DNA methylation analysis of AKT1 promoter and HTR2A exon-I of Malaysian schizophrenia multiplex families with lower cognitive performance

Dysfunction of cognitive performance in schizophrenia has been associated with aberrant alteration of DNA methylation of several schizophrenia-risk genes. AKT1 and HTR2A are among the candidate genes for schizophrenia. Their expressions were found reduced in schizophrenia patients. Thus, we aimed to study the methylation status of AKT1 promoter and HTR2A exon-I in Malaysian schizophrenia patients and their affected family members. In this study, each participant was required to perform Trail Making Test (TMT) part A and B to measure their cognitive performance. Genomic DNA extracted from the peripheral blood of 12 Malaysian schizophrenia families and 12 controls families, was subjected to bisulfite conversion. The methylation status of CpG sites of AKT1 promoter at Chr14: 104796054 and HTR2A exon-I at Chr13: 46896918 were identified using methylation-specific polymerase chain reaction (MSP). Our results showed that schizophrenia patients performed worse in both TMT-A and B (p<0.0001) than healthy controls. The patients also displayed significantly (p=0.023) high level of methylation in AKT1 promoter compared to controls. Meanwhile, no significant difference (p=0.248) in methylation status was observed in HTR2A exon-I between schizophrenia and control groups. Therefore, methylation of AKT1 promoter in peripheral bloods of patients may involve in cognitive impairment and schizophrenia pathology. In addition, we were able to demonstrate the heritability of DNA methylation status across family members

Revisiting the Marrow Metabolic Changes after Chemotherapy in Lymphoma: A Step towards Personalized Care

Purpose. The aims were to correlate individual marrow metabolic changes after chemotherapy with bone marrow biopsy (BMBx) for its potential value of personalized care in lymphoma. Methods. 26 patients (mean age, 58 ± 15 y; 13 female, 13 male) with follicular lymphoma or diffuse large B-cell lymphoma, referred to FDG-PET/CT imaging, who had BMBx from unilateral or bilateral iliac crest(s) before chemotherapy, were studied retrospectively. The maximal standardized uptake value (SUV) was measured from BMBx site over the same area on both initial staging and first available restaging FDG-PET/CT scan. Results. 35 BMBx sites in 26 patients were evaluated. 12 of 35 sites were BMBx positive with interval decrease in SUV in 11 of 12 sites (92%). The remaining 23 of 35 sites were BMBx negative with interval increase in SUV in 21 of 23 sites (91%). The correlation between SUV change over the BMBx site before and after chemotherapy and BMBx result was significant (P < 0.0001). Conclusions. This preliminary result demonstrates a strong correlation between marrow metabolic changes (as determined by FDG PET) after chemotherapy and bone marrow involvement proven by biopsy. This may provide a retrospective means of personalized management of marrow involvement in deciding whether to deliver more extended therapy or closer followup of lymphoma patients

Genetic association of single nucleotide polymorphisms in dystrobrevin binding protein 1 gene with schizophrenia in a Malaysian population

Dystrobrevin binding protein 1 (DTNBP1) gene is pivotal in regulating the glutamatergic system. Genetic variants of the DTNBP1 affect cognition and thus may be particularly relevant to schizophrenia. We therefore evaluated the association of six single nucleotide polymorphisms (SNPs) with schizophrenia in a Malaysian population (171 cases; 171 controls). Associations between these six SNPs and schizophrenia were tested in two stages. Association signals with p < 0.05 and minor allele frequency > 0.05 in stage 1 were followed by genotyping the SNPs in a replication phase (stage 2). Genotyping was performed with sequenced specific primer (PCR-SSP) and restriction fragment length polymorphism (PCR-RFLP). In our sample, we found significant associations between rs2619522 (allele p = 0.002, OR = 1.902, 95%CI = 1.266 &#8211; 2.859; genotype p = 0.002) and rs2619528 (allele p = 0.008, OR = 1.606, 95%CI = 1.130 &#8211; 2.281; genotype p = 6.18 &#215; 10&#8722;5) and schizophrenia. Given that these two SNPs may be associated with the pathophysiology of schizophrenia, further studies on the other DTNBP1 variants are warranted

Startle habituation: a tool for assessing information processing deficits in zebrafish model of schizophrenia

Prepulse inhibition (PPI) and habituation of acoustic startle reflex have been extensively used to assess deficits in the sensorimotor functions of human patients and animal models of schizophrenia. These assays require expensive and sophisticated experimental setup for fine control of acoustic stimuli and sound attenuation. In this study, we investigate whether startle habituation assay based on mechanical (tap) stimuli can induce similar impairment in the habituation response in the schizophrenia model of larval zebrafish. For this purpose, a custom startle apparatus consisting of a 9 V push and pull solenoid and an Arduino Uno microcontroller was used to generate tap stimuli at desired intervals. Our results showed that tap stimuli at 1 Hz effectively evoked startle response in the control fishes which habituated after a few trials. The habituation response was significantly impaired in the MK801-induced schizophrenia model, similar to that elicited by acoustic startle stimuli in a previous study. We propose this simple and inexpensive method as an alternative tool for studying information processing and attention deficits in the pharmacological model of schizophrenia in zebrafish

Integrative Roles of Dopamine Pathway and Calcium Channels Reveal a Link between Schizophrenia and Opioid Use Disorder

Several theories have been proposed to explain the mechanisms of substance use in schizophrenia. Brain neurons pose a potential to provide novel insights into the association between opioid addiction, withdrawal, and schizophrenia. Thus, we exposed zebrafish larvae at 2 days post-fertilization (dpf) to domperidone (DPM) and morphine, followed by morphine withdrawal. Drug-induced locomotion and social preference were assessed, while the level of dopamine and the number of dopaminergic neurons were quantified. In the brain tissue, the expression levels of genes associated with schizophrenia were measured. The effects of DMP and morphine were compared to vehicle control and MK-801, a positive control to mimic schizophrenia. Gene expression analysis revealed that α1C, α1Sa, α1Aa, drd2a, and th1 were up-regulated after 10 days of exposure to DMP and morphine, while th2 was down-regulated. These two drugs also increased the number of positive dopaminergic neurons and the total dopamine level but reduced the locomotion and social preference. The termination of morphine exposure led to the up-regulation of th2, drd2a, and c-fos during the withdrawal phase. Our integrated data implicate that the dopamine system plays a key role in the deficits in social behavior and locomotion that are common in the schizophrenia-like symptoms and opioid dependence

Receptor-mediated AKT/PI3K signalling and behavioural alterations in zebrafish larvae reveal association between schizophrenia and opioid use disorder

The link between substance abuse and the development of schizophrenia remains elusive. In this study, we assessed the molecular and behavioural alterations associated with schizophrenia, opioid addiction, and opioid withdrawal using zebrafish as a biological model. Larvae of 2 days post fertilization (dpf) were exposed to domperidone (DMP), a dopamine-D2 dopamine D2 receptor antagonist, and morphine for 3 days and 10 days, respectively. MK801, an N-methyl-D-aspartate (NMDA) receptor antagonist, served as a positive control to mimic schizophrenia-like behaviour. The withdrawal syndrome was assessed 5 days after the termination of morphine treatment. The expressions of schizophrenia susceptibility genes, i.e., pi3k, akt1, slc6a4, creb1 and adamts2, in brains were quantified, and the levels of whole-body cyclic adenosine monophosphate (cAMP), serotonin and cortisol were measured. The aggressiveness of larvae was observed using the mirror biting test. After the short-term treatment with DMP and morphine, all studied genes were not differentially expressed. As for the long-term exposure, akt1 was downregulated by DMP and morphine. Downregulation of pi3k and slc6a4 was observed in the morphine-treated larvae, whereas creb1 and adamts2 were upregulated by DMP. The levels of cAMP and cortisol were elevated after 3 days, whereas significant increases were observed in all of the biochemical tests after 10 days. Compared to controls, increased aggression was observed in the DMP-, but not morphine-, treated group. These two groups showed reduction in aggressiveness when drug exposure was prolonged. Both the short- and long-term morphine withdrawal groups showed downregulation in all genes examined except creb1, suggesting dysregulated reward circuitry function. These results suggest that biochemical and behavioural alterations in schizophrenia-like symptoms and opioid dependence could be controlled by common mechanisms

Traditional Chinese medicine body constitutions and psychological determinants of depression among university students in Malaysia: a pilot study

Depression is commonly observed in university students, who are a high risk group for developing psychiatric disorders during adulthood. This study aimed to determine the prevalence of depression and its traditional Chinese medicine body constitutions and psychological determinants among university students in Malaysia. A cross-sectional pilot study was conducted between 9 and 28 September 2020 among 80 university students in Malaysia. Participants completed online survey questionnaires, including the validated Patient Health Questionnaire (PHQ-9), Constitution in Chinese Medicine Questionnaire (CMCQ), Dysfunctional Attitude Scale (DAS), Depression Anxiety Stress Scale (DASS-21) stress subscale, Perceived Stress Scale (PSS-10), and Rosenberg Self-Esteem Scale (RSES), which assess depression, body constitution, dysfunctional attitude, stress, perceived stress, and self-esteem. Multiple linear regression analyses were performed to determine the associated risk factors for depression. The overall prevalence of depression among university students was 33.8%. The multiple regression analysis showed a significant relationship between depression and qi-stagnation constitution (B = 0.089, p = 0.011), balanced constitution (B = −0.077, p = 0.049), and self-esteem (B = −0.325, p = 0.001). Our findings suggest that some traditional Chinese medicine body constitutions and self-esteem are significant risk factors affecting depression among university students. Identifying risk factors of depression is vital to aid in the early detection of depression among university students

Identification of potential protein biomarkers in a depressed chinese malaysian university student using liquid chromatography-tandem mass spectrometry

Depression is a serious psychological disorder with high prevalence rates, especially among university students. Serum proteins related to the immune system and oxygen and lipid transfer could have contributing roles in the development of depression and could act as biomarkers for depression. Currently, there is a lack of accurate biological methods that can be used to diagnose depression. Biomarkers could be an inexpensive and convenient way to predict depression and understand its pathophysiology. This study aimed to screen the serum proteome profile of a depressed student for the identification of potential depression biomarkers. A Malaysian private university student who was recruited from the pre-test study (n = 10) was further analyzed for serum proteome due to the fact that he was depressed, with scores of 15 out of 27 on the Patient Health Questionnaire (PHQ-9). After depleting the high-abundance proteins from the serum sample, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to identify the expressed proteins. A total of 224 proteins were identified. Globins, globulins, apolipoproteins and glycoproteins were most commonly detected. Here, we show the potential biomarkers that can be used to identify depression vulnerable individuals. These findings may be relevant to the development of new diagnostic and treatment strategies. However, further studies with larger sample sizes and healthy controls are needed to confirm the role of these candidate biomarkers for the prediction and diagnosis of depression