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Different anesthetics exert different effects on the long-term outcomes of various cancers. The TWIK-related acid sensitive potassium 3 (TASK-3) channel is an important target of anesthetics and is upregulated in various cancers. However, the role and underlying mechanism of TASK-3 channel in the effects of anesthetics on ovarian cancer remain unknown. Here, we tested whether the TASK-3 channel contributes to the effects of anesthetics on ovarian cancers. We found that the TASK-3 channel was overexpressed in human ovarian cancer and ovarian cancer cell lines. Clinically relevant concentrations of lidocaine, as a TASK-3 channel inhibitor, exert inhibitory effects on tumor growth and metastasis of ovarian cancer cells in vitro and in vivo, whereas the TASK-3 channel potent activator sevoflurane had protumor effects and propofol had no significant effects on tumor growth and metastasis of ovarian cancer. Knockdown of the TASK-3 channel by TASK-3 shRNA attenuated the effects of lidocaine and sevoflurane. Moreover, mitochondrial TASK-3 channel contributes to the effects of lidocaine and sevoflurane on the mitochondrial functions of ovarian cancer. Taken together, the TASK-3 channel, especially the mitochondrial TASK-3 (MitoTASK-3) channel, is a molecular substrate for the effects of lidocaine and sevoflurane on the tumor growth and metastasis of ovarian cancer.

BackgroundAlthough diaphragm ultrasound can be used for detecting residual neuromuscular blockade post-surgery, there exists notable dearth in contemporary research exploring the correlation between preoperative Child-Pugh classification and the effectiveness of sugammadex in reversing rocuronium-induced blockade as evaluated by diaphragmatic ultrasonography.MethodsThis was a prospective, double-blind, non-randomized controlled clinical trial conducted on patients scheduled for laparoscopic liver resection surgery. The participants were categorized into two groups, A and B, based on their preoperative Child-Pugh classification. Prior to anesthesia induction, baseline diaphragm thickness was evaluated using ultrasonography. Throughout the surgical procedure, a deep neuromuscular blockade was maintained with rocuronium. Post-surgery, sugammadex (2 mg/kg) was intravenously administered to patients in both groups upon reaching a train-of-four ratio of 0.2. Diaphragm thickness was assessed at 0, 10, and 30 min, as well as 2 h after extubation, to analyze thickening fractioning (TF) and thickness recovery fractioning (TRF).ResultsNo significant differences in TF or TRF were observed between the two groups at 0, 10, and 30 min, as well as 2 h after extubation. Furthermore, there were no significant variances in hemodynamic stability following sugammadex administration. However, patients in the Child-Pugh B group experienced a significantly prolonged time from sugammadex administration to tracheal extubation (19 ± 8.0 min vs. 11 ± 6.1 min) and an extended post-anesthesia care unit stay (123 ± 28.3 min vs. 103 ± 26.0 min) compared to those in the Child-Pugh A group.ConclusionThe preoperative Child-Pugh grades may not exhibit a significant association with the reversal effect of sugammadex on rocuronium, as evaluated through diaphragmatic ultrasonography.Clinical trial registrationRegistered in the ClinicalTrials.gov (NCT05028088) on July 18, 2021.

Abstract The Notch gene, a highly evolutionarily conserved gene, was discovered approximately 110 years ago and has been found to play a crucial role in the development of multicellular organisms. Notch receptors and their ligands are single-pass transmembrane proteins that typically require cellular interactions and proteolytic processing to facilitate signal transduction. Recently, mounting evidence has shown that aberrant activation of the Notch is correlated with neuropathic pain. The activation of the Notch signaling pathway can cause the activation of neuroglia and the release of pro-inflammatory factors, a key mechanism in the development of neuropathic pain. Moreover, the Notch signaling pathway may contribute to the persistence of neuropathic pain by enhancing synaptic transmission and calcium inward flow. This paper reviews the structure and activation of the Notch signaling pathway, as well as its potential mechanisms of action, to provide novel insights for future treatments of neuropathic pain.

Abstract. Background:. Dysfunction of the gap junction channel protein connexin 43 (Cx43) contributes to myocardial ischemia/reperfusion (I/R)-induced ventricular arrhythmias. Cx43 can be regulated by small ubiquitin-like modifier (SUMO) modification. Protein inhibitor of activated STAT Y (PIASy) is an E3 SUMO ligase for its target proteins. However, whether Cx43 is a target protein of PIASy and whether Cx43 SUMOylation plays a role in I/R-induced arrhythmias are largely unknown. Methods:. Male Sprague–Dawley rats were infected with PIASy short hairpin ribonucleic acid (shRNA) using recombinant adeno-associated virus subtype 9 (rAAV9). Two weeks later, the rats were subjected to 45 min of left coronary artery occlusion followed by 2 h reperfusion. Electrocardiogram was recorded to assess arrhythmias. Rat ventricular tissues were collected for molecular biological measurements. Results:. Following 45 min of ischemia, QRS duration and QTc intervals statistically significantly increased, but these values decreased after transfecting PIASy shRNA. PIASy downregulation ameliorated ventricular arrhythmias induced by myocardial I/R, as evidenced by the decreased incidence of ventricular tachycardia and ventricular fibrillation, and reduced arrythmia score. In addition, myocardial I/R statistically significantly induced PIASy expression and Cx43 SUMOylation, accompanied by reduced Cx43 phosphorylation and plakophilin 2 (PKP2) expression. Moreover, PIASy downregulation remarkably reduced Cx43 SUMOylation, accompanied by increased Cx43 phosphorylation and PKP2 expression after I/R. Conclusion:. PIASy downregulation inhibited Cx43 SUMOylation and increased PKP2 expression, thereby improving ventricular arrhythmias in ischemic/reperfused rats heart.

Aims: The treatment of sepsis remains challenging and the liver is a non-neglectful target of sepsis-induced injury. Uncontrolled inflammatory responses exert a central role in the pathophysiological process of sepsis-induced acute liver injury (SI-ALI). Maresin1 (MaR1) is a derivative of omega-3 docosahexaenoic acid (DHA), which has been shown to have anti-inflammatory effects and is effective in a variety of sepsis-related diseases. This study aimed to determine the effect of MaR1 on cecal ligation and puncture (CLP)-caused SI-ALI and explore its possible mechanisms. Main methods: Mice were subjected to CLP, and then intravenously injected via tail vein with low-dose MaR1 (0.5 ng, 200 μL) or high-dose MaR1 (1 ng, 200 μL) or sterile normal saline (NS) (200 μL) 1 h later. Then, the survival rate, body weight change, liver function, bacterial load, neutrophil infiltration, and inflammatory cytokines were detected. Results: MaR1 significantly increased the 7-day survival rate and reduced the bacterial load in peritoneal lavage fluid and blood in a dose-dependent manner in mice with SI-ALI. Treatment with MaR1 could also restore the function of the liver in septic mice. Besides, MaR1 exerted anti-inflammatory effects by decreasing the expression of pro-inflammatory molecules (TNF-α, IL-6 and IL-1β), bacterial load, and neutrophil infiltration and increasing the expression of anti-inflammatory molecules (IL-10). Significance: Our experimental results showed that MaR1 alleviated liver injury induced by sepsis. This work highlighted a potential clinic use of MaR1 in treating acute inflammation of SI-ALI, but also provided new insight into the underlying molecular mechanism.

Pulmonary hypertension (PH) is a devastating cardiopulmonary disorder with poor prognosis and limited curative options. Recent studies revealed a strong association between adipose tissue dysfunction (e.g., obesity) and PH. Adipokines are bioactive polypeptides with pleiotropic effects mainly produced by adipose tissue, and it is suggested that imbalanced production of adipokines in obesity may play a key role in the pathogenesis of PH. Alternations in the production and secretion of adipokines have been observed in PH patients and rodents PH models. In this review, we summarize the expressions and functions of several well-recognized adipokines, the roles of adipokines in the pathogenesis of PH and recent advances in the pharmacological and molecular modulation of adipokines in the treatment of PH. We found that several adipokines (e.g., leptin, resistin, and chemerin) have been demonstrated to display pro-proliferation, pro-inflammatory, and pro-oxidative properties and exacerbate PH. Other adipokines (e.g., adiponectin, apelin, and omentin-1) have anti-proliferation, anti-inflammatory, anti-fibrotic and anti-oxidative impacts on the pulmonary vascular remodeling of PH and are suggested as protective factors against PH, and targeting imbalanced adipokines appears to be a potential novel therapeutic strategy for the treatment of PH.

The immune response plays a pivotal role in the pathogenesis of diseases. Toll-like receptor 4 (TLR4), as an intrinsic immune receptor, exhibits widespread in vivo expression and its dysregulation significantly contributes to the onset of various diseases, encompassing cardiovascular disorders, neoplastic conditions, and inflammatory ailments. This comprehensive review centers on elucidating the architectural and distributive characteristics of TLR4, its conventional signaling pathways, and its mode of action in diverse disease contexts. Ultimately, this review aims to propose novel avenues and therapeutic targets for clinical intervention.

Abstract Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a devastating respiratory disorder with high rates of mortality and morbidity, but the detailed underlying mechanisms of ALI/ARDS remain largely unknown. Mechanosensitive ion channels (MSCs), including epithelial sodium channel (ENaC), Piezo channels, transient receptor potential channels (TRPs), and two-pore domain potassium ion (K2P) channels, are highly expressed in lung tissues, and the activity of these MSCs can be modulated by mechanical forces (e.g., mechanical ventilation) and other stimuli (e.g., LPS, hyperoxia). Dysfunction of MSCs has been found in various types of ALI/ARDS, and MSCs play a key role in regulating alveolar fluid clearance, alveolar epithelial/endothelial barrier function, the inflammatory response and surfactant secretion in ALI/ARDS lungs. Targeting MSCs exerts therapeutic effects in the treatment of ALI/ARDS. In this review, we summarize the structure and functions of several well-recognized MSCs, the role of MSCs in the pathogenesis of ALI/ARDS and recent advances in the pharmacological and molecular modulation of MSCs in the treatment of ALI/ARDS. According to the current literature, targeting MSCs might be a very promising therapeutic approach against ALI/ARDS.

Abstract Heat stroke (HS) is a life-threatening systemic disease characterized by an elevated core body temperature of more than 40 ℃ and subsequent multiple organ dysfunction syndrome. With the growing frequency of global heatwaves, the incidence rate of HS has increased significantly, which has caused a huge burden on people's lives and health. Liver injury is a well-documented complication of HS and usually constitutes the direct cause of patient death. In recent years, a lot of research has been carried out on the pathogenesis and treatment strategies of HS-induced liver injury. In this review, we summarized the important pathogenesis of HS-induced liver injury that has been confirmed so far. In addition to the comprehensive effect of systemic factors such as heat cytotoxicity, coagulopathy, and systemic inflammatory response syndrome, excessive hepatocyte cell pyroptosis, dysfunction of Kupffer cells, abnormal expression of heat shock protein expression, and other factors are also involved in the pathogenesis of HS-induced liver injury. Furthermore, we have also established the current therapeutic strategies for HS-induced liver injury. Our study is of great significance in promoting the understanding of the pathogenesis and treatment of HS-induced liver injury.

Background: Acute respiratory distress syndrome (ARDS) remains a challenge because of its high morbidity and mortality. Circulation histones levels in ARDS patients were correlated to disease severity and mortality. This study examined the impact of histone neutralization in a rat model of acute lung injury (ALI) induced by a lipopolysaccharide (LPS) double-hit.Methods: Sixty-eight male Sprague-Dawley rats were randomized to sham (N = 8, received saline only) or LPS (N = 60). The LPS double-hit consisted of a 0.8 mg/kg intraperitoneal injection followed after 16 h by 5 mg/kg intra-tracheal nebulized LPS. The LPS group was then randomized into five groups: LPS only; LPS +5, 25, or 100 mg/kg intravenous STC3141 every 8 h (LPS + L, LPS + M, LPS + H, respectively); or LPS + intraperitoneal dexamethasone 2.5 mg/kg every 24 h for 56 h (LPS + D). The animals were observed for 72 h.Results: LPS animals developed ALI as suggested by lower oxygenation, lung edema formation, and histological changes compared to the sham animals. Compared to the LPS group, LPS + H and +D groups had significantly lower circulating histone levels and lung wet-to-dry ratio, and the LPS + D group also had lower BALF histone concentrations; the blood neutrophils and platelets counts in LPS + D group did not change, meanwhile, the LPS + L, +M and +H groups had significantly lower neutrophil counts and higher platelet counts in the blood; the total number of BALF WBC, platelet counts, MPO and H3 were significantly lower in the LPS + L, +M, +H and +D groups than in the LPS only group; and the degree of inflammation was significantly less in the LPS + L, +M, +H and +D groups, moreover, inflammation in the LPS + L, +M and +H animals showed a dose-dependent response; finally, the LPS + L, +M, +H and +D groups had improved oxygenation compared to the LPS group, and there were no statistical differences in PCO2 or pH among groups. All animals survived.Conclusion: Neutralization of histone using STC3141, especially at high dose, had similar therapeutic effects to dexamethasone in this LPS double-hit rat ALI model, with significantly decreased circulating histone concentration, improved acute lung injury and oxygenation.

Abstract Introduction Blood–brain barrier (BBB) dysfunction may occur at the onset of Alzheimer’s disease (AD). Pericytes are a vital part of the neurovascular unit and the BBB, acting as gatekeepers of the BBB. Amyloid β (Aβ) deposition and neurofibrillary tangles in the brain are the central pathological features of AD. CD36 promotes vascular amyloid deposition and leads to vascular brain damage, neurovascular dysfunction, and cognitive deficits. However, the molecular mechanism by which pericytes of the BBB are disrupted remains unclear. Objectives To investigate the effect of low-dose Aβ1-40 administration on pericyte outcome and the molecular mechanism of BBB injury. Methods We selected 6-month-old and 9-month-old APP/PS1 mice and wild-type (WT) mice of the same strain, age, and sex as controls. We assessed the BBB using PET/CT. Brain pericytes were extracted and cocultured with endothelial cells (bEnd.3) to generate an in vitro BBB model to observe the effect of Aβ1-40 on the BBB. Furthermore, we explored the intracellular degradation and related molecular mechanisms of Aβ1-40 in cells. Results BBB permeability and the number of pericytes decreased in APP/PS1 mice. Aβ1-40 increased BBB permeability in an in vivo model and downregulated the expression of CD36, which reversed the Aβ-induced changes in BBB permeability. Aβ1-40 was uptaked in pericytes with high CD36 expression. We observed that this molecule inhibited pericyte proliferation, caused mitochondrial damage, and increased mitophagy. Finally, we confirmed that Aβ1-40 induced pericyte mitophagy-dependent ferroptosis through the CD36/PINK1/Parkin pathway. Conclusion PDGFRβ (a marker of pericytes), CD36, and Aβ colocalized in vitro and in vivo, and Aβ1-40 caused BBB disruption by upregulating CD36 expression in pericytes. The mechanism by which Aβ1-40 destroys the BBB involves the induction of pericyte mitophagy-dependent ferroptosis through the CD36/PINK1/Parkin pathway.

The dysfunctional immune response and multiple organ injury in sepsis is a recurrent theme impacting prognosis and mortality, while the lung is the first organ invaded by sepsis. To systematically elucidate the transcriptomic changes in the main constituent cells of sepsis-injured lung tissue, we applied single-cell RNA sequencing to the lung tissue samples from septic and control mice and created a comprehensive cellular landscape with 25044 cells, including 11317 immune and 13727 non-immune cells. Sepsis alters the composition of all cellular compartments, particularly neutrophils, monocytes, T cells, endothelial, and fibroblasts populations. Our study firstly provides a single-cell view of cellular changes in septic lung injury. Furthermore, by integrating bulk sequencing data and single-cell data with the Scissors-method, we identified the cell subpopulations that are most associated with septic lung injury phenotype. The phenotypic-related cell subpopulations identified by Scissors-method were consistent with the cell subpopulations with significant composition changes. The function analysis of the differentially expressed genes (DEGs) and the cell-cell interaction analysis further reveal the important role of these phenotype-related subpopulations in septic lung injury. Our research provides a rich resource for understanding cellular changes and provides insights into the contributions of specific cell types to the biological processes that take place during sepsis-induced lung injury.

Hepatocellular carcinoma (HCC) is a common malignant tumor with a poor prognosis. Epigenetic dysregulation is now considered to be related to hepatocarcinogenesis. However, it is unclear how epigenetic-related genes (ERGs) contribute to the prognosis of HCC. In this study, we used the TCGA database to identify prognostic ERGs that were differentially expressed in HCC patients. Then, using least absolute shrinkage and selection operator (LASSO) regression analysis, a six-gene signature was constructed, and patients were divided into high- and low-risk groups. Validation was performed on HCC patients from the ICGC database. Patients in the high-risk group had a significantly lower chance of survival than those in the low-risk group (p < 0.001 in both databases). The predictive ability of the signature was determined by the receiver operating characteristic (ROC) curve. The risk score was then shown to be an independent prognostic factor for the overall survival (OS) of HCC patients based on the results of univariate and multivariate analyses. We also created a practical nomogram combining the prognostic model with other clinical features. Moreover, functional enrichment analysis revealed that these genes are linked to tumor immunity. In conclusion, our findings showed that a novel six-gene signature related to epigenetics can accurately predict the occurrence and prognosis of HCC.

Abstract Alteration in the polybromo‐1 (PBRM1) protein encoding gene PBRM1 is the second most frequent mutation in clear cell renal cell carcinoma (ccRCC). It causes a series of changes in the tumorigenesis, progression, prognosis, and immune response of ccRCC patients. This study explored the PBRM1‐associated immunological features and identified the immune‐related genes (IRGs) linked to PBRM1 mutation using bioinformatics methods. A total of 37 survival IRGs associated with PBRM1 mutation in ccRCC patients were identified. To further explore the role of these IRGs in ccRCC and their association with immune status, eight IRGs with remarkable potential as individual targets were selected. An immune model that was constructed showed good performance in stratifying patients into different subgroups, showing clinical application potential compared to traditional clinical factors. Patients in the high‐risk group were inclined to have more advanced stage and higher grade tumors with node metastasis, distant metastasis, and poorer prognosis. Furthermore, these patients had high percentages of regulatory T cells, follicular helper T cells, and M0 macrophages and exhibited high expression levels of immune checkpoints proteins, such as CTLA‐4, PD‐1, LAG‐3, TIGIT, and CD47. Finally, a nomogram integrating the model and clinical factors for clinical application showed a more robust predictive performance for prognosis. The prediction model associated with PBRM1 mutation status and immunity can serve as a promising tool to stratify patients depending upon their immune status, thus facilitating immunotherapy in the future.

Our study is the first to illustrate the age and geographic distribution differences in the epidemiology of prostate cancer from 1990 to 2019 in China. Prostate cancer (PC) is a malignant tumor derived from prostate epithelial cells and is one of the most commonly diagnosed cancers in men. In recent years, the global incidence and the annual deaths number of PC showed a continuous increase, which has caused a huge disease burden on human health. In terms of the global average, the incidence and mortality of PC in China are relatively low. However, the age-standardized incidence rate of PC was 17.3/100,000 in 2019 in China, with a 95.2% rise compared to 1990, while the global growth rate of incidence rate over the same period is 13.2%. This showed that the development trend of PC in China is not optimistic. There are few precise studies on the epidemiology of PC in China. After the general analysis strategy used in the Global Burden of Diseases, Injuries and Risk Factors Study (GBD) 2019, we elaborated on the incidence, mortality, and disability-adjusted life-years (DALYs) and the corresponding age-standardized rate of the Chinese PC population from 1990 to 2019 according to different ages and provinces. We used joinpoint regression analysis to estimate the incidence and mortality trends. Our analysis shows that elderly people over 80 are still the main focus of incidence and death. The epidemiology and disease burden of PC of different provinces in China show obvious regional differences, and some certain provinces such as HongKong, Macao, and Zhejiang should be paid more attention. More targeted and effective strategies should be developed to reduce the burden of PC in China.

Gamma-delta (γδ) T cells are a small subset of T cells that are reported to have a proinflammatory role in the pathophysiology of cerebral ischemia stroke (CIS). Upon activation by interleukin-1 beta (IL-1β), IL-23 and IL-18, γδ T cells are stimulated to secrete various cytokines, such as IL-17a, IL-21, IL-22, and interferon-gamma (IFN-γ). In addition, they all play a pivotal role in the inflammatory and immune responses in ischemia. Nevertheless, the exact mechanisms responsible for γδ T cell proinflammatory functions remain poorly understood, and more effective therapies targeting at γδ T cells and cytokines they release remain to be explored, particularly in the context of CIS. CIS is the second most common cause of death and the major cause of permanent disability in adults worldwide. In this review, we focus on the neuroinflammatory and immune functions of γδ T cells and related cytokines, intending to understand their roles in CIS, which may be crucial for the development of novel effective clinical applications.

Abstract Background Myocardial infarction (MI) affects the expression of a large number of lncRNAs, while the functions of those dysregulated lncRNAs are mostly unclear. Materials and methods Expression of MORT and miR-93 in hearth tissues and plasma of both MI mice and Sham mice and both MI patients and healthy controls was detected by RT-qPCR. Correlations of expression levels of MORT and miR-93 between hear tissues and plasma of MI mice were explored by performing linear regression. Results In the present study we found that MORT expression levels were higher, while expression levels of miR-93 were lower in both plasma and heart tissues of mice MI mice models compared with Sham mice. Plasma levels of MORT and miR-93 were largely consistent with expression levels of MORT and miR-93 in heart tissue of MI mice. MORT expression levels were also higher, while levels of miR-93 were also lower in plasma of MI patients compared with healthy controls. MORT and miR-93 were inversely correlated in MI patients but not in healthy controls. MORT overexpression resulted in inhibited miR-93 expression in cardiomyocytes (AC16 cell line), while miR-93 overexpression did not significantly affect MORT expression. MORT overexpression promoted cardiomyocyte apoptosis, while miR-93 overexpression played and opposite role and attenuated the effects of MORT overexpression. Conclusion Therefore, lncRNA MORT is upregulated in myocardial infarction and promotes the apoptosis of cardiomyocyte by downregulating miR-93.

Acute lung injury (ALI) is the most common type of organ injury in sepsis, with high morbidity and mortality. Sepsis is characterized by an inappropriate inflammatory response while neutrophils exert an important role in the excessive inflammatory response. The discovery of specialized pro-resolving mediators (SPMs) provides a new direction for the treatment of a series of inflammatory-related diseases including sepsis. Among them, the regulation of Maresin1 on immune cells was widely demonstrated. However, current research on the regulatory effects of Maresin1 on immune cells has remained at the level of certain cell types. Under inflammatory conditions, the immune environment is complex and immune cells exhibit obvious heterogeneity. Neutrophils play a key role in the occurrence and development of septic lung injury. Whether there is a subpopulation bias in the regulation of neutrophils by Maresin1 has not been elucidated. Therefore, with the well-established cecal ligation and puncture (CLP) model and single-cell sequencing technology, our study reveals for the first time the regulatory mechanism of Maresin1 on neutrophils at the single-cell level. Our study suggested that Maresin1 can significantly reduce neutrophil infiltration in septic lung injury and that this regulatory effect is more concentrated in the Neutrophil-Cxcl3 subpopulation. Maresin1 can significantly reduce the infiltration of the Neutrophil-Cxcl3 subpopulation and inhibit the expression of related inflammatory genes and key transcription factors in the Neutrophil-Cxcl3 subpopulation. Our study provided new possibilities for specific modulation of neutrophil function in septic lung injury.

Abstract Postoperative remote lung injury is a complication following various surgeries and is associated with short and long-term mortality and morbidity. The release of proinflammatory cytokines, damage-associated molecular patterns such as high-mobility group box-1, nucleotide-biding oligomerization domain (NOD)-like receptor protein 3 and heat shock protein, and cell death signalling activation, trigger a systemic inflammatory response, which ultimately results in organ injury including lung injury. Except high financial burden, the outcome of patients developing postoperative remote lung injury is often not optimistic. Several risk factors had been classified to predict the occurrence of postoperative remote lung injury, while lung protective ventilation and other strategies may confer protective effect against it. Understanding the pathophysiology of this process will facilitate the design of novel therapeutic strategies and promote better outcomes of surgical patients. This review discusses the cause and pathology underlying postoperative remote lung injury. Risk factors, surgical outcomes and potential preventative/treatment strategies against postoperative remote lung injury are also addressed.

Ambient carbon monoxide (CO) has been linked with mortality and morbidity. Little evidence is available regarding the relation between CO and years of life lost (YLL). Using data from 48 major cities in China from 2013 to 2017, we applied generalized additive models and random effects meta-analyses to explore the effects of CO on YLL from various diseases. Stratified analyses and meta-regression were performed to estimate potential effect modifications of demographic factors, regions, meteorological factors, co-pollutants, urbanization rate, economic level and health service level. Additional life gains due to avoidable YLL under certain scenario were also evaluated. Results indicated that a 1-mg/m³ increase of CO concentrations (lagged over 0–3 d), was associated with 2.08% (95% confidence interval [CI], 1.35%, 2.80%), 2.35% (95% CI: 1.39%, 3.30%), 1.47% (95% CI: -0.01%, 2.93%), 2.28% (95% CI: 1.09%, 3.47%), 2.42% (95% CI: 1.31%, 3.54%), 2.09% (95% CI: 0.47%, 3.72%) increments in daily YLL from non-accidental causes, cardiovascular diseases, respiratory diseases, coronary heart disease, stroke and chronic obstructive pulmonary disease, respectively. These associations were robust to the adjustment of co-pollutants and varied substantially by geography and demographic characteristics. Associations were stronger in the elder people (≥65 years), females, population with low education attainment, and lived in south region, than younger people, males, high educated populations and those lived in north region. Moreover, the harmful impact of increasing CO concentration could be attenuated by city-level characteristics, including the growth of urbanization rate, gross domestic product (GDP), GDP per capita, number of hospital beds, doctors and hospitals. Finally, an estimated life of 0.081 (95% CI: -0.027, 0.190) years would be gained per deceased people if CO concentration could fall to 1 mg/m3. In conclusions, this nationwide analysis showed significant associations between short-term CO exposure and cause-specific YLL. The heterogeneity of both individual- and city-level characteristics should be considered for relevant intervention. These findings may have significant public health implications for the reduction of CO-attributed disease burden in China.

MicroRNAs are small noncoding RNAs which regulate gene expression at the posttranscriptional level. miR-155 is encoded by the miR-155 host gene (miR155HG), also known as the noncoding B cell integration cluster (BIC). MicroRNAs are widely expressed in various hematopoietic cells and are involved in regulating the immune system. In this review, we summarized how miR-155 modulates specific immune cells and the regulatory role of miR-155 in sepsis. miR-155 is expressed by different populations of innate and adaptive immune cells and is involved in the regulation of development, proliferation, and function in these cells. Sepsis is associated with uncontrollable inflammatory responses, accompanied by unacceptably high mortality. Due to the inadequacy of diagnostic markers as well as treatment strategies, treating sepsis can be a huge challenge. So far, a large number of experiments have shown that the expression of miR-155 is increased at an early stage of sepsis and that this increase is positively correlated with disease progression and severity. In addition, by blocking the proinflammatory effects of miR-155, it can effectively improve sepsis-related organ injury, providing novel insights to identify potential biomarkers and therapeutic targets for sepsis. However, since most of the current research is limited to animal experiments, further clinical research is required to determine the function of miR-155 and its mechanism related to sepsis.

Endoplasmic reticulum (ER) stress is an evolutionarily conserved adaptive response that contributes to deal with the misfolded or unfolded protein in the lumen of the ER and restore the ER homeostasis. However, excessive and prolonged ER stress can trigger the cell-death signaling pathway which causes cell death, usually in the form of apoptosis. It is generally accepted that inappropriate cellular apoptosis and a series of the subsequent inflammatory response and oxidative stress can cause disturbance of normal physiological functions and organ damage. A lot of evidence shows that the excessive activation of the ER stress contributes to the pathogenesis of many kinds of diseases and inhibiting the inappropriate stress is of great significance for maintaining the normal physiological function. In recent years, Sirtuin1 (SIRT1) has become a research hotspot on ER stress. As a master regulator of ER stress, increasing evidence suggests that SIRT1 plays a positive role in a variety of ER stress-induced organ damage via multiple mechanisms, including inhibiting cellular apoptosis and promoting autophagy. Furthermore, a lot of factors have shown effective regulation of SIRT1, which indicates the feasibility of treating SIRT1 as a target for the treatment of ER stress-related diseases. We summarize and reveal the molecular mechanisms underlying the protective effect of SIRT1 in multiple ER stress-mediated organ damage in this review. We also summed up the possible adjustment mechanism of SIRT1, which provides a theoretical basis for the treatment of ER stress-related diseases.

Background: Emergence agitation is a reformed state of mindfulness, which starts with a sudden form of anesthesia and progresses through the early repossession age. Thus, the purpose of this study is to evaluate 1:3 ketofol performance on children 3–15 years old undergoing adenotonsillectomy.Methods: A total of 60 children aged 3–15 years undergoing adenotonsillectomy were randomly allocated to receive low-dose ketamine 0.15 mg/kg followed by propofol 0.45 mg/kg i.v. ketofol (1:3) about 10 min before the end of surgery in comparison to 60 children aged 3–15 years who received only normal saline and dextrose. Anesthesia was induced and maintained with sevoflurane. Postoperative pain and EA were assessed with objective pain score (OPS) and the Pediatric Anesthesia Emergence Delirium (PAED) scale, respectively. EA was defined as a PAED 10 points. Recovery profile and postoperative complications were also recorded.Results: The incidence and severity of EA were found significantly lower in the ketofol group in comparison to the control group with a percentage of (13.33% vs 48.33%) (8% vs 15%) respectively (P < 0.05). Also, the time for interaction from anesthetic tainted to extubating in the ketofol set was significantly less than in the control group (P < 0.05). Interestingly, there are no opposing events such as nausea, laryngospasm, bronchospasm, hypotension, bradycardia, bleeding, or postoperative respiratory depression (respiratory rate: 0.05). Moreover, the heart rate was meaningfully higher in the control group starting at the time of tracheal extubating in comparison to the children undergone ketofol (P < 0.05). Alert score and time from painkilling tainted till liberation from PACU showed substantial significant changes at ketofol set (P < 0.05).Conclusion: Ketofol (1:3) shows significant performance to reduce postoperative agitation in the children undergone adenotonsillectomy.

Acute kidney injury (AKI) is one of the most common and serious complications of sepsis in which the inflammatory cascade plays a crucial role. There is now increasing evidence that lipid mediators derived from the omega-3 fatty acid docosahexaenoic acid (DHA) have potent anti-inflammatory effects that promote the timely regression of acute inflammation. In this study, we investigated the protective effects and molecular mechanism of a novel DHA-derived lipid mediator Maresin 1 (MaR1) on AKI in septic mice. The cecal ligation and puncture (CLP) was used to establish a sepsis mice model. As a result, we found that MaR1 significantly increased the 7-day survival rate of septic mice and the anti-inflammatory factor IL-10 while reducing bacterial load and pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β). In addition, MaR1 dose dependently reduced renal injury scores and serum creatinine and urea nitrogen levels in septic mice while inhibiting renal neutrophil infiltration and myeloperoxidase (MPO) activity. In terms of signaling pathway, we found that MaR1 inhibits the expression of phosphorylated p65, Stat3, JNK, ERK, and p38 and significantly reduces nuclear translocation of p65. In conclusion, our results indicate that MaR1 is able to reduce neutrophil infiltration and inhibit nuclear factor-kappa B/signal transducer and activator of transcriptor 3/mitogen-activated protein kinase (NF-κB/STAT3/MAPK) activity and regulate inflammatory cytokine level to inhibit inflammatory response and thereby weaken sepsis-associated AKI in mice.

Background: This study aimed to evaluate the protective effect and mechanisms of remote limb ischaemic postconditioning (RIPostC) against myocardial ischaemia/reperfusion (IR) injury. Methods: Male mice underwent 45 min of coronary artery occlusion followed by 2 h of reperfusion. RIPostC was achieved by three cycles of 5 min of ischaemia and 5 min of reperfusion in the left hind limb at the start of the reperfusion period. After 2 h of cardiac reperfusion, myocardial infarct size, cardiac enzyme release, apoptosis and oxidative stress were assessed. Protein expression and phosphorylation were measured by Western blotting. Results: RIPostC significantly decreased cardiac IR injury, as reflected by reduced infarct size and cellular apoptosis (22.9 ± 3.3% vs 40.9 ± 6.2% and 13.4% ± 3.1% vs 26.2% ± 3.1%, respectively, both P < 0.01) as well as plasma creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) release (21.97 ± 4.08 vs 35.86 ± 2.91 ng/ml and 6.17 ± 0.58 vs 8.37 ± 0.89 U/ml, respectively, both P < 0.01) compared with the IR group. RIPostC significantly increased the phosphorylation of myocardial STAT3, Akt and eNOS (P < 0.01). In addition, RIPostC elevated the nuclear translocation of Nrf2 and the expression of HO-1 and reduced myocardial oxidative stress (P < 0.05). Interestingly, pretreatment with the JAK/STAT3 inhibitor AG490 blocked the cardioprotective effect of RIPostC accompanied by decreased phosphorylation of myocardial STAT3, Akt and eNOS (P < 0.05), decreased nuclear translocation of Nrf2 and expression of HO-1, as well as increased oxidative stress (P < 0.05). Conclusion: RIPostC attenuates apoptosis and protects against myocardial IR injury, possibly through the activation of JAK/STAT3-mediated Nrf2-antioxidant signalling.

Abstract Significant individual susceptibility to intravenous anesthetic propofol exists. The etiology of individual variability in the response to propofol may be influenced by genetic polymorphisms in metabolic and functional pathways. With current pharmacogenetics and modern molecular biology technologies, it is possible to study the influence of genetic polymorphisms on susceptibility to propofol. When inducing general anesthesia with intravenous propofol, high individual susceptibility to propofol was found. Using Sequenom MassARRAY single-nucleotide polymorphism (SNP) genotyping, we identified a mutation (rs6313) in the 5HT2A gene that was correlated to individual susceptibility to propofol effect-site concentration (Cep) and onset time of propofol induction. Carriers of the minor allele (G) of 5HT2A rs6313 required less propofol (20% decrease in Cep) and less time (40% decrease in onset time) to induce anesthesia. Moreover, associations were found between the gamma-aminobutyric acid (GABA) receptor SNP rs2279020 and the SCN9A SNP rs6746030 and the susceptibility of bispectral index (BIS) after propofol-induced anesthesia. In addition, dominant mutations in GABAA1 rs2279020, GABAA2 rs11503014, and CHRM2 rs1824024 were putatively associated with cardiovascular susceptibility to propofol anesthesia. No gene-gene interactions were found through a standardized measure of linkage disequilibrium and a multifactor dimensionality reduction analysis. Our results suggest that genetic polymorphisms related to mechanisms of propofol anesthesia are involved in propofol susceptibility.

Abstract Recently, a serial of studies have demonstrated that lipid mediators derived from Omega-3 fatty acid docosahexaenoic acid have pro-resolving or anti-inflammatory effects in many inflammatory diseases. Here, we sought to evaluate whether Protectin DX (PDX, an isomer of Protecin D1), a newly identified lipid mediator, could protect mice against sepsis and explore the underling mechanism. Animal model of sepsis was established by cecum ligation and puncture (CLP). We found that PDX increased overall survival rate within eight days and attenuated multiple organ injury in septic mice. In addition, PDX reduced pro-inflammatory cytokines and bacterial load 24 h after CLP. Moreover, PDX promoted phagocytosis of peritoneal macrophages and increased the percentage of M2 macrophages in peritoneum of septic mice. In vitro, M2 macrophage markers (Arg1 and Ym1) and its transcriptional regulator (peroxisome proliferator-activated receptor-γ, PPAR-γ) were upregulated in Raw264.7 macrophages challenged with PDX. GW9662 (a PPAR-γ inhibitor) and PPAR-γ siRNA abrogated the induction of Arg1 and Ym1 by PDX in Raw264.7 cells. Taken together, our results suggest that PDX is able to promote M2 polarization, enhance phagocytosis activity of macrophage and accelerate resolution of inflammation, finally leading to increased survival rate of septic mice.

Neuroinflammation has been identified as a causative factor of multiple neurological diseases. The nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome, a subcellular multiprotein complex that is abundantly expressed in the central nervous system (CNS), can sense and be activated by a wide range of exogenous and endogenous stimuli such as microbes, aggregated and misfolded proteins, and adenosine triphosphate, which results in activation of caspase-1. Activated caspase-1 subsequently leads to the processing of interleukin-1β (IL-1β) and interleukin-18 (IL-18) pro-inflammatory cytokines and mediates rapid cell death. IL-1β and IL-18 drive inflammatory responses through diverse downstream signaling pathways, leading to neuronal damage. Thus, the NLRP3 inflammasome is considered a key contributor to the development of neuroinflammation. In this review article, we briefly discuss the structure and activation the NLRP3 inflammasome and address the involvement of the NLRP3 inflammasome in several neurological disorders, such as brain infection, acute brain injury and neurodegenerative diseases. In addition, we review a series of promising therapeutic approaches that target the NLRP3 inflammasome signaling including anti-IL-1 therapy, small molecule NLRP3 inhibitors and other compounds, however, these approaches are still experimental in neurological diseases. At present, it is plausible to generate cell-specific conditional NLRP3 knockout (KO) mice via the Cre system to investigate the role of the NLRP3 inflammasome, which may be instrumental in the development of novel pharmacologic investigations for neuroinflammation-associated diseases.

The CONCERT-CL closed-loop infusion system designed by VERYARK Technology Co., Ltd. (Guangxi, China) is an innovation using TCI combined with closed-loop controlled intravenous anesthesia under the guide of BIS. In this study we performed a randomized, controlled, multicenter study to compare closed-loop control and open-loop control of propofol by using the CONCERT-CL closed-loop infusion system.180 surgical patients from three medical centers undergone TCI intravenous anesthesia with propofol and remifentanil were randomly assigned to propofol closed-loop group and propofol opened-loop groups. Primary outcome was global score (GS, GS = (MDAPE+Wobble)/% of time of bispectral index (BIS) 40-60). Secondary outcomes were doses of the anesthetics and emergence time from anesthesia, such as, time to tracheal extubation.There were 89 and 86 patients in the closed-loop and opened-loop groups, respectively. GS in the closed-loop groups (22.21±8.50) were lower than that in the opened-loop group (27.19±15.26) (p=0.009). The higher proportion of time of BIS between 40 and 60 was also observed in the closed-loop group (84.11±9.50%), while that was 79.92±13.17% in the opened-loop group, (p=0.016). No significant differences in propofol dose and time of tracheal extubation were observed. The frequency of propofol regulation in the closed-loop group (31.55±9.46 times/hr) was obverse higher than that in the opened-loop group (6.84±6.21 times/hr) (p=0.000).The CONCERT-CL closed-loop infusion system can automatically regulate the TCI of propofol, maintain the BIS value in an adequate range and reduce the workload of anesthesiologists better than open-loop system.ChiCTR ChiCTR-OOR-14005551.

Background: Early recognition of the risk of acute respiratory distress syndrome (ARDS) after cardiopulmonary bypass (CPB) may improve clinical outcomes. The main objective of this study was to identify proteomic biomarkers and develop an early prediction model for CPB-ARDS. Methods: The authors conducted three prospective nested cohort studies of all consecutive patients undergoing cardiac surgery with CPB at Union Hospital of Tongji Medical College Hospital. Plasma proteomic profiling was performed in ARDS patients and matched controls (Cohort 1, April 2021-July 2021) at multiple timepoints: before CPB (T1), at the end of CPB (T2), and 24 h after CPB (T3). Then, for Cohort 2 (August 2021-July 2022), biomarker expression was measured and verified in the plasma. Furthermore, lung ischemia/reperfusion injury (LIRI) models and sham-operation were established in 50 rats to explore the tissue-level expression of biomarkers identified in the aforementioned clinical cohort. Subsequently, a machine learning-based prediction model incorporating protein and clinical predictors from Cohort 2 for CPB-ARDS was developed and internally validated. Model performance was externally validated on Cohort 3 (January 2023-March 2023). Results: A total of 709 proteins were identified, with 9, 29, and 35 altered proteins between ARDS cases and controls at T1, T2, and T3, respectively, in Cohort 1. Following quantitative verification of several predictive proteins in Cohort 2, higher levels of thioredoxin domain containing 5 (TXNDC5), cathepsin L (CTSL), and NPC intracellular cholesterol transporter 2 (NPC2) at T2 were observed in CPB-ARDS patients. A dynamic online predictive nomogram was developed based on three proteins (TXNDC5, CTSL, and NPC2) and two clinical risk factors (CPB time and massive blood transfusion), with excellent performance (precision: 83.33%, sensitivity: 93.33%, specificity: 61.16%, and F1 score: 85.05%). The mean area under the receiver operating characteristics curve (AUC) of the model after 10-fold cross-validation was 0.839 (95% CI: 0.824-0.855). Model discrimination and calibration were maintained during external validation dataset testing, with an AUC of 0.820 (95% CI: 0.685-0.955) and a Brier Score of 0.177 (95% CI: 0.147-0.206). Moreover, the considerably overexpressed TXNDC5 and CTSL proteins identified in the plasma of patients with CPB-ARDS, exhibited a significant upregulation in the lung tissue of LIRI rats. Conclusions: This study identified several novel predictive biomarkers, developed and validated a practical prediction tool using biomarker and clinical factor combinations for individual prediction of CPB-ARDS risk. Assessing the plasma TXNDC5, CTSL, and NPC2 levels might identify patients who warrant closer follow-up and intensified therapy for ARDS prevention following major surgery. [ABSTRACT FROM AUTHOR]