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Myocardial ischemia/reperfusion (I/R) injury is still a lack of effective therapeutic drugs, and its molecular mechanism is urgently needed. Studies have shown that the intestinal flora plays an important regulatory role in cardiovascular injury, but the specific mechanism has not been fully elucidated. In this study, we found that an increase in Ang II in plasma was accompanied by an increase in the levels of myocardial injury during myocardial reperfusion in patients with cardiopulmonary bypass. Furthermore, Ang II treatment enhanced mice myocardial I/R injury, which was reversed by caveolin-1 (CAV-1)-shRNA or strengthened by angiotensin-converting enzyme 2 (ACE2)-shRNA. The results showed that CAV-1 and ACE2 have protein interactions and inhibit each other's expression. In addition, propionate, a bacterial metabolite, inhibited the elevation of Ang II and myocardial injury, while GPR41-shRNA abolished the protective effects of propionate on myocardial I/R injury. Clinically, the propionate content in the patient's preoperative stool was related to Ang II levels and myocardial I/R injury levels during myocardial reperfusion. Taken together, propionate alleviates myocardial I/R injury aggravated by Ang II dependent on CAV-1/ACE2 axis through GPR41, which provides a new direction that diet to regulate the intestinal flora for treatment of myocardial I/R injury.

Intestinal ischemia/reperfusion (I/R) injury is a severe clinical condition lacking diagnostic markers and has poorly understood molecular mechanisms. Although plasma exosomal circular RNAs (circRNAs) are valuable biomarkers and therapeutic targets for various diseases, their role in intestinal I/R injury remains unknown. This study screens the expression profile of circRNAs in intestinal tissue exosomes collected from intestinal I/R mice and identified circEZH2_005 as a significantly downregulated exosomal circRNA in the plasma of clinical cardiac surgery patients who developed postoperative intestinal I/R injury. The expression of plasma exosomal circEZH2_005 was negatively correlated with the intestinal injury grade. Notably, exosomal circEZH2_005 displayed a significant diagnostic value for intestinal injury induced by I/R. Mechanistically, circEZH2_005 was highly expressed in intestinal crypt cells. CircEZH2_005 upregulation significantly promoted the proliferation of Lgr5+ stem cells by direct interaction with hnRNPA1 and enhanced Gprc5a stability, thereby alleviating I/R-induced intestinal mucosal damage. Hence, exosomal circEZH2_005 may help intestinal I/R injury diagnosis and treatment.

Myocardial injury is a major complication of sepsis and a key factor affecting prognosis. Therefore, early and accurate diagnosis and timely management of sepsis-induced cardiomyopathy (SICM) are of great significance for the prevention and treatment of sepsis. The gut microbiota has been shown to be closely associated with sepsis or myocardial injury, but the association between the gut microbiota and SICM is not fully understood. This study aimed to explore the link between gut microbiota composition and SICM.A case-control and single-center study of clinical features and gut microbiota profiles by Metagenome and Virome was conducted in SICM patients (n = 15) and sepsis-uninduced cardiomyopathy patients (SNICM, n = 16).Compared with SNICM patients, SICM patients showed significant myocardial injury and higher 28-day mortality, SOFA scores, lactate levels, and infection levels on admission. Meanwhile, differences in the composition of gut bacteria, archaea, fungi, and viruses were analyzed between the two groups. Differential gut bacteria or viruses were found to have a good predictive effect on SICM. Furthermore, gut bacteria and viruses that differed between the two groups were strongly related. The abundance of Cronobacter and Cronobacter phage was higher in the SICM group than in the SNICM group, and the receiver operating characteristic curve showed that Cronobacter and Cronobacter phage both had a good predictive effect on SICM.SICM patients may have specific gut microbiota signatures, and Cronobacter and Cronobacter phages have a good ability to identify and diagnose SICM.

Background Evidence suggests a potential relationship between gut microbiota and chronic postoperative pain (CPP). This study aimed to explore the predictive and preventive potential of preoperative gut microbiota in CPP in breast cancer survivors. Methods In the clinical experiments, we designed a nested case-control study to compared preoperative gut microbiota of breast cancer survivors with and without CPP using 16s rRNA sequencing. The primary outcome was clinically meaningful pain in or around the operative area 3 months after surgery. Logistic prediction models based on previously identified risk factors for CPP in breast cancer survivors were tested with and without differential bacteria to evaluate the model's potential for improvement with the addition of gut microbiota information. In the animal experiments, preoperative fecal microbiota was transplanted from patients with and without CPP to mice, and a spared nerve injury (SNI) model was used to mimic neuropathic pain in CPP. Mechanical hyperalgesia and the expression of markers of spinal microglia and peroxisome proliferator-activated receptor-γ (PPAR-γ) were assessed. Results Sixty-six CPP patients and 66 matched controls were analyzed. Preoperative gut microbiota composition was significantly different in the 2 groups at phylus, family, and genera levels. The discrimination of the clinical prediction model (determined by area under the receiver operating characteristic curve) improved by 0.039 and 0.099 after the involvement of differential gut microbiota at the family and genus levels, respectively. After fecal microbiota transplantation (FMT), "CPP microbiota" recipient mice exhibited significantly increased mechanical hyperalgesia and decreased expression of Ppar-γ and arginase-1 (Arg-1) in the spinal cord. Conclusions Preoperative gut microbiota has the potential to predict and prevent the development of CPP and plays a causal role in its development via the PPAR-γ-microglia pathway in the spinal cord. Thus, it could be targeted to develop a prevention strategy for CPP in breast cancer survivors.

Neuropathic pain is a chronic condition with little specific treatment. Insulin-like growth factor 1 (IGF1), interacting with its receptor, IGF1R, serves a vital role in neuronal and brain functions such as autophagy and neuroinflammation. Yet, the function of spinal IGF1/IGF1R in neuropathic pain is unclear. Here, we examined whether and how spinal IGF1 signaling affects pain-like behaviors in mice with chronic constriction injury (CCI) of the sciatic nerve. To corroborate the role of IGF1, we injected intrathecally IGF1R inhibitor (nvp-aew541) or anti-IGF1 neutralizing antibodies. We found that IGF1 (derived from astrocytes) in the lumbar cord increased along with the neuropathic pain induced by CCI. IGF1R was predominantly expressed on neurons. IGF1R antagonism or IGF1 neutralization attenuated pain behaviors induced by CCI, relieved mTOR-related suppression of autophagy, and mitigated neuroinflammation in the spinal cord. These findings reveal that the abnormal IGF1/IGF1R signaling contributes to neuropathic pain by exacerbating autophagy dysfunction and neuroinflammation.

Intestinal ischemia/reperfusion is a grave condition with high morbidity and mortality in perioperative and critical care settings and causes multiple organ injuries beyond the intestine, including brain injury. Exosomes act as intercellular communication carriers by the transmission of their cargo to recipient cells. Here, we investigate whether exosomes derived from the intestine contribute to brain injury after intestinal ischemia/reperfusion via interacting with microglia in the brain. Intestinal ischemia/reperfusion was established in male C57/BL mice by clamping the superior mesenteric artery for 30 min followed by reperfusion. The sham surgery including laparotomy and isolation of the superior mesenteric artery without occlusion was performed as control. Male C57 mouse was intracerebral ventricular injected with intestinal exosomes from mice of intestinal ischemia/reperfusion or sham surgery. Primary microglia were cocultured with intestinal exosomes; HT-22 cells were treated with intestinal exosomes or microglia conditioned media. Intestinal ischemia/reperfusion-induced microglial activation, neuronal loss, synaptic stability decline, and cognitive deficit. Intracerebral ventricular injection of intestinal exosomes from intestinal ischemia/reperfusion mice causes microglial activation, neuronal loss, synaptic stability decline, and cognitive impairment. Microglia can incorporate intestinal exosomes both in vivo and in vitro. Microglia activated by intestinal exosomes increases neuron apoptotic rate and decreases synaptic stability. This study indicates that intestinal exosomes mediate memory impairment after intestinal ischemia/reperfusion via activating microglia. Inhibiting exosome secretion or suppressing microglial activation can be a therapeutic target to prevent memorial impairment after intestinal ischemia/reperfusion.

Emerging evidence has suggested that miRNAs are important regulators of intestinal I/R injury, but their function in this context remains elusive. To evaluate the role of miR-26b-5p in intestinal I/R injury. We utilized in vivo murine models of intestinal I/R and in vitro Mode-K cell-based models of oxygen and glucose deprivation/reperfusion (OGD/R) to examine the function of miR-26b-5p in intestinal I/R injury. The expression of miR-26b-5p in intestinal mucosa and Mode-K cell was detected by RT-PCR. HE staining and Chiu’s score were used to evaluate intestinal mucosa injury severity. Apoptosis was detected by TUNEL stain, flow cytometry, and western blot. TargetScan and StarBase prediction algorithms were applied to predict putative target genes of miR-26b-5p and validated by luciferase reporter analyses. We found that the expression of miR-26b-5p in intestinal mucosa was markedly decreased during I/R injury. We additionally found miR-26b-5p overexpression to markedly disrupt intestinal I/R- or OGD/R-induced injury in vivo and in vitro, whereas inhibiting this miRNA had an adverse impact and resulted in increased intestinal tissue injury and Mode-K cell damage. From a mechanistic perspective, miR-26b-5p was predicted to target DAPK1, which was related to cellular apoptosis. Luciferase reporter assay results confirmed that miR-26b-5p directly targets DAPK1 in Mode-K cells, thereby suppressing OGD/R-induced cell apoptosis. Our findings show that miR-26b-5p may prevent intestinal I/R injury via targeting DAPK1 and inhibiting intestinal mucosal cell apoptosis, suggesting that this miRNA may be a viable target for the treatment of intestinal I/R injury.

Epithelial regeneration is essential for homeostasis and mucosal barrier repair. In this study, we aimed to define the effect of IL-10 on mucosal healing. Intestinal stem cells (ISCs) cultures and mice were treated with recombinant mice IL-10 (rmIL-10). The level of cell proliferation, differentiation, death and related signaling pathways for self-renewal of ISCs were measured in vitro and in vivo. It was uncovered that rmIL-10 increased the size and death, but reduced the total number of organoids. In addition, rmIL-10 depleted Lgr5+ ISCs and reduced epithelial proliferation, but enhanced the differentiation of epithelial cells and expanded numbers of transit-amplifying (TA) cells. These changes are related to the decrease of Wnt and Notch signals in vivo and in vitro. Meanwhile, increased expression of Paneth cells and decreased expression of enteroendocrine cells and goblet cells were induced by rmIL-10. Thus, our data indicate that IL-10 reduces the survival of Lgr5+ ISCs and proliferation of epithelial cells by inhibiting Notch and Wnt signaling, but promotes enhanced the differentiation of epithelial cells and expanded numbers of TA cells. Therefore, IL-10 acts as an anti-inflammatory factor, but may damage intestinal mucosa repair and maybe a potential target for the treatment of intestinal injury.

Purpose Our study was designed to examine the possible relationship between gut microbiota, sleep disturbances, and acute postoperative pain. Methods Using 16S rRNA sequencing, we analyzed preoperative fecal samples from women undergoing breast cancer surgery. Preoperative sleep disturbance was evaluated with the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Peak and average pain at rest and movement were evaluated 24 h after surgery, using a numerical rating scale (NRS). Preoperative symptoms of depression and anxiety were assessed with the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7), respectively. Inflammation was measured using white blood cell and neutrophil counts, together with platelet-lymphocyte ratio, and neutrophil-lymphocyte ratio. Results Preoperative sleep disturbance was associated with more severe acute postoperative pain. At the phylum level, women with poor sleep quality had higher relative abundance of Firmicutes (p = 0.021) and lower relative abundance of Bacteroidetes (p = 0.013). At the genus level, women with poor sleep quality harbored higher relative abundance of Acidaminococcus and lower relative abundance of several genera. The genus Alloprevotella was negatively associated with peak pain at movement during the first 24 h (r = − 0.592, p < 0.001). The genus Desulfovibrio was negatively associated with symptoms of anxiety (r = − 0.448, p = 0.006). However, partial correlations suggested that the relationship between Alloprevotella and peak pain at movement during the first 24 h was not statistically significant after controlling for sleep (r = − 0.134, p = 0.443). Conclusion These findings suggest that the changed gut microbiota may be involved in sleep-pain interaction and could be applied as a potential preventive method for postoperative pain. Trial registration The present clinical study has been registered on Chinese Clinical Trial Registry (www.chictr.org.cn); the clinical trial registration number is ChiCTR1900021730; the date of registration is March 7, 2019.

Liver injury induced by intestinal ischemia/reperfusion (I/R) is accompanied by the polarization of Kupffer cells, which are specialized macrophages located in the liver. However, the causes of hepatic macrophage polarization after intestinal I/R remain unknown. This study investigated whether gut-derived exosomes contribute to the pathogenesis of liver injury triggered by intestinal I/R in a murine model and explored the underlying mechanisms. Intestinal I/R models were established by temporally clamping the superior mesenteric arteries of mice. Exosomes were isolated from the intestinal tissue of mice that underwent intestinal I/R or sham surgery according to a centrifugation-based protocol. Exosomes were co-cultured with RAW 264.7 macrophages or injected intravenously in mice. Liposomal clodronate was administered intraperitoneally to deplete the macrophages. Macrophage polarization was determined by flow cytometry, immunohistochemistry, and quantitative polymerase chain reaction. Liver injury was assessed by histological morphology and increased serum aspartate aminotransferase and alanine aminotransferase levels. Exosomes from mice intestines subjected to I/R (IR-Exo) promoted macrophage activation in vitro. Intravenous injection of IR-Exo caused hepatic M1 macrophage polarization and led to liver injury in mice. Depleting macrophages ameliorated liver injury caused by intestinal I/R or the injection of IR-Exo. Furthermore, inhibiting exosome release improved intestinal injury, liver function, and survival rates of mice subjected to intestinal I/R. Our study provides evidence that gut-derived exosomes induce liver injury after intestinal I/R by promoting hepatic M1 macrophage polarization. Inhibition of exosome secretion could be a therapeutic target for preventing hepatic impairment after intestinal I/R.

Intestinal ischemia/reperfusion (I/R) is a common pathophysiological process in clinical severe patients, and the effect of intestinal I/R injury on the patient's systemic pathophysiological state is far greater than that of primary intestinal injury. In recent years, more and more evidence has shown that intestinal microbiota and its metabolites play an important role in the occurrence, development, diagnosis and treatment of intestinal I/R injury. Intestinal microbiota is regulated by host genes, immune response, diet, drugs and other factors. The metabolism and immune potential of intestinal microbiota determine its important significance in host health and diseases. Therefore, targeting the intestinal microbiota and its metabolites may be an effective therapy for the treatment of intestinal I/R injury and intestinal I/R-induced extraintestinal organ injury. This review focuses on the role of intestinal microbiota and its metabolites in intestinal I/R injury and intestinal I/R-induced extraintestinal organ injury, and summarizes the latest progress in regulating intestinal microbiota to treat intestinal I/R injury and intestinal I/R-induced extraintestinal organ injury.

BackgroundRecently, an increasing number of studies have reported the roles of competitive endogenous RNA (ceRNA) networks in ischemia/reperfusion (I/R) injury, which include the liver, kidney, heart, brain, and intestine. However, the functions and mechanisms of long non-coding RNAs (lncRNAs), which serve as ceRNA networks in intestinal I/R injury, are still unclear. MethodsIn this study, bioinformatics methods were used to filter and construct the lncRNA-miRNA-mRNA networks in intestinal I/R injury. RNA expression data were retrieved from NCBI GEO datasets, the expression profiles between mouse small intestine with superior mesenteric artery occlusion and Sham operation was analyzed, and 189 microRNA differential expressed genes(miDEGs) were discovered successfully from miRNA GEO dataset (GSE83701). Next, targeted lncRNAs and mRNA in the database were matched based on miDEGs. Then, lncRNA-miRNA-mRNA networks were constructed with Cytoscape. The hub lncRNA-miRNA-mRNA networks were selected via Cytoscape plug-in CytoHubba and intersected mRNAs of datasets GSE96733 and GSE83701. Finally, the vital nodes of the ceRNA networks were validated by qPCR. ResultsThe 1700020114Rik/mmu-miR-7a-5p/Klf4 axis was postulated to play a potential role in intestinal I/R injury.ConclusionThe results shed novel insight into the molecular mechanism of ceRNA networks in intestinal I/R injury and highlighted the potential of 170002700020114Rik/mmu-miR-7a-5p/Klf4 ceRNA network in the prevention and treatment of intestinal I/R injury.

Intestinal ischemia/reperfusion (I/R) injury is a grave condition with high morbidity and mortality. We previously confirmed that intestinal I/R induces intestinal flora disorders and changes in metabolites, but the role of different metabolites in intestinal I/R injury is currently unclear. Based on targeted metabolic sequencing, pravastatin (PA) was determined to be a metabolite of the gut microbiota. Further, intestinal I/R model mice were established through superior mesenteric artery obstruction. In addition, a co-culture model of small intestinal organoids and type II innate lymphoid cells (ILC2s) was subjected to hypoxia/reoxygenation (H/R) to simulate an intestinal I/R model. Moreover, correlation analysis between the PA level in preoperative feces of patients undergoing cardiopulmonary bypass and the indices of postoperative intestinal I/R injury was carried out. IL-33-deficient mice, ILC2-deleted mice, and anti-IL-13 neutralizing antibodies were also used to explore the potential mechanism through which PA attenuates intestinal I/R injury. We demonstrated that PA levels in the preoperative stool of patients undergoing cardiopulmonary bypass were negatively correlated with the indices of postoperative intestinal I/R injury. Furthermore, PA alleviated intestinal I/R injury and improved the survival of mice. We further showed that PA promotes IL-13 release from ILC2s by activating IL-33/ST2 signaling to attenuate intestinal I/R injury. In addition, IL-13 promoted the self-renewal of intestinal stem cells by activating Notch1 and Wnt signals. Overall, results indicated that the gut microbial metabolite PA can attenuate intestinal I/R injury by promoting the release of IL-13 from ILC2s via IL-33/ST2 signaling, revealing a novel mechanism of and therapeutic strategy for intestinal I/R injury.

Background Patients undergoing major non-cardiac surgery are at risk of cardiovascular complications. Raised levels of high-sensitivity troponin are frequently detected before operation among these patients. However, the prognostic value of high-sensitivity troponin in predicting postoperative outcomes remains unclear. Methods A systematic search of PubMed, Embase and Science Citation Index Expanded was undertaken for observational studies published before March 2018 that reported associations between raised preoperative levels of high-sensitivity troponin and postoperative major adverse cardiac events and/or mortality after non-cardiac surgery. Meta-analyses were performed, where possible, using random-effects models. Results Seven cohort studies with a total of 4836 patients were included. A raised preoperative high-sensitivity troponin level was associated with a higher risk of short-term major adverse cardiac events (risk ratio (RR) 2·92, 95 per cent c.i. 1·96 to 4·37; I2 = 82·6 per cent), short-term mortality (RR 5·39, 3·21 to 9·06; I2 = 0 per cent) and long-term mortality (RR 2·90, 1·83 to 4·59, I2 = 74·2 per cent). The addition of preoperative high-sensitivity troponin measurement provided improvements in cardiovascular risk discrimination (increase in C-index ranged from 0·058 to 0·109) and classification (quantified by continuous net reclassification improvement) compared with Lee's Revised Cardiac Risk Index alone. There was substantial heterogeneity and inadequate risk stratification analysis in the included studies. Conclusion Raised preoperative levels of high-sensitivity troponin appear to represent a risk for postoperative major adverse cardiac events and mortality. Further study is required before high-sensitivity troponin can be used to predict risk stratification in routine clinical practice.

Fluid resuscitation is the first-line antishock treatment in severe acute pancreatitis (SAP). Currently, although mentions of complications related to aggressive fluid resuscitation are very frequent, a lack of proper handling of complications remains. One of the most important complications is intestinal barrier injury, including intestinal ischemia-reperfusion injury following aggressive fluid resuscitation. Once injured, the intestinal barrier may serve as the source of additional diseases, including systemic inflammatory response syndrome and multiple organ dysfunction syndrome, which aggravate SAP. This study focused on the underlying mechanisms of gut barrier dysfunction in rats induced by aggressive fluid resuscitation in SAP. This study further indicated the important role of necroptosis in intestinal barrier injury which could be relieved by using necroptosis-specific inhibitor Nec-1 before aggressive fluid resuscitation, thus reducing intestinal barrier damage. We also found pancreas damage after intestinal ischemia/reperfusion challenge and indicated the effects of high mobility group protein B1 in the vicious cycle between SAP and intestinal barrier damage.

Intestinal ischemia/reperfusion (I/R) injury is a serious clinical event that may induce intestinal mucosal injury, whose major underlying mechanisms include reactive oxygen species (ROS) generation, release of inflammatory mediators and induction of apoptosis. Irisin is considered an agent with potent protection against many pathological injures. The aim of this study was to investigate the protective effect of irisin pretreatment on intestinal injury and explore its underlying mechanisms in a mouse model of intestinal I/R injury as well as a cell model (IEC-6 cell) of hypoxia/reoxygenation (H/R). The results showed that irisin pretreatment ameliorated I/R and H/R-induced injury in vivo and in vitro. In addition, irisin reduced the levels of tumor necrosis factor (TNF)-α, interleukin(IL)-1β and interleukin(IL)-6 in the intestine. Compared with the I/R group, irisin pretreatment effectively reduced malondialdehyde (MDA) and myeloperoxidase (MPO) levels, but increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the intestine, and significantly reduced oxidative stress. Furthermore, irisin pretreatment downregulated Bax and cleaved Caspase-3 at the protein level, and increased Bcl-2 protein amounts, significantly reducing apoptosis in the intestine of I/R mice. Moreover, both in vivo and in vitro results showed that irisin pretreatment significantly upregulated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein. Meanwhile, Nrf2 siRNA treatment partially abrogated the protective effects of irisin pretreatment on H/R induced cellular damage, inflammatory response, oxidative stress, and apoptosis in IEC-6 cells. These findings suggest that irisin pretreatment improves I/R-induced intestinal inflammatory response, reduces oxidative stress and inhibits apoptosis, which could be, at least partially, associated with Nrf2 pathway activation.

Limb ischemia/reperfusion (LI/R) injury is associated with high morbidity and mortality. The hypothesis of this study is that hydrogen-rich solution could attenuateacute lung injury and improve mortality via chemerin and NLRP3 after LI/R in rats. A rat model of LI/R was performed by clamping the bilateral femoral arteries for 3 h followed by reperfusion. Hydrogen-rich saline (HRS) was administered intraperitoneally (10 mL/kg or 2.5 mL/kg) when the atraumatic micro clips were released. The rats were euthanized at 2 h after reperfusion and then the arterial blood and lung specimens were harvested for further analyses. Meanwhile, survival rate was observed. The results showed that HRS improved the survival rate and attenuated pulmonary edema, injury, and apoptosis. HRS also decreased the levels of tumor necrosis factor-α, interleukin-6, myeloperoxidase and malondialdehyde, and increased the activity of superoxide dismutase in serum and lung after the LI/R event. HRS downregulated the expression of chemerin and NLRP3 in lung. The study demonstrated that chemerin and NLRP3 could serve as important response factors that were involved in the lung injury following LI/R. HRS could significantly attenuate LI/R-mediated acute lung injury, at least in part, by inhibiting the activated chemerin/NLRP3 signaling pathway.

Intestinal ischemia-reperfusion (I/R) injury is a serious condition with unacceptable mortality rates. Our previous study revealed a protective effect of dexmedetomidine (DEX) on intestinal I/R injury, but its underlying mechanism remains unclear. Gut microbiota imbalance is associated with the progression of I/R injury. We hypothesized that DEX would attenuate intestinal I/R injury via modulating gut microbiota.An I/R injury model was established in C57BL/6 mice in the presence or absence of DEX preconditioning. Some mice were treated with antibiotics to deplete intestinal bacteria. Fecal microbiota transplantation (FMT) was performed by transplanting the feces of DEX-pretreated mice into a new batch of I/R mice. We analyzed the expression ofDEX reversed I/R-induced bacterial abnormalities by increasing the ratio ofThis study revealed that DEX can alleviate intestinal I/R injury through a microbiota-related mechanism, providing a potential avenue for the management of intestinal I/R injury.

IntroductionAcute lung injury (ALI) is a major cause of morbidity and mortality after intestinal ischaemia/reperfusion (I/R). The gut microbiota and its metabolic byproducts act as important modulators of the gut–lung axis. This study aimed to define the role of succinate, a key microbiota metabolite, in intestinal I/R-induced ALI progression.MethodsGut and lung microbiota of mice subjected to intestinal I/R were analysed using 16S rRNA gene sequencing. Succinate level alterations were measured in germ-free mice or conventional mice treated with antibiotics. Succinate-induced alveolar macrophage polarisation and its effects on alveolar epithelial apoptosis were evaluated in succinate receptor 1 (Sucnr1)-deficient mice and in murine alveolar macrophages transfected withSucnr1-short interfering RNA. Succinate levels were measured in patients undergoing cardiopulmonary bypass, including intestinal I/R.ResultsSuccinate accumulated in lungs after intestinal I/R, and this was associated with an imbalance of succinate-producing and succinate-consuming bacteria in the gut, but not the lungs. Succinate accumulation was absent in germ-free mice and was reversed by gut microbiota depletion with antibiotics, indicating that the gut microbiota is a source of lung succinate. Moreover, succinate promoted alveolar macrophage polarisation, alveolar epithelial apoptosis and lung injury during intestinal I/R. Conversely, knockdown ofSucnr1or blockage of SUCNR1in vitroandin vivoreversed the effects of succinate by modulating the phosphoinositide 3-kinase-AKT/hypoxia-inducible factor-1α pathway. Plasma succinate levels significantly correlated with intestinal I/R-related lung injury after cardiopulmonary bypass.ConclusionGut microbiota-derived succinate exacerbates intestinal I/R-induced ALI through SUCNR1-dependent alveolar macrophage polarisation, identifying succinate as a novel target for gut-derived ALI in critically ill patients.

One‐lung ventilation (OLV), a common ventilation technique, is associated with perioperative lung injury, tightly connected with inflammatory responses. Dexmedetomidine has shown positive anti‐inflammatory effects in lung tissues in pre‐clinical models. This study investigated the efficacy of dexmedetomidine for suppressing inflammatory responses in patients requiring OLV. We searched PubMed, MEDLINE, Embase, Scopus, Ovid, and Cochrane Library for randomized controlled trials focusing on dexmedetomidine’s anti‐inflammatory effects on patients requiring OLV without any limitation on the year of publication or languages. 20 clinical trials were assessed with 870 patients in the dexmedetomidine group and 844 in the control group. Our meta‐analysis investigated the anti‐inflammatory property of dexmedetomidine perioperatively [T1 (30‐min OLV), T2 (90‐min OLV), T3 (end of surgery) and T4 (postoperative day 1)], demonstrating that dexmedetomidine’s intraoperative administration resulted in a significant reduction in serum concentration of interleukin‐6, tumor necrosis factor‐α and other inflammatory cytokines perioperatively. By calculating specific I 2 index, significant heterogeneity was observed on all occasions, with I 2 index ranging from 95% to 99%. For IL‐6 changes, sensitivity analysis showed that the exclusion of a single study led to a significant decrease of heterogeneity (96%–0%; p

Background: Propofol is a widely used anesthetic and sedative, which has been reported to exert an anti-inflammatory effect. TLR4 plays a critical role in coordinating the immuno-inflammatory response during sepsis. Whether propofol can act as an immunomodulator through regulating TLR4 are still unclear. In view of its potential as a sepsis therapy, we investigated the mechanisms underlying the immunomodulatory activity of propofol. Methods: The effects of propofol on TLR4 and Rab5a (a master regulator involved in intracellular trafficking of immune factors) were investigated in macrophage (from Rab5a -/- and WT mice) following treatment with lipopolysaccharide or cecal ligation and puncture in vitro and in vivo, and in peripheral blood monocyte from sepsis patients. Findings: We showed that propofol reduced membrane TLR4 expression on macrophage in vitro and in vivo. Rab5a participated in TLR4 intracellular trafficking and both Rab5a expression and the interaction between Rab5a and TLR4 were inhibited by propofol. We also showed Rab5a upregulation in peripheral blood monocyte of septic patients, accompanied by increased TLR4 expression on the cell surface. Both were correlated with SOFA score of sepsis patients and higher expression of Rab5a were found in septic non-survivors. Interpretation: We demonstrated that Rab5a regulates intracellular trafficking of TLR4 and that propofol reduces membrane TLR4 expression on macrophages by targeting Rab5a. Our study not only reveals a novel mechanism for the immunomodulatory effect of propofol but also indicates that Rab5a may be a potential therapeutic target against sepsis. Funding: National Natural Science Foundation of China [81671955, 81730058] Declaration of Interest: The authors declare that they have no conflict of interest. Ethical Approval: C57/BL mice were obtained from Guangdong Medical Laboratory Animal Center (Guangzhou, China). Rab5a knockout mice were purchased from Cyagen Biosciences (Guangzhou, China). All animal experiments were reviewed and approved by the Ethics Committee of Southern Medical University.

Intestinal ischemia/reperfusion (I/R) injury is a grave condition with high morbidity and mortality. We previously confirmed that intestinal I/R induces intestinal flora disorders and changes in metabolites, but the role of different metabolites in intestinal I/R injury is currently unclear. Based on targeted metabolic sequencing, pravastatin (PA) was determined to be a metabolite of the gut microbiota. Further, intestinal I/R model mice were established through superior mesenteric artery obstruction. In addition, a co-culture model of small intestinal organoids and type II innate lymphoid cells (ILC2s) was subjected to hypoxia/reoxygenation (H/R) to simulate an intestinal I/R model. Moreover, correlation analysis between the PA level in preoperative feces of patients undergoing cardiopulmonary bypass and the indices of postoperative intestinal I/R injury was carried out. IL-33-deficient mice, ILC2-deleted mice, and anti-IL-13 neutralizing antibodies were also used to explore the potential mechanism through which PA attenuates intestinal I/R injury. We demonstrated that PA levels in the preoperative stool of patients undergoing cardiopulmonary bypass were negatively correlated with the indices of postoperative intestinal I/R injury. Furthermore, PA alleviated intestinal I/R injury and improved the survival of mice. We further showed that PA promotes IL-13 release from ILC2s by activating IL-33/ST2 signaling to attenuate intestinal I/R injury. In addition, IL-13 promoted the self-renewal of intestinal stem cells by activating Notch1 and Wnt signals. Overall, results indicated that the gut microbial metabolite PA can attenuate intestinal I/R injury by promoting the release of IL-13 from ILC2s via IL-33/ST2 signaling, revealing a novel mechanism of and therapeutic strategy for intestinal I/R injury.

Background: The reviews on the risk factors with ARDS and the worse outcomes concluded lacking robust data of risk factors to prevent COVID-19 and identified an urgent need for large sample and high-quality research in this area, as well as the features of the ARDS.Methods: This retrospective cohort study included 333 COVID-19 inpatients at two hospitals in Hubei of China in 2020. The COVID-19-related ARDS was diagnosed according to the Berlin criteria. The outcomes were ARDS development and the intubation or in-hospital death. The cox proportional hazard ratio (HR) models were employed to determine the significant risk factors. Results: The median number of days from symptom onset to ARDS diagnosis was 11.0 (IQR, 8.0–13.0). Up to 84.1% COVID-19-related ARDS patients demonstrated multiple organ injuries. The mortality rates were 41.9% and 85.7% in moderate and severe ARDS. The survival patients on invasive mechanical ventilation (IMV) had been intubated earlier since ARDS diagnosis than those who had not survived (5.5 median days, IQR 4.0-7.0 days versus 11.5 median days, IQR 6.0-14.0 days, P < 0.001). Males and all abnormal laboratory indices associated with the higher risk of ARDS (P0.05). The sensitivity analyses found that lymphocyte count of < 1000 per mm3 at hospital admission were still significantly associated with developing ARDS when adjusting for age and male gender (HR, 4.10; 95% CI, 2.40-7.10), and oxygenation index (OI) ratio < 150 were more likely to predict the intubation/death after age adjustment (HR, 2.50; 95% CI, 1.17-5.30). Conclusion: The SARS-CoV-2-caused ARDS was not the typical ARDS according to Berlin criteria. The alive patients with IMV had been intubated earlier since ARDS diagnosis than those who had not survived. We identified male gender and abnormal laboratory indices associated with the ARDS but were not linked with the intubation/death. Sensitivity analysis concluded lymphocyte count of < 1000 per mm3 could predict ARDS while OI ratio less than 150 could predict intubation/death.

Ferroptosis, a new type of cell death has been found to aggravate intestinal ischemia/reperfusion (I/R) injury. However, little is known about the changes of gut microbiota and metabolites in intestinal I/R and the role of gut microbiota metabolites on ferroptosis-induced intestinal I/R injury. This study aimed to establish a mouse intestinal I/R model and ileum organoid hypoxia/reoxygenation (H/R) model to explore the changes of the gut microbiota and metabolites during intestinal I/R and protective ability of capsiate (CAT) against ferroptosis-dependent intestinal I/R injury. Intestinal I/R induced disturbance of gut microbiota and significant changes in metabolites. We found that CAT is a metabolite of the gut microbiota and that CAT levels in the preoperative stool of patients undergoing cardiopulmonary bypass were negatively correlated with intestinal I/R injury. Furthermore, CAT reduced ferroptosis-dependent intestinal I/R injury in vivo and in vitro. However, the protective effects of CAT against ferroptosis-dependent intestinal I/R injury were abolished by RSL3, an inhibitor of glutathione peroxidase 4 (Gpx4), which is a negative regulator of ferroptosis. We also found that the ability of CAT to promote Gpx4 expression and inhibit ferroptosis-dependent intestinal I/R injury was abrogated by JNJ-17203212, an antagonist of transient receptor potential cation channel subfamily V member 1 (TRPV1). This study suggests that the gut microbiota metabolite CAT enhances Gpx4 expression and inhibits ferroptosis by activating TRPV1 in intestinal I/R injury, providing a potential avenue for the management of intestinal I/R injury.

Xiao Yang,* Lin Zhu,* Bingcheng Zhao, Jingjuan Hu, Fan Deng, Shaohui Lei, Zhi-Wen Yao, Kexuan Liu Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhi-Wen Yao; Kexuan LiuDepartment of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of ChinaTel/Fax +86 20 61641881Email xingyzw@i.smu.edu.cn; liukexuan705@163.comPurpose: Neuropathic pain is a devastating complex condition occurring post-nervous system damage. Microglia in dorsal horn drives neuropathic pain as a kind of immune cell. We aimed to find potential differentially expressed genes (DEGs) and candidate pathways, which induced neuropathic pain, and to identify some new transcription factors and therapeutic drugs via bioinformatic analysis.Methods: The microarray profile GSE60670 was downloaded and analyzed. DEGs were screened and analyzed through Gene Ontology (GO), pathway enrichment, and protein-to-protein interaction (PPI) network. Respectively, transcription factors (TFs) and potential therapeutic drugs for DEGs were predicted through NetworkAnalyst and DGIdb databases. At last, we chose top 10 DEGs for external validation.Results: A total of 100 DEGs were identified. The results of pathway and GO analyses were closely related to malaria inflammatory pathway and inflammatory response. Three necessary PPI modules and 9 hub genes were identified in PPI analysis, and 277 DEG-TF pairs were found among 54 DEGs and 32 TF. Moreover, 22 candidate drugs were found to match 9 hub genes. External validation of 9 of the top 10 DEGs were consistent with bioinformatic analysis.Conclusion: This study provided comprehensive analyses for the functional gene sets and pathways related to neuropathic pain and promoted our understanding of the mechanism or therapy of neuropathic pain.Keywords: neuropathic pain, dorsal horn, microglia, bioinformatic analysis

Background: More evidence in understanding the heterogeneity of COVID-19-associated acute respiratory distress syndrome (ARDS) and in improving strategy to increase the survival from the critical patients intubated is always needed. The study aimed to comprehensively explore the features of COVID-19-associated ARDS and the features and outcomes between the early and late intubation groups. Methods: This retrospective cohort included 65 adult COVID-19 inpatients with ARDS at two hospitals in Hubei, China. The ARDS in these patients was diagnosed according to the Berlin criteria. We defined intubation within 7 days of ARDS diagnosis as ‘early’ intubation and that performed from the eighth day as ‘late’ intubation based on literatures. The outcomes were invasive mechanical ventilation and in-hospital death. The log-binomial regression models were used to explore the risk factors and the Kaplan-Meier statistic was used to estimate the risk of mortality. Results: The median number of days from symptom onset to ARDS diagnosis was 11.0 (IQR, 8.0–13.0). Up to 84.1% COVID-19-related ARDS patients demonstrated multiple organ injuries. The mortality rates were 41.9% and 85.7% in moderate and severe ARDS. The early intubation and the late intubation had the differences in days from symptom onset/hospital admission/ARDS diagnosis to intubation (P = 0.023, P = 0.011, P < 0.001). Compared with the early-intubation group, the late-intubation group showed less severity at admission (median oxygenation index 159.0 95% CI 134.0-203.0 vs. 133.9 95% CI 98.3-183.2), but required more aggressive therapies (ICU 80% vs. 70%, CRRT 50% vs. 10%, prone-position 50% vs. 30%, and ECMO 50% vs. 10%) and had higher risk to die at hospital (RR, 3.18; 95% CI 1.98-5.12). Conclusion: The ARDS caused by COVID-19 was not typical ARDS due to prolonged onset time, multiple organ injuries, and higher mortalities. The late-intubation group showed less severity at admission but higher risk of in-hospital death than the early-intubation group.

BackgroundIntestinal ischemia/reperfusion (I/R) injury has high morbidity and mortality. Gut microbiota is one of the potential key factors affecting intestinal I/R injury. Different populations exhibit different sensitivities to intestinal I/R injury, but whether this is related to differences in gut microbiota is unclear. Here, to elucidate the interaction between the gut microbiome and intestinal I/R injury, we conducted 16S rRNA gene sequencing and fecal microbiota transplantation experiment in an I/R mouse model. Toll-like receptor 2 (TLR2)-deficient mice, interleukin-10 (IL-10)-deficient mice as well as the transwell co-culture system of small intestine organoids and macrophages were used to explore the potential mechanism of bacteria attenuating intestinal I/R injury.ResultsThe intestinal I/R-sensitive (Sen) and resistant (Res) mice were first defined according to different survival outcomes of mice suffering from intestinal I/R. Fecal microbiota composition and diversity prior to intestinal ischemia were different between in Sen and Res mice. The relative abundance of Lactobacillus murinus (L. murinus) at the species level was higher in Res mice than in Sen mice, and the fold change was the largest. Clinically, the abundance of L. murinus in preoperative feces of patients undergoing cardiopulmonary bypass surgery was closely related to the degree of intestinal I/R injury after surgery. Treatment with L. murinus significantly prevented from intestinal I/R-induced intestinal injury and improved the survival of mice, which depends on the participation of macrophages. Further, in vivo and vitro experiments indicated that L. murinus promoted the release of IL-10 from M2 macrophages via activating TLR2 signaling to alleviate intestinal I/R injury. ConclusionGut microbiome is involved in the postoperative outcome of intestinal I/R. L. murinus promotes the release of IL-10 from M2 macrophages through TLR2 signaling to alleviate intestinal I/R injury, revealing a novel mechanism of intestinal I/R injury and new therapeutic strategy for clinical practice.

Ferroptosis, a new type of cell death has been found to aggravate intestinal ischemia/reperfusion (I/R) injury. However, little is known about the changes of gut microbiota and metabolites in intestinal I/R and the role of gut microbiota metabolites on ferroptosis-induced intestinal I/R injury. This study aimed to establish a mouse intestinal I/R model and ileum organoid hypoxia/reoxygenation (H/R) model to explore the changes of the gut microbiota and metabolites during intestinal I/R and protective ability of capsiate (CAT) against ferroptosis-dependent intestinal I/R injury. Intestinal I/R induced disturbance of gut microbiota and significant changes in metabolites. We found that CAT is a metabolite of the gut microbiota and that CAT levels in the preoperative stool of patients undergoing cardiopulmonary bypass were negatively correlated with intestinal I/R injury. Furthermore, CAT reduced ferroptosis-dependent intestinal I/R injury in vivo and in vitro. However, the protective effects of CAT against ferroptosis-dependent intestinal I/R injury were abolished by RSL3, an inhibitor of glutathione peroxidase 4 (Gpx4), which is a negative regulator of ferroptosis. We also found that the ability of CAT to promote Gpx4 expression and inhibit ferroptosis-dependent intestinal I/R injury was abrogated by JNJ-17203212, an antagonist of transient receptor potential cation channel subfamily V member 1 (TRPV1). This study suggests that the gut microbiota metabolite CAT enhances Gpx4 expression and inhibits ferroptosis by activating TRPV1 in intestinal I/R injury, providing a potential avenue for the management of intestinal I/R injury.

BackgroundThe clinical significance of cardiac troponin measurement in patients hospitalised for coronavirus disease 2019 (covid-19) is uncertain. We investigated the prevalence of elevated troponins in these patients and its prognostic value for predicting mortality.MethodsStudies were identified by searching electronic databases and preprint servers. We included studies of hospitalised covid-19 patients that reported the frequency of troponin elevations above the upper reference limit and/or the association between troponins and mortality. Meta-analyses were performed using random-effects models.ResultsFifty-one studies were included. Elevated troponins were found in 20.8% (95% confidence interval [CI] 16.8–25.0 %) of patients who received troponin test on hospital admission. Elevated troponins on admission were associated with a higher risk of subsequent death (risk ratio 2.68, 95% CI 2.08–3.46) after adjusting for confounders in multivariable analysis. The pooled sensitivity of elevated admission troponins for predicting death was 0.60 (95% CI 0.54–0.65), and the specificity was 0.83 (0.77–0.88). The post-test probability of death was about 42% for patients with elevated admission troponins and was about 9% for those with non-elevated troponins on admission. There was significant heterogeneity in the analyses, and many included studies were at risk of bias due to the lack of systematic troponin measurement and inadequate follow-up.ConclusionElevated troponins were relatively common in patients hospitalised for covid-19. Troponin measurement on admission might help in risk stratification, especially in identifying patients at high risk of death when troponin levels are elevated. High-quality prospective studies are needed to validate these findings.Systematic review registrationPROSPEROCRD42020176747

Postoperative ileus (POI) after abdominal surgery is associated with prolonged hospital stay and increased costs. The aim of this study is to investigate the incidence of, risk factors for, and outcomes associated with POI in patients undergoing hysterectomy for benign indications. A retrospective review of 1017 consecutive patients undergoing benign hysterectomy over the period 2012–2017 in a single center was performed. POI was predefined as absence of flatus and defecation for more than 2 days with the presence of one or more of the following symptoms: nausea, vomiting, and abdominal distention. The association between perioperative variables and the risk of POI was evaluated by univariate analysis. Independent risk factors were identified by multivariate logistic regression analysis. Overall incidence of POI was 9.2%. Incidence of POI did not differ significantly among three different surgical approaches (abdominal hysterectomy, 10.6%; laparoscopic hysterectomy, 7.8%; vaginal hysterectomy, 11.3%; P = 0.279). Independent risk factors of POI identified by multivariate analysis included anesthesia technique (odds ratio [OR] 2.662, 95% interval [CI] 1.533–4.622, P = 0.001), adhesiolysis (odds ratio [OR] 1.818, 95% interval [CI] 1.533–4.622, P = 0.011), duration of operation (odds ratio [OR] 1.005, 95% interval [CI] 0.942–6.190, P = 0.029), previous cancer (odds ratio [OR] 4.789, 95% interval [CI] 1.232–18.626, P = 0.024), and dysmenorrhea (odds ratio [OR] 1.859, 95% interval [CI] 1.182–2.925, P = 0.007). POI is a common complication after hysterectomy. This study identified risk factors of POI specifically for gynecologic patients. Patients exposed to these factors should be monitored closely for the development POI.