ABSTRACT
The multifunctional influenza virus protein PB1-F2 plays several roles in deregulation of host innate immune responses and is a known immunopathology enhancer of the 1918 influenza pandemic. Here, we show that the 1918 PB1-F2 protein not only interferes with the mitochondria-dependent pathway of type I interferon (IFN) signaling, but also acquired a novel IFN antagonist function by targeting the DEAD-box helicase DDX3, a key downstream mediator in antiviral interferon signaling, toward proteasome-dependent degradation. Interactome analysis revealed that 1918 PB1-F2, but not PR8 PB1-F2, binds to DDX3 and causes its co-degradation. Consistent with intrinsic protein instability as basis for this gain-of-function, internal structural disorder is associated with the unique cytotoxic sequences of the 1918 PB1-F2 protein. Infusing mice with recombinant DDX3 protein completely rescued them from lethal infection with the 1918 PB1-F2-producing virus. Alongside NS1 protein, 1918 PB1-F2 therefore constitutes a potent IFN antagonist causative for the severe pathogenicity of the 1918 influenza strain. Our identification of molecular determinants of pathogenesis should be useful for the future design of new antiviral strategies against influenza pandemics.
Subject(s)
DEAD-box RNA Helicases/metabolism , Influenza, Human/virology , Interferons/metabolism , Orthomyxoviridae/pathogenicity , Viral Proteins/physiology , A549 Cells , Animals , Dogs , Female , HEK293 Cells , History, 20th Century , Humans , Influenza, Human/epidemiology , Influenza, Human/history , Madin Darby Canine Kidney Cells , Mice , Mice, Inbred BALB C , Orthomyxoviridae/metabolism , Pandemics , Proteolysis , Signal Transduction , U937 Cells , Viral Proteins/metabolism , Virulence/physiologyABSTRACT
Serine hydroxymethyltransferase 2 (SHMT2) converts serine into glycine in the mitochondrial matrix, transferring a methyl group to tetrahydrofolate. SHMT2 plays an important role in the maintenance of one-carbon metabolism. Previously, we found a negative correlation between the serine concentration and the progression of fatty liver disease (FLD). However, little is known about the role of SHMT2 in hepatic lipid metabolism. We established SHMT2 knockdown (KD) mouse primary hepatocytes using RNA interference to investigate the role of SHMT2 in lipid metabolism. SHMT2 KD hepatocytes showed decreased lipid accumulation with reduced glycine levels compared to the scramble cells, which was restored upon reintroducing SHMT2. SHMT2 KD hepatocytes showed downregulation of the mTOR/PPARÉ£ pathway with decreased gene expression related to lipogenesis and fatty acid uptake. Pharmacological activation of mTOR or PPARÉ£ overexpression blocked the inhibitory effect of SHMT2 KD on lipid accumulation. We also showed that glycine activated mTOR/PPARÉ£ signaling and identified glycine as a mediator of SHMT2-responsive lipid accumulation in hepatocytes. In conclusion, silencing SHMT2 in hepatocytes ameliorates lipid accumulation via the glycine-mediated mTOR/PPARÉ£ pathway. Our findings underscore the possibility of SHMT2 as a therapeutic target of FLD.
Subject(s)
Glycine Hydroxymethyltransferase , Glycine , Animals , Glycine/metabolism , Glycine Hydroxymethyltransferase/genetics , Glycine Hydroxymethyltransferase/metabolism , Hepatocytes/metabolism , Hydroxymethyl and Formyl Transferases , Lipid Metabolism , Lipids , Mice , PPAR gamma/metabolism , Serine/metabolism , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolismABSTRACT
Chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) are biocidal preservatives and the active ingredients in Kathon CG, which contains ca. 1.5% mixture of CMIT and MIT at a ratio of 3:1 (CMIT/MIT). CMIT/MIT was misused as humidifier disinfectant products, which caused serious health problems in Korea. Here, the vascular effects of CMIT/MIT were investigated to evaluate claims of putative cardiovascular toxicity observed in humidifier disinfectant users. CMIT/MIT did not affect the basal tension of the rat thoracic aorta up to 2.5 µg/mL in myograph experiments. Instead, pretreatment with CMIT/MIT impaired phenylephrine- or 5-hydroxytryptamine-induced vasoconstriction in a range of 0.5-2.5 µg/mL, which was largely irreversible and not recovered by washing out the CMIT/MIT. Similarly, the application of CMIT/MIT to pre-contracted aorta caused a gradual loss of tension. In primary cultured vascular smooth muscle cells (VSMCs), CMIT/MIT caused thiol depletion, which in turn led to cytosolic Zn2+ elevation and reactive oxygen species (ROS) formation. CMIT/MIT-induced shrinkage, detachment, and lysis of VSMCs depending on the concentration and the treatment time. All events induced by CMIT/MIT were prevented by a thiol donor N-acetylcysteine (NAC). Cytolysis could be inhibited by a Zn2+ chelator TPEN and a superoxide scavenger TEMPOL, whereas they did not affect shrinkage and detachment. In accordance with these results, CMIT/MIT-exposed aortas exhibited dissociation and collapse of tissue in histology analysis. Taken together, CMIT/MIT causes functional impairment and tissue damage to blood vessels by depleting thiol and thereby elevating cytosolic Zn2+ and generating ROS. Therefore, exposure to CMIT/MIT in consumer products may be a risk factor for cardiovascular disorders.
Subject(s)
Muscle, Smooth, Vascular/drug effects , Reactive Oxygen Species/metabolism , Sulfhydryl Compounds/metabolism , Thiazoles/toxicity , Zinc/metabolism , Animals , Calcium/metabolism , Cells, Cultured , Disinfectants/toxicity , HEK293 Cells , Humans , Humidifiers , Male , Preservatives, Pharmaceutical/toxicity , Rats , Rats, Sprague-Dawley , Republic of Korea , Vasoconstriction/drug effectsABSTRACT
Microsatellite instability (MSI) is a critical mechanism that drives genetic aberrations in cancer. To identify the entire MS mutation, we performed the first comprehensive genome- and transcriptome-wide analyses of mutations associated with MSI in Korean gastric cancer cell lines and primary tissues. We identified 18,377 MS mutations of five or more repeat nucleotides in coding sequences and untranslated regions of genes, and discovered 139 individual genes whose expression was down-regulated in association with UTR MS mutation. In addition, we found that 90.5% of MS mutations with deletions in gene regions occurred in UTRs. This analysis emphasizes the genetic diversity of MSI-H gastric tumors and provides clues to the mechanistic basis of instability in microsatellite unstable gastric cancers.
Subject(s)
Asian People/genetics , Genome-Wide Association Study , Microsatellite Instability , Mutation , Stomach Neoplasms/genetics , Transcriptome , Cell Line, Tumor , Frameshift Mutation , Gene Expression Regulation, Neoplastic , Gene Frequency , High-Throughput Nucleotide Sequencing , Humans , Microsatellite Repeats , RNA Processing, Post-Transcriptional , RNA Stability , Republic of Korea , Sequence Deletion , Untranslated RegionsABSTRACT
This study aimed to explore the influence of metaverse technology (MT) factors like presence, usability, and enjoyment on patients' satisfaction, with a focus on examining potential mediating effects. In addition, it sought to assess whether the yoga practice as an intervention therapy in MT induces changes in the pain, anxiety, and depression levels of patients experiencing back pain. From the pool of 202 participants, this study chose participants who had reported enduring low back pain over 12 weeks, with a visual analogue scale (VAS) rating of 4 or higher. After completing the questionnaire, patients were randomly assigned to either the control group (COG, n=100) or the yoga exercise group (YEG, n=99). Results showed that the construct validity for questionnaires and a reasonable model fit were confirmed, and that presence showed a statistically significant effect on psychological satisfaction via the mediating path of enjoyment (ß=0.592, P=0.001). Following 8 weeks of the yoga practice, the VAS increased for the COG, while it decreased significantly by ~29% for the YEG (P=0.001). YEG also exhibited a decrease in the Oswestry Disability Index by ~17%, anxiety by ~7%, and depression by ~10% (P=0.001). In conclusion, psychological satisfaction in a yoga practice using a metaverse cannot be achieved solely through the sense of presence; enjoyment is necessary for patients' satisfaction. Moreover, it was verified that virtual yoga practice is effective in ameliorating psychological factors resulting from back pain.
ABSTRACT
Donepezil and tadalafil, commonly prescribed among older persons to treat dementia and erectile dysfunction, respectively, are primarily metabolized by cytochrome P450 (CYP) 3A4. However, the drug-drug interactions (DDIs) of these drugs are unknown. Therefore, this study evaluated the CYP-mediated metabolic interaction between donepezil and tadalafil using pooled human liver microsomes (HLMs) to predict their DDI potential. Donepezil metabolism was tadalafil-concentration dependently changed in HLMs incubated with 0.1 µM donepezil and showed the maximum 32.3% increase in the donepezil half-life at 1 µM tadalafil. The formation rates of donepezil metabolites, such as N-desbenzyl donepezil and 3-hydroxy donepezil, decreased by 28.3% and 30.3%, respectively, in HLMs incubated with 1 µM tadalafil and 0.1 µM donepezil. In contrast, neither the half-life of tadalafil nor the production rate of its metabolite, desmethylene tadalafil, was changed by >20% in the presence of donepezil (up to 1 µM). CYP3A4 activity was inhibited by tadalafil with an IC50 value of 22.6 µM but not by donepezil. After pre-incubating HLMs with tadalafil and NADPH, the tadalafil IC50 value against CYP3A4 was approximately 7.04-fold lower, suggesting time-dependent tadalafil inhibition. This study shows that the DDI between donepezil and tadalafil is primarily due to time-dependent inhibition against CYP3A4 by tadalafil.
ABSTRACT
[This corrects the article DOI: 10.1007/s43188-023-00223-y.].
ABSTRACT
Smoking is a well-established risk factor for various pathologies, including pulmonary diseases, cardiovascular disorders, and cancers. The toxic effects of cigarette smoke (CS) are mediated through multiple pathways and diverse mechanisms. A key pathogenic factor is oxidative stress, primarily induced by excessive formation of reactive oxygen species. However, it remains unclear whether smoking directly induces systemic oxidative stress or if such stress is a secondary consequence. This study aimed to determine whether short-term inhalation exposure to CS induces oxidative stress in extrapulmonary organs in addition to the lung in a murine model. In the experiment, 3R4F reference cigarettes were used to generate CS, and 8-week-old male BALB/c mice were exposed to CS at a total particulate matter concentration of either 0 or 800 µg/L for four consecutive days. CS exposure led to an increase in neutrophils, eosinophils, and total cell counts in bronchoalveolar lavage fluid. It also elevated levels of lactate dehydrogenase and malondialdehyde (MDA), markers indicative of tissue damage and oxidative stress, respectively. Conversely, no significant changes were observed in systemic oxidative stress markers such as total oxidant scavenging capacity, MDA, glutathione (GSH), and the GSH/GSSG ratio in blood samples. In line with these findings, CS exposure elevated NADPH oxidase (NOX)-dependent superoxide generation in the lung but not in other organs like the liver, kidney, heart, aorta, and brain. Collectively, our results indicate that short-term exposure to CS induces inflammation and oxidative stress in the lung without significantly affecting oxidative stress in extrapulmonary organs under the current experimental conditions. NOX may play a role in these pulmonary-specific events.
ABSTRACT
Gastric cancer (GC) is the fourth most common cancer worldwide. In spite of the mortality incidence associated with GC, no reliable prognostic biomarkers are currently available for this malignancy. The sulfatases (or SULFs), SULF1 and SULF2, play a critical role in the pathogenesis of a variety of human cancers. We sought to evaluate the potential of SULFs as biomarkers for GC. Thirty pairs of GC and corresponding normal tissues were analysed for the expression and methylation status of SULFs. Furthermore, the functional role of SULF overexpression was investigated in GC cell lines and tumour xenograft animal models. Lastly, we validated the expression of SULF1 protein in a large cohort of 450 GC patients. GC tissues showed conspicuously higher expression of SULF1 (p = 0.0002) and SULF2 (p = 0.001) compared to normal mucosa, which was correlated with its promoter hypomethylation. Furthermore, high expression of SULFs caused marked acceleration in the growth of xenograft tumours in nude mice. The expression of SULF1 protein significantly correlated with higher recurrence rates (p = 0.0002) and worse overall survival (p < 0.0001) in GC patients. Multivariate analysis revealed that SULF1 is an independent prognostic (p = 0.0123) and lymph node metastasis predictive factor (p = 0.0003) in patients with GC. We provide novel evidence that hypomethylation of promoter CpG islands within SULF genes imparts them with oncogenic potential in GC. Moreover, our data suggest that SULF1 may serve as a promising biomarker for patients with GC.
Subject(s)
Adenocarcinoma/enzymology , Biomarkers, Tumor/metabolism , Stomach Neoplasms/enzymology , Sulfotransferases/metabolism , Adenocarcinoma/diagnosis , Adenocarcinoma/mortality , Aged , Animals , Cell Line, Tumor , CpG Islands/genetics , DNA Methylation , Female , Gastric Mucosa/metabolism , Gene Expression Regulation, Neoplastic , Humans , Lymph Nodes/pathology , Lymphatic Metastasis , Male , Mice , Mice, Inbred C57BL , Mice, Nude , Middle Aged , Neoplasm Staging , Neoplasms, Experimental/enzymology , Neoplasms, Experimental/pathology , Prognosis , Stomach Neoplasms/diagnosis , Stomach Neoplasms/mortality , Sulfatases , Survival Rate , Tissue Array Analysis , Up-Regulation , Xenograft Model Antitumor Assays/methodsABSTRACT
The prognosis of peritoneal carcinomatosis is regarded as poor because safe, effective therapeutic modalities are lacking. Intraperitoneal chemotherapy is one treatment option, involving the delivery of a high concentration of chemotherapeutic drugs into the abdominal cavity, but the severe side effects associated with such treatment are a major obstacle in clinical application. We evaluated the anti-cancer effects of intraperitoneal delivery of a thermosensitive polymeric hydrogel containing chemotherapeutics in an animal model of carcinomatosis. The progress of peritoneal carcinomatosis, introduced by injecting a luciferase-transfected human gastric cancer cell line (HSC44Luc) into the peritoneal cavity of nude mice, was quantitatively evaluated by in vivo bioluminescence imaging. Three days after intraperitoneal (IP) injection of HSC44Luc cells, treatment solutions were injected into the peritoneal cavity. Mice were categorized into four groups depending on treatment method; these were (1) a control PBS group (n = 5), (2) a hydrogel-only group (n = 5), (3) a paclitaxel solution (30 mg/kg) group (n = 3), and (4) a hydrogel-with-paclitaxel (15 mg/kg) group (n = 5). Quantitative photon counting was performed weekly in each animal. Mice were sacrificed on the 5th or 28th day after treatment, for pathologic evaluation. In vivo bioluminescence imaging showed that photon counts in the hydrogel-with-paclitaxel and paclitaxel solution groups were significantly lower than in the PBS group over the entire experimental period. Although neither group of responding mice showed any peritoneal nodules on the 28th day after treatment, only the paclitaxel solution group exhibited dilated edematous changes in the intestine; these side effects were absent in animals treated with hydrogel-with-paclitaxel group. In conclusion, a thermosensitive hydrogel containing paclitaxel may be a safe and effective treatment option for peritoneal carcinomatosis.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Carcinoma/drug therapy , Drug Carriers , Hydrogels , Paclitaxel/pharmacology , Peritoneal Neoplasms/prevention & control , Polymers/chemistry , Stomach Neoplasms/drug therapy , Temperature , Animals , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/chemistry , Carcinoma/genetics , Carcinoma/metabolism , Carcinoma/secondary , Cell Line, Tumor , Chemistry, Pharmaceutical , Female , Humans , Luciferases, Firefly/biosynthesis , Luciferases, Firefly/genetics , Luminescent Measurements , Mice , Mice, Inbred BALB C , Mice, Nude , Paclitaxel/administration & dosage , Paclitaxel/chemistry , Peritoneal Neoplasms/genetics , Peritoneal Neoplasms/metabolism , Peritoneal Neoplasms/secondary , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Time Factors , Transfection , Xenograft Model Antitumor AssaysABSTRACT
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare, potentially life-threatening, delayed, drug-induced hypersensitivity reaction. Immediate withdrawal of the culprit drug and administration of systemic corticosteroids is the most widely accepted treatment. However, it is difficult to manage patients with DRESS syndrome who are not responsive to systemic steroids. We studied the efficacy of intravenous immunoglobulins (IVIGs) in patients with DRESS syndrome unresponsive to systemic steroids. We retrospectively reviewed patients with DRESS syndrome who received IVIG in addition to systemic steroids during 2012-2017 and compared the clinical features and course of DRESS syndrome, before and after IVIG treatment. Eighteen DRESS patients (9 men) were included. The most frequent offending drugs were dapsone in five patients, followed by vancomycin in three patients, and carbamazepine in three patients. Rash, fever, lymphadenopathy, atypical lymphocytes, and hepatic involvement were common clinical findings. IVIG treatment was added within a median time of 7 days from the commencement of systemic steroid therapy. After IVIG treatment (total dosage: 1-2 g/kg), the fever resolved within a median time of 1 day (range, 0-3) and liver enzymes improved substantially within a median time of 13 days (range, 0-27). No severe adverse reactions related to IVIG therapy were observed in this study; however, there was one case of mortality. The addition of IVIG in DRESS syndrome in cases refractory to systemic steroid treatment may be helpful in hastening recovery. However, comparative studies using a placebo group are needed.
Subject(s)
Drug Hypersensitivity Syndrome , Eosinophilia , Drug Hypersensitivity Syndrome/diagnosis , Drug Hypersensitivity Syndrome/drug therapy , Drug Hypersensitivity Syndrome/etiology , Eosinophilia/chemically induced , Eosinophilia/diagnosis , Eosinophilia/drug therapy , Female , Humans , Immunoglobulins, Intravenous/adverse effects , Male , Retrospective Studies , Steroids/adverse effectsABSTRACT
BACKGROUND: This study investigated the daily lifestyle changes, prevalence of psychological depression, physical health status, and immunity of adolescents in Korea resulting from increased isolation and social restriction due to the COVID-19 pandemic. MATERIALS AND METHODS: All subjects included 17-year-old male adolescents. A total of 117 subjects were assigned to one of four groups according to the degree of depression based on item #6 in the Center for Epidemiologic Studies Depression (CES-D) questionnaire as follows: no-depression group (NDG, n = 71; 61.0%), low-depression group (LDG, n = 23; 19.0%), moderate-depression group (MDG, n = 15; 13.0%), and high-depression group (HDG, n = 8; 7.0%). This study analyzed the data using quantitative and qualitative methods to understand how the COVID-19 pandemic affects adolescents' daily lives, psychophysiological conditions, and immune function. RESULTS: This study found that the COVID-19 pandemic significantly affects the daily lifestyle pattern, psychophysical condition, and immunocytes of adolescents. In terms of depression, 39.0% of adolescents felt depressed, and 7% of them felt depressed almost every day. Overall, HDG considered themselves unhealthy and felt prone to immune diseases, such as colds. HDG were prone to sleep late, eat more frequently, and work out less. Regarding physical fitness factors, the cardiorespiratory endurance, strength, and power of HDG were significantly lower than those of NDG, LDG, and MDG. Moreover, HDG had the worst body composition, including the lowest muscle mass. Finally, natural killer (NK) cells and T cells were significantly different among groups, with the levels in HDG being significantly lower than those of the other three groups. CONCLUSIONS: Since the COVID-19 pandemic negatively affects the daily lives, psychophysical conditions, and immunocytes of adolescents, there is an urgent need to create and provide solutions to adolescents with depression though the number of subjects is few.
ABSTRACT
BACKGROUND: Chuna Manual Therapy (CMT) has been widely used in Korea, and coverage in Korean National Health Insurance (NHI) was finally implemented in 2019. The objectives of this study were to analyze the process of NHI coverage for CMT qualitatively, and to summarize important roles, streams, and implications regarding its inclusion in the modern public health insurance system. METHODS: Related literature was collected and 8 key personnel involved in the policy-making process were qualitatively interviewed, and Zahariadis' version of the Multiple Streams Framework (MSF) was applied to analyze the policy agenda setting and the roles of stakeholders. RESULTS: Through the collaborative efforts of various stakeholders, a pilot coverage project for CMT was implemented in 2017, and coverage was expanded nationwide in 2019. MSF showed that it was mainly achieved through three streams: governmental change (political stream), demand from the general public and KM doctors (problem stream), and strengthening/reinforcement of the feasibility and acceptability of the policy (policy steam). Also, the roles of policy entrepreneurs and resulting changes were shown to be significant for the overall process. CONCLUSION: NHI coverage for CMT was realized through collective policy and research efforts from the government and academic sectors. The roles of stakeholders were shown to be significant in the overall process, and documentation of their involvement is hoped to be of use of other countries that utilize traditional and/or manual medicine.
ABSTRACT
BACKGROUND: Manipulation and improper handling of a tumor during surgery may increase the risk of cancer cell dissemination after a curative gastrectomy. This study investigated the effect of improper handling of lymphovascular pedicles of stomach on tumor spillage during surgical procedure. METHODS: Thirty-eight gastric cancer patients were enrolled. Three pairs of wash samples were obtained from each patient: (1) intraperitoneal wash samples obtained before (P0) and after gastrectomy (P1), (2) intragastric wash samples obtained before any manipulation (G0) and just before resection of the stomach (G1), and (3) ex vivo wash samples obtained by rinsing resected stomach with the lymphovascular pedicles closed by clips (S0) or with the pedicles open (S1). Cytologic examination was performed from all washes, and real-time reverse transcriptase-polymerase chain reaction analysis for carcinoembryonic antigen was performed from washes P0, P1, S0, and S1. RESULTS: Cytologic examination detected cancer cells in 34.2% (13 of 38) of G0 samples and in 39.5% (15 of 38) of G1 samples. The rate of conversion from G0-negative to G1-positive increased as T stage increased. Cytologic examination detected cancer cells in 2.6% (1 of 38) of S0 samples and in 13.2% (5 of 38) of S1 samples. The carcinoembryonic antigen mRNA level of the S1 sample was 2-fold greater than that of the S0 sample in 50.0% (7 of 14). CONCLUSIONS: Free cancer cells can be released from gastric lumen or lymphovascular pedicles opened during gastric cancer surgery, especially in advanced-stage disease. Care should be taken to minimize spillage from the gastric lumen and lymphovascular pedicles.
Subject(s)
Gastrectomy , Neoplasm Seeding , Neoplastic Cells, Circulating/pathology , Peritoneal Neoplasms/surgery , Stomach Neoplasms/surgery , Vascular Neoplasms/surgery , Carcinoembryonic Antigen/analysis , Cytodiagnosis , Female , Humans , Immunoenzyme Techniques , Lymphatic Metastasis , Male , Middle Aged , Neoplastic Cells, Circulating/metabolism , Peritoneal Lavage , Peritoneal Neoplasms/secondary , Prognosis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Stomach Neoplasms/pathology , Vascular Neoplasms/secondaryABSTRACT
microRNAs (miRNAs) play integral roles in diverse processes including tumorigenesis. miRNA gene loci are often found in close conjunction, and such clustered miRNA genes are transcribed from a common promoter to generate polycistronic primary transcript. The primary transcript (pri-miRNA) is then processed by two RNase III proteins to release the mature miRNAs. Although it has been speculated that the miRNAs in the same cluster may play related biological functions, this has not been experimentally addressed. Here we report that the miRNAs in two clusters (miR-106b approximately 93 approximately 25 and miR-222 approximately 221) suppress the Cip/Kip family members of Cdk inhibitors (p57(Kip2), p21(Cip1) and p27(Kip1)). We show that miR-25 targets p57 through the 3'-UTR. Furthermore, miR-106b and miR-93 control p21 while miR-222 and miR-221 regulate both p27 and p57. Ectopic expression of these miRNAs results in activation of Cdk2 and facilitation of G1/S phase transition. Consistent with these results, both clusters are abnormally upregulated in gastric cancer tissues compared to the corresponding normal tissues. Ectopic expression of miR-222 cluster enhanced tumor growth in the mouse xenograft model. Our study demonstrates the functional associations between clustered miRNAs and further implicates that effective cancer treatment may require a combinatorial approach to target multiple oncogenic miRNA clusters.
Subject(s)
Cyclin-Dependent Kinase Inhibitor Proteins/genetics , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , MicroRNAs/metabolism , Multigene Family , Stomach Neoplasms/genetics , Animals , Cell Cycle/genetics , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Cyclin-Dependent Kinase Inhibitor p27 , Cyclin-Dependent Kinase Inhibitor p57/genetics , Cyclin-Dependent Kinase Inhibitor p57/metabolism , Gene Expression Profiling , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Nude , Stomach Neoplasms/metabolismABSTRACT
Body homeostasis is predominantly controlled by hormones secreted by endocrine organs. The central nervous system contains several important endocrine structures, including the hypothalamic-pituitary axis. Conventionally, neurohormones released by the hypothalamus and the pituitary gland (hypophysis) have received much attention owing to the unique functions of the end hormones released by their target peripheral organs (e.g., glucocorticoids released by the adrenal glands). Recent advances in mouse genetics have revealed several important metabolic functions of hypothalamic neurohormone-expressing cells, many of which are not readily explained by the action of the corresponding classical downstream hormones. Notably, the newly identified functions are better explained by the action of conventional neurotransmitters (e.g., glutamate and GABA) that constitute a neuronal circuit. In this review, we discuss the regulation of appetite and metabolism by hypothalamic neurohormone-expressing cells, with a focus on the distinct contributions of neurohormones and neurotransmitters released by these neurons.
Subject(s)
Appetite/physiology , Energy Metabolism , Neurosecretory Systems/physiology , Animals , Homeostasis , Humans , Hypothalamo-Hypophyseal System/metabolism , Hypothalamus/metabolism , Neuroendocrine Cells/immunology , Neuroendocrine Cells/metabolism , Neurons/metabolism , Neurotransmitter Agents/metabolism , Thyroid Gland/metabolismABSTRACT
This study investigated the effects of participating in an educational exercise program on physical fitness and gross motor function (GMF) in adults with varying degrees of autistic spectrum disorder (ASD). The subjects consisted of 35 voluntary male participants between 20 and 29 years of age who were allocated to one of two groups: mild ASD (n=17) group and severe ASD (n=18) group. All selected tests for physical fitness, including body composition and GMF, have been used in previous studies. The results were as follows: first, with the exception of the basal metabolic rate, there were significant differences in the interaction of all other body composition variables. Second, there were significant differences in the interaction of almost all physical fitness variables, except for muscle strength. Finally, although there were significant differences in the interaction of all variables, except the locomotion skill for hopping, there were significant differences in the interaction of all variables of object control skill. Specifically, although the Δ% in the sum of locomotion skill in mild ASD group increased ~19.81%, that of severe ASD group decreased ~4.78%. The Δ% in the sum of object control skill in mild ASD group improved ~29.96%, while that of severe ASD group reduced ~15.2%. In conclusion, it is thought that these results are due to the better understanding of educational exercise and better performance of educational exercise in adults with mild ASD compared to adults with severe ASD.
ABSTRACT
RATIONALE: Hepatocellular carcinomas (HCCs) with metastases to the right atrium (RA) and lungs are rare, with a poor prognosis. Furthermore, the treatment outcomes in patients with advanced HCCs remain unsatisfactory. PATIENT CONCERNS: A 46-year-old man presented to our hospital for dyspnea on exertion and abdominal pain. DIAGNOSES: HCC and extra-hepatic metastases to the lung and RA. INTERVENTIONS: Multidisciplinary treatment including radiotherapy (RT), transarterial chemoembolization (TACE), and sorafenib. During a follow-up evaluation computed tomography, he experienced a radio-contrast-induced anaphylaxis. After the event, treatment such as RT, TACE, and sorafenib were continued. OUTCOMES: His tumor burden decreased, finally leading to a complete response as per the modified Response Evaluation Criteria in Solid Tumors. The patient is still alive, 30 months after the episode. Subsequent blood tests showed increased natural killer (NK) cell activity, which was significantly higher than that seen in other age-matched HCC patients with an identical stage of the tumor, receiving sorafenib. This suggests that the increase in NK cells induced by anaphylaxis influenced the tumor burden. LESSONS: We report here a rare case of long-term survival of an HCC patient with multiple metastases treated with multidisciplinary modalities, in which high NK cell activity was observed after a radio-contrast-induced anaphylactic reaction during follow-up investigations.
Subject(s)
Antineoplastic Protocols , Carcinoma, Hepatocellular/therapy , Heart Neoplasms/therapy , Liver Neoplasms/therapy , Lung Neoplasms/therapy , Antineoplastic Agents/administration & dosage , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/secondary , Chemoembolization, Therapeutic/methods , Combined Modality Therapy/methods , Heart Atria/pathology , Heart Neoplasms/pathology , Heart Neoplasms/secondary , Humans , Killer Cells, Natural/drug effects , Killer Cells, Natural/radiation effects , Liver Neoplasms/pathology , Lung/pathology , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Male , Middle Aged , Niacinamide/administration & dosage , Niacinamide/analogs & derivatives , Phenylurea Compounds/administration & dosage , Radiotherapy, Adjuvant/methods , Remission Induction/methods , Response Evaluation Criteria in Solid Tumors , Sorafenib , Tumor BurdenABSTRACT
Porcine reproductive and respiratory syndrome virus (PRRSV) infection is difficult to control because the virus undergoes antigenic variation during infection and also modulates the protective host immune response. Although current vaccines do not provide full protection, they have provided insight into the mechanisms of protection. Live PRRSV vaccines induce partial protection before the appearance of neutralizing antibody, suggesting cell-mediated immunity or other mechanisms may be involved. Herein, we demonstrate recovery from infection is associated with development of cytotoxic T-lymphocytes (CTL) that can kill PRRSV-infected target cells. Initial experiments showed survival of PRRSV-infected monocyte derived macrophage (MDM) targets is reduced when overlaid with peripheral blood mononuclear cells (PBMC) from gilts that had recovered from PRRSV infection. Further studies with PBMC depleted of either CD4+ or CD8+ T-cells and positively selected subpopulations of CD4+ and CD8+ T-cells showed that both CD4+ and CD8+ T-cells were involved in killing. Examination of killing at different time points revealed killing was biphasic and mediated by CTL of different phenotypes. CD4+CD8+high were associated with killing target cells infected for 3-6 hours. CD4+CD8- CTL were associated with killing at 16-24 hours. Thus, all the anti-PRRSV CTL activity in pigs was attributed to two phenotypes of CD4+ cells which is different from the anti-viral CD4-CD8+ CTL phenotype found in most other animals. These findings will be useful for evaluating CTL responses induced by current and future vaccines, guiding to a novel direction for future vaccine development.