-
Chonnam Medical Journal May 2016Nitric oxide (NO) is synthesized by a family of NO synthases (NOS), including neuronal, inducible, and endothelial NOS (n/i/eNOS). NO-mediated effects can be beneficial... (Review)
Review
Nitric oxide (NO) is synthesized by a family of NO synthases (NOS), including neuronal, inducible, and endothelial NOS (n/i/eNOS). NO-mediated effects can be beneficial or harmful depending on the specific risk factors affecting the disease. In hypertension, the vascular relaxation response to acetylcholine is blunted, and that to direct NO donors is maintained. A reduction in the activity of eNOS is mainly responsible for the elevation of blood pressure, and an abnormal expression of iNOS is likely to be related to the progression of vascular dysfunction. While eNOS/nNOS-derived NO is protective against the development of atherosclerosis, iNOS-derived NO may be proatherogenic. eNOS-derived NO may prevent the progression of myocardial infarction. Myocardial ischemia/reperfusion injury is significantly enhanced in eNOS-deficient animals. An important component of heart failure is the loss of coronary vascular eNOS activity. A pressure-overload may cause severer left ventricular hypertrophy and dysfunction in eNOS null mice than in wild-type mice. iNOS-derived NO has detrimental effects on the myocardium. NO plays an important role in regulating the angiogenesis and slowing the interstitial fibrosis of the obstructed kidney. In unilateral ureteral obstruction, the expression of eNOS was decreased in the affected kidney. In triply n/i/eNOS null mice, nephrogenic diabetes insipidus developed along with reduced aquaporin-2 abundance. In chronic kidney disease model of subtotal-nephrectomized rats, treatment with NOS inhibitors decreased systemic NO production and induced left ventricular systolic dysfunction (renocardiac syndrome).
PubMed: 27231671
DOI: 10.4068/cmj.2016.52.2.81 -
Frontiers in Oncology 2020mutations are widespread in human cancers. An expanding body of evidence highlights that, in addition to their manifold cell-intrinsic activities boosting tumor... (Review)
Review
mutations are widespread in human cancers. An expanding body of evidence highlights that, in addition to their manifold cell-intrinsic activities boosting tumor progression, missense p53 mutants enhance the ability of tumor cells to communicate amongst themselves and with the tumor stroma, by affecting both the quality and the quantity of the cancer secretome. In this review, we summarize recent literature demonstrating that mutant p53 enhances the production of growth and angiogenic factors, inflammatory cytokines and chemokines, modulates biochemical and biomechanical properties of the extracellular matrix, reprograms the cell trafficking machinery to enhance secretion and promote recycling of membrane proteins, and affects exosome composition. All these activities contribute to the release of a promalignant secretome with both local and systemic effects, that is key to the ability of mutant p53 to fuel tumor growth and enable metastatic competence. A precise knowledge of the molecular mechanisms underlying the interplay between mutant p53 and the microenvironment is expected to unveil non-invasive biomarkers and actionable targets to blunt tumor aggressiveness.
PubMed: 33505920
DOI: 10.3389/fonc.2020.614230 -
JCPP Advances Dec 2022Mind-wandering has been linked to negative affect and depressive symptoms in adolescents. However, mind-wandering is an extremely broad and heterogenous cognitive...
BACKGROUND
Mind-wandering has been linked to negative affect and depressive symptoms in adolescents. However, mind-wandering is an extremely broad and heterogenous cognitive construct. Some features of spontaneous thought may be related to increased negative affect, whereas others may improve affect, or have no emotional influence. We used ecological momentary assessment (EMA) to investigate the characteristics of spontaneous thoughts in adolescents and their differential relations with moment-to-moment affect.
METHOD
One-hundred and sixteen adolescents (ages 13-18; Typical Mood (TM) = 58; Low Mood (LM) = 58) completed 5 days (2-3 times/day) of EMA (total 1,037 surveys) assessing current positive and negative affect (PA and NA) and dimensions of spontaneous thought. Multilevel models tested the relation between thought characteristics and affect.
RESULTS
Relative to the TM group, LM adolescents had a higher frequency of mind-wandering (38% vs. 56%) and negatively-valanced thoughts during episodes of mind-wandering (21% vs. 37%). Negatively-valenced, self-referential and past-oriented thoughts were each associated with higher NA, even when controlling for plausible confounds (e.g., engagement in an unpleasant activity or social interaction, depressive symptom severity). In contrast, task-focused and positively-valenced thoughts were uniquely linked to higher PA.
CONCLUSION
Characteristics of spontaneous thought - including temporal orientation, self-referential quality, and task-relatedness - were differentially related to NA vs. PA in adolescents. If replicated, these findings could inform more nuanced assessments of and targeted interventions for specific dimensions of mind-wandering contributing to high NA vs. blunted PA in teens.
PubMed: 36817188
DOI: 10.1002/jcv2.12110 -
Journal of Psychiatric Research Jun 2022Clinical interviews and laboratory-based emotional induction paradigms provide consistent evidence that facial affect is blunted in many individuals with schizophrenia....
Clinical interviews and laboratory-based emotional induction paradigms provide consistent evidence that facial affect is blunted in many individuals with schizophrenia. Although it is clear that blunted facial affect is not a by-product of diminished emotional experience in schizophrenia, factors contributing to blunted affect remain unclear. The current study used a combination of ambulatory video recordings that were evaluated via computerized facial affect analysis and concurrently completed ecological momentary assessment surveys to assess whether blunted affect reflects insufficient reactivity to affective or contextual factors. Specifically, whether individuals with schizophrenia require more intense affective experiences to produce expression, or whether they are less reactive to social factors (i.e. being in the presence of others, social motivation). Participants included outpatients with schizophrenia (n = 33) and healthy controls (n = 31) who completed six days of study procedures. Multilevel linear models were evaluated using both Null-Hypothesis Statistical Testing and Bayesian analyses. Individuals with schizophrenia displayed comparable expression of positive and negative emotion to controls during daily life, and no evidence was found for a different intensity of experience required for expression in either group. However, social factors differentially influenced facial expression in schizophrenia compared to controls, such that individuals with schizophrenia did not modulate their expressions based on social motivation to the same extent as controls. These findings suggest that social motivation may play an important role in determining when blunting occurs.
Topics: Bayes Theorem; Emotions; Facial Expression; Humans; Schizophrenia; Social Factors; Video Recording
PubMed: 35366600
DOI: 10.1016/j.jpsychires.2022.03.024 -
Frontiers in Psychology 2023Cardiovascular reactivity refers to changes in blood pressure and heart rate in response to internal or external stimuli. Previous research has shown that excessively...
INTRODUCTION
Cardiovascular reactivity refers to changes in blood pressure and heart rate in response to internal or external stimuli. Previous research has shown that excessively high and low cardiovascular reactivity are associated with an increased risk of cardiac problems. Dispositional optimism has been associated with numerous health benefits, including better cardiovascular responses to stressors, and reduced mortality risk. Conversely, pessimism has been associated with negative health outcomes and worse cardiovascular reactivity to stress. Mood, comprising positive and negative affect, can significantly impact psychological adjustment and physical health. Therefore, it is important to consider mood as a potential confounding variable in the link between optimism and cardiovascular reactivity. The study hypothesized that optimism and pessimism would still influence cardiovascular reactivity even when mood variables were controlled for.
METHODS
A within-subjects correlational design with 107 young adult participants was used. Sociodemographic and clinical questionnaires were administered to collect information on participants' characteristics. The Dispositional Optimism Scale (LOT-R) and the Positive and Negative Affect Scale (PANAS) were used to assess participants' levels of optimism, pessimism, and mood. Measures of cardiovascular reactivity, including systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR), were taken during a stressor task (PASAT).
RESULTS
There is a moderate positive correlation between dispositional optimism and positive affect, while pessimism demonstrated a moderate positive association with negative affect. Linear regression analyses were conducted, controlling baseline reactivity variables, gender, and body mass index. The results showed that pessimism had a significant negative effect on SBP reactivity, suggesting that higher levels of pessimism decreased SBP response. Optimism had a significant positive effect on DBP reactivity, while pessimism had a significant negative effect.
DISCUSSION
Overall, these results suggest that dispositional optimism and pessimism are related to cardiovascular reactivity, even after controlling for positive and negative affect. Pessimism was associated with lower SBP reactivity, while both optimism and pessimism influenced DBP reactivity. These findings are consistent with previous research indicating that optimism enables more effective stress management during challenging events, whereas pessimism can serve as a risk factor, heightening the likelihood of experiencing future cardiac issued caused by blunted cardiovascular reactivity.
PubMed: 37908813
DOI: 10.3389/fpsyg.2023.1233900 -
Histopathology Jan 2015Tropical sprue (TS) is a malabsorption syndrome of presumed infectious aetiology that affects residents of (or visitors to) the tropics. The histological changes of TS... (Review)
Review
Tropical sprue (TS) is a malabsorption syndrome of presumed infectious aetiology that affects residents of (or visitors to) the tropics. The histological changes of TS are similar to those of coeliac disease, with increased intraepithelial lymphocytes being central to both. Unlike in coeliac disease, however, a completely flat small bowel biopsy is uncommon in TS. TS typically involves the terminal ileum, whereas coeliac disease does not. Small intestinal bacterial overgrowth (SIBO) has been defined as an increase in number and/or a change in the type of bacteria in the upper gut. Conditions that predispose to SIBO are largely those that decrease or interfere with small bowel motility. The mucosal histology is variable, and may include modest villous blunting accompanied by increased lamina propria and epithelial inflammation. Autoimmune enteropathy (AE) is a family of rare diseases that share common themes such as immunodeficiency states and autoantibodies. AE cases typically have marked villous atrophy similar to that in fully developed coeliac disease, but they lack the intense surface epithelial lymphocytosis. Apoptosis and lymphocyte infiltration at the base of the crypts, crypt abscesses and cryptitis are also seen. Patients with anti-goblet cell antibodies can have a lack of goblet cells, endocrine cells, and Paneth cells.
Topics: Biopsy; Blind Loop Syndrome; Humans; Intestine, Small; Polyendocrinopathies, Autoimmune; Sprue, Tropical
PubMed: 25234408
DOI: 10.1111/his.12522 -
Annals of General Psychiatry Jul 2022Aberrant salience is a well-known construct associated with the development and maintenance of psychotic symptoms in schizophrenia. However, only a few studies have...
BACKGROUND
Aberrant salience is a well-known construct associated with the development and maintenance of psychotic symptoms in schizophrenia. However, only a few studies have investigated aberrance salience as a trait, with no study investigating the association between the five aberrant salience domains and psychotic symptoms. We aimed to explore the role of aberrant salience and its domains on psychotic dimensions in both clinically remitted and non-remitted patients.
METHODS
A sample of 102 patients diagnosed with schizophrenia spectrum disorders was divided according to the Positive and Negative Syndrome Scale (PANSS) remission criteria into two groups: remitted and non-remitted. Differences regarding psychotic symptomatology assessed by the PANSS and aberrant salience measured by the Aberrant Salience Inventory (ASI) were explored. Finally, a correlation analysis between the PANSS and the ASI was run.
RESULTS
Significantly higher ASI scores were evident among non-remitted patients. Positive symptoms (i.e. delusions, conceptual disorganization, and hallucinatory behaviour) and general psychopathology (i.e. postural mannerisms, unusual thought content) were correlated to the aberrant salience subscales 'sharpening of senses', 'heightened emotionality' and 'heightened cognition' and with the ASI total score. Significant correlations emerged between negative symptoms (blunted affect and social withdrawal) and 'heightened cognition'. Finally, lack of spontaneity of conversation was related to the subscales 'heightened emotionality' and 'heightened cognition', as well as to the ASI total score.
CONCLUSIONS
These preliminary results support the hypothesis of an association between aberrant salience and psychotic symptoms in schizophrenia. Further research is needed, especially into the mechanisms underlying salience processing, in addition to social and environmental factors and cognitive variables.
PubMed: 35786401
DOI: 10.1186/s12991-022-00402-5 -
Breast Cancer Research : BCR Jul 2023The receptor for advanced glycation end products (RAGE) is implicated in diabetes and obesity complications, as well as in breast cancer (BC). Herein, we evaluated...
The receptor for advanced glycation end products (RAGE) is implicated in diabetes and obesity complications, as well as in breast cancer (BC). Herein, we evaluated whether RAGE contributes to the oncogenic actions of Insulin, which plays a key role in BC progression particularly in obese and diabetic patients. Analysis of the publicly available METABRIC study, which collects gene expression and clinical data from a large cohort (n = 1904) of BC patients, revealed that RAGE and the Insulin Receptor (IR) are co-expressed and associated with negative prognostic parameters. In MCF-7, ZR75 and 4T1 BC cells, as well as in patient-derived Cancer-Associated Fibroblasts, the pharmacological inhibition of RAGE as well as its genetic depletion interfered with Insulin-induced activation of the oncogenic pathway IR/IRS1/AKT/CD1. Mechanistically, IR and RAGE directly interacted upon Insulin stimulation, as shown by in situ proximity ligation assays and coimmunoprecipitation studies. Of note, RAGE inhibition halted the activation of both IR and insulin like growth factor 1 receptor (IGF-1R), as demonstrated in MCF-7 cells KO for the IR and the IGF-1R gene via CRISPR-cas9 technology. An unbiased label-free proteomic analysis uncovered proteins and predicted pathways affected by RAGE inhibition in Insulin-stimulated BC cells. Biologically, RAGE inhibition reduced cell proliferation, migration, and patient-derived mammosphere formation triggered by Insulin. In vivo, the pharmacological inhibition of RAGE halted Insulin-induced tumor growth, without affecting blood glucose homeostasis. Together, our findings suggest that targeting RAGE may represent an appealing opportunity to blunt Insulin-induced oncogenic signaling in BC.
Topics: Female; Humans; Breast Neoplasms; Insulin; Proteomics; Receptor for Advanced Glycation End Products; Signal Transduction
PubMed: 37461077
DOI: 10.1186/s13058-023-01686-5 -
PloS One 2022Messenger RNA (mRNA) translation can lead to higher rates of mRNA decay, suggesting the ribosome plays a role in mRNA destruction. Furthermore, mRNA features, such as...
Messenger RNA (mRNA) translation can lead to higher rates of mRNA decay, suggesting the ribosome plays a role in mRNA destruction. Furthermore, mRNA features, such as codon identities, which are directly probed by the ribosome, correlate with mRNA decay rates. Many amino acids are encoded by synonymous codons, some of which are decoded by more abundant tRNAs leading to more optimal translation and increased mRNA stability. Variable translation rates for synonymous codons can lead to ribosomal collisions as ribosomes transit regions with suboptimal codons, and ribosomal collisions can promote mRNA decay. In addition to different translation rates, the presence of certain codons can also lead to higher or lower rates of amino acid misincorporation which could potentially lead to protein misfolding if a substituted amino acid fails to make critical contacts in a structure. Here, we test whether Geneticin-G418, an aminoglycoside antibiotic known to promote amino acid misincorporation-affects mRNA stability. We observe that G418 decreases firefly luciferase mRNA stability in an in vitro translation system and also reduces mRNA stability in mouse embryonic stem cells (mESCs). G418-sensitive mRNAs are enriched for certain optimal codons that contain G or C in the wobble position, arguing that G418 blunts the stabilizing effects of codon optimality.
Topics: Amino Acids; Animals; Codon; Gentamicins; Mice; Protein Biosynthesis; RNA Stability; RNA, Messenger
PubMed: 35901009
DOI: 10.1371/journal.pone.0272058 -
Social Cognitive and Affective... Sep 2020Acetaminophen, an analgesic and antipyretic available over-the-counter and used in over 600 medicines, is one of the most consumed drugs in the USA. Recent research has... (Randomized Controlled Trial)
Randomized Controlled Trial
Acetaminophen, an analgesic and antipyretic available over-the-counter and used in over 600 medicines, is one of the most consumed drugs in the USA. Recent research has suggested that acetaminophen's effects extend to the blunting of negative as well as positive affect. Because affect is a determinant of risk perception and risk taking, we tested the hypothesis that acute acetaminophen consumption (1000 mg) could influence these important judgments and decisions. In three double-blind, placebo-controlled studies, healthy young adults completed a laboratory measure of risk taking (Balloon Analog Risk Task) and in Studies 1 and 2 completed self-report measures of risk perception. Across all studies (total n = 545), acetaminophen increased risk-taking behavior. On the more affectively stimulating risk perception measure used in Study 2, acetaminophen reduced self-reported perceived risk and this reduction statistically mediated increased risk-taking behavior. These results indicate that acetaminophen can increase risk taking, which may be due to reductions in risk perceptions, particularly those that are highly affect laden.
Topics: Acetaminophen; Adolescent; Affect; Analgesics, Non-Narcotic; Decision Making; Double-Blind Method; Female; Humans; Judgment; Male; Risk-Taking; Treatment Outcome; Young Adult
PubMed: 32888031
DOI: 10.1093/scan/nsaa108