Huisheng Wu

Serum levels of irisin predict short-term outcomes in ischemic stroke

OBJECTIVEnIrisin is a 112-amino acid peptide found in rat and human skeletal muscle after exercise. Previous studies had suggested that higher circulating irisin levels were associated with an increased risk of vascular atherosclerosis and cardiovascular diseases. In this study, we determined irisin levels in serum, and investigated their associations with functional outcomes in a 3-month follow-up study in Chinese patients with first-ever acute ischemic stroke (AIS).nnnMETHODSnFrom September 2015 to December 2016, consecutive first-ever AIS patients admitted to the Department of Emergency of our hospital were identified. Serum irisin levels were measured at admission. Functional impairment was evaluated at discharge using the modified Rankin scale. The levels of irisin were expressed as median and interquartile ranges [IQR].nnnRESULTSnThe irisin level was obtained in 324 patients (97.6%) with a median value of 291.2u202fng/ml (IQR: 214.1-404.2u202fng/ml). There were significantly negative correlations between levels of irisin and NHISS (ru202f=u202f-0.272; Pu202f<u202f0.001) and BMI (ru202f=u202f-0.193; Pu202f=u202f0.003). A poor functional outcome was found in 99 patients (30.6%; 95%CI: 25.5-35.6%). The poor functional outcome distribution across the irisin quartiles ranged between 51.9% (first quartile: Q1) to 12.4% (fourth quartile: Q4). In a multivariate model using the Q1 of irisin vs. Q2-4 together with the clinical variables, the marker displayed prognostic information and increased risk of poor outcomes by 94% (OR for Q1, 1.94 [95% CI, 1.19-3.42]; Pu202f=u202f0.018) and mortality 66% (OR for Q1, 1.66 [95% CI, 1.11-3.07]; Pu202f=u202f0.009). In addition, a model containing known risk factors plus irisin compared with a model containing known risk factors without irisin showed a greater discriminatory ability to predict poor outcomes (Pu202f=u202f0.01) and mortality (Pu202f=u202f0.02).nnnCONCLUSIONSnA low serum irisin level is a predictor of poor early functional outcome in ischemic stroke patients. The underlying mechanisms of these associations remain to be investigated.

Hydroxybutyrate promotes the recovery from cerebral infarction by activating Amp‑activated protein kinase signaling

Recent studies have shown that hydroxybutyrate (GHB) is effective for protection against ischemia/brain damage in rat models. However, the specific underlying mechanism is poorly understood. In line with the previous studies, the present data showed that GHB improves cerebral blood flow (CBF) and physiological variables, including pH, pCO2 and pO2. Using CD31-immunofluorescence staining, a reduction of blood vessel density was indicated in the middle cerebral artery occlusion (MCAO) group; however, GHB treatment enhanced the cerebral vascular density in the ischemic area. In addition, GHB treatment increased the number of BrdU/lectin double-positive cells. Furthermore, the reduction of nestin-positive cells was identified in the brain of MCAO rats, while the number of nestin-positive cells was significantly increased after GHB administration. Compared with the sham group, the activation of Amp-activated protein kinase (AMPK) was identified in MCAO rats, suggesting stress-mediated AMPK activation after ischemia. Furthermore, the western blot assay showed that GHB treatment resulted in further activation of AMPK and endothelial nitric oxide synthase (eNOS), suggesting an enhanced energy supply. In summary, the present novel data indicates that GHB promotes the recovery from cerebral infarction mainly by activating AMPK and eNOS signaling, thereby enhancing angiogenesis and neuron regeneration.

Methylene blue relieves the development of osteoarthritis by upregulating lncRNA MEG3

Methylene blue (MB) is a long-term inhibitor of peripheral nerve axons, thereby alleviating or permanently eliminating pain. However, it remains unknown whether MB is safe and effective method of treating osteoarthritis (OA). MB was injected into the knee joints of rabbits and they were monitored for any histological structural changes. The results revealed no evident changes in the histological structure of the normal knee joint following injection of 1 mg/kg MB at 1, 4, 8 and 24 weeks post-injection. Compared with the vehicle control, MB treatment significantly enhanced the weight distribution and significantly decreased the swelling ratio of the rabbits. Additionally, levels of long non-coding RNA (lncRNA) maternally expressed 3 (MEG3) mRNA were significantly increased following treatment with MB, but the protein expression of P2X purinoceptor 3 (P2X3) was significantly suppressed compared with the vehicle control. The levels of interleukin (IL) 6, tumor necrosis factor (TNF)α, IL-1β and IL-8 were significantly suppressed following MB treatment, indicating that MB protects against OA progression. It was also revealed that MEG3 overexpression significantly suppresses levels of P2X3 protein. ELISA indicated that the MEG3-induced reduction of IL-6, TNFα, IL-1β and IL-8 expression was significantly reversed following P2X3 overexpression. Therefore, the results of the present study demonstrated that MB is an effective method of treating OA-associated pain by upregulating lncRNA MEG3 levels. Additionally, lncRNA MEG3 relieves the OA-associated pain and inflammation in a rabbit model of OA by inhibiting P2X3 expression.

Reduced peripheral blood miR‑140 may be a biomarker for acute lung injury by targeting Toll‑like receptor 4 (TLR4)

Acute lung injury (ALI) is a common complication of sepsis to which patients often succumb due to poor effective pharmacological interventions. Recent studies have focused on the potential application of circulating microRNAs (miRs or miRNAs) as novel prognostic and therapeutic biomarkers. The present study focuses mainly on miR-140, the role of which is poorly understood in the progression of ALI. The results of the present study revealed that toll-like receptor 4 (TLR4) expression was upregulated the lungs of rats with ALI. Meanwhile, serum levels of tumor necrosis factor-α, interleukin (IL)-6 and IL-1β were significantly increased in rats with ALI compared with normal control rats. These data indicated the successful establishment of LPS-induced ALI. Furthermore, miR-140 was decreased in the peripheral blood of patients with ALI compared with control subjects. Receiver operator characteristic analysis indicated that miR-140 could be used to screen ALI patients and distinguish them from healthy controls. MiR-140 was demonstrated to be downregulated in the plasma and lungs of rats with ALI compared with the normal control group. A dual luciferase reporter assay indicated that TLR4 was a target gene of miR-140. To investigate whether miR-140 exerted its role via TLR4, a specific TLR4-targeting small interfering RNA was selected. It was revealed that TLR4 silencing was able to suppress the phosphorylation of NF-κB even in cells transfected with miR-140 inhibitor. In summary, reduced miR-140 expression and increased TLR4 signaling activation may serve a key role in the progression of ALI.

Effects of L-655,708 on expression changes of GABA, glutamate, and beta-endorphin induced by propofol anesthesia in rats

Anesthetics are considered to be one of the important inducing factors of postoperative cognitive dysfunction (POCD). The hippocampal region of the rat is one of the action sites of general anesthesia drugs. L 655,708, a reverse agonist of gamma aminobutyric acid (GABA) receptor, can significantly improve short-term memory dysfunction in mice after anesthetized with isoflurane. So the purpose of this study is to investigate the effects of L-655,708 on expression of GABA, glutamate (GLU), and beta-endorphin (β-EP) in the dentate gyrus region of the hippocampus and cognition of rats anesthetized with propofol. In all, 30 male Sprague–Dawley (SD) rats were randomly allocated into the control group, sham group, and L-655,708 group, with 10 in each group. The cognitive function of rats was measured by Morris water maze before and 1u2009h after administration. Then the rats were sacrificed for brain tissues. Immunohistochemistry was used to study the expression of GABA, GLU, and β-EP in the hippocampus of anesthetized rats in each group. Compared with the control group, the latency of the sham group and L-655,708 group were significantly prolonged after administration (Pu2009<u20090.05). However, L-655,708 could shorten the prolonged latency (Pu2009<u20090.05). There was no significant difference in times of accessing original platform area between the three groups before and after medication (Pu2009>u20090.05). The expression level of GABA in the dentate gyrus region of hippocampus of rats in the sham group was significantly higher than that in the control group (Pu2009<u20090.05), while the expression level in the L-655,708 group was significantly lower than that in the sham group (Pu2009<u20090.05). No significant difference was found in the expression of GLU in the dentate gyrus region of hippocampus of rats in each group (Pu2009>u20090.05). Compared with the control group, the expression of β-EP was significantly lower in the dentate gyrus region of the hippocampus of sham group rats (Pu2009<u20090.05). However, the expression of β-EP in the L-655,708 group was significantly higher than that in the sham group (Pu2009<u20090.05). Cognitive dysfunction in rats anesthetized with propofol may be related to high expression of GABA and low expression of β-EP in the hippocampus. The mechanism of L-655,708 in reducing the cognitive impairment in propofol anesthetized rats may be bound up with down-regulating the expression of GABA and increasing the expression of β-EP in the hippocampus.

Effects of Lipoxin A4 Pretreatment on Cognitive Function of Aged Rats after Global Cerebral Ischemia Reperfusion

SummaryThe aim of the present study was to investigate the effect of lipoxin A4 (LXA4) pretreatment on cognitive function of aged rats after global cerebral ischemia reperfusion, and to explore its possible mechanism. Thirty-six aged male Sprague-Dawley rats were randomly divided into three groups (n=2 each): sham-operation group (S group), global cerebral ischemia reperfusion group (I/R group) and LXA4-pretreatment group (L group). The rat model of global cerebral ischemia reperfüsion was established by occlusion of the bilateral common carotid artery with hypotension. The cognitive function of rats was determined by a step-down type passive avoidance test and Morris Water Maze test on the third day after reperfUsion. Rats were sacrificed after Water Maze test and the pathological changes of hippocampal CAI region were observed and the related inflammatory mediators were determined. As compared with S group, the escape latency in I/R group was prolonged from the first day to the fifth day, while that in L group was prolonged from the first day to the third day. The retention time in I/R group and L group in the first quadrant was shortened. The reaction time, frequency of reaction mistake and frequency of escape mistake in I/R group increased, and the latent period shortened. The frequency of escape mistake in L group increased, and the damage in the hippocampal CAI region of I/R group and L group was obvious. The levels of S-100β, TNP-α, IL-lβ, IL-10 and NF-κB in I/R group and L group increased. As compared with I/R group, the escape latency in L group was shortened from the first day to the fifth day, and the retention time in the first quadrant prolonged. The reaction time, frequency of reaction mistake and frequency of escape mistake in L group decreased, and the latent period prolonged. The damage in the hippocampal CAI region of L group was alleviated as well. The levels of S-100β, TNP-α, IL-lβ and NF-κB in L group decreased, and those of IL-10 increased. It can be concluded that LXA4 pretreatment can improve the cognitive function in aged rats after global cerebral ischemia reperfusion probably by inhibiting the inflammatory reaction.

Ketamine ameliorates ischemia–reperfusion injury after liver autotransplantation by suppressing activation of Kupffer cells in rats

This study aimed to investigate the protective effects of ketamine against hepatic ischemia-reperfusion (I/R) injury by suppressing activation of Kupffer cells (KCs) in rat liver autotransplantation. Male Sprague-Dawley rats were randomized into 3 groups (n = 10 each). Group I, the sham group, received saline. Group II received saline and underwent orthotopic liver autotransplantation (OLAT). Group III received 10 mg/kg ketamine and underwent OLAT. Blood samples were obtained at 3, 6, 12, and 24 h after I/R, and following ALT, AST, LDH, IL-6, TNF-α, IL-1β, and IL-10 in serum were detected. Model rats were sacrificed at the indicated time points and the graft liver tissues were evaluated histologically. KCs were isolated from rat liver tissues, and inflammatory products and proteins of NF-κB signaling pathway were detected using quantitative RT-PCR and Western blotting. Our results showed that ketamine significantly decreased ALT, AST, LDH, IL-6, TNF-α, and IL-1β levels and increased IL-10 level. Furthermore, ketamine alleviated the histopathology changes, by less KC infiltration and lower hepatocyte apoptosis. Moreover, activity of NF-κB signaling pathway in KCs was suppressed. In addition, production of pro- and anti-inflammatory factors is consistent with the results in tissues. Ketamine ameliorated I/R injury after liver transplantation by suppressing activation of KCs in rats.

Flurbiprofen axetil attenuates cerebral ischemia/reperfusion injury by reducing inflammation in a rat model of transient global cerebral ischemia/reperfusion

Ischemic stroke has been ranked as the second cause of death in patients worldwide. Inflammation which is activated during cerebral ischemia/reperfusion (I/R) is an important mechanism leading to brain injury. The present study aimed to investigate the effect of flurbiprofen axetil on cerebral I/R injury and the role of inflammation in this process. Rats were subjected to sham operation or global cerebral I/R with or without flurbiprofen axetil (5 or 10 mg/kg). Global cerebral ischemia was achieved by occlusion of bilateral common carotid arteries combined with hypotension for 20 min followed by reperfusion for 72 h. Then the neurological deficit score, hippocampal cell apoptosis, levels of aquaporin (AQP) 4, AQP9, intercellular cell adhesion molecule-1 (ICAM-1), nuclear factor-κB (NF-κB), tumor necrosis factor (TNF-α), interleukin-1 β (IL-1β), thromboxane B2 (TXB2), and 6-keto-PGI1α were assessed. After reperfusion, neurological deficit score was significantly increased accompanied by severe neuronal damage (exacerbated morphological deficit, increased terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL)-positive cells and cleaved caspase-3 protein expression in hippocampal CA1 region). Cerebral I/R injury also enhanced expressions of TNF-α, IL-1β, NF-κB, AQP4 and AQP9 as well as TXB2 and TXB2/6-keto-PGI1α. All these changes were reversed by pretreatment with flurbiprofen axetil. Flurbiprofen axetil protects the brain from cerebral I/R injury through reducing inflammation and brain edema.

Erratum for “Protective effect of quercetin on bupivacaineinduced neurotoxicity via T-type calcium channel inhibition”

Jin et al Trop J Pharm Res 2017, 16(8): 1827-1833 http://dx.doi.org/10.4314/tjpr.v16i8.11 The correct name of the First Author is Zhao as provided above and not Chao earlier published. Citation: Jin Z, Wu H, Tang C, Ke J, Wang Y. Protective effect of quercetin on bupivacaineinduced neurotoxicity via T-type calcium channel inhibition. Trop J Pharm Res 2017; 16(8) :1827-1833 Erratum: 2017; 16(9) :2051 http://dx.doi.org/10.4314/tjpr.v16i9.1