Impact of Omicron variant infection on the liver, kidney, and coagulation system in patients undergoing elective surgery: a retrospective case-control study.

Purpose: We aimed to investigate the impact of Omicron variant infection on the perioperative organ function in patients undergoing elective surgery. Methods: A total of 5029 patients who underwent elective surgery between October 2022 and January 2023 at our hospital were enrolled. Among them, the patients who underwent elective surgery between October 2022 and November 2022 composed Group 1 (not infected with the Omicron variant) the control group; those who underwent elective surgery between December 2022 and January 2023 composed Group 2 (one month after Omicron variant infection) the experimental group. We further divided the patients into two subgroups for analysis: the tumor subgroup and the nontumor subgroup. Data on organ system function indicators, including coagulation parameters, liver function, complete blood count (CBC), and kidney function, were collected before and after surgery. Differences between the two groups were subsequently analyzed via binary logistic regression analysis. Results: Compared with those in the uninfected patient group, the following changes were observed in patients with Omicron variant infection who underwent elective surgery one month after infection: prothrombin activity (PTa), prothrombin time (PT), fibrinogen, albumin/globulin, alanine aminotransferase (ALT), mean corpuscular hemoglobin concentration (MCHC), platelet (PLT), and anemia were increased AST/ALT, indirect bilirubin (IBILI), eosinophils, and uric acid were decreased before surgery; and lung infection/pneumonia and fibrinogen were increased, while AST/ALT, globulin, total bilirubin (TBIL), white blood cell count (WBC), and uric acid were decreased after surgery. There was no significant difference in the mortality rate or length of hospital stay (LOS) between the two groups. Subgroup analysis revealed elevated monocyte, PLT, and fibrinogen classification, levels and decreased globulin, prealbumin (PBA), eosinophil, and uric acid levels in the tumor subgroup of patients who underwent elective surgery one month after Omicron infection compared with those in the uninfected patients. Compared with the nontumor subgroup, fibrinogen levels, lung infection/pneumonia, TBIL, and PLT count were increased in the uninfected patients, while the globulin and eosinophil levels were decreased. Conclusion: Compared with uninfected patients, patients who underwent elective surgery one month after Omicron variant infection exhibited minimal changes in perioperative coagulation parameters, liver function, CBC counts, and kidney function. Additionally, no significant differences in postoperative mortality or LOS were observed between the two groups.

The Outcomes of Patients with Omicron Variant Infection who Undergo Elective Surgery: A Propensity-score-matched Case-control Study.

Aim: To investigate whether it is safe for patients with Omicron variant infection to undergo surgery during perioperative period. Methods: A total of 3,661 surgical patients were enrolled: 3,081 who were not infected with the Omicron variant and 580 who were infected with the Omicron variant. We conducted propensity score matching (PSM) with a ratio of 1:4 and a caliper value of 0.1 to match the infected and uninfected groups based on 13 variables. After PSM, we further divided the Infected group (560 cases) by the number of days between the preoperative Omicron variant infection and surgery: 0-7, 8-14, 15-30, and >30 days. Multivariate logistic regression analysis was subsequently conducted on the categorical variables and continuous variables with a P value below 0.05, thereby comparing the infected group (0-7, 8-14, 15-30, >30 days) and the uninfected group for perioperative complications. Results: Multivariate logistic regression analysis revealed that, compared to the uninfected group, among the four subgroups of the infected patients (0-7, 8-14, 15-30, >30 days), only renal insufficiency in the 8-14 days subgroup (OR: 0.09, 95%CI 0.01-0.74, P = 0.025) and anemia in the > 30 days subgroup (OR 0.6, 95%CI 0.4-0.9, P < 0.017) showed significant difference. However, there was no statistically significant difference in the incidence rate of blood transfusion, postoperative intensive care unit transfer, lung infection/pneumonia, pleural effusion, atelectasis, respiratory failure, sepsis, postoperative deep vein thrombosis, hypoalbuminemia, urinary tract infections, and medical expenses. Conclusion: Omicron infection does not significantly increase the risk of perioperative major complications. The Omicron infection may not be a sufficient risk factor to postpone elective surgery.

A quantitative study of airway ultrasound in predicting difficult laryngoscopy: A prospective study.

PURPOSE: As common clinical screening tests cannot effectively predict a difficult airway, and unanticipated difficult laryngoscopy remains a challenge for physicians. We herein used ultrasound to develop some point-of-care predictors for difficult laryngoscopy. METHODS: This prospective observational study included 502 patients who underwent laryngoscopy and a detailed sonographic assessment. Patients under 18 years old, or with maxillofacial deformities or fractures, limited mouth opening, limited neck movement or history of neck surgery were excluded from the study. Laryngoscopic views of all patients were scored and grouping using the modified Cormack-Lehane (CL) scoring system. The measurements acquired comprised tongue width, the longitudinal cross-sectional area of the tongue, tongue volume, the mandible-hyoid bone distance, the hyoid bone-glottis distance, the mandible-hyoid bone-glottis angle, the skin-thyrohyoid membrane distance, the glottis-superior edge of the thyroid cartilage distance (DGTC), the skin-hyoid bone distance, and the epiglottis midway-skin distance. ANOVA and Chi-square were used to compare differences between groups. Logistic regression was used to identify risk factors for difficult laryngoscopy and it was visualized by receiver operating characteristic curves and nomogram. R version 3.6.3 and SPSS version 26.0 were used for statistical analyses. RESULTS: Difficult laryngoscopy was indicated in 49 patients (CL grade Ⅲ - Ⅳ) and easy laryngoscopy in 453 patients (CL grade Ⅰ - Ⅱ). The ultrasound-measured mandible-hyoid bone-glottis angle and DGTC significantly differed between the 2 groups (p < 0.001). Difficult laryngoscopy was predicted by an area under the curve (AUC) of 0.930 with a threshold mandible-hyoid bone-glottis angle of 125.5° and by an AUC of 0.722 with a threshold DGTC of 1.22 cm. The longitudinal cross-sectional area of the tongue, tongue width, tongue volume, the mandible-hyoid distance, and the hyoid-glottis distance did not significantly differ between the groups. CONCLUSION: Difficult laryngoscopy may be anticipated in patients in whom the mandible-hyoid bone-glottis angle is smaller than 125.5° or DGTC is larger than 1.22 cm.

Effects of Malate Ringer's solution on myocardial injury in sepsis and enforcement effects of TPP@PAMAM-MR.

BACKGROUND: Myocardial dysfunction played a vital role in organ damage after sepsis. Fluid resuscitation was the essential treatment in which Lactate Ringer's solution (LR) was commonly used. Since LR easily led to hyperlactatemia, its resuscitation effect was limited. Malate Ringer's solution (MR) was a new resuscitation crystal liquid. Whether MR had a protective effect on myocardial injury in sepsis and the relevant mechanism need to be studied. METHODS: The cecal ligation and puncture (CLP) inducing septic model and lipopolysaccharide (LPS) stimulating cardiomyocytes were used, and the cardiac function, the morphology and function of mitochondria were observed. The protective mechanism of MR on myocardial injury was explored by proteomics. Then the effects of TPP@PAMAM-MR, which consisted of the mitochondria- targeting polymer embodied malic acid, was further observed. RESULTS: Compared with LR, MR resuscitation significantly prolonged survival time, improved the cardiac function, alleviated the damages of liver, kidney and lung following sepsis in rats. The proteomics of myocardial tissue showed that differently expressed proteins between MR and LR infusion involved oxidative phosphorylation, apoptosis. Further study found that MR decreased ROS, improved the mitochondrial morphology and function, and ultimately enhanced mitochondrial respiration and promoted ATP production. Moreover, MR infusion decreased the expression of apoptosis-related proteins and increased the expression of anti-apoptotic proteins. TPP@PAMAM@MA was a polymer formed by wrapping L-malic acid with poly amido amine (PAMAM) modified triphenylphosphine material. TPP@PAMAM-MR (TPP-MR), which was synthesized by replacing the L-malic acid of MR with TPP@PAMAM@MA, was more efficient in targeting myocardial mitochondria and was superior to MR in protecting the sepsis-inducing myocardial injury. CONCLUSION: MR was suitable for protecting myocardial injury after sepsis. The mechanism was related to MR improving the function and morphology of cardiomyocyte mitochondria and inhibiting cardiomyocyte apoptosis. The protective effect of TPP-MR was superior to MR.

Cardiorespiratory impact of intrathoracic pressure overshoot during artificial carbon dioxide pneumothorax: a randomized controlled study.

BACKGROUND: The aim of this study is to evaluate cardiovascular and respiratory effects of intrathoracic pressure overshoot (higher than insufflation pressure) in patients who underwent thoracoscopic esophagectomy procedures with carbon dioxide (CO2) pneumothorax. METHODS: This prospective research included 200 patients who were scheduled for esophagectomy from August 2016 to July 2020. The patients were randomly divided into the Stryker insufflator (STR) group and the Storz insufflator (STO) group. We recorded the changes of intrathoracic pressure, peak airway pressure, blood pressure, heart rate and central venous pressure (CVP) during artificial pneumothorax. The differences in blood gas analysis, the administration of vasopressors and the recovery time were compared between the two groups. RESULTS: We found that during the artificial pneumothorax, intrathoracic pressure overshoot occurred in both the STR group (8.9 mmHg, 38 times per hour) and the STO group (9.8 mmHg, 32 times per hour). The recorded maximum intrathoracic pressures were up to 58 mmHg in the STR group and 51 mmHg in the STO group. The average duration of intrathoracic pressure overshoot was significantly longer in the STR group (5.3 ± 0.86 s) vs. the STO group (1.2 ± 0.31 s, P < 0.01). During intrathoracic pressure overshoot, a greater reduction in systolic blood pressure (SBP) (5.6 mmHg vs. 1.1 mmHg, P < 0.01), a higher elevation in airway peak pressure (4.8 ± 1.17 cmH2O vs. 0.9 ± 0.41 cmH2O, P < 0.01), and a larger increase in CVP (8.2 ± 2.86 cmH2O vs. 4.9 ± 2.35 cmH2O, P < 0.01) were observed in the STR group than in the STO group. Vasopressors were also applied more frequently in the STR group than in the STO group (68% vs. 43%, P < 0.01). The reduction of SBP caused by thoracic pressure overshoot was significantly correlated with the duration of overshoot (R = 0.76). No obvious correlation was found between the SBP reduction and the maximum pressure overshoot. CONCLUSIONS: Intrathoracic pressure overshoot can occur during thoracoscopic surgery with artificial CO2 pneumothorax and may lead to cardiovascular adverse effects which highly depends on the duration of the pressure overshoot. TRIAL REGISTRATION: Clinicaltrials.gov ( NCT02330536 ; December 24, 2014).

DNMT3a-triggered downregulation of K2p 1.1 gene in primary sensory neurons contributes to paclitaxel-induced neuropathic pain.

Antineoplastic drugs induce dramatic transcriptional changes in dorsal root ganglion (DRG) neurons, which may contribute to chemotherapy-induced neuropathic pain. K2p 1.1 controls neuronal excitability by setting the resting membrane potential. Here, we report that systemic injection of the chemotherapy agent paclitaxel time-dependently downregulates the expression of K 2p 1.1 mRNA and its coding K2p 1.1 protein in the DRG neurons. Rescuing this downregulation mitigates the development and maintenance of paclitaxel-induced mechanical allodynia and heat hyperalgesia. Conversely, in the absence of paclitaxel administration, mimicking this downregulation decreases outward potassium current and increases excitability in the DRG neurons, leading to the enhanced responses to mechanical and heat stimuli. Mechanically, the downregulation of DRG K 2p 1.1 mRNA is attributed to paclitaxel-induced increase in DRG DNMT3a, as blocking this increase reverses the paclitaxel-induced the decrease of DRG K2p 1.1 and mimicking this increase reduces DRG K2p 1.1 expression. In addition, paclitaxel injection increases the binding of DNMT3a to the K 2p 1.1 gene promoter region and elevates the level of DNA methylation within this region in the DRG. These findings suggest that DNMT3a-triggered downregulation of DRG K2p 1.1 may contribute to chemotherapy-induced neuropathic pain.

Role of dorsal root ganglion K2p1.1 in peripheral nerve injury-induced neuropathic pain.

Abstract: Peripheral nerve injury-caused hyperexcitability and abnormal ectopic discharges in the primary sensory neurons of dorsal root ganglion (DRG) play a key role in neuropathic pain development and maintenance. The two-pore domain background potassium (K2P) channels have been identified as key determinants of the resting membrane potential and neuronal excitability. However, whether K2P channels contribute to neuropathic pain is still elusive. We reported here that K2P1.1, the first identified mammalian K2P channel, was highly expressed in mouse DRG and distributed in small-, medium-, and large-sized DRG neurons. Unilateral lumbar (L) 4 spinal nerve ligation led to a significant and time-dependent reduction of K2P1.1 mRNA and protein in the ipsilateral L4 DRG, but not in the contralateral L4 or ipsilateral L3 DRG. Rescuing this reduction through microinjection of adeno-associated virus-DJ expressing full-length K2P1.1 mRNA into the ipsilateral L4 DRG blocked spinal nerve ligation-induced mechanical, thermal, and cold pain hypersensitivities during the development and maintenance periods. This DRG viral microinjection did not affect acute pain and locomotor function. Our findings suggest that K2P1.1 participates in neuropathic pain development and maintenance and may be a potential target in the management of this disorder.

DNMT3a contributes to the development and maintenance of bone cancer pain by silencing Kv1.2 expression in spinal cord dorsal horn.

Abstract: Metastatic bone tumor-induced changes in gene transcription and translation in pain-related regions of the nervous system may participate in the development and maintenance of bone cancer pain. Epigenetic modifications including DNA methylation regulate gene transcription. Here, we report that intrathecal injection of decitabine, a DNA methyltransferase (DNMT) inhibitor, dose dependently attenuated the development and maintenance of bone cancer pain induced by injecting prostate cancer cells into the tibia. The level of the de novo DNMT3a, but not DNMT3b, time dependently increased in the ipsilateral L4/5 dorsal horn (not L4/5 dorsal root ganglion) after prostate cancer cells injection. Blocking this increase through microinjection of recombinant adeno-associated virus 5 (AAV5) expressing Dnmt3a shRNA into dorsal horn rescued prostate cancer cells-induced downregulation of dorsal horn Kv1.2 expression and impaired prostate cancer cells-induced pain hypersensitivity. In turn, mimicking this increase through microinjection of AAV5 expressing full-length Dnmt3a into dorsal horn reduced dorsal horn Kv1.2 expression and produced pain hypersensitivity in the absence of prostate cancer cells injection. Administration of neither decitabine nor virus affected locomotor function and acute responses to mechanical, thermal, or cold stimuli. Given that Dnmt3a mRNA is co-expressed with Kcna2 mRNA (encoding Kv1.2) in individual dorsal horn neurons, our findings suggest that increased dorsal horn DNMT3a contributes to bone cancer pain through silencing dorsal horn Kv1.2 expression. DNMT3a may represent a potential new target for cancer pain management.

Contribution of the Suppressor of Variegation 3-9 Homolog 1 in Dorsal Root Ganglia and Spinal Cord Dorsal Horn to Nerve Injury-induced Nociceptive Hypersensitivity.

BACKGROUND: Peripheral nerve injury-induced gene alterations in the dorsal root ganglion (DRG) and spinal cord likely participate in neuropathic pain genesis. Histone methylation gates gene expression. Whether the suppressor of variegation 3-9 homolog 1 (SUV39H1), a histone methyltransferase, contributes to nerve injury-induced nociceptive hypersensitivity is unknown. METHODS: Quantitative real-time reverse transcription polymerase chain reaction analysis, Western blot analysis, or immunohistochemistry were carried out to examine the expression of SUV39H1 mRNA and protein in rat DRG and dorsal horn and its colocalization with DRG µ-opioid receptor (MOR). The effects of a SUV39H1 inhibitor (chaetocin) or SUV39H1 siRNA on fifth lumbar spinal nerve ligation (SNL)-induced DRG MOR down-regulation and nociceptive hypersensitivity were examined. RESULTS: SUV39H1 was detected in neuronal nuclei of the DRG and dorsal horn. It was distributed predominantly in small DRG neurons, in which it coexpressed with MOR. The level of SUV39H1 protein in both injured DRG and ipsilateral fifth lumbar dorsal horn was time dependently increased after SNL. SNL also produced an increase in the amount of SUV39H1 mRNA in the injured DRG (n = 6/time point). Intrathecal chaetocin or SUV39H1 siRNA as well as DRG or intraspinal microinjection of SUV39H1 siRNA impaired SNL-induced allodynia and hyperalgesia (n = 5/group/treatment). DRG microinjection of SUV39H1 siRNA also restored SNL-induced DRG MOR down-regulation (n = 6/group). CONCLUSIONS: The findings of this study suggest that SUV39H1 contributes to nerve injury-induced allodynia and hyperalgesia through gating MOR expression in the injured DRG. SUV39H1 may be a potential target for the therapeutic treatment of nerve injury-induced nociceptive hypersensitivity.

Impact of artificial capnothorax on coagulation in patients during video-assisted thoracoscopic esophagectomy for squamous cell carcinoma.

BACKGROUND: Compared with the lung isolation using double-lumen endobronchial tube intubation, the artificial capnothorax using single-lumen endotracheal tube intubation has shown to be a safe, more convenient, and cost-effective procedure for thoracoscopic esophagectomy. However, the impact of capnothorax on coagulation is not well defined. Herein, we evaluate the impact of a capnothorax on coagulation and fibrinolysis in patients who undergoing thoracoscopic esophagectomy. METHODS: Between March 2014 and August 2014, 24 patients underwent thoracoscopic esophagectomies for esophageal cancer with the procedure of artificial capnothorax (group P); we also performed 24 thoracoscopic esophagectomy cases without using capnothorax (group N). The demographics and arterial blood gas, as well as the parameters of coagulation and fibrinolysis, of the two groups were analyzed. RESULTS: The pH value of group P after CO2 insufflation was significantly lower than in group N (P < 0.05), and the partial pressure of carbon dioxide (PaCO2) was significantly increased compared with group N (P < 0.05). The R and K values after CO2 insufflation were significantly longer than before anesthesia (P < 0.05), and both α angle and MA value after CO2 insufflation were significantly lower than those before anesthesia (P < 0.05). No significant differences in R value, K value, α angle, or MA value were observed between pre-anesthesia and termination of capnothorax. No significant difference in LY30 data was found between different groups (P > 0.05). CONCLUSION: Artificial capnothorax in patients receiving endoscopic resection of esophageal carcinoma had a significant impact on coagulation. These patients showed significant impairments in coagulation not observed in patients without artificial capnothorax.

Blast-Burn Combined Injury Followed by Immediate Seawater Immersion Induces Hemodynamic Changes and Metabolic Acidosis: An Experimental Study in a Canine Model.

BACKGROUND: Severe burn-blast combined injury often causes systematic dysfunction related to blood coagulation, anticoagulation, and fibrinolysis. However, studies of burn-blast combined injury followed by immersion in seawater are rarely reported. METHODS: A canine burn-blast combined injury model was established including blast injury caused by explosion immediately followed by burning with gelatinized gasoline flames. The dogs were randomly divided into four groups: burn-blast injury (BB group); burn-blast injury followed by seawater immersion for four hours (BBI group); only immersed in seawater (I group); and sham treatment with no injury or immersion (S group). Rectal temperature, hemodynamic parameters, arterial blood gas levels, and respiratory function were measured. RESULTS: The dogs in the BB group showed relatively more stable hemodynamic features than those in the BBI group. The pH, base excess (BE), HCO3-, PaO2, and PaCO2 levels in the S, I, and BB groups after injury did not differ from those before injury (p > 0.05). The PaO2 level in the BBI group decreased initially after injury and returned to a normal level by 10 hours after injury. The pH, BE, HCO3-, and PaCO2 values in the BBI group decreased continuously after injury and were significantly less than those in the other groups (p < 0.05). CONCLUSIONS: Burn-blast combined injury followed by seawater immersion induced hemodynamic changes and metabolic acidosis. Knowledge of the early symptoms and unique pathophysiology of the combined injury will be valuable in determining the appropriate management of such patients. Level of evidence: Prognostic study, level IV.

Prognostic gene landscapes and therapeutic insights in sepsis-induced coagulopathy.

BACKGROUND: Sepsis is a common and critical condition encountered in clinical practice that can lead to multi-organ dysfunction. Sepsis-induced coagulopathy (SIC) significantly affects patient outcomes. However, the precise mechanisms remain unclear, making the identification of effective prognostic and therapeutic targets imperative. METHODS: The analysis of transcriptome data from the whole blood of sepsis patients, facilitated the identification of key genes implicated in coagulation. Then we developed a prognostic model and a nomogram to predict patient survival. Consensus clustering classified sepsis patients into three subgroups for comparative analysis of immune function and immune cell infiltration. Single-cell sequencing elucidated alterations in intercellular communication between platelets and immune cells in sepsis, as well as the role of the coagulation-related gene FYN. Real-time quantitative PCR determined the mRNA levels of critical coagulation genes in septic rats' blood. Finally, administration of a FYN agonist to septic rats was observed for its effects on coagulation functions and survival. RESULTS: This study identified four pivotal genes-CFD, FYN, ITGAM, and VSIG4-as significant predictors of survival in patients with sepsis. Among them, CFD, FYN, and ITGAM were underexpressed, while VSIG4 was upregulated in patients with sepsis. Moreover, a nomogram that incorporates the coagulation-related genes (CoRGs) risk score with clinical features of patients accurately predicted survival probabilities. Subgroup analysis of CoRGs expression delineated three molecular sepsis subtypes, each with distinct prognoses and immune profiles. Single-cell sequencing shed light on heightened communication between platelets and monocytes, T cells, and plasmacytoid dendritic cells, alongside reduced interactions with neutrophils in sepsis. The collagen signaling pathway was found to be essential in this dynamic. FYN may affect platelet function by modulating factors such as ELF1, PTCRA, and RASGRP2. The administration of the FYN agonist can effectively improve coagulation dysfunction and survival in septic rats. CONCLUSIONS: The research identifies CoRGs as crucial prognostic markers for sepsis, highlighting the FYN gene's central role in coagulation disorders associated with the condition and suggesting novel therapeutic intervention strategies.

Corrigendum: Integrative single-cell RNA sequencing and metabolomics decipher the imbalanced lipid-metabolism in maladaptive immune responses during sepsis.

[This corrects the article DOI: 10.3389/fimmu.2023.1181697.].

Association Between Low Serum Albumin and Preoperative Deep Vein Thrombosis in Patients Undergoing Total Joint Arthroplasty: A Retrospective Study.

To investigate the association between albumin and preoperative deep vein thrombosis (DVT) in patients undergoing total joint arthroplasty (TJA). This study enrolled 2133 patients. We created the receiver operator characteristic curve to determine the cut-off values for preoperative albumin (bromocresol green method) and DVT in TJA patients. We divided the patients into groups based on the albumin cut-off value and then assessed the risk factors in a multivariate logistic regression analysis. DVT occurred in 110 cases. The cut-off value for albumin was 37.2 g/L and the area under the curve was 0.611. Multivariate logistic regression analysis revealed that the risk for DVT before TJA in patients with albumin <37.2 g/L was increased by 1.99 times (P = .001, 95% confidence interval [CI] [1.34-2.97]); albumin of 30 to 37.2 g/L group and the albumin < 30 g/L group increased by 1.9 times (P = .002, 95% CI [1.28-2.88]) and 3.25 times (P = .015, 95% CI [1.26-8.4]), respectively. The patients in the albumin of 30 to 37.2 g/L and the albumin < 30 g/L group had 1.6 times (P < .001, 95% CI [1.3-1.99] and 6.1 times (P < .001, 95% CI [3.46-10.75]), respectively, higher risk of perioperative transfusion. Patients older than 69.5 years had a 3.8-fold increased risk of preoperative DVT (P = .005, 95% CI [2.47-5.78]). Corticosteroid use had a 3 times higher risk of preoperative DVT (P = .013, 95% CI [1.26-7.2]). We found that albumin < 37.2 g/L, patients older than 69.5 years, and corticosteroid use were independent risk factors for preoperative DVT in TJA patients. Additionally, the lower the preoperative albumin level, the greater the odds of preoperative DVT formation, and the higher the risk of perioperative transfusion.

Spinal apolipoprotein E is involved in inflammatory pain via regulating lipid metabolism and glial activation in the spinal dorsal horn.

INTRODUCTION: Inflammation and nerve injury promote astrocyte activation, which regulates the development and resolution of pain, in the spinal dorsal horn. APOE regulates lipid metabolism and is predominantly expressed in the astrocytes. However, the effect of astrocytic APOE and lipid metabolism on spinal cellular function is unclear. This study aimed to investigate the effect of spinal Apoe on spinal cellular functions using the complete Freund's adjuvant (CFA)-induced inflammatory pain mouse model. METHODS: After intraplantar injection of CFA, we assessed pain behaviors in C57BL6 and Apoe knockout (Apoe-/-) mice using von Frey and Hargreaves' tests and analyzed dorsal horn samples (L4-5) using western blotting, immunofluorescence, quantitative real-time polymerase chain reaction, and RNA sequencing. RESULTS: The Apoe levels were markedly upregulated at 2 h and on days 1 and 3 post-CFA treatment. Apoe was exclusively expressed in the astrocytes. Apoe-/- mice exhibited decreased pain on day 1, but not at 2 h, post-CFA treatment. Apoe-/- mice also showed decreased spinal neuron excitability and paw edema on day 1 post-CFA treatment. Global transcriptomic analysis of the dorsal horn on day 1 post-CFA treatment revealed that the differentially expressed mRNAs in Apoe-/- mice were associated with lipid metabolism and the immune system. Astrocyte activation was impaired in Apoe-/- mice on day 1 post-CFA treatment. The intrathecal injection of Apoe antisense oligonucleotide mitigated CFA-induced pain hypersensitivity. CONCLUSIONS: Apoe deficiency altered lipid metabolism in astrocytes, exerting regulatory effects on immune response, astrocyte activation, and neuronal activity and consequently disrupting the maintenance of inflammatory pain after peripheral inflammation. Targeting APOE is a potential anti-nociception and anti-inflammatory strategy.

Integrative single-cell RNA sequencing and metabolomics decipher the imbalanced lipid-metabolism in maladaptive immune responses during sepsis.

Background: To identify differentially expressed lipid metabolism-related genes (DE-LMRGs) responsible for immune dysfunction in sepsis. Methods: The lipid metabolism-related hub genes were screened using machine learning algorithms, and the immune cell infiltration of these hub genes were assessed by CIBERSORT and Single-sample GSEA. Next, the immune function of these hub genes at the single-cell level were validated by comparing multiregional immune landscapes between septic patients (SP) and healthy control (HC). Then, the support vector machine-recursive feature elimination (SVM-RFE) algorithm was conducted to compare the significantly altered metabolites critical to hub genes between SP and HC. Furthermore, the role of the key hub gene was verified in sepsis rats and LPS-induced cardiomyocytes, respectively. Results: A total of 508 DE-LMRGs were identified between SP and HC, and 5 hub genes relevant to lipid metabolism (MAPK14, EPHX2, BMX, FCER1A, and PAFAH2) were screened. Then, we found an immunosuppressive microenvironment in sepsis. The role of hub genes in immune cells was further confirmed by the single-cell RNA landscape. Moreover, significantly altered metabolites were mainly enriched in lipid metabolism-related signaling pathways and were associated with MAPK14. Finally, inhibiting MAPK14 decreased the levels of inflammatory cytokines and improved the survival and myocardial injury of sepsis. Conclusion: The lipid metabolism-related hub genes may have great potential in prognosis prediction and precise treatment for sepsis patients.

VDAC2 malonylation participates in sepsis-induced myocardial dysfunction via mitochondrial-related ferroptosis.

Sepsis-induced myocardial dysfunction (SIMD) is a prevalent and severe form of organ dysfunction with elusive underlying mechanisms and limited treatment options. In this study, the cecal ligation and puncture and lipopolysaccharide (LPS) were used to reproduce sepsis model in vitro and vivo. The level of voltage-dependent anion channel 2 (VDAC2) malonylation and myocardial malonyl-CoA were detected by mass spectrometry and LC-MS-based metabolomics. Role of VDAC2 malonylation on cardiomyocytes ferroptosis and treatment effect of mitochondrial targeting nano material TPP-AAV were observed. The results showed that VDAC2 lysine malonylation was significantly elevated after sepsis. In addition, the regulation of VDAC2 lysine 46 (K46) malonylation by K46E and K46Q mutation affected mitochondrial-related ferroptosis and myocardial injury. The molecular dynamic simulation and circular dichroism further demonstrated that VDAC2 malonylation altered the N-terminus structure of the VDAC2 channel, causing mitochondrial dysfunction, increasing mitochondrial ROS levels, and leading to ferroptosis. Malonyl-CoA was identified as the primary inducer of VDAC2 malonylation. Furthermore, the inhibition of malonyl-CoA using ND-630 or ACC2 knock-down significantly reduced the malonylation of VDAC2, decreased the occurrence of ferroptosis in cardiomyocytes, and alleviated SIMD. The study also found that the inhibition of VDAC2 malonylation by synthesizing mitochondria targeting nano material TPP-AAV could further alleviate ferroptosis and myocardial dysfunction following sepsis. In summary, our findings indicated that VDAC2 malonylation plays a crucial role in SIMD and that targeting VDAC2 malonylation could be a potential treatment strategy for SIMD.

Associations Between Plasma Klotho with Renal Function and Cerebrospinal Fluid Amyloid-ß Levels in Alzheimer's Disease: The Chongqing Ageing & Dementia Study.

BACKGROUND: The kidney-brain crosstalk has been involved in Alzheimer's disease (AD) with the mechanism remaining unclear. The anti-aging factor Klotho was reported to attenuate both kidney injury and AD pathologies. OBJECTIVE: To investigate whether plasma Klotho participated in kidney-brain crosstalk in AD. METHODS: We enrolled 33 PiB-PET-positive AD patients and 33 amyloid-ß (Aß)-negative age- and sex-matched cognitively normal (CN) controls from the Chongqing Ageing & Dementia Study (CADS). The levels of plasma Klotho, Aß, and tau in the cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay. RESULTS: We found higher plasma Klotho and lower estimated glomerular filtration rate (eGFR) levels in AD patients compared with CN. The eGFR was positively associated with Aß42, Aß40 levels in CSF and negatively associated with CSF T-tau levels. Plasma Klotho levels were both negatively correlated with CSF Aß42 and eGFR. Mediation analysis showed that plasma Klotho mediated 24.96% of the association between eGFR and CSF Aß42. CONCLUSION: Renal function impacts brain Aß metabolism via the kidney-brain crosstalk, in which the plasma Klotho may be involved as a mediator. Targeting Klotho to regulate the kidney-brain crosstalk provides potential therapeutic approaches for AD.

The Landscape of Featured Metabolism-Related Genes and Imbalanced Immune Cell Subsets in Sepsis.

Sepsis is a heterogeneous disease state triggered by an uncontrolled inflammatory host response with high mortality and morbidity in severely ill patients. Unfortunately, the treatment effectiveness varies among sepsis patients and the underlying mechanisms have yet to be elucidated. The present aim is to explore featured metabolism-related genes that may become the biomarkers in patients with sepsis. In this study, differentially expressed genes (DEGs) between sepsis and non-sepsis in whole blood samples were identified using two previously published datasets (GSE95233 and GSE54514). A total of 66 common DEGs were determined, namely, 52 upregulated and 14 downregulated DEGs. The Gene Set Enrichment Analysis (GSEA) results indicated that these DEGs participated in several metabolic processes including carbohydrate derivative, lipid, organic acid synthesis oxidation reduction, and small-molecule biosynthesis in patients with sepsis. Subsequently, a total of 8 hub genes were screened in the module with the highest score from the Cytoscape plugin cytoHubba. Further study showed that these hub DEGs may be robust markers for sepsis with high area under receiver operating characteristic curve (AUROC). The diagnostic values of these hub genes were further validated in myocardial tissues of septic rats and normal controls by untargeted metabolomics analysis using liquid chromatography-mass spectrometry (LC-MS). Immune cell infiltration analysis revealed that different infiltration patterns were mainly characterized by B cells, T cells, NK cells, monocytes, macrophages, dendritics, eosinophils, and neutrophils between sepsis patients and normal controls. This study indicates that metabolic hub genes may be hopeful biomarkers for prognosis prediction and precise treatment in sepsis patients.

Transcriptome analysis of microRNAs, circRNAs, and mRNAs in the dorsal root ganglia of paclitaxel-induced mice with neuropathic pain.

The microtubule-stabilizing drug paclitaxel (PTX) is a chemotherapeutic agent widely prescribed for the treatment of various tumor types. The main adverse effect of PTX-mediated therapy is chemotherapy-induced peripheral neuropathy (CIPN) and neuropathic pain, which are similar to the adverse effects associated with other chemotherapeutic agents. Dorsal root ganglia (DRG) contain primary sensory neurons; any damage to these neurons or their axons may lead to neuropathic pain. To gain molecular and neurobiological insights into the peripheral sensory system under conditions of PTX-induced neuropathic pain, we used transcriptomic analysis to profile mRNA and non-coding RNA expression in the DRGs of adult male C57BL/6 mice treated using PTX. RNA sequencing and in-depth gene expression analysis were used to analyze the expression levels of 67,228 genes. We identified 372 differentially expressed genes (DEGs) in the DRGs of vehicle- and PTX-treated mice. Among the 372 DEGs, there were 8 mRNAs, 3 long non-coding RNAs (lncRNAs), 16 circular RNAs (circRNAs), and 345 microRNAs (miRNAs). Moreover, the changes in the expression levels of several miRNAs and circRNAs induced by PTX have been confirmed using the quantitative polymerase chain reaction method. In addition, we compared the expression levels of differentially expressed miRNAs and mRNA in the DRGs of mice with PTX-induced neuropathic pain against those evaluated in other models of neuropathic pain induced by other chemotherapeutic agents, nerve injury, or diabetes. There are dozens of shared differentially expressed miRNAs between PTX and diabetes, but only a few shared miRNAs between PTX and nerve injury. Meanwhile, there is no shared differentially expressed mRNA between PTX and nerve injury. In conclusion, herein, we show that treatment with PTX induced numerous changes in miRNA expression in DRGs. Comparison with other neuropathic pain models indicates that DEGs in DRGs vary greatly among different models of neuropathic pain.