The effect of long-term moderate exercise on myocardial metabolome in rats.

Regular moderate physical exercise is beneficial for the cardiovascular system. Our prior study has demonstrated a long-term moderate exercise (4-week of 60-min 74.0% V̇O2max treadmill running) is optimal in protecting from exhaustive exercise-induced cardiac ischemic injury. This study is aimed to investigate the effect of long-term moderate exercise on myocardial metabolome in rats. Thirteen male Sprague-Dawley rats were randomly assigned into the control group (C) and the long-term moderate exercise group (E). The targeted metabolomics of the myocardium was analyzed by ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) system. Results showed that the metabolites categories of bile acids (BAs), fatty acids (FAs), and phenylpropanoic acids were significantly decreased. The biosynthesis of unsaturated FAs pathway was significantly downregulated. The altered metabolites in the E Group included decreased FAs (pentadecanoic acid, 10Z-heptadecenoic acid, dihomo-gamma-linolenic acid, docosahexaenoic acid, docosapentaenoic acid, and 10Z-nonadecenoic acid), decreased BAs (chenodeoxycholic acid and beta-muricholic acid), decreased organic acids (glycolic acid and 2-hydroxyglutaric acid), decreased carbohydrate (N-acetylneuraminic acid, Neu5Ac), decreased amino acids (α-aminobutyric acid and norvaline), decreased phenylpropanoic acids (hydroxyphenyllactic acid), and benzoic acids (4-hydroxybenzoic acid and phthalic acid). The results indicated that long-term moderate exercise has promoted lipids utilization in myocardium while exerted little influence on carbohydrate metabolism and diminished many detrimental metabolites. Notably, decrease of myocardial carbohydrate Neu5Ac after long-term moderate exercise might predict a prospective metabolomics biomarker for cardioprotection. This research has displayed the effect of long-term moderate exercise on myocardial metabolomic profiling in rats and indicated some promising metabolites which can be applied for exercise benefits in future.

[Experimental study of mitochondrion-targeted small molecule IR-61 ameliorated exhaustive exercise-induced cardiac injury in rats].

OBJECTIVE: To investigate the effects of mitochondrion-targeted cyanine fluorescent small molecule IR-61 on cardiac injury induced by exhaustive exercise in rats. METHODS: Thirty-six adult male SD rats were randomly divided into 3 groups(n=12),control group (Ctrl), exhaustive exercise group (EE) and IR-61+ exhaustive exercise group (IR-61+EE). IR-61+EE group were intraperitoneally injected with 2 mg/kg IR-61 at the same time on day 1, 4 and 7. One hour after the end of the last drug administration, the two exhaustive exercise groups were subjected to exhaustive exercise modeling. The rats were placed on an animal treadmill with a slope of 0° at a speed of 10~15 m/min to coordinate their limbs running posture, and then ran at a speed of 25~30 m/min until exhaustion about 15 minutes later. After the animal models established, ECG was recorded by physiological recorder, myocardial injury was observed by light microscope, mitochondrial injury was observed by transmission electron microscope, myocardial cell apoptosis was detected by TUNEL method, markers of myocardial injury were detected by ELISA, and myocardial mitochondrial respiration rate was measured by high-resolution Oxygraph-2K mitochondrial instrument. RESULTS: ① Compared with Ctrl group, heart rate was increased, PR interval was shortened, QRS interval was prolonged, QTc was prolonged and ST segment was depressed significantly in EE group (P＜0.05). In EE group, myocardial fiber fracture and mitochondrial inner chamber swelling were obvious, mitochondrial crest was fuzzy, mitochondrial outer membrane was incomplete, and a large number of mitochondrial rupture and fusion were visible. In EE group, TUNEL staining cells were abundant, chromatin concentration and marginalization, nuclear membrane lysis, chromatin fragmentation into massive apoptotic bodies, apoptosis score increased (P＜0.05). The levels of creatine kinase isoenzyme-MB (CK-MB), cardiac troponin I(cTn-I) and N-terminal B-type natriuretic peptide (NT-proBNP) were increased in EE group (P＜0.05). Basal respiration rate, oxidative respiration rate of fatty acids and respiration rate of complex Ⅰ, Ⅱ and Ⅳ were all decreased (P＜ 0.05). ② Compared with EE group, the heart rate in IR-61+EE group was increased, PR interval was prolonged, QRS interval was shortened, QTc was shortened, ST segment was not significantly depressed (P＜0.05). In IR-61+EE group, myocardial fiber arrangement was loose, no obvious fracture was observed, mitochondrial inner ventricle was swelling, mitochondrial outer membrane was intact, TUNEL stained cells and unstained cells were observed, the overall morphology was more similar to Ctrl group. Apoptosis index was decreased (P＜0.05), the levels of CK-MB and cTn-I were decreased in IR-61+EE group (P＜0.05). The oxidative respiration rate of fatty acids and the respiration rate of complex Ⅱ and Ⅳ were increased (P＜0.05). CONCLUSION: Mitochondrion-targeted cyanine fluorescent small molecule IR-61 can improve cardiac electrical activity, reduce myocardial cell injury and mitochondrial injury, reduce myocardial cell apoptosis, and improve the myocardial mitochondrial energy metabolism condition in exhausted rats.

Exploring the Inhibitory Effect of Low-frequency Magnetic Fields on Epileptiform Discharges in Juvenile Rat Hippocampus.

Stimulation with a low frequency electromagnetic field (LF-EMF) has proven to represent a powerful method for the suppression of seizures, as demonstrated in select clinical and laboratory studies. However, the mechanism by which LF-EMF suppresses seizures remains unclear. The purpose of the present study was to explore the modulatory effect of LF-EMF on epileptiform discharges (EDs) using rat hippocampal slices and investigate the underlying mechanisms that mediate these effects. EDs in hippocampal slices was induced by magnesium-free (zero-Mg2+) artificial cerebrospinal fluid (ACSF) and recorded using an in vitro micro-electrode array (MEA). A small sub-decimeter coil was designed and incorporated in a flexible magnetic stimulation device that allowed electromagnetic fields with different parameters to be delivered to slices. After a stable ED event was recorded, magnetic fields of 0.5 Hz (30 min) with a magnetic intensity of 0.13 mT (5 Vpp voltage input) and 0.25 mT (20 Vpp voltage input) were applied. The results indicated that a high-amplitude 0.5 Hz magnetic field could lead to persistent suppression of ictal discharges (IDs), while low-amplitude magnetic fields did not influence IDs. The persistent suppression of complex ED was prevented if the magnetic fields were applied in the presence of 10 µmol/L bicuculline (BIC), a γ-aminobutyric acid type A (GABAA) receptor antagonist, while the application of BIC subsequent to a magnetic field application led to the reappearance of ID. The addition of BIC resulted in EDs that had previously been inhibited by magnetic fields, reappearing. Low-frequency magnetic stimulation was able to inhibit the conversion from interictal discharges (IIDs) or preictal discharges (PIDs) to IDs. This suppression was attributed to the modulation of GABAA receptor activity.

Incidence of de novo autoimmune hepatitis in children and adolescents with increased autoantibodies after liver transplantation: a meta-analysis.

The objective of this meta-analysis was to assess the incidence of de novo autoimmune hepatitis (AIH) in children and adolescents with increased autoantibodies after liver transplantation. We systematically retrieved studies from PubMed, Embase, Central, CNKI, VIP and Wanfang published before February 1, 2020. All analyses were conducted using R-4.0.1 statistical package (Meta). Seven studies with high quality were pooled in our final analysis (N = 251 participants). The incidence of de novo AIH was 9% [95% confidence interval (CI) 1-23%, I2  = 86%]. Subgroup analysis suggested that publications not using the International Autoimmune Hepatitis Group (IAIHG) criteria have marginally significantly higher incidence of de novo AIH than those using IAIHG criteria (P for interaction = 0.08). The incidence of chronic rejection was 8% (95% CI 2-17%, I2  = 72%). Meta-regression indicated significant correlation (P = 0.04; estimate: 1.51) between the incidence of de novo AIH and the rate of increase of antibodies to liver/kidney microsome (anti-LKM). It is still challenging to distinguish de novo AIH and chronic rejection in children and adolescents with increased autoantibodies after liver transplantation. The diagnostic criteria for de novo AIH in children and adolescents and the role of anti-LKM in the development of de novo AIH deserve future investigation.

Effect of priming low-frequency magnetic fields on zero-Mg2+ -induced epileptiform discharges in rat hippocampal slices.

During the process of seizures, the addition of low-frequency magnetic fields has been proved to be an effective method to suppress epileptic discharges. However, whether adding magnetic fields before the appearance of epileptic discharges can produce this inhibition has not been studied. In the present study, we first constructed epilepsy models on brain slices by perfusing them with Mg2+-free artificial cerebrospinal fluid (aCSF). The events of seizures evolved from inter-ictal epileptiform discharges (IIDs) to inter-epileptiform discharges (IDs). Combined with the multi-electrode array platform, we designed a flexible moving coil to generate a 0.5 Hz magnetic field on the brain slices. Using this method, we added the magnetic fields to brain slices for 30 min before epileptiform discharges were induced. The experimental results demonstrated that although the priming magnetic fields could not completely inhibit epileptiform discharges, they can significantly reduce the frequency of IDs and increase the frequency of IIDs in the CA3 region of the hippocampal slices. In the control group, the rates of IDs and IIDs were 0.0024 ± 0.0006 Hz and 0.0138 ± 0.0043 Hz, respectively, while in the magnetic stimulation group, the rates were 0.0012 ± 0.0004 Hz and 0.0251 ± 0.0067 Hz. Moreover, the results indicated that changing the frequency of interictal discharges did not affect ictogenesis. The results demonstrated that the priming magnetic fields had a certain weakening effect on the frequency of IDs, which was achieved by reducing the signal propagation speed and increasing the excitability threshold of hippocampal neurons.

Physiological and ecological characteristics of Periploca sepium Bunge under drought stress on shell sand in the Yellow River Delta of China.

This study investigated the physiological and ecological changes in P. sepium Bunge and elucidated the physiological regulatory mechanisms underlying the adaptation of P. sepium to drought stress in shell sand. Drought stress led to a significant decrease in the net photosynthesis rate (Pn) and respiration rate of leaves and a decrease in low-intensity light-use efficiency (LUE) and light ecological amplitude. An increase in drought stress led to a considerable decrease in the photosynthetic electron transport rate in the P. sepium leaves and a significant increase in the amount of light energy dissipated as heat. In addition, the photosynthesis process suffered from severe photoinhibition. P. sepium plants counteracted the effects of drought stress primarily by increasing their peroxidase (POD) activity and by regulating membrane lipid peroxidation by secreting greater numbers of osmotic adjustment substances (proline (Pro) and soluble sugars (Ss)) and malondialdehyde (MDA). As drought stress increased, both the stem sap flow rate and the cumulative sap flow of P. sepium decreased considerably. P. sepium Bunge adapts to drought stress through interregulatory activity between photosynthesis, water-related physiological activities, and physiological and biochemical processes, and this species exhibits relatively high adaptive plasticity to drought.

Exploring the form- And time-dependent effect of low-frequency electromagnetic fields on maintenance of hippocampal long-term potentiation.

Low-frequency electromagnetic field (LF-EMF) stimulation is an emerging neuromodulation tool that is attracting more attention because of its non-invasive and well-controlled characteristics. However, the effect of different LF-EMF features including the forms and the time of addition on neuronal activity has not been completely understood. In this study, we used multi-electrode array (MEA) systems to develop a flexible in vitro magnetic stimulation device with plug-and-play features that allows for real-time delivery of LF-EMFs to biological tissues. Crucially, the method enables different forms of LF-EMF to be added at any time to a long-term potentiation (LTP) experiment without interrupting the process of LTP induction. We demonstrated that the slope of field excitatory postsynaptic potentials (fEPSPs) decreased significantly under post or priming uninterrupted sine LF-EMFs. The fEPSPs slope would continue to decline significantly when LF-EMFs were added two times with a 20-min interval. Paired-pulse ratio (PPR) was analyzed and the results reflected that LF-EMFs induced LTP was expressed postsynaptically. The results of pharmacological experiments indicated that AMPA receptor activity was involved in the process of LTP loss caused by post-LF-EMFs. Moreover, the effect of priming sine or Quadripulse stimulation (QPS)-patterned LF-EMFs depended on the time interval between the end of LF-EMF and the beginning of baseline recording. Interestingly, the effect of sine LF-EMFs on LTP would not disappear within 120 min, while the impact of QPS-patterned LF-EMFs on LTP might disappear after 90 min. These results indicated that LF-EMF might have a form- and time-dependent effect on LTP.

[The effects of salidroside on the apoptosis pathway of myocardial cells in acute exhausted rats].

OBJECTIVE: To investigate whether salidroside (Sal) plays a part in protecting myocardial cell through reducing the myocardial ischemia and the apoptosis pathway of both death receptors and mitochondria in acute exhausted rats. METHODS: Male SD rats were randomly divided into 4 groups (n=6): control group(Con), acute exhaustive swimming group (EE), low-dose and high-dose Sal pre-treatment exhaustive swimming group (SLE, SHE). Rats were treated with Sal solution (15 or 30 mg/(kg·d)) or 0.9%NaCl (3 ml/(kg·d)) by intraperitoneal injection for 15 d, respectively. The Con group did not carry out swimming training. The next day after the end of intraperitoneal administration, the rats in EE, SLE and SHE group were forced to swim until they were exhausted followed the standard of Thomas. After the end of exhaustive exercise, the rats were anesthetized and the blood samples and hearts were collected immediately. The myocardial ischemia and hypoxia area and myocardial apoptosis index (AI) were also observed. Serum ischemia modified albumin (IMA), cardiac troponin I (cTnI), brain natriuretic peptide(BNP) and myocardial cell Bcl-2-associated X protein (Bax), B-cell lymphoma-2 (Bcl-2) were determined. The expressions of myocardial TNF receptor superfamily member 6 (Fas), cytochrome C (Cyto-c), aspartate proteolytic enzyme-3(Caspase-3), aspartate proteolytic enzyme-8(Caspase-8), and aspartate proteolytic enzyme-9(Caspase-9) were detected. RESULTS: Compared with the Con group, the myocardial ischemia and hypoxia area in EE group was increased significantly. The serum levels of IMA, cTnI and BNP, AI and Bax levels and cardiac Fas, Cyto-C, Caspase-3, Caspase-8 and Caspase-9 protein expressions of EE group were also increased significantly (P＜0.01), while the protein expression of Bcl-2 in cardiac tissues was decreased significantly (P＜0.01). Compared with the EE group, the myocardial ischemia and hypoxia area, serum levels of IMA, cTnI and BNP, AI and Bax levels, and the protein expressions of cardiac Fas, Cyto-C, Caspase-3, Caspase-8 and Caspase-9 in Sal group were all decreased significantly(P＜0.01). while the protein expression of cardiac Bcl-2 in Sal group were increased significantly (P＜0.01). CONCLUSION: Sal plays a role in protecting myocardial cell through reducing the myocardial ischemia and inhibiting myocardial cell apoptosis in exhaustive exercise rats. The mechanism of reducing myocardial cell apoptosis may be related to inhibiting the expressions of Fas, Cyto-C, Caspase-3, Caspase-8, Caspase-9 and increasing the expression of Bcl-2.

Effects of Modulation of Ion Channel Currents by Salidroside in H9C2 Myocardial Cells in Hypoxia and Reoxygenation.

Salidroside, a phenyl-propanoid glycoside isolated from the medicinal plant Rhodiola rosea, has potent cardioprotective effects, especially against myocardial hypoxia and reoxygenation injury. However, the molecular mechanism underlying its action is still unclear. The aim of this study was to determine the effect of salidroside on sodium channel current (INa) and transient outward potassium channel current (Ito) in H9C2 cardiomyocytes. H9C2 cells were subcultured under anoxic conditions to mimic myocardial hypoxia and subsequently treated with salidroside. Whole cell patch clamp was performed to determine the effect of hypoxia/reoxygenation and salidroside on myocardial electrophysiological properties. In the differentiated H9C2 cells, hypoxia/reoxygenation reduced INa and Ito amplitude, while salidroside significantly restored both and altered the INa and Ito activation/inactivation kinetics in a dose-dependent manner. Our findings demonstrate that salidroside protects myocardial cells against hypoxia-reoxygenation by restoring the function of sodium and potassium channels.

[Protective effects of short-term and long-term exercise preconditioning on myocardial injury in rats].

OBJECTIVE: To study the role and mechanism of myocardial apoptosis after short-term and long-term exercise preconditioning. METHODS: Forty-eight male SD rats were randomly divided into control group (C), exhaust group (E), short-exercise preconditioning (S-EP) and long-term exercise preconditioning group (L-EP). Short-term and long-term exercise preconditioning were conducted for 3 days and 3 weeks of repeated intermittent swimming training program. The changes of myocardial cells were observed under light microscope. The serum levels of ischemia-modified albumin(IMA) and creatine kinase-isoenzyme(CK-MB) were detected by ELISA. Real time fluorescence quantitative PCR and Western blot were used to detect the expressions of tumor necrosis factor-α(TNF-α),Caspase-8, Caspase-3 genes and proteins in myocardial tissue. The apoptosis of cardiomyocytes was observed by TUNEL method. RESULTS: Compared with group C, group E had serious myocardial injury. The levels of serum IMA, CK-MB and the expressions of TNF-α, Caspase-8 and Caspase-3 in myocardium were increased (P<0.05). Compared with group E, serum CK-MB and TNF-α and Caspase-8 mRNA in S-EP group were significantly lower than those in group E (P<0.05), but there was no significant difference in serum IMA and Caspase-3 mRNA and protein (P>0.05). The levels of serum IMA, CK-MB and TNF-α, Caspase-8 and Caspase-3 mRNA in L-EP group were significantly lower than those in control group (P<0.05). The apoptosis of cardiomyocytes in group E was obvious. Short-term and long-term exercise preconditioning could inhibit apoptosis. Compared with S-EP group, the apoptosis of L-EP group was significantly decreased. CONCLUSIONS: Short-term and long-term exercise preconditioning can reduce myocardial injury after exhaustive exercise, but short-term exercise preconditioning does not alter the expression of Caspase protease. Long-term exercise preconditioning significantly inhibits Caspase-8, 3 mRNA expression and reduces protein synthesis. The inhibitive effects of long-term exercise preconditioning on myocardial cell apoptosis were stronger than those of short-term exercise preconditioning.

Chinese medicine syndromes in congestive heart failure: A literature study and retrospective analysis of clinical cases.

OBJECTIVE: To discuss the characteristics of Chinese medicine (CM) syndrome factors and distribution of congestive heart failure (CHF), and provide a basis for the diagnosis criteria of essential syndromes. METHODS: Based on databases of China National Knowledge Infrastructure (CNKI, 1980-2012) and Chinese Journal of Chongqing VIP Database (1989-2012), the eligible studies in CHF and extracted factors associated with compound syndromes were analyzed. All the syndromes were classified into deficiency, excess, and deficiency-excess in complexity syndrome were classified. Compound syndromes were separated into syndrome factors including single, double, three or four factors, along with the frequency of occurrence. The relation of CHF syndromes with age, gender, primary disease, brain natriuretic peptide (BNP) and cardiac functional grade was studied in 1,451 CHF cases (between December 2010 and September 2012), and the clinical distribution of common CHF syndromes was summarized. RESULTS: The literature study involved 6,799 CHF cases in 66 literatures after screening. Of the different factors affecting CHF, qi deficiency was the most important one. In deficiency syndrome, Xin (Heart)-qi-deficiency was the most common single factor, and deficiency of both qi and yin was the most common double factor. The retrospective analysis involved 1,451 CHF cases (431 cases with test results of BNP). The xin blood stasis and obstruction and deficiency of both qi and yin syndrome were mostly seen in female patients, and phlegm-blocking-Xin-vessel and qi-deficiency-blood-stasis syndrome mostly in males. Xin-qi-deficiency and qi-deficiency-blood-stasis syndrome were mostly seen in patients aged 50-60 years. Patients aged over 60 years likely manifest deficiency of both qi and yin and Xin blood stasis and obstruction syndrome. The severity of syndrome is aggravated with increased BNP and cardiac functional grade. CONCLUSIONS: The essential syndromes of CHF include qi-deficiency-blood-stasis and deficiency of both qi and yin. The clinical distribution is linked to patients' age and gender. BNP and cardiac functional grade is closely related to CHF syndromes, which may indicate the severity of CM syndromes of CHF.

[The effect of nuclear factor erythroid-2-related factor2 on the changes of cardiac function and electrocardiogram in rats after exhausted exercise].

OBJECTIVE: In order to provide the experimental basis for the prevention of exercise-induced cardiac injury, we evaluated the effects of nuclear factor erythroid-2-related factor2(Nrf2) on the changes of cardiac function and electrocardiogram in rats after exhaustive exercise. METHODS: SD rats were randomly divided into 5 groups (n=6):control group (Con), exhaustied exercise group (EE), 6h, 12 h, 24 h recovery from exhaustied exercise group(EER6 EER12 EER24). The animal models of exercise-induced myocardial injury were established according to Thomas' method.Rats were forced to swim until they were exhausted.The electrocardiograms were recorded in conscious rats. Cardiac function of rats was recorded and analyzed by Millar pressure-volume system. The changes of catalase(CAT), glutathione peroxidase(GPX), Nrf2 and reactive oxygen speies(ROS) were detected by ELISA, respectively. RESULTS: ①Compared with the control group and recovery groups(EER6, EER12, and EER24), the heart rate (HR), left ventricular end systolic pressure (Pes), arterial elasticity (Ea), the maximum rate of left ventricular pressure rise (dP/dtmax), peak rate of left ventricular pressure decline (-dP/dtmin) and left ventricular end diastolic pressure volume relationship curve slope (ESPVR) in the EE group decreased significantly, while left ventricular end diastolic volume (Ved), Pes, left ventricular end systolic volume (Ves), stroke volume, and Tau value increased significantly. Besides, HR, Pes, dP/dtmax, -dP/dtmin in recovery groups were significantly different with those in EE group, but there had no difference with those in the Con group. ②Compared with the control group, heart rate was increased, QT intervals were prolonged P wave, R wave and ST segments were increased in EE and recovery groups, but the changes of above-mentioned indexes in recovery groups had no statistical significant difference with those in EE group.③ Compared with the control group,the contents of ROS, Nrf2 were increased in EE group, while the content of GPX was decreased. Moreover, the content of CAT in EER6 group was the lowest in all groups. ④ The level of Nrf2 in serum was positively correlated with ROS and -dP/dtmin, and negatively correlated with HR, Ea. The level of ROS in Serum was positively correlated with EF, -dP/dtmin, and was negatively correlated with HR, Ea, dP/dtmax. CONCLUSIONS: Exhausted exercise caused changes of cardiac bioelectricity, impaired both the cardiac systolic and diastolic function, especially the diastolic disfunction. However, with recovery time after exhausted exercise prolonged, cardiac systolic and diastolic function recovered gradually, which was related to the reduced oxidative stress levels modulated by the increased Nrf2-induced changes of GPX and CAT.

The Protective Effects of Salidroside from Exhaustive Exercise-Induced Heart Injury by Enhancing the PGC-1 α -NRF1/NRF2 Pathway and Mitochondrial Respiratory Function in Rats.

OBJECTIVE: To test the hypothesis that salidroside (SAL) can protect heart from exhaustive exercise-induced injury by enhancing mitochondrial respiratory function and mitochondrial biogenesis key signaling pathway PGC-1α-NRF1/NRF2 in rats. METHODS: Male Sprague-Dawley rats were divided into 4 groups: sedentary (C), exhaustive exercise (EE), low-dose SAL (LS), and high-dose SAL (HS). After one-time exhaustive swimming exercise, we measured the changes in cardiomyocyte ultrastructure and cardiac marker enzymes and mitochondrial electron transport system (ETS) complexes activities in situ. We also measured mitochondrial biogenesis master regulator PGC-1α and its downstream transcription factors, NRF1 and NRF2, expression at gene and protein levels. RESULTS: Compared to C group, the EE group showed marked myocardium ultrastructure injury and decrease of mitochondrial respiratory function (P < 0.05) and protein levels of PGC-1α, NRF1, and NRF2 (P < 0.05) but a significant increase of PGC-1α, NRF1, and NRF2 genes levels (P < 0.05); compared to EE group, SAL ameliorated myocardium injury, increased mitochondrial respiratory function (P < 0.05), and elevated both gene and protein levels of PGC-1α, NRF-1, and NRF-2. CONCLUSION: Salidroside can protect the heart from exhaustive exercise-induced injury. It might act by improving myocardial mitochondrial respiratory function by stimulating the expression of PGC-1α-NRF1/NRF2 pathway.

Influence of simvastatin on dopaminergic neurons of lipopolysaccharide-induced rat model of Parkinson's disease.

OBJECTIVE: To investigate the neuroprotective effects of simvastatin on lipopolysaccharide (LPS)-induced rat model of Parkinson's disease (PD) and the mechanisms involved. METHODS: Hemiparkinsonian rat models were induced by stereotaxieal injection of LPS in the right substantia nigra compacta. After 2 weeks of simvastatin treatment, rotational behavior test was performed after the intraperitoneal injection of apomorphine. Expression of tyroxine hydroxylase (TH) and glial fibrillary acidic protein were analyzed through immunohistochemical staining of substantia nigra and striatum, and the level of TNF- α was evaluated using enzyme-linked immunosorbent assay. RESULTS: Comparing with untreated group, behavioral symptoms of the rats were significantly less in the rats that received simvastatin treatment. The TH positive cell count in substantia nigra and striatum were significantly increased (P<0.05) and TNF- α expression was significantly decreased (P<0.05) in simvastatin group compared to untreated group. CONCLUSIONS: Simvastatin could effectively inhibit the activation of astrocytes, reduce TNF- α expression, and exert anti-inflammatory effects, and thus protect the dopaminergic neurons in substantia nigra and striatum of the rat model of PD.

Short-term rosuvastatin treatment for the prevention of contrast-induced acute kidney injury in patients receiving moderate or high volumes of contrast media: a sub-analysis of the TRACK-D study.

BACKGROUND: Current randomized trials have demonstrated the effects of short-term rosuvastatin therapy in preventing contrast-induced acute kidney injury (CIAKI). However, the consistency of these effects on patients administered different volumes of contrast media is unknown. METHODS: In the TRACK-D trial, 2998 patients with type 2 diabetes and concomitant chronic kidney disease (CKD) who underwent coronary/peripheral arterial angiography with or without percutaneous intervention were randomized to short-term (2 days before and 3 days after procedure) rosuvastatin therapy or standard-of-care. This prespecified analysis compared the effects of rosuvastatin versus standard therapy in patients exposed to (moderate contrast volume [MCV], 200-300 ml, n = 712) or (high contrast volume [HCV], ≥ 300 ml, n = 220). The primary outcome was the incidence of CIAKI. The secondary outcome was a composite of death, dialysis/hemofiltration or worsened heart failure at 30 days. RESULTS: Rosuvastatin treatment was associated with a significant reduction in CIAKI compared with the controls (2.1% vs. 4.4%, P = 0.050) in the overall cohort and in patients with MCV (1.7% vs. 4.5%, P = 0.029), whereas no benefit was observed in patients with HCV (3.4% vs. 3.9%, P = 0.834). The incidence of secondary outcomes was significantly lower in the rosuvastatin group compared with control group (2.7% vs. 5.3%, P = 0.049) in the overall cohort, but it was similar between the patients with MCV (2.0% vs. 4.2%, P = 0.081) or HCV (5.1% vs. 8.8%, P = 0.273). CONCLUSIONS: Periprocedural short-term rosuvastatin treatment is effective in reducing CIAKI and adverse clinical events for patients with diabetes and CKD after their exposure to a moderate volume of contrast medium.

Doxazosin selectively potentiates contraction to serotonin via 5-HT2A receptors in longitudinal muscle strips of the rabbit gastric body.

The aims of this study were to examine the effects of doxazosin on contractile responses to 5-hydroxytryptamine (5-HT), carbachol, and histamine, and to compare them with those of prazosin, alfuzosin, and terazosin, and then characterize a pharmacological profile of the 5-HT-induced contractile response using preparations of isolated longitudinal muscle strips from the rabbit gastric body. The results from these preparations showed that the contraction response to 5-HT, but not to carbachol or histamine, was found to be dose-dependently potentiated by doxazosin and its enantiomers. The specific potentiation effect on 5-HT was not observed in the preparations that were treated with prazosin, terazosin, or alfuzosin. The contractile response to 5-HT and its potentiation by doxazosin were not affected by treatment with phenoxybenzamine. However, 5-HT-induced contraction was competitively antagonized by nefazodone (with pA2 value of 8.64 ± 0.17), and was almost completely inhibited by treatment with indomethacin. In conclusion, doxazosin, but not prazosin, alfuzosin, or terazosin, selectively potentiates 5-HT-induced contraction in the rabbit gastric body strips via an α1-adrenoceptor-independent mechanism, without chiral recognition of its enantiomers. Additionally, the contraction to 5-HT was found to be mediated via 5-HT(2) receptors, and was similar to PGs synthesis in the preparations.

Inhibition of carotid sinus baroreflex in neonatal rats exposed to chronic intermittent hypobaric hypoxia.

Chronic intermittent hypobaric hypoxia (CIHH) facilitates carotid sinus baroreflex (CSB) in adult rats, but the effect of CIHH on CSB in young rats is not known. The purpose of present study was to investigate the effect of CIHH on CSB in the young rat treated with CIHH from neonatal age, and the role of nitric oxide (NO) and Ca²âº in the effect of CIHH. Neonatal male Sprague-Dawley rats were randomly divided into three groups: 42-day CIHH treatment group (CIHH42), 56-day CIHH treatment group (CIHH56), and an age-matched control group (control). CIHH neonatal rats with the maternal rats were exposed to a simulated high-altitude hypoxia in a hypobaric chamber mimicking 5,000-m altitude (O2 at 11.1%) for 42 or 56 days, 6 h per day, respectively. Isolated carotid sinus perfusion technique was used to test CSB of the rats. After 42-day and 56-day CIHH exposure, the CSB of the rats was inhibited significantly, manifesting as decrease of peak slope (PS) and reflex decrease (RD), and increase of threshold pressure (TP), equilibrium pressure (EP) and saturation pressure (SP). This inhibitory effect was canceled by L-type calcium channel activator Bay K 8644, but not by nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME). The data showed that CIHH inhibited CSB in anesthetized young rats through blocking L-type calcium channels in carotid sinus baroreceptor.

[Effects of doxazosin and its enantiomers on serum lipid levels in rabbits fed by an atherogenic diet].

OBJECTIVE: To observe the effects of (-)doxazosin(DOX), (+)DOX and (+/-)DOX on serum lipid levels and the mortality rates of the rabbits fed by an atherogenic diet. METHODS: Male white New Zealand rabbits were fed by an atherogenic diet for 4 weeks. 8 rabbits whose serum TC <10 mmol/L were confirmed as normal diet group and were fed normally. 40 rabbits whose serum TC >10 mmol/L were randomly divided into 4 groups (n=10): atherogenic diet group, atherogenic diet with (-)DOX group, atherogenic diet with (+)DOX group and atherogenic diet with (+/-)DOX group, which were intraperitoneally injected with (-)DOX, (+)DOX and (+/-)DOX for 9 weeks respectively. Normal and atherogenic diet group were intraperitoneally injected with double distilled water. After 9 weeks administration of (+/-)doxazosin and its enantiomers, effects of the three agents on serum levels of total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) were observed. RESULTS: The mortality rate of the rabbits fed by an atherogenic diet for 13 weeks was 40%, and it was much higher than that of the rabbits fed by a normal diet (10%). The mortality rates in the rabbits treated with (-)DOX and (+/-)DOX were lower than that in the rabbits fed by a normal diet (10%). Serum LDL-C level of the rabbits was increased markedly after 4 weeks of atherogenic diet, and it was further increased significantly (P < 0.05 and P < 0.01) during the continued 9 weeks of atherogenic diet. However, serum LDL-C levels were not further increased significantly (P > 0.05) during the continued 9 weeks of atherogenic diet in the rabbits treated with (-)DOX, (+)DOX and (+/-)DOX, respectively. CONCLUSION: (-)DOX and (+/-)DOX increase the survival rate and improve LDL-C disorder mildly in the rabbits fed by an atherogenic diet. The improvements in LDL-C induced by (-)DOX and (+/-)DOX, however, might not be the reason for exploration about the increased survival rate in the rabbits fed by an atherogenic diet.

[Nitroglycerin tolerance aggravates arterial ischemia/reperfusion injury by increasing nitrotyrosine and ONOO- production].

OBJECTIVE: To investigate the influence of nitroglycerin tolerance (NT) on arterial ischemia (90 min) and reperfusion (120 min). METHODS: Male Sprague-Dawley rats were infused with nitroglycerin (GTN) or saline for 12 h and ascending aorta was rapidly isolated. The isolated aorta was subjected to one of the following treatments: stimulative ischemia/reperfusion, stimulative ischemia/reperfusion (I/R) plus glutathione (GSH, 0.1 mmol/L) during reperfusion, or control solution (Kreb's solution for 3.5 h). RESULTS: Compared with I/R group, contractile function, vasorelaxation responses to Ach, NO production were significantly decreased and CK, LDH activity as well as nitrotyrosine formation in reperfusion solution were significantly increased in I/R + NT group and these effects could be prevented with addition of GSH in I/R + NT aortas. CONCLUSIONS: Our results demonstrated that NT could aggravate arterial I/R injury by increasing the production of ONOO- and GSH may play a cardioprotective role against NT-induced myocardial injury by attenuating the formation of ONOO-.