三康胶囊对高原移居者运动后NO乳酸及血氨的影响

目的探讨三康胶囊对高原人体运动后一氧化氮(NO)及其合酶(NOS)、乳酸(BLA)、血氨(Ammo)的影响.方法选择进驻海拔3 700 m高原1年的10名健康青年,口服三康胶囊15 d,在服药前后分别采用功量自行车进行渐增负荷运动,测定其血清 NO、NOS、BLA及Ammo含量.结果服药后较服药前运动后NO水平[(101.02±6.49) Vs (77.10±8.11)]和NOS活性[(71.40±7.23) Vs (56.29±6.28)]均增高, BLA[(7.58±0.79)Vs (6.13±0.74)]和Ammo[(80.11±9.44)Vs (69.38±8.86)]降低,有非常显著性差异(P＜0.01).结论 三康胶囊能增强高原移居者运动后NOS活性,加速乳酸清除,减缓运动疲劳的发生.     

Ischaemic episodes of less than 5 minutes produce preconditioning but not stunning in the isolated rat heart

The aim of the present study was to examine whether ischaemic episodes of less than 5 min could induce preconditioning or stunning in the isolated rat heart. Hearts were subjected to total global ischaemia of 1, 2 and 4 min followed by 10 min of reperfusion before an 18-min main ischaemic period and 30 min of reperfusion. The effects on physiology, purine metabolism and anaerobic glycolysis were compared with a control group subjected to the main ischaemia only. The brief ischaemic episodes did not produce stunning based on the recovery of left ventricular developed pressure (LVDP) and heart rate (HR) product during the first reperfusion. Preconditioning of 11–14% increased recovery of LVDP x HR during the second reperfusion was observed in the 1- and 4-min group. In the 2-min group a low repayment of flow debt during the first reperfusion was associated with a slightly reduced recovery of LVDP x HR compared to the other preconditioned groups during the second reperfusion. Only in the 4-min group was preconditioning associated with fewer breakdown products of the purine nucleotide pool (adenosine) and anaerobic glycolysis (lactate) in both tissue and effluate after the main ischaemia. Preconditioning (reflected in recovery of function) could be produced with ischaemic episodes of less than 5 min that did not produce stunning. Thus, stunning is probably not the primary cause of preconditioning.     

Complex pattern of Th1 and Th2 activation with a preferential increase of autoreactive Th1 cells in BALB/c mice with proteoglycan (aggrecan)-induced arthritis

The central role of CD4+ T cells and the balance between T helper (Th) subpopulations in the pathogenesis of autoimmune diseases have been extensively studied. Proteoglycan (aggrecan)-induced arthritis (PGIA) is a murine model for rheumatoid arthritis (RA), which is characterized by a Th1 dominance at the onset of the disease. In addition to CD4+ T cells, antigen-presenting B cells and autoantibodies seem to play an important role in the development and regulation of PGIA. To identify proteoglycan-specific CD4+ T cell subsets and Th1- and Th2-supported antibody isotypes during the progression of PGIA, spleen cells of proteoglycan-immunized BALB/c mice were harvested at different times of immunization, and at different stages of the disease, and their cytokine production and antigen-specific antibody isotype profiles were determined by enzyme-linked immunospot (ELISPOT) assays. Both Th1 and Th2 cytokine-producing cells, with the predominance of IL-4/IL-5-secreting cells, were detected during the prearthritic stage, and a shift toward a Th1 dominance was observed at the time of onset of arthritis. Tissue homogenates of acutely inflamed joints contained significantly higher levels of interferon-gamma than IL-4. The prearthritic period and both the acute and chronic phases of joint inflammation were characterized by IgG1 dominance in the sera and this correlated with the number of IgG1-secreting B cells in the spleen. However, the ratio of autoreactive IgG1/IgG2a-secreting cells decreased in arthritic animals. These results indicate the activation and possible regulatory roles of both Th1 and Th2 subsets in the autoimmune process, with the necessity of a relative increase of autoreactive Th1 cells for the induction of joint inflammation.     

Aberrant crypt focus promotion and glucose intolerance: correlation in the rat across diets differing in fat, n-3 fatty acids and energy

McKeown-Eyssen (Cancer Epidemiol. Biomarkers Prevent., 3, 687-695, 1994) and Giovannucci (Cancer Causes Control, 6, 164-179, 1995), noting the striking similarity in lifestyle risk factors for colorectal cancer and insulin resistance, proposed that the hyperinsulinemia, glycemia and hypertriglyceridemia associated with insulin resistance promotes colon cancer. To compare the effect of diet on colon cancer promotion and insulin resistance in the F344 rat, we assessed the effect of fat, n-3 fatty acids and energy in pairwise comparisons on average size of aberrant crypt foci (ACF) and on glucose intolerance in the same animals in a single experiment. Diets high in fat and energy increased and diets with increased n-3 fatty acids and calorie restriction decreased both ACF growth and glucose intolerance compared with control diets. The measures of promotion of colon cancer and insulin resistance were strongly correlated (n = 98, r = 0.67, P < 0.001). In addition, both were highly correlated with daily energy intake (r = 0.62 and 0.66) and were also correlated with basal (post-prandial) insulin, glucose and triglycerides (r = 0.31-0.53, P < 0.01). We concluded that ACF growth and glucose intolerance are correlated for a wide range of diets and that increased circulating energy (glucose and triglycerides) may lead to both colon cancer promotion and insulin resistance.      

Enhanced neutrophil extravasation and rapid progression of proteoglycan-induced arthritis in TSG-6-knockout mice

OBJECTIVE: To gain insight into the mechanisms of the antiinflammatory effect of tumor necrosis factor alpha (TNFalpha)-induced protein 6 (Tnfip6) in arthritis, using Tnfip6-deficient animals. METHODS: TNFalpha-stimulated gene 6 (TSG-6) coding for Tnfip6 was disrupted. Tnfip6-deficient mice were backcrossed into proteoglycan-induced arthritis (PGIA)-susceptible BALB/c mice, and arthritis was induced by systemic immunization with cartilage proteoglycan (PG). Thioglycollate-induced sterile peritonitis was also assessed, to monitor the early events of neutrophil extravasation in wild-type and Tnfip6-deficient mice in the presence or absence of treatment with recombinant murine Tnfip6. RESULTS: The onset of PGIA was similar, but progression and severity were significantly greater, in Tnfip6-deficient mice compared with wild-type BALB/c mice. However, this was not associated with enhanced T or B cell responses to cartilage PGs, but rather, an early and more extensive infiltration of the synovium with neutrophil leukocytes was the most prominent histopathologic feature of PGIA in Tnfip6-deficient mice. This was accompanied by elevated serum levels of interleukin-6 and amyloid A, and significantly increased activities of the enzymes plasmin, myeloperoxidase, and neutrophil elastase in the inflamed paw joints of Tnfip6-null mice, when compared with that of the wild-type littermates. Loss of control over several components of inflammation resulted in extensive and rapid cartilage degradation, bone erosion, joint ankylosis, and deformities in Tnfip6-null animals. In support of the antiinflammatory effect of Tnfip6 via the inhibition of polymorphonuclear (PMN) cell efflux, neutrophil invasion during thioglycollate-induced peritonitis was 2-fold higher in Tnfip6-deficient animals than in wild-type animals, but was dramatically suppressed by intravenous injection of recombinant murine Tnfip6. CONCLUSION: Tnfip6 is a multifunctional antiinflammatory protein that is produced at the site of inflammation and can be retained by the hyaluronan-rich extracellular matrix. A major effect of Tnfip6 is the inhibition of the extravasation of PMN cells, predominantly neutrophils, into the site of inflammation, most likely via a CD44/hyaluronan/Tnfip6-mediated blocking mechanism.     

Hyperbaric oxygen therapy improves angiogenesis and bone formation in critical sized diaphyseal defects

Besides the use of autologous bone grafting several osteoconductive and osteoinductive methods have been reported to improve bone healing. However, persistent non‐union occurs in a considerable number of cases and compromised angiogenesis is suspected to impede bone regeneration. Hyperbaric oxygen therapy (HBO) improves angiogenesis. This study evaluates the effects of HBO on bone defects treated with autologous bone grafting in a bone defect model in rabbits. Twenty‐four New‐Zealand White Rabbits were subjected to a unilateral critical sized diaphyseal radius bone defect and treated with autologous cancellous bone transplantation. The study groups were exposed to an additional HBO treatment regimen. Bone regeneration was evaluated radiologically and histologically at 3 and 6 weeks, angiogenesis was assessed by immunohistochemistry at three and six weeks. The additional administration of HBO resulted in a significantly increased new bone formation and angiogenesis compared to the sole treatment with autologous bone grafting. These results were apparent after three and six weeks of treatment. The addition of HBO therapy to autologous bone grafts leads to significantly improved bone regeneration. The increase in angiogenesis observed could play a crucial role for the results observed. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:513–520, 2015.     

Proteoglycan-induced arthritis in balb/c mice

Immunization with chondroitinase ABC–digested fetal human cartilage proteoglycan and Freund's complete adjuvant induced polyarthritis and ankylosing spondylitis in female BALB/c mice. The initial external symptoms of the joint inflammation were swelling and redness. This was associated with edema of the synovium and periarticular tissues and gross proliferation of cells, which reached a peak during weeks 7–9 of the experiment. Mononuclear cell infiltration, with perivascular concentration and occlusion of small vessels, was common. Synovitis increased in severity, villous pannus developed, and erosions of bone, articular cartilage, and occasionally, growth plate were observed. The lumbar spine and the proximal intervertebral discs of the tail also exhibited inflammatory and degenerative changes. As the arthritis progressed, sometimes with acute inflammatory exacerbations, more joints became involved and, by the sixteenth to the twentieth weeks of the experiment, a progressive polyarthritis, with gross joint deformities and restricted function, developed in the majority of the limb joints. Clinical and morphologic features of the disease correlated well with radiologic analysis and with an increased deposition of ^99mTc–methylene diphosphonate (determined by radionuclide imaging). The development of this arthritis was accompanied by the expression of cell-mediated and humoral immunity to the immunizing antigen. However, this immunity was also observed, although it was generally less well developed, in mice that received the intact or digested proteoglycan without adjuvant. These mice did not usually develop arthritis. Control mice that received only adjuvant did not develop arthritis.     

Naive transgenic T cells expressing cartilage proteoglycan-specific TCR induce arthritis upon in vivo activation

Proteoglycan (PG)-induced arthritis (PGIA), a murine model for rheumatoid arthritis (RA), is driven by antigen (PG)-specific T and B cell activation. In order to analyze the pathogenic role of antigen-specific T cells in the development of autoimmune arthritis, we have generated a transgenic (Tg) mouse. The CD4(+) T cells of this TCR-5/4E8-Tg line express a functional T cell receptor (TCR) composed of the Valpha1.1 and Vbeta4 chains with specificity for the dominant arthritogenic T cell epitope of human cartilage PG. Adoptive transfer of naive TCR-5/4E8-Tg cells induced arthritis with severe clinical symptoms in syngeneic immunodeficient BALB/c.RAG2(-/-) mice. In vivo activation of TCR-5/4E8-Tg CD4(+)Vbeta4(+) cells with cartilage PG seemed to be critical for arthritis induction. Arthritis never developed after transfer of naive wild-type cells. The arthritis was characterized as a chronic progressive disease with intermittent spontaneous exacerbations and remissions. Inflamed joints showed extensive cartilage damage and bone erosions leading to massive ankylosis in peripheral joints. These PG epitope-specific TCR-5/4E8-Tg mice can be valuable research tools for studying antigen-driven T cell regulation in arthritis, and migration of T cells to the joints. In addition the model may be used for the development of immune modulating strategies in T cell-mediated autoimmune diseases.     

Trafficking of CD44-deficient murine lymphocytes under normal and inflammatory conditions

CD44 has been implicated in hyaluronan (HA)-dependent primary adhesion between leukocytes and endothelium. We studied the trafficking of lymphocytes of CD44-deficient DBA/1 mice under normal conditions, and during chronic and transient forms of inflammation. Animals homozygous for the CD44 mutation (CD44(-/-)) showed no abnormalities in the composition of the lympho-hemopoietic system, but their leukocytes could not recognize HA as an adhesion ligand. T cells from CD44-deficient mice responded normally to immunization with type II collagen or stimulation with a bacterial superantigen. Lymphocytes harvested from naive CD44(-/-) and wild-type (WT) animals showed similar trafficking properties when injected into naive recipients. However, cells from WT and CD44-deficient mice with collagen-induced arthritis showed distinct migration kinetics upon transfer to arthritic recipients. While lymphocytes from CD44(-/-) mice preferentially homed to lymph nodes, their entry into the inflamed synovial joints was delayed as compared with WT cells. Similar differences were observed in the migration kinetics of CD44-deficient and CD44-competent (CD44(+/+)) lymphocytes in bacterial superantigen-induced peritonitis. These results suggest that CD44 plays opposite roles in the regulation of leukocyte traffic to inflammatory sites versus the lymph nodes. CD44-deficient lymphocytes from animals with chronic arthritis, but not from those with transient peritonitis, expressed markedly reduced levels of the lymph node homing receptor, L-selectin. Extreme down-modulation of L-selectin from CD44(-/-) cells in arthritic condition might be a counter-regulatory response, which, by extending lymphocyte transit time in the circulation at the expense of lymph node homing, allows CD44-deficient cells to gain entry to the site of chronic inflammation via secondary adhesion mechanisms.