Abnormal structure and function of white matter in obsessive-compulsive disorder.

BACKGROUND: Abnormal structure and function of gray matter (GM) have been discovered in the cortico-striatal-thalamic-cortical (CSTC) circuit in obsessive-compulsive disorder (OCD). The GM structure and function may be influenced by the structure and function of the white matter (WM). Therefore, it is crucial to explore the characteristics of WM in OCD. METHODS: Diffusion tensor imaging and resting-state functional magnetic resonance imaging data of 52 patients with OCD and 39 healthy controls (HCs) were collected. The tract-based spatial statistics, amplitude of low-frequency fluctuations (ALFF), and structural-functional coupling approaches were utilized to explore the WM structure and function. Furthermore, the relationship between the abnormal WM structure and function and clinical symptoms of OCD was investigated using Pearson's correlation. Support vector machine was performed to evaluate whether patients with OCD could be identified with the changed WM structure and function. RESULTS: Compared to HCs, the lower fractional anisotropy (FA) values of four clusters including the superior corona radiata, anterior corona radiata, right superior longitudinal fasciculus, corpus callosum, left posterior corona radiata, fornix, and the right anterior limb of internal capsule, reduced ALFF/FA ratio in the left anterior thalamic radiation (ATR), and the decreased functional connectivity between the left ATR and the left dorsal lateral prefrontal cortex within CSTC circuit at rest were observed in OCD. The decreased ALFF/FA ratio in the left ATR negatively correlated with Yale-Brown Obsessive-Compulsive Scale obsessive thinking scores and Hamilton Anxiety Rating Scale scores in OCD. Furthermore, the features that combined the abnormal WM structure and function performed best in distinguishing OCD from HCs with the appropriate accuracy (0.80), sensitivity (0.82), as well as specificity (0.80). CONCLUSION: Current research discovered changed WM structure and function in OCD. Furthermore, abnormal WM structural-functional coupling may lead to aberrant GM connectivity within the CSTC circuit at rest in OCD. TRIAL REGISTRATION: Study on the mechanism of brain network in obsessive-compulsive disorder with multi-model magnetic resonance imaging (ChiCTR-COC-17013301).

Identification of Immune-Related Gene Signature in Schizophrenia.

BACKGROUND: Schizophrenia (SCZ) is a type of psychiatric disorder characterized by multiple symptoms. Our aim is to decipher the relevant mechanisms of immune-related gene signatures in SCZ. METHODS: The SCZ dataset and its associated immunoregulatory genes were retrieved using Gene Expression Omnibus (GEO) and single-sample gene set enrichment analysis (ssGSEA). Co-expressed gene modules were determined through weighted gene correlation network analysis (WGCNA). To elucidate the functional characteristics of these clusters, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used. Additionally, gene set enrichment analysis (GSEA) and Gene Set Variation Analysis (GSVA) were conducted to identify enriched pathways for the immune subgroups. A protein-protein interaction (PPI) network analysis was performed to identify core genes relevant to SCZ. RESULTS: A significantly higher immune score was observed in SCZ compared to control samples. Seven distinct gene modules were identified, with genes highlighted in green selected for further analysis. Using the Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) method, degrees of immune cell adhesion and accumulation related to 22 different immune cell types were calculated. Significantly enriched bioprocesses concerning the immunoregulatory genes with differential expressions included interferon-beta, IgG binding, and response to interferon-gamma, according to GO and KEGG analyses. Eleven hub genes related to immune infiltration emerged as key players among the three top-ranked GO terms. CONCLUSIONS: This study underscores the involvement of immunoregulatory reactions in SCZ development. Eleven immune-related genes (IFITM1 (interferon induced transmembrane protein 1), GBP1 (guanylate binding protein 1), BST2 (bone marrow stromal cell antigen 2), IFITM3 (interferon induced transmembrane protein 3), GBP2 (guanylate binding protein 2), CD44 (CD44 molecule), FCER1G (Fc epsilon receptor Ig), HLA-DRA (major histocompatibility complex, class II, DR alpha), FCGR2A (Fc gamma receptor IIa), IFI16 (interferon gamma inducible protein 16), and FCGR3B (Fc gamma receptor IIIb)) were identified as hub genes, representing potential biomarkers and therapeutic targets associated with the immune response in SCZ patients.

Lavender essential oil alleviates depressive-like behavior in alcohol-withdrawn rats: Insights from gut metabolites and hippocampal transcriptome analysis.

Lavender, an aromatic plant with a history dating back to ancient Egypt and Greece, is consumed because of its diverse pharmacological properties, including sedation, sleep aid, and antidepressant effects. However, the mechanisms underlying these antidepressant properties remain unclear. In this study, we explored the impact of lavender essential oil (LEO) inhalation on the diversity of gut microbiota, metabolites, and differential gene expression in the hippocampus of alcohol-withdrawn depressive rats. Additionally, we examined alterations in the hippocampal transient receptor potential (TRP) channel-mediated inflammatory regulation within the brain-gut axis of depressive rats. The results demonstrated a significant decrease in sucrose preference, diminished activity in the central zone of the open field test, and prolonged immobility time in the forced swim test in alcohol-withdrawn depressive rats, indicating the amelioration of depressive states following lavender essential oil inhalation. 16 S rDNA sequencing analysis revealed a significant reduction in Bacteroidota and Muribaculaceae in the gut of alcohol-withdrawn depressive rats, whereas lavender essential oil significantly increased the relative abundance of Muribaculaceae and other bacterial species. Metabolomic analysis identified 646 distinct metabolites as highly correlated biomarkers between the model and lavender essential oil groups. Furthermore, lavender essential oil inhalation significantly attenuated hippocampal inflammatory factors IL-2, IL-6, IL-1ß, and TNF-α. This study identified elevated expression of Trpv4 and Calml4 in the hippocampal region of alcohol-withdrawn depressed rats and showed that lavender essential oil inhalation regulated aberrantly expressed genes. Our research suggests that lavender essential oil downregulates Trpv4, modulates inflammatory factors, and alleviates depressive-like behavior in alcohol withdrawal rats.

Two multimodal neuroimaging subtypes of obsessive-compulsive disorder disclosed by semi-supervised machine learning.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a highly heterogeneous mental condition with a diverse symptom. Existing studies classified OCD on the basis of conventional phenomenology-based taxonomy ignoring the fact that the same subtype identified in accordance with clinical symptom may have different mechanisms and treatment responses. METHODS: This research involved 50 medicine-free patients with OCD and 50 matched healthy controls (HCs). All the participants were subjected to structural and functional magnetic resonance imaging (MRI). Voxel-based morphometry (VBM) and amplitude of low frequency fluctuation (ALFF) were used to evaluate gray matter volume (GMV) and spontaneous neuronal activities at rest respectively. Similarity network fusion (SNF) was utilized to integrate GMVs and spontaneous neuronal activities, and heterogeneity by discriminant analysis was applied to characterise OCD subtypes. RESULTS: Two OCD subtypes were identified: Subtype 1 exhibited decreased GMVs (i.e., left inferior temporal gyrus, right supplementary motor area and right lingual gyrus) and increased ALFF value (i.e., right orbitofrontal cortex), whereas subtype 2 exhibited increased GMVs (i.e., left cuneus, right precentral gyrus, left postcentral gyrus and left hippocampus) and decreased ALFF value (i.e., right caudate nucleus). Furthermore, the altered GMVs was negatively correlated with abnormal ALFF values in both subtype 1 and 2. LIMITATIONS: This study requires further validation via a larger, independent dataset and should consider the potential influences of psychotropic medication on OCD patients' brain activities. CONCLUSIONS: Results revealed two reproducible subtypes of OCD based on underlying multimodal neuroimaging and provided new perspectives on the classification of OCD.

Preparation, in vitro anti-tumour activity and in vivo pharmacokinetics of RGD-decorated liposomes loaded with shikonin.

Shikonin (SHK) has been evidenced to possess effects against various cancer cells. However, poor aqueous solubility and high toxicity restrict its application. In the study, RGD-decorated liposomes loaded with SHK (RGD-Lipo-SHK) were prepared via thin-film hydration method. Characterization and cellular uptake of liposomes was evaluated. Cytotoxicity of blank liposomes and different SHK formulations was measured against breast cancer cells (MDA-MB-231, MCF-7, and MCF-10A). Anti-tumour effects and pharmacokinetic parameters of different SHK formulations were appraised in tumour spheroids and in rat model, respectively. Liposomes displayed a particle size of less than 127 nm with a polydispersity index about 0.21. The encapsulation efficiency was about 91% for SHK, and drug leakage rate of liposomes was less than 6%. RGD-Lipo-SHK showed superior cellular internalization in the αvß3-positive MDA-MB-231 cells. Blank liposomes had no cytotoxicity to MDA-MB-231 and MCF-7 cells. Howbeit, different SHK formulations obviously inhibited proliferation of MCF-10A cells, especially free SHK. Meanwhile, RGD-Lipo-SHK significantly inhibited growth inhibition of tumour spheroids. The pharmacokinetics study indicated that the peak concentration, area under plasma concentration-time curves, half-life, and mean residence time of RGD-Lipo-SHK distinctly increased compared with those of free SHK. Altogether, these results demonstrated RGD-Lipo-SHK could reduce cytotoxicity, strengthen the antitumor-targeted effect, and prolong circulation time, which provides a foundation for further in vivo experimentations.

Decreased gray matter volume and dynamic functional alterations in medicine-free obsessive-compulsive disorder.

BACKGROUND: Previous studies discovered the presence of abnormal structures and functions in the brain regions of patients with obsessive-compulsive disorder (OCD). Nevertheless, whether structural changes in brain regions are coupled with alterations in dynamic functional connectivity (dFC) at rest in medicine-free patients with OCD remains vague. METHODS: Three-dimensional T1-weighed magnetic resonance imaging (MRI) and resting-state functional MRI were performed on 50 medicine-free OCD and 50 healthy controls (HCs). Firstly, the differences in gray matter volume (GMV) between OCD and HCs were compared. Then, brain regions with aberrant GMV were used as seeds for dFC analysis. The relationship of altered GMV and dFC with clinical parameters in OCD was explored using partial correlation analysis. Finally, support vector machine was applied to examine whether altered multimodal imaging data might be adopted to distinguish OCD from HCs. RESULTS: Our findings indicated that GMV in the left superior temporal gyrus (STG) and right supplementary motor area (SMA) was reduced in OCD, and the dFC between the left STG and the left cerebellum Crus I and left thalamus, and between the right SMA and right dorsolateral prefrontal cortex (DLPFC) and left precuneus was decreased at rest in OCD. The brain regions both with altered GMV and dFC values could discriminate OCD from HCs with the accuracy of 0.85, sensitivity of 0.90 and specificity of 0.80. CONCLUSION: The decreased gray matter structure coupling with dynamic function in the left STG and right SMA at rest may be crucial in the pathophysiology of OCD. TRIAL REGISTRATION: Study on the mechanism of brain network in obsessive-compulsive disorder with multi-model magnetic resonance imaging (registration date: 08/11/2017; registration number: ChiCTR-COC-17,013,301).

The passive recipient: Neural correlates of negative self-view in depression.

INTRODCTION: Previous studies have argued that people tend to isolate themselves from negative information. This tendency is modulated by the individual's role in social interaction, that is, as an initiative actor (e.g., "I hit Tom") or a passive recipient (e.g., "Paul hits me"). Depressed patients tend to focus on negative aspects of themselves and cope with situations passively. It is still an open question how the actor/recipient role affects the behavioral and neural responses to self in depression. METHODS: The present study adopted functional magnetic resonance imaging (fMRI) technology to investigate behavioral and neural responses to self (as an actor/recipient) in depressed patients and the matched healthy controls when attributing negative events. RESULTS: Compared with healthy controls, depressed patients showed more self-attribution for negative events. Depressed patients showed increased brain activity in the dorsal medial prefrontal cortex (dmPFC) subsystem of the default mode network (DMN) when they played recipient role in self-related negative events. Activity of the dmPFC subsystem was negatively correlated with depressed patients' self-attribution for negative events in recipient condition. While decreased brain activity in the medial temporal lobe (MTL) subsystem was observed in depressed patients when they played the actor or recipient role in self-related negative events. Activity of the MTL subsystem was negatively correlated with depressed patients' reaction time when they played recipient role in selfrelated negative events. CONCLUSION: These results implicated that depressed patients manifested the negative self-view. Actor/recipient role affected their activation patterns in the DMN which were different from the healthy controls. The correlation between the abnormal brain activations of the DMN and the behavioral performances might manifest more easily when depressed patients played recipient role in negative events.

Maintenance treatment of transcranial magnetic stimulation (TMS) for treatment-resistant depression patients responding to acute TMS treatment.

A growing body of studies has demonstrated that acute transcranial magnetic stimulation (TMS) therapy for treatment-resistant major depressive disorder (MDD) has achieved significant antidepressant effects and can alleviate other related symptoms. However, MDD has a high relapse rate, and patients with depressive symptoms can relapse weeks or months after acute TMS treatment. The lack of necessary TMS maintenance protocols after completing acute TMS treatment with full remission might be one of the reasons for the high relapse rates in MDD patients. Thus, investigating post-TMS treatment maintenance guidelines is important for decreasing relapse in treatment-resistant depression patients who had initially responded to acute TMS therapy. Therefore, we recommend a scientific approach to decrease relapse in treatment-resistant depression patients who had initially responded to acute TMS treatment.

Altered Global Brain Functional Connectivity in Drug-Naive Patients With Obsessive-Compulsive Disorder.

Abnormal functional connectivity (FC) within discrete brain networks is involved in the pathophysiology of obsessive-compulsive disorder (OCD) with inconsistent results. In the present study, we investigated the FC patterns of 40 drug-naive patients with OCD and 38 healthy controls (HCs) through an unbiased voxel-wise global brain FC (GFC) analysis at rest. Compared with HCs, patients with OCD showed decreased GFC within the default mode network (DMN) (i.e., left posterior cingulate cortex/lingual gyrus) and sensorimotor network (i.e., left precentral gyrus/postcentral gyrus) and increased GFC within the executive control network (ECN) (i.e., left dorsal lateral prefrontal cortex and left inferior parietal lobule). Receiver operating characteristic curve analyses further indicated that the altered GFC values within the DMN, ECN, and sensorimotor network may be used as neuroimaging markers to differentiate patients with OCD from HCs. These findings indicated the aberrant FC patterns of the DMN, ECN, and sensorimotor network associated with the pathophysiology of OCD and provided new insights into the changes in brain organization function in OCD.

ß-asarone relieves chronic unpredictable mild stress induced depression by regulating the extracellular signal-regulated kinase signaling pathway.

The present study aimed to investigate the effect of ß-asarone treatment in a rat model of depression induced by chronic unpredictable mild stress (CUMS) and to further explore the underlying molecular mechanisms. A rat model of depression was established by subjecting rat to CUMS and treated with various concentrations of ß-asarone (12.5, 25 and 50 mg/kg/day) and fluoxetine (20 mg/kg/day). Next, behavioral tests, including an open field, sucrose preference and forced swimming tests, were performed. In addition, the apoptosis of hippocampal neuronal cells was determined by flow cytometry, gene expression levels were detected by reverse transcription-quantitative polymerase chain reaction and protein levels were determined by western blot assay. The results revealed that ß-asarone significantly mitigated CUMS-induced depression-like behavior, evidenced by the increased sucrose intake, crossing and rearing numbers, and decreased immobility time in the forced swimming test. Furthermore, ß-asarone significantly decreased the apoptosis rate of hippocampal neuronal cells in rats subjected to CUMS. ß-asarone was also found to enhance CREB, BDNF, Trk-B and Bcl-2 levels, and reduce Bad level in the hippocampus of CUMS-treated rats. In addition, the activation of extracellular signal-regulated kinase pathway inhibited by CUMS was promoted by ß-asarone treatment. In conclusion, the present study findings indicated the antidepressant-like effects of ß-asarone on CUMS-induced depression in rats.

The Effects of Ketogenic Diet Treatment in Kcna1-Null Mouse, a Model of Sudden Unexpected Death in Epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is a leading cause of abrupt death in patient with epilepsy. It represents 5-30% of all rapid deaths in individuals with epilepsy. Ketogenic diet (KD) has been used in clinic for treatment of epilepsy for many decades. However, the cellular and molecular mechanisms underlying the SUDEP and the relationship between KD and SUDEP remain uncertain. Kcna1-null (Kcna1-/-) mouse, an animal model of SUDEP, is frequently used to study mechanisms underlying SUDEP. The current mini-review focus on risk factors for SUDEP and their relationship with KD treatment in Kcna1-/- mice. Emerging data suggest that factors including seizure frequency, longevity, rest, age, and gender both in Kcna1-/- mice and KD treated Kcna1-/-mice are involved in SUDEP. This provides valuable prediction for clinical application of KD for treatment of SUDEP.

Altered network homogeneity of the default-mode network in drug-naive obsessive-compulsive disorder.

BACKGROUND: Default-mode network (DMN) plays a key role in the pathophysiology of obsessive-compulsive disorder (OCD). However, the network homogeneity (NH) of DMN in OCD remains equivocal. OBJECTIVE: This study aimed to investigate abnormalities in the NH of the DMN at rest and the correlation between the NH of DMN and clinical variables in patients with OCD. METHODS: This study used the independent component analysis and unbiased hypothesis-driven NH method to analyze the resting-state functional magnetic resonance imaging data of 40 drug-naive patients with OCD and 40 age-, gender-, and education-matched healthy controls (HCs). RESULTS: Patients with OCD exhibited decreased NH values in the left ventral medial prefrontal cortex and bilateral posterior cingulate cortex (PCC)/precuneus (PCu) compared with HCs. Furthermore, analyses of receiver operating characteristic curves indicated that the decreased NH values in the right PCC/PCu may be used as a candidate neuroimaging marker to distinguish patients with OCD from HCs. CONCLUSION: These findings contribute new evidence of the participation of the altered NH of the DMN in the pathophysiology of OCD. TRIAL REGISTRATION: Study on the mechanism of brain network in obsessive-compulsive disorder with multi-model magnetic resonance imaging (ChiCTR-COC-17013301).

Decreased Intrinsic Functional Connectivity of the Salience Network in Drug-Naïve Patients With Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) patients have difficulty in switching between obsessive thought and compulsive behavior, which may be related to the dysfunction of the salience network (SN). However, little is known about the changes in intra- and inter- intrinsic functional connectivity (iFC) of the SN in patients with OCD. In this study, we parceled the SN into 19 subregions and investigated iFC changes for each of these subregions in 40 drug-naïve patients with OCD and 40 healthy controls (HCs) using seed-based functional connectivity resting-state functional magnetic resonance imaging (rs-fMRI). We found that patients with OCD exhibited decreased iFC strength between subregions of the SN, as well as decreased inter-network connectivity between SN and DMN, and ECN. These findings highlight a specific alteration in iFC patterns associated with SN in patients with OCD and provide new insights into the dysfunctional brain organization of the SN in patients with OCD.

Changes in Gray Matter Density, Regional Homogeneity, and Functional Connectivity in Methamphetamine-Associated Psychosis: A Resting-State Functional Magnetic Resonance Imaging (fMRI) Study.

BACKGROUND Using regional homogeneity (ReHo) blood oxygen level-dependent functional MR (BOLD-fMRI), we investigated the structural and functional alterations of brain regions among patients with methamphetamine-associated psychosis (MAP). MATERIAL AND METHODS This retrospective study included 17 MAP patients, 16 schizophrenia (SCZ) patients, and 18 healthy controls. Informed consent was obtained from all patients before the clinical assessment, the severity of clinical symptoms was evaluated prior to the fMRI scanning, and then images were acquired and preprocessed after each participant received 6-min fRMI scanning. The participants all underwent BOLD-fMRI scanning. Voxel-based morphometry was used to measure gray matter density (GMD). Resting-state fMRI (rs-fMRI) was conducted to analyze functional MR, ReHo, and functional connectivity (FC). RESULTS GMD analysis results suggest that MAP patients, SCZ patients, and healthy volunteers show different GMDs within different brain regions. Similarly, the ReHo analysis results suggest that MAP patients, SCZ patients, and healthy volunteers have different GMDs within different brain regions. Negative correlations were found between ReHo- and the PANSS-positive scores within the left orbital interior frontal gyrus (L-orb-IFG) of MAP patients. ReHo- and PANSS-negative scores of R-SFG were negatively correlated among SCZ patients. The abnormal FC of R-MFG showed a negative correlation with the PANSS score among MAP patients. CONCLUSIONS The abnormalities in brain structure and FC were associated with the development of MAP.

Hi1a as a Novel Neuroprotective Agent for Ischemic Stroke by Inhibition of Acid-Sensing Ion Channel 1a.

Strokes are the second-leading cause of death worldwide, and the cellular and molecular mechanisms underlying stroke-induced brain damage are still uncertain. The present therapy for acute ischemic stroke is limited to thrombolysis with the recombinant tissue plasminogen activator (rtPA). However, rtPA has a narrow therapeutic timeframe of 3-4.5 h, and only approximately 5% of stroke patients can benefit from rtPA treatment. Neuroprotective agents, such as N-methyl-D-aspartate receptor antagonists, have shown great promise in preclinical studies. However, due to a limited therapeutic time window and/or intolerable side effects, they have failed in clinical trials. Extending the time window and reducing side effects for neuroprotective drugs against strokes are critical for effective therapy for stroke patients. A recent study published in Proceedings of the National Academy of Sciences by Irène R. Chassagnon et al. (2017) indicates that Hi1a, a disulfide-rich spider venom peptide, is a highly neuroprotective agent in both in vitro and in vivo studies against experimental stroke. Hi1a reveals neuroprotection through inhibition of acid-sensing ion channel 1a. Thus, Hi1a might be a promising neuroprotective agent to protect the brain from ischemic injury in humans.

Role of CACNA1C gene polymorphisms and protein expressions in the pathogenesis of schizophrenia: a case-control study in a Chinese population.

The study aimed to investigate the correlations of CACNA1C genetic polymorphisms and protein expression with the pathogenesis of schizophrenia in a Chinese population. This research included 139 patients diagnosed with schizophrenia (case group) and 141 healthy volunteers (control group). Case and control samples were genotyped using denaturing high-performance liquid chromatography (DHPLC). Haplotypes of rs10848683, rs2238032, and rs2299661 were analyzed using the Shesis software. A mouse model of schizophrenia was established and assigned to test and blank groups. Western blotting was used to detect CACNA1C protein expression. The genotype and allele distribution of rs2238032 and rs2299661 differed between the case and control groups. TT genotype of rs2238032 and G allele of rs2299661 could potentially reduce the risk of schizophrenia. The distribution of rs2238032 genotype has a close connection with cognitive disturbance and the results of the general psychopathology classification exam. The distribution of rs2299661 genotypes was closely related to sensory and perceptual disorders, negative symptom subscales, and the results of the general psychopathology classification exam. CTC haplotype increased and CTG decreased the risk of schizophrenia in healthy people. In the brain tissues of mice with schizophrenia, the CACNA1C protein expression was higher in the test group than in the blank group. Our study demonstrated that CACNA1C gene polymorphisms and CACNA1C protein expression were associated with schizophrenia and its clinical phenotypes.

(­)­Epigallocatechin­3­gallate induces apoptosis in human pancreatic cancer cells via PTEN.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a cancer suppressor gene and an important negative regulator in the phosphatidylinositide 3­kinase (PI3K)/protein kinase B (Akt)/ mechanistic target of rapamycin (mTOR) signaling pathway. The PI3K/Akt/mTOR pathway can promote cancer cell survival, proliferation and progression. In the present study, the effects of (­)­epigallocatechin­3­gallate (EGCG) on PI3K/Akt/mTOR signaling in pancreatic cancer cells and PTEN knockdown cells were measured, in addition to assessing its therapeutic potential in pancreatic cancer. The apoptosis and proliferation of the cancer cells were examined by flow cytometry and Cell Counting kit­8 assay, respectively. The expression of genes and proteins in the PI3K/Akt/mTOR signaling pathway were investigated by reverse transcription­polymerase chain reaction and western blotting, respectively. The results suggested that the EGCG­induced apoptosis, proliferation inhibition and downregulated expression of phosphorylated (p)­Akt and p­mTOR were partially attenuated in PTEN­knockdown cells. In conclusion, the results indicated that EGCG is able to reduce proliferation and induce the apoptosis of pancreatic cancer cells associated with the expression of PTEN. Additionally, EGCG can suppress the expression of p­Akt and p­mTOR via PTEN to regulate the PI3K/Akt/mTOR pathway. The results suggest that EGCG may represent a potential treatment for pancreatic cancer, based on PTEN activation.

Matrix solid-phase dispersion extraction followed by high performance liquid chromatography-diode array detection and ultra performance liquid chromatography-quadrupole-time of flight-mass spectrometer method for the determination of the main compounds from Carthamus tinctorius L. (Hong-hua).

A simple and low-cost method based on matrix solid-phase dispersion (MSPD) extraction, HPLC separation, diode array detection and UPLC-Q-TOF-MS have been developed for the determination of Hydroxysafflor yellow A (HSYA), Kaempferol and other main compounds in Carthamus tinctorius. The experimental parameters that may affect the MSPD method, including dispersing sorbent, ratio of dispersing sorbent to sample, elution solvent, and volume of the elution solvent were examined and optimized. The optimized conditions were determined to be that silica gel was used as dispersing sorbent, the ratio of silica gel to sample mass was selected to be 3:1, and 10 mL of methanol: water (1:3, v:v) was used as elution solvent. The highest extraction yields of the two compounds were obtained under the optimized conditions. The method showed good linearity (r(2)≥0.999 2) and precision (RSD≤3.4%) for HSYA and Kaempferol, with the limits of detection of 35.2 and 14.5 ng mL(-1), respectively. The recoveries were in the range of 92.62-101.7% with RSD values ranging from 1.5 to 3.5%. At the meanwhile, there were 21 compounds in the extraction by MSPD method were identified by TOF-MS method to improve the quality control for safflower. Comparing to ultrasonic and soxhlet methods, the proposed MSPD procedure was more convenient and less time-consuming with reduced requirements on sample and solvent amounts. The proposed procedure was applied to analyze four real samples that were collected from different localities.

Puerarin induces the upregulation of glutathione levels and nuclear translocation of Nrf2 through PI3K/Akt/GSK-3ß signaling events in PC12 cells exposed to lead.

Oxidative stress is thought to be involved in lead-induced toxicity, especially affecting the brain. We reported previously that puerarin possesses antioxidative properties in the nervous system. Therefore, the aim of the present study was to test the hypothesis that puerarin inhibits lead acetate-induced oxidative stress in PC12 cells by interrupting phosphatidylinositol-3 kinase (PI3K)/Akt signaling through increasing glutathione (GSH) synthesis. Our results showed that puerarin attenuates oxidative stress in a concentration-dependent manner in PC12 cells exposed to lead acetate demonstrated by scavenging reactive oxygen species (ROS) and reducing lipid peroxidation (LPO). Treatment with puerarin significantly up-regulates glutamate cysteine ligase catalytic subunit (GCLc) expression both at its mRNA and protein levels, but not glutamate cysteine ligase modifier (GCLm) subunit, accompanying the elevation of cellular glutathione level. The increased nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) was not because of increased transcription of Nrf2 as Nrf2 transcript levels did not change after puerarin treatment. The effects of puerarin could be partially blocked by pharmacologic inhibition of PI3K and the glycogen synthase kinase 3ß (GSK-3ß) pathways with LY294002 and LiCl, respectively. On the other hand, puerarin treatment promoted Akt and GSK-3ß phosphorylation in PC12 cells exposed to lead acetate. Moreover, puerarin failed to modulate the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), p-c-Jun N-terminal kinases (JNK), and p-p38 mitogen-activated protein kinase (MAPK) demonstrating some specificity for its action on the PI3K/GSK-3ß pathway. These findings suggest that puerarin as a phytoestrogen might be an attractive agent for prevention and treatment of chronic diseases related to lead neurotoxicity.

Analyzing 395,793 samples shows significant association between rs999737 polymorphism and breast cancer.

Large-scale genome-wide association studies (GWAS) have been conducted and reported the association between rs999737 polymorphism at 14q24.1 (RAD51L1) and breast cancer risk. Following studies investigated rs999737 polymorphism in European and Asian populations. However, some of these studies reported weak and no significant association. Here, we reevaluated this association using large-scale samples from previous 11 studies (n=395,793; 162,261 cases and 233,532 controls) from the PubMed database. We evaluated the genetic heterogeneity among the selected studies. The pooled odds ratio (OR) is calculated by the fixed effect model. All statistical tests for heterogeneity and meta-analysis were computed using R package. We did not identify significant heterogeneity among the included studies using the allele model (P=0.1314 and I (2)=33.4 %). We observed significant association between rs999737 and breast cancer using the allele model (P=2.47E - 35, OR=0.92, 95 % confidence interval (CI) 0.91-0.93). Our analysis further supports previous findings that the rs999737 polymorphism contributes to breast cancer susceptibility. We believe that our finding will be very useful for future genetic studies in breast cancer.