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1.
Eur J Neurosci ; 59(10): 2702-2714, 2024 May.
Article in English | MEDLINE | ID: mdl-38469656

ABSTRACT

This study aims to analyse hyperechoic substantia nigra (HSN) characteristics and the correlation of HSN with clinical features and blood biomarkers in patients with Parkinson's disease (PD). Transcranial sonography (TCS) evaluations of the substantia nigra (SN) were performed in 40 healthy controls and 71 patients with PD, including patients with SN hyperechogenicity (SN+) and those with normal SN echogenicity (SN-). Evaluation of motor and non-motor symptoms was assessed by a series of rating scales. The uricase method was used to determine serum uric acid (UA) levels, and enzyme-linked immunosorbent assay (ELISA) was used to measure plasma interleukin (IL)-1ß levels. TCS showed 92.50% specificity and 61.97% sensitivity in differentiating PD patients from controls. The area of SN+ contralateral to the side of initial motor symptoms (SNcontra) was larger than that ipsilateral to the side of initial motor symptoms (SNipsi). The PDSN+ group had lower Argentine Hyposmia Rating Scale (AHRS) scores and UA levels than the PDSN- group. Binary logistic regression analysis revealed that AHRS scores and UA levels could be independent predictors for HSN. The larger SN echogenic area (SNL) sizes positively correlated with plasma IL-1ß levels in PD patients with SN+. The present study provides further evidence of the potential of SN echogenicity as an imaging biomarker for PD diagnosis. PD patients with HSN have more severe non-motor symptoms of hyposmia. HSN in PD patients is related to the mechanism of abnormal iron metabolism and microglial activation.


Subject(s)
Interleukin-1beta , Parkinson Disease , Substantia Nigra , Ultrasonography, Doppler, Transcranial , Humans , Parkinson Disease/diagnostic imaging , Male , Female , Middle Aged , Substantia Nigra/diagnostic imaging , Substantia Nigra/metabolism , Aged , Ultrasonography, Doppler, Transcranial/methods , Interleukin-1beta/blood , Interleukin-1beta/metabolism , Uric Acid/blood , Biomarkers/blood
2.
J Neurosci Res ; 102(2): e25303, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38361408

ABSTRACT

Lipocalin-2 (LCN2) is essential for the regulation of neuroinflammation and cellular uptake of iron. This study aimed to evaluate plasma LCN2 levels and explore their correlation with clinical and neuroimaging features in Parkinson's disease (PD) patients. Enzyme-linked immunosorbent assay (ELISA) was used to measure plasma LCN2 levels in 120 subjects. Evaluation of motor symptoms and nonmotor symptoms in PD patients was assessed by the associated scales. Voxel-based morphometry (VBM) was used to evaluate brain volume alterations, and quantitative susceptibility mapping (QSM) was used to quantitatively analyze brain iron deposition in 46 PD patients. Plasma LCN2 levels were significantly higher in PD patients than those in healthy controls. LCN2 levels were negatively correlated with Montreal Cognitive Assessment (MoCA) scores, total brain gray matter volume (GMV), and GMV/total intracranial volume (TIV) ratio, but positively correlated with Hamilton Anxiety Rating Scale (HAMD) scores and mean QSM values of the bilateral substantial nigra (SN). Receiver operating characteristic (ROC) curves confirmed that plasma LCN2 levels had good predictive accuracy for PD. The results suggest that plasma LCN2 levels have potential as a biomarker for the diagnosis of PD. LCN2 may be a therapeutic target for neuroinflammation and brain iron deposition.


Subject(s)
Parkinson Disease , Humans , Parkinson Disease/complications , Parkinson Disease/diagnostic imaging , Lipocalin-2 , Neuroinflammatory Diseases , Magnetic Resonance Imaging/methods , Neuroimaging , Iron/metabolism
3.
Neurol Sci ; 45(1): 47-54, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37718350

ABSTRACT

OBJECTIVE: This study was designed to investigate the diagnostic value of plasma SIRT1 levels and whole-brain gray matter (GM) volume in Parkinson's disease (PD) patients with cognitive impairment. METHODS: Automated enzymatic analysis was performed to measure plasma SIRT1 levels in 80 healthy controls and 77 PD patients. Motor symptoms and nonmotor symptoms in PD patients were assessed using the corresponding scales. A Siemens MAGNETOM Prisma 3 T MRI scanner was used to acquire images in 35 of 77 PD patients. RESULTS: Plasma SIRT1 levels in PD patients were lower than those in healthy controls. Plasma SIRT1 levels were negatively correlated with the age, Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) scores, anxiety, depression, excessive daytime sleepiness (EDS), quality of life, and especially cognitive impairment. Thus, it showed that plasma SIRT1 levels were relevant to visuospatial/executive function, memory, and language. Receiver-operating characteristic (ROC) analysis confirmed that plasma SIRT1 levels had good diagnostic accuracy for PD with anxiety and EDS. Furthermore, plasma SIRT1 levels had a significant positive correlation with GM volume in the whole brain, and ROC analysis confirmed that plasma SIRT1 levels and the total GM volume had good diagnostic accuracy for PD with cognitive impairment. CONCLUSIONS: This study showed that plasma SIRT1 levels were correlated with the nonmotor symptoms of anxiety, depression, EDS, and especially cognitive impairment as well as the total GM volume. Furthermore, the combination of plasma SIRT1 levels and the total GM volume had good diagnostic accuracy for PD with cognitive impairment.


Subject(s)
Cognitive Dysfunction , Disorders of Excessive Somnolence , Parkinson Disease , Humans , Gray Matter/diagnostic imaging , Parkinson Disease/complications , Parkinson Disease/diagnostic imaging , Quality of Life , Sirtuin 1 , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/etiology , Brain/diagnostic imaging
4.
Neurobiol Dis ; 190: 106379, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38104911

ABSTRACT

BACKGROUND: Cognitive impairment is a serious nonmotor symptom in patients with Parkinson's disease (PD). Currently, there are few studies investigating the relationship of serum markers and retinal structural changes with cognitive function in PD. OBJECTIVE: To investigate the relationship between retinal structural changes, serum high mobility group box-1 (HMGB1) levels and cognitive function and motor symptoms in PD patients. METHODS: Eighty-nine participants, including 47 PD patients and 42 healthy subjects, were enrolled. PD patients were divided into Parkinson's disease with normal cognitive (PD-NC), Parkinson's disease with mild cognitive impairment (PD-MCI), and Parkinson's disease with dementia (PDD) groups. The motor and nonmotor symptoms of PD patients were evaluated with clinical scale. Serum HMGB1 levels were detected by enzyme-linked immunosorbent assay (ELISA), and ganglion cell-inner plexiform layer complex (GCIPL) thickness changes in the macula were quantitatively analyzed by swept source optical coherence tomography (SS-OCT) in all patients. RESULTS: Compared with the control group, the macular GCIPL (t = -2.308, P = 0.023) was thinner and serum HMGB1 (z = -2.285, P = 0.022) was increased in PD patients. Macular GCIPL thickness in patients with PD-MCI and PDD were significantly lower than that in PD-NC patients, but there were no significant difference between the PD-MCI and PDD groups. Serum HMGB1 levels in patients with PD-MCI and PDD were significantly higher than those in PD-NC patients, and serum HMGB1 levels in PDD patients were higher than those in PD-MCI patients. Correlation analysis showed that serum HMGB1 levels in PD patients were positively correlated with disease duration, HY stage, UPDRS-I score, UPDRS-III score, and UPDRS total score and negatively correlated with MOCA score. Macular GCIPL thickness was negatively correlated with HY stage and positively correlated with MOCA score, and macular GCIPL thickness was negatively correlated with serum HMGB1 level. Logistic regression analysis showed that elevated serum HMGB1 level, thinner macular GCIPL thickness, and higher HY stage were independent risk factors for Parkinson's disease with cognitive impairment (PD-CI). The areas under the receiver operating characteristic curve (AUC) for the serum HMGB1 level and macular GCIPL thickness-based diagnosis of PD-MCI, PDD and PD-CI based on in patients with PD were 0.786 and 0.825, 0.915 and 0.856, 0.852 and 0.841, respectively. The AUC for the diagnosis of PD-MCI, PDD and PD-CI with serum HMGB1 level and GCIPL thickness combined were 0.869, 0.967 and 0.916, respectively. CONCLUSION: The macular GCIPL thickness and serum HMGB1 level are potential markers of cognitive impairment in PD patients, and their combination can significantly improve the accuracy of the diagnosis of cognitive impairment in PD.


Subject(s)
Alzheimer Disease , Cognitive Dysfunction , HMGB1 Protein , Parkinson Disease , Humans , Cognition , Retina
5.
Neurol Sci ; 44(12): 4333-4342, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37452260

ABSTRACT

BACKGROUND: Dopamine dysregulation syndrome (DDS) is a complication of Parkinson's disease (PD) that seriously affects the quality of life of PD patients. Currently, the risk factors for DDS are poorly known, and it is critical to identify them in the early stages of PD. OBJECTIVE: To explore the incidence of and risk factors for DDS in patients with early PD. METHODS: A retrospective cohort study was conducted on the general data, clinical features, and imaging data of patients with early PD in the PPMI database. Multivariate Cox regression analysis was performed to analyze the risk factors for the development of DDS in patients with early PD, and Kaplan‒Meier curves examined the frequency and predictors of incident DDS symptoms. RESULTS: At baseline, 2.2% (n = 6) of patients with early PD developed DDS, and the cumulative incidence rates of DDS during the 5-year follow-up period were 2.8%, 6.4%, 10.8%, 15.5%, and 18.7%, respectively. In the multivariate Cox regression model controlling for age, sex, and drug use, hypersexuality (HR = 3.088; 95% CI: 1.416~6.732; P = 0.005), compulsive eating (HR = 3.299; 95% CI: 1.665~6.534; P = 0.001), compulsive shopping (HR = 3.899; 95% CI: 1.769~8.593; P = 0.001), anxiety (HR = 4.018; 95% CI: 2.136~7.599; P < 0.01), and lower Hoehn-Yahr (H-Y) stage (HR = 0.278; 95% CI: 0.152~0.509; P < 0.01) were independent risk factors for DDS in patients with early PD. PD patients with DDS had lower DAT uptake values than those patients without DDS. CONCLUSION: Early PD patients with hypersexuality, compulsive eating, compulsive shopping, anxiety, and lower H-Y stage were at increased risk for DDS. The occurrence of DDS may be related to the decrease in the average DAT uptake of the caudate and putamen.


Subject(s)
Disruptive, Impulse Control, and Conduct Disorders , Parkinson Disease , Humans , Dopamine , Parkinson Disease/complications , Parkinson Disease/epidemiology , Retrospective Studies , Quality of Life , Syndrome
6.
Neurosci Lett ; 804: 137219, 2023 05 01.
Article in English | MEDLINE | ID: mdl-37023526

ABSTRACT

OBJECTIVE: Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and Neurofilament light chain (NfL) are associated with Lewy body formation, Lewy bodies are the main pathological feature of Parkinson's disease (PD). The relationship between UCH-L1 and PD cognition remains unclear, and NfL is an important marker of cognitive impairment. The aim of this study is to investigate the relationship among serum UCH-L1 levels, plasma NfL levels and cognitive dysfunction in PD patients. RESULTS: There were significant differences in UCH-L1 and NfL levels among PD patients with normal cognitive function (PD-CN), PD patients with mild cognitive impairment (PD-MCI), and PD-dementia patients (PDD) (P < 0.001; P < 0.001). The PDD group had lower levels of UCH-L1 (Z = 6.721, P < 0.001; Z = 7.577, P < 0.001) and higher levels of NfL (Z = -3.626, P = 0.001; Z = -2.616P = 0.027) than the PD-NC and PD-MCI groups. Serum UCH-L1 levels were positively correlated with MMSE scores, MoCA scores, and its subitems in PD patients (P < 0.001), and plasma NfL levels were negatively correlated with MMSE scores, MoCA scores, and its items (P < 0.01) (except for "abstract"). CONCLUSION: Decreased UCH-L1 levels and elevated NfL levels in the blood are associated with cognitive dysfunction in PD; thus, these proteins are potential biomarkers for the diagnosis of cognitive dysfunction in PD patients.


Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Parkinson Disease , Humans , Biomarkers , Cognition , Cognitive Dysfunction/diagnosis , Parkinson Disease/metabolism , Ubiquitin Thiolesterase/metabolism
7.
Oxid Med Cell Longev ; 2022: 7671324, 2022.
Article in English | MEDLINE | ID: mdl-35936219

ABSTRACT

Background: Ferroptosis is a type of iron-dependent programmed cell death. Ferroptosis has been shown to be a significant factor for the pathogenesis of Parkinson's disease (PD). However, the mechanism involved in ferroptosis has not been fully elucidated in PD. Methods: Repressor element-1 silencing transcription factor (REST) and specificity protein 1 (SP1) expressions were monitored by qRT-PCR. Cell viability, reactive oxygen species (ROS), and mitochondrial injury were validated by CCK-8, flow cytometry, and transmission electron microscope. The levels of neurons-related proteins and ferroptosis-associated proteins were identified by western blot and immunofluorescence assays. The interaction between miR-494-3p and REST or SP1 and ACSL4 was analyzed by luciferase, chromatin immunoprecipitation, or EMSA assay. Results: Erastin could dose-dependently induce neuron injury and ferroptosis of LUHMES cells. miR-494-3p overexpression induced ROS production, mitochondrial damage, ferroptosis, and neuron injury in erastin-induced LUHMES cells. Likewise, miR-494-3p inhibition had the opposite effects. We also showed that REST was a target gene of miR-494-3p and could repress erastin-induced ferroptosis, neuron injury, ROS, and mitochondrial injury via SP1 in LUHMES cells. Moreover, we demonstrated that SP1 could interact with ACSL4. We also confirmed that miR-494-3p could aggravate the pathological changes of substantia nigra and corpus striatum in the MPTP-induced PD mouse model. Conclusion: miR-494-3p significantly promotes ferroptosis by regulating the REST/SP1/ACSL4 axis in PD. Thus, our results open potential therapeutic targets for PD.


Subject(s)
Ferroptosis , MicroRNAs , Parkinson Disease , Animals , Coenzyme A Ligases/genetics , Coenzyme A Ligases/metabolism , Mice , MicroRNAs/genetics , MicroRNAs/metabolism , Parkinson Disease/genetics , Piperazines , Reactive Oxygen Species/metabolism , Transcription Factors
8.
Int J Clin Exp Pathol ; 13(12): 3120-3127, 2020.
Article in English | MEDLINE | ID: mdl-33425112

ABSTRACT

Gastric cancer is one of the common gastrointestinal tumors. Tumor recurrence leads to a high death rate of gastric cancer. It is very important to find markers to effectively predict gastric cancer recurrence. We constructed a gastric cancer tissue microarray containing 89 tumors and corresponding normal tissues to explore the relationship between some proteins' expression and gastric cancer recurrence. The expression of JWA, Cullin1, p53, XRCC1, CHIP, FAK, MMP-2, MDM2 and p21 was determined on the microarray by immunohistochemistry. The relationship between the expression of these proteins and gastric cancer recurrence was analyzed. Tumor diameter, lymph node metastasis, and TNM stage were closely related with gastric cancer recurrence by Fisher's exact test (P<0.05). We used the univariate Cox regression analysis to find that JWA, XRCC1 were related to gastric cancer recurrence (P<0.05); Lymph node metastasis and TNM stage were closely related to gastric cancer recurrence (P<0.05). Multivariate Cox regression analysis revealed that XRCC1 or lymph node metastasis were independent risk factors of gastric cancer recurrence (P<0.05). Kaplan-Meier survival curve assay indicated that patients with low JWA or XRCC1 expression in gastric cancer had significantly shorter DFS than those with high-expressed proteins (P<0.05). JWA or XRCC1 may be effective markers to predict gastric cancer recurrence.

9.
J Geriatr Cardiol ; 16(7): 540-551, 2019 Jul.
Article in English | MEDLINE | ID: mdl-31447893

ABSTRACT

BACKGROUND: Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase (XO), may be used in the prevention and management of atrial fibrillation (AF). The purpose of this study was to evaluate the effects of febuxostat on atrial remodeling in a rabbit model of AF induced by rapid atrial pacing (RAP) and the mechanisms by which it acts. METHODS: Twenty-four rabbits were randomly divided into four groups: sham-operated group (Group S), RAP group (Group P), RAP with 5 mg/kg per day febuxostat group (Group LFP), and RAP with 10 mg/kg per day febuxostat group (Group HFP). All rabbits except those in Group S were subjected to RAP at 600 beats/min for four weeks. The effects of febuxostat on atrial electrical and structural remodeling, markers of inflammation and oxidative stress, and signaling pathways involved in the left atrium were examined. RESULTS: Shortened atrial effective refractory period (AERP), increased AF inducibility, decreased mRNA levels of Cav1.2 and Kv4.3, and left atrial enlargement and dysfunction were observed in Group P, and these changes were suppressed in the groups treated with febuxostat. Prominent atrial fibrosis was observed in Group P, as were increased levels of TGF-ß1, Collagen I, and α-SMA and decreased levels of Smad7 and eNOS. Treatment with febuxostat attenuated these differences. Changes in inflammatory and oxidative stress markers induced by RAP were consistent with the protective effects of febuxostat. CONCLUSIONS: This study is the first to find that febuxostat can inhibit atrial electrical and structural remodeling of AF by suppressing XO and inhibiting the TGF-ß1/Smad signaling pathway.

10.
JMIR Mhealth Uhealth ; 7(3): e11437, 2019 03 05.
Article in English | MEDLINE | ID: mdl-30835243

ABSTRACT

BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. The asymptomatic nature and paroxysmal frequency of AF lead to suboptimal early detection. A novel technology, photoplethysmography (PPG), has been developed for AF screening. However, there has been limited validation of mobile phone and smart band apps with PPG compared to 12-lead electrocardiograms (ECG). OBJECTIVE: We investigated the feasibility and accuracy of a mobile phone and smart band for AF detection using pulse data measured by PPG. METHODS: A total of 112 consecutive inpatients were recruited from the Chinese PLA General Hospital from March 15 to April 1, 2018. Participants were simultaneously tested with mobile phones (HUAWEI Mate 9, HUAWEI Honor 7X), smart bands (HUAWEI Band 2), and 12-lead ECG for 3 minutes. RESULTS: In all, 108 patients (56 with normal sinus rhythm, 52 with persistent AF) were enrolled in the final analysis after excluding four patients with unclear cardiac rhythms. The corresponding sensitivity and specificity of the smart band PPG were 95.36% (95% CI 92.00%-97.40%) and 99.70% (95% CI 98.08%-99.98%), respectively. The positive predictive value of the smart band PPG was 99.63% (95% CI 97.61%-99.98%), the negative predictive value was 96.24% (95% CI 93.50%-97.90%), and the accuracy was 97.72% (95% CI 96.11%-98.70%). Moreover, the diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of mobile phones with PPG for AF detection were over 94%. There was no significant difference after further statistical analysis of the results from the different smart devices compared with the gold-standard ECG (P>.99). CONCLUSIONS: The algorithm based on mobile phones and smart bands with PPG demonstrated good performance in detecting AF and may represent a convenient tool for AF detection in at-risk individuals, allowing widespread screening of AF in the population. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-OOC-17014138; http://www.chictr.org.cn/showproj.aspx?proj=24191 (Archived by WebCite at http://www.webcitation/76WXknvE6).


Subject(s)
Atrial Fibrillation/diagnosis , Electrocardiography/instrumentation , Photoplethysmography/standards , Adult , Aged , Cell Phone/instrumentation , Cell Phone/statistics & numerical data , Chi-Square Distribution , Electrocardiography/methods , Electrocardiography/standards , Female , Humans , Male , Mass Screening/instrumentation , Mass Screening/methods , Middle Aged , Photoplethysmography/instrumentation , Photoplethysmography/methods , Pilot Projects , Sensitivity and Specificity , Statistics, Nonparametric
11.
Chin J Physiol ; 61(4): 210-220, 2018 Aug 31.
Article in English | MEDLINE | ID: mdl-30139242

ABSTRACT

The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is expressed in the vasculature; our previous work showed that FXR regulated vascular reactivity through NO mechanism. The underlying mechanism for the regulation of vascular tension by FXR remains unclear. The present work was designed to investigate whether FXR regulates calcium homeostasis in aortic vascular smooth muscle cells (VSMCs). Protein abundances of angiotensin II type 1 and 2 receptors (AT1R, AT2R), bradykinin type 1 and 2 receptors (B1R, B2R), and the inositol 1,4,5-trisphosphate receptor (IP3R) were analyzed by western blotting. Kallikrein activity and bradykinin content were assayed by using spectrophotometry and a bradykinin assay kit, respectively. Aortic contraction, intracellular Ca²âº concentrations ([Ca²âº]i), sarco/endoplasmic reticulum Ca²âº ATPase (SERCA) activities, and IP3-evoked Ca²âº release were investigated, following FXR activation in the presence or absence of AT2R and B2R blockade. We found that the FXR agonists GW4064 and INT-747 increased the protein abundance of AT2R and B2R in rat aortic VSMCs. AT2R blockade with PD123319 reversed the effects of FXR agonists on kallikrein activity, B2R, and bradykinin levels. Moreover, we found that GW4064 and INT-747 decreased intracellular [Ca²âº], increased SERCA activity, downregulated IP3R1 expression, and attenuated IP3-induced Ca²âº release. These effects were partially reversed by AT2R and B2R blockade with PD123319 and HOE140, respectively. Our data suggest that FXR regulates vascular tension by modulating extracellular Ca²âº influx and intracellular Ca²âº release from the sarcoplasmic reticulum via activation of an AT2R-B2R pathway in rat aortic VSMCs.


Subject(s)
Homeostasis , Muscle, Smooth, Vascular , Animals , Calcium , Myocytes, Smooth Muscle , Rats , Sarcoplasmic Reticulum
12.
J Geriatr Cardiol ; 13(4): 344-54, 2016 May.
Article in English | MEDLINE | ID: mdl-27403144

ABSTRACT

BACKGROUND: The clinical efficacy and safety of adjunctive thrombus aspiration (TA) in patients with ST-segment elevation myocardial infarction (STEMI) during percutaneous coronary intervention (PCI) remain controversial. METHODS: Twenty five eligible randomized controlled trials were included to compare the use of thrombus aspiration (TA) with PCI and PCI-only for STEMI. The primary endpoint was all-cause mortality and death. The secondary endpoints were major adverse cardiac events (MACE), recurrent infarction (RI), target vessel revascularization (TVR), stent thrombosis (ST), perfusion surrogate markers and stroke. RESULTS: TIMI flow grade 3 and MBG 2-3 were significantly increased in the TA plus PCI arm compared with the PCI-only arm [relative risk (RR): 1.05, 95% confidence intervals (CI): 1.02-1.09, P = 0.004] and (RR: 1.68, 95% CI: 1.40-2.00, P < 0.001), respectively. There were no significant differences in all-cause mortality, MACEs, TVR and ST rates between the two groups. The RI rate was lower in the TA plus PCI arm than that in the PCI-only arm with short-term follow-up duration (RR: 0.60, 95% CI: 0.38-0.96, P = 0.03), but there was no significant difference in RI incidence over the medium- or long-term follow-up periods (RR: 1.00, 95% CI: 0.77-1.29, P = 0.98), and (RR: 0.96, 95% CI: 0.81-1.15, P = 0.69), respectively. There were statistically significant differences in the rates of crude stroke and stroke over the medium- or long-term follow-up periods and the crude stroke rate in the TA plus PCI (RR: 1.60, 95% CI: 1.08-2.38, P = 0.02) and (RR: 1.43, 95% CI: 1.03-1.98, P = 0.03), respectively; this was not observed between the two arms during the short-term follow-up period (RR: 1.47, 95% CI: 0.97-2.21, P = 0.07). CONCLUSIONS: Routine TA-assisted PCI in STEMI patients can improve myocardial reperfusion and get limited benefits related to the clinical endpoints, which may be associated with stroke risk.

13.
Neurochem Res ; 41(7): 1587-603, 2016 Jul.
Article in English | MEDLINE | ID: mdl-27038931

ABSTRACT

Stromal cell-derived factor 1 (SDF-1)/chemokine CXC motif ligand 12 (CXCL12), a chemokine that is upregulated in dorsal root ganglion (DRG) during chronic pain models, has recently been found to play a central role in pain hypersensitivity. The purpose of present study is to investigate the functional impact of SDF-1 and its receptor, chemokine CXC motif receptor 4 (CXCR4), on two TTXR sodium channels in rat DRG using electrophysiological techniques. Preincubation with SDF-1 caused a concentration-dependent increase of Nav1.8 and Nav1.9 currents amplitudes in acutely isolated small diameter DRG neurons in short-term culture. As to Nav1.9, changes in current density and kinetic properties of Nav1.9 current evoked by SDF-1(50 ng/ml) was eliminated by CXCR4 antagonist AMD3100 and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. The increase in Nav1.9 current was also blocked by pertussis toxin (PTX) but not cholera toxin (CTX), showing involvement of Gi/o but not Gs subunits. As to Nav1.8, inhibitors (AMD3100, PTX, CTX, LY294002) used in present study didn't inhibit the increased amplitude of Nav1.8 current and shifted activation curve of Nav1.8 in a hyperpolarizing direction in the presence of SDF-1 (50 ng/ml). In conclusion, our data demonstrated that SDF-1 may excite primary nociceptive sensory neurons by acting on the biophysical properties of Nav1.8 and Nav1.9 currents but via different mechanisms.


Subject(s)
Chemokine CXCL12/pharmacology , Ganglia, Spinal/physiology , NAV1.8 Voltage-Gated Sodium Channel/physiology , NAV1.9 Voltage-Gated Sodium Channel/physiology , Sodium Channel Blockers/pharmacology , Tetrodotoxin/pharmacology , Action Potentials/drug effects , Action Potentials/physiology , Animals , Cells, Cultured , Dose-Response Relationship, Drug , Ganglia, Spinal/drug effects , Rats , Rats, Sprague-Dawley
14.
Med Sci Monit ; 21: 542-9, 2015 Feb 19.
Article in English | MEDLINE | ID: mdl-25694200

ABSTRACT

BACKGROUND: Sleep deprivation contributes to the development and recurrence of ventricular arrhythmias. However, the electrophysiological changes in ventricular myocytes in sleep deprivation are still unknown. MATERIAL AND METHODS: Sleep deprivation was induced by modified multiple platform technique. Fifty rats were assigned to control and sleep deprivation 1, 3, 5, and 7 days groups, and single ventricular myocytes were enzymatically dissociated from rat hearts. Action potential duration (APD) and transient outward current (Ito) were recorded using whole-cell patch clamp technique. RESULTS: Compared with the control group, the phases of APD of ventricular myocytes in 3, 5, and 7 days groups were prolonged and APD at 20% and 50% level of repolarization (APD20 and APD50) was significantly elongated (The APD20 values of control, 1, 3, 5, and 7 days groups: 5.66±0.16 ms, 5.77±0.20 ms, 8.28±0.30 ms, 11.56±0.32 ms, 13.24±0.56 ms. The APD50 values: 50.66±2.16 ms, 52.77±3.20 ms, 65.28±5.30 ms, 83.56±7.32 ms, 89.24±5.56 ms. P<0.01, n=18). The current densities of Ito significantly decreased. The current density-voltage (I-V) curve of Ito was vitally suppressed downward. The steady-state inactivation curve and steady-state activation curve of Ito were shifted to left and right, respectively, in sleep deprivation rats. The inactivation recovery time of Ito was markedly retarded and the time of closed-state inactivation was markedly accelerated in 3, 5, and 7 days groups. CONCLUSIONS: APD of ventricular myocytes in sleep deprivation rats was significantly prolonged, which could be attributed to decreased activation and accelerated inactivation of Ito.


Subject(s)
Action Potentials/physiology , Heart Ventricles/pathology , Myocytes, Cardiac/metabolism , Sleep Deprivation/physiopathology , Animals , Ion Channel Gating , Male , Potassium Channels , Rats, Sprague-Dawley , Time Factors
15.
PLoS One ; 9(4): e95916, 2014.
Article in English | MEDLINE | ID: mdl-24759683

ABSTRACT

Exposure to microgravity results in post-flight cardiovascular deconditioning and orthostatic intolerance in astronauts. Vascular oxidative stress injury and mitochondrial dysfunction have been indicated in this process. To elucidate the mechanism for this condition, we investigated whether mitochondria regulated NADPH oxidase in hindlimb unweighting (HU) rat cerebral and mesenteric arteries. Four-week HU was used to simulate microgravity in rats. Vascular superoxide generation, protein and mRNA levels of Nox2/Nox4, and the activity of NADPH oxidase were examined in the present study. Compared with control rats, the levels of superoxide increased in cerebral (P<0.001) but not in mesenteric vascular smooth muscle cells. The protein and mRNA levels of Nox2 and Nox4 were upregulated significantly (P<0.001 and P<0.001 for Nox2, respectively; P<0.001 and P<0.001 for Nox4, respectively) in HU rat cerebral arteries but not in mesenteric arteries. NADPH oxidases were activated significantly by HU (P<0.001) in cerebral arteries but not in mesenteric arteries. Chronic treatment with mitochondria-targeted antioxidant mitoTEMPO attenuated superoxide levels (P<0.001), decreased the protein and mRNA expression levels of Nox2/Nox4 (P<0.01 and P<0.05 for Nox2, respectively; P<0.001 and P<0.001 for Nox4, respectively) and the activity of NADPH oxidase (P<0.001) in HU rat cerebral arteries, but exerted no effects on HU rat mesenteric arteries. Therefore, mitochondria regulated the expression and activity of NADPH oxidases during simulated microgravity. Both mitochondria and NADPH oxidase participated in vascular redox status regulation.


Subject(s)
Antioxidants/administration & dosage , Cerebral Arteries/enzymology , Hindlimb Suspension/methods , Mitochondria/enzymology , NADPH Oxidases/metabolism , Organophosphorus Compounds/administration & dosage , Oxidative Stress/drug effects , Piperidines/administration & dosage , Animals , Gene Expression Regulation , Male , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Mesenteric Arteries/enzymology , NADPH Oxidase 2 , NADPH Oxidase 4 , NADPH Oxidases/genetics , Rats , Rats, Sprague-Dawley , Superoxides/metabolism , Weightlessness Simulation/methods
16.
FASEB J ; 28(6): 2715-24, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24604081

ABSTRACT

Exposure to microgravity results in cardiovascular deconditioning, and cerebrovascular oxidative stress injury has been suggested to occur. To elucidate the mechanism for this condition, we investigated whether simulated microgravity induces mitochondrial dysfunction in rat arteries. Four-week hindlimb unweighting (HU) was used to simulate microgravity in rats. Mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (Δψm), mitochondrial permeability transition pore (mPTP) opening, mitochondrial respiratory control ratio (RCR), MnSOD/GPx activity and expression, and mitochondrial malondialdehyde (MDA) were examined in rat cerebral and mesenteric VSMCs. Compared with the control rats, mitochondrial ROS levels, mPTP opening, and MDA content increased significantly (P<0.001, P<0.01, and P<0.01, respectively), Δψm, RCR, MnSOD/GPx activity (P<0.001 for Δψm and RCR; P<0.05 for MnSOD; and P<0.001 for GPx activity) and protein abundance of mitochondrial MnSOD/GPx-1 decreased (P<0.001 for MnSOD and GPx-1) in HU rat cerebral but not mesenteric arteries. Chronic treatment with NADPH oxidase inhibitor apocynin and mitochondria-targeted antioxidant mitoTempol promoted recovery of mitochondrial function in HU rat cerebral arteries, but exerted no effects on HU rat mesenteric arteries. Therefore, simulated microgravity resulted in cerebrovascular mitochondrial dysfunction, and crosstalk between NADPH oxidase and mitochondria participated in the process.


Subject(s)
Cerebral Arteries/physiopathology , Mitochondria/metabolism , Weightlessness Simulation/adverse effects , Acetophenones/pharmacology , Animals , Cerebral Arteries/ultrastructure , Glutathione Peroxidase/metabolism , Hindlimb Suspension , Male , Membrane Potential, Mitochondrial/physiology , Mesenteric Arteries/ultrastructure , Mitochondria/drug effects , Mitochondrial Membrane Transport Proteins/metabolism , Mitochondrial Permeability Transition Pore , NADPH Oxidases/metabolism , Organophosphorus Compounds/pharmacology , Piperidines/pharmacology , Rats , Reactive Oxygen Species/metabolism , Superoxide Dismutase/metabolism
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