ABSTRACT
OBJECTIVE Although it is generally believed that nicotine accounts for the beneficial effect of smoking on ulcerative colitis, the underlying mechanisms remain not well understood. Our previous finding that nicotine inhibits inflammatory responses through inducing miRNA-124 prompted us to ask whether the miRNA is involved in the protective action of nicotine on UC. METHODS MiR-124 expres-sion in colon tissues and cells was determined by q-PCR and in situ hybridization.The effect of miR-124 on protective role of nicotine in ulcerative colitis was evaluated in DSS-treated mice and IL-6-treated Caco-2 colon epithelial cells. Expression of p-STAT3/STAT3 was detected by immunohistochemistry and Western-blot analysis. RESULTS miR-124 expression is upregulated in colon tissues from UC patients and DSS-induced colitis mice. Nicotine treatment further elevated miR-124 level in lympho-cytes isolated from human ulcerative colonic mucosa and ulcerative colon tissues from DSS mice,both in infiltrated lymphocytes and epithelial cells. Administration of nicotine also reduced weight loss, improved DAI and decreased HE score in DSS-induced colitis mice.Moreover,knockdown of miR-124 in vivo significantly diminished the beneficial effect of nicotine on murine colitis, and in vitro on IL-6-treated Caco-2 colon epithelial cells.Further analysis indicated that nicotine inhibited STAT3 activation in vivo and in IL-6-treated Caco-2 colon epithelial cells and Jurkat human T lymphocytes,in which miR-124 knockdown led to increased activation of STAT3. Blocking STAT3 activity alone is beneficial for DSS colitis and also abolished nicotine′s protective effect in this model.CONCLUSION These data indicated that nicotine exerts its protective action in UC through inducing miR-124 and its effect on STAT3, and suggest that the miR-124/STAT3 system is a potential target for the therapeutic intervention of UC.
ABSTRACT
Gender differences in fatigue manifest as females being more prone to feel exhaustion and having lower muscle endurance. However, the mechanisms of these effects remain unclear. We investigated whether orosomucoid, an endogenous anti-fatigue protein that enhances muscle endurance, is involved in this regulation. Female rats exhibited lower muscle endurance, and this gender difference disappeared in orosomucoid-1-deficient mice. Female rats also exhibited weaker orosomucoid induction in serum, liver and muscle in response to fatigue compared with male rats. Ovariectomy elevated orosomucoid levels and increased swimming time, and estrogen replenishment reversed these effects. Exogenous estrogen treatment in male and female mice produced opposite effects. Estrogen decreased orosomucoid expression and its promoter activity in C2C12 muscle and Chang liver cells in vitro, and estrogen receptor or p38 mitogen-activated protein kinase blockade abolished this effect. Therefore, estrogen negatively regulates orosomucoid expression that is responsible for the weaker muscle endurance in females.
ABSTRACT
Despite of great strides already made, China is still lagging behind Western countries in terms of scientific innovation, which is not parallel with China's economic achievement. Here I would like to summarize my experience in 30-year science research from the following two aspects: one is the motivation and source of innovation and the other is the value and implication of innovation. I will mainly focus on the relation of innovation with accidental discovery, reversed thought, long term accumulation, and challenge of the authorities. I will also discuss the great role of innovation in developing new theories, guiding medical practice,and dealing with emergencies.
ABSTRACT
Objective:Clonidine,by activating peripheral α-sbrenoceptors, produces transient pressor response after i.v.injection in anesthetized animals.Moxonidine, with at least 40-fold higher affinity to I1-imidazoline receptors than to α2-adrenoceptors,produces also a transient pressor response. This work was designed to investigate whether I1-imidazoline receptors are involved in this pressor effect of moxonidine. Methods:Female spontaneously hypertensive rats(SHRs,aged 14-16 weeks)were anesthetized with urethane.To observe the transient pressor responses,moxonidine 0.1,0.3,1.0mg/kg(intravenous,i.v),2.0μg(intracerebroventricular,i.c.v.)and 1.0,10.0mg/kg(intragastric,i.g.)were administrated in different groups of rats.To evaluate the roles of α1-adrenoceptors,α2-adrenoceptors and I1-imidazoline receptors in the transient pressor responses to moxonidine, prazosin(10.0μg/kg),yohimbine(2.0mg/kg),phentolamine(0.2mg/kg),idazoxan(1.0mg/kg)or yohimbine+idazoxan(2.0mg/kg+1.0mg/kg)were intravenously given to the animals before moxonidine 0.3mg/kg (i.v.).Results:It was found that i.v.moxonidine produced a greater pressor response than clonidine when producing a similar reduction of blood pressure.This effect of moxonidine was not influenced by prazosin, but was partly inhibited by yohimbine, phentolamine or idazoxan,and completely blocked by the combination of yohimbine and idzaxon.Neither i.c.v.injection nor i.g. administration of moxonidine induced transient pressor responses.Conclusion:The transient pressor response of i.v. moxonidine is mediated by both peripheral I1-imidazoline receptors and α2-adrenoceptors.
ABSTRACT
Objective:Clonidine,by activating peripheral α-sbrenoceptors, produces transient pressor response after i.v.injection in anesthetized animals.Moxonidine, with at least 40-fold higher affinity to I1-imidazoline receptors than to α2-adrenoceptors,produces also a transient pressor response. This work was designed to investigate whether I1-imidazoline receptors are involved in this pressor effect of moxonidine. Methods:Female spontaneously hypertensive rats(SHRs,aged 14-16 weeks)were anesthetized with urethane.To observe the transient pressor responses,moxonidine 0.1,0.3,1.0mg/kg(intravenous,i.v),2.0μg(intracerebroventricular,i.c.v.)and 1.0,10.0mg/kg(intragastric,i.g.)were administrated in different groups of rats.To evaluate the roles of α1-adrenoceptors,α2-adrenoceptors and I1-imidazoline receptors in the transient pressor responses to moxonidine, prazosin(10.0μg/kg),yohimbine(2.0mg/kg),phentolamine(0.2mg/kg),idazoxan(1.0mg/kg)or yohimbine+idazoxan(2.0mg/kg+1.0mg/kg)were intravenously given to the animals before moxonidine 0.3mg/kg (i.v.).Results:It was found that i.v.moxonidine produced a greater pressor response than clonidine when producing a similar reduction of blood pressure.This effect of moxonidine was not influenced by prazosin, but was partly inhibited by yohimbine, phentolamine or idazoxan,and completely blocked by the combination of yohimbine and idzaxon.Neither i.c.v.injection nor i.g. administration of moxonidine induced transient pressor responses.Conclusion:The transient pressor response of i.v. moxonidine is mediated by both peripheral I1-imidazoline receptors and α2-adrenoceptors.
ABSTRACT
It is well known that the arterial baroreflex(ABR)plays a key role in the regulation of heart rate and stabilization of blood pressure.Currently,it appears that ABR dysfunction is involved in the pathophysiology of cardiovascular disease states.Since the mid-1990s,a number of studies have been carried out in our laboratory to explore the pathological significance of ABR function in cardiovascular damage.This minireview summarizes our research work on the topic of ABR and left ventricular hypertrophy(LVH).On the basis of discussion concerning the importance of ABR dysfunction in hypertensive LVH and sinoaortic denervation-induced LVH,we advance a new strategy for reversal of LVH,that is,restoration of impaired ABR function.We tested this hypothesis in animal models with ABR deficiency.It was found that improvement of impaird ABR function with long-term treatment of ketanserin or candesartan was accompanied by reversal of LVH.The preliminary results indicate that it is feasible to target ABR for treatment of LVH.
ABSTRACT
Objective:Glucose-insulin-potassium(GIK) is clinically used for reducing mortality in acute myocardial infarction(MI). It is known that ventricular arrhythmia, left ventricular dysfunction and impaired baroreflex sensitivity(BRS) are the three major determinants for predicting the mortality after acute MI. The present work was designed to study the effects of GIK on BRS, ventricular arrhythmia, and left ventricular function in rats with coronary artery ligature. Sprague-Dawley rats were used and the myocardial infarction was produced by ligature of the left anterior descending artery. Five weeks after coronary artery ligation, BRS was measured in conscious state with a computerized blood pressure monitoring system and left ventricular function and electrocardiogram were determined in the anaesthetized state in the subacute phase of myocardial infarction. It was found that GIK did not affect the blood pressure and heart period in both conscious and anaesthetized rats. GIK did not enhance BRS, but reduced ventricular arrhythmia and improved left ventricular function by reducing left ventricular end diastolic pressure in anaesthetized rats with MI. It is proposed that reducing ventricular arrhythmia and improving left ventricular function contribute to the effect of GIK on reducing the mortality after MI.
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Objective:It has been proposed that blood pressure variability(BPV) is positively related to end-organ damage(EOD) in hypertension.The present work was designed to observe the effects of long-term treatment with nitrendipine and hydralazine on BPV and EOD in spontaneously hypertensive rats(SHR),to examine the hypothesis that lowering BPV with an antihypertensive drug is an important factor in organ protection.Design and methods:Drugs were mixed in rat chow.After 4 months of drug administration,blood pressure was recorded continuously in conscious freely moving rats for 24 h.The heart,kidneys,and brain were then isolated and examined.Results:It was found that nitrendipine significantly decreased blood pressure and BPV,and significantly decreased EOD score in SHR.Hydralazine decreased blood pressure,but did not lower BPV.No effect on EOD was found in hydralazine-treated rats.In control rat(n=38),EOD score was weakly related to systolic blood pressure(r=0.331,P<0.05) and closely related to long-term systolic BPV(r=0.551,P<0.01).In nitrendipine-treated rats,EOD score was closely related to long-term systolic BPV(r=0.602,P<0.01),but not to blood pressure level(r=0.174,P>0.05).Conclusion:BPV plays an important role in the organ-protecting effects of nitrendipine.
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Objective:The present study was designed to test the hypothesis that inflammation is involved in the end-organ damage(EOD) induced by sinoaortic denervation(SAD) in rats.Method:SAD was performed in male Sprague-Dawley rats at the age of 10 weeks.Under anaesthesia,aortic nerves were cut and the sinus region of the carotid artery was stripped and painted with 10% phenol.Pathological evaluation of EOD and the determination of plasma or tissue levels of the factors related to inflammation,including thromboxane B2(TXB2) interleukin-1(IL-1),tumour necrosis factor α(TNF-α) and reactive oxygen species(ROS) were performed at 16 weeks after SAD.Pathological evaluation of EOD included heart weigh ratio,myocardial and blood vessel hydroxyproline and collagen volume fraction,glomerular injury score and number of infiltrating inflammatory cells.Indomethacin(20 mg/kg per day,orally) or vitamin E(100 mg/kg per day,orally) was administered for 12 weeks,beginning from4 weeks after SAD,to observe their effects on SAD-induced EOD.Results:There were significant fibrosis and inflammatory infiltration in the myocardium and blood vessels,represented by higher hydroxyproline and collagen volume fraction,and a large amount of inflammatory cells in the tissues of SAD rats.Heart weight and kidney glomerular injury score were significantly higher in ed significantly after SAD.Indomethacin and vitamin E significantly decreased the contents of some factors related to inflammation in SAD rats.Both drugs also alleviated myocardial and vessel fibrosis,inflammatory infiltration and kidney damage.Conclusion:Inflammation is involved in the organ damage induced by SAD in rats.
ABSTRACT
It is well known that the arterial baroreflex(ABR)plays a key role in the regulation of heart rate and stabilization of blood pressure.Currently,it appears that ABR dysfunction is involved in the pathophysiology of cardiovascular disease states.Since the mid-1990s,a number of studies have been carried out in our laboratory to explore the pathological significance of ABR function in cardiovascular damage.This minireview summarizes our research work on the topic of ABR and left ventricular hypertrophy(LVH).On the basis of discussion concerning the importance of ABR dysfunction in hypertensive LVH and sinoaortic denervation-induced LVH,we advance a new strategy for reversal of LVH,that is,restoration of impaired ABR function.We tested this hypothesis in animal models with ABR deficiency.It was found that improvement of impaird ABR function with long-term treatment of ketanserin or candesartan was accompanied by reversal of LVH.The preliminary results indicate that it is feasible to target ABR for treatment of LVH.
ABSTRACT
Objective:Glucose-insulin-potassium(GIK) is clinically used for reducing mortality in acute myocardial infarction(MI). It is known that ventricular arrhythmia, left ventricular dysfunction and impaired baroreflex sensitivity(BRS) are the three major determinants for predicting the mortality after acute MI. The present work was designed to study the effects of GIK on BRS, ventricular arrhythmia, and left ventricular function in rats with coronary artery ligature. Sprague-Dawley rats were used and the myocardial infarction was produced by ligature of the left anterior descending artery. Five weeks after coronary artery ligation, BRS was measured in conscious state with a computerized blood pressure monitoring system and left ventricular function and electrocardiogram were determined in the anaesthetized state in the subacute phase of myocardial infarction. It was found that GIK did not affect the blood pressure and heart period in both conscious and anaesthetized rats. GIK did not enhance BRS, but reduced ventricular arrhythmia and improved left ventricular function by reducing left ventricular end diastolic pressure in anaesthetized rats with MI. It is proposed that reducing ventricular arrhythmia and improving left ventricular function contribute to the effect of GIK on reducing the mortality after MI.
ABSTRACT
Objective:It has been proposed that blood pressure variability(BPV) is positively related to end-organ damage(EOD) in hypertension.The present work was designed to observe the effects of long-term treatment with nitrendipine and hydralazine on BPV and EOD in spontaneously hypertensive rats(SHR),to examine the hypothesis that lowering BPV with an antihypertensive drug is an important factor in organ protection.Design and methods:Drugs were mixed in rat chow.After 4 months of drug administration,blood pressure was recorded continuously in conscious freely moving rats for 24 h.The heart,kidneys,and brain were then isolated and examined.Results:It was found that nitrendipine significantly decreased blood pressure and BPV,and significantly decreased EOD score in SHR.Hydralazine decreased blood pressure,but did not lower BPV.No effect on EOD was found in hydralazine-treated rats.In control rat(n=38),EOD score was weakly related to systolic blood pressure(r=0.331,P<0.05) and closely related to long-term systolic BPV(r=0.551,P<0.01).In nitrendipine-treated rats,EOD score was closely related to long-term systolic BPV(r=0.602,P<0.01),but not to blood pressure level(r=0.174,P>0.05).Conclusion:BPV plays an important role in the organ-protecting effects of nitrendipine.
ABSTRACT
Objective:The present study was designed to test the hypothesis that inflammation is involved in the end-organ damage(EOD) induced by sinoaortic denervation(SAD) in rats.Method:SAD was performed in male Sprague-Dawley rats at the age of 10 weeks.Under anaesthesia,aortic nerves were cut and the sinus region of the carotid artery was stripped and painted with 10% phenol.Pathological evaluation of EOD and the determination of plasma or tissue levels of the factors related to inflammation,including thromboxane B2(TXB2) interleukin-1(IL-1),tumour necrosis factor α(TNF-α) and reactive oxygen species(ROS) were performed at 16 weeks after SAD.Pathological evaluation of EOD included heart weigh ratio,myocardial and blood vessel hydroxyproline and collagen volume fraction,glomerular injury score and number of infiltrating inflammatory cells.Indomethacin(20 mg/kg per day,orally) or vitamin E(100 mg/kg per day,orally) was administered for 12 weeks,beginning from4 weeks after SAD,to observe their effects on SAD-induced EOD.Results:There were significant fibrosis and inflammatory infiltration in the myocardium and blood vessels,represented by higher hydroxyproline and collagen volume fraction,and a large amount of inflammatory cells in the tissues of SAD rats.Heart weight and kidney glomerular injury score were significantly higher in ed significantly after SAD.Indomethacin and vitamin E significantly decreased the contents of some factors related to inflammation in SAD rats.Both drugs also alleviated myocardial and vessel fibrosis,inflammatory infiltration and kidney damage.Conclusion:Inflammation is involved in the organ damage induced by SAD in rats.
ABSTRACT
Our previous data demonstrate that impairment of arterial baroreceptor reflex (ABR) plays an independent role in hypertension target organ damage. To elucidate the mechanisms responsible for the dysfunction of ABR associated organ damage, sinoaortic denervated (SAD) rats were used as an animal model of ABR dysfunction. Twenty-four-hour continuous blood pressure (SBP and DBP), blood pressure variability (BPV), heart rate (HR) and HR variability (HRV) were measured in conscious and unrestrained rats. Angiotensin II (Ang II) in plasma, heart and kidney was assayed by raio-immunological assay (RIA) 1 or 18 weeks after denervation. In short-term SAD rats, twenty-four-hour mean SBP and DBP increased compared with that of sham-operated rats and long-term SAD rats. No significant difference in SBP, DBP or HR was found between long-term SAD rats and sham-operated ones. Compared with the sham-operated rats, long-term SAD rats had elevated BPV. No significant change in Ang II levels of caridiac and renal tissues was found in short-term SAD rats. In long-term SAD rats, Ang II level of plasma was not increased while the Ang II content in the heart and kidney increased. Ang II contents of plasma and tissues in long-term SAD rats exposed to chronic stress were higher than those in the control rats. These results show (1) in short-term SAD rats blood pressure increased, while in long-term SAD rats 24 h mean blood pressure did not increase, although BPV elevated in long-term SAD rats; (2) in long-term SAD rats, secretion of Ang II in cardiac and renal tissues was enhanced and more Ang II released when the animals were exposed to chronic stress. These results suggest that elevated BPV and secretion of Ang II may be related to the development of organ damage induced by ABR dysfunction.