Characterizing neuroanatomical changes in parvalbumin and perineuronal nets in a rat DISC-1 knock out model

BACKGROUND: Schizophrenia is a debilitating disorder that has a profound impact on quality of life due to the presence of both cognitive deficits and psychotic symptoms. Despite having significant global economic and social costs and a worldwide prevalence of 1%, schizophrenia is still not well understood. Research has been making strides in uncovering the pathophysiology and the etiology that drive this disease, ranging from genetic abnormalities, disrupted circuitry, changes in microarchitecture, to impaired synaptic connectivity. Evidence suggests that disrupted-in-schizophrenia-1 (DISC1) driven genetic disturbances in fast-spiking parvalbumin (PV) neurons and their surrounding perineuronal nets (PNNs) likely contribute to schizophrenia etiology as they are part of the microcircuits required for working memory, a cognitive function that has been consistently impaired in schizophrenic patients. OBJECTIVE: To identify the neuroanatomical changes in PV neurons and surrounding PNNs in the superficial and deep layers of the prelimbic and infralimbic prefrontal cortex of a rat DISC-1 knockout model. METHODS: 19 DISC1-KO male rats and 15 wildtype rats were treated with saline or MK-801. They were sacrificed between P268-269 and brains were extracted and separated at the corpus callosum. After fixing and preserving, the brains were sliced then stained to visualize parvalbumin and perineuronal nets with immunohistochemistry. Slices were imaged and analyzed for PV, PNN, and PV+PNN counts in the superficial and deep regions of the prelimbic and infralimbic cortices. Averages counts within each group were taken and analyzed via 2-way ANOVAs for each brain region and dependent variable. RESULTS: DISC1-KO rats displayed the following trending changes: decreased PV cells in deep layers of infralimbic and decreased PNNs throughout the prelimbic cortex. MK-801 appears to increase the number of unsheathed PV cells in the superficial layers of prelimbic and infralimbic cortex. It decreased the number of PNNs in the prelimbic of wildtype animals but not in the DISC1-KO cohort. MK-801 moderately increased PV counts in DISC1-KO. CONCLUSIONS: This DISC1-KO model is a promising model of schizophrenia as we see the same directionality of decreases in PV and PNN as post mortem human studies. Furthermore, MK-801 is seen to have an increasing trend effect on PV cells, which should be considered when interpreting findings in future studies that look at these markers

Correlation of Serum Biomarkers and Magnetic Resonance Spectroscopy in Monitoring Disease Progression in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes Due to mtDNA A3243G Mutation

Background: Analysis of serum biomarkers and magnetic resonance spectroscopy (MRS) are useful for monitoring disease progression in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). We evaluated the correlation of serum biomarkers and MRS parameters during changes associated with stroke-like episodes.Methods: In 13 symptomatic MELAS patients carrying the A3243G mutation, we retrospectively obtained 207 voxels from 41 MRS studies, which were divided into three groups according to the temporal association with stroke-like episodes. The MRS NAA/Cr, Cho/Cr, NAA/Cho ratios, the presence of a lactate peak, serum biomarkers, serum lactate level and the pyruvate (Lac/Pyr) ratio were determined.Results: In regions with acute infarcts, the severity of serum Lac/Pyr and that of the MRS lactate peak (P = 0.0007) correlated; serum lactate (P = 0.02), severity of elevated serum lactate (P = 0.04), and serum Lac/Pyr (P = 0.02) correlated weakly. In previously infarcted regions, the severity of the MRS lactate peak and serum Lac/Pyr (P = 0.03), as well as the severity of serum Lac/Pyr (P = 0.02) were weakly correlated. In structurally normal regions, we found a weak to moderate negative correlation between serum lactate and MRS NAA/Cr (P = 0.008), and between the severity of elevated serum lactate and MRS NAA/Cr (P = 0.002) as well as MRS NAA/Cho (P = 0.02).Conclusions: MRS parameters correlate with specific serum biomarkers, and are useful for monitoring changes in brain metabolites, particularly as related to stroke-like episodes

Effects of Irritable Bowel Syndrome on Daily Activities Vary Among Subtypes Based on Results From the IBS in America Survey

Background & Aims Irritable bowel syndrome (IBS) is associated with significant disease burden and decreased quality of life (QOL). We investigated the effects of IBS on different areas of daily function and compared these among disease subtypes. Methods The Life with IBS survey was conducted by Gfk Public Affairs & Corporate Communications from September through October 2015. Respondents met Rome III criteria for constipation-predominant or diarrhea-predominant IBS (IBS-C and IBS-D, respectively). Data were collected from 3254 individuals (mean age, 47 years; 81% female; and 90% Caucasian) who met IBS criteria. Results Respondents who were employed or in school (n = 1885) reported that IBS symptoms affected their productivity an average of 8.0 days out of the month and they missed approximately 1.5 days of work/school per month because of IBS. More than half the individuals reported that their symptoms were very bothersome. Individuals with IBS-C were more likely than with IBS-D to report avoiding sex, difficulty concentrating, and feeling self-conscious. Individuals with IBS-D reported more avoidance of places without bathrooms, difficulty making plans, avoiding leaving the house, and reluctance to travel. These differences remained when controlling for symptom bothersomeness, age, sex, and employment status. In exchange for 1 month of relief from IBS, more than half of the sample reported they would be willing to give up caffeine or alcohol, 40% would give up sex, 24.5% would give up cell phones, and 21.5% would give up the internet for 1 month. Conclusions Although the perceived effects of IBS symptoms on productivity are similar among its subtypes, patients with IBS-C and IBS-D report differences in specific areas of daily function

Gyejigachulbu-Tang Relieves Oxaliplatin-Induced Neuropathic Cold and Mechanical Hypersensitivity in Rats via the Suppression of Spinal Glial Activation

Activation of spinal glial cells plays a crucial role in the pathogenesis of neuropathic pain. An administration of oxaliplatin, an important anticancer drug, often induces acute neuropathic cold hypersensitivity and/or mechanical hypersensitivity in patients. Gyejigachulbu-tang (GBT), a herbal formula comprising Cinnamomi Cortex, Paeoniae Radix, Atractylodis Lanceae Rhizoma, Zizyphi Fructus, Glycyrrhizae Radix, Zingiberis Rhizoma, and Aconiti Tuber, has been used in East Asia to treat various pain symptoms, especially in cold patients. This study investigated whether and how GBT alleviates oxaliplatin-induced cold and mechanical hypersensitivity in rats. The behavioral signs of cold and mechanical hypersensitivity were evaluated by a tail immersion test in cold water (4°C) and a von Frey hair test, respectively. The significant cold and mechanical hypersensitivity were observed 3 days after an oxaliplatin injection (6 mg/kg, i.p.). Daily oral administration of GBT (200, 400, and 600 mg/kg) for 5 days markedly attenuated cold and mechanical hypersensitivity. Immunoreactivities of glial fibrillary acidic protein (GFAP, astrocyte marker) and OX-42 (microglia marker) in the spinal dorsal horn were significantly increased by an oxaliplatin injection, which were restored by GBT administration. These results indicate that GBT relieves oxaliplatin-induced cold and mechanical hypersensitivity in rats possibly through the suppression of spinal glial activation

Idiopathic acute eosinophilic pneumonia in a 14-month-old girl

Idiopathic acute eosinophilic pneumonia (IAEP), characterized by acute febrile respiratory failure associated with diffuse radiographic infiltrates and pulmonary eosinophilia, is rarely reported in children. Diagnosis is based on an association of characteristic features including acute respiratory failure with fever, bilateral infiltrates on the chest X-ray, severe hypoxemia and bronchoalveolar lavage fluid >25% eosinophils or a predominant eosinophilic infiltrate in lung biopsies in the absence of any identifiable etiology. We present a 14-month-old girl who was admitted to our pediatric intensive care unit because of acute respiratory distress. She had a fever, dry cough, and progressive dyspnea for 1 day. Chest X-ray showed multifocal consolidations, increased interstitial markings, parenchymal emphysema and pneumothorax. IAEP was confirmed by marked pulmonary infiltrates of eosinophils in the lung biopsy specimen. Most known causes of acute eosinophilic pneumonia, such as exposure to causative drugs, toxins, second-hand smoking and infections were excluded. Her symptoms were resolved quickly after corticosteroid therapy

Transcriptome analysis of skeletal muscle in dermatomyositis, polymyositis, and dysferlinopathy, using a bioinformatics approach

BackgroundPolymyositis (PM) and dermatomyositis (DM) are two distinct subgroups of idiopathic inflammatory myopathies. Dysferlinopathy, caused by a dysferlin gene mutation, usually presents in late adolescence with muscle weakness, degenerative muscle changes are often accompanied by inflammatory infiltrates, often resulting in a misdiagnosis as polymyositis.ObjectiveTo identify differential biological pathways and hub genes related to polymyositis, dermatomyositis and dysferlinopathy using bioinformatics analysis for understanding the pathomechanisms and providing guidance for therapy development.MethodsWe analyzed intramuscular ribonucleic acid (RNA) sequencing data from seven dermatomyositis, eight polymyositis, eight dysferlinopathy and five control subjects. Differentially expressed genes (DEGs) were identified by using DESeq2. Enrichment analyses were performed to understand the functions and enriched pathways of DEGs. A protein–protein interaction (PPI) network was constructed, and clarified the gene cluster using the molecular complex detection tool (MCODE) analysis to identify hub genes.ResultsA total of 1,048, 179 and 3,807 DEGs were detected in DM, PM and dysferlinopathy, respectively. Enrichment analyses revealed that upregulated DEGs were involved in type 1 interferon (IFN1) signaling pathway in DM, antigen processing and presentation of peptide antigen in PM, and cellular response to stimuli in dysferlinopathy. The PPI network and MCODE cluster identified 23 genes related to type 1 interferon signaling pathway in DM, 4 genes (PDIA3, HLA-C, B2M, and TAP1) related to MHC class 1 formation and quality control in PM, and 7 genes (HSPA9, RPTOR, MTOR, LAMTOR1, LAMTOR5, ATP6V0D1, and ATP6V0B) related to cellular response to stress in dysferliniopathy.ConclusionOverexpression of genes related to the IFN1 signaling pathway and major histocompatibility complex (MHC) class I formation was identified in DM and PM, respectively. In dysferlinopathy, overexpression of HSPA9 and the mTORC1 signaling pathway genes was detected

Quercetin attenuates fasting and postprandial hyperglycemia in animal models of diabetes mellitus

The objective of this study was to investigate the hypoglycemic effects of quercetin (QE) in animal models of diabetes mellitus (DM). A starch solution (1 g/kg) with and without QE (100 mg/kg) or acarbose (40 mg/kg) was orally administered to streptozotocin (STZ)-induced diabetic rats after an overnight fast. Postprandial plasma glucose levels were measured and incremental areas under the response curve were calculated. To study the effects of chronic feeding of QE, five-week-old db/db mice were fed an AIN-93G diet, a diet containing QE at 0.08%, or a diet containing acarbose at 0.03% for 7 weeks after 1 week of adaptation. Plasma glucose and insulin, blood glycated hemoglobin, and maltase activity of the small intestine were measured. Oral administration of QE (100 mg/kg) or acarbose (40 mg/kg) to STZ-treated rats significantly decreased incremental plasma glucose levels 30-180 min after a single oral dose of starch and the area under the postprandial glucose response, compared with the control group. QE (0.08% of diet) or acarbose (0.03% of diet) offered to db/db mice significantly reduced both plasma glucose and blood glycated hemoglobin compared to controls without significant influence on plasma insulin. Small intestine maltase activities were significantly reduced by consumption of QE or acarbose. Thus, QE could be effective in controlling fasting and postprandial blood glucose levels in animal models of DM

Dual oxidase 1 and NADPH oxidase 2 exert favorable effects in cervical cancer patients by activating immune response

Background Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived reactive oxygen species (ROS) not only can promote cancer progression, but also they have recently emerged as mediators of the mucosal immune system. However, the roles and clinical relevance of the collective or individual NADPH oxidase (NOX) family genes in cervical cancer have not been studied. Methods We investigated the clinical significance of the NOX family genes using data from 307 patients with cervical cancer obtained from The Cancer Genome Atlas. Bioinformatics and experimental analyses were performed to examine NOX family genes in cervical cancer patients. Results Dual Oxidase1 (DUOX1) and Dual Oxidase 2 (DUOX2) mRNA levels were upregulated 57.9- and 67.5-fold, respectively, in cervical cancer patients. The protein expression of DUOX1, DUOX2, and NOX2 also identified in cervical squamous cell carcinoma tissues. Especially, DUOX1 and DUOX2 mRNA levels were significantly increased in patients infected with human papillomavirus (HPV) 16. Moreover, high DUOX1 mRNA levels were significantly associated with both favorable overall survival and disease-free survival in cervical cancer patients. High NOX2 mRNA levels was significantly associated with favorable overall survival. Gene set enrichment analyses revealed that high DUOX1 and NOX2 expression was significantly correlated with the enrichment of immune pathways related to interferon (IFN)-alpha, IFN-gamma, and natural killer (NK) cell signaling. Cell-type identification by estimating relative subsets of known RNA transcript analyses indicated that the fraction of innate immune cells, including NK cells, monocytes, dendritic cells, and mast cells, was elevated in patients with high DUOX1 expression. Conclusions DUOX1 and NOX2 expression are associated with mucosal immunity activated in cervical squamous cell carcinoma and predicts a favorable prognosis in cervical cancer patients.This work was supported by a grant from Korea Institute of Oriental Medicine (K18123), National Research Foundation of Korea funded by the Korean government (NRF-2017R1C1B1004924) and Bio & Medical Technology Development Program of the National Research Foundation (NRF) & funded by the Korean government (NRF-2019M3E5D1A02068557). The funding bodies had no involvement in the design of the study, collection, analysis, and interpretation of data and in writing the manuscript

Hypoglycemic effects of Welsh onion in an animal model of diabetes mellitus

Tight control of blood glucose is the most important strategy for the treatment of diabetes mellitus. Here, we investigated the beneficial effects of Welsh onion on fasting and postprandial hyperglycemia. Inhibitory activities of hot water extracts from the green stalk and white bulb, which are the edible portions of the Welsh onion, and the fibrous root extract against yeast α-glucosidase were measured in vitro. To study the effects of Welsh onion on postprandial hyperglycemia, a starch solution (1 g/kg) with and without Welsh onion fibrous root extract (500 mg/kg) or acarbose (50 mg/kg) was administered to streptozotocin-induced diabetic rats after an overnight fast. Postprandial plasma glucose levels were measured and incremental areas under the response curve were calculated. To study the hypoglycemic effects of chronic feeding of Welsh onion, five-week-old db/db mice were fed an AIN-93G diet or a diet containing either Welsh onion fibrous root extract at 0.5% or acarbose at 0.05% for 7 weeks after 1 week of adaptation. Fasting plasma glucose and blood glycated hemoglobin were measured. Compared to the extract from the edible portions of Welsh onion, the fibrous root extract showed stronger inhibition against yeast α-glucosidase, with an IC50 of 239 µg/mL. Oral administration of Welsh onion fibrous root extract (500 mg/kg) and acarbose (50 mg/kg) significantly decreased incremental plasma glucose levels 30-120 min after oral ingestion of starch as well as the area under the postprandial glucose response curve, compared to the control group (P < 0.01). The plasma glucose and blood glycated hemoglobin levels of the Welsh onion group were significantly lower than those of the control group (P < 0.01), and were not significantly different from those fed acarbose. Thus, we conclude that the fibrous root of Welsh onion is effective in controlling hyperglycemia in animal models of diabetes mellitus

Growth Inhibition and Apoptosis with H31 Metabolites from Marine Bacillus SW31 in Head and Neck Cancer Cells

ObjectivesTo determine whether a novel marine micro-organism with anticancer properties, H31, the metabolic product of Bacillus SW31, has anti-tumor effects on head and neck cancer, and potential for apoptotic-enhancing anti-cancer treatment of affected patients.MethodsThe cell viability and apoptosis assays were performed. Changes in the signal pathway related to apoptosis were investigated. Then, the therapeutic effects of H31 were explored in mouse xenograft model and drug toxicity of H31 was examined in zebrafish model.ResultsWe identified the anticancer activity of H31, a novel metabolic product of Bacillus SW31. Bacillus SW31, a new marine micro-organism, has 70% homology with Bacillus firmus and contains potent cytotoxic bioactivity in head and neck cancer cells using MTT assay. Combined with c-JUN, p53, cytochrome C, and caspase-3, H31 induced apoptosis of KB cells, a head and neck cancer cell line. In a separate in vivo model, tumor growth in C3H/HeJ syngeneic mice was suppressed by H31. In addition, in a zebrafish model used for toxicity testing, a considerable dose of H31 did not result in embryo or neurotoxicity.ConclusionGrowth inhibition and apoptosis were achieved both in vitro and in vivo in head and neck cancer cells after exposure to H31, a metabolite from the marine Bacillus species, without any significant toxicity effects even at considerable H31 dose concentrations