Progresses in therapeutic strategies for thymic rejuvenation / 生理学报

The thymus is a vital primary lymphoid organ that provides unique microenvironments for the proliferation, differentiation, and maturation of T cells. With advancing age, however, the thymus gradually undergoes age-related involution and reduction in immune function, which are characterized by decreases in tissue size, cellularity, and naïve T cell output. This dynamic process leads to the reduced efficacy of the immune system with age and contributes to the increased susceptibility to infection, autoimmune disease, and cancer. In addition, bone marrow transplantation, radio-chemotherapy and virus infection also impair the thymus and give rise to the decline in immune function. Therefore, understanding the molecular mechanisms involved in age-related thymic involution and development of novel therapeutic strategies for thymic rejuvenation have gained considerable interests in recent years. This review emphasizes thymic microenvironments and thymocyte-stromal cell interactions and summarizes our current knowledge about thymic rejuvenation in terms of sex steroid, cytokines, growth factors, hormones, transcription factors, cell graft, and microRNAs. At the end of each discussion, we also highlight unanswered issues and describe possible future research directions.

Antagonism role of adenosine in right ventricular hypertrophy induced by hypoxia in rat / 中华实用儿科临床杂志

Objective To investigate the antagonism role of adenosine and its agonists in hypoxia-induced right ventricular hypertrophy in rat.Methods Fifty-six Sprague-Dawley rats were randomly divided into 7 groups,including normoxia control group,hypoxia control group,hypoxia plus adenosine group,hypoxia plus adenosine A1 receptor agonist(CPA) group,hypoxia plus adenosine A2 receptor agonist(NECA) group,hypoxia plus CPA and adenosine A1 receptor antagonist (DPCPX) group,hypoxia plus NECA and adenosine A2b receptor antagonist(MRS1754) group.There were 8 rats in each group.Rats in all groups except normoxia group were exposed to hypoxia for 21 days(oxygen volume concentration of 95-105 mL/L).On the 7th day,agents were continuously delivered with micro osmotic pump for 14 days.At the end of the experiment,both right ventricular to left ventricular plus septum weight[RV/(LV + S)] ratio and right ventricular to body weight (RV/BW) ratio were measured,and the expression of myosin heavy chain (β-MHC) mRNA and regulator of G protein signaling 4(RGS4) mRNA in the right ventricular myocardial tissues were detected by PCR method.Results 1.After chronic hypoxia for 21 days,the ratios of RV/(LV + S) and RV/ BW in the hypoxia control group were significantly higher than those in the normoxia control group respectively(all P ＜ 0.001) ; the ratios of RV/(LV + S) and RV/BW in the hypoxia plus adenosine group and hypoxia plus CPA group were significantly lower than those in the hypoxia control group (all P ＜ 0.05) ; the ratio of RV/(LV + S) in the hypoxia plus NECA group was significantly lower than that in the hypoxia control group(P ＜ 0.05).2.The expression level of β-MHC mRNA in the hypoxia control group was higher than that in the normoxia control group(P ＜ 0.001),and the expression level of RGS4 mRNA in the hypoxia group was lower than that in the normoxia group(P ＜ 0.001) ; the expression levels of β-MHC mRNA in the hypoxia plus adenosine group,hypoxia plus CPA group,or hypoxia plus NECA group were lower than those in the hypoxia control group (all P ＜ 0.001) ; the expression levels of RGS4 mRNA in hypoxia plus adenosine group,hypoxia plus CPA group,and hypoxia plus NECA group were higher than those in the hypoxia control group(all P ＜ 0.001).Conclusions Adenosine can attenuate hypoxia-induced right ventricular hypertrophy through RGS4 mediated pathway.

Adenosine receptors agonists mitigated PAH of rats induced by chronic hypoxia through reduction of renin activity/angiotensin II levels and increase of inducible nitric oxide synthase-nitric oxide levels / 中华儿科杂志

<p><b>OBJECTIVE</b>Recent studies showed that adenosine played important roles in vasodilation. This study aimed to investigate the effects of adenosine, its A1 and A2b receptor agonists on pulmonary artery hypertension (PAH) induced by chronic hypoxia in rats by continuously subcutaneous administration with an osmotic pump for 14 days, and to see if rennin angiotensin system and inducible nitric oxygen synthase (iNOS)/nitric oxide (NO) mediate the effects.</p><p><b>METHOD</b>Fifty-six male SD rats were randomly assigned to seven groups. Each group included eight rats. They were normoxic group, hypoxic group, adenosine-treated group [adenosine was administered at a dose of 150 µg(kg·min) under the hypoxic condition], adenosine A1 receptor agonist CPA-treated group [CPA was administered at a dose of 20 µg/(kg·min) under the hypoxic condition], CPA plus selective adenosine A1 antagonist DPCPX-treated group [CPA and DPCPX were administered simultaneously under the hypoxic condition, the dose of CPA was the same as the above, and the dose of DPCPX was 25 µg/(kg·min)], adenosine A2b receptor agonist NECA-treated group [NECA was administered at a dose of 30 µg/(kg·min) under the hypoxic condition], NECA plus selective adenosine A2b receptor antagonist MRS-treated group[ NECA and MRS1754 were administered simultaneously under the hypoxic condition, the dose of NECA was the same as the above, and the dose of MRS1754 was 50 µg/(kg·min)]. Osmotic pumps containing adenosine or selective adenosine A1 receptor agonist (CPA), or nonselective but potent adenosine A2b receptor agonist (NECA) were placed subcutaneously 7 days after hypoxia and continuously administered the agents for 14 days.Mean pulmonary artery pressure (mPAP) was detected after administration of the agents. Then blood samples were taken from heart for measurement of renin activity, angiotensin II (AngII) and endothelin-1 (ET-1) concentration by radioimmunoassay, NO by measuring nitrate. Small pulmonary arteries were prepared for immunoreactivity staining of proliferating cell nuclear antigen (PCNA) and iNOS.</p><p><b>RESULT</b>(1) Chronic hypoxia induced PAH [mPAP: (31.38 ± 3.42) mm Hg]. Adenosine or CPA or NECA administered for 14 days by subcutaneous route attenuated the mPAP [(21.17 ± 3.56) mm Hg, (22.88 ± 2.95) mm Hg, (19.81 ± 2.39) mm Hg, respectively], which showed significant difference when compared with hypoxia group (P < 0.05 respectively). (2) Plasma rennin activity and AngII level in hypoxia group [(2.51 ± 0.25) ng/(ml·h), (83.01 ± 9.38) pg/ml] were significantly higher than that in normoxic group (P < 0.05, respectively).(3) Adenosine treatment decreased the rennin activity and AngII level when compared with hypoxic group(P < 0.05, respectively);CPA and NECA attenuated respectively the rennin activity and AngII level of rats induced by chronic hypoxia (P < 0.05, respectively). (4) Adenosine administration for 14 days attenuated the wall thickness induced by chronic hypoxia (P < 0.05). CPA showed no effect on wall thickness, but NECA significantly attenuated the wall thickness (P < 0.05). (5) The number of iNOS staining positive cells in small pulmonary artery was higher in hypoxia group than in that in normoxic rats (23.75 ± 7.91 vs. 8.00 ± 2.20, P < 0.05). Adenosine or CPA, or NECA administration increased respectively the iNOS expression in rats treated with chronic hypoxia. Chronic hypoxia caused significant decrease of nitric oxide level. Adenosine treatment increased the nitric oxide level in rats treated with chronic hypoxia. CPA and NECA also increased respectively the nitric oxide level in rats treated with chronic hypoxia. Chronic hypoxia caused significant increase of ET-1 level. The ET-1 level in rats treated with adenosine, CPA or NCEA respectively were lower than that in chronic hypoxia rats (P < 0.05). (6) Adenosine treatment partially attenuated the number of PCNA-positively stained cells. NECA treatment also attenuated the PCNA expression, but CPA showed no effect.</p><p><b>CONCLUSION</b>Adenosine and its agonists CPA, NECA administered continually by subcutaneous route attenuate mPAP of rats induced by chronic hypoxia. CPA attenuates mPAP through reduction of RA/AngII activity and balance of NO/ET-1 level. NECA attenuates mPAP by inhibiting PCNA expression and proliferation of mooth muscle of pulmonary artery.</p>

Effects of continuous adenosine infusion on pulmonary hypertension in chronically hypoxic rats / 南方医科大学学报

<p><b>OBJECTIVE</b>To observe the effects of continuous subcutaneous adenosine infusion on pulmonary hypertension in chronically hypoxic rats.</p><p><b>METHODS</b>Twenty-four SD rats were randomized into normoxic group, hypoxic group and adenosine-treated hypoxic group. Hypoxic environment was simulated in a chamber filled with 10% oxygen and 90% nitrogen. After 7 days of hypoxia, adenosine were administered subcutaneously in the rats in adenosine-treated group at the rate of 100 microg kg(-1) min(-1) via an Alzet micro-osmotic pump for 14 days, while the pumps in the other two groups contained normal saline. After 21 days of hypoxia, pulmonary artery pressure and tail-cuff blood pressure were measured, with the plasma rennin activity (RA), angiotensin II (AngII), endothelin (ET)-1, and nitric oxide (NO) determined. Inducible nitric oxide synthase (iNOS) expression in the pulmonary artery of the rats was detected using immunohistochemical method.</p><p><b>RESULTS</b>The mean pulmonary artery pressure (mPAP) was significantly higher in the hypoxic group than that in the normoxic group (P<0.01) and in the adenosine-treated group (P<0.01). Plasma ET-1 was significantly higher but plasma NO significantly lower in the hypoxic group than in the normoxic group (P<0.01) and the adenosine-treated group (P<0.01). iNOS expression in the pulmonary artery was higher in the hypoxic group than in normoxic group (P<0.01), and adenosine significantly increased iNOS expression in comparison with the normoxic and hypoxic groups (P<0.01). Plasma RA and AngII in the hypoxic group were significantly higher than those in the normoxic group (P<0.01) and the adenosine-treated (P<0.01).</p><p><b>CONCLUSION</b>Adenosine administered by continuous subcutaneous infusion alleviates chronically hypoxia-induced pulmonary hypertension in rats, in which rennin angiotensin system, ET-1, and iNOS/NO play a role.</p>

Effect of adenosine on activity of transcription factor NF-kappa B and cytokines in myocardial tissue of experimental rats with pneumonia / 中华儿科杂志

<p><b>OBJECTIVE</b>Recent studies have shown that cytokines TNF-alpha and IL-6 play important roles in myocardial injury or dysfunction. Transcription nuclear factor (NF-kappa B) have been implicated in the regulation of a variety of cytokines in response to cellular defense. The authors observed the activity of NF-kappa B and cytokines TNF-alpha, IL-6 mRNA expression in myocardium to further investigate the mechanism of myocardial injury caused by infectious pneumonia. The therapeutic effect of exogenous adenosine was also studied by observing the influence on NF-kappa B and cytokines.</p><p><b>METHODS</b>Thirty rats were divided into three experimental groups at random, each group had 10 rats. The model of pneumonia was induced by the injection of Staphylococcus aureus into the trachea of rats. Adenosine-treated rats were given daily slow intravenous injection of adenosine at a dose of 150 microg/kg.min for 3 days from the second day. All rats were killed on the fifth day. Myocardial tissues were preserved in liquid nitrogen for examination. Pathological examination of myocardium was done and TNF-alpha and IL-6 mRNA expression was detected by reverse transcription polymerase chain reaction (RT-PCR). NF-kappa B activity was measured by electrophoretic mobility shift assay (EMSA).</p><p><b>RESULTS</b>(1) The myocardium in pneumonia group showed significant pathological lesion when compared with control group (P < 0.01). The pathological lesion of myocardium in adenosine-treated group significantly decreased when compared to pneumonia group (P < 0.05). (2) Significant increase of TNF-alpha and IL-6 mRNA expression was observed in myocardium of pneumonic rats when compared with control group (2.27 +/- 0.27 vs. 1.05 +/- 0.16; 1.89 +/- 0.31 vs. 1.12 +/- 0.25: P < 0.01, respectively). NF-kappa B activity of myocardium in pneumonia group was significantly higher than that in control group (13,033 +/- 1286 vs. 383 +/- 15: P < 0.01). (3) TNF-alpha and IL-6 mRNA expression was significantly decreased in adenosine-treated group when compared with pneumonia group (1.25 +/- 0.18 vs. 2.27; 1.31 +/- 0.25 vs. 1.89 +/- 0.31, P < 0.01, respectively). Comparing to that in pneumonia group, NF-kappa B activity of myocardium in adenosine-treated group was significantly decreased (4 487 +/- 562 vs. 13033 +/- 1286, P < 0.01), but it was still significantly higher than that in control group (4487 +/- 562 vs.383 +/- 15, P < 0.01).</p><p><b>CONCLUSIONS</b>Increased activity of NF-kappa B and subsequent upregulation of TNF-alpha and IL-6 mRNA expression probably play a pivotal role in the mechanism of myocardial injury in rats with pneumonia. Exogenous adenosine can inhibit inflammatory change by lowering NF-kappa B activity and subsequent down-regulation of TNF-alpha and IL-6 expression. Our findings provide novel therapeutic evidence of adenosine in myocardial injury induced by pneumonia in clinic.</p>

ONE NEW SPECIE OF CITEROMYCES FROM CHINA SWEET FLOUR PASTE / 微生物学通报

The investigators isolated one yeast from China Huaimao sweet flour paste. The strain was identified into Citeromyces, and claimed being a new species. The strain was named as Ctieromyces baadingensis zhang sp. Nov., which differed markedly from Citeromyces matritensis in physiological and biochemical characteristics. Citeromyces baod-ingensis didn't ferment sucrose and raffinose, and assimilated galactose and cellobiose, and didn't assimilate galactose and ceflobiose. The G+C mol% was 48.5.

Mechanisms of Calcineurin Signaling Pathway Mediating Myocardium Apoptosis of Right Heart in Rats with Chronic Hypoxia / 实用儿科临床杂志

Objective To investigate calcineurin signaling pathway which mediates myocardium apoptosis of right heart in rats with chronic hypoxia and the potential mechanisms of it.Methods A rat model of right ventricular hypertrophy(RVH) was established induced by chronic hypoxia(95-105 mL?L-1 O2).Used randomized block design based on different brood,30 rats were divided into 3 groups:treatment group with cyclosporine A(CsA,10 mg?kg-1?d-1,intraperitoneal injection),chronic hypoxia group,normal control group(with normal oxygen).The rats in CsA treatment group and chronic hypoxia group were exposed to normobaric chronic hypoxia(95-105 mL?L-1 O2,21 days).Apoptotic index(AI),calcineurin A?(CnA?) mRNA levels,Bcl-2 mRNA levels and the protein expression levels of CnA?,nuclear factor 3 of activated T cells(NFAT3) and Bcl-2 in right ventricle were investigated.Results 1.The AI of treatment group with CsA was higher than that in chronic hypoxia group(P

Continuous Administration of Adenosine by Peripheral Pathway Attenuate Myocardial Hypertrophy and Pulmonary Arterial Hypertension Induced by Hypoxia in Rats / 实用儿科临床杂志

Objective To explore if continuous administration of adenosine by peripheral pathway can attenuate myocardial hypertrophy and pulmonary arterial hypertension(PAH)caused by chronic hypoxia and analyze the dose-effect relationships between them.Methods Forty-eight Sprague-Dawley(SD)rats were randomly divided into 8 groups:the hypoxia group(n=6),the hypoxia ade-nosine-treated groups [n=18,adenosine was administrated with different doses 50,100,150 ?g/(kg?min),the hypoxia adenosine-treated group A,B,C],the control group(n=6),the control adenosine-treated control groups [n=18,adenosine was administrated with different doses 50,100,150 ?g/(kg?min),the control adenosine-treated control group A,B,C].On the 21st day of the experiment,the Medlab-U/4CS was used to determined the right ventricular systolic pressure(RVSP)and the mean pulmonary arterial pressure(mPAP)of each rat.The ratio of the weight of right ventricle/left ventricle and septum[RV/(LV+S)] and the ratio of the weight of right ventricle/body weight(RV/BW)were also calculated.The morphological changes in myocardium cells and pulmonary vascular structure were observed.SAS 8.0 software was used to analyze the data.Results Twenty-one days after hypoxia,RVSP,mPAP,RV/(LV+S),RV/BW in hypoxia groups were higher significantly than those in control group and hypoxia adenosine-treated groups(Pa