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Frontiers in Neuroscience 2019Alzheimer's disease (AD) and type 2 diabetes (T2D) are both diseases with increasing prevalence in aging populations. T2D, characterized by insulin resistance and... (Review)
Review
Alzheimer's disease (AD) and type 2 diabetes (T2D) are both diseases with increasing prevalence in aging populations. T2D, characterized by insulin resistance and defective insulin signaling, is a common co-morbidity and a risk factor for AD, increasing the risk approximately two to fourfold. Insulin exerts a wide variety of effects as a growth factor as well as by regulating glucose, fatty acid, and protein metabolism. Certain lifestyle factors, physical inactivity and typical Western diet (TWD) containing high fat and high sugar are strongly associated with insulin resistance and T2D. The PI3K-Akt signaling pathway is a major mediator of effects of insulin and plays a crucial role in T2D pathogenesis. Decreased levels of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) subunits as well as blunted Akt kinase phosphorylation have been observed in the AD brain, characterized by amyloid-β and tau pathologies. Furthermore, AD mouse models fed with TWD have shown to display altered levels of PI3K subunits. How impaired insulin-PI3K-Akt signaling in peripheral tissues or in the central nervous system (CNS) affects the development or progression of AD is currently poorly understood. Interestingly, enhancement of PI3K-Akt signaling in the CNS by intranasal insulin (IN) treatment has been shown to improve memory in mice and in human trials. Insulin is known to augment neuronal growth and synapse formation through the PI3K-Akt signaling pathway. However, PI3K-Akt pathway mediates signaling related to different functions also in other cell types, like microglia and astrocytes. In this review, we will discuss the most prominent molecular mechanisms related to the PI3K-Akt pathway in AD and how T2D and altered insulin signaling may affect the pathogenesis of AD.
PubMed: 31275108
DOI: 10.3389/fnins.2019.00629 -
Vascular Pharmacology Dec 2023Despite advances in pharmacotherapy and device innovation, in-stent restenosis (ISR) and stent thrombosis (ST) remain serious complications following percutaneous...
AIMS
Despite advances in pharmacotherapy and device innovation, in-stent restenosis (ISR) and stent thrombosis (ST) remain serious complications following percutaneous coronary intervention (PCI) procedure with stent implantation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme involved in plasma cholesterol homeostasis and recently emerged as a therapeutic target for hypercholesterolemia. Antibody-based PCSK9 inhibition is increasingly used in different subsets of patients, including those undergoing PCI. However, whether PCSK9 inhibition affects outcome after stent implantation remains unknown.
METHODS AND RESULTS
12 to 14 weeks old C57Bl/6 mice underwent carotid artery bare-metal stent implantation. Compared to sham intervention, stent implantation was associated with increased expression of several inflammatory mediators, including PCSK9. The increase in PCSK9 protein expression was confirmed in the stented vascular tissue, but not in plasma. To inhibit PCSK9, alirocumab was administered weekly to mice before stent implantation. After 6 weeks, histological examination revealed increased intimal hyperplasia in the stented segment of alirocumab-treated animals compared to controls. In vitro, alirocumab promoted migration and inhibited the onset of senescence in primary human vascular smooth muscle cells (VSMC). Conversely, it blunted the migration and increased the senescence of endothelial cells (EC).
CONCLUSION
Antibody-based PCSK9 inhibition promotes in-stent intimal hyperplasia and blunts vascular healing by increasing VSMC migration, while reducing that of EC. This effect is likely mediated, at least in part, by a differential effect on VSMC and EC senescence. The herein-reported data warrant additional investigations concerning the use of PCSK9 inhibitors in patients undergoing PCI with stent implantation.
Topics: Humans; Animals; Mice; Proprotein Convertase 9; Percutaneous Coronary Intervention; Hyperplasia; Endothelial Cells; Stents
PubMed: 37659608
DOI: 10.1016/j.vph.2023.107170 -
Clinical Interventions in Aging 2013Obesity is a global epidemic associated with aging-like cellular processes; in both aging and obesity, resistance to hormones such as insulin and leptin can be observed.... (Review)
Review
Obesity is a global epidemic associated with aging-like cellular processes; in both aging and obesity, resistance to hormones such as insulin and leptin can be observed. Leptin is a circulating hormone/cytokine with central and peripheral effects that is released mainly by subcutaneous white adipose tissue. Centrally, leptin controls food intake, energy expenditure, and fat distribution, whereas it controls (among several others) insulin sensitivity, free fatty acids (FFAs) oxidation, and lipolysis in the periphery. Aging is associated with important changes in both the distribution and the composition of adipose tissue. Fat is redistributed from the subcutaneous to the visceral depot and increased inflammation participates in adipocyte dysfunction. This redistribution of adipose tissue in favor of visceral fat influences negatively both longevity and healthy aging as shown in numerous animal models. These modifications observed during aging are also associated with leptin resistance. This resistance blunts normal central and peripheral functions of leptin, which leads to a decrease in neuroendocrine function and insulin sensitivity, an imbalance in energy regulation, and disturbances in lipid metabolism. Here, we review how age-related leptin resistance triggers metabolic disturbances and affects the longevity of obese patients. Furthermore, we discuss the potential impacts of leptin resistance on the decline of brown adipose tissue thermogenesis observed in elderly individuals.
Topics: Adipose Tissue; Aged; Aging; Animals; Humans; Insulin Resistance; Leptin; Longevity; Obesity
PubMed: 23869170
DOI: 10.2147/CIA.S36367 -
Journal of Affective Disorders Jul 2021Intermittent theta burst stimulation (iTBS) over the dorsomedial prefrontal cortex (DMPFC) has shown promise in open-label trials of depression. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Intermittent theta burst stimulation (iTBS) over the dorsomedial prefrontal cortex (DMPFC) has shown promise in open-label trials of depression.
METHODS
In this randomized, double-blind, sham controlled trial we evaluate iTBS over the DMPFC for anhedonia, avolition, and blunted affect in patients with schizophrenia or depression. Active iTBS was delivered over the DMPFC with 1200 pulses per session, twice daily over ten weekdays at target intensity with an angled figure-of eight coil. Sham condition comprised the magnetically shielded side of the coil and simultaneous transcutaneous electrical nerve stimulation. Primary outcome was change on the Clinical Assessment Interview for Negative Symptoms (CAINS).
RESULTS
Twenty-eight patients were randomized to active iTBS and 28 to sham. Mean (standard deviation) change in CAINS score from baseline to the day after last treatment was -5.3 (8.1) in active iTBS and -2.1 (7.1) in sham. A linear model showed no significant effect of treatment, accounting for baseline scores p=.088. Sub analyses per diagnostic group showed a significant effect in patients with depression, p=.038, but not in the schizophrenia group, p=.850. However, overall depressive symptoms did not change significantly in patients with depression. There were three serious adverse events, all in the sham group.
LIMITATIONS
Possibly too short treatment course and few patients with schizophrenia.
CONCLUSION
In this first transdiagnostic randomized controlled trial of iTBS over DMPFC for anhedonia, avolition, and blunted affect it can be concluded that it was generally tolerable and safe but only more effective than sham in the subgroup of patients with depression.
Topics: Anhedonia; Depression; Depressive Disorder, Treatment-Resistant; Humans; Prefrontal Cortex; Schizophrenia; Theta Rhythm; Transcranial Magnetic Stimulation
PubMed: 34020205
DOI: 10.1016/j.jad.2021.04.053 -
Current Topics in Medicinal Chemistry 2016Schizophrenia is a chronic and debilitating neuropsychiatric disorder affecting approximately 1% of the world's population. This disease is associated with considerable... (Review)
Review
Schizophrenia is a chronic and debilitating neuropsychiatric disorder affecting approximately 1% of the world's population. This disease is associated with considerable morbidity placing a major financial burden on society. Antipsychotics have been the mainstay of the pharmacological treatment of schizophrenia for decades. The traditional typical and atypical antipsychotics demonstrate clinical efficacy in treating positive symptoms, such as hallucinations and delusions, while are largely ineffective and may worsen negative symptoms, such as blunted affect and social withdrawal, as well as cognitive function. The inability to treat these latter symptoms may contribute to social function impairment associated with schizophrenia. The dysfunction of multiple neurotransmitter systems in schizophrenia suggests that drugs selectively targeting one neurotransmission pathway are unlikely to meet all the therapeutic needs of this heterogeneous disorder. Often, however, the unintentional engagement of multiple pharmacological targets or even the excessive engagement of intended pharmacological targets can lead to undesired consequences and poor tolerability. In this article, we will review marketed typical and atypical antipsychotics and new therapeutic agents targeting dopamine receptors and other neurotransmitters for the treatment of schizophrenia. Representative typical and atypical antipsychotic drugs and new investigational drug candidates will be systematically reviewed and compared by reviewing structure-activity relationships, pharmacokinetic properties, drug metabolism and safety, pharmacological properties, preclinical data in animal models, clinical outcomes and associated side effects.
Topics: Antipsychotic Agents; Dopamine; Drug Design; Humans; Schizophrenia
PubMed: 27291902
DOI: 10.2174/1568026616666160608084834 -
Cancer Science Jun 2022Neutrophils are the first defenders of the innate system for injury and infection. They have gradually been recognized as important participants in tumor initiation and...
Neutrophils are the first defenders of the innate system for injury and infection. They have gradually been recognized as important participants in tumor initiation and development due to their heterogeneity and plasticity. In the tumor microenvironment (TME), neutrophils can exert antitumor and protumor functions, depending on the surroundings. Tumor cells systemically alter intracellular amino acid (AA) metabolism and extracellular AA distribution to meet their proliferation need, leading to metabolic reprogramming and TME reshaping. However, the underlying mechanisms that determine how altered AAs affect neutrophils in TME are less-explored. Here, we identified that abundant glutamate releasing from tumor cells blunted neutrophils' cell-killing effects toward tumor cells in vitro and in vivo. Mass spectrometric detection, flow cytometry, and western blot experiments proved that increased levels of pSTAT3/RAB10/ARF4, mediated by glutamate, were accompanied with immunosuppressive phenotypes of neutrophils in TME. We also discovered that riluzole, an FDA-approved glutamate release inhibitor, significantly inhibited tumor growth by restoring neutrophils' cell-killing effects and decreasing glutamate secretion from tumor cells. These findings highlight the importance of tumor-released glutamate on neutrophil transformation in TME, providing new possible cancer treatments targeting altered glutamate metabolism.
Topics: Apoptosis; Glutamic Acid; Humans; Neoplasms; Neutrophils; Tumor Microenvironment
PubMed: 35363928
DOI: 10.1111/cas.15355 -
Current Neuropharmacology 2016Stress of different origin is known to alter so called "braingut axis" and contributes to a broad array of gastrointestinal disorders including inflammatory bowel... (Review)
Review
BACKGROUND
Stress of different origin is known to alter so called "braingut axis" and contributes to a broad array of gastrointestinal disorders including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and other functional gastrointestinal diseases. The stressful situations and various stressors including psychosocial events, heat, hypo- and hyperthermia may worsen the course of IBD via unknown mechanism. The aims of this paper were to provide an overview of experimental and clinical evidences that stress activates the brain-gut axis which results in a mucosal mast cells activation and an increase in the production of proinflammatory cytokines and other endocrine and humoral mediators.
METHODS
Research and online content related to effects of stress on lower bowel disorders are reviewed and most important mechanisms are delineated.
RESULTS
Brain conveys the neural, endocrine and circulatory messages to the gut via brain-gut axis reflecting changes in corticotrophin releasing hormone, mast cells activity, neurotransmission at the autonomic nerves system and intestinal barrier function all affecting the pathogenesis of animal colitis and human IBD. Stress triggers the hypothalamus-pituitary axis and the activation of the autonomic nervous system, an increase in cortisol levels and proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-8, interleukin-1beta and interleukin-6.
CONCLUSION
The acute or chronic stress enhances the intestinal permeability weakening of the tight junctions and increasing bacterial translocation into the intestinal wall. An increased microbial load in the colonic tissue, excessive cytokine release and a partially blunted immune reactivity in response to stress result in its negative impact on IBD.
Topics: Animals; Brain; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Inflammatory Bowel Diseases; Stress, Psychological
PubMed: 27040468
DOI: 10.2174/1570159x14666160404124127 -
Ulusal Travma Ve Acil Cerrahi Dergisi =... Nov 2018The purpose of this study was to investigate factors affecting wound dehiscence due to blunt trauma following penetrating keratoplasty (PK) and the clinical outcomes.
BACKGROUND
The purpose of this study was to investigate factors affecting wound dehiscence due to blunt trauma following penetrating keratoplasty (PK) and the clinical outcomes.
METHODS
The medical records of patients who experienced blunt traumatic wound dehiscence after PK between 1995 and 2015 were analyzed retrospectively. The incidence and etiology of the trauma, the time interval between PK and globe rupture, final graft clarity, best-corrected visual acuity, complications, secondary surgeries, and factors potentially affecting wound dehiscence size were recorded.
RESULTS
This study included a total of 39 patients with a mean age of 42.66±16.66 years, of whom 23 patients were male and 16 patients were female. The incidence of wound dehiscence was 2.3%. The mean interval between the PK procedure and wound dehiscence was 25.91±47.24 months and the mean follow-up time was 34.43±51.02 months. The most common trauma mechanism was force with a blunt object (53.8%) and the most frequent site of wound dehiscence was the temporal quadrant (30.8%), the wound ranging from 30° to 270° in size. The patients were divided into 4 groups according to wound dehiscence size. As the size of the wound dehiscence size increased, the male ratio increased, wound dehiscence was more commonly located in the nasal and superior quadrants, lens injury and posterior segment complications were more frequent, and graft transparency was achieved at a lower rate.
CONCLUSION
Traumatic wound dehiscence after PK is rare, but may lead to serious, lifelong consequences, including eye loss. Patients should be well informed about the risks and potential sequelae of wound dehiscence.
Topics: Adult; Eye Injuries; Female; Humans; Keratoplasty, Penetrating; Male; Middle Aged; Retrospective Studies; Surgical Wound Dehiscence; Wounds, Nonpenetrating
PubMed: 30516257
DOI: 10.5505/tjtes.2018.44450 -
Clinical Neurophysiology : Official... Jul 2021Negative psychiatric symptoms are often resistant to treatments, regardless of the disorder in which they appear. One model for a cause of negative symptoms is...
OBJECTIVES
Negative psychiatric symptoms are often resistant to treatments, regardless of the disorder in which they appear. One model for a cause of negative symptoms is impairment in higher-order cognition. The current study examined how particular bottom-up and top-down mechanisms of selective attention relate to severity of negative symptoms across a transdiagnostic psychiatric sample.
METHODS
The sample consisted of 130 participants: 25 schizophrenia-spectrum disorders, 26 bipolar disorders, 18 unipolar depression, and 61 nonpsychiatric controls. The relationships between attentional event-related potentials following rare visual targets (i.e., N1, N2b, P2a, and P3b) and severity of the negative symptom domains of anhedonia, avolition, and blunted affect were evaluated using frequentist and Bayesian analyses.
RESULTS
P3b and N2b mean amplitudes were inversely related to the Positive and Negative Syndrome Scale-Negative Symptom Factor severity score across the entire sample. Subsequent regression analyses showed a significant negative transdiagnostic relationship between P3b amplitude and blunted affect severity.
CONCLUSIONS
Results indicate that negative symptoms, and particularly blunted affect, may have a stronger association with deficits in top-down mechanisms of selective attention.
SIGNIFICANCE
This suggests that people with greater severity of blunted affect, independent of diagnosis, do not allocate sufficient cognitive resources when engaging in activities requiring selective attention.
Topics: Adult; Evoked Potentials, Visual; Female; Humans; Male; Mental Disorders; Middle Aged; Photic Stimulation; Severity of Illness Index; Young Adult
PubMed: 34030054
DOI: 10.1016/j.clinph.2021.02.398 -
Communications Biology Apr 2023Mechanical force loading is essential for maintaining bone homeostasis, and unloading exposure can lead to bone loss. Osteoclasts are the only bone resorbing cells and...
Mechanical force loading is essential for maintaining bone homeostasis, and unloading exposure can lead to bone loss. Osteoclasts are the only bone resorbing cells and play a crucial role in bone remodeling. The molecular mechanisms underlying mechanical stimulation-induced changes in osteoclast function remain to be fully elucidated. Our previous research found Ca-activated Cl channel Anoctamin 1 (Ano1) was an essential regulator for osteoclast function. Here, we report that Ano1 mediates osteoclast responses to mechanical stimulation. In vitro, osteoclast activities are obviously affected by mechanical stress, which is accompanied by the changes of Ano1 levels, intracellular Cl concentration and Ca downstream signaling. Ano1 knockout or calcium binding mutants blunts the response of osteoclast to mechanical stimulation. In vivo, Ano1 knockout in osteoclast blunts loading induced osteoclast inhibition and unloading induced bone loss and. These results demonstrate that Ano1 plays an important role in mechanical stimulation induced osteoclast activity changes.
Topics: Anoctamin-1; Chloride Channels; Osteoclasts; Signal Transduction
PubMed: 37055517
DOI: 10.1038/s42003-023-04806-1