Energy stress promotes P-bodies formation via lysine-63-linked polyubiquitination of HAX1.

Energy stress, characterized by the reduction of intracellular ATP, has been implicated in various diseases, including cancer. Here, we show that energy stress promotes the formation of P-bodies in a ubiquitin-dependent manner. Upon ATP depletion, the E3 ubiquitin ligase TRIM23 catalyzes lysine-63 (K63)-linked polyubiquitination of HCLS1-associated protein X-1 (HAX1). HAX1 ubiquitination triggers its liquid‒liquid phase separation (LLPS) and contributes to P-bodies assembly induced by energy stress. Ubiquitinated HAX1 also interacts with the essential P-body proteins, DDX6 and LSM14A, promoting their condensation. Moreover, we find that this TRIM23/HAX1 pathway is critical for the inhibition of global protein synthesis under energy stress conditions. Furthermore, high HAX1 ubiquitination, and increased cytoplasmic localization of TRIM23 along with elevated HAX1 levels, promotes colorectal cancer (CRC)-cell proliferation and correlates with poor prognosis in CRC patients. Our data not only elucidate a ubiquitination-dependent LLPS mechanism in RNP granules induced by energy stress but also propose a promising target for CRC therapy.

N-acetyltransferase 10 mediates cognitive dysfunction through the acetylation of GABABR1 mRNA in sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is a critical neurological complication of sepsis and represents a crucial factor contributing to high mortality and adverse prognosis in septic patients. This study explored the contribution of NAT10-mediated messenger RNA (mRNA) acetylation in cognitive dysfunction associated with SAE, utilizing a cecal ligation and puncture (CLP)-induced SAE mouse model. Our findings demonstrate that CLP significantly upregulates NAT10 expression and mRNA acetylation in the excitatory neurons of the hippocampal dentate gyrus (DG). Notably, neuronal-specific Nat10 knockdown improved cognitive function in septic mice, highlighting its critical role in SAE. Proteomic analysis, RNA immunoprecipitation, and real-time qPCR identified GABABR1 as a key downstream target of NAT10. Nat10 deletion reduced GABABR1 expression, and subsequently weakened inhibitory postsynaptic currents in hippocampal DG neurons. Further analysis revealed that microglia activation and the release of inflammatory mediators lead to the increased NAT10 expression in neurons. Microglia depletion with PLX3397 effectively reduced NAT10 and GABABR1 expression in neurons, and ameliorated cognitive dysfunction induced by SAE. In summary, our findings revealed that after CLP, NAT10 in hippocampal DG neurons promotes GABABR1 expression through mRNA acetylation, leading to cognitive dysfunction.

Suppression of Skp2 contributes to sepsis-induced acute lung injury by enhancing ferroptosis through the ubiquitination of SLC3A2.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The inflammatory cytokine storm causes systemic organ damage, especially acute lung injury in sepsis. In this study, we found that the expression of S-phase kinase-associated protein 2 (Skp2) was significantly decreased in sepsis-induced acute lung injury (ALI). Sepsis activated the MEK/ERK pathway and inhibited Skp2 expression in the pulmonary epithelium, resulting in a reduction of K48 ubiquitination of solute carrier family 3 member 2 (SLC3A2), thereby impairing its membrane localization and cystine/glutamate exchange function. Consequently, the dysregulated intracellular redox reactions induced ferroptosis in pulmonary epithelial cells, leading to lung injury. Finally, we demonstrated that intravenous administration of Skp2 mRNA-encapsulating lipid nanoparticles (LNPs) inhibited ferroptosis in the pulmonary epithelium and alleviated lung injury in septic mice. Taken together, these data provide an innovative understanding of the underlying mechanisms of sepsis-induced ALI and a promising therapeutic strategy for sepsis.

Acetylcysteine synergizes PD-1 blockers against colorectal cancer progression by promoting TCF1+PD1+CD8+ T cell differentiation.

BACKGROUND: Programmed cell death protein 1 (PD-1) blockade is essential in treating progressive colorectal cancer (CRC). However, some patients with CRC do not respond well to immunotherapy, possibly due to the exhaustion of CD8+ T cells in the tumor microenvironment. N-Acetylcysteine (NAC) can reduce CD8+ T cell exhaustion in vitro and induce their differentiation into long-lasting phenotypes, thus enhancing the anti-tumor effect of adoptive T cell transfer. However, whether NAC can be combined with PD-1 blockade in CRC treatment and how NAC regulates CD8+ T cell differentiation remain unclear. Hence, in this study, we aimed to investigate whether NAC has a synergistic effect with PD-1 blockers against CRC progression. METHODS: We constructed a mouse CRC model to study the effect of NAC on tumors. The effect of NAC on CD8 + T cell differentiation and its potential mechanism were explored using cell flow assay and other studies in vitro and ex vivo. RESULTS: We demonstrated that NAC synergized PD-1 antibodies to inhibit CRC progression in a mouse CRC model mediated by CD8+ T cells. We further found that NAC can induce TCF1+PD1+CD8+ T cell differentiation and reduce the formation of exhausted T cells in vitro and in vivo. Moreover, NAC enhanced the expression of Glut4 in CD8+ T cells, promoting the differentiation of TCF1+PD1+CD8+ T cells. CONCLUSIONS: Our study provides a novel idea for immunotherapy for clinically progressive CRC and suggests that Glut4 may be a new immunometabolic molecular target for regulating CD8+ T cell differentiation.

Long Noncoding RNA HOTAIRM1 Promotes Immunosuppression in Sepsis by Inducing T Cell Exhaustion.

Sepsis is an acute life-threatening disorder associated with multiorgan dysfunction that remains the leading cause of death in intensive care units. As sepsis progresses, it causes prolonged immunosuppression, which results in sustained mortality, morbidity, and susceptibility to secondary infections. Using a mouse model of sepsis, we found that the long noncoding RNA HOTAIRM1 (HOXA transcript antisense RNA myeloid-specific 1) was highly expressed in mice during the late phase of sepsis. The upregulation of HOTAIRM1 was induced by Notch/Hes1 activation and, moreover, was critical for the formation of an immunosuppressive microenvironment. HOTAIRM1 induced T cell exhaustion by increasing the percentage of PD-1+ T cells and regulatory T cells, accompanied by elevated PD-L1. Blockade of either Notch/Hes1 signaling or HOTAIRM1 inhibited T cell exhaustion in late sepsis, having alleviated lung injury and improved survival of mice. Further mechanistic studies identified HOXA1 as a key transcription factor targeted by HOTAIRM1 to regulate PD-L1 expression in lung alveolar epithelial cells. These results implicated that the Notch/Hes1/HOTAIRM1/HOXA1/PD-L1 axis was critical for sepsis-induced immunosuppression and could be a potential target for sepsis therapies.

Surgical Stress and Cancer Progression: New Findings and Future Perspectives.

PURPOSE OF REVIEW: The stress response to surgery is essential for maintaining homeostasis and exhibits anti-tumor effects; however, an ongoing and exaggerated stress response may have adverse clinical consequences and even promote cancer progression. This review will discuss the complex relationship between surgical stress and cancer progression. RECENT FINDINGS: Surgical stress exhibits both anti-tumor and cancer-promoting effects by causing changes in the neuroendocrine, circulatory, and immune systems. Many studies have found that many mechanisms are involved in the process, and the corresponding targets could be applied for cancer therapy. Although surgical stress may have anti-tumor effects, it is necessary to inhibit an excessive stress response, mostly showing cancer-promoting effects.

MTDCNet: A 3D multi-threading dilated convolutional network for brain tumor automatic segmentation.

Glioma is one of the most threatening tumors and the survival rate of the infected patient is low. The automatic segmentation of the tumors by reliable algorithms can reduce diagnosis time. In this paper, a novel 3D multi-threading dilated convolutional network (MTDC-Net) is proposed for the automatic brain tumor segmentation. First of all, a multi-threading dilated convolution (MTDC) strategy is introduced in the encoder part, so that the low dimensional structural features can be extracted and integrated better. At the same time, the pyramid matrix fusion (PMF) algorithm is used to integrate the characteristic structural information better. Secondly, in order to make the better use of context semantical information, this paper proposed a spatial pyramid convolution (SPC) operation. By using convolution with different kernel sizes, the model can aggregate more semantic information. Finally, the multi-threading adaptive pooling up-sampling (MTAU) strategy is used to increase the weight of semantic information, and improve the recognition ability of the model. And a pixel-based post-processing method is used to prevent the effects of error prediction. On the brain tumors segmentation challenge 2018 (BraTS2018) public validation dataset, the dice scores of MTDC-Net are 0.832, 0.892 and 0.809 for core, whole and enhanced of the tumor, respectively. On the BraTS2020 public validation dataset, the dice scores of MTDC-Net are 0.833, 0.896 and 0.797 for the core tumor, whole tumor and enhancing tumor, respectively. Mass numerical experiments show that MTDC-Net is a state-of-the-art network for automatic brain tumor segmentation.

Intraoperative lidocaine infusion in patients undergoing pancreatectomy for pancreatic cancer: a mechanistic, multicentre randomised clinical trial.

BACKGROUND: Intravenous lidocaine has been postulated to improve long-term survival after surgery for pancreatic cancer through anti-inflammatory effects, anti-tumour effects, or both. We investigated whether intraoperative lidocaine improves survival after pancreatectomy for pancreatic cancer and whether lidocaine modified the formation of neutrophil extracellular traps (NETs), high levels of which are associated with poor prognosis. METHODS: Patients undergoing pancreatectomy were randomly assigned to i.v. lidocaine (continuous intraoperative infusion of 2 mg kg-1 h-1, after 1.5 mg kg-1 bolus at induction of anaesthesia) or saline placebo. The co-primary outcomes were survival/disease-free survival 3 yr after surgery. Secondary outcomes (masked to treatment allocation) included intraoperative opioid (sufentanil) dose, postoperative complications, and circulating and tumour-associated NETs (immunofluorescence assay, enzyme-linked immune assay, or both). RESULTS: A total of 563 participants (34.6% female; median age, 64 yr) completed 3 yr of clinical follow-up. Overall, 283 participants were randomised to lidocaine infusion, and 280 participants were randomised to placebo. Infusion of lidocaine did not alter overall (hazard ratio [HR]=0.98; 95% confidence interval [CI], 0.81-1.17; P=0.79) or disease-free survival (HR=0.91; 95% CI, 0.71-1.17; P=0.44). Mean intraoperative sufentanil dose was reduced by lidocaine infusion (47.6 µg [4.6]) compared with placebo (68.4 µg [4.8]; P<0.001), but postoperative complications and length of hospital stay were similar between groups. Circulating NETs were lower after lidocaine infusion up to 3 days after surgery, but tumour-associated NETs were not altered by intraoperative treatment. CONCLUSION: In patients undergoing pancreatectomy for pancreatic cancer, intraoperative infusion of lidocaine did not improve overall or disease-free survival. Reduced formation of circulating NETs was absent in pancreatic tumour tissue. CLINICAL TRIAL REGISTRATION: NCT03245346; updated in Chi-CTR-2000035469.

NBPF4 mitigates progression in colorectal cancer through the regulation of EZH2-associated ETFA.

Colorectal cancer (CRC) is one of the leading causes of death worldwide, and hence, there is a need to elucidate the molecular mechanisms contributing to the progression of CRC. In this study, we aimed at assessing the role of long non-coding RNA NBPF4 on the tumorigenesis of CRC. Silencing or overexpression experiments were performed on HCT116 and SW260 in vitro models. BALB/c athymic female nude mice aged 5-6 weeks were used as in vivo models. To assess the relationship between NBPF4 and its regulatory RNA pull-down assay, RNA immunoprecipitation, luciferase activity, Western blotting and qRT-PCR were employed. Initially, we identified that NBPF4 was downregulated in CRC tissues and cell lines. Furthermore, we observed that NBPF4 decreased tumorigenesis in both in vitro and in vivo models. Additionally, we identified that ETFA was highly expressed in CRCs and was negatively associated with NBPF4. Subsequently, we identified that EZH2, a transcriptional factor, activated ETFA by enhancing the methylation of its promoter, and EZH2 was also highly regulated in CRCs. Using COAD and READ databases, we confirmed that EZH2 and ETFA were positively correlated. Furthermore, we identified NBPF4 and EZH2 were targets for ZFP36, which bound and positively regulated NBPF4. This prevented NBPF4 from binding to its negative regulator miR-17-3p. Our results demonstrated that NBPF4 downregulated EZH2 and stabilized itself by binding to ZFP36, thus escaping from inhibition by miR-17-3p, which allowed mitigation of CRC through inhibition of ETFA.

Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer.

Morphine, a mu-opioid receptor (MOR) agonist, has been extensively used to treat advanced cancer pain. In particular, in patients with cancer metastasis, both morphine and anticancer drugs are given simultaneously. However, evidence showed that morphine might be a risk factor in promoting the tumor's malignant potential. In this study, we report that treatment with morphine could activate MOR and lead to the promotion of proliferation, migration, and invasion in HCT116 and DLD1 colorectal cancer (CRC) cells with time-concentration dependence. Moreover, morphine can also contribute to cetuximab's drug resistance, a targeted drug widely used to treat advanced CRC by inducing the activation of epidermal growth factor receptor (EGFR). The cell phenotype includes proliferation, migration, invasion, and drug resistance, which may be reversed by MOR knockdown or adding nalmefene, the MOR receptor antagonist. Receptor tyrosine kinase array analysis revealed that morphine selectively induced the transactivation of EGFR. EGFR transactivation resulted in the activation of ERK1/2 and AKT. In conclusion, morphine induces the transactivation of EGFR via MOR. It activates the downstream signal pathway AKT-MTOR and RAS-MAPK, increases proliferation, migration, and invasion, and promotes resistance to EGFR inhibitors in a CRC cell line. Furthermore, we verified that EGFR inhibition by cetuximab strongly reversed the protumoral effects of morphine in vitro and in vivo. Collectively, we provide evidence that morphine-EGFR signaling might be a promising therapeutic target for CRC patients, especially for cetuximab-resistant CRC patients.

Targeting the mu-Opioid Receptor for Cancer Treatment.

PURPOSE OF REVIEW: Opioids are still the most effective and widely used treatments for acute and chronic pain in cancer patients. This review focuses on the impact of opioids and mu-opioid receptors (MOR) on tumor progression and providing new ideas for targeting the MOR in cancer treatment. RECENT FINDINGS: Studies estimated that opioids facilitate tumor progression and are related to the worse prognosis in cancer patients. As the primary receptor of opioids, MOR is involved in the regulation of malignant transformation of tumors and participating in proliferation, invasion, metastasis, and angiogenesis. MOR may be a new molecular marker of malignant tumors and thus become a new target for cancer therapy, which may be beneficial to the outcomes of cancer patients.

Impact of perioperative red blood cell transfusion on postoperative recovery and long-term outcome in patients undergoing surgery for ovarian cancer: A propensity score-matched analysis.

BACKGROUND: The impact of perioperative red blood cell transfusion (PRBCT) on cancer survival has remained controversial. METHODS: We conducted a retrospective study in patients undergoing primary debulking surgery (PDS) for ovarian cancer between January 2013 and December 2017. The patients were divided into two groups based on whether they received PRBCT. Clinical characteristics were compared between groups. After propensity score matching, perioperative systemic inflammation-based scores, quality of recovery, postoperative outcomes, disease-free survival (DFS), and overall survival (OS) were compared between groups. Univariate and multivariable Cox proportional hazard models were used to evaluate the association between covariates and survival outcomes. RESULTS: A total of 1037 patients were enrolled in this study, and 31.7% of patients received PRBCT. After propensity matching, there was no significant difference in the clinical characteristics between groups. Patients receiving PRBCT had more postoperative fluctuations in systemic inflammatory response-related indicators (P < 0.001), a higher incidence of postoperative grade II complications (28.4% vs. 14.8%), a longer length of stay (10.6 d vs. 6.2 d) and higher 30-day and total readmission rates (7.1% vs. 4.4% and 11.2% vs. 8.1%, P < 0.001, respectively) than patients who did not receive PRBCT. The OS and DFS rates 3 years after surgery were significantly lower in the patients receiving PRBCT than in patients not receiving PRBCT (58.9% vs. 74.5%, 39.6% vs. 52.3%). CONCLUSIONS: PRBCT was significantly associated with more fluctuations in systemic inflammatory indicators, a prolonged length of stay, higher postoperative complication rates and increased cancer recurrence and overall mortality in ovarian cancer patients undergoing PDS.

Increased mu-opioid receptor expression is associated with reduced disease-free and overall survival in laryngeal squamous cell carcinoma.

BACKGROUND: Expression of the mu-opioid receptor (MOR) is associated with poor long-term outcomes in various types of cancer. The association between MOR expression and clinical outcomes in laryngeal squamous cell carcinoma (LSCC) is not clear. METHODS: This retrospective study included patients who underwent laryngectomy for LSCC. The expression pattern of the MOR protein and OPRM1 gene in tumours and corresponding adjacent non-carcinoma specimens was measured. Propensity score matching was used to minimise bias. The primary endpoints were overall survival (OS) and disease-free survival (DFS). The secondary endpoints were intraoperative sufentanil consumption, grade of surgical complications according to the Clavien-Dindo classification, and hospital length of stay. RESULTS: A total of 207 LSCC patients were enrolled. After propensity score matching, there was a significant difference in DFS between groups at 1, 3, and 5 yr (60.2% vs 81.2%, P=0.019; 39.4% vs 50.2%, P=0.026; 37.5% vs 42.5%, P=0.023, respectively) in patients with high MOR expression. The OS rates at 1, 3, and 5 yr were significantly lower in the high MOR expression group (81.2% vs 93.2%, P=0.027; 57.7% vs 78.3%, P<0.001; 42.5% vs 60.3%, P<0.001, respectively). The multivariate analysis indicated that high MOR expression was associated with worse DFS and OS (hazard ratio: 1.52, 95% confidence interval: 1.07, 2.25, P=0.034; hazard ratio: 1.42, 95% confidence interval: 1.17, 2.34, P=0.032). CONCLUSION: High MOR expression may be associated with poor prognosis in patients with LSCC, suggesting that MOR could be used as a valuable molecular biomarker to predict prognosis of LSCC patients.

Association between intraoperative intravenous lidocaine infusion and survival in patients undergoing pancreatectomy for pancreatic cancer: a retrospective study.

BACKGROUND: Intravenous lidocaine has been shown to reduce opioid consumption and is associated with favourable outcomes after surgery. In this study, we explored whether intraoperative lidocaine reduces intraoperative opioid use and length of stay (LOS) and improves long-term survival after pancreatic cancer surgery. METHODS: This retrospective study included 2239 patients who underwent pancreatectomy from January 2014 to December 2017. The patients were divided into non-lidocaine and lidocaine (bolus injection of 1.5 mg kg-1 at the induction of anaesthesia followed by a continuous infusion of 2 mg kg-1 h-1 intraoperatively) groups. The overall use of postoperative rescue analgesia and LOS were recorded. Propensity score matching was used to minimise bias, and disease-free survival and overall survival were compared between the two groups. RESULTS: After propensity score matching, patient characteristics were not significantly different between groups. Intraoperative sufentanil consumption and use of postoperative rescue analgesia in the lidocaine group were significantly lower than those in the non-lidocaine group. The LOS was similar between groups. There was no significant difference in disease-free survival between groups (hazard ratio [HR]=0.913; 95% confidence interval [CI], 0.821-1.612; P=0.316). The overall survival rates at 1 and 3 yr were significantly higher in the lidocaine group than in the non-lidocaine group (68.0% vs 62.6%, P<0.001; 34.1% vs 27.2%, P=0.011). The multivariable analysis indicated that intraoperative lidocaine infusion was associated with a prolonged overall survival (HR=0.616; 95% CI, 0.290-0.783; P=0.013). CONCLUSION: Intraoperative intravenous lidocaine infusion was associated with improved overall survival in patients undergoing pancreatectomy.

High glucose inhibits vascular endothelial Keap1/Nrf2/ARE signal pathway via downregulation of monomethyltransferase SET8 expression.

Hyperglycemia-mediated reactive oxygen species (ROS) accumulation plays an important role in hyperglycemia-induced endothelial injury. Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway inhibition participates in hyperglycemia-induced ROS accumulation. Our previous study indicated that SET8 overexpression inhibits high glucose-mediated ROS accumulation in human umbilical vein endothelial cells (HUVECs). In the present study, we hypothesize that SET8 may play a major role in high glucose-induced ROS accumulation via modulation of Keap1/Nrf2/ARE pathway. Our data indicated that high glucose mediated cell viability reduction, ROS accumulation, and Nrf2/ARE signal pathway inhibition via upregulation of Keap1 expression in HUVECs. Moreover, high glucose inhibited the expressions of SET8 and H4K20me1 (a downstream target of SET8). SET8 overexpression improved high glucose-mediated Keap1/Nrf2/ARE pathway inhibition and endothelial oxidation. Consistently, the effects of sh-SET8 were similar to that of high glucose treatment and were reversed by si-Keap1. A mechanistic study found that H4K20me1 was enriched at the Keap1 promoter region. SET8 overexpression attenuated Keap1 promoter activity and its expression, while mutant SET8 R259G did not affect Keap1 promoter activity and expression. The results of this study demonstrated that SET8 negatively regulates Keap1 expression, thus participating in high glucose-mediated Nrf2/ARE signal pathway inhibition and oxidative injury in HUVECs.

Propofol attenuates the adhesion of tumor and endothelial cells through inhibiting glycolysis in human umbilical vein endothelial cells.

Propofol is one of the most commonly used intravenous anesthetics and plays an important role in tumor suppression. In the present study, we aimed to investigate the mechanism by which propofol attenuates tumor endothelial cells (TECs) and tumor cell adhesion to inhibit tumor metastasis in vitro. Human umbilical vein endothelial cells (HUVECs) cultured in Dulbecco's modified Eagle's medium were treated with tumor conditioned medium for 24 h, followed by 4 h of treatment with or without 25 µM of propofol, 10 µM of KN93, 500 µM of MK801, or 20 µM of rapastinel. It was found that propofol inhibited TEC adhesion and the glycolysis level of TECs. Consistently, propofol inhibited the expressions of adhesion molecules (E-selectin, ICAM-1, and VCAM-1) and glycolysis proteins (GLUT1, HK2, and LDHA) in TECs. Moreover, propofol attenuated the expression of HIF-1α, the phosphorylation of AKT and Ca2+/calmodulin-dependent protein kinase II (CaMKII), and the Ca2+ concentration in TECs. MK801, an inhibitor of NMDA receptor, and KN93, an inhibitor of CaMKII, both inhibited the expressions of adhesion molecules and glycolysis proteins, in a manner similar to propofol. Additionally, rapastine, an activator of NMDA receptor, could counteract the effects of propofol. Our results indicated that propofol attenuates intracellular Ca2+ concentration, CaMKII and AKT phosphorylation, and HIF-1α expression, probably via inhibiting the NMDA receptor, thus inhibiting glycolysis and adhesion of tumor and endothelial cells.

Nalmefene attenuates malignant potential in colorectal cancer cell via inhibition of opioid receptor.

Morphine is postulated a risk factor in promoting tumor growth and metastasis during the preoperative period, and high glycolysis of tumor cells is proved to accelerate tumor progression. In this study, we investigated whether nalmefene, an opioid receptor inhibitor, could inhibit CT26 colon cancer cell growth through influencing cell glycolysis. CCK8 and transwell migration assays showed that nalmefene inhibited CT26 cells viability and migration in a concentration-dependent manner. Extracellular acidification rate and oxygen consumption rate showed that nalmefene inhibited glycolysis of CT26 cells. Moreover, western blot analysis and quantitative real-time PCR revealed that nalmefene decreased the expressions of enzymes related to glycolysis. Flow cytometry results revealed that intracellular calcium (Ca2+) level was changed by nalmefene, western blot analysis showed that nalmefene decreased calmodulin expression and calcium/calmodulin dependent protein kinases II (CaMK II) phosphorylation, thus inhibiting the serine/threonine kinase (AKT)-glycogen synthase kinase-3ß (GSK-3ß) pathway. Furthermore, the effects of KN93, an inhibitor of CaMK II, were similar to the effects of nalmefene, and the anti-tumor effect of nalmefene could be counteracted by morphine. In conclusion, the anti-tumor effect of nalmefene may be achieved by inhibiting opioid receptor and down-regulating calmodulin expression and CaMK II phosphorylation, thus inhibiting AKT-GSK-3ß pathway and the glycolysis of CT26 cells.

Ultrasound-Guided Intercostal Nerve Block Following Esophagectomy for Acute Postoperative Pain Relief in the Postanesthesia Care Unit.

OBJECTIVE: To explore the feasibility, effectiveness, and safety of ultrasound-guided intercostal nerve block (ICNB) for immediate relief of moderate and severe pain following esophagectomy in a postanesthesia care unit (PACU). METHODS: Eighty-one patients who complained of moderate to severe pain on arrival to the PACU after an Ivor Lewis esophagectomy were randomly assigned to 2 groups: a sufentanil treatment group (Group A, n = 41) and an intercostal nerve block treatment group (Group B, n = 40). The visual analog scale (VAS) pain scores at rest and on cough at 1, 2, 4, 12, 24, and 48 hours after treatment were monitored. The heart rate, blood pressure, and pulse oxygen saturation (SpO2 ) 2 hours after treatment and the patients' length of stay in the PACU after treatment were recorded. Patient-controlled intravenous analgesia consumption and the incidence of nausea, vomiting, and other adverse reactions were also recorded. RESULTS: Ultrasound-guided ICNB was performed successfully in all patients in Group B without puncture-related complications. The VAS pain scores at rest and on cough at 1, 2, and 4 hours after treatment in Group B were significantly lower than those in Group A (P < 0.05). The consumption of sufentanil and the incidence of nausea and vomiting were significantly decreased in Group B compared with those in Group A. CONCLUSION: Ultrasound-guided ICNB could provide effective and safe pain relief for patients who suffer from moderate to severe pain (VAS score ≥ 5) after esophagectomy in the PACU.

General anesthesia combined with epidural anesthesia ameliorates the effect of fast-track surgery by mitigating immunosuppression and facilitating intestinal functional recovery in colon cancer patients.

PURPOSE: The purpose of this study is to investigate the influence of anesthetic methods on markers of anti-tumor immunity and intestinal functions in fast-track surgery in colon cancer (CC) patients during the perioperative period. PATIENTS AND METHODS: A total of 53 patients with American Society of Anesthesiologists (ASA) I-II status randomly received general anesthesia (G group, n = 27) or general anesthesia combined with epidural anesthesia (E group, n = 26) for surgical tumor resection. The recovery times of intestinal function were evaluated in both groups postoperatively. The frequencies of different subsets of CD4+ T cells and myeloid-derived suppressor cells and C-reactive protein (CRP) were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively, before anesthesia (t0), 1 h after the beginning of surgery (t1), 1 h after the end of surgery (t2), and on day 2 (t3) and day 5 (t4) post-surgery. RESULTS: There was no significant difference in demographic characteristics between the two groups, but the E group of patients received significantly lower amounts of morphine and sevoflurane. In comparison with those in the G group, significantly greater numbers of lymphocytes and elevated frequencies of Th1 cells were detected at t3 and t4 post-surgery in the E group (p < 0.01). Significantly lower percentages of Th2 cells and regulatory T cells were detected in the E group at t2-4 post-surgery. Whereas the levels of plasma CRP increased post-surgery in both groups, the levels of CRP were significantly lower in the E group than those in the G group at t3-4 post-surgery (p < 0.05). The times to the first flatus and to tolerate a full diet were significantly shorter in the E group than those in the G group (p < 0.01). CONCLUSION: General anesthesia combined with epidural anesthesia plays an important role in fast-track surgery, mitigating the surgical stress-related impairment of anti-tumor immune responses and hastening the recovery of intestinal function. This combination might also help to improve long-term outcomes for CC patients.

Propofol protects against high glucose-induced endothelial apoptosis and dysfunction in human umbilical vein endothelial cells.

BACKGROUND: Perioperative hyperglycemia is a common clinical metabolic disorder. Hyperglycemia could induce endothelial apoptosis and dysfunction. Propofol is a widely used IV anesthetic drug in clinical settings. In the present study, we examined whether and how propofol reduced high glucose-induced endothelial apoptosis and dysfunction in human umbilical vein endothelial cells (HUVECs). METHODS: HUVECs were cultured with different concentrations (5, 10, 15, and 25 mM) of glucose for different times (4, 8, 12, and 24 hours). To study the effect of propofol, cells were incubated with different concentrations (0.2, 1, 5, and 25 µM) of propofol for 2 hours. In parallel experiments, cells were incubated in 5 mM glucose as control. Nitric oxide (NO) production was measured with a nitrate reductase assay. Cell viability was determined with a Cell Counting Kit-8. Protein expression of active caspase 3, cytochrome c, endothelial NO synthase (eNOS), p-eNOS-Thr, p66, protein kinase C ßII (PKCßII), and p-PKCßII-Ser was measured by Western blot analysis. Accumulation of superoxide anion (O2˙) was measured with the reduction of ferricytochrome c. Cell apoptosis was determined with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining. RESULTS: Compared with control, high glucose decreased NO production (P < 0.0001) and reduced cells viability (P < 0.0001) in HUVECs. Compared with high glucose treatment, pretreatment of cells with propofol (5 µM, 2 hours) reduced high glucose-induced inhibitory p-eNOS-Thr phosphorylation (P < 0.0001), increasing NO production (P = 0.0007), decreased high glucose-induced p66 expression (P < 0.0001) and p66 mitochondrial translocation (P < 0.0001), O2˙ accumulation (P < 0.0001), mitochondrial cytochrome c release (P < 0.0001), active caspase 3 expression (P < 0.0001), and enhancing endothelial viability (P < 0.0001). Furthermore, propofol inhibited high glucose-induced PKCßII expression (P = 0.0002) and p-PKCßII-Ser phosphorylation (P < 0.0001). Moreover, the observed protective effect of propofol was quite similar to that of PKCßII inhibitor. CONCLUSIONS: Propofol, by a mechanism of decreasing high glucose-induced PKCßII expression and p-PKCßII-Ser phosphorylation, inhibits high glucose-induced p66 mitochondrial translocation, therefore protecting HUVECs from high glucose-induced endothelial dysfunction and apoptosis.