Ghrelin inhibits IKKß/NF-κB activation and reduces pro-inflammatory cytokine production in pancreatic acinar AR42J cells treated with cerulein.

BACKGROUND: Previous studies have provided conflicting results regarding whether the serum ghrelin concentration can reflect the severity of acute pancreatitis (AP). The present study examined the correlation between the serum ghrelin concentration and AP severity in animal models and investigated whether altered ghrelin expression in pancreatic acinar cells influences IKKß/NF-κB signaling and pro-inflammatory cytokine production. METHODS: Mild or severe AP was induced in rats by intraperitoneal injection of cerulein or retrograde cholangiopancreatic duct injection of sodium taurocholate, respectively. After successful model induction, serum ghrelin, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) concentrations were determined by enzyme-linked immunosorbent assay, and IKKß/NF-κB activation was assessed by immunohistochemistry. Subsequently, stable overexpression or knockdown of ghrelin in AR42J cells was achieved by lentiviral transfection. After transfected cells and control cells were treated with cerulein for 24 h, the TNF-α and IL-1ß levels in the supernatants were determined by enzyme-linked immunosorbent assay, and the expression levels of p-p65, IKKß, and p-IKKß were detected by Western blotting. RESULTS: In rat AP models, AP severity was correlated with increased IKKß/NF-κB activation, pro-inflammatory cytokine production, and ghrelin secretion. The levels of pro-inflammatory cytokines TNF-α and IL-1ß as well as IKKß/NF-κB signaling activity were increased upon knockdown of ghrelin in the AP acinar cell model and decreased with ghrelin overexpression. CONCLUSIONS: Serum ghrelin is related to the severity of AP. Ghrelin may play a protective role in the pathogenesis of AP by inhibiting the pro-inflammatory cytokines and the activation of the IKKß/NF-κB signaling pathway.

Minocycline attenuates post-operative cognitive impairment in aged mice by inhibiting microglia activation.

Although it is known that isoflurane exposure or surgery leads to post-operative cognitive dysfunction in aged rodents, there are few clinical interventions and treatments available to prevent this disorder. Minocycline (MINO) produces neuroprotection from several neurodegenerative diseases and various experimental animal models. Therefore, we set out to investigate the effects of MINO pre-treatment on isoflurane or surgery induced cognitive impairment in aged mice by assessing the hippocampal-dependent spatial memory performance using the Morris water maze task. Hippocampal tissues were isolated from mice and evaluated by Western blot analysis, immunofluorescence procedures and protein array system. Our results elucidate that MINO down-regulated the isoflurane-induced and surgery-induced enhancement in the protein levels of pro-inflammatory cytokine tumour necrosis factor alpha, interleukin (IL)-1ß, interferon-γ and microglia marker Iba-1, and up-regulated protein levels of the anti-inflammatory cytokine IL-4 and IL-10. These findings suggest that pre-treatment with MINO attenuated isoflurane or surgery induced cognitive impairment by inhibiting the overactivation of microglia in aged mice.

Aberrant PTPRO methylation in tumor tissues as a potential biomarker that predicts clinical outcomes in breast cancer patients.

BACKGROUND: Aberrant hypermethylation of gene promoter regions is a primary mechanism by which tumor suppressor genes become inactivated in breast cancer. Epigenetic inactivation of the protein tyrosine phosphatase receptor-type O gene (PTPRO) has been described in several types of cancer. RESULTS: We screened primary breast cancer tissues for PTPRO promoter hypermethylation and assessed potential associations with pathological features and patient outcome. We also evaluated its potential as a breast cancer biomarker. PTPRO methylation was observed in 53 of 98 (54%) breast cancer tissues but not in adjacent normal tissue. Among matched peripheral blood samples from breast cancer patients, 33 of 98 (34%) exhibited methylated PTPRO in plasma. In contrast, no methylated PTPRO was observed in normal peripheral blood from 30 healthy individuals. PTPRO methylation was positively associated with lymph node involvement (P = 0.014), poorly differentiated histology (P = 0.037), depth of invasion (P = 0.004), and HER2 amplification (P = 0.001). Multivariate analysis indicated that aberrant PTPRO methylation could serve as an independent predictor for overall survival hazard ratio (HR): 2.7; 95% CI: 1.1-6.2; P = 0.023), especially for patients with HER2-positive (hazard ratio (HR): 7.5; 95% CI: 1.8-31.3; P = 0.006), but not in ER + and PR + subpopulation. In addition, demethylation induced by 5-azacytidine led to gene reactivation in PTPRO-methylated and -silenced breast cancer cell lines. CONCLUSIONS: Here, we report that tumor PTPRO methylation is a strong prognostic factor in breast cancer. Methylation of PTPRO silences its expression and plays an important role in breast carcinogenesis. The data we present here may provide insight into the development of novel therapies for breast cancer treatment. Additionally, detection of PTPRO methylation in peripheral blood of breast cancer patients may provide a noninvasive means to diagnose and monitor the disease.

[Dynamic changes of intestinal 16S rDNA metagenome in 5 infants].

OBJECTIVE: To investigate the dynamic changes of intestinal 16S rDNA metagenome in healthy infants. METHODS: Seventeen fecal samples were collected at ages of 3 days, 1 month, 6 months and 1 year in 5 infants. Total bacterial DNAs were extracted and submitted high throughout sequencing on the V6 viable region of 16S rDNA. Tags and Operational Taxonomic Units (OTU) were then obtained and analysis of taxonomy, abundance and alpha diversity were performed. RESULTS: In total 2,190.66 Mbp raw data in 17 samples were produced. The OTU numbers ranged from 36 to 308. The dominate phylum included Proteobacteria, Firmicutes and Bacteroidetes and Actinobacteria. The bacterial families>1% increased from only 2-4 per sample on day 3 to 7 at 1 or 6 months, 10 at 12 months. The average npShannon and Simpson index on day 3, at 1 month, 6 months and 1 year were 1.117, 1.460, 2.088, 2.50 and 0.443, 0.408, 0.229, 0.143 respectively. CONCLUSIONS: Infants' intestines harbor abounding bacterial genomes. Distinct individual differences exist in infants in terms of intestinal bacterial abundance and composition. The abundance and diversity of gut bacteria increase over time.

Improving the anti-tumor effect of EGCG in colorectal cancer cells by blocking EGCG-induced YAP activation.

(-)-Epigallocatechin-3-gallate (EGCG) is the primary active ingredient in green tea and has been used for cancer prevention in clinical trials. The anti-tumor effects of EGCG stem from its ability to inhibit the activities of many oncoproteins, such as AKT, VEGFR, STAT3, and mutant p53. However, the clinical efficacy of EGCG is unsatisfactory. How to improve the anti-tumor effects of EGCG is an open question. Here we report that EGCG inhibits the tumor suppressive Hippo signaling pathway and activates downstream YAP in colorectal cancer (CRC) cells. Activation of YAP impedes the anti-tumor effects of EGCG. YAP blockade increases the sensitivity of CRC cells to EGCG treatment.

Effects of salvianolic Acid B on protein expression in human umbilical vein endothelial cells.

Salvianolic acid B (Sal B), a pure water-soluble compound extracted from Radix Salviae miltiorrhizae, has been reported to possess potential cardioprotective efficacy. To identify proteins or pathways by which Sal B might exert its protective activities on the cardiovascular system, two-dimensional gel electrophoresis-based comparative proteomics was performed, and proteins altered in their expression level after Sal B treatment were identified by MALDI-TOF MS/MS. Human umbilical vein endothelial cells (HUVECs) were incubated at Sal B concentrations that can be reached in human plasma by pharmacological intervention. Results indicated that caldesmon, an actin-stabilizing protein, was downregulated in Sal B-exposed HUVECs. Proteins that showed increased expression levels upon Sal B treatment were vimentin, T-complex protein 1, protein disulfide isomerase, tropomyosin alpha, heat shock protein beta-1, UBX domain-containing protein 1, alpha enolase, and peroxiredoxin-2. Additionally, Sal B leads to increased phosphorylation of nucleophosmin in a dose-dependent manner and promotes proliferation of HUVECs. We found that Sal B exhibited a coordinated regulation of enzymes and proteins involved in cytoskeletal reorganization, oxidative stress, and cell growth. Our investigation would provide understanding to the endothelium protection information of Sal B.

[Construction of a melon genetic map with fruit and seed QTLs].

A genetic map of melon was constructed using 143 F2 population developed from a cross between two distant lines Ano2 of Japan and Hami melon K413. The map contains 12 linkage groups and 142 markers, including 121 AFLPs, 16 SSRs, 3 STSs, 2 trait markers and covers 1 014.2 cM. Composite interval mapping (CIM) method was used to detect QTLs involved in melon fruit and seed traits: fruit length (FL), fruit width (FW), fruit shape (length/width, FS), centre sugar (CS), edge sugar (ES), flesh texture (FT), seed length (SL), seed width (SW), seed shape (SS), and seed weight (SW). The result showed that Flesh was located between AFLP markers NDAA and NCFA on C9. A total of 25 QTLs were detected for other traits and some QTLs were co-located with each other. The QTLs Sl5.1, Sw5.1, and Swt5.1 located on linkage C5 between NCA and N73C explained a significant portion of associated phenotypic variation (R2=17%, 19%, 23%). The allele from Ano2 obviously suppressed the length, width, and weight of melon seed; the QTLs between N73A and NFDA on C8 were involved in seed width, shape, and weight; the QTL Fs8.1 on C8 was detected using both F2 and F3 fruit data and explained a significant portion of phenotypic variation 25% and 19%. Fs8.1 showed partly dominant, and the allele from Ano2 sup-pressed elongation of fruit to form round melon. The QTLs related to centre sugar, edge sugar, and fruit texture were also detected in this research.

Prognostic value of AKAP13 methylation and expression in lung squamous cell carcinoma.

Aim: This study aimed to analyze the prognostic value and clinical significance of AKAP13 mRNA expression and AKAP13 methylation in lung squamous cell carcinoma (LUSC). Materials & methods: The mRNA expression and methylation of AKAP13 data of LUSC patients were downloaded from the Broad GDAC Firehose database and analyzed. Results:AKAP13 mRNA expression was downregulated and methylation was upregulated in LUSC tissue. Three CpG sites of AKAP13 were associated with overall survival. Combination of AKAP13 mRNA and methylation revealed 11 CpG sites associated with overall survival of LUSC patients. AKAP13 mRNA expression was associated with distant metastasis of LUSC, no associations were found between methylation status of CpG sites and clinical features. Conclusion:AKAP13 mRNA and its methylated CpG sites are potential prognostic indicators in LUSC patients.

Down-regulation of DJ-1 Augments Neuroinflammation via Nrf2/Trx1/NLRP3 Axis in MPTP-induced Parkinson's Disease Mouse Model.

Microglia-mediated neuroinflammation plays a significant role in the pathogenesis of Parkinson's disease (PD). Down-regulation of DJ-1, a PD-associated protein, has been recently found to increase microglial sensitivity to lipopolysaccharides (LPS). However, the role of DJ-1 in microglia-mediated neuroinflammation in PD remains unclear. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to establish a PD model with mice and tyrosine hydroxylase (TH) staining was performed to validate the model. Adenovirus strategy and shRNA was employed to knockdown the expression of DJ-1 in mice and BV2 microglia, respectively. Western Blot and quantitative PCR were carried out to determine the expression of cytokines, DJ-1, Nrf2, Trx1 and NRLP3. Immunoprecipitation was used to examine the potential interaction between DJ-1 and Nrf2 or Trx1. Flow cytometry-based Annexin V/7-AAD assay were performed to evaluate cell apoptosis. We found that down-regulation of DJ-1 exacerbated neuroinflammation in PD mice. DJ-1 and Nrf2 knockdown promoted inflammation and cell apoptosis in BV2 microglia, while NLRP3 knockdown had opposite effects. Furthermore, DJ-1 regulated the expression of NLRP3 by upregulating Nrf2/Trx1 axis. Taken together, these data suggested that down-regulation of DJ-1 accelerated microglia-mediated neuroinflammation and cell apoptosis via Nrf2/Trx1/NLRP3 axis. Thus, our results demonstrated the important role of DJ-1 in PD pathogenesis and warranted further investigation of DJ-1 as a therapeutic target for PD.

Prognostic value of preoperative serum bilirubin levels in ovarian cancer.

Bilirubin is a promising prognostic factor for non-liver disease-related deaths in various cancers. We investigated the association between preoperative serum bilirubin levels and oncological outcomes in patients with ovarian cancer. We retrospectively analyzed the clinical data of 282 patients with epithelial ovarian carcinoma (EOC), and grouped them according to optimal threshold values of total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBL) measured by receiver operating characteristic curve analysis. Univariate and multivariate Cox proportional hazards regression analyses were used to evaluate various parameters that might affect overall survival (OS) and progression-free survival (PFS) in patients with EOC. The optimal cutoff values for TBIL, DBIL, and IBIL levels were 9.65 µmol/L, 2.95 µmol/L, and 6.75 µmol/L, respectively. Increased TBIL, DBIL, and IBIL levels correlated with the serum carbohydrate antigen (CA)-125 levels, International Federation of Gynecology and Obstetrics stage, and pathological differentiation (all P<0.05). Univariate analysis revealed longer OS and PFS in patients with high TBIL (≥9.65 µmol/L) and IBIL (≥6.75 µmol/L) levels (P<0.05). Multivariate analysis showed that patients with high IBIL levels (≥6.75 µmol/L) had significantly longer OS and PFS than those with low IBIL levels (<6.75 µmol/L) [hazard ratio (HR) = 0.333, 95% confidence interval (CI): 0.123~0.904, P<0.05; HR = 1.814, 95% CI: 1.169~2.816, P<0.05]. Therefore, IBIL is a potential independent prognostic factor for OS and PFS in patients with EOC. The higher the IBL level, the better the prognosis of patients with EOC.

Reciprocal Regulation Between Indoleamine 2,3-Dioxigenase 1 and Notch1 Involved in Radiation Response of Cervical Cancer Stem Cells.

Cervical cancer is the fourth most common cancer in women around the world. Cancer stem cells (CSCs) are responsible for cancer initiation, as well as resistance to radiation therapy, and are considered as the effective target of cancer therapy. Indoleamine 2,3-dioxygenase 1 (IDO1) mediates tryptophan metabolism and T cell suppression, but the immune-independent function of IDO1 in cancer behavior is not fully understood. Using tumorsphere cultivation for enriched CSCs, we firstly found that IDO1 was increased in HeLa and SiHa cervical cancer cells and in these two cell lines after radiation treatment. The radiosensitivity of HeLa and SiHa tumorsphere cells was increased after the inhibition of IDO1 through RNA interference or by the treatment of INCB-024360, an IDO1 inhibitor. With the treatment of kynurenine, the first breakdown product of the IDO1-mediated tryptophan metabolism, the radiosensitivity of HeLa and SiHa cells decreased. The inhibition of Notch1 by shRNA downregulated IDO1 expression in cervical CSCs and the binding of the intracellular domain of Notch (NICD) on the IDO1 promoter was reduced by Ro-4929097, a γ-secretase inhibitor. Moreover, the knockdown of IDO1 also decreased NICD expression in cervical CSCs, which was correlated with the reduced binding of aryl hydrocarbon receptor nuclear translocator to Notch1 promoter. In vivo treatment of INCB-0234360 sensitized SiHa xenograft tumors to radiation treatment in nude mice through increased DNA damage. Furthermore, kynurenine increased the tumorsphere formation capability and the expression of cancer stemness genes including Oct4 and Sox2. Our data provide a reciprocal regulation mechanism between IDO1 and Notch1 expression in cervical cancer cells and suggest that the IDO1 inhibitors may potentially be used as radiosensitizers.

[Genetic diagnosis and prenatal diagnosis of Angelman syndrome].

OBJECTIVE: To evaluate the conventional cytogenetic methods in genetic diagnosis and prenatal diagnosis in the family with a proband of Angelman syndrome (AS). METHODS: High-resolution G-banding karyotyping and fluorescence in situ hybridization (FISH) on metaphase chromosomes were performed. RESULTS: Two AS patients and 1 normal fetus in the family were successfully detected by FISH. CONCLUSION: Our result demonstrated that patient with type I AS could be detected by combining the techniques of high-resolution G-banding and FISH with clinical observation, which would offer accurate genetic counseling information to the geneticists and provide the prenatal diagnosis for the AS family.

The role of mesh technology with tumor prosthesis reconstruction to reconstruct the extensor mechanism of knee joint after resection of proximal tibial tumors.

PURPOSE: The aim of this study was to evaluate the role of mesh technique in the reconstruction of the extensor mechanism after resection of proximal tibial tumors. METHODS: We retrospectively analyzed the cases of 14 patients who were diagnosed with proximal tibial tumors at our center and reconstructed with tumor prosthesis, gastrocnemius muscle, and mesh between 2012 and 2017. The treatment strategies for patellar tendon reconstruction primarily involve gastrocnemius reconstruction to cover the tumor prosthesis and mesh reconstruction for the patellar ligament. RESULTS: Among the 14 patients, the mean was 1.57° (range 0-12°) for active extension versus 105.00° (range 80-120°) for active flexion. The mean for passive extension was 0°. The passive flexion mean was 115.00° (range 90-120°). The extensor lag averaged 1.57° (range 0-12°), and the mean Musculoskeletal Tumor Society score (MSTS) was 23.57 (range 19-27). The average follow-up for all patients was 23.50 months (range 14-37). During the recent follow-up, all patients were able to walk without crutches. Two patients underwent above-the-knee amputation for local recurrence of the tumor, and lung metastasis occurred in three patients after operation. There were no postoperative complications. CONCLUSIONS: Extensor lag was remarkably reduced in the surgery group in comparison to previous study reports. Surgical resection is a simple, reliable, and effective method to remove and control the tumor. Mesh reconstruction of patellar ligament is effective to reconstruct the extensor mechanism of the knee after excision of tumor.

Efficacy and Safety of Chinese Herbal Medicine for Primary Intracerebral Hemorrhage: A Systematic Review of Randomized Controlled Trials.

Background: Primary intracerebral hemorrhage (ICH) is the most harmful subtype of stroke, but there have yet been no specific proven therapies. Chinese herbal medicine (CHM) has been used for ICH for more than a thousand years; however, currently it is still lacking of available evidence. The objective of this study is to assess the current available evidence of CHM for acute ICH according to randomized controlled trials. Methods: Eight databases were searched from the year of their respective inception to November 2017. Only the studies that assessed at least four domains with "yes" according to the Cochrane risk of bias tool were selected for analysis. All the data were analyzed by using Review Manager 5.3 software. P < 0.05 was considered to be statistically significant. Results: Forty-five studies with 4,517 individuals were identified. CHM paratherapy can improve dependency, neurological function deficit, volume of hematoma, clinical effective rate, and volume of perihematomal edema compared with CHM alone or placebo (all P < 0.05). By contrast, it was not significant for improving the mortality rate of ICH patients (P > 0.05). In addition, adverse events were reported in 16 studies, whereas 29 studies did not mention it. The frequency of adverse events was 70/972 in the trial group and 48/944 in the control group. Conclusion: The present study provided supportive evidence of CHM for improving dependency of ICH and showed generally safety; however, there is still lack of evidence for improving mortality rate, and it opens for further study.

Tribbles Homolog 3 Involved in Radiation Response of Triple Negative Breast Cancer Cells by Regulating Notch1 Activation.

Breast cancer is the most common cancer for women in Taiwan and post-lumpectomy radiotherapy is one of the therapeutic strategies for this malignancy. Although the 10-year overall survival of breast cancer patients is greatly improved by radiotherapy, the locoregional recurrence is around 10% and triple negative breast cancers (TNBCs) are at a high risk for relapse. The aim of this paper is to understand the mechanisms of radioresistance in breast cancers which may facilitate the development of new treatments in sensitizing breast cancer toward radiation therapy. Tribbles homolog 3 (TRIB3) is a pseudokinase protein and known to function as a protein scaffold within cells. It has been reported that higher TRIB3 expression is a poor prognostic factor in breast cancer patients with radiotherapy. In this study, we investigate the involvement of TRIB3 in the radiation response of TNBC cells. We first found that the expression of TRIB3 and the activation of Notch1, as well as Notch1 target genes, increased in two radioresistant TNBC cells. Knockdown of TRIB3 in radioresistant MDA-MB-231 TNBC cells decreased Notch1 activation, as well as the CD24-CD44⁺ cancer stem cell population, and sensitized cells toward radiation treatment. The inhibitory effects of TRIB3 knockdown in self-renewal or radioresistance could be reversed by forced expression of the Notch intracellular domain. We also observed an inhibition in cell growth and accumulated cells in the G0/G¹ phase in radioresistant MDA-MB-231 cells after knockdown of TRIB3. With immunoprecipitation and mass spectrometry analysis, we found that, BCL2-associated transcription factor 1 (BCLAF1), BCL2 interacting protein 1 (BNIP1), or DEAD-box helicase 5 (DDX5) were the possible TRIB3 interacting proteins and immunoprecipitation data also confirmed that these proteins interacted with TRIB3 in radioresistant MDA-MB-231 cells. In conclusion, the expression of TRIB3 in radioresistant TNBC cells participated in Notch1 activation and targeted TRIB3 expression may be a strategy to sensitize TNBC cells toward radiation therapy.

Effects of warm-supplementing kidney yang (WSKY) capsule added on risperidone on cognition in chronic schizophrenic patients: a randomized, double-blind, placebo-controlled, multi-center clinical trial.

OBJECTIVE: To evaluate the effects of warm-supplementing kidney yang (WSKY) capsule added on risperidone on cognition in chronic schizophrenic patients. METHODS: A randomized, double-blind, placebo-controlled, multi-center clinical trial was conducted. All 200 patients who met the DSM-IV diagnostic criteria for schizophrenia were randomly assigned to double-blind treatment with WSKY capsule (n = 100) or placebo (n = 100) added on risperidone for 8 weeks. The primary outcome measure was the cognitive function assessment assessed by the classic form of the Wisconsin Card Sorting Test (WCST) at baseline and week 8. The secondary outcome measures were assessed including the positive and negative symptoms scale (PANSS), the social disability screening schedule (SDSS), and the Hamilton rating scale for depression (HAM-D-17) at baseline, week 2, week 4, and week 8. The extrapyramidal side effects were assessed each week using the abnormal involuntary movement scale (AIMS) and rating scale for extrapyramidal side effects (RSESE), while adverse events were assessed using treatment emergent symptoms scale (TESS) as additional indicators of tolerability throughout the trial. RESULTS: The response rates of the WSKY group for the number of completed categories (CC), errors responses number (ER), perseveringly errors responses number (PER), and conceptual level (CL) of WCST assessment were significantly higher than those of placebo. The reduction in the SDSS score from baseline to endpoint was significantly greater in the WSKY group than those in the placebo. There were no significant differences in the response rates for the correct responses number, perseveringly responses number (PR) of WCST between the treatment groups. The improvements in the WCST indexes, PANSS score, HAM-D-17 score were no significant differences from baseline to endpoint between the two groups at week 8. There were no significant differences in AIMS, RSESE, and TESS compared patients treated with WSKY capsule with those in placebo during treatment. CONCLUSION: WSKY capsule added on risperidone may improve cognitive function, social function of the chronic schizophrenic patients, and the WSKY safely during treatment.

Effectiveness and tolerability of warm-supplementing kidney yang added to risperidone in improving cognitive impairment in patients with schizophrenia: An 8-week, multicenter, randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Certain herbal medicines have been reported to be effective in the treatment of psychiatric conditions, and combination treatment with drugs and herbal medicines has been reported to be useful in enhancing treatment efficacy and reducing recovery time and adverse events (AEs). OBJECTIVE: The purpose of this study was to investigate the effectiveness and tolerability of warm-supplementing kidney yang (WSKY) added to risperidone in improving cognitive impairment and negative symptoms (ie, cognitive function) in patients with schizophrenia. METHODS: This 8-week, multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted in patients who met the clinical classification for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Patients were recruited from 3 centers (including inpatient and outpatient clinics) and were evenly randomized to receive WSKY or placebo added to risperidone for 8 weeks. Primary assessments were conducted at weeks 2, 4, and 8. A clinical response was defined as a ≥50% reduction score (from baseline) on the Positive and Negative Syndrome Scale (PANSS), a ≥30% reduction score (from baseline) on the Scale for the Assessment of Negative Symptoms (SANS), or a ≥50% reduction score (from baseline) on the Hamilton Rating Scale for Depression (HAM-D-17). Cognitive function was assessed using the Wisconsin Card Sorting Test (WCST) at baseline and end point. Extrapyramidal AEs were assessed weekly using the Abnormal Involuntary Movement Scale (AIMS) and the Rating Scale for Extrapyramidal Side Effects (RSESE). AEs were assessed by patient interviews conducted at each clinic visit and also by the Treatment Emergent Symptoms Scale (TESS) scores. RESULTS: One-hundred twenty patients (62 males, 58 females; mean [SD] age, 34.4 [9.4] years; range, 18-45 years; baseline mean [SD] PANSS score, 88.7 [12.3]) were included in this study. Risperidone- and WSKY-treated patients had statistically significant improvements at end point in the number of completed categories (P = 0.019), perseverative responses (P = 0.041), perseverative errors (P = 0.040), and total errors (P = 0.049) on the WCST compared with placebo. The improvements in the PANSS, SANS, and HAM-D-17 scores were not significantly different between the 2 groups at week 8 for observed case and last-observation-carried-forward (LOCF) analyses. The response rates (LOCF) for the PANSS scores in the WSKY and placebo groups were 55.0% and 35.0%, respectively (P = 0.028), while the SANS scores were 63.3% and 45.0% (P = 0.044) and the HAM-D-17 were 35.0% and 45.0% (P = 0.264). There were no significant between-group differences in scores on the AIMS, RSESE, or TESS. CONCLUSIONS: The results of this study suggest that WSKY added to risperidone significantly improved cognitive function in these patients, as measured by the number of completed categories, perseverative responses, perseverative errors, and total errors on the WCST compared with placebo. The response rates in the WSKY group for the PANSS and SANS scores were significantly higher compared with placebo. All treatments were generally well tolerated.

Effect of Atractylodes macrocephala rhizoma on isoproterenol­induced ventricular remodeling in rats.

Myocardial infarction (MI) is the primary cause of ventricular remodeling (VR). The aim of the present study was to determine the effect of Atractylodis macrocephalae rhizoma (AMR) on VR induced by isoproterenol (ISO) in rats. Male Sprague Dawley rats were randomly divided into the normal control, ISO­induced and AMR groups. Rats in the ISO­induced and AMR groups were subcutaneously injected with 85 mg/kg/day ISO for two consecutive days. Compared with the ISO­induced group, AMR normalized the levels of hemodynamic parameters, markedly attenuated myocardial pathological damage, decreased the level of N­terminal prohormone of brain natriuretic peptide, and inhibited cardiac hypertrophy and myocardial fibrosis. In addition, AMR inhibited oxidative stress and activation of the rennin­angiotensin­aldosterone system (RAAS) when compared with the ISO­induced group. The results of the present study suggest that AMR may reverse VR via its antioxidative effect and inhibition of RAAS activation.

Effect of fermented Cordyceps sinensis on doxorubicin­induced cardiotoxicity in rats.

Cordyceps sinensis (CS) is a prominent medicinal herb in traditional Chinese medicine, and fermented CS is frequently used as a substitute for natural CS. Doxorubicin (DOX), an antitumor drug used in chemotherapy, is limited by its poor cardiotoxicity. The aim of the present study was to evaluate the protective effect of fermented CS against DOX­induced cardiotoxicity and the potential underlying mechanisms. Male Sprague­Dawley rats (180­200 g) were randomly assigned to seven different treatment groups: Normal control, DOX control, DOX+captopril (0.05 g/kg), 0.75, 1.5 and 3 g/kg DOX+CS, and the CS (1.5 g/kg) control. Histopathological changes, cardiac energy metabolism, cyclic adenosine monophosphate (cAMP) signaling and the associated mRNA expression of AMP­activated protein kinase (AMPK) were then evaluated. Fermented CS decreased the left ventricular weight index, heart weight index and mortality; however, it increased diastolic blood pressure and mean arterial pressure. In addition, it shortened the duration of the QRS complex and Sα­T segment, decreased serum creatine kinase (CK) and aspartate aminotransferase activity, inhibited histopathological changes and reduced brain natriuretic peptide content. Treatment with fermented CS also increased the activities of superoxide dismutase and glutathione peroxidase, reduced malondialdehyde content, increased the mitochondrial activities of Na+K+­adenosine 5'­triphosphate (ATP) ase, Ca2+Mg2+­ATPase and CK, and increased the creatine phosphate/ATP ratio and AMP/ATP ratio. Furthermore, it decreased the ATP/adenosine 5'­diphosphate (ADP) ratio, upregulated AMPKα2 expression, reduced the activity of serum phosphodiesterases (PDEs) and increased myocardial cAMP content. The results of the present study demonstrated that fermented CS attenuated DOX­induced cardiotoxicity by inhibiting myocardial hypertrophy and myocardial damage, ameliorating systolic function and the antioxidant enzyme system, improving cardiac energy metabolism, depressing the activities of PDEs, and by upregulating the cAMP and AMPK signaling pathways. Thus, fermented CS may be a candidate for the prevention of DOX­induced cardiotoxicity, cardiac energy impairment and against a number of cardiac diseases.