The role of STAT3 in inflammatory bowel disease and colitis-associated cancer and research progress of the related drugs / 药学学报

Signal transducer and activator of transcription (STAT) 3 is a critical transcription factor for cell proliferation and survival. It is activated within cells by many cytokines to mediate immune and inflammatory responses to injury. Inflammatory bowel disease (IBD), represented by Crohn′s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease of the intestinal tract. STAT3 has been shown to be abnormally activated in IBD colon tissues by many pro-inflammatory cytokines, leading to disruption of the intestinal mucosal barrier and excessive innate immune and Th17 responses. The persistent chronic inflammation eventually leads to intestinal fibrosis and stenosis. In addition to immune responses, STAT3 is also involved in intestinal fibrosis in IBD by promoting the transcription of fibrosis-related genes. Colitis-associated cancer (CAC) is a particularly aggressive subtype of colorectal cancer and is associated with chronic inflammation-induced IBD. STAT3 has also been associated with CAC initiation and development. STAT3 is overactivated in tumors, which leads to suppression of the anti-tumor activity of immune cells and promotion of cancer cell proliferation, tumor angiogenesis, invasion, and migration. In the present article, we summarize the role of STAT3 in IBD and CAC and the research progress of the related drugs developed for UC and CAC treatment.

Basic research and application of microRNA--a novel target for regulating cardiac arrhythmias / 药学学报

Translational medicine is a novel concept about combination of basic research and clinical application. The aim of translational medicine is to realize the translation of basic research into clinical practice. microRNAs (miRNAs) are non-coding single-stranded RNAs with 21-25 nucleotides in length as newly discovered factors in regulating gene expression. Recently, the key regulatory role of miRNA in the cardiovascular system has been elucidated and amount of remarkable results has been achieved, particularly in the regulation of cardiac arrhythmias. A series of studies demonstrate that miRNAs are involved in the regulation of expression of a variety of proteins associated with cardiac electrical activity, and are the potential targets of occurrence of cardiac arrhythmias and anti-arrhythmic drugs. miRNAs as a therapeutic target regulate the stability of mRNAs of target genes or play an inhibitory role in the translation process. Stability of the corresponding miRNA expression levels in the target organ may be a new approach for the disease therapy. Regarding the dysfunction of miRNA, we employed miRNA re-expression strategy and anti-miRNA strategy to correct target protein function and provide a new entry for the therapy of arrhythmia. With the technology of miRNA mimics and antagomirs, miRNAs are expected to treat various cardiovascular diseases and will provide a fresh impetus to achieve transform medicine.

Probucol attenuates atrial autonomic remodeling in a canine model of atrial fibrillation produced by prolonged atrial pacing / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>We hypothesize that increased atrial oxidative stress and inflammation may play an important role in atrial nerve sprouting and heterogeneous sympathetic hyperinnervation during atrial fibrillation (AF). To test the hypothesis, we examined whether the antioxidant and anti-inflammatory treatment with probucol attenuates atrial autonomic remodeling in a canine model of AF produced by prolonged rapid right atrial pacing.</p><p><b>METHODS</b>Twenty-one dogs were divided into a sham-operated group, a control group and a probucol group. Dogs in the control group and probucol group underwent right atrial pacing at 400 beats per minute for 6 weeks, and those in the probucol group received probucol 1 week before rapid atrial pacing until pacing stopped. After 6-week rapid atrial pacing, general properties including left atrial structure and function, atrial hemodynamics and the inducibility and duration of AF were measured in all the groups. Atrial oxidative stress markers and serum C-reactive protein (CRP) concentration were estimated. The degree of nerve sprouting and sympathetic innervation at the right atrial anterior wall (RAAW) and the left atrial anterior wall (LAAW) were quantified by immunohistochemistry, atrial norepinephrine contents were also detected. Atrial beta-nerve growth factor (beta-NGF) mRNA and protein expression at the RAAW and LAAW were assessed by real-time quantitative RT-PCR and Western blotting respectively.</p><p><b>RESULTS</b>Atrial tachypacing induced significant nerve sprouting and heterogeneous sympathetic hyperinnervation, and the magnitude of nerve sprouting and hyperinnervation was higher in the RAAW than in the LAAW. Atrial beta-NGF mRNA and protein levels were significantly increased at the RAAW and LAAW, and the upregulation of beta-NGF expression was greater at the RAAW than at the LAAW in the control group. The beta-NGF protein level was positively correlated with the density of sympathetic nerves in all groups. Probucol decreased the increase of CRP concentration and attenuated atrial oxidative stress caused by atrial tachypacing. In addition, probucol could effectively inhibit atrial beta-NGF upregulation, significantly attenuate atrial nerve sprouting and heterogeneous sympathetic hyperinnervation, and dramatically reduce the inducibility and duration of AF.</p><p><b>CONCLUSIONS</b>The atrial over-expression of beta-NGF possibly caused by increased oxidative stress and inflammation may be the main mechanism underlying atrial autonomic remodeling during AF. Probucol attenuates atrial autonomic remodeling possibly by its antioxidant and anti-inflammatory actions.</p>

Molecular biological mechanisms of choline-modulated arsenic trioxide-induced electrocardiogram QT interval prolongation in guinea pig / 中国地方病学杂志

Objective To observe the therapeutic action of choline on As2O3 induced electrecardiogram (ECG)QT interval prolongation and to further explore molecular biological mechanisms.Methods 40 guinea pigs were divided into 5 groups randomly with 8 rats in each group:control group intravenously injected with saline, experimental group with 0.4,0.8,1.6 ms/kg of choline and As2O3 group with 8 mg/kg choline plus 1.6 mg/kg As2O3.After a series of concentration of As2O3 was intravenously given,ECG was monitored at different time(0,10, 30,60,90,120 min),and corrected QT interval(QTc)was studied.Total RNA Wa$abstracted from the guinea pigs hearts after 6 h,and the effects of choline on altered L-type calcium channel α1c and potassium channel GPERG mRNA expression caused by As2O3 in cardiomyocytes of guinea pig were studied by the method of reverse transcription polyme,chain reaction(RT-PCR).Results In 0.8 mg/kg As2O3 group,the value of QTc at 60, 90 and 120 min respectively being 354 ±22.366± 31 and 368 ±29 waa significantly higher than that of control groups[(325±26,336 ±26 and 324 ±20)at same time] with a significant difference(P<0.05 or<0.01);the value of QTc at 90 and 120 rain was significantly higher than that of O min group(334 ±12),the difference being statistically significant(P<0.05).In 1.6 mg/kg As2O3 group,the value of QTc at 10,30,60,90 and 120 min respectively being 362±33,380±21,382±35,388±39 and 388 ±31 was significantly higher than that of control groups[(328 ±20.324 ±25,325 ±26,336±26 and 324 ±20)at same time]with a significant difference (P<0.05 or<0.01);the value of QTc at 10,30,60,90 and 120 min Was significantly higher than that of O min group(329 ±31),the difference being statistically significant(P<0.05).In choline+As2O3group,the value of qrc at 30,60,90 and 120 min was 337 ±17,341±15,344 ±22 and 343 ±19,significantly lower than that of 1.6 mg/kg As2O3 group,the difference being statistically significant(P<0.05 or<0.01).The RT-PCR results indicated that the value of L-type calcium channel α1c mRNA expression at the concentration of 1.6 mg/kg As2O3 was 1.27±0.14 vs 1.02±0.12 of control group(P<0.01),and it was 1.10 ±0.13 in choline+As2O3 group(P<0.05 Vs 1.6 mg/kg As2O3 group).The value of potassium channel GPERG mRNA expression were 1.29 ±0.11,1.22±0.12 and 1.27±0.16 at the dose of 0.4,0.8,1.6 mg/kg As2O3(P>0.05 VS 1.23±0.08 of control group).In choline+ As2O3 group,the value was 1.30±0.14(compared with 1.6 mg/kg As2O3 group,P>0.05).Conclusions Choline normalizes QTc abnormality during As2O3 application,and modulating changed calcium channel mRNA expression induced by As2O3 may be one of the mechanisms.

The cardioprotective effect and mechanism of lumbrokinase / 药学学报

<p><b>AIM</b>To investigate the protective effect of lumbrokinase against myocardial ischemia and to further explore its underlying mechanisms.</p><p><b>METHODS</b>The effect of lumbrokinase on myocardial ischemia was observed by a model of acute myocardial infarction due to permanent ligation of the left anterior descending coronary artery in rats. Patch-clamp technique and laser scanning confocal microscopy were utilized to study the action of lumbrokinase on L-type calcium current (ICa-L) and intracellular calcium concentration ([Ca2+]i).</p><p><b>RESULTS</b>Lumbrokinase decreased the infarct size of myocardium in a dose-dependent manner. The inhibitory rate of lumbrokinase at the dose of 20, 40 and 80 mg x kg(-1) was 7.7%, 34.6% and 46.2%, respectively. The electrophysiological studies displayed that, at + 10 mV, the ICa-L was markedly reduced from (-14.42 +/- 1.53) pA/pF to (-11.33 +/- 1.40) pA/pF (decreased by 21.4%, P <0.01) and (-9.92 +/- 1.31) pA/pF (decreased by 36.5%, P <0.01) by lumbrokinase (10 and 50 micromol x L(-1)), respectively. Confocal experiments showed that 10 micromol x L(-1) lumbrokinase showed no obvious effects on [Ca2+]i at resting states (P > 0.05). However, the increase of [Ca2+]i induced by 60 mmol x L(-1) KCl was distinctly limited by 10 micromol x L(-1) lumbrokinase (P <0.01). Within 240 s, the no obvious peak value of fluorescent intensity (FI) was shown.</p><p><b>CONCLUSION</b>Lumbrokinase showed protective action against myocardial infarction in rats. The possible mechanisms of anti-ischemia could be attributed to decreasing ICa-L and [Ca2+] of ventricular myocytes in rats.</p>

Arsenic trioxide-induced hela cell death is partially prevented by K+ channel blockers / 药学学报

<p><b>AIM</b>To investigate the effects of K+ channel blockers on arsenic trioxide-induced HeLa cell death.</p><p><b>METHODS</b>Viability of HeLa cells was assessed by mitochondrial dehydrogenase activity using colorimetric MTT assay and the voltage-dependent K+ currents were recorded by using patch-clamp technique.</p><p><b>RESULTS</b>Exposure of As2O3 (5 micromol x L(-1)) for 24 h caused marked HeLa cell death. The rest living cells after As2O3 24 h-incubation showed significant increase of K+ currents densities. At +80 mV, the densities of K+ currents (61 +/- 18) pA/10 pF (n = 8) in As2O3 24 h-incubation group were significantly more than that in the control group (38 +/- 10) pA/10 pF (n = 8, P < 0.05). The HeLa cells were prevented partially from As2O3-induced cell death by co-application for 24 h with typical voltage-dependent K+ channel blockers, 4-aminopyridine (3 mmol x L(-1)) or tetraethylammonium (5 mmol x L(-1)). 4-Aminopyridine (3 mmol x L(-1)) or tetraethylammonium (5 mmol x L(-1)) did not show any toxic effects on HeLa cells.</p><p><b>CONCLUSION</b>Chronic treatment with As2O3 increased voltage-dependent K+ currents in HeLa cells and the cell death induced by As2O3 was reduced partially by voltage-dependent K+ channel blockers, 4-aminopyridine or tetraethylammonium.</p>

Establishment of a novel arrhythmia model in rats / 药学学报

<p><b>AIM</b>To establish a novel arrhythmia model in rats.</p><p><b>METHODS</b>Coronary artery occlusion was produced in hyperlipidemic rats after the animals were fed a high fat and cholesterol chow for 15 days. The incidence, duration and score of arrhythmias were determined 1 hour after coronary occlusion.</p><p><b>RESULTS</b>The incidence, duration and score of arrhythmia induced by coronary artery occlusion increased significantly in hyperlipidemic rats compared with those in normal rats (P < 0.05). In normal rats, pretreatment with amiodarone 60 mg x kg(-1) or verapamil 25 mg x kg(-1) 3 days before coronary artery occlusion did not influence the incidence, duration and score of arrhythmia (P > 0.05). In hyperlipidemic rats, amiodarone 60 mg x kg(-1) decreased the incidence, duration and score of arrhythmia (P < 0.05), but not verapamil 25 mg x kg(-1) (P > 0.05).</p><p><b>CONCLUSION</b>The novel arrhythmia model induced by coronary artery occlusion in hyperlipidemic rats is reliable and similar to the pathophysiological state in human being.</p>

Inhibitory effects of chloride channel blockers NPPB on proliferation of human glomerular mesangial cells / 药学学报

<p><b>AIM</b>To investigate the effects of NPPB, a chloride channel blocker, on proliferation of mesangial cells.</p><p><b>METHODS</b>Cell proliferation was determined by measuring cell number and 3H-thymidine incorporation. The LDH activity released from these cells was measured as evaluation of cell viability. The phase of cell cycle was detected by flow cytometry.</p><p><b>RESULTS</b>Cell proliferation assays showed that treatment with both NPPB (50 and 25 micromol x L(-1)) and in hypertonic media (100% increased osmolarity with D-mannitol ) significantly reduced the number of human MC and 3H-thymidine incorporation in a dose-dependent manner. But the LDH activity was not significantly altered in the treatment with 50 micromol x L(-1) NPPB. Flow cytometry experiments showed that 50 and 25 micromol x L(-1) NPPB arrested (84.2 +/- 2.4) % and (80.8 +/- 2.9) % of cells at G0/G1 stage, versus (70.5 +/- 1.4) % of control cells. Conclusion NPPB suppresses cell proliferation and produces growth arrest at G0/G1 phase in human MC by a mechanism probably associated with changes in cell volume.</p>

M3-R/IK(M3)--a new target of antiarrhythmic agents / 药学学报

<p><b>AIM</b>To investigate the relationship between M3-R/IK(M3) and arrhythmia in order to find a new target for antiarrhythmic agents.</p><p><b>METHODS</b>Using the acute ischemic model of rats and patch-clamp techniques, the effects of the M3 receptor on the occurrence of arrhythmias and its possible mechanisms were studied.</p><p><b>RESULTS</b>In acute ischemic model of rats, the M3 receptor antagonist 4-diphenylacetoxy-N-methylpiperidine-methiodide (4DAMP) increased the occurrence of arrhythmias, and the M3 receptor agonist choline suppressed the onset and the development of arrhythmias (P < 0. 01). No change was observed after treatment with other receptor antagonists (M1, M2, and M4). With patch-clamp techniques, it was found that choline induced K+ current could be inhibited by 4DAMP. Antagonists toward M1, M2, and M4 receptors all failed to alter the current.</p><p><b>CONCLUSION</b>Choline modulates the cellular electrical properties of the heart, probably by activating a K+ current via stimulation of the M3 receptor. M3-R/IK(M3) may act as a new target for antiarrhythmic agents.</p>

The ion targets of arrhythmias induced by ouabain and aconitine in guinea pig and rat ventricular myocytes / 药学学报

<p><b>AIM</b>To observe the effects of ouabain and aconitine on APD and ion channels in isolated guinea pig and rat ventricular myocytes; to elucidate the action mechanisms of these two drugs and set up new arrhythmic models on cellular level.</p><p><b>METHODS</b>In isolated ventricular myocytes of guinea pig and rat, the effects of ouabain and aconitine on APD, ICa-L, Ik, Ito and Ik1 were observed using the whole cell patch clamp technique.</p><p><b>RESULTS</b>Ouabain (5 micromol x L(-1)) obviously prolonged the APD90, increased ICa-L, decreased Ik and Ik1 in guinea pig ventricular myocytes. Aconitine (1 micromol x L(-1)) lengthened the APD90, increased ICa-L, decreased Ito and increased Ik1 in rat ventricular myocytes.</p><p><b>CONCLUSION</b>The targets on ouabain- and aconitine-induced arrhythmias included APD, ICa-L, Ik, Ito, and Ik1. APD, ICaL, Ik and Ito must be the powerful ones, both in arrhythmic and antiarrhythmic courses. The ouabain- and aconitine- induced arrhythmic models on cellular level were built to study the antiarrhythmic mechanisms of chemicals and evaluate new drugs. These two new-type models in vitro were stable, liable, repeatable and economic, which were superior to those typical models in vivo.</p>

Comparison of the anti-arrhythmic effects of matrine and berbamine with amiodarone and RP58866 / 药学学报

<p><b>AIM</b>To clarify mechanisms that the antiarrhythmic effects of matrine and berbamine are weaker than those of amiodarone and RP58866.</p><p><b>METHODS</b>Experimental arrhythmic models were induced by aconitine, coronary artery ligation and electric stimulation in rats and rabbits. Whole-cell patch-clamp techniques were used to record IK1, IKr, IKs and Ito.</p><p><b>RESULTS</b>Matrine and berbamine significantly increased the dose of aconitine for induction of ventricular premature and ventricular tachycardia in rats, decreased the number of arrhythmias induced by coronary artery ligation in rats and increased ventricular fibrillation threshold (VFT) induced by electric stimulation in rabbits, but the anti-arrhythmic potency of matrine and berbamine was lower than that of amiodarone and RP58866. The inhibitory actions of matrine and berbamine on IK1, IKr, IKs, Ito were lower than those of amiodarone and RP58866. The IC50 of matrine for IK1, IKr, IKs, Ito were (46 +/- 3), (32.9 +/- 1.2), (37 +/- 8) and (7.6 +/- 0.5) mol x L(-1), respectively. The IC50 of amiodarone for IK1, IKr, IKs, Ito were (21 +/- 5) , (3.7 +/- 0.7), (5.9 +/- 0.9) and (5.9 +/- 0.6) mol x L(-1), respectively.</p><p><b>CONCLUSION</b>The inhibitory actions of matrine and berbamine on IK1, IKr, IKs, Ito were lower than those of amiodarone and RP58866, which might be the reason that the antiarrhythmic effects of matrine and berbamine were weaker than those of amiodarone and RP58866.</p>