Dexmedetomidine Ameliorated Cognitive Dysfunction Induced by Intestinal Ischemia Reperfusion in Mice with Possible Relation to the Anti-inflammatory Effect Through the Locus Coeruleus Norepinephrine System.

Cognitive impairment is a common central nervous system complication that occurs following surgery or organs damage outside the nervous system. Neuroinflammation plays a key role in the molecular mechanisms of cognitive impairment. Dexmedetomidine alleviates neuroinflammation and reduces cognitive dysfunction incidence; however, the mechanism by which dexmedetomidine alleviates cognitive dysfunction remains unclear. This study evaluated the effect of dexmedetomidine on attenuation of early cognitive impairment induced by intestinal ischemia-reperfusion in mice and examined whether the locus coeruleus norepinephrine (LCNE) system participates in the anti-inflammatory effect of dexmedetomidine. The superior mesenteric artery was clamped for 45 min to induce intestinal ischemia reperfusion injury. Dexmedetomidine alone or combined with DSP-4, a selective locus coeruleus noradrenergic neurotoxin, was used for pretreatment. Postoperative cognition was assessed using the Morris water maze. Serum and hippocampal levels of IL-1ß, TNF-α, norepinephrine (NE), and malondialdehyde (MDA) were assessed by enzyme-linked immunosorbent assay. Immunofluorescence, immunohistochemistry, and hematoxylin and eosin staining were used to evaluate the expression of tyrosine hydroxylase (TH) in the locus coeruleus, hippocampal microglia, and intestinal injury. Pretreatment with dexmedetomidine alleviated intestinal injury and decreased the serum and hippocampal levels of NE, IL-1ß, TNF-α, and MDA at 24 h after intestinal ischemia reperfusion, decreased TH-positive neurons in the locus coeruleus, and ameliorated cognitive impairment. Similarly, DSP-4 pre-treatment alleviated neuroinflammation and improved cognitive function. Furthermore, α2-adrenergic receptor antagonist atipamezole or yohimbine administration diminished the neuroprotective effects and improved cognitive function with dexmedetomidine. Therefore, dexmedetomidine attenuated early cognitive dysfunction induced by intestinal ischemia-reperfusion injury in mice, which may be related to its anti-inflammatory effects through the LCNE system.

Activation of LRP1 Ameliorates Cerebral Ischemia/Reperfusion Injury and Cognitive Decline by Suppressing Neuroinflammation and Oxidative Stress through TXNIP/NLRP3 Signaling Pathway in Mice.

Cerebral ischemia/reperfusion (I/R) injury is a clinical event associated with high morbidity and mortality. Neuroinflammation plays a crucial role in the pathogenesis of I/R-induced brain injury and cognitive decline. Low-density lipoprotein receptor-related protein-1 (LRP1) can exert strong neuroprotection in experimental intracerebral hemorrhage. However, whether LRP1 can confer neuroprotective effects after cerebral I/R is yet to be elucidated. The present study is aimed at investigating the effects of LRP1 activation on cerebral I/R injury and deducing the underlying mechanism involving TXNIP/NLRP3 signaling pathway. Cerebral I/R injury was induced in mice by bilateral common carotid artery occlusion. LPR1 ligand, apoE-mimic peptide COG1410, was administered intraperitoneally. To elucidate the underlying mechanism, overexpression of TXNIP was achieved via the hippocampal injection of AAV-TXNIP before COG1410 treatment. Neurobehavioral tests, brain water content, immunofluorescence, Western blot, enzyme-linked immunosorbent assay, HE, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were performed. Our results showed that the expressions of endogenous LRP1, TXNIP, NLRP3, procaspase-1, and cleaved caspase-1 were increased after cerebral I/R. COG1410 significantly ameliorated cerebral I/R-induced neurobehavioral deficits, brain edema, histopathological damage, and poor survival rate. Interestingly, COG1410 inhibited microglia proinflammatory polarization and promoted anti-inflammatory polarization, decreased oxidative stress, attenuated apoptosis, and inhibited the expression of the TXNIP/NLRP3 signaling pathway. However, the benefits of COG1410 were abolished by TXNIP overexpression. Thus, our study suggested that LRP1 activation with COG1410 attenuated cerebral I/R injury at least partially related to modulating microglial polarization through TXNIP/NLRP3 signaling pathway in mice. Thus, COG1410 treatment might serve as a promising therapeutic approach in the management of cerebral I/R patients.

PINK1/Parkin-mediated mitophagy in mechanical ventilation-induced diaphragmatic dysfunction.

BACKGROUND: Mechanical ventilation (MV) often leads to ventilation-induced diaphragm dysfunction (VIDD). Although the development of this disorder had been linked to oxidative stress, mitochondrial energy deficiency, autophagy activation, and apoptosis in the diaphragm, it remains unclear whether the activation of mitophagy can induce VIDD. With our research, our endeavor is to uncover whether PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy affects the MV-caused diaphragmatic dysfunction. METHODS: Sprague-Dawley rats were subjected to MV treatment for 6 h (MV-6h), 12 h (MV-12h), or 24 h (MV-24h). Post MV, the diaphragm muscle compound action potential (CMAP) and cross-sectional areas (CSAs) of the diaphragm of these rats were measured. The levels of proteins of interest were examined to assess muscle health, mitochondrial dynamics, and mitophagy in the diaphragm. The co-localization of PINK1 with the mitochondrial protein marker tom20 was examined, as well as transmission electron microscopy analysis to detect changes in diaphragm mitochondrial ultrastructure. RESULTS: MV-12h and MV-24h treatments resulted in a decrease in CSA of diaphragm and CMAP amplitude. In addition, the expressions of F-box (MFAbx), muscle-specific ring finger 1 (MURF1), PINK1, and p62 were elevated in rats treated with MV for 12 h and 24 h, while mfn2 expression was reduced. Rats following MV-24h treatment displayed an increase in mitochondrial dynamic protein (Drp1) and Parkin expression and microtubule-associated protein 1 light chain 3/1 (LC3II/I) ratio. Moreover, decreased SOD and GSH activity and membrane potential were observed after MV-12h and MV-24h treatment, while H2O2 activity increased after MV-24h treatment. In addition, a strong co-localization between PINK1 and tom20 was identified. CONCLUSION: These results reveal that MV leads to various changes in mitochondrial dynamics and significantly increases the mitophagy levels, which subsequently cause the variation in diaphragmatic function and muscle atrophy, indicating that mitophagy could be one of the possible mechanisms by which MV induces diaphragmatic dysfunction.The reviews of this paper are available via the supplemental material section.

lncRNA MALAT1 Accelerates Skeletal Muscle Cell Apoptosis and Inflammatory Response in Sepsis by Decreasing BRCA1 Expression by Recruiting EZH2.

Sepsis is a serious and elusive syndrome caused by infection, which is accompanied by a high mortality worldwide. Recent evidence has documented the regulatory role of long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) during the inflammatory process, the effects of which in the development of sepsis have become the focus of the current study. An in vivo mouse model and in vitro cell model of sepsis induced by lipopolysaccharide (LPS) were developed. High expression of lncRNA MALAT1 along with low expression of breast cancer susceptibility gene 1 (BRCA1) were identified in septic mice and human skeletal muscle cells of sepsis. Then, lncRNA MALAT1 expression was altered in vivo and in vitro to examine serum levels of inflammatory factors, as well as skeletal muscle cell apoptosis. lncRNA MALAT1 was noted to regulate the expression and export from the nucleus of BRCA1 by recruiting zeste homolog 2 (EZH2) in skeletal muscle cells of sepsis. Silencing lncRNA MALAT1 resulted in reduced serum levels of interleukin (IL)-6, IL-8, and tumor necrosis factor alpha (TNF-α), neutrophil migration, skeletal muscle cell apoptosis, and AKT-1 phosphorylation. Taken together, lncRNA MALAT1 interacting with EZH2 stimulated AKT-1 phosphorylation and decreased BRCA1 expression, consequently aggravating the progression of sepsis, highlighting a promising therapeutic option for sepsis.

Neuregulin-1ß modulates myogenesis in septic mouse serum-treated C2C12 myotubes in vitro through PPARγ/NF-κB signaling.

Sepsis-induced skeletal muscle atrophy is a pathological condition characterized by the loss of strength and muscle mass. Cytokine-induced apoptosis and impaired myogenesis play key roles in the development of this condition. However, the complete underlying mechanism remains largely unknown. Neuregulins are glial growth factors essential for myogenesis that regulate muscle metabolism. We investigated the role of neuregulin-1ß (NRG-1ß) in sepsis-induced apoptosis and myogenesis in skeletal muscle using a serum-based in vitro sepsis model. C2C12 myoblasts were differentiated by treatment with proliferative medium for 7 days. Then, cells were treated with 2% sham mouse serum, 1 nM NRG-1ß in 2% sham mouse serum, 2% septic mouse serum (SMS), or 1 nM NRG-1ß in 2% SMS. Exposure to SMS induced apoptosis, impaired myogenesis, and downregulated PPARγ. NRG-1ß co-incubation remedied all these effects and inhibited NF-κB transcriptional activity. A specific PPARγ antagonist (GW9662) was also administered as a 2-h pretreatment to block PPARγ-mediated signaling and appeared to attenuate the effects of NRG-1ß. Taken together, our results demonstrate that NRG-1ß functions via a PPARγ/NF-κB-dependent pathway to modulate myogenesis and protect against apoptosis in SMS-treated C2C12 myotubes.

Protective and Therapeutic Effects of Engeletin on LPS-Induced Acute Lung Injury.

Acute lung injury (ALI) is a serious disease with morbidity and mortality in patients. Engeletin (dihydrokaempferol 3-rhamnoside) is a flavanonol glycoside. It can be found in the skin of white grapes and white wine and is widely distributed in southeast Asia. In our study, we evaluated the protective and therapeutic effects of engeletin on lipopolysaccharide (LPS)-induced ALI in animal model. We determined the level of peroxisome proliferator-activated receptor-γ (PPAR-γ), nuclear factor kappaB (NF-κB), and IκBα by western blotting. The myeloperoxidase (MPO) activity and lung wet/dry (W/D) ratio in lung tissues were also detected. Histopathological changes and the pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß were determined by H&E staining and ELISA. The MPO activity and lung W/D ratio induced by LPS were attenuated by engeletin. The numbers of inflammatory cells and the levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were ameliorated by engeletin. Furthermore, the results also showed that engeletin significantly suppressed LPS-induced NF-κB activation. The expression of PPAR-γ was upregulated by treatment of engeletin. In conclusion, we found that engeletin had protective and therapeutic effects against LPS-induced ALI by activating PPAR-γ. Engeletin is a potentially effective agent for the treatment of lung injury.

Network-based method for detecting dysregulated pathways in glioblastoma cancer.

The knowledge on the biological molecular mechanisms underlying cancer is important for the precise diagnosis and treatment of cancer patients. Detecting dysregulated pathways in cancer can provide insights into the mechanism of cancer and help to detect novel drug targets. Based on the wide existing mutual exclusivity among mutated genes and the interrelationship between gene mutations and expression changes, this study presents a network-based method to detect the dysregulated pathways from gene mutations and expression data of the glioblastoma cancer. First, the authors construct a gene network based on mutual exclusivity between each pair of genes and the interaction between gene mutations and expression changes. Then they detect all complete subgraphs using CFinder clustering algorithm in the constructed gene network. Next, the two gene sets whose overlapping scores are above a specific threshold are merged. Finally, they obtain two dysregulated pathways in which there are glioblastoma-related multiple genes which are closely related to the two subtypes of glioblastoma. The results show that one dysregulated pathway revolving around epidermal growth factor receptor is likely to be associated with the primary subtype of glioblastoma, and the other dysregulated pathway revolving around TP53 is likely to be associated with the secondary subtype of glioblastoma.

Bidirectional Regulatory Effects of Dexmedetomidine on Porcine Coronary Tone In Vitro.

BACKGROUND Studies in vivo have shown that dexmedetomidine (DEX) could protect the myocardium and modulate the coronary blood flow. This study aimed to investigate the direct and concentration-dependent effects of DEX on the tone of porcine coronary artery in vitro and the underlying mechanisms. MATERIAL AND METHODS Distal branches of the porcine anterior descending coronary arteries were dissected and cut into 3-5 mm rings. The tones of coronary rings in response to cumulative DEX were measured using the PowerLab system. Coronary rings were divided into three groups: 1) endothelium-intact coronary rings without drug pretreatment (control); 2) endothelium-intact coronary rings pretreated with either yohimbine, tetraethylamine (TEA) or NG-nitro-L-arginine methyl ester (L-NAME); and 3) endothelium-denuded coronary rings pretreated with either yohimbine or TEA. RESULTS DEX induced coronary ring relaxation at lower concentrations (10^-9 to 10^-7 M) followed by constriction at higher concentrations (10^-6 to 10^-5 M). The coronary constrictive effect of higher DEX (10^-5 M) was greater in the endothelium-denuded rings than in the endothelium-intact rings. Yohimbine reduced the coronary constrictive effect of DEX at higher concentrations (10^-6 to 10^-5 M). TEA and L-NAME significantly reduced the coronary relaxing effect of DEX at lower concentrations (10^-9 to 10^-7 M) in endothelium-intact rings. TEA attenuated the coronary relaxation induced by DEX in endothelium-denuded rings. CONCLUSIONS DEX exerts bidirectional effects on porcine coronary tone. The coronary relaxing effect of DEX at lower concentrations is likely associated with endothelium integrity, NO synthesis and BKCa channel activation, while the coronary constrictive effect of DEX at higher concentrations is mediated by a2 adrenoceptors in the coronary smooth muscle cells.

Increased Consumption of Fruit and Vegetables Is Related to a Reduced Risk of Cognitive Impairment and Dementia: Meta-Analysis.

Background: Increased consumption of fruit and vegetables has been shown to be associated with a reduced risk of cognitive impairment and dementia in many epidemiological studies. The purpose of this study was to assess the strength of this association in a meta-analysis. Methods: We identified relevant studies by searching Medline, Embase, and Cochrane Library electronic databases (from 1970 to January 2016). Study were included if they reported relative risks and corresponding 95% confidence intervals (CIs) of cognitive impairment and dementia with respect to frequency of fruit and vegetable intake. Results: Nine studies (five cohort studies and four cross-sectional studies) met the inclusion criteria and were included in the meta-analysis. There were a total of 31,104 participants and 4,583 incident cases of cognitive impairment and dementia. The meta-analysis showed that an increased consumption of fruit and vegetables was associated with a significant reduction in the risk of cognitive impairment and dementia (OR = 0.80, 95% CI 0.71-0.89). Subgroup analysis indicated this inverse association was only found among participants with mean age over 65 years and combined sexes. Dose-response meta-analysis showed that an increment of 100 g per day of fruit and vegetable consumption was related to an approximately 13% (OR = 0.87, 95% CI 0.77-0.99) reduction in cognitive impairment and dementia risk. There was no potential publication bias in the meta-analysis and the dose-response meta-analysis. Conclusion: The increased consumption of fruit and vegetables is associated with a reduced risk of cognitive impairment and dementia.

Electroacupuncture pretreatment with different waveforms prevents brain injury in rats subjected to cecal ligation and puncture via inhibiting microglial activation, and attenuating inflammation, oxidative stress and apoptosis.

Sepsis is associated with high morbidity and mortality. This study was to investigate the protective effects of electroacupuncture (EA) pretreatment with different waveforms on septic brain injury in rats and its mechanism. Male Sprague-Dawley rats were pretreated by EA with different waveforms (continuous wave, dilatational wave, or intermittent wave) at Baihui (GV20) and Tsusanli (ST36) acupoints for 30min, and underwent cecal ligation and puncture (CLP) or sham operation. The results showed that EA pretreatment with different waveforms improved survival rate, attenuated encephaledema, brain injury, neuronal apoptosis and cognitive dysfunction, and preserved blood-brain barrier (BBB). EA pretreatment decreased the production of tumor necrosis factor(TNF)-α, interleukin(IL)-6, malondialdehyde (MDA), and increased the activity of superoxide dismutase (SOD) and catalase (CAT) in serum and hippocampus at 48h after sham or CLP operation. Additionally, EA pretreatment downregulated the expressions of toll-like receptor-4 (TLR-4), nuclear factor-kappa B (NF-κB) and ionized calcium binding adaptor molecule 1(Iba 1). The effect of dilatational wave was the most significant, followed by intermittent wave, and continuous wave was relatively poor. In conclusion, our results demonstrate that EA pretreatment with three waveforms alleviates sepsis-induced brain injury by inhibition of microglial activation and attenuation of inflammation, oxidative stress and apoptosis. These findings suggest that EA pretreatment with dilatational wave at Baihui and Tsusanli acupoints might be a promising therapeutic strategy for relieving septic brain injury.

Investigation of single nucleotide polymorphisms based on the intronic sequences of the propylene alcohol dehydrogenase gene in Chinese tobacco genotypes.

A pair of primers was designed to amplify the propylene alcohol dehydrogenase gene sequence based on the cDNA sequence of the tobacco allyl-alcohol dehydrogenase gene. All introns were sequenced using traditional polymerase chain reaction (PCR) methods and T-A cloning. The sequences from common tobacco (Nicotiana tabaccum L.) and rustica tobacco (Nicotiana rustica L.) were analysed between the third intron and the fourth intron of the propylene alcohol dehydrogenase gene. The results showed that the alcohol dehydrogenase gene is a low-copy nuclear gene. The intron sequences have a combination of single nucleotide polymorphisms and length polymorphisms between common tobacco and rustica tobacco, which are suitable to identify the different germplasms. Furthermore, there are some single nucleotide polymorphism sites in the target sequence within common tobacco that can be used to distinguish intraspecific varieties.

Effects of sevoflurane on cytokine balance in patients undergoing coronary artery bypass graft surgery.

OBJECTIVE: The effects of sevoflurane on proinflammatory cytokines related to ischemic-reperfusion injury are not clear. The hypothesis was tested that sevoflurane decreases myocardial ischemic-reperfusion injury by suppressing proinflammatory cytokines. DESIGN: Prospective, randomized study. SETTING: A medical university heart center. PARTICIPANTS: Twenty-three patients undergoing coronary artery bypass surgery allocated randomly into 2 groups. INTERVENTIONS: Anesthesia for 23 patients undergoing coronary artery bypass surgery was maintained using either fentanyl (30 microg/kg) with propofol (2-8 mg/kg/h) in the control group (n = 10) or fentanyl (30 microg/kg) with 0.5% to 1.0% sevoflurane in the sevoflurane group (n = 13). MEASUREMENTS AND MAIN RESULTS: Interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonist (IL-1ra) were measured by enzyme-linked immunosorbent assay. Troponin-T and creatine kinase-MB isoenzyme (CK-MB) were measured by enzyme immunoassay and ultraviolet absorption spectrophotometry, respectively. Serum IL-6 and IL-8 concentrations in both groups increased significantly over baseline from 60 minutes after declamping the aorta (p < 0.001). The increases were greater in the control group than in the sevoflurane group (p < 0.05). Serum IL-10 and IL-1ra concentrations in both groups increased significantly over baseline from 60 minutes after declamping the aorta (p < 0.001). There were no differences between the two groups. Serum troponin-T and CK-MB concentrations increased significantly in both groups from 60 minutes after declamping the aorta (p < 0.001); the increases were greater in the control group (p < 0.05). CONCLUSION: Sevoflurane suppressed the production of IL-6 and IL-8, but not IL-10 and IL-1ra. Changes in the balance between pro- and anti-inflammatory cytokines may be one of the most important mechanisms of myocardial protection caused by sevoflurane.

[Changes of hemodynamics during establishment of animal model of acute myocardial infarction induced by ligation of left coronary artery in goat].

OBJECTIVE: To study the changes in hemodynamics in experimental acute myocardial infarction induced by ligation of the left coronary artery in goat. METHODS: Animal model of acute myocardial infarction was reproduced in 20 goats by ligation of the left coronary artery through xyphoid process. ST segment of electrocardiogram (ECG), mean artery blood pressure (MAP), central venous pressure (CVP), and heart rate (HR) were observed before, immediately, 30 minutes, 1 hour and 2 hours after ligation of the left coronary artery. RESULTS: ECG of all goats was normal before operation. Immediately and 30 minutes after ligation, elevation of ST-segment was seen in 8 and 10 goats respectively, and in 18 goats elevation of ST-segment was observed 2 hours after ligation. Four weeks after the operation, pathological Q wave was shown in the chest leads of ECG in 18 goats. There was no significant difference in MAP, CVP and HR between before and after ligation. Frequent ventricular premature beats were found in 6 goats, but they were stopped after intravenous infusion of lidocaine. CONCLUSION: Small area of experimental acute myocardial infarction in goats shows slight effect on hemodynamics, though the production of myocardial infarction is reliable, and the life of the goats could be maintained for a long time after the ligation of the left coronary artery. The experiment provides a valuable animal model for the study of coronary heart disease.

Nicorandil attenuates NF-kappaB activation, adhesion molecule expression, and cytokine production in patients with coronary artery bypass surgery.

Nicorandil (NCR), a KATP channel opener, has been reported to preserve microvascular integrity in patients with reperfused myocardial infarction. We tested the hypothesis that NCR suppresses myocardial ischemia and reperfusion injury via the attenuation of cytokine production. Forty patients who underwent coronary artery bypass graft surgery were studied. The patients were randomly divided into two groups, i.e., the patients with NCR (4-6 mg/h; N group, n = 20) or without NCR (C group, n = 20). Cardiac surgery was performed under anesthesia using fentanyl and propofol. Blood were sampled at the time of induction of anesthesia, pre-cardiopulmonary bypass, 60 min after aortic occlusion, and 60, 120, and 180 min after declamping the aorta. The activation of NF-kappaB, expression of adhesion molecules, and cytokine production were evaluated in blood samples from the control volunteers by flow cytometric analysis with or without lipopolysaccharide (LPS) stimulation in vitro. Serum IL-6 and IL-8 levels in both groups increased 60 min after declamping the aorta compared with the preoperative value (P < 0.001); the increases of these parameters in N group were lower than those in C group (P < 0.05). Serum creatine kinase with muscle and brain subunits and troponin-T levels increased 60 min after declamping the aorta in two groups (P < 0,001), but the increases of both parameters in N group were lower than those in C group (P < 0.05). NF-kappaB activation, CD11b/CD18 expression, and the production of TNF-alpha, IL-8, and IL-6 in monocytes and granulocytes were inhibited by NCR in vitro. NCR suppressed the increase of inflammatory cytokines such as IL-6 and IL-8 levels, and reduced myocardial reperfusion injury. The inhibition on NF-kappaB activation, adhesion molecule expression, and cytokine production may be one of the important mechanisms of myocardial protection of NCR.

Usefulness of nitric oxide treatment for pulmonary hypertensive infants during cardiac anesthesia.

BACKGROUND: The beneficial effect of inhaled nitric oxide (NO) on pulmonary hypertension is well known. However, the indications for NO inhalation therapy for pulmonary hypertension associated with congenital heart lesions are still unclear. The aim of the current study was to seek a measure that would predict the effectiveness of inhaled NO in infants undergoing cardiac surgery. METHODS: Forty-six infants with pulmonary hypertension were studied. Pulmonary vascular resistance (PVR) measured at the time of cardiac catheterization was used as an indicator and compared with pulmonary arterial pressure/systemic blood pressure ratio (Pp/Ps) at the time of weaning from cardiopulmonary bypass. The effect of 40 ppm of inhaled NO for 15 min was evaluated in patients whose Pp exceeded systemic values. RESULTS: Preoperative PVR correlated positively with Pp/Ps at the time of weaning from cardiopulmonary bypass (r2 = 0.86; P < 0.05; n = 46). A Pp/Ps greater than or equal to 1 was not observed in any cases in which the preoperative PVR values were less than 7 Wood units m2; Pp/Ps ratio greater than or equal to 1 occurred in four patients. Each of these had PVR values greater than 7 Wood units m2. Three of these patients who had PVR values in the 7-12 Wood units m2 range were responsive to inhaled NO. The fourth patient, whose PVR value was greater than 15 Wood units m2, was unresponsive. Lung biopsy specimens were obtained in two patients whose preoperative PVR values were greater than 10 Wood units m2. CONCLUSION: Preoperative PVR correlates reasonably well with postbypass Pp/Ps.