Analysis of Plasma Biopterin Levels in Psychiatric Disorders Suggests a Common BH<Subscript>4</Subscript> Deficit in Schizophrenia and Schizoaffective Disorder

Tetrahydrobiopterin (BH₄) is an essential cofactor for amine neurotransmitter synthesis. BH₄ also stimulates and modulates the glutamatergic system, and regulates the synthesis of nitric oxide by nitric oxide synthases. A connection between BH₄ deficiencies and psychiatric disorders has been previously reported; major depression and obsessive-compulsive disorder have been found in subjects with a BH₄ deficiency disorder and more recently we have observed a robust plasma deficit of biopterin (a measure of BH₄), in a large group of schizophrenic patients compared to control subjects. To extend our previous finding in schizophrenia, we analyzed plasma biopterin levels from patients with schizoaffective and bipolar disorders. A significant difference in biopterin was seen among the diagnostic groups (P < 0.0001). Post hoc analyses indicated significant biopterin deficits relative to the normal control group for the schizoaffective group, who had biopterin levels comparable to the schizophrenic group. Bipolar disorder subjects had plasma biopterin levels that were higher that the schizoaffective disorder group and significantly higher than the schizophrenic group. The demonstrated significant biopterin deficit in both schizophrenia and schizoaffective disorder, may suggest an etiological role of a BH₄ deficit in these two disorders, via dysregulation of neurotransmitter systems.     

Heartache of the State,Enemy of the Self: Bipolar Disorder and Cultural Change in Urban China

Past works in anthropology and psychology have described the Chinese orientation toward life as situation-centered with an external locus of control. This model has also been applied to the understanding of affect disorders in China—depressive patients have been found to focus on outside circumstances surrounding dysphoric moods. However, dramatic economic, sociopolitical and cultural changes in post-Mao China may be affecting these cognitive orientations toward emotional distress. This paper focuses on the subjective experiences of individuals diagnosed with bipolar disorder in China. The study is based on semistructured interviews with patients at a Western-style mental health institution in Shenzhen, the first successful Special Economic Zone in China. My data suggest that the location of agency has shifted across generations. Whereas those who grew up in the Maoist era are inclined to use external circumstances to explain the control over and responsibility for their illness, younger patients tend to emphasize self-blame and individual responsibility. I argue that these intergenerational differences in ethnopsychology relate to the multifaceted rise of individualism in post-Mao China. The paper ends with an examination of this observed shift vis-à-vis recent theories of neoliberal discipline in China and a discussion of potential psychological implications.

Anti-atherosclerotic activities of flavonoids from the flowers of Helichrysum arenarium L. MOENCH through the pathway of anti-inflammation

We have successfully established AS model using thoracic aortas vascular ring which evaluated by the morphological changes of blood vessels, the proliferation of VSMC, and the expression of inflammation factors VEGF, CRP, JNK2 and p38. This AS model has the advantages of low cost, convenient and short period of established time. Moreover, we investigated the anti-AS activities of 7 flavonoids Narirutin (1), Naringin (2), Eriodictyol (3), Luteolin (4), Galuteolin (5), Astragalin (6), Kaempferol (7) from flowers of Helichrysum arenarium L. MOENCH by examining the vascular morphology, the inhibition on the expression of inflammation factors CRP, VEGF, JNK2, p38. In addition, we investigated the anti-AS activities of these 7 flavonoids by examining NO secretion of RAW264.7 cells in response to LPS. All above inflammation factors have been proved to be involved in the formation of AS. After comprehensive analysis of all results to discuss the structure–activity relationship, we summarized the conclusions at follow: compounds 1–7 could inhibit the expression of VEGF, CRP, JNK2, p38 and NO at different level, and we evaluated that flavonol aglycone have more significant anti-inflammation than it’s glycoside, and the anti-AS activity of flavonols were stronger than flavanones and flavones, which means that 3-group might be the effective group. Eventually, we supposed the main anti-inflammatory mechanism of these compounds was to reduce the expression of CRP, inhibit the kinases activity of JNK2 and p38, and then the MAPK pathway was suppressed, which resulted in the decrease of NO synthesis, VEGF expression and endothelial adhesion factor expression. And eventually, the scar tissue and vascular stenosis formations were prevented. This conclusion suggested flavonoids have the potential of preventing AS formation.     

Chemical constituents of the root bark of Ulmus davidiana var. japonica and their potential biological activities

The root bark of Ulmus davidiana var. japonica (Ulmaceae), commonly known as yugeunpi, has been used as a traditional Korean medicine for the treatment of gastroenteric and inflammatory disorders. As part of continuing projects to discover bioactive natural products from traditional medicinal plants with pharmacological potential, phytochemical investigation of the root bark of this plant was carried out. This led to the successful isolation of a new chromane derivative (1) and 22 known compounds: catechin derivatives (2–5), megastigmane glycoside (6), dihydrochalcone glycosides (7 and 8), flavanone glycosides (9 and 10), coumarins (11 and 12), lignan derivatives (13–17), and phenolic compounds (18–23). The structure of the new compound (1) was determined with 1D and 2D NMR spectroscopy and HR-ESIMS, and its absolute configurations were achieved by chemical reactions and the gauge-including atomic orbital (GIAO) NMR chemical shifts calculations. All the isolated compounds were evaluated for their potential biological activities including neuro-protective, anti-neuroinflammatory, and anti-Helicobacter pylori activities. Among the isolates, compounds 1, 8, and 20 displayed stronger potency by causing a greater increase in the production and the activity of nerve growth factor (NGF) in C6 glioma cells (147.04 ± 4.87, 206.27 ± 6.70, and 143.70 ± 0.88%, respectively), whereas compounds 11, 14, and 19 inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated murine microglial cells (IC₅₀ of 18.72, 12.31, and, 21.40 µM, respectively). In addition, compounds 1, 11, 18, and 20 showed anti-H. pylori activity with MIC values of 25 or 50 µM against two strains of H. pylori 51 and 43504. These findings provide scientific evidence that supports the traditional usage of U. davidiana var. japonica root bark in the treatment of gastroenteric and inflammatory disorders.     

A profile of the in vitro anti-tumor activity of imidazolium-based ionic liquids

The anti-cancer activity and cytotoxicity of imidazolium-based ionic liquids has been determined for the first time via NCI’s in vitro 60 human tumor cell lines. The preliminary SAR showed that the chain length of alkyl substitution at N-3 position of imidazole ring plays crucial role towards anti-tumor activity and cytotoxicity of these ionic liquids. The ionic liquids with alkyl substitution of C-12 chain length were found to be effective against all 60 tumor cell lines and show very low cytotoxicity in most of the cases. Further increase in chain length resulted in enhanced growth inhibition of tumor cell lines as well as high cytotoxicity. Interestingly, active compounds 1-dodecyl-3-methylimidazolium chloride (8), 1-dodecyl-3-methylimidazolium tetrafluoroborate (9), 1-hexadecyl-3-methylimidazoium chloride (10), 1-octadecyl-3-methylimidazolium chloride (11), 1-octadecyl-3-methylimidazolium hexafluorophosphate (12), 1-octadecyl-3-methylimidazolium bis(triflic)imide (13) and 1-octadecyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate (14) were highly active against leukemia cell lines, especially compounds 13 and 14 where the cytotoxicity was also very low as given by LC₅₀ >100 μM in all six leukemia cell lines.     

Further insight into the neurobehavioral pattern of children carrying the 2p16.3 heterozygous deletion involving NRXN1: Report of five new cases

Increasing evidence links heterozygosity for NRXN1 gene deletions to a clinically wide spectrum of neurodevelopmental, psychiatric, and neurological disorders. However, to date, the neurocognitive and social communication features of children carrying this genomic rearrangement have not been assessed in detail. The cognitive and behavioral profiles of five children carrying a heterozygous NRXN1 deletion were investigated through systematic assessment of the cognitive and developmental levels, adaptive profile and presence of behavioral symptoms and autistic features. Furthermore, four transmitting parents were assessed by means of cognitive, psychopathological and parental stress tests. A below‐average cognitive level was documented in all children, and defective adaptive levels were observed in four of them. Three of the five children were diagnosed as having autism spectrum disorder in comorbidity with intellectual disability/global developmental delay, with a major impairment in social communication skills. The remaining two children presented with isolated intellectual disability and an unclassifiable neurodevelopmental disorder, respectively. This study provide data contributing to a more accurate characterization of the neurobehavioral phenotype of individuals carrying heterozygous NRXN1 deletions. This analysis indicates that these structural rearrangements are associated with a variable expression of neuropsychiatric symptoms, and cast some doubts about the incomplete penetrance of the disorder.     

Monohydroxycarotenoids from diphenylamine-inhibited cultures of Rhodospirillum rubrum

The monohydroxycarotenoids formed by diphenylamine-inhibited cultures of Rhodospirillum rubrum have been investigated. Nine have been isolated and identified as 1-hydroxy-1,2-dihydrophytofluene (1), 1-Hydroxy-1,2,7′,8′,11′,12′-hexahydrolycopene (2), chloroxanthin (3), 1-methoxy-1′-hydroxy-1,2,1′,2′-tetrahydrophytofluene (4a), 1′-hydroxy-3,4,1′,2′,11′,12′-hexahydrospheroidene (5, 1′-hydroxy-3,4,1′,2′-tetrahydrospheroidene (6, 1′-hydroxy 1′,2′-dihydrospheroidene (7), rhodovibrin (8a) and monodeme thylated spirilloxanthin (9). 4a, 5 and 6 are novel carotenoids, and a definite structure has been assigned to 2 for the first time; the structure of 1 has been amended. The possible role of these carotenoids in spirilloxanthin biosynthesis is discussed.     

Polygenic risk for psychiatric disorders correlates with executive function in typical development

Executive functions are a diverse and critical suite of cognitive abilities that are often disrupted in individuals with psychiatric disorders. Despite their moderate to high heritability, little is known about the molecular genetic factors that contribute to variability in executive functions and how these factors may be related to those that predispose to psychiatric disorders. We examined the relationship between polygenic risk scores built from large genome‐wide association studies of psychiatric disorders and executive functioning in typically developing children. In our discovery sample (N = 417), consistent with previous reports on general cognitive abilities, polygenic risk for autism spectrum disorder was associated with better performance on the Dimensional Change Card Sort test from the NIH Cognition Toolbox, with the largest effect in the youngest children. Polygenic risk for major depressive disorder was associated with poorer performance on the Flanker test in the same sample. This second association replicated for performance on the Penn Conditional Exclusion Test in an independent cohort (N = 3681). Our results suggest that the molecular genetic factors contributing to variability in executive function during typical development are at least partially overlapping with those associated with psychiatric disorders, although larger studies and further replication are needed.     

The parametric, psychological, neuropsychological, and neuroanatomical properties of self and world evaluation

Background

As an individual moves from adolescence to adulthood, they need to form a new sense of self as their environment changes from a limited to a more expansive structure. During this critical stage in development the last dramatic steps of neural development occur and numerous psychiatric conditions begin to manifest. Currently, there is no measure that aids in the quantification of how the individual is adapting to, and conceptualizing their role in, these new structures. To fill this gap we created the Self and World Evaluation Expressions Test(SWEET).

Method

Sixty-five young adults (20.6 years-old), 36 with a history of drug use, completed the SWEET. A factor analysis was performed on the SWEET and the resultant factors were correlated with psychological, neuropsychological, and neuroanatomical battery that included both T1-wieghted and diffusion tensor magnetic resonance imaging scans.

Results

We derived four factors: Self, Social-Emotional, Financial-Intellectual, and Spirituality. While showing limited relationships to psychological and neuropsychological measures, both white matter integrity and gray matter density showed significant relationships with SWEET factors.

Conclusions

These findings suggest that while individual responses may not be indicative of psychological or cognitive processes they may relate to changes in brain structure. Several of these structures, such as the negative correlation of the affective impact of world with the dorsal anterior corpus callosum white matter integrity have been observed in psychiatric conditions (e.g., obsessive-compulsive disorder). Further longitudinal research using the SWEET may help understand the impact of dramatic shifts in self/world conceptualization and potentially link these shifts to underlying changes in brain structure.     

Generation and Characterization of Conditional Heparin-Binding EGF-Like Growth Factor Knockout Mice

Recently, neurotrophic factors and cytokines have been shown to be associated in psychiatric disorders, such as schizophrenia, bipolar disorder, and depression. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family, serves as a neurotrophic molecular and plays a significant role in the brain. We generated mice in which HB-EGF activity is disrupted specifically in the ventral forebrain. These knockout mice showed (a) behavioral abnormalities similar to those described in psychiatric disorders, which were ameliorated by typical or atypical antipsychotics, (b) altered dopamine and serotonin levels in the brain, (c) decreases in spine density in neurons of the prefrontal cortex, (d) reductions in the protein levels of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and post-synaptic protein-95 (PSD-95), (e) decreases in the EGF receptor, and in the calcium/calmodulin-dependent protein kinase II (CaMK II) signal cascade. These results suggest the alterations affecting HB-EGF signaling could comprise a contributing factor in psychiatric disorder.     

精神障碍的神经电生理循证医学证据

寻找客观标记物是精神医学研究最重要的课题之一,近期融合了循证医学的神经电生理研究为此提供了重要的途径,并取得了较为可观的研究成果,然而现有的研究结果仍然存在较多争议,难以取得一致共识.本文全面总结和归纳了结合以元分析(meta-analysis)为代表的循证医学方法和以脑电图(electroencephalography)为代表的神经电生理技术的精神障碍相关脑电研究成果,将事件相关电位划分为早期和晚期成分,并结合定量EEG分析,从感知加工、认知控制、情绪反应和社会认知等不同认知过程出发,系统分析和评述了精神障碍患者及高危人群的神经认知功能异常情况.我们发现:精神分裂症患者存在从早期到晚期的各种感知、情感和社会认知方面的缺陷,注意缺陷/多动障碍(ADHD)患者存在从早期到晚期的认知控制缺陷,焦虑和强迫障碍患者则存在早期的认知控制缺陷,而孤独症谱系障碍(ASD)患者则存在早期的感知加工和社会认知缺陷.此外,反映注意资源分配和认知加工速度的P300异常特征跨越了多个诊断类型,这表明该脑电成分可能反映了精神障碍的一般性认知缺陷.未来研究可利用多中心大样本数据库探寻精神疾病的神经电生理客观标记物...     

The Promise of Pharmacogenomics in Reducing Toxicity During Acute Lymphoblastic Leukemia Maintenance Treatment

Pediatric acute lymphoblastic leukemia(ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2–3 years. While the primary drugs used in the maintenance phase, 6-mercaptopurine(6-MP) and methotrexate(MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment.6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase(TPMT), nudix hydrolase 15(NUDT15), and potentially inosine triphosphatase(ITPA), which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1(SLCO1B1) and dihydrofolate reductase(DHFR). Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1(SLC19A1)and thymidylate synthetase(TYMS), but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.     

Effects of interleukin-1beta polymorphisms on brain function and behavior in healthy and psychiatric disease conditions

A high level of Interleukin-1beta (IL1B), a key mediator of inflammation, is expressed in the brain, particularly in the hippocampus, which plays a pivotal role in memory and mood regulation. In the brain, IL1B exerts a myriad of effects such as neuronal proliferation, differentiation, apoptosis, and long-term potentiation. Considering its pleiotropic effects in the brain, IL1B has been implicated in the pathogenesis of various psychiatric disorders as well as cognitive function in normal individuals. Thus, IL1B has been considered a candidate gene for the study of psychiatric diseases as well as brain function in normal individuals. The polymorphisms of IL1B have been described in relation to various expression levels in response to stimulation. This review describes previous studies on the genetic effects of IL1B, which relate it to psychiatric diseases such as major depressive disorder, bipolar disorder, schizophrenia, and Alzheimer’s disease, as well as cognitive function in normal individuals. Although many reports have indicated a possible role of the genetic effects of IL1B or its phenotypes in psychiatric diseases, some reports were unable to confirm these findings. IL1B release is mediated by an inflammatory response or psychological stress, leading to a cascade of immune reactions involving numerous immune components. To further explore the genetic effects of IL1B on mental diseases and brain function, gene–gene and gene–environment interactions should also be considered.     

Umbelliferone derivatives exert neuroprotective effects by inhibiting monoamine oxidase A,self-amyloidβ aggregation,and lipid peroxidation

Umbelliferone has been demonstrated to have a wide range of biological activities. However, the effect of incorporating a formyl moiety in the umbelliferone scaffold has not been investigated. In this paper, we investigated the inhibitory activity of six coumarins, namely umbelliferone (1), 6-formyl umbelliferone (2), 8-formyl umbelliferone (3), umbelliferone-6-carboxylic acid (4), esculetin (5), and scopoletin (6) against human monoamine oxidases (hMAOs), self-amyloid β (Aβ) aggregation, and lipid peroxidation. We found that all compounds had high selectivity for hMAO-A in comparison with hMAO-B. Among the compounds, 2 exhibited the highest hMAO inhibitory activity with an IC₅₀ value of 3.23 µM for hMAO-A and 15.31 µM for hMAO-B. Enzyme kinetic analysis showed that 2 and 3 were competitive hMAO inhibitors. In silico hydrated molecular docking simulations revealed that the coumarins interacted with substrate-binding site residues of the enzymes and the isoalloxazine ring of FAD. In addition, formyl coumarins 2 and 3 significantly inhibited lipid peroxidation in rat brain homogenates and self-Aβ_25-35 aggregation compared to other derivatives. These represent the first experimental and modelling data for hMAO-A/B inhibition by umbelliferone derivatives. Together, the data suggest that introduction of a formyl moiety in the 7-hydroxycoumarin scaffold, especially at the 6 position, plays an important role in the inhibition of hMAOs, Aβ self-aggregation, and lipid peroxidation. Umbelliferone derivative 2 is a promising therapeutic lead scaffold for developing anti-neuropsychiatric disorder drugs that function via selective hMAO-A inhibition.     

Neolignans from the seeds of Prunus tomentosa (Rosaceae) and their chemotaxonomic interest

The role of neolignans in the chemotaxonomy of the genus Prunus has long been neglected. In this study, two new dihydrobenzofuran neolignans tomentosanans A (12) and B (14), together with 15 known neolignans, were isolated from the seeds of Prunus tomentosa. This is the first report on the occurrence of compounds 1–12, 14, 15 and 17 in the genus Prunus. The biosynthetic pathways of these neolignans are also summarized. Together, these neolignans represent a phytochemical fingerprint for P. tomentosa, which may be used for identification of Prunus species.     

AMP-activated protein kinase (AMPK) activators from Myristica fragrans (nutmeg) and their anti-obesity effect

AMP-activated protein kinase (AMPK) is a potential therapeutic target for the treatment of metabolic syndrome including obesity and type-2 diabetes. As part of an ongoing search for new AMPK activators from plants, this study found that the total extract of Myristica fragrans (nutmeg) activated the AMPK enzyme in differentiated C2C12 cells. As active constituents, seven 2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignans, tetrahydrofuroguaiacin B (1), saucernetindiol (2), verrucosin (3), nectandrin B (4), nectandrin A (5), fragransin C₁ (6), and galbacin (7) were isolated from this extract. Among the isolates, compounds 1, 4, and 5 at 5 μM produced strong AMPK stimulation in differentiated C2C12 cells. In addition, the preventive effect of a tetrahydrofuran mixture (THF) on weight gain in a diet-induced animal model was further examined. These results suggest that nutmeg and its active constituents can be used not only for the development of agents to treat obesity and possibly type-2 diabetes but may also be beneficial for other metabolic disorders.     

The financial situation before and after first-time psychiatric in-patient diagnosis of schizophrenia spectrum,bipolar, and major depressive disorder

Schizophrenia spectrum, bipolar, and major depressive disorders are severe mental illnesses (SMIs) that not only entail great suffering for those affected but also major societal costs. In this study, I use administrative register data to provide a detailed picture of the financial situation of people with SMI in Sweden during a period of $\pm$10 years around first-time psychiatric in-patient diagnosis of schizophrenia spectrum, bipolar, and major depressive disorders. Receiving a diagnosis was associated with a considerable drop in earnings, which was largely compensated for by social transfers: mainly sickness and disability insurance. However, there were also large and increasing pre-diagnosis earnings gaps, relative to matched comparison groups, especially among those with schizophrenia spectrum disorders. These gaps were to a lesser extent compensated for by social transfers. Consequently, there were permanent and increasing – due to lost earnings growth – income differentials. Hence, findings in previous studies are confirmed: even in an advanced welfare state, people with SMI – especially those with schizophrenia – have an extremely weak position on the labour market and an equally difficult financial situation.