Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Associations between stress and health outcomes have now been carefully documented, but the mechanisms by which stress specifically influences disease susceptibility and outcome remain poorly understood. Recent evidence indicates that glucocorticoids (GCs) and catecholamines (CAs), the major stress hormones, inhibit systemically IL-12, TNF-alpha, and INF-gamma, but upregulate IL-10, IL-4, and TGF-beta production. Thus, during an immune and inflammatory response, the activation of the stress system, through induction of a Th2 shift may protect the organism from systemic "overshooting" with T helper lymphocyte 1 (Th1)/proinflammatory cytokines. In certain local responses and under certain conditions, however, stress hormones may actually facilitate inflammation, through induction of IL-1, IL-6, IL-8, IL-18, TNF-alpha, and CRP production, and through activation of the corticotropin-releasing hormone (CRH)/substance P(SP)-histamine axis. Autoimmunity, chronic infections, major depression, and atherosclerosis are characterized by a dysregulation of the pro/anti-inflammatory and Th1/Th2 cytokine balance. Thus, hyperactive or hypoactive stress system, and a dysfunctional neuroendocrine-immune interface associated with abnormalities of the "systemic anti-inflammatory feedback" and/or "hyperactivity" of the local proinflammatory factors may contribute to the pathogenesis of these diseases. Conditions that are associated with significant changes in stress system activity, such as acute or chronic stress, cessation of chronic stress, pregnancy and the postpartum period, or rheumatoid arthritis (RA) through modulation of the systemic or local pro/anti-inflammatory and Th1/Th2 cytokine balance, may suppress or potentiate disease activity and/or progression. Thus, stress hormones-induced inhibition or upregulation of innate and Th cytokine production may represent an important mechanism by which stress affects disease susceptibility, activity, and outcome of various immune-related diseases.
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PMID:Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases. 1685 35

Adoptive immunotherapy for melanoma appears to be a promising approach. The aim of our study was to discuss the role of "tumour tissue" immunogenicity in response to adoptive immunotherapy. We thus studied the potential correlation between the expression of some melanocyte differentiation antigens, adhesion molecules and cytokines expressed by the tumour cells and the survival of patients receiving an adoptive immunotherapy with autologous Tumour Infiltrating Lymphocytes (TIL). An immunohistochemical study was performed on the lymph node samples obtained from 38 patients who received autologous TIL plus interleukin-2. Frozen sections were immunostained for melanocyte differentiation antigens (Melan-A and gp100), MHC molecules (Class I and II), adhesion molecules (ICAM-1, LFA-3) and suppressive cytokines (IL-10, TGF-beta and alpha-MSH). Expression levels of each marker were evaluated using a semi-quantitative visual scale. Using a multivariate analysis, a low expression level of TGF-beta by tumour cells was significantly associated with a prolonged relapse-free survival. A low expression level of TGF-beta, IL-10, ICAM-1 and alpha-MSH by tumour cells was significantly associated with a longer overall survival. This work suggests that a weak expression of immunosuppressive cytokines (IL-10, TGF-beta and alpha-MSH) could be a favourable prognostic marker for patients receiving autologous TIL.
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PMID:Tissue prognostic markers for adoptive immunotherapy in melanoma. 1754 Jun 35

The hypothalamic-pituitary-adrenal axis is an essential component for the maintenance of homeostasis following trauma. Major surgical trauma often induces overwhelming inflammatory responses leading to sepsis and organ dysfunction. This study was designed to evaluate the adrenal responses both before and after various degrees of surgical trauma and to determine the incidence of postoperative relative adrenal insufficiency resulting in the marked inflammatory response often associated with postoperative complications. Fifty-one surgical patients were divided into groups who underwent major, moderate, and minor surgeries. Before the operation and during resting conditions, a short corticotropin (ACTH) stimulation test was performed in each patient. The postoperative concentrations of serum cortisol, interleukin (IL)-6, IL-10, C-reactive protein (CRP), and plasma ACTH were measured. Fifty of 51 patients were identified as responders to ACTH. The postoperative cortisol levels were the same as those obtained by ACTH stimulation in highly and moderately stressful surgeries. The increases in postoperative IL-6 and CRP levels were greatest with major surgery, intermediate with moderate surgery, and least with minor surgery. Furthermore, plasma ACTH levels increased after major and moderate surgeries; however, there was no significant differences in postoperative serum IL-10 levels. Systemic inflammatory response syndrome (SIRS) was found in 11 of 17 patients (64.7%) who underwent major surgery and in 4 of 16 patients (25%) who underwent moderate surgery (p=0.037). The duration of SIRS was significantly longer in patients undergoing major surgery (62+/-20 hrs) than in patients undergoing moderate surgery (21+/-3 hrs, p=0.038). Postoperative complications were more frequent in patients undergoing major surgery (41.2%) than in patients undergoing moderate surgery (6.3%, p=0.039). Furthermore, there were significant differences in the length of the postoperative stay among the three groups (p<0.01). One nonresponder had serious postoperative inflammatory complications. These results suggest that a short ACTH stimulation test performed preoperatively is a helpful method for determining the maximal cortisol response to surgical trauma and to identify high-risk individuals and that a relative postoperative adrenal insufficiency may be closely related to the decreased cortisol secretion following major surgical trauma.
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PMID:Surgical trauma-induced adrenal insufficiency is associated with postoperative inflammatory responses. 1787 97

Lumbar puncture (LP) is an attractive route to deliver drugs to the nervous system because it is a safe bedside procedure. Its use for gene therapy has been complicated by poor vector performance and failure to target neurons. Here we report highly effective gene transfer to the primary sensory neurons of the dorsal root ganglia (DRGs) with self-complementary recombinant adeno-associated virus serotype 8 (sc-rAAV8) modeling an LP. Transgene expression was selective for these neurons outlining their cell bodies in the DRGs and their axons projecting into the spinal cord. Immunohistochemical studies demonstrated transduction of cells positive for the nociceptive neuron marker vanilloid receptor subtype 1, the small peptidergic neuron markers substance P and calcitonin gene-related peptide, and the nonpeptidergic neuron marker griffonia simplicifolia isolectin B4. We tested the efficacy of the approach in a rat model of chronic neuropathic pain. A single administration of sc-rAAV8 expressing the analgesic gene prepro-beta-endorphin (ppbetaEP) led to significant (P < 0.0001) reversal of mechanical allodynia for >/=3 months. The antiallodynic effect could be reversed by the mu-opioid antagonist naloxone 4 months after gene transfer (P < 0.001). Testing of an alternative nonopioid analgesic gene, IL-10, alone or in combination with ppbetaEP was equally effective (P < 0.0001). All aspects of the procedure, such as the use of an atraumatic injection technique, isotonic diluent, a low-infusion pressure, and a small injection volume, are consistent with clinical practice of intrathecal drug use. Therefore, gene transfer by LP may be suitable for developing gene therapy-based treatments for chronic pain.
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PMID:Sensory neuron targeting by self-complementary AAV8 via lumbar puncture for chronic pain. 1821 93

Pneumonia constitutes a serious medical complication and major cause of death in patients after cerebral stroke. In a mouse model of cerebral ischemia (MCAO), we have recently demonstrated that stroke animals spontaneously develop severe bacterial pneumonia which is preceded by a stress-mediated suppression of cellular immune responses in primary and secondary lymphoid organs. However, little is known about the mechanisms leading to impaired pulmonary antimicrobial immune response after cerebral ischemia. In this study, we demonstrate a rapid up-regulation of the immunomodulatory neuropeptide alpha-melanocyte-stimulating hormone (MSH) in the lung within 24 h after cerebral ischemia. Systemic administration of the naturally occurring alpha-MSH receptor-1 (MC-1R) antagonist agouti immediately after MCAO significantly reduced pulmonary bacterial burden at 72 h. In contrast, administration of recombinant alpha-MSH further increased bacterial load in lungs of MCAO animals. In addition, cerebral ischemia resulted in a strong modulation of local pulmonary immunity with increased production of IL-10 by lung macrophages, reduced pulmonary lymphocyte counts, as well as decreased lymphocytic IFN-gamma but increased IL-4 production. However, alpha-MSH blockade by administration of agouti did not prevent changes in lung immune cell numbers or cytokine production suggesting that suppression of cellular immune responses is not the primary mechanism of alpha-MSH mediated inhibition of pulmonary antibacterial defenses. This study indicates an important role of alpha-MSH for the increased infectious susceptibility after cerebral ischemia and may provide new therapeutic strategies to prevent post-stroke infectious complications.
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PMID:Alpha-MSH promotes spontaneous post-ischemic pneumonia in mice via melanocortin-receptor-1. 1830 33

Sepsis remains a serious problem in critically ill patients with the mortality increasing to over half when there is attendant acute kidney injury. alpha-Melanocyte-stimulating hormone is a potent anti-inflammatory cytokine that inhibits many forms of inflammation including that with acute kidney injury. We tested whether a new alpha-melanocyte-stimulating hormone analogue (AP214), which has increased binding affinity to melanocortin receptors, improves sepsis-induced kidney injury and mortality using a cecal ligation and puncture mouse model. In the lethal cecal ligation-puncture model of sepsis, severe hypotension and bradycardia resulted and AP214 attenuated acute kidney injury of the lethal model with a bell-shaped dose-response curve. An optimum AP214 dose reduced acute kidney injury even when it was administered 6 h after surgery and it significantly improved blood pressure and heart rate. AP214 reduced serum TNF-alpha and IL-10 levels with a bell-shaped dose-response curve. Additionally; NF-kappaB activation in the kidney and spleen, and splenocyte apoptosis were decreased by the treatment. AP214 significantly improved survival in both lethal and sublethal models. We have shown that AP214 improves hemodynamic failure, acute kidney injury, mortality and splenocyte apoptosis attenuating pro- and anti-inflammatory actions due to sepsis.
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PMID:AP214, an analogue of alpha-melanocyte-stimulating hormone, ameliorates sepsis-induced acute kidney injury and mortality. 1835 76

Prevention of type 1 diabetes mellitus (T1DM) requires early intervention in the autoimmune process directed against beta-cells of the pancreatic islets of Langerhans, which is believed to result from a disorder of immunoregulation. According to this concept, a T-helper lymphocyte of type 1 (Th1) subset of T-lymphocytes and their cytokine products, the type 1 cytokines [e.g. interleukin 2 (IL-2), interferon gamma (IFN-gamma) and tumour necrosis factor beta (TNF-beta)] prevail over immunoregulatory (anti-inflammatory) Th2 subset and its cytokine products, i.e. type 2 cytokines (e.g. IL-4, IL-6 and IL-10). This allows type 1 cytokines to initiate a cascade of immune/inflammatory processes in the islet (insulitis), culminating in beta-cell destruction. Activation of sympathetic-corticotropin-releasing hormone (CRH) axis by psychological stress induces specifically Th1 cell overactivity that determines enhanced glutamine utilization and consequent poor L-arginine supply for nitric oxide (NO)-assisted insulin secretion. This determines the shift of intraislet glutamate metabolism from the synthesis of glutathione (GSH) to that of L-arginine, leading to a redox imbalance that activates nuclear factor kappaB exacerbating inflammation and NO-mediated cytotoxicity. Physical exercise is capable of inducing changes in the pattern of cytokine production and release towards type 2 class and to normalize the glutamine supply to the circulation, which reduces the need for glutamate, whose metabolic fate may be restored in the direction of GSH synthesis and antioxidant defence. Also, the 70-kDa heat shock protein (hsp70), which is immunoregulatory, may modulate exercise-induced anti-inflammation. In this work, we envisage how exercise can intervene in the mechanisms involved in the autoimmune process against beta-cells and how novel therapeutic approaches may be inferred from these observations.
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PMID:Type 1 diabetes: can exercise impair the autoimmune event? The L-arginine/glutamine coupling hypothesis. 1838 59

Alpha-MSH is a tridecapeptide derived from proopiomelanocortin. Many studies over the last few years have provided evidence that alpha-MSH has potent protective and antiinflammatory effects. These effects can be elicited via centrally expressed melanocortin receptors that orchestrate descending neurogenic antiinflammatory pathways. alpha-MSH can also exert antiinflammatory and protective effects on cells of the immune system and on peripheral nonimmune cell types expressing melanocortin receptors. At the molecular level, alpha-MSH affects various pathways implicated in regulation of inflammation and protection, i.e., nuclear factor-kappaB activation, expression of adhesion molecules and chemokine receptors, production of proinflammatory cytokines and mediators, IL-10 synthesis, T cell proliferation and activity, inflammatory cell migration, expression of antioxidative enzymes, and apoptosis. The antiinflammatory effects of alpha-MSH have been validated in animal models of experimentally induced fever; irritant and allergic contact dermatitis, vasculitis, and fibrosis; ocular, gastrointestinal, brain, and allergic airway inflammation; and arthritis, but also in models of organ injury. One obstacle limiting the use of alpha-MSH in inflammatory disorders is its pigmentary effect. Due to its preserved antiinflammatory effect but lack of pigmentary action, the C-terminal tripeptide of alpha-MSH, KPV, has been delineated as an alternative for antiinflammatory therapy. KdPT, a derivative of KPV corresponding to amino acids 193-195 of IL-1beta, is also emerging as a tripeptide with antiinflammatory effects. The physiochemical properties and expected low costs of production render both agents suitable for the future treatment of immune-mediated inflammatory skin and bowel disease, fibrosis, allergic and inflammatory lung disease, ocular inflammation, and arthritis.
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PMID:Alpha-melanocyte-stimulating hormone and related tripeptides: biochemistry, antiinflammatory and protective effects in vitro and in vivo, and future perspectives for the treatment of immune-mediated inflammatory diseases. 1861 39

The melanocortin (MC) receptor type-1 (MC1-R) is the only one of the five MC receptor subtypes expressed in human adipose tissue explants, human mesenchymal stem cells (MSCs), and MSC-derived adipocytes. Following our recent expression studies (Obesity 2007, 15, 40-49), we now investigated the functional role of MC1-R in these tissues and cells to deduce the coupling state of MC1-R to intracellular output signals in human fat cells and tissue. Expression of MC1-R by undifferentiated and differentiated MSCs was quantified by real-time TaqMan PCR. Intracellular output signals (cAMP, lipolysis, secretion of IL-6, IL-10, and TNF-alpha), as well as effects on the metabolic rate and proliferation of human MSCs were analyzed by standard assays, exposing undifferentiated and differentiated MSCs and, in part, human adipose tissue explants to the potent MC1-R agonist, [Nle(4), D-Phe(7)]-alpha-MSH (NDP-MSH). This agonist induced a weak cAMP signal in MSC-derived adipocytes. However, it did not affect lipolysis in these cells or in adipose tissue explants, nor did it modulate cytokine release and mRNA expression of IL-6, IL-8, and TNF-alpha upon LPS stimulation. In undifferentiated MSCs, NDP-MSH did not alter the metabolic rate, but it showed a significant antiproliferative effect. Therefore, it appears that MC1-R-effector coupling in (differentiated) human adipocytes is too weak to induce a regulatory effect on lipolysis or inflammation; by contrast, MC1-R stimulation in undifferentiated MSCs induces an inhibitory signal on cell proliferation.
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PMID:Weak functional coupling of the melanocortin-1 receptor expressed in human adipocytes. 1894 69

alpha-Melanocyte-stimulating hormone (alpha-MSH) is a pro-opiomelanocortin (POMC)-derived peptide that exerts multiple protective effects on host cells. Previous investigations showed that treatment with alpha-MSH or synthetic melanocortin agonists reduces heart damage in reperfusion injury and transplantation. The aim of this preclinical research was to determine whether melanocortin treatment induces preconditioning-like cardioprotection. In particular, the plan was to assess whether melanocortin administration causes phenotype changes similar to those induced by repetitive ischemic events. The idea was conceived because both ischemic preconditioning and melanocortin signaling largely depend on cAMP response element binding protein (CREB) phosphorylation. Rats received single i.v. injections of 750microg/kg of the alpha-MSH analogue Nle(4),DPhe(7)-alpha-MSH (NDP-MSH) or saline and were sacrificed at 0.5, 1, 3, or 5h. Western blot analysis showed that rat hearts expressed melanocortin 1 receptor (MC1R) protein. Treatment with NDP-MSH was associated with early and marked increase in interleukin 6 (IL-6) mRNA. This was followed by signal transducer and activator of transcription 3 (STAT3) phosphorylation and induction of suppressor of cytokine signaling 3 (SOCS3). There were no changes in expression of other cytokines of the IL-6 family. Expression of IL-10, IL-1beta, and TNF-alpha was likewise unaltered. In hearts of rats treated with NDP-MSH there was increased expression of the orphan nuclear receptor Nur77. The data indicate that NDP-MSH induces phenotype changes that closely resemble ischemic preconditioning and likely contribute to its established protection against reperfusion injury. In addition, the increased expression of Nur77 and SOCS3 could be part of a broader anti-inflammatory effect.
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PMID:The peptide NDP-MSH induces phenotype changes in the heart that resemble ischemic preconditioning. 1979 52


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