LY333531 attenuates contraction of tumor necrosis factor-α-sensitized human airway smooth muscle cells.

OBJECTIVE: Protein kinase C (PKC) has been implicated in the increased contraction of human airway smooth muscle cells (HASMCs) in asthma. Using the three-dimensional collagen gel contraction system, the study aimed to determine the effects of LY333531, a specific inhibitor of the PKC-ß isoform, on the contraction of tumor necrosis factor (TNF)-α-sensitized HASMCs. METHODS: Cultured HASMCs were divided into five groups: the control group received no treatment, and the cells in the TNF-α group were sensitized with 10 ng/mL TNF-α for 48 h, while TNF-α was administered to sensitize HASMCs in the presence of 0.1, 0.2, and 0.5 µM LY333531 for 48 h in the 0.1LY, 0.2LY, and 0.5LY groups, respectively. Following this, HASMCs contraction was stimulated with 1 mM acetylcholine (ACh) for up to 24 h in each group and assessed using a three-dimensional collagen gel contraction assay. Furthermore, western blot and immunofluorescence analysis were performed. RESULTS: The collagen gel contraction assay revealed that TNF-α increased the protein expression of phosphorylated PKC-ß2, CPI-17, and MLC while exacerbating ACh-induced HASMCs contraction. LY333531 significantly attenuated HASMCs contraction and downregulated the protein expression of both p-CPI-17 and p-MLC. CONCLUSIONS: At least in part by regulating CPI-17 and MLC phosphorylation, LY333531 attenuates augmented contraction of TNF-α-sensitized HASMCs in a collagen gel contraction system.

A prospective, randomized, single-blinded study comparing the efficacy and safety of dexmedetomidine and propofol for sedation during endoscopic retrograde cholangiopancreatography.

BACKGROUND: Balanced propofol sedation is extensively used in endoscopic retrograde cholangiopancreatography (ERCP), but sedation-related adverse events (SRAEs) are common. In various clinical settings, the combination of dexmedetomidine with opioids and benzodiazepines has provided effective sedation with increased safety. The aim of this investigation was to compare the efficacy and safety of dexmedetomidine and propofol for sedation during ERCP. METHODS: Forty-one patients were randomly divided into two groups: the dexmedetomidine (DEX) group and the propofol (PRO) group. Patients in the DEX group received an additional bolus of 0.6 µg kg-1 dexmedetomidine followed by a dexmedetomidine infusion at 1.2 µg kg-1 h-1, whereas the PRO group received 1-2 mg kg-1 of propofol bolus followed by a propofol infusion at 2-3 mg kg-1 h-1. During ERCP, the primary outcome was the incidence of hypoxemia (SpO2 < 90% for > 10 s). Other intraoperative adverse events were also recorded as secondary outcomes, including respiratory depression (respiratory rate of < 10 bpm min-1), hypotension (MAP < 65 mmHg), and bradycardia (HR < 45 beats min-1). RESULTS: The incidence of hypoxemia was significantly reduced in the DEX group compared to the PRO group (0% versus 28.6%, respectively; P = 0.032). Patients in the PRO group exhibited respiratory depression more frequently than patients in the DEX group (35% versus 81%, respectively; P = 0.003). There were no significant differences in terms of hypotension and bradycardia episodes between groups. During the procedures, the satisfaction scores of endoscopists and patients, as well as the pain and procedure memory scores of patients were comparable between groups. CONCLUSION: In comparison with propofol, dexmedetomidine provided adequate sedation safety with no adverse effects on sedation efficacy during ERCP. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2200061468, 25/06/2022.

PICK1 modulates glycolysis and angiogenesis of hypoxic endothelial cells by regulating iron homeostasis.

Iron accumulation, which is controlled by transferrin receptor 1 (TfR1), modulates hypoxia-inducible factor-1α (HIF-1α) activation and angiogenesis of hypoxic endothelial cells. The study examined the role of protein interacting with C-kinase 1 (PICK1), a scaffold protein containing PDZ domain, in regulating glycolysis and angiogenesis of hypoxic vascular endothelial cells through its potential effect on TfR1, which features a supersecondary structure that interacts with the PDZ domain. Iron chelator deferoxamine and TfR1 siRNA were employed to assess the impact of iron accumulation on angiogenesis, while the effects of PICK1 siRNA and overexpressing lentivirus on TfR1-mediated iron accumulation were also investigated in hypoxic human umbilical vein vascular endothelial cells (HUVECs). The study found that 72-h hypoxia impaired the proliferation, migration, and tube formation of HUVECs, and reduced the upregulation of vascular endothelial growth factor, HIF-1α, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, and PICK1, while increasing the expression of TfR1 as compared to 24-h hypoxia. Administration of deferoxamine or TfR1 siRNA reversed these effects and led to increased glycolysis, ATP content, and phosphofructokinase activity, along with increased PICK1 expression. PICK1 overexpression improved glycolysis, enhanced angiogenic capacity, and attenuated TfR1 protein upregulation in hypoxic HUVECs, with higher expression of angiogenic markers, which could be significantly reversed by the PDZ domain inhibitor. PICK1 knockdown exerted opposite effects. The study concluded that PICK1 modulated intracellular iron homeostasis, thereby promoting glycolysis and angiogenesis of HUVECs in response to prolonged hypoxia, at least in part, by regulating TfR1 expression.

The effects of intravenous remifentanil on umbilical artery serum-derived exosomes in parturients undergoing epidural anesthesia: a randomized trail.

BACKGROUND: Umbilical artery serum-derived exosomes (UEs) serve as messengers for maternal-fetal information exchange and cellular regulation. Intravenous remifentanil could be considered as an effective adjunct to epidural anesthesia in providing a favorable analgesia effect for cesarean section (C-section), but its effects on UEs are currently unknown. METHODS: From 01/12/2021 to 30/06/2022, eligible parturients scheduled for repeated C-section at the First Affiliated Hospital of Wenzhou Medical University were randomized to receive either an intravenous bolus (0.15 µg/kg) followed by a continuous infusion (0.075 µg/kg/min) of remifentanil or normal saline throughout the procedure. The primary outcome was the number of UEs. Secondary outcomes included the size and protein amount of UEs, the vital signs, visceral pain score, sedation score, maternal satisfaction score, Apgar score, the incidence of neonatal asphyxia, umbilical arterial pH, and the presence of complications. RESULTS: Nanoparticle tracking analysis indicated similar size of UEs between the two groups, but the number and protein amount of UEs were increased in the remifentanil group  compared to the control group (P < 0.05). In parturients receiving remifentanil, visceral pain scores were decreased, which was accompanied by the increased scores of maternal satisfaction with the anesthetic method (P < 0.05). Other maternal and neonatal outcomes were comparable between the two groups (P > 0.05). CONCLUSION: The intravenous administration of remifentanil increased the number of UEs in parturients undergoing repeated C-section under epidural anesthesia, with improved birth experience and minimal neonatal complications.

Efficacy and safety of ciprofol vs. propofol for the induction and maintenance of general anaesthesia: A multicentre, single-blind, randomised, parallel-group, phase 3 clinical trial.

BACKGROUND: HSK3486 (ciprofol) is a 2,6-disubstituted phenol derivative that acts like propofol as an agonist at the gamma-aminobutyric acid-A (GABA A ) receptor. OBJECTIVE: To investigate the efficacy and safety of HSK3486 for general anaesthesia induction and maintenance. DESIGN: A single-blinded, randomised, parallel-group, phase 3 trial. SETTING: Involving 10 study centres, from November 24, 2020 to January 25, 2021. PATIENTS: A total of 129 patients undergoing nonemergency, noncardiothoracic, and nonneurosurgical elective surgery. INTERVENTION: Patients were randomly assigned at a 2:1 ratio into HSK3486 or propofol groups, to receive HSK3486 (0.4 mg kg -1 ) or propofol (2.0 mg kg -1 ) for induction before a maintenance infusion at initial rates of 0.8 and 5.0 mg kg -1 h -1 , and were adjusted to maintain a bispectral index (BIS) of 40-60 until the end of surgery. MAIN OUTCOME MEASURES: Noninferiority between the drugs was evaluated as the lower limit of the 95% confidence interval (CI) for the between-group difference in the success rate of anesthetic maintenance (primary outcome) >-8%. Secondary outcomes included successful anaesthetic induction, full alertness and spontaneous breathing recovery, time until leaving the postanaesthesia care unit and changes in BIS. Safety profiles were also measured. RESULTS: Of 129 enrolled patients, 128 completed the trial, with 86 in the HSK3486 group and 42 in the propofol group. The success rate for the maintenance of general anaesthesia was 100% for both groups, and noninferiority of HSK3486 was confirmed (95% CI -4.28% to 8.38%). No significant differences were found between the two groups of patients with regard to secondary outcomes (all P  > 0.05). There appeared to be a comparable incidence of treatment for emergency adverse events (TEAEs) (80.2% vs. 81.0%, P  = 1.000) and drug-related TEAEs (57.0% vs. 64.3%, P  = 0.451) in the HSK3486 and propofol groups. CONCLUSION: HSK3486 had a noninferior efficacy profile compared to propofol, exhibiting excellent tolerance. TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT04511728.

Ultrasound-Guided Clavipectoral Fascial Plane Block With Intermediate Cervical Plexus Block for Midshaft Clavicular Surgery: A Prospective Randomized Controlled Trial.

BACKGROUND: Regional anesthesia such as interscalene brachial plexus block (ISBPB) with intermediate cervical plexus block (ICPB) is generally a preferred choice for clavicular surgery. However, various studies have shown that these blocks, especially ISBPB, could cause phrenic nerve paralysis and decrease diaphragmatic motion. The study aimed to evaluate the efficacy of clavipectoral fascial plane block (CPB), an alternative technique to ISBPB, with ICPB, in reducing hemidiaphragmatic paralysis during midshaft clavicular surgery. METHODS: Forty patients scheduled for right midshaft clavicular surgery were randomized (1:1) into an ultrasound-guided ISBPB with ICPB (BC) group or ultrasound-guided CPB with ICPB (CC) group. Five milliliter of 0.375% ropivacaine was used for ICPB, another 20 mL for ISBPB or CPB, and no administration of additional sedative or general anesthetic was planned. Primary outcome was measured by the incidence of hemidiaphragmatic paralysis using M-mode ultrasonography, while secondary outcomes were measured by bedside pulmonary function test, the success rate of block, the time required for the block procedure and onset of block, and motor block score in right upper extremity. RESULTS: In comparison with BC group, the incidence of hemidiaphragmatic paralysis postblock was decreased in CC group (50% vs 0%; P < .001), and measurement of bedside pulmonary function was significantly improved. There was a 100% success rate for anesthetic block in both BC and CC groups, and CC group showed lower motor block score in upper extremity and less block procedure time than BC group (7.1 ± 1.2 vs 3.2 ± 0.6 minutes; P < .001). Moreover, no significant differences were found between time of onset of block and other anesthetic complications in the 2 groups. CONCLUSIONS: Ultrasound-guided CPB with ICPB could significantly reduce hemidiaphragmatic paralysis and provide an adequate surgical anesthesia with fewer complications such as motor block in upper extremity during right midshaft clavicular surgery.

Necrostatin-1 Synergizes the Pan Caspase Inhibitor to Attenuate Lung Injury Induced by Ischemia Reperfusion in Rats.

BACKGROUND: Both apoptosis and necroptosis have been recognized to be involved in ischemia reperfusion-induced lung injury. We aimed to compare the efficacies of therapies targeting necroptosis and apoptosis and to determine if there is a synergistic effect between the two therapies in reducing lung ischemia reperfusion injury. METHODS: Forty Sprague-Dawley rats were randomized into 5 groups: sham (SM) group, ischemia reperfusion (IR) group, necrostatin-1+ischemia reperfusion (NI) group, carbobenzoxy-Val-Ala-Asp-fluoromethylketone+ischemia reperfusion (ZI) group, and necrostatin-1+carbobenzoxy-Val-Ala-Asp-fluoromethylketone+ischemia reperfusion (NZ) group. The left lung hilum was exposed without being clamped in rats from the SM group, whereas the rats were subjected to lung ischemia reperfusion by clamping the left lung hilum for 1 hour, followed by reperfusion for 3 hours in the IR group. 1 mg/kg necrostatin-1 (Nec-1: a specific necroptosis inhibitor) and 3 mg/kg carbobenzoxy-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk: a pan caspase inhibitor) were intraperitoneally administrated prior to ischemia in NI and ZI groups, respectively, and the rats received combined administration of Nec-1 and z-VAD-fmk in the NZ group. Upon reperfusion, expressions of receptor-interacting protein 1 (RIP1), receptor-interacting protein 3 (RIP3), and caspase-8 were measured, and the flow cytometry analysis was used to assess the cell death patterns in the lung tissue. Moreover, inflammatory marker levels in the bronchoalveolar lavage fluid and pulmonary edema were evaluated. RESULTS: Both Nec-1 and z-VAD-fmk, either alone or in combination, significantly reduced morphological damage, inflammatory markers, and edema in lung tissues following reperfusion, and cotreatment of z-VAD-fmk with Nec-1 produced the optimal effect. The rats treated with Nec-1 had lower levels of inflammatory markers in the bronchoalveolar lavage fluid than those receiving z-VAD-fmk alone (P < 0.05). Interestingly, the z-VAD-fmk administration upregulated RIP1 and RIP3 expressions in the lung tissue from the ZI group compared to those in the IR group (P < 0.05). Reperfusion significantly increased the percentages of necrotic and apoptotic cells in lung tissue single-cell suspension, which could be decreased by Nec-1 and z-VAD-fmk, respectively (P < 0.05). CONCLUSIONS: Nec-1 synergizes the pan caspase inhibitor to attenuate lung ischemia reperfusion injury in rats. Our data support the potential use of Nec-1 in lung transplantation-related disorders.

Effect of Shenmai injection on cognitive function after cardiopulmonary bypass in cardiac surgical patients: a randomized controlled trial.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after cardiac surgery that influences the clinical outcomes and quality of life of patients. This study aimed to evaluate the effects of Shenmai injection (SMI) on POCD of patients who underwent cardiac valve replacement under cardiopulmonary bypass (CPB). METHODS: This prospective, randomized, controlled trial was conducted from September 2014 to January 2017. Eighty-eight patients receiving cardiac valve replacement under CPB were randomized into the control (C) or the SMI (S) group. SMI (0.6 mL/kg) was administered intravenously from the time of anesthesia induction to the beginning of CPB. Cognitive function was assessed at 3 days before surgery and 3 days, 7 days, and 1 month after surgery using the Beijing version of the Montreal Cognitive Assessment (MoCA-BJ) score. The serum levels of neuroglobin (Ngb), hypoxia-inducible factor-1α (HIF-1α), and neuron-specific enolase (NSE) were measured at 30 min after induction (T0), immediately after the endonasal temperature rewarmed to 36 °C (T1), and 1 h (T2), 6 h (T3), 24 h (T4), 48 h (T5), and 72 h (T6) after CPB. RESULTS: Compared with the baseline values at T0, the serum Ngb levels in group C were significantly decreased at T1-2 and then increased at T3-6, while the levels in group S were decreased at T1-2 and increased at T4-6, compared to group C (p < 0.05). The serum HIF-1α levels at T1-4 and the serum NSE levels at T1-6 were significantly increased in both groups (p < 0.05). The serum levels of Ngb at T3, HIF-1α at T1-3, and NSE at T3-4,6 were lower in group S, compared to group C (p < 0.01). The MoCA-BJ scores were decreased at 3 and 7 days after surgery in both groups, and the MoCA-BJ scores in group S were higher than those in group C at 3 and 7 days after surgery (p < 0.01). CONCLUSION: Cognitive function is impaired postoperatively in patients who have undergone cardiac valve replacement under CPB. In addition, treatment with the traditional Chinese medicine SMI decreases the serum levels of Ngb, HIF-1α, and NSE as well as attenuates cognitive dysfunction. TRIAL REGISTRATION: This trial was registered with Clinicaltrials.gov as ChiCTR-TRC-14004373 on March 11, 2014.

Methylene Blue Attenuates Lung Injury Induced by Hindlimb Ischemia Reperfusion in Rats.

OBJECTIVE: This study was aimed to investigate the protective effect of methylene blue against lung injury induced by reperfusion of ischemic hindlimb in a rat model. METHODS: Twenty-four healthy adult male Sprague-Dawley rats were equally randomized into three groups: sham (SM) group, ischemia reperfusion (IR) group, and methylene blue (MB) group. Rats in both IR and MB groups were subjected to 4 h of ischemia by clamping the left femoral artery and then followed by 4 h of reperfusion. Treatment with 1% methylene blue (50 mg/kg) was administrated intraperitoneally at 10 min prior to reperfusion in the MB group. After 4 h of reperfusion, malondialdehyde (MDA) level, myeloperoxidase (MPO), and superoxide dismutase (SOD) activities in lung tissue were detected; inflammatory cytokines, including IL-1ß and IL-6, were measured in bronchoalveolar lavage fluid (BALF); correspondingly, the morphological changes and water content in both gastrocnemius muscle and lung samples were evaluated. RESULTS: Hindlimb IR caused remarkable morphological abnormalities and edema in both muscle and lung tissues. SOD activity was decreased, both the MPO activity and MDA level in lung tissue, as well as IL-1ß and IL-6 levels in BALF, were increased in the IR group (p < 0.05). Compared with the IR group, SOD activity was increased, whereas MPO activity and MDA level in lung tissue and IL-1ß and IL-6 levels in BALF were decreased in the MB group (p < 0.05). Also, the histological damage and edema in both lung and muscle tissues were significantly attenuated by the treatment of methylene blue. CONCLUSION: Methylene blue attenuates lung injury induced by hindlimb IR in rats, at least in part, by inhibiting oxidative stress.

Effects of FTY720 on Lung Injury Induced by Hindlimb Ischemia Reperfusion in Rats.

BACKGROUND: Sphingosine-1-phosphate (S1P) is a biologically active lysophospholipid mediator involved in modulating inflammatory process. We investigated the effects of FTY720, a structural analogue of S1P after phosphorylation, on lung injury induced by hindlimb ischemia reperfusion (IR) in rats. METHODS: Fifty Sprague-Dawley rats were divided into groups SM, IR, F3, F5, and F10. Group SM received sham operation, and bilateral hindlimb IR was established in group IR. The rats in groups F3, F5, and F10 were pretreated with 3, 5, and 10 mg/kg/d FTY720 for 7 days before IR. S1P lyase (S1PL), sphingosine kinase (SphK) 1, and SphK2 mRNA expressions, wet/dry weight (W/D), and polymorphonuclear/alveolus (P/A) in lung tissues were detected, and the lung injury score was evaluated. RESULTS: W/D, P/A, and mRNA expressions of S1PL, SphK1, and SphK2 were higher in group IR than in group SM, while these were decreased in both groups F5 and F10 as compared to IR (p < 0.05). The lung tissue presented severe lesions in group IR, which were attenuated in groups F5 and F10 with lower lung injury scores than in group IR (p < 0.05). CONCLUSIONS: FTY720 pretreatment could attenuate lung injury induced by hindlimb IR by modulating S1P metabolism and decreasing pulmonary neutrophil infiltration.

The Effect of Transcutaneous Electrical Acupoint Stimulation on Inflammatory Response in Patients Undergoing Limb Ischemia-Reperfusion.

Reperfusion after tourniquet use can induce inflammation and cause remote organ injury. We evaluated the therapeutic effect of transcutaneous electrical acupoint stimulation (TEAS) on inflammatory mediators and lung function in patients receiving lower limb tourniquets. Forty patients undergoing unilateral lower extremity surgery with tourniquet were randomly assigned to two groups: the TEAS group and ischemia-reperfusion (I/R) group. The C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 8 (CXCL8), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and arterial blood gas analysis were measured preoperatively and 6 h after tourniquet removal. The levels of CXCL8, IL-1, IL-6, TNF-α, and CCL2 were significantly increased compared to baseline values in both groups, but the increase was significantly smaller in the TEAS group. In the TEAS group, the partial pressure of oxygen and arterial-alveolar oxygen tension ratio were significantly decreased, and the alveolar-arterial oxygen tension difference and respiratory index were significantly increased, compared to those in the I/R group at 6 h after reperfusion. In conclusion, TEAS diminished the upregulation of proinflammatory factors in response to lower limb ischemia-reperfusion and improved pulmonary gas exchange.

Low-Dose Alfentanil Inhibits Sufentanil-Induced Cough During Anesthesia Induction: A Prospective, Randomized, Double-Blind Study.

Background: Cough is one of the most common complications following intravenous administration of sufentanil during anesthesia induction. The study aimed to investigate the protective effect of alfentanil, afentanyl derivative with short onset time and short duration, in reducing sufentanil-induced cough. Patients and methods: Eighty patients that scheduled for thyroid surgery under general anesthesia were randomly divided into the alfentanil group and normal saline group, with 40 cases per group. Patients in the alfentanil group received intravenous administration of 2 µg/kg alfentanil prior to sufentanil injection during general anesthesia induction, while the same dose of normal saline was administered in the normal saline group. The outcomes measures included the incidence and severity of cough and common side effects of opioids following the administration of sufentanil during the induction of general anesthesia, intraoperative hemodynamics parameters and major adverse events during anesthesia recovery period. Results: The incidence of cough within one minute after the injection of sufentanil during anesthesia induction was 40% in the normal saline group, and the pretreatment of alfentanil significantly reduced the incidence of sufentanil-induced cough to 5% (p < 0.05). Correspondingly, the patients in the alfentanil group had decreased severity of sufentanil-induced cough compared with the normal saline group (p < 0.05). No significant differences in the incidences of common side effects of opioids (dizziness, nausea and vomiting, chest tightness and respiratory depression) within one minute after sufentanil injection were found (p > 0.05). Furthermore, there were no significant differences between the two groups in intraoperative hemodynamic parameters, extubation time, or the incidences of emergence agitation, respiratory depression, delayed recovery from anesthesia and postoperative nausea and vomiting during Postanesthesia Care Unit stay (p > 0.05). Conclusion: Pretreatment with low-dose alfentanil (2 µg/kg) effectively and safely reduced both the incidence and severity of sufentanil-induced cough during anesthesia induction. Clinical Trial Registration Number: Chinese Clinical Trial Registry (identifier: ChiCTR2300069286).

Necrostatin-1 prevents skeletal muscle ischemia reperfusion injury by regulating Bok-mediated apoptosis.

BACKGROUND: Receptor interacting serine/threonine kinase 1 (RIPK1) mediates apoptosis by regulating the classic proapoptotic effectors Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak). Although Bcl-2-related ovarian killer (Bok) is structurally similar to Bak and Bax, it is unclear whether it mediates apoptosis in skeletal muscle ischemia reperfusion (IR) injury. We hypothesized that by regulating Bok-mediated apoptosis, inhibiting RIPK1 with necrostatin-1 would reduce skeletal muscle IR injury. METHODS: Rats were randomized into four groups: sham (SM), IR, IR treated with necrostatin-1 (NI), or vehicle dimethyl sulfoxide (DI). For the IR group, the right femoral artery was clamped for 4 hours and then reperfused for 4 hours, and for the NI and DI groups, necrostatin-1 (1.65 mg/kg) and the equal volume of dimethyl sulfoxide were intraperitoneally administered prior to IR induction. The structural damage of muscle tissue and protein expression of Bok, Bcl-2, and cleaved caspase-3 were investigated, and apoptotic cells were identified with terminal dUTP nick-end labeling (TUNEL) staining. In vitro, human skeletal muscle cells (HSMCs) were exposed to 6 hours of oxygen-glucose deprivation followed by normoxia for 6 hours to establish an oxygen-glucose deprivation/reoxygenation (OGD/R) model. To determine the role of Bok, cell viability, lactate dehydrogenase (LDH) release, and flow cytometry were examined to demonstrate the effects of necrostatin-1 and Bok knockdown on the OGD/R insult of HSMCs. RESULTS: Necrostatin-1 pretreatment markedly reduced IR-induced muscle damage and RIPK1, Bok, and cleaved caspase-3 expression, whereas upregualted Bcl-2 expression (p < 0.05). Furthermore, necrostatin-1 prevented mitochondrial damage and decreased TUNEL-positive muscle cells (p < 0.05). In vitro, HSMCs treated with necrostatin-1 showed reduced Bok expression, increased cell viability, and reduced LDH release in response to OGD/R (p < 0.05), and Bok knockdown significantly blunted the OGD/R insult in HSMCs. CONCLUSION: Necrostatin-1 prevents skeletal muscle from IR injury by regulating Bok-mediated apoptosis.

RIP1 Regulates Mitochondrial Fission during Skeletal Muscle Ischemia Reperfusion Injury.

BACKGROUND: Dynamin related protein-1 (Drp1)-mediated mitochondrial fission relates to ischemia reperfusion (IR) injury, and its association with necroptosis is implied. We hypothesized that receptor-interacting protein 1 (RIP1), a key kinase in necroptosis, acted as an upstream of Drp1-mediated mitochondrial fission during skeletal muscle IR. METHODS: Thirty rats were randomized into the SM, IR, NI, MI, and DI group (n = 6). The rats in the SM group were shamly operated, and those in the IR group were subjected to 4-hour ischemia of the right hindlimb that was followed by 4-hour reperfusion. Intraperitoneal administration of Nec-1 1 mg/kg, Mdivi-1 1.2 mg/kg and same volume of DMSO were given before ischemia in the NI, MI and DI groups, respectively. Upon reperfusion, the soleus muscles were harvested to determine morphological changes and the expression of RIP1, total Drp1 and p-Drp1 (Ser616). Moreover, the muscular oxidative stress indicators and plasma muscle damage biomarkers were detected. RESULTS: IR led to impaired histopathological structures and mitochondrial fragmentation in the soleus muscle tissue, accompanied with increased muscular oxidative stress and muscle injury biomarkers, which could be similarly alleviated by Mdivi-1 and Nec-1 (p < 0.05). RIP1 and p-Drp1 (Ser616) protein levels were significantly upregulated in the soleus muscle subjected to IR injury, this upregulation was attenuated in the NI group, and Mdivi-1 downregulated the protein expression of p-Drp1 (Ser616) but not of RIP1 (p < 0.05). CONCLUSION: RIP1 functions as an upstream of Drp1-mediated mitochondrial fission in the execution of necroptosis during skeletal muscle IR.

Effect of Shenmai injection, a traditional Chinese medicine, on pulmonary dysfunction after tourniquet-induced limb ischemia-reperfusion.

BACKGROUND: Tourniquet has been considered as a recognized cause of lower limb ischemia-reperfusion injury in the orthopedic field. This study investigates pulmonary function after tourniquet deflation and the protective effect of Shenmai injection (SMI), a traditional Chinese medicine. METHODS: Twenty-eight patients undergoing lower extremity surgery were randomized into a control group (group C) and a SMI group (group S), 14 patients in each group. Blood gas and circulating indicators (malondialdehyde, interleukin [IL]-6, and IL-8) were measured immediately before tourniquet inflation and at 0.5 hour, 2 hours, 6 hours, and 24 hours after tourniquet deflation. RESULTS: Plasma levels of malondialdehyde, IL-6, and IL-8 in group C were significantly increased over baselines from 2 hours to 24 hours after tourniquet deflation and the levels reached their peaks at 6 hours after tourniquet deflation, when arterial partial pressures of oxygen and arterial-alveolar oxygen tension ratio were decreased, whereas alveolar-arterial oxygen difference was increased significantly. Both the changes in blood gas variables and plasma mediators were attenuated in group S. CONCLUSION: Pulmonary gas exchange is impaired after lower limb ischemia-reperfusion induced by clinical tourniquet application. Pretreatment with SMI, a traditional Chinese medicine, attenuates lipid peroxidation and systemic inflammatory response and mitigates pulmonary dysfunction.

[Role of vascular endothelial active facters in gas exchange impairment induced by tourniquet and the effect of shenmai injection].

OBJECTIVE: To investigate the effect of Shenmai injection on vascular endothelial active facters nitric oxide (NO) and endothelin-1 (ET-1), and pulmonary gas exchange induced by tourniquet deflation in patients undergoing lower extremity surgery. METHOD: Twenty-six patients scheduled for unilateral lower extremity surgery were randomly divided into 2 groups: control group (group C, n = 14) and Shenmai injection group (group SM, n = 12). All the patients agreed to a combined spinal-epidural anesthesia at the L2-L3 interspace and a radial artery catheter was placed for sampling. Patients in group SM were injected Shenmai injection 0.6 mL x kg(-1) and physiological saline 100 mL, while patients in group C were injected equal volume of normal saline instead 15 min before tourniquet inflation. Blood samples which were used for blood gas analysis and measurement of nitric oxide (NO) and endothelin-1 (ET-1) were taken before tourniquet inflation (T0, baseline) and 30 min (T1), 2 h (T2), 6 h (T3), 24 h (T4) after tourniquet deflation. RESULT: Compared with the baseline values at T0, in group C at T3 P(a) O2 and the levels of NO were significantly decreased, while P(A-a) DO2 and the levels of ET-1 at T3 were significantly increased (P < 0.05 or P < 0.01), in group SM, the levels of NO at T3 were significantly decreased (P < 0.05). Compared with group C, the changes of P(a)O2, P(A-a) DO2, NO and ET-1 were significantly mitigated in group SM. CONCLUSION: The concentrations of NO and ET-1 is connected with the pulmonary gas exchange impairment induced by tourniquet application. Shenmai injection can improve the pulmonary gas exchange based on rising the level of NO, reducing the level of ET-1.

[Characteristics of Phosphorus Adsorption in Aqueous Solution by Si-modified Peanut Shell Biochar].

In this work, a novel sodium silicate-modified peanut shell biochar(Si-PSB) was synthesized and used as phosphorus adsorbents. Compared with unmodified biochar(PSB), the adsorption capacity of Si-PSBs increased significantly. The adsorption capacity of 8% sodium silicate solution modified biochar(8%Si-PSB) was 3.9 times higher than that of PSB. The biochar was characterized using scanning electron microscopy(SEM), Fourier transformed infrared(FTIR), and X-ray diffraction(XRD), which confirmed that silica was present on the surface of 8%Si-PSB. The introduction of silica improved the reaction activity of biochar's own metal ions by affecting the morphology of calcium carbonate. The 8%Si-PSB had a good adsorption effect on phosphorus in both acid and alkali environments. Phosphorus adsorption by 8%Si-PSB and PSB was described well by the pseudo-second-order model, and the adsorption capacity after equilibrium fluctuated between 2.79 mg·g-1 and 0.71 mg·g-1, respectively. Further, the isothermal adsorption experimental data fitted well to the Langmuir model. The presence of humic acid in the solution inhibited the adsorption of phosphorus by the 8%Si-PSB and PSB. The 8%Si-PSB, as a new low-cost phosphorus removal material, can improve the utilization of metal ions in peanut shell itself.