The physiological effects of physical exercise are ubiquitously reported as beneficial to the cardiovascular and musculoskeletal systems. Exercise is widely promoted by medical professionals to aid ...both physical and emotional wellbeing; however, mechanisms through which this is achieved are less well understood. Despite numerous beneficial attributes, certain types of exercise can inflict significant significant physiological stress. Several studies document a key relationship between exercise and immune activation. Activation of the innate immune system occurs in response to exercise and it is proposed this is largely mediated by cytokine signalling. Cytokines are typically classified according to their inflammatory properties and evidence has shown that cytokines expressed in response to exercise are diverse and may act to propagate, modulate or mitigate inflammation in musculoskeletal health. The review summarizes the existing literature on the relationship between exercise and the immune system with emphasis on how exercise-induced cytokine expression modulates inflammation and the immune response.
Corticotropin‐releasing factor (CRF) receptor agonists administered peripherally increase colonic propulsive motility and fecal output in experimental animals. In addition, endogenous CRF‐related ...peptides are found in the lower gastrointestinal (GI) tissues, suggesting a local expression of CRF receptors. In the present study, we report the expression of both CRF receptor type 1 (CRF1) and 2 (CRF2) in the rat colon at the mRNA and protein levels. For the purpose of receptor protein mapping, a specific antiserum against the C‐terminus of CRF2 (2064a‐CRF2) was generated and characterized. This antiserum in conjunction with a selective anti‐CRF1 antiserum (4467a‐CRF1) was used in immunofluorescent staining to demonstrate the anatomical distribution of receptor protein expression. Using RT‐PCR for the CRF1 and CRF2 genes, both receptor gene transcripts were found in RNA isolated from crude colonic samples. CRF1 was found in the goblet and stem cells of the colonic crypts and in scattered cells of the surface epithelium and the lamina propria of the proximal colonic mucosa. In addition, double staining against neuron‐specific antigens revealed CRF1 expression in the myenteric and submucosal nervous plexus. CRF2 expression was localized mainly in the luminal surface of the crypts and in blood vessels of the submucosal layer. These results demonstrate expression of both CRF receptor types in the rat colon and support a role for their involvement in regulating peripheral effects of CRF ligands.
The stress response involves the activation of two corticotropin-releasing factor (CRF) receptor subtypes. We investigated the role of CRF1 in stress-related visceral responses. A novel water-soluble ...tricyclic CRF1 antagonist, NBI 35965 was developed that displayed a high affinity for CRF1 (Ki approximately 4 nM) while having no binding affinity to CRF2. This antagonist also inhibited the stimulation of cAMP induced by sauvagine in CRF1 transfected cells. NBI 35965 administered per orally (p.o.) in rats (1, 3, 10 or 30 mg/kg) inhibited dose-dependently 125Isauvagine binding selectively at brain sites of CRF1 distribution as shown by ex vivo receptor autoradiography. At the highest doses, NBI 35965 completely prevented 125Isauvagine labeling in the cortex. NBI 35965 (10 mg/kg) administered p.o. or subcutaneously (s.c.) 1 h before intravenous CRF completely blocked the 81% shortening of distal colonic transit time induced by CRF. NBI 35965 (20 mg/kg s.c.) significantly reduced the defecation in response to water avoidance stress but not that induced by s.c. carbachol. In adult male Long-Evans rats that had undergone maternal separation, acute water avoidance stress significantly increased the visceromotor response to colorectal distention (20-80 mmHg) by 42+/-19% compared with the response before stress. Stress-induced visceral hyperalgesia was abolished by NBI 35965 (20 mg/kg, s.c.). The data show that NBI 35965 is a novel water-soluble selective CRF1 antagonist with bioavailability to the brain upon peripheral administration and that CRF1 receptor signaling pathways are involved in water avoidance stress-induced hyperalgesia to colorectal distention and stimulation of colonic transit.
Tendinopathy and enthesitis share clinical, anatomical, and molecular parallels. However, their relationship is complex, presenting challenges in diagnosis and treatment. The biomechanics underlying ...these pathologies, together with relative immune and stromal contributions to pathology, are characterised by crucial comparative elements. However, methodologies used to study enthesitis and tendinopathy have been divergent, which could account for discrepancies in how these conditions are perceived and treated. In this Review, we summarise key clinical parallels between these two common presentations in musculoskeletal medicine and address factors that currently preclude development of more effective therapeutics. Furthermore, we describe molecular similarities and disparities that govern pathological mechanisms in tendinopathy and enthesitis, thus informing translational studies and treatment strategies.
Analogues of the known H1-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On ...the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing. Compound 2a did not show an in vivo cardiovascular effect from weak hERG channel inhibition.
The nonobese diabetic (NOD) mouse is a good model for human type 1 diabetes, which is characterized by autoreactive T-cell-mediated destruction of insulin-producing islet beta-cells of the pancreas. ...The 9-23 amino acid region of the insulin B-chain B((9-23)) is an immunodominant T-cell target antigen in the NOD mouse that plays a critical role in the disease process. By testing a series of B((9-23)) peptide analogs with single or double alanine substitutions, we identified a set of altered peptide ligands (APLs) capable of inhibiting B((9-23))-induced proliferative responses of NOD pathogenic T-cell clones. These APLs were unable to induce proliferation of these clones. However, vaccinations with the APLs induced strong cellular responses, as measured by in vitro lymphocyte proliferation and Th2 cytokine production (i.e., interleukin IL-4 and IL-10, but not gamma-interferon IFN-gamma). These responses were cross-reactive with the native antigen, B((9-23)), suggesting that the APL-induced Th2 responses may provide protection by controlling endogenous B((9-23))-specific Th1 (i.e., IFN-gamma-producing) pathogenic responses. One of these APLs that contained alanine substitutions at residues 16 and 19 (16Y-->A, 19C-->A; NBI-6024) was further characterized for its therapeutic activity because it consistently induced T-cell responses (e.g., T-cell lines and clones) that were of the Th2 type and that were cross-reactive with B((9-23)). Subcutaneous injections of NBI-6024 to NOD mice administered either before or after the onset of disease substantially delayed the onset and reduced the incidence of diabetes. This study is the first to report therapeutic activity of an APL derived from an islet beta-cell-specific antigen in type 1 diabetes.
The 9-23 amino acid region of the insulin B chain (B9-23) is a dominant epitope recognized by pathogenic T lymphocytes in nonobese diabetic mice, the animal model for type 1 diabetes. We describe ...herein similar (B9-23)-specific T-cell responses in peripheral lymphocytes obtained from patients with recent-onset type 1 diabetes and from prediabetic subjects at high risk for disease. Short-term T-cell lines generated from patient peripheral lymphocytes showed significant proliferative responses to (B9-23), whereas lymphocytes isolated from HLA and/or age-matched nondiabetic normal controls were unresponsive. Antibody-mediated blockade demonstrated that the response was HLA class II restricted. Use of the highly sensitive cytokine-detection ELISPOT assay revealed that these (B9-23)-specific cells were present in freshly isolated lymphocytes from only the type 1 diabetics and prediabetics and produced the proinflammatory cytokine IFN-gamma. This study is, to our knowledge, the first demonstration of a cellular response to the (B9-23) insulin epitope in human type 1 diabetes and suggests that the mouse and human diseases have strikingly similar autoantigenic targets, a feature that should facilitate development of antigen-based therapeutics.
Peripheral corticotropin‐releasing factor (CRF) receptor ligands inhibit gastric acid secretion and emptying while stimulating gastric mucosal blood flow in rats. Endogenous CRF ligands are expressed ...in the upper gastrointestinal (GI) tissues pointing to local expression of CRF receptors. We mapped the distribution of CRF receptor type 1 (CRF1) and 2 (CRF2) in the rat upper GI. Polyclonal antisera directed against the C‐terminus of the CRF receptor protein were generated in rabbits and characterized by western blotting and immunofluorescence using CRF1‐ and CRF2‐transfected cell lines and in primary cultured neurons from rat brain cortex. A selective anti‐CRF1 antiserum (4467a‐CRF1) was identified and used in parallel with another antiserum recognizing both CRF1 and CRF2 (4392a‐CRF1&2) to immunostain gastric tissue sections. Antiserum 4467a‐CRF1 demonstrated specific immunostaining in a narrow zone in the upper oxyntic gland within the stomach corpus. Conversely, 4392a‐CRF1&2 labeled cells throughout the oxyntic gland and submucosal blood vessels. Pre‐absorption with the specific antigen peptide blocked immunostaining in all experiments. Doublestaining showed co‐localization of 4392a‐CRF1&2 but not 4467a‐CRF1 immunoreactivity with H/K‐ATPase and somatostatin immunostaining in parietal and endocrine cells of the oxyntic gland. No specific staining was observed in the antrum with either antisera, whereas only antiserum 4392a‐CRF1&2 showed modest immunoreactivity in the duodenal mucosa. Finally, co‐localization of CRF2 and urocortin immunoreactivity was found in the gastric glands. These results indicate that both CRF receptor subtypes are expressed in the rat upper GI tissues with a distinct pattern and regional differences suggesting differential function.
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