The emerging role of regulated cell death in ischemia and reperfusion-induced acute kidney injury: current evidence and future perspectives.

Renal ischemia‒reperfusion injury (IRI) is one of the main causes of acute kidney injury (AKI), which is a potentially life-threatening condition with a high mortality rate. IRI is a complex process involving multiple underlying mechanisms and pathways of cell injury and dysfunction. Additionally, various types of cell death have been linked to IRI, including necroptosis, apoptosis, pyroptosis, and ferroptosis. These processes operate differently and to varying degrees in different patients, but each plays a role in the various pathological conditions of AKI. Advances in understanding the underlying pathophysiology will lead to the development of new therapeutic approaches that hold promise for improving outcomes for patients with AKI. This review provides an overview of the recent research on the molecular mechanisms and pathways underlying IRI-AKI, with a focus on regulated cell death (RCD) forms such as necroptosis, pyroptosis, and ferroptosis. Overall, targeting RCD shows promise as a potential approach to treating IRI-AKI.

IL-2Rα-biased agonist enhances antitumor immunity by invigorating tumor-infiltrating CD25+CD8+ T cells.

To avoid regulatory T cell promotion and vascular toxicity, the interleukin-2 receptor-ß/interleukin-2 receptor-γ (IL-2Rßγ)-biased approach is used by most IL-2 analogs in immuno-oncology. However, recent clinical disappointments in these IL-2 agonists have questioned this strategy. Here we show that both wild-type (IL-2wt) and IL-2Rßγ-attenuated (IL-2α-bias) agonists that preserve IL-2Rα (CD25) activities can effectively expand tumor-specific CD8+ T cells (TSTs) and exhibit better antitumor efficacy and safety than the 'non-α' counterpart (IL-2nα). Mechanistically, TSTs coexpress elevated CD25 and PD-1 and are more susceptible to stimulation by IL-2Rα-proficient agonists. Moreover, the antitumor efficacy of anti-PD-1 depends on activation of PD-1+CD25+ TSTs through autocrine IL-2-CD25 signaling. In individuals with cancer, a low IL-2 signature correlates with non-responsiveness to anti-PD-1 treatment. In mouse models, IL-2α-bias, but not IL-2nα, restores the IL-2 signature and synergizes with anti-PD-1 to eradicate large established tumors. These findings underscore the indispensable function of CD25 in IL-2-based immunotherapy and provide rationales for evaluating IL-2Rα-biased agonists in individuals with cancer.

Diagnosis, pathophysiology and preventive strategies for cardiac surgery-associated acute kidney injury: a narrative review.

Acute kidney injury (AKI) is a common and serious complication of cardiac surgery and is associated with increased mortality and morbidity, accompanied by a substantial economic burden. The pathogenesis of cardiac surgery-associated acute kidney injury (CSA-AKI) is multifactorial and complex, with a variety of pathophysiological theories. In addition to the existing diagnostic criteria, the exploration and validation of biomarkers is the focus of research in the field of CSA-AKI diagnosis. Prevention remains the key to the management of CSA-AKI, and common strategies include maintenance of renal perfusion, individualized blood pressure targets, balanced fluid management, goal-directed oxygen delivery, and avoidance of nephrotoxins. This article reviews the pathogenesis, definition and diagnosis, and pharmacological and nonpharmacological prevention strategies of AKI in cardiac surgical patients.

A Highly Active Chondroitin Sulfate Lyase ABC for Enzymatic Depolymerization of Chondroitin Sulfate.

Enzymatic preparation of low-molecular-weight chondroitin sulfate (LMWCS) has received increasing attention. In this work, a chondroitin sulfate lyase ABC (Chon-ABC) was successfully cloned, expressed, and characterized. The Km and Vmax of the Chon-ABC were 0.54 mM and 541.3 U mg-1, respectively. The maximal activity was assayed as 500.4 U mg-1 at 37 °C in pH 8.0 phosphate buffer saline. The half-lives of the Chon-ABC were 133 d and 127 min at 4 °C and 37 °C, respectively. Enzymatic preparation of LMWCS was performed at room temperature for 30 min. The changes between the substrate and product were analyzed with mass spectrometry (MS), high-performance liquid chromatography (HPLC), gel permeation chromatography (GPC), and nuclear magnetic resonance (NMR). Overall, the Chon-ABC from Bacteroides thetaiotaomicron is competitive in large-scale enzymatic preparation of LMWCS for its high activity, stability, and substrate specificity.

Ultrapotent neutralizing antibodies against SARS-CoV-2 with a high degree of mutation resistance.

Many SARS-CoV-2 neutralizing antibodies (nAbs) lose potency against variants of concern. In this study, we developed 2 strategies to produce mutation-resistant antibodies. First, a yeast library expressing mutant receptor binding domains (RBDs) of the spike protein was utilized to screen for potent nAbs that are least susceptible to viral escape. Among the candidate antibodies, P5-22 displayed ultrahigh potency for virus neutralization as well as an outstanding mutation resistance profile. Additionally, P14-44 and P15-16 were recognized as mutation-resistant antibodies with broad betacoronavirus neutralization properties. P15-16 has only 1 binding hotspot, which is K378 in the RBD of SARS-CoV-2. The crystal structure of the P5-22, P14-44, and RBD ternary complex clarified the unique mechanisms that underlie the excellent mutation resistance profiles of these antibodies. Secondly, polymeric IgG enhanced antibody avidity by eliminating P5-22's only hotspot, residue F486 in the RBD, thereby potently blocking cell entry by mutant viruses. Structural and functional analyses of antibodies screened using both potency assays and the yeast RBD library revealed rare, ultrapotent, mutation-resistant nAbs against SARS-CoV-2.

Cancer immune therapy with PD-1-dependent CD137 co-stimulation provides localized tumour killing without systemic toxicity.

Expression of the cell surface receptor CD137 has been shown to enhance anti-cancer T cell function via engagement with its natural ligand 4-1BBL. CD137 ligation with engineered ligands has emerged as a cancer immunotherapy strategy, yet clinical development of agonists has been hindered by either toxicity or limited efficacy. Here we show that a CD137/PD-1 bispecific antibody, IBI319, is able to overcome these limitations by coupling CD137 activation to PD-1-crosslinking. In CT26 and MC38 syngeneic mouse tumour models, IBI319 restricts T cell co-stimulation to PD-1-rich microenvironments, such as tumours and tumour-draining lymph nodes, hence systemic (liver) toxicity arising from generalised T cell activation is reduced. Besides limiting systemic T cell co-stimulation, the anti-PD-1 arm of IBI319 also exhibits checkpoint blockade functions, with an overall result of T and NK cell infiltration into tumours. Toxicology profiling in non-human primates shows that IBI319 is a well-tolerated molecule with IgG-like pharmacokinetic properties, thus a suitable candidate for further clinical development.

The emerging roles of neutrophil extracellular traps in wound healing.

Delayed wound healing causes problems for many patients both physically and psychologically, contributing to pain, economic burden, loss of function, and even amputation. Although many factors affect the wound healing process, abnormally prolonged or augmented inflammation in the wound site is a common cause of poor wound healing. Excessive neutrophil extracellular trap (NET) formation during this phase may amplify inflammation and hinder wound healing. However, the roles of NETs in wound healing are still unclear. Herein, we briefly introduce NET formation and discuss the possible NET-related mechanisms in wound healing. We conclude with a discussion of current studies, focusing on the roles of NETs in diabetic and normoglycemic wounds and the effectiveness of NET-targeting treatments in wound healing.

Postoperative sufentanil intravenous patient-controlled analgesia within the first 24 hours: a retrospective study.

BACKGROUND: Intravenous patient-controlled analgesia (IV-PCA) is recommended for postoperative systemic analgesia by the American Pain Society. As there is no efficacy advantage and a higher probability of adverse events, routine basal infusion of opioids is not recommended for opioid-naïve adults. However, the opioids referred to in postoperative pain management guidelines were mainly morphine. Nowadays, sufentanil is widely used in postoperative acute pain management. In this retrospective study, we evaluated and compared the analgesic effect, PCA use, as well as adverse events among different basal infusions with sufentanil-based postoperative PCA. METHODS: The data of 322 eligible postoperative patients who received sufentanil-based IV-PCA from January 2018 to December 2019 were collected in this study. According to the settings of background infusions, patients were allocated to 3 groups: 2, 1, or 0.5 mL/hour. The primary endpoint was PCA attempts and successful delivery. We also evaluated the occurrence of adverse events associated with sufentanil-based PCA and the intensity of postoperative pain using the Numeric Rating Scale (NRS). RESULTS: PCA attempts, successful deliveries, total volume of PCA and patient NRS scores were significantly different between the 3 groups (P<0.05). Through pairwise comparison, there was only a statistical difference between the 2 mL/hour and the 0.5 mL/hour group in PCA attempts, successful deliveries, and total volumes of PCA. There were no statistical differences in adverse events between groups (P>0.05). CONCLUSIONS: We found that a smaller background infusion with sufentanil required more bolus infusions and a higher total volume of PCA within 24 hours after surgery. However, NRS scores were higher in the smaller background infusion group. Our results highlight the need for further studies to optimize doses for sufentanil IV-PCA basal infusions, which will also provide useful information to enhance the quality of pain control in the future.

[Validity and reliability of the Chinese version of Mobile Phone Involvement Questionnaire in college students].

OBJECTIVE: To test the validity and reliability of the Chinese version of Mobile Phone Involvement Questionnaire (MPIQ) in college students. METHODS: We assessed the degree of phone dependence using the MPIQ among 2122 college students. One month later, 60 students were randomly selected for assessment with the MPIQ, and the ROC curve was generated to evaluate the true positive rate (sensitivity) and false positive rate at different cutoff values to determine the optimal cutoff score of the MPIQ. RESULTS: Among 98.9% of the participants who finished all the items, their MPIQ scores show a positive skew distribution and a one-factor structure. The load scores of the items ranged from 0.54 to 0.77. The Cronbach's α coefficient and the Spearman Brown split reliability were 0.84 and 0.83, respectively, the correlation coefficients between the items and total score ranged from 0.54 to 0.76, and the test-retest reliability was 0.48 (P < 0.001). At the optimal cut-off score of 32, the sensitivity and the specificity of the MPIQ were 0.634 and 0.652, respectively. CONCLUSIONS: At the optimal cut-off score of 32, the MPIQ has good validity and reliability for assessing phone dependence among college students.

Erratum to Transperitoneal versus extraperitoneal robot-assisted laparoscopic radical prostatectomy on postoperative hepatic and renal function.

[This corrects the article DOI: 10.21037/gs-20-533.].

Transperitoneal versus extraperitoneal robot-assisted laparoscopic radical prostatectomy on postoperative hepatic and renal function.

Background: In this retrospective study, we evaluated the effect of two approaches of robotic-assisted laparoscopic radical prostatectomy (RALP). The first approach was pneumoperitoneum via transperitoneal (TP-RALP), and the second approach was extraperitoneal (EP-RALP) on visceral function. We aimed to provide clinical evidence for the perioperative safety with RALP and to help the surgical team choose an appropriate approach for those with hepatic or renal insufficiency. Methods: One hundred and fifty-seven eligible prostate cancer patients from 2015 to 2019 were included in this study. The postoperative related laboratory tests were compared between transperitoneal and extraperitoneal. The primary endpoint was hepatic and renal function. We also evaluate the intraoperative amount of bleeding, the length of postoperative hospital stays, the occurrence of postoperative complications (lymphatic leakage, bleeding, and infection), and the prostate-specific antigen (PSA). Results: Postoperative total bilirubin and bound bilirubin in both groups were significantly increased, while total protein, albumin, globulin, urea, and uric acid were significantly decreased (P<0.05). The total protein, albumin, and globulin are significantly higher in the EP-RALP group than in the TP-RALP group (P<0.05) postoperatively. There are no statistical differences in estimated glomerular filtration rate (eGFR) and creatinine clearance (CCR) between these two groups, postoperatively. Conclusions: RALP had a significant effect on hepatic function after both TP-RALP and EP-RALP approaches, while the latter showed a lesser extent. Our results suggested that pneumoperitoneal pathways have significant effects on protein consumption. Thus, we should require a more cautious choice of surgical approaches when it comes to patients with impaired hepatic function or under risk of hepatic malfunction.

Upregulation of GLT-1 via PI3K/Akt Pathway Contributes to Neuroprotection Induced by Dexmedetomidine.

Perioperative ischemic stroke usually leads to neurological dysfunction caused by neuron death. During the ischemic condition, excitotoxity due to extracellular glutamate accumulation is a main mechanism of neuron damage. The clearance of glutamate mainly depends on glutamate transporter-1 (GLT-1) which is expressed in astrocytes. Dexmedetomidine, an α2 adrenergic receptor agonist, is proved to induce neuroprotection. This study was set out to investigate the glutamate-related mechanism involved in the neuroprotective effect of dexmedetomidine. Middle cerebral artery occlusion (MCAO) was used as a model of ischemic stroke in our study. We determined Neurological deficit scores (NDS) and Magnetic resonance imaging (MRI) at three points (2, 6, and 24 h) after middle cerebral artery occlusion (MCAO) to evaluate the neuroprotective effect of dexmedetomidine. Besides, we performed western blot (6 and 24 h after MACO) and immunofluorescent staining (24 h after MCAO) to observe the expression of GLT-1. The effect and mechanism of dexmedetomidine on GLT-1 in primary cultured astrocytes were investigated using western blot and RT-PCR. Our results showed that pretreatment with dexmedetomidine improved NDS and reduced infarct volume as well as upregulating GLT-1 expression. Furthermore, using Atipamezole and LY294002, we found that dexmedetomidine significantly increased GLT-1 levels in astrocytes via activating α2 adrenergic receptor and PI3K/AKT pathway both in vitro and in vivo study. Overall, our present study indicated that dexmedetomidine had neuroprotective effects on ischemia stroke and upregulation of GLT-1 levels by PI3K/AKT dependent pathway might be the potential mechanism.

Maternal Sevoflurane Exposure Causes Abnormal Development of Fetal Prefrontal Cortex and Induces Cognitive Dysfunction in Offspring.

Maternal sevoflurane exposure during pregnancy is associated with increased risk for behavioral deficits in offspring. Several studies indicated that neurogenesis abnormality may be responsible for the sevoflurane-induced neurotoxicity, but the concrete impact of sevoflurane on fetal brain development remains poorly understood. We aimed to investigate whether maternal sevoflurane exposure caused learning and memory impairment in offspring through inducing abnormal development of the fetal prefrontal cortex (PFC). Pregnant mice at gestational day 15.5 received 2.5% sevoflurane for 6 h. Learning function of the offspring was evaluated with the Morris water maze test at postnatal day 30. Brain tissues of fetal mice were subjected to immunofluorescence staining to assess differentiation, proliferation, and cell cycle dynamics of the fetal PFC. We found that maternal sevoflurane anesthesia impaired learning ability in offspring through inhibiting deep-layer immature neuron output and neuronal progenitor replication. With the assessment of cell cycle dynamics, we established that these effects were mediated through cell cycle arrest in neural progenitors. Our research has provided insights into the cell cycle-related mechanisms by which maternal sevoflurane exposure can induce neurodevelopmental abnormalities and learning dysfunction and appeals people to consider the neurotoxicity of anesthetics when considering the benefits and risks of nonobstetric surgical procedures.

Using concanavalinA as a spacer for immobilization of E. coli onto magnetic nanoparticles.

ConcanavalinA (conA) is a protein extracted from the concanavalin, which has specific recognition through mannose components on bacterial cell surfaces. A magnetic nanocarrier with the structure of a dopamine functionalized magnetic nanoparticles was grafted with conA, and was used for immobilization of recombinant Escherichia coli harboring glycerol dehydrogenase with the specific recognition between glycoconjugates and glycoprotein. The effect of various factors on the immobilization including temperature, pH, cell concentration and immobilization time were investigated. The highest immobilization yield of 91% was obtained under the conditions: enzyme/support 1.28mg/mg, pH 8.0, immobilization time 2h and temperature 4°C. The obtained immobilized cell was characterized and exhibited higher thermal stability compared with the free cell. After ten cycles, the immobilized cell remained 62% initial activity. These results indicate that the cell immobilized onto conA-grafted nanoparticles by specific recognition of glycoconjugates and glycoprotein is a potential method for preparation of stable cell, and the immobilized cell showed perspective applications in the biocatalysis and biosensors.

Pressure-controlled versus volume-controlled ventilation during one-lung ventilation for video-assisted thoracoscopic lobectomy.

BACKGROUND: It is controversial as to which ventilation mode is better during one-lung ventilation (OLV). This study was designed to figure out whether there was any difference between volume controlled ventilation (VCV) and pressure controlled ventilation (PCV) on oxygenation and postoperative complications under the condition of protective ventilation (PV). METHODS: Sixty-five patients undergoing video-assisted thoracoscopic lobectomy were randomized into two groups. Patients in group V received VCV mode during OLV while patients in group P received PCV. The tidal volume (VT) in both groups was 6 mL per predicted body weight (PBW). Positive end-expiratory pressure (PEEP) was set at the level of 5 cmH2O in both groups. Arterial gas analysis were performed preoperatively with room air (T0), at 15 mins (T1) and 1 h (T2) after OLV, at the end of OLV (T3), 30 min after PACU admission (T4), 24 h after surgery (post-operative day 1, POD1) and 48 h after surgery (post-operative day 2, POD2). Peak inspiratory airway pressure (Ppeak) and plateau airway pressure (Pplat) were recorded at T1, T2 and T3. The perioperative complications were also recorded. RESULT: Sixty-four patients completed this study. Ppeak in group V was significantly higher than that in group P (T1 22.3±2.9 vs. 18.7±2.1 cmH2O; T2 22.2±2.8 vs. 18.7±2.6 cmH2O). There were no differences with Pplat and intraoperative oxygenation index (T1 203.3±109.7 vs. 198.1±93.4; T2 216.8±79.1 vs. 232.1±101.4). The postoperative oxygenation index (T4 525.0±160.9 vs. 520.7±127.1, post-operative day 1 (POD1) 452.1±161.3 vs. 446.1±109.1; post-operative day 2 (POD2) 403.8±93.4 vs. 396.7±92.8) and postoperative complications were also comparable between these two groups. CONCLUSIONS: When they were utilized during OLV, PCV and VCV had the same performance on the intraoperative oxygenation and postoperative complications under the condition of PV.

Multiple sevoflurane anesthesia in pregnant mice inhibits neurogenesis of fetal hippocampus via repressing transcription factor Pax6.

Sevoflurane is widely used in non-obstetric surgeries of pregnant women, but its influences on fetal brain are still not fully known. We set out to assess the effects of multiple maternal sevoflurane exposure on neurogenesis and cognitive dysfunction in fetus and offspring. Pregnant mice (gestational day 15.5) and cultured mouse neural stem cells (NSCs) received daily sevoflurane exposure (2.5%×2h and 4.1%×2h respectively) for three consecutive days. Cognitive function of the offspring was determined with the Morris water maze. The expression of Ccnd1 and Pax6 in fetal brains and NSCs were analyzed by immunofluorescence, Western blot and qPCR. The neurogenesis was evaluated by BrdU staining. Results showed that multiple sevoflurane exposure in pregnant mice caused the decrease of Pax6 and Ccnd1 expression, the inhibition of NSCs proliferation and fetal hippocampus neurogenesis, which may contribute to the impaired learning and memory in offspring at P28. Moreover, lithium mitigated the sevoflurane-induced reduction in Pax6, Ccnd1 and neurogenesis. All these results suggest that multiple sevoflurane exposure may induce detrimental effects in the developing brains of fetus and offspring by the depression of neurogenesis through Pax6 pathway.

The hippocampal cyclin D1 expression is involved in postoperative cognitive dysfunction after sevoflurane exposure in aged mice.

AIMS: Increasing evidence has suggested cognitive impairment and neuronal apoptosis induced by anaesthetics are due to abnormal hyperphosphorylation of tau protein, but the detailed mechanism remains unknown. MAIN METHODS: Aged mice and neurons were both exposed to 2.5% sevoflurane for 2h. Spatial learning ability of the aged mice was tested with Morris water maze. The changes of neuroapoptosis, tau protein and cell-cycle-related factors (cyclin D1, p27) were determined using Western blot analysis. The effect of sevoflurane exposure on DNA synthesis was tested with immunofluorescent staining. KEY FINDINGS: We found that sevoflurane significantly impaired spatial learning ability in aged mice. In addition, total tau protein. phosphorylated tau protein, Caspase-3 and cyclin D1, but not p27Kip1 were drastically increased in the hippocampus. Consistent with the results from in vivo study, sevoflurane significantly increased the expression of cyclin D1 and Brdu positive neurons in cultured hippocampal neurons. The enhancement of cyclin D1 was partially reversed by the pharmacological inhibition of hyperphosphorylation of tau. SIGNIFICANCE: Our results suggested that cyclin D1 overexpression may result in the neuronal apoptosis through cell cycle re-entry and the deficits in postoperative cognitive dysfunction after sevoflurane exposure. Our research will improve the current understanding of the mechanisms underlying the postoperative cognitive dysfunction by anaesthetics exposure.

Effect of parecoxib combined with thoracic epidural analgesia on pain after thoracotomy.

BACKGROUND: Thoracotomy results in severe postoperative pain potentially leading to chronic pain. We investigated the potential benefits of intravenous parecoxib on postoperative analgesia combined with thoracic epidural analgesia (TEA). METHODS: Eighty-six patients undergoing thoracic surgery were randomized into two groups. Patient-controlled epidural analgesia (PCEA) was used until chest tubes were removed. Patients received parecoxib (group P) or placebo (group C) intravenously just 0.5 h before the operation and every 12 h after operation for 3 days. The intensity of pain was measured by using a visual analogue scale (VAS) and recorded at 2, 4, 8, 24, 48, 72 h after operation. The valid number of PCA, the side effects and the overall satisfaction to analgesic therapy in 72 h were recorded. Venous blood samples were taken before operation, the 1(st) and 3(rd) day after operation for plasma cortisol, adrenocorticotropic hormone (ACTH), interleukin-6 and tumor necrosis factor-α level. The occurrence of residual pain was recorded using telephone questionnaire 2 and 12 months after surgery. RESULTS: Postoperative pain scores at rest and on coughing were significantly lower with the less valid count of PCA and greater patient satisfaction in group P (P<0.01). Adverse effect and the days fit for discharge were comparable between two groups. The cortisol levels in placebo group were higher than parecoxib group at T2. The level of ACTH both decreased in two groups after operation but it was significantly lower in group P than that in group C. There were no changes in plasma IL-6 and TNF-α levels before and after analgesia at T1 and T2 (P>0.05). The occurrence of residual pain were 25% and 51.2% separately in group P and C 3 months postoperatively (P<0.05). CONCLUSIONS: Intravenous parecoxib in multimodal analgesia improves postoperative analgesia provided by TEA, relieves stress response after thoracotomy, and may restrain the development of chronic pain.

Covalent Immobilization of Penicillin G Acylase onto Fe3O4@Chitosan Magnetic Nanoparticles.

Penicillin G acylase (PGA) was immobilized on magnetic Fe3O4@chitosan nanoparticles through the Schiff base reaction. The immobilization conditions were optimized as follows: enzyme/support 8.8 mg/g, pH 6.0, time 40 min, and temperature 25°C. Under these conditions, a high immobilization efficiency of 75% and a protein loading of 6.2 mg/g-support were obtained. Broader working pH and higher thermostability were achieved by the immobilization. In addition, the immobilized PGA retained 75% initial activity after ten cycles. Kinetic parameters Vmax and Km of the free and immobilized PGAs were determined as 0.91 mmol/min and 0.53 mmol/min, and 0.68 mM and 1.19 mM, respectively. Synthesis of amoxicillin with the immobilized PGA was carried out in 40% ethylene glycol at 25°C and a conversion of 72% was obtained. These results showed that the immobilization of PGA onto magnetic chitosan nanoparticles is an efficient and simple way for preparation of stable PGA.