under receiver operating characteristic curve was moderate (0.69). The K6 had high specificity and was a stronger screen-out than screen-in tool for SMI. The weighted prevalence estimate of SMI in Hong Kong was 6.5%. A person scoring 13 or above on the K6 has a probability of at least 22.2% of having SMI. CONCLUSION: The Chinese K6 is reliable and generates the likelihood of SMI with substantial concordance with face-to-face clinical interviews in Hong Kong. It is a valuable tool for screening SMI, behavioral risk factor surveillance, and community epidemiological surveys.

Production and radioprotective effects of pyrroloquinoline quinone.

Pyrroloquinoline quinone (PQQ) was produced by fermentation of the Methylovorus sp. MP688 strain and purified by ion-exchange chromatography, crystallization and recrystallization. The yield of PQQ reached approximately 125 mg/L and highly pure PQQ was obtained. To determine the optimum dose of PQQ for radioprotection, three doses (2 mg/kg, 4 mg/kg, 8 mg/kg) of PQQ were orally administrated to the experimental animals subjected to a lethal dose of 8.0 Gy in survival test. Survival of mice in the irradiation + PQQ (4 mg/kg) group was found to be significantly higher in comparison with the irradiation and irradiation + nilestriol (10 mg/kg) groups. The numbers of hematocytes and bone marrow cells were measured for 21 days after sublethal 4 Gy gamma-ray irradiation with per os of 4 mg/kg of PQQ. The recovery of white blood cells, reticulocytes and bone marrow cells in the irradiation + PQQ group was faster than that in the irradiation group. Furthermore, the recovery of bone marrow cell in the irradiation + PQQ group was superior to that in irradiation + nilestriol group. Our results clearly indicate favourable effects on survival under higher lethal radiation doses and the ability of pyrroloquinoline quinine to enhance haemopoietic recovery after sublethal radiation exposure.

Prevalence and correlates of active and ever-smokers in metropolitan China.

This study investigated the prevalence and demographic correlates of active and ever-smokers in Beijing and Shanghai. Using a multi-stage household probability sampling method, 5201 participants aged 18-70 underwent face-to-face interviews using the Composite International Diagnostic Interview. 67.1% and 55.5% of male and 7.1% and 5.5% of female respondents were ever-smokers and active smokers respectively. Quitting was less common by proportion among those no longer married or never-married, middle-aged or working adults. After adjusting for other sociodemographic factors, the oldest age-group (>54 years) showed a significantly negative association with active smoking while those no longer married had significantly positive association with active smoking, among ever-smokers. Although the high prevalence of male smoking in Beijing and Shanghai was expected, the prevalence of female smoking was significantly higher than those found in previous surveys. This pattern of more female smoking not accompanied by an obvious decrease in male smoking defies the expectation of an orderly transition of smoking patterns and may foreshadow smoking patterns in other parts of China.

An epidemiological survey of alcohol use disorders in a Tibetan population.

We performed an epidemiological survey in order to detect the prevalence of alcohol use disorders in a sub-group of the population of Tibet. The Alcohol Use Disorders Identification Test (AUDIT) questionnaire, the Severity of Alcohol Dependence Questionnaire (SADQ), and a 12-item version of the General Health Questionnaire (GHQ12) were used to obtain epidemiological data on alcohol use disorders and to assess the severity of 'problem drinking' and general mental health status. The AUDIT is a reliable and valid screening tool for both alcohol abuse and dependence in the Tibetan population to identify individuals with alcohol use problems. The cut-off points were set to be 10 and 13 of the AUDIT scores as a diagnostic discriminator of alcohol abuse and alcohol dependence, respectively, with both sensitivity and specificity>0.84. The prevalence of alcohol abuse, was 2.7% (female: 2.0%; male: 6.2%), alcohol dependence 13.5% (female: 7.6%; male: 25.4%) and alcohol use disorders 16.2% (female: 9.6%; male: 31.6%). Age and sex were the main factors affecting an individual's alcohol use and general mental health status. The epidemiological data on alcohol use disorders documented in this project may be helpful in future work seeking more valid causal inferences or interpretations related to this prevalent health problem in Tibet.