Effect of Different Doses of Propofol on Pulmonary Function and Inflammatory Response in Patients with Lung Ischemia Reperfusion Injury Induced by One-Lung Ventilation Based on Big Data Analysis.

Objective: To analyze the effect of different doses of propofol on pulmonary function and inflammatory response in patients with lung ischemia reperfusion injury (LIRI) induced by one-lung ventilation (OLV) based on big data analysis. Methods: A retrospective study was performed on 105 patients who underwent lobectomy in our hospital (January 2018 to January 2022). According to the doses of propofol, they were split into low-dose group (LDG), middle-dose group (MDG), and high-dose group (HDG), which received the continuous micropump infusion of propofol at the doses of 2 mg/(kg·h), 5 mg/(kg·h), and 10 mg/(kg·h) after induction, respectively, with 35 cases in each group. The indexes, such as the pulmonary function and inflammatory factors of patients, at different times were compared. The logistic regression analysis was performed according to the occurrence of LIRI. Results: With no notable difference at T0 among the three groups (P > 0.05), the Cdyn levels significantly decreased at T1 (P < 0.05) and gradually increased at T2. The Cdyn levels at T1 and T2 were remarkably higher in HDG and MDG than in LDG (P < 0.05). With no notable differences at T0 and T1 among the three groups (P > 0.05), the PA-aO2 levels and RI values at T2 in MDG and HDG were lower compared with LDG (P < 0.05). The RI values at T1 and T2 in HDG were higher compared with MDG, with no obvious difference (P > 0.05). The OI levels at T1 and T2 in HDG were lower compared with the other two groups (P < 0.05), and the OI levels at T1, T2, and T3 in LDG were higher compared with MDG, with no obvious difference (P > 0.05). The TNF-α and ICAM-1 levels at T1 and T2 in MDG and HDG were lower compared with LDG, with no obvious difference between MDG and HDG (P > 0.05). Compared with LDG, the MDG and HDG at T1 and T2 had lower MDA levels (P < 0.05) and higher SOD levels (P < 0.05). Logistic regression analysis showed that Cdyn, PA-aO2, and OLV time were independent risk factors for LIRI in patients undergoing lobectomy. Conclusion: Propofol has a good protective effect on lung function in patients with OLV-induced LIRI. Appropriately increasing the dose of propofol can effectively improve the local cerebral hypoxia and lung compliance of patients and reduce the inflammatory response and oxidative stress response, with 5 mg/(kg·h) as the clinical reference. Preoperative assessment and preparation should be made for patients, close attention should be paid to risk factors, such as Cdyn and PA-aO2, and OLV time should be controlled.

Effect of Geumgwe-Sinkihwan on Renal Dysfunction in Ischemia/Reperfusion-Induced Acute Renal Failure Mice.

Renal ischemia-reperfusion (I/R) injury is an important cause of acute renal failure (ARF). Geumgwe-sinkihwan (GSH) was recorded in a traditional Chines medical book named "Bangyakhappyeon" in 1884. GSH has been used for treatment for patients with diabetes and glomerulonephritis caused by deficiency of kidney yang and insufficiency of kidney gi. Here we investigate the effects of GSH in mice model of ischemic acute kidney injury. The mice groups are as follows; sham group: C57BL6 male mice, I/R group: C57BL6 male mice with I/R surgery, GSH low group: I/R + 100 mg/kg/day GSH, and GSH high group: I/R + 300 mg/kg/day GSH. Ischemia was induced by clamping both renal arteries and reperfusion. Mice were orally given GSH (100 and 300 mg/kg/day) during 3 days after surgery. Treatment with GSH significantly ameliorated creatinine clearance, creatinine, and blood urea nitrogen levels. Treatment with GSH reduced neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), specific renal injury markers. GSH also reduced the periodic acid-Schiff and picro sirius red staining intensity in kidney of I/R group. Western blot and real-time RT-qPCR analysis demonstrated that GSH decreased protein and mRNA expression levels of the inflammatory cytokines in I/R-induced ARF mice. Moreover, GSH inhibited protein and mRNA expression of inflammasome-related protein including NLRP3 (NOD-like receptor pyrin domain-containing protein 3, cryoprin), ASC (Apoptosis-associated speck-like protein containing a CARD), and caspase-1. These findings provided evidence that GSH ameliorates renal injury including metabolic dysfunction and inflammation via the inhibition of NLRP3-dependent inflammasome in I/R-induced ARF mice.

High dose zoledronic acid increases ischemia-reperfusion damage of the liver.

OBJECTIVE: Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, has been reported to exhibit a protective effect against cancers and prevent bone fractures. It also induces apoptosis by increasing proinflammatory cytokines and oxidative stress. Oxidative stress increases significantly during ischemia-reperfusion (IR) injury. The liver is highly sensitive to IR injury. In this study, we aim to investigate whether high-dose ZA treatment affects the liver during IR. MATERIALS AND METHODS: We used twenty-one Sprague-Dawley male rats in our study, and they were subdivided randomly into three groups, each containing seven rats. A single dose of 100 µg/kg ZA was administered via the intraperitoneal route in the ZA group. Forty-eight hours after the ZA administration, infrarenal abdominal aortic cross ligation was performed on the ZA and IR groups. After 2 hours of ischemia, 2 hours of reperfusion was applied. RESULTS: The malondialdehyde (MDA) level of the control group was significantly lower than the IR (p = 0.006) and ZA (p<0.001) groups. However, the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) values of the control group were significantly higher than the values of the IR group (p<0.05, p<0.001, and p<0.05) and ZA group (p = 0.002, p<0.001, and p<0.001). Caspase-3 activity was significantly higher in the IR group as compared to the control group (p<0.001). The caspase-3 activity in the ZA group, on the other hand, was higher than both the control (p<0.001) and IR groups (p<0.001). CONCLUSIONS: High-dose ZA may exacerbate liver injury during IR by increasing reactive oxygen species production and apoptosis.

The role and mechanism of the annexin A1 peptide Ac2-26 in rats with cardiopulmonary bypass lung injury.

The main causes of lung injury after cardiopulmonary bypass (CPB) are systemic inflammatory response syndrome (SIRS) and pulmonary ischaemia-reperfusion injury (IR-I). SIRS and IR-I are often initiated by a systemic inflammatory response. The present study investigated whether the annexin A1 (ANX-A1) peptidomimetic Ac2-26 by binding to formyl peptide receptors (FPRs) inhibit inflammatory cytokines and reduce lung injury after CPB. Male rats were randomized to the following five groups (n = 6, each): sham, exposed to pulmonary ischaemic-reperfusion (IR-I), IR-I plus Ac2-26, IR-I plus the FPR antagonist, BoC2 (N-tert-butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe) and IR-I plus Ac2-26 and BoC2. Treatment with Ac2-26 improved the oxygenation index, an effect blocked by BoC2. Histopathological analysis of the lung tissue revealed that the degree of lung injury was significantly less (P < 0.05) in the Ac2-26-treated rats compared to the other experimental groups exposed to IR-I. Ac2-26 treatment reduced the levels of the inflammatory cytokines TNF-α, IL-1ß, ICAM-1 and NF-κB-p65 (P < 0.05) compared to the vehicle-treated group exposed to IR-I. In conclusion, the annexin A1 (ANX-A1) peptidomimetic Ac2-26 by binding to formyl peptide receptors inhibit inflammatory cytokines and reduce ischaemic-reperfusion lung injury after cardiopulmonary bypass.

Na+ , K+ -ATPase participates in the protective mechanism of rat cerebral ischemia-reperfusion through the interaction with glutamate transporter-1.

Glutamate excitotoxicity in cerebral ischemia/reperfusion is an important cause of neurological damage. The aim of this study was to investigate the mechanism of Na+, K+-ATPase (NKA) involved in l ow concentration of ouabain (Oua, activating NKA)-induced protection of rat cerebral ischemia-reperfusion injury. The 2,3,5-triphenyltetrazolium chloride (TTC) staining and neurological deficit scores (NDS) were performed to evaluate rat cerebral injury degree respectively at 2 h, 6 h, 1 d and 3 d after reperfusion of middle cerebral artery occlusion (MCAO) 2 h in rats. NKA α1/α2 subunits and glutamate transporter-1 (GLT-1) protein expression were investigated by Western blotting. The cerebral infarct volume ratio were evidently decreased in Oua group vs MCAO/R group at 1 d and 3 d after reperfusion of 2 h MCAO in rats (*p ＜ 0.05 ). Moreover, NDS were not significantly different (p ＞ 0.05 ). NKA α1 was decreased at 6 h and 1 d after reperfusion of 2 h MCAO in rats, and was improved in Oua group. However, NKA α1 and α2 were increased at 3 d after reperfusion of 2 h MCAO in rats, and was decreased in Oua group. GLT-1 was decreased at 6 h, 1 d and 3 d after reperfusion of 2 h MCAO in rats, and was improved in Oua group. These data indicated that l ow concentration of Oua could improve MCAO/R injury through probably changing NKA α1/α2 and GLT-1 protein expression, then increasing GLT-1 function and promoting Glu transport and absorption, which could be useful to determine potential therapeutic strategies for patients with stroke. Low concentration of Oua improved rat MCAO/R injury via NKA α1/α2 and GLT-1.

Differential role of nicotinamide adenine dinucleotide deficiency in acute and chronic kidney disease.

BACKGROUND: Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous coenzyme involved in electron transport and a co-substrate for sirtuin function. NAD+ deficiency has been demonstrated in the context of acute kidney injury (AKI). METHODS: We studied the expression of key NAD+ biosynthesis enzymes in kidney biopsies from human allograft patients and patients with chronic kidney disease (CKD) at different stages. We used ischaemia-reperfusion injury (IRI) and cisplatin injection to model AKI, urinary tract obstruction [unilateral ureteral obstruction (UUO)] and tubulointerstitial fibrosis induced by proteinuria to investigate CKD in mice. We assessed the effect of nicotinamide riboside (NR) supplementation on AKI and CKD in animal models. RESULTS: RNA sequencing analysis of human kidney allograft biopsies during the reperfusion phase showed that the NAD+de novo synthesis is impaired in the immediate post-transplantation period, whereas the salvage pathway is stimulated. This decrease in de novo NAD+ synthesis was confirmed in two mouse models of IRI where NR supplementation prevented plasma urea and creatinine elevation and tubular injury. In human biopsies from CKD patients, the NAD+de novo synthesis pathway was impaired according to CKD stage, with better preservation of the salvage pathway. Similar alterations in gene expression were observed in mice with UUO or chronic proteinuric glomerular disease. NR supplementation did not prevent CKD progression, in contrast to its efficacy in AKI. CONCLUSION: Impairment of NAD+ synthesis is a hallmark of AKI and CKD. NR supplementation is beneficial in ischaemic AKI but not in CKD models.

Reoxygenation induces reactive oxygen species production and ferroptosis in renal tubular epithelial cells by activating aryl hydrocarbon receptor.

During the reperfusion phase of ischemia­reperfusion injury, reactive oxygen species (ROS) production aggravates the course of many diseases, including acute kidney injury. Among the various enzymes implicated in ROS production are the enzymes of the cytochromes P450 superfamily (CYPs). Since arylhydrocarbon receptor (AhR) controls the expression of certain CYPs, the involvement of this pathway was evaluated in reperfusion injury. Because AhR may interact with the nuclear factor erythroid 2­related factor 2 (Nrf2) and the hypoxia­inducible factor­1α (HIF­1α), whether such an interaction takes place and affects reperfusion injury was also assessed. Proximal renal proximal tubular epithelial cells were subjected to anoxia and subsequent reoxygenation. At the onset of reoxygenation, the AhR inhibitor CH223191, the HIF­1α activator roxadustat, or the ferroptosis inhibitor α­tocopherol were used. The activity of AhR, Nrf2, HIF­1α, and their transcriptional targets were assessed with western blotting. ROS production, lipid peroxidation and cell death were measured with colorimetric assays or cell imaging. Reoxygenation induced ROS production, lipid peroxidation and cell ferroptosis, whereas CH223191 prevented all. Roxadustat did not affect the above parameters. Reoxygenation activated AhR and increased CYP1A1, while CH223191 prevented both. Reoxygenation with or without CH223191 did not alter Nrf2 or HIF­1α activity. Thus, AhR is activated during reoxygenation and induces ROS production, lipid peroxidation and ferroptotic cell death. These detrimental effects may be mediated by AhR­induced CYP overexpression, while the Nrf2 or the HIF­1α pathways remain unaffected. Accordingly, the AhR pathway may represent a promising therapeutic target for the prevention of reperfusion injury.

Quercetin and lithium chloride potentiate the protective effects of carvedilol against renal ischemia-reperfusion injury in high-fructose, high-fat diet-fed Swiss albino mice independent of renal lipid signaling.

Renal ischemia-reperfusion injury (R-IRI) is the main cause of acute renal failure. Carvedilol has been shown to protect against R-IRI. However, the underlying mechanisms are still not completely clarified. This study aimed to investigate the role of lipid signaling in mediating carvedilol protective effects against R-IRI in insulin-resistant mice by using two different lipid signaling modulators, quercetin and lithium chloride (LiCl). Mice were fed high-fructose, high-fat diet (HFrHFD) for 16 weeks to induce insulin resistance. At the end of feeding period, mice were randomly distributed into five groups; Sham, R-IRI, Carvedilol (20 mg/kg, i.p.), Carvedilol + Quercetin (10 mg/kg, i.p.), Carvedilol + LiCl (200 mg/kg, i.p.). R-IRI was performed by applying 30 min of unilateral renal ischemia followed by one hour of reperfusion. Quercetin and LiCl were administered 30 min before carvedilol administration and carvedilol was administered 30 min before ischemia. Changes in kidney function tests, histopathology, fibrosis area, lipid signaling, inflammatory, apoptosis and oxidative stress markers in the kidney were measured. Results showed that R-IRI decreased kidney function, impaired renal tissue integrity, modulated lipid signaling and increased renal inflammation, apoptosis and oxidative stress. Carvedilol treatment decreased the detrimental effects induced by R-IRI. In addition, pre-injection of both quercetin and LiCl potentiated the reno-protective effects of carvedilol against R-IRI independent of changes in lipid mediators like phosphatidyl inositol 4,5 bisphosphate (PIP2) and diacylglycerol (DAG). In conclusion, quercetin and LiCl potentiate the protective effects of carvedilol against R-IRI in HFrHFD-fed mice by reducing inflammation and oxidative stress independent of lipid signaling.

Quercitrin inhibits platelet activation in arterial thrombosis.

BACKGROUND: The ingestion of flavonoids has been reported to be associated with reduced cardiovascular disease risk. Quercitrin is a common flavonoid in nature, and it exhibits antioxidant properties. Although the process of thrombogenesis is intimately related to cardiovascular disease risk, it is unclear whether quercitrin plays a role in thrombogenesis. PURPOSE: The aim of this study was to examine the antiplatelet effect of quercitrin in platelet activation. METHODS: Platelet aggregation, granule secretion, calcium mobilization, and integrin activation were used to assess the antiplatelet activity of quercitrin. Antithrombotic effect was determined in mouse using ferric chloride (FeCl3)-induced arterial thrombus formation in vivo and thrombus formation on collagen-coated surfaces under arteriolar shear in vitro. Transection tail bleeding time was used to evaluate whether quercitrin inhibited primary hemostasis. RESULTS: Quercitrin significantly impaired collagen-related peptide-induced platelet aggregation, granule secretion, reactive oxygen species generation, and intracellular calcium mobilization. Outside-in signaling of αIIbß3 integrin was significantly inhibited by quercitrin in a concentration-dependent manner. The inhibitory effect of quercitrin resulted from inhibition of the glycoprotein VI-mediated platelet signal transduction during cell activation. Further, the antioxidant effect is derived from decreased phosphorylation of components of the TNF receptor-associated factor 4/p47phox/Hic5 axis signalosome. Oral administration of quercitrin efficiently blocked FeCl3-induced arterial thrombus formation in vivo and thrombus formation on collagen-coated surfaces under arteriolar shear in vitro, without prolonging bleeding time. Studies using a mouse model of ischemia/reperfusion-induced stroke indicated that treatment with quercitrin reduced the infarct volume in stroke. CONCLUSIONS: Our results demonstrated that quercitrin could be an effective therapeutic agent for the treatment of thrombotic diseases.

Protective Effects of Rocuronium Bromide on Ischemia-Reperfusion Injury in Skeletal Muscle Induced by Tourniquet in Patients Undergoing Elective Unilateral Total Knee Arthroplasty: A Prospective, Double Blind, Randomized, Controlled Study.

PURPOSE: To investigate the effects of different doses of rocuronium on ischemia-reperfusion injury in skeletal muscle induced by tourniquet in patients undergoing elective unilateral total knee arthroplasty. PATIENTS AND METHODS: A total of 90 patients undergoing elective unilateral knee arthroplasty under general anesthesia combined with femoral nerve block were randomly divided into 3 groups: normal saline group (group S), rocuronium 0.6 mg/kg group (group L), and rocuronium 1.2 mg/kg group (group H). The primary outcome was the expression of dystrophin in skeletal muscle at 60 min after ischemia. Secondary outcomes included the concentration of malondialdehyde (MDA) and neuronal nitric oxide synthase (nNOS) in blood at 5 min and 30 min after reperfusion. In addition, thigh girth at 24 h and 48 h after operation, the leaving bed time, the incidence of tourniquet-related hypertension and short-term (3 days after operation) complications (nausea and vomiting, swelling, blister, wound infection) and long-term (3 months after operation) complications (joint instability, stiffness, nerve paralysis, pain) were recorded. MAIN RESULTS: The expression of dystrophin in the rocuronium group was higher than that in group S after ischemia (P <0.05). The concentration of MDA in the rocuronium 1.2 mg/kg group was lower at 30 min after reperfusion (P < 0.05). There was no significant difference in nNOS among groups at each time point (P > 0.05). The change of thigh girth was the smallest in the rocuronium 1.2 mg/kg group after operation (P<0.05). The leaving bed time was significantly earlier after operation in the rocuronium group than that in group S (P <0.05). CONCLUSION: Rocuronium can protect skeletal muscle from ischemia-reperfusion injury induced by tourniquet. The mechanism may be related to the fact that rocuronium can reduce the loss of dystrophin in skeletal muscle and have the effects of anti-oxidation and anti-stress. TRIAL REGISTRATION: The study was registered at http://www.chictr.org.cn (ChiCTR1800019221, registered on 2018-10-31).

Lysophosphatidic acid increased infarct size in the early stage of cerebral ischemia-reperfusion with increased BBB permeability.

BACKGROUND: We investigated whether exogenous lysophosphatidic acid (LPA), a phospholipid extracellular signaling molecule, would increase infarct size and blood-brain barrier (BBB) disruption during the early stage of cerebral ischemia-reperfusion, and whether it works through Akt-mTOR-S6K1 intracellular signaling. MATERIAL AND METHODS: Rats were given either vehicle or LPA 1 mg/kg iv three times during reperfusion after one hour of middle cerebral artery (MCA) occlusion. In another group, prior to administration of LPA, 30 mg/kg of PF-4708671, an S6K1 inhibitor, was injected. After one hour of MCA occlusion and two hours of reperfusion the transfer coefficient (Ki) of 14C-α-aminoisobutyric acid and the volume of 3H-dextran distribution were determined to measure the degree of BBB disruption. At the same time, the size of infarct was determined and western blot analysis was performed to determine the levels of phosphorylated Akt (p-Akt) and phosphorylated S6 (pS6). RESULTS: LPA increased the Ki in the ischemic-reperfused cortex (+43%) when compared with Control rats and PF-4708671 pretreatment prevented the increase of Ki by LPA. LPA increased the percentage of cortical infarct out of total cortical area (+36%) and PF-4708671 pretreatment prevented the increase of the infarct size. Exogenous LPA did not significantly change the levels of p-Akt as well as pS6 in the ischemic-reperfused cortex. CONCLUSION: Our data demonstrate that the increase in BBB disruption could be one of the reasons of the increased infarct size by LPA. S6K1 may not be the major target of LPA. A decrease of LPA during early cerebral ischemia-reperfusion might be beneficial for neuronal survival.

Neuroprotective Effects of Dexmedetomidine Preconditioning on Oxygen-glucose Deprivation-reoxygenation Injury in PC12 Cells via Regulation of Ca2+-STIM1/Orai1 Signaling.

Dexmedetomidine (DEX), a potent and highly selective agonist for α2-adrenergic receptors (α2AR), exerts neuroprotective effects by reducing apoptosis through decreased neuronal Ca2+ influx. However, the exact action mechanism of DEX and its effects on oxygen-glucose deprivation-reoxygenation (OGD/R) injury in vitro are unknown. We demonstrate that DEX pretreatment reduced OGD/R injury in PC12 cells, as evidenced by decreased oxidative stress, autophagy, and neuronal apoptosis. Specifically, DEX pretreatment decreased the expression levels of stromal interaction molecule 1 (STIM1) and calcium release-activated calcium channel protein 1 (Orai1), and reduced the concentration of intracellular calcium pools. In addition, variations in cytosolic calcium concentration altered apoptosis rate of PC12 cells after exposure to hypoxic conditions, which were modulated through STIM1/Orai1 signaling. Moreover, DEX pretreatment decreased the expression levels of Beclin-1 and microtubule-associated protein 1A/1B-light chain 3 (LC3), hallmark markers of autophagy, and the formation of autophagosomes. In conclusion, these results suggested that DEX exerts neuroprotective effects against oxidative stress, autophagy, and neuronal apoptosis after OGD/R injury via modulation of Ca2+-STIM1/Orai1 signaling. Our results offer insights into the molecular mechanisms of DEX in protecting against neuronal ischemia-reperfusion injury.

Prognostic value of plasma HMGB1 in ischemic stroke patients with cerebral ischemia-reperfusion injury after intravenous thrombolysis.

BACKGROUND: To investigate the value of plasma high mobility group box protein 1 (HMGB1) in evaluating the prognosis of cerebral ischemia-reperfusion injury (CIRI) in ischemic stroke patients. METHODS: 132 ischemic stroke patients were recruited. Before and after thrombolytic therapy at 2 h, 6 h, 12 h, 24 h, and 36 h, the Glasgow Coma Scale (GCS) and National Institutes of Health Stroke Scale (NIHSS) were recorded. The Modified Rankin scale (mRS) was used to assess the prognosis at 3 months. RESULTS: The NIHSS score, GCS score and plasma HMGB1 level peaked at 6 h after thrombolytic therapy, and plasma HMGB1 level was positively correlated with infarct volume and NIHSS score, and negatively correlated with GCS score. Plasma HMGB1 level at 6 h had the highest value in identifying patients with poor unfavorable functional outcome after 3 months, with a sensitivity of 86.8% and a specificity of 74.0%. Logistic regression results showed that plasma HMGB1 had a strong association with unfavorable functional outcome [odds ratio (OR) =1.621, P<0.001]. After adjusting for infarct volume and NIHSS score did not attenuate the association (OR=1.381, P=0.005). Finally, we found that plasma HMGB1 at 6 h had the highest value in identifying patients with non-survival after 3 months (χ2=28.655, P<0.001). Logistic regression results showed that plasma HMGB1 had a strong association with non-survival (OR=2.315, P<0.001). After adjusting for infarct volume and NIHSS score did not attenuate the association (OR=2.013, P<0.001). CONCLUSION: Plasma HMGB1 exerts a good predictive value for CIRI in ischemic stroke patients, and its increased expression is correlated with worse prognosis.

Long Non-Coding RNA (lncRNA) NEAT1 Aggravates Cerebral Ischemia-Reperfusion Injury by Suppressing the Inhibitory Effect of miR-214 on PTEN.

BACKGROUND Cerebral ischemia-reperfusion injury is a form of serious nervous system injury. Activation of the PI3K/Akt pathway can effectively relieve cerebral ischemia-reperfusion injury. miR-214 can target and inhibit the expression of PTEN, thereby alleviating its inhibitory effect on the PI3K/Akt pathway. Moreover, lncRNA NEAT1 was reported to affect proliferation and metastasis of tumor cells by targeting and suppressing the expression of miR-214. However, whether lncRNA NEAT1 affects the cerebral ischemia-reperfusion-induced damage by regulating the miR-214/PTEN/PI3K/Akt pathway is unclear. MATERIAL AND METHODS The miR-214 agomir and miR-214 antagomir were designed and injected into the encephalocele of MCAO rats. Next, the production of oxidative stress kinase and apoptosis of brain cells were detected using commercial kits. The levels of PTEN, PI3K, Akt, p-Akt, and VEGF in brain tissues were determined. Next, the targeting effect of lncRNA NEAT1 and miR-214 was determined with luciferase reporter assay. RESULTS Overexpression of miR-214 relieved the apoptosis and oxidative stress of brain tissues. Overexpression of miR-214 promoted the expression of PI3K, Akt, p-Akt, and VEGF by inhibiting the production of PTEN. However, overexpression of lncRNA NEAT1 repressed the remission effect of miR-214 on cerebral ischemia-reperfusion-induced damage and inhibited the production of PI3K, Akt, p-Akt, and VEGF by rescuing the levels of PTEN. CONCLUSIONS lncRNA NEAT1 aggravates cerebral ischemia-reperfusion injury by abolishing the activation effect of miR-214 on the PI3K/Akt pathway.

AMPK activation by ozone therapy inhibits tissue factor-triggered intestinal ischemia and ameliorates chemotherapeutic enteritis.

Chemotherapeutic enteritis is a major dose-limiting adverse reaction to chemotherapy, with few effective drugs in clinic. Intestinal ischemic injury plays prominent role in chemotherapeutic enteritis clinically. However, mechanism is not clear. In this article, irinotecan (CPT-11) was used to establish chemotherapeutic enteritis mice model. Western blotting, gelatin zymography, immunohistochemistry (IHC), Laser Doppler flowmetry (LDF) were used to detect the pathogenesis of ischemia-hypoxia injury. CPT-11 increased levels of tissue factor (TF) both in the blood and in intestines, and decreased the intestinal blood flow in mice. Interestingly, the elevation of TF in the blood displayed "double-peak," which was consistent with the intestinal mucosal "double-strike" injury trend. Intestinal microthrombus and mixed thrombus formation were detectable in chemotherapeutic enteritis. Furthermore, ozone therapy relieved chemotherapeutic enteritis in mice. Ozone inhibited TF expression induced by CPT-11 via activating AMPK/SOCS3, and effectively ameliorated the intestinal mucosal injury in mice. Moreover, ozone autotransfusion therapy effectively attenuated chemotherapeutic enteritis and the blood hypercoagulability in patients. For the first time, we proposed that TF-induced thrombotic intestinal ischemic injury is a core trigger pathological mechanism of chemotherapeutic enteritis, and provided a new treatment strategy, ozone therapy, to suppress TF expression and treat chemotherapeutic enteritis.

Vagus nerve stimulation even after injury ameliorates cisplatin-induced nephropathy via reducing macrophage infiltration.

The efficacy of prior activation of an anti-inflammatory pathway called the cholinergic anti-inflammatory pathway (CAP) through vagus nerve stimulation (VNS) has been reported in renal ischemia-reperfusion injury models. However, there have been no reports that have demonstrated the effectiveness of VNS after injury. We investigated the renoprotective effect of VNS in a cisplatin-induced nephropathy model. C57BL/6 mice were injected with cisplatin, and VNS was conducted 24 hours later. Kidney function, histology, and a kidney injury marker (Kim-1) were evaluated 72 hours after cisplatin administration. To further explore the role of the spleen and splenic macrophages, key players in the CAP, splenectomy, and adoptive transfer of macrophages treated with the selective α7 nicotinic acetylcholine receptor agonist GTS-21 were conducted. VNS treatment significantly suppressed cisplatin-induced kidney injury. This effect was abolished by splenectomy, while adoptive transfer of GTS-21-treated macrophages improved renal outcomes. VNS also reduced the expression of cytokines and chemokines, including CCL2, which is a potent chemokine attracting monocytes/macrophages, accompanied by a decline in the number of infiltrating macrophages. Taken together, stimulation of the CAP protected the kidney even after injury in a cisplatin-induced nephropathy model. Considering the feasibility and anti-inflammatory effects of VNS, the findings suggest that VNS may be a promising therapeutic tool for acute kidney injury.

Tuning Macrophage Phenotype to Mitigate Skeletal Muscle Fibrosis.

Myeloid cells are critical to the development of fibrosis following muscle injury; however, the mechanism of their role in fibrosis formation remains unclear. In this study, we demonstrate that myeloid cell-derived TGF-ß1 signaling is increased in a profibrotic ischemia reperfusion and cardiotoxin muscle injury model. We found that myeloid-specific deletion of Tgfb1 abrogates the fibrotic response in this injury model and reduces fibro/adipogenic progenitor cell proliferation while simultaneously enhancing muscle regeneration, which is abrogated by adaptive transfer of normal macrophages. Similarly, a murine TGFBRII-Fc ligand trap administered after injury significantly reduced muscle fibrosis and improved muscle regeneration. This study ultimately demonstrates that infiltrating myeloid cell TGF-ß1 is responsible for the development of traumatic muscle fibrosis, and its blockade offers a promising therapeutic target for preventing muscle fibrosis after ischemic injury.

Prevention of renal ischemia and reperfusion injury by penehyclidine hydrochloride through autophagy activation.

Penehyclidine hydrochloride (PHC) suppresses renal ischemia and reperfusion (I/R) injury (IRI); however, the underlying mechanism of action that achieves this function remains largely unknown. The present study aimed to investigate the potential role of autophagy in PHC­induced suppression of renal IRI, as well as the involvement of cell proliferation and apoptosis. A rat IRI model and a cellular hypoxia/oxygenation (H/R) model were established; PHC, 3­methyladenine (3­MA) and rapamycin (Rapa) were administered to the IRI model rats prior to I/R induction and to H/R cells following reperfusion. Serum creatinine was measured using a biochemistry analyzer, whereas aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) expression levels were detected using ELISA kits. Renal tissue injury was evaluated by histological examination. In addition, microtubule­associated protein light chain 3B (LC3B) expression, autophagosome formation, cell proliferation and apoptosis were detected in the cellular H/R model. The results demonstrated that I/R induced renal injury in IRI model rats, upregulated serum creatinine, ALAT and ASAT expression levels, and increased autophagic processes. In contrast, pretreatment with PHC or Rapa significantly prevented these I/R­induced changes, whereas the administration of 3­MA enhanced I/R­induced injuries through suppressing autophagy. PHC and Rapa increased LC3B and Beclin­1 expression levels, but decreased sequestome 1 (p62) expression in the cellular H/R model, whereas 3­MA prevented these PHC­induced changes. PHC and Rapa promoted proliferation and autophagy in the cellular H/R model; these effects were accompanied by increased expression levels of LC3B and Beclin­1, and reduced p62 expression levels, whereas these levels were inhibited by 3­MA. Furthermore, PHC and Rapa inhibited apoptosis in the cellular H/R model through increasing Bcl­2 expression levels, and suppressing Bax and caspase­3 expression levels; the opposite effect was induced by 3­MA. In conclusion, PHC suppressed renal IRI through the induction of autophagy, which in turn promoted proliferation and suppressed apoptosis in renal cells.

Favorable Effects of Astaxanthin on Brain Damage due to Ischemia- Reperfusion Injury.

BACKGROUND: Activated inflammation and oxidant stress during cerebral ischemia reperfusion injury (IRI) lead to brain damage. Astaxanthin (ASX) is a type of carotenoid with a strong antioxidant effect. OBJECTIVE: The aim of this study was to investigate the role of ASX on brain IRI. METHODS: A total of 42 adult male Sprague-Dawley rats were divided into 3 groups as control (n=14) group, IRI (n=14) group and IRI + ASX (n=14) group. Cerebral ischemia was instituted by occluding middle cerebral artery for 120 minutes and subsequently, reperfusion was performed for 48 hours. Oxidant parameter levels and protein degradation products were evaluated. Hippocampal and cortex cell apoptosis, neuronal cell count, neurological deficit score were evaluated. RESULTS: In the IRI group, oxidant parameter levels and protein degradation products in the tissue were increased compared to control group. However, these values were significantly decreased in the IRI + ASX group (p<0.05). There was a significant decrease in hippocampal and cortex cell apoptosis and a significant increase in the number of neuronal cells in the IRI + ASX group compared to the IRI group alone (p<0.05). The neurological deficit score which was significantly lower in the IRI group compared to the control group was found to be significantly improved in the IRI + ASX group (p<0.05). CONCLUSION: Astaxanthin protects the brain from oxidative damage and reduces neuronal deficits due to IRI injury.

Carvacryl acetate, a semisynthetic monoterpenic ester obtained from essential oils, provides neuroprotection against cerebral ischemia reperfusion-induced oxidative stress injury via the Nrf2 signalling pathway.

Carvacryl acetate (CA) is a semisynthetic monoterpenic ester obtained from essential oils, and it exerts an antioxidation effect. The purpose of our study was to investigate whether CA could provide neuroprotection against oxidative stress caused by cerebral ischemia-reperfusion injury (CIRI) and elucidate the underlying mechanism. Middle cerebral artery occlusion (MCAO)-induced damage was established in Sprague Dawley (SD) rats and PC12 cells were exposed to hydrogen peroxide (H2O2) to imitate oxidative stress damage. TTC, HE and Nissl staining were used to observe the pathological morphology of lesions. The contents of ROS and MDA, and the activity of SOD were measured to reflect the level of oxidative stress. In addition, the TUNEL method was used to assess injuries in vitro, and the expression of Nrf2 was determined by immunohistochemical staining and western blot analysis. Importantly, we constructed and validated Nrf2 knockdown PC12 cells to confirm the key role of Nrf2 in the neuroprotective effect of CA against oxidative stress injuries. CA alleviated CIRI in rats with MCAO, as shown by brain tissue pathophysiology. The contents of ROS and MDA were reduced, and the SOD activity was augmented by the simultaneous promotion of Nrf2 expression. In addition, the H2O2-induced injury in Nrf2-knockdown PC12 cells was more serious than it was in control cells, and CA-mediated neuroprotection was exclusively inhibited by the knock down of Nrf2 in PC12 cells. In conclusion, it is shown here that CA has the effect of relieving cerebral ischemia reperfusion-induced oxidative stress injury via the Nrf2 signalling pathway.