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The Role of the Innate Immune System in ALS  [PDF]
Sudarshan Phani
Frontiers in Pharmacology , 2012, DOI: 10.3389/fphar.2012.00150
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset neurodegenerative disease that is characterized by the death of upper and lower motor neurons. Recent studies have made it clear that although motor neurons are the primary targets of the degenerative process, other cell types play key roles in the death of motor neurons. Most notably, cells of the immune system, including astrocytes and microglia have come under increasing scrutiny, after multiple lines of evidence have shown these cells to be deleterious to motor neurons. Both in vitro and in vivo experiments have shown that astrocytes and microglia containing mutated SOD1 are harmful to motor neurons. Several studies on ALS and other neurodegenerative diseases have revealed that reactive astrocytes and microglia are capable of releasing pro-inflammatory factors such as cytokines and chemokines, which are harmful to neighboring neurons. In addition, it is believed that diseased astrocytes can specifically kill motor neurons through the release of toxic factors. Furthermore, in an animal model of the disease, it has been shown that the reduction of SOD1 in microglia may be able to slow the progression of ALS symptoms. Although the exact pathways of motor neuron death in ALS have yet to be elucidated, studies have suggested that they die through aBax-dependent signaling pathway. Mounting evidence suggests that neuroinflammation plays an important role in the degeneration of motor neurons. Based on these findings, anti-inflammatory compounds are currently being tested for their potential to reduce disease severity; however, these studies are only in the preliminary stages. While we understand that astrocytes and microglia play a role in the death of motor neurons in ALS, much work needs to be done to fully understand ALS pathology and the role the immune system plays in disease onset and progression.
Trauma: the role of the innate immune system
F Hietbrink, L Koenderman, GT Rijkers, LPH Leenen
World Journal of Emergency Surgery , 2006, DOI: 10.1186/1749-7922-1-15
Abstract: Trauma is one of the major causes of mortality in people under the age of 50 in the Western world. Patients die as a direct consequence of their sustained injuries, or by the additional damage caused by subsequent immune reactions [1]. About 5% of the patients admitted after severe trauma develops (multiple) organ failure (MOF). Multiple organ failure is a clinical syndrome in which the functionality of several organs fail subsequently or simultaneously (i.e. liver, lungs, kidneys, heart). This review outlines the initiating factors and underlying mechanisms for the development of post-traumatic organ failure. It provides a pathophysiological basis for the so-called damage control concept. This concept involves a treatment strategy in which a staged approach of surgery in severely injured patients and post-traumatic immunomonitoring have become important aspects, to minimize the negative effects of a dysfunctional innate immune system.Multiple organ failure after trauma has a multifactorial etiology, which can be divided in endogenous and exogenous factors. Endogenous factors, such as genetic predisposition and physical condition form the basis of the patient s susceptibility for the development of organ failure. Recent studies have shown that genetic variations (e.g. TNF-α polymorphisms) are strongly associated with the development of organ failure [2]. Exogenous factors, like the injury itself (the "first hit" or "trauma-load") and the resuscitation or surgical intervention (the "second hit" or "intervention load") play a key role in the development and clinical presentation of organ failure. Organ damage and subsequent organ failure is the result of a dysfunctional immune system. A localized inflammatory reaction after injury is physiological, which can be explained by the "danger model", an immunological theory coined by Matzinger. The "danger model" explains that alarm signals can provoke an inflammatory reaction [3]. These alarm signals can be secreted by heal
A possible role for the endocannabinoid system in the neurobiology of depression  [cached]
Serra Gino,Fratta Walter
Clinical Practice and Epidemiology in Mental Health , 2007, DOI: 10.1186/1745-0179-3-25
Abstract: The present review synthetically describes the currently advanced hypotheses for a neurobiological basis of depression, ranging from the classical monoaminergic to the more recent neurotrophic hypothesis. Moreover, the Authors review the available preclinical and clinical evidence suggesting a possible role for the endocannabinoid system in the physiopathology of depression. Indeed, in spite of the reporting of conflicting results, the pharmacological enhancement of endocannabinoid activity at the CB1 cannabinoid receptor level appears to exert an antidepressant-like effect in some animal models of depression. On the contrary, a reduced activity of the endogenous cannabinoid system seems to be associated with the animal model of depression, namely the chronic mild stress model. Moreover, a few studies have reported an interaction of antidepressants with the endocannabinoid system. With regard to clinical studies, several authors have reported an alteration of endocannabinoid serum levels in depression, while post mortem studies have demonstrated increased levels of endocannabinoids associated to a concomitant hyperactivity of CB1 receptor in the prefrontal cortex of suicide victims. No clinical trials carried out using cannabinoids in the treatment of affective disorders have been published to date, although anecdotal reports have described both antidepressant and antimanic properties of cannabis as well as the ability of cannabis to induce mania that has also been documented. These findings are discussed, leading us to conclude that, although data available are sufficient to suggest a possible involvement of the endogenous cannabinoid system in the neurobiology of depression, additional studies should be performed in order to better elucidate the role of this system in the physiopathology of depression.
Role of Vitamin D in the Immune System  [cached]
Gonca Tamer,Banu Mes?i
Turkish Journal of Endocrinology and Metabolism , 2013,
Abstract: Vitamin D is suggested to be an important immune system regulator. 1,25 dihydroxyvitamin D (1,25(OH)2D3), which is the active form of vitamin D, decreases the proliferation of purified T-helper (Th)1 cells as well as the production of interferon (IFN) , interleukin (IL)-2, IL-5 and tumor necrosis factor-alpha (TNF-) . In Th2 cells, 1,25 (OH)2D3 stimulates IL-4 and transforming growth factor TGF production, which in turn may suppress inflammatory T cell activity. In the absence of vitamin D signaling, the T cell compartment has a potentially stronger Th1 phenotype. Furthermore, 1,25(OH)2D3 inhibits dendritic cell (DC) differentiation and maturation, leading to down-regulated expression of major histocompatibility complex class II molecules (MHC-II), co-stimulatory molecules and IL-12; enhances IL-10 production and promotes DC apoptosis. Because of these effects, 1,25(OH)2D3 inhibits DC-dependent T cell activation. In vitro, it is determined that 1,25(OH)2D3 stimulates phagocytosis and killing of bacteria by macrophages, but suppresses the antigen presenting capacity of these cells and dendritic cells. Additionally, Chen et al. have suggested that vitamin D might have a role in regulating antibody production. They have found that 1,25(OH)2D3 not only inhibits activated B cell proliferation but induces their apoptosis as well. Turk Jem 2013; 17: 5-7
The role of nitrergic system in antidepressant effects of acute administration of zinc, magnesium and thiamine on progesterone induced postpartum depression in mice
Nikseresht S,Etebary S,Sadeghipour Roodsari HR,Zarrindast MR
Tehran University Medical Journal , 2010,
Abstract: "nBackground: Postpartum depression is a mood disorder that has harmful effects on mothers, infants, family and relationships. Acute decrease of progesterone after delivery has been proposed as a cause for postpartum depression. This hormone can affect neurotransmitters' function. Zinc (Zn) and magnesium (Mg) as trace elements exert their antidepressant effects through neurotransmitter pathways. On the other hand, thiamin (Vit B1) deficiency leads to depression in animal models. The aim of this study was to evaluate effects of combination of zinc, magnesium and thiamine on postpartum depression and role of nitrergic system. "n"nMethods: One hundred ten female mice in five groups were used. Postpartum depression was conducted using progesterone injections. Combinations of Zinc chloride, magnesium chloride and thiamine HCL were administered 30 minutes before open field and forced swimming test (FST). In order to investigate role of nitrergic system, L-arginine and LNAME were administered. "n"nResults: All treatment groups spent less immobility time than the control group (p< 0.05). Combined administration of Zn+ Mg+ Vit B1 caused the most reduction in immobility time. Administration of L-NAME in Zn+ Mg+ Vit B1 group caused reduction in immobility time while administration of L-arginine caused increase in immobility time in the same group. "nConclusion: Zinc, magnesium and thiamine can improve depressive symptoms by nitrergic pathway. These elements as supplement compounds could be alternatives for antidepressants in postpartum period.
The Role of the Immune System in Obesity and Insulin Resistance  [PDF]
Payal S. Patel,Eric D. Buras,Ashok Balasubramanyam
Journal of Obesity , 2013, DOI: 10.1155/2013/616193
Abstract: The innate immune system provides organisms with rapid and well-coordinated protection from foreign pathogens. However, under certain conditions of metabolic dysfunction, components of the innate immune system may be activated in the absence of external pathogens, leading to pathologic consequences. Indeed, there appears to be an intimate relationship between metabolic diseases and immune dysfunction; for example, macrophages are prime players in the initiation of a chronic inflammatory state in obesity which leads to insulin resistance. In response to increases in free fatty acid release from obese adipose depots, M1-polarized macrophages infiltrate adipose tissues. These M1 macrophages trigger inflammatory signaling and stress responses within cells that signal through JNK or IKKβ pathways, leading to insulin resistance. If overnutrition persists, mechanisms that counteract inflammation (such as M2 macrophages and PPAR signaling) are suppressed, and the inflammation becomes chronic. Although macrophages are a principal constituent of obese adipose tissue inflammation, other components of the immune system such as lymphocytes and mast cells also contribute to the inflammatory cascade. Thus it is not merely an increased mass of adipose tissue that directly leads to attenuation of insulin action, but rather adipose tissue inflammation activated by the immune system in obese individuals that leads to insulin resistance. 1. Introduction The obesity epidemic in the USA continues to expand at an alarming rate, with a 75% increase in prevalence since 1980 [1]. The Centers for Disease Control and Prevention (CDC) reports that more than one-third of USA adults and over one-sixth of children and adolescents are obese. The frequencies of other metabolic disorders have increased pari passu, including dyslipidemia, nonalcoholic steatohepatitis, and type 2 diabetes. Dysfunctional adipose tissue is central to all these conditions. Adipose tissue is increasingly recognized as a complex endocrine organ and not merely a depot for storage of fat. Adipose tissue in obese persons develops an inflammatory milieu which ultimately leads to insulin resistance. Although many components of the immune system have been found to play a role in either promoting or attenuating adipose tissue inflammation, macrophages are key players. This paper discusses the various stimuli and networks that lead to insulin resistance, with a primary focus on the role of macrophages in adipose tissue inflammation. 2. Macrophage Accumulation in Visceral Adipose Tissue in Obesity Adipose tissue
Neuropsychological and Neurological Deficits in Obsessive-Compulsive Disorder: The Role of Comorbid Depression  [PDF]
Habibollah Ghassemzadeh, Ramin Mojtabai, Nargess Karamghadiri, Maryam Noroozian, Vandad Sharifi, Nargess Ebrahimkhani
International Journal of Clinical Medicine (IJCM) , 2012, DOI: 10.4236/ijcm.2012.33040
Abstract: Past research has found a high prevalence of neuropsychological deficits and neurological soft signs in patients with obsessive-compulsive disorder (OCD). A close relationship between OCD and depression has also been indicated in the literature. However, many aspects of this association remain unclear. In this study we compared neuropsychological functioning and neurological soft signs of 46 OCD patients who were off psychotropic medication (21 with significant depressive symptoms and 25 without) with 25 non-patient comparison subjects. The patients were matched to the comparison group with regard to age, sex, education, marital status and handedness. There were significant differences between OCD patients and the non-patient comparison group on neuropsychological functioning but not on neurological soft signs. As far as working memory concerns there was a significant difference between the OCD depressed and non-depressed groups. But we found no evidence that the neuropsychological functions such as cognitive flexibility, problem solving and spatial perception in OCD to be attributable to comorbid depression. The pattern of neuropsychological deficits in this sample of OCD patients is suggestive of orbito-frontal as well as dorsolateral prefrontal cortical dysfunction.
Targeting Tumor Microenvironment: The Key Role of Immune System  [cached]
Jaleh Barar
BioImpacts , 2012,
Abstract: In recent years, huge investigations on cancer progression and invasion have led to understand the pivotal role of tumor microenvironment. The current era of cancer therapy is based on the concept of simply targeting precise mechanisms to kill or to suppress the growth and expansion of malignant cells. Clinical data clearly correlate with in vitro results, emphasizing the direct impact of cancer environment on disease progression. This provides the opportunity to advance cancer therapy by virtue of targeting cancerous cells and non-cancerous component of tumor in a combinatorial manner. This tailor-made strategy demands the profound knowledge of cross talk between the biofactors of tumor environment and corresponding pharmacology of drug candidates. The neighborhood of tumor is critical for how cancer cells grow and invade surrounding tissues. It appears that the tumor microenvironment as a “co-op” includes malignant cells, blood vessels, immune/inflammatory factors and extracellular matrix. As a longstanding dilemma, it is well-proved that immune system plays a direct role in the existence and progression of such coop. In some cases, immune cells e.g. tumor associated macrophages (TAMs) infiltrate into tumor and instead of fighting cancer cells, support them to grow. As an important fact, this tumor complexity should not be taken as granted where it can be advantageous in cancer therapy as well as early detection and prevention. The central aim of this editorial article is to highlight the importance of tumor microenvironment for successful cancer therapy.
The role of major depression in neurocognitive functioning in patients with posttraumatic stress disorder
Mirjam J. Nijdam,Berthold P. R. Gersons,Miranda Olff
European Journal of Psychotraumatology , 2013, DOI: 10.3402/ejpt.v4i0.19979
Abstract: Background: Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) frequently co-occur after traumatic experiences and share neurocognitive disturbances in verbal memory and executive functioning. However, few attempts have been made to systematically assess the role of a comorbid MDD diagnosis in neuropsychological studies in PTSD. Objective: The purpose of the current study is to investigate neurocognitive deficits in PTSD patients with and without MDD. We hypothesized that PTSD patients with comorbid MDD (PTSD+MDD) would have significantly lower performance on measures of verbal memory and executive functioning than PTSD patients without MDD (PTSD–MDD). Method: Participants included in this study were 140 treatment-seeking outpatients who had a diagnosis of PTSD after various single traumatic events and participated in a randomized controlled trial comparing different treatment types. Baseline neuropsychological data were compared between patients with PTSD+MDD (n=84) and patients with PTSD–MDD (n=56). Results: The PTSD+MDD patients had more severe verbal memory deficits in learning and retrieving words than patients with PTSD alone. There were no differences between the groups in recall of a coherent paragraph, recognition, shifting of attention, and cognitive interference. Conclusions: The results of this study suggest that a more impaired neurocognitive profile may be associated with the presence of comorbid MDD, with medium-sized group differences for verbal memory but not for executive functioning. From a clinical standpoint, being aware that certain verbal memory functions are more restricted in patients with comorbid PTSD and MDD may be relevant for treatment outcome of trauma-focused psychotherapy.
Some Aspects of the Normal Role of Neuromodulators in the Immune System  [PDF]
John Smythies
Neuroscience & Medicine (NM) , 2011, DOI: 10.4236/nm.2011.23035
Abstract: This review covers recent advances in our knowledge of the role of a group of the most prominent neurotransmitters and neuromodulators in the field of the immune reactions of the body. The neurotransmitters and neuromodulators covered are the three catecholamines (epinephrine, noradrenaline and dopamine), serotonin, acetylcholine (both nicotinic and muscarinic functions), and histamine.
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