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Long-term hyperglycemia can lead to diabetic cardiomyopathy (DCM), a main lethal complication of diabetes. However, the mechanisms underlying DCM development have not been fully elucidated. Heat shock protein A12A (HSPA12A) is the atypic member of the Heat shock 70kDa protein family. In the present study, we found that the expression of HSPA12A was upregulated in the hearts of mice with streptozotocin-induced diabetes, while ablation of HSPA12A improved cardiac systolic and diastolic dysfunction and increased cumulative survival of diabetic mice. An increased expression of HSPA12A was also found in H9c2 cardiac cells following treatment with high glucose (HG), while overexpression of HSPA12A-enhanced the HG-induced cardiac cell death, as reflected by higher levels of propidium iodide cells, lactate dehydrogenase leakage, and caspase 3 cleavage. Moreover, the HG-induced increase of oxidative stress, as indicated by dihydroethidium staining, was exaggerated by HSPA12A overexpression. Further studies demonstrated that the HG-induced increases of protein kinase B and forkhead box transcription factors 1 phosphorylation were diminished by HSPA12A overexpression, while pharmacologically inhibition of protein kinase B further enhanced the HG-induced lactate dehydrogenase leakage in HSPA12A overexpressed cardiac cells. Together, the results suggest that hyperglycemia upregulated HSPA12A expression in cardiac cells, by which induced cell death to promote DCM development. Targeting HSPA12A may serve as a potential approach for DCM management.
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Diabetes Mellitus Experimental , Cardiomiopatías Diabéticas , Hiperglucemia , Animales , Ratones , Diabetes Mellitus Experimental/metabolismo , Cardiomiopatías Diabéticas/complicaciones , Cardiomiopatías Diabéticas/metabolismo , Proteínas de Choque Térmico/metabolismo , Hiperglucemia/complicaciones , Hiperglucemia/metabolismo , Lactato Deshidrogenasas/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , RatasRESUMEN
Myocardial ischemia/reperfusion (MI/R) injury is a major cause of adverse outcomes of revascularization following myocardial infarction. Anaerobic glycolysis during myocardial ischemia is well studied, but the role of aerobic glycolysis during the early phase of reperfusion is incompletely understood. Lactylation of Histone H3 (H3) is an epigenetic indicator of the glycolytic switch. Heat shock protein A12A (HSPA12A) is an atypic member of the HSP70 family. In the present study, we report that, during reperfusion following myocardial ischemia, HSPA12A was downregulated and aerobic glycolytic flux was decreased in cardiomyocytes. Notably, HSPA12A KO in mice exacerbated MI/R-induced aerobic glycolysis decrease, cardiomyocyte death, and cardiac dysfunction. Gain- and loss-of-function studies demonstrated that HSPA12A was required to support cardiomyocyte survival upon hypoxia/reoxygenation (H/R) challenge and that its protective effects were mediated by maintaining aerobic glycolytic homeostasis for H3 lactylation. Further analyses revealed that HSPA12A increased Smurf1-mediated Hif1α protein stability, thus increasing glycolytic gene expression to maintain appropriate aerobic glycolytic activity to sustain H3 lactylation during reperfusion and, ultimately, improving cardiomyocyte survival to attenuate MI/R injury.
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Infarto del Miocardio , Isquemia Miocárdica , Daño por Reperfusión Miocárdica , Animales , Ratones , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Infarto del Miocardio/metabolismo , Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Miocitos Cardíacos/metabolismoRESUMEN
INTRODUCTION: Cardiac fibrosis is the main driver for adverse remodeling and progressive functional decline in nearly all types of heart disease including myocardial infarction (MI). The activation of cardiac fibroblasts (CF) into myofibroblasts is responsible for cardiac fibrosis. Unfortunately, no ideal approach for controlling CF activation currently exists. OBJECTIVES: This study investigated the role of Heat shock protein A12A (HSPA12A), an atypical member of the HSP70 family, in CF activation and MI-induced cardiac fibrosis. METHODS: Primary CF and Hspa12a knockout mice were used in the experiments. CF activation was indicated by the upregulation of myofibroblast characters including alpha-Smooth muscle actin (αSMA), Collagen, and Fibronectin. Cardiac fibrosis was illustrated by Masson's trichrome and picrosirius staining. Cardiac function was examined using echocardiography. Glycolytic activity was indicated by levels of extracellular lactate and the related protein expression. Protein stability was examined following cycloheximide and MG132 treatment. Protein-protein interaction was examined by immunoprecipitation-immunoblotting analysis. RESULTS: HSPA12A displayed a high expression level in quiescent CF but showed a decreased expression in activated CF, while ablation of HSPA12A in mice promoted CF activation and cardiac fibrosis following MI. HSPA12A overexpression inhibited the activation of primary CF through inhibiting glycolysis, while HSPA12A knockdown showed the opposite effects. Moreover, HSPA12A upregulated the protein expression of transcription factor p53, by which mediated the HSPA12A-induced inhibition of glycolysis and CF activation. Mechanistically, this action of HSPA12A was achieved by acting as a scaffolding protein to bind p53 and ubiquitin specific protease 10 (USP10), thereby promoting the USP10-mediated p53 protein stability and the p53-medicated glycolysis inhibition. CONCLUSION: The present study provided clear evidence that HSPA12A is a novel endogenous inhibitor of CF activation and cardiac fibrosis. Targeting HSPA12A in CF could represent a promising strategy for the management of cardiac fibrosis in patients.
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The present study aimed to dynamically observe the segmental and global myocardial movements of the left ventricle during coronary artery bypass grafting by transesophageal speckle-tracking echocardiography, and to assess the effect of sevoflurane on cardiac function. Sixty-four patients scheduled for the off-pump coronary artery bypass grafting were randomly divided into a sevoflurane-based anesthesia (AS) group and a propofol-based total intravenous anesthesia (AA) group. The AS group demonstrated a higher absolute value of left ventricular global longitudinal strain than that of the AA group at both T 1 (after harvesting all grafts and before coronary anastomosis) and T 2 (30 min after completing all coronary anastomoses) ( P < 0.05). Moreover, strain improvement in the segment with the highest preoperative strain was significantly reduced in the AS group, compared with the AA group at both T 1 and T 2 ( P < 0.01). The flow of the left internal mammary artery-left anterior descending artery graft was superior, and the postoperative concentration of troponin T decreased rapidly in the AS group, compared with the AA group ( P < 0.05). Compared with total intravenous anesthesia, sevoflurane resulted in a significantly higher global longitudinal strain, stroke volume, and cardiac output. Sevoflurane also led to an amelioration in the condition of the arterial graft. Furthermore, sevoflurane significantly reduced strain improvement in the segmental myocardium with a high preoperative strain value. The findings need to be replicated in larger studies.
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Neonatal maternal separation (NMS) is an early-life stress (ELS) that can result in adult visceral hypersensitivity, which is usually manifested as chronic visceral pain. Although mast cells and corticotropin-releasing hormone (CRH) neurons are involved in stress response, whether there is an interaction between mast cells and CRH neurons in hypothalamic paraventricular nucleus (PVN) during the ELS-induced visceral hypersensitivity remains elusive. Herein, we established an NMS model by separating neonatal mice from their mothers, and observed that these mice presented visceral hypersensitivity in adulthood, as indicated by elevated abdominal withdrawal reflex and lowered visceral pain threshold. The NMS-induced adult visceral hypersensitivity was accompanied by activation of mast cells and CRH neurons in PVN. Also, NMS increased the histamine content (an inflammatory mediator mainly released by mast cells) and histamine H2 receptor (H2R) expression of CRH neurons in PVN. Remarkably, intra-PVN administration with mast cell stabilizer attenuated the NMS-induced CRH neuronal activation and adult visceral pain, while histamine administration showed the opposite effects. Moreover, intra-PVN injection with H2R antagonist alleviated the NMS-induced CRH neuronal activation, PKA and CREB phosphorylation, and importantly, adult visceral pain. Together, our findings revealed a role of an interaction between paraventricular mast cells and CRH neurons in NMS-induced adult visceral hypersensitivity, thereby providing a perspective for the management of visceral pain.
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BACKGROUND: The aim of this study was to investigate the analgesic effect and safety of ultrasound-guided thoracic paravertebral block (UG-TPVB) in Chinese elderly patients undergoing video-assisted thoracic lobectomy (VATL) and to study the influence of aging factors on these effects. METHODS: This study was a single-center, single-blind, prospective, randomized, controlled trial. A total of 300 patients scheduled for VATL were recruited and randomly divided into the UG-TPVB group (T group) and conventional anesthesia group (C group) according to the recruitment order, and subgroups were set up according to whether the age was ≥65 years old or not. The postoperative 12, 24, and 48 h static/dynamic visual analog scale (VAS) scores, intraoperative fentanyl consumption, postoperative extubation time, post-anesthesia care unit (PACU) stay time, hospitalization days, postoperative complications, and other indicators were compared between the two groups. RESULTS: The postoperative 12, 24, and 48 h static/dynamic VAS scores of the T group were significantly lower than those of the C group. The intraoperative fentanyl consumption, postoperative extubation time, PACU stay time, and postoperative hospitalization days were significantly lower than those of the C group. The incidence of postoperative 48 h urinary retention in the T group was significantly lower than that in the C group. These advantages showed no significant difference or slight difference between elderly patients and nonelderly patients, indicating that UG-TPVB did not influence the analgesic effect and safety of VATL patients by age or age difference. CONCLUSION: UG-TPVB is an effective and safe perioperative analgesia method for elderly VATL patients. Its application improves the quality of life and prognosis of elderly VATL patients.
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Analgesia , Dolor Postoperatorio , Humanos , Anciano , Dolor Postoperatorio/tratamiento farmacológico , Estudios Prospectivos , Calidad de Vida , Método Simple Ciego , Cirugía Torácica Asistida por Video/métodos , Complicaciones Posoperatorias , Analgésicos , Ultrasonografía Intervencional , FentaniloRESUMEN
Mood instability, a subjective emotional state defined as rapid mood oscillations of up and down, is a symptom that occurs in several psychiatric disorders, particularly major depressive disorder and bipolar disorder. Heat shock protein A12A (HSPA12A) shows decreased expression in the brains of schizophrenia patients. However, the causal effects of HSPA12A in any psychiatric disorders are completely unknown. To investigate whether HSPA12A affects mood stability, Hspa12a-knockout mice (Hspa12a-/-) and wild-type (WT) littermates were subjected to tests of open field, forced swimming, elevated plus maze, and sucrose preference. Cerebral lactate levels were measured in cerebrospinal fluid (CSF). Adult hippocampal neurogenesis (AHN) was assessed by BrdU labeling. We found that acute mood stress increased hippocampal HSPA12A expression and CSF lactate levels in mice. However, Hspa12a-/- mice exhibited behaviors of mood instability (anhedonia, lower locomotor activity, antidepression, and anxiety), which were accompanied by impaired AHN, decreased CSF lactate levels, and downregulated hippocampal glycolytic enzyme expression. By contrast, HSPA12A overexpression increased lactate production and glycolytic enzyme expression of primary hippocampal neurons. Intriguingly, lactate administration alleviated the mood instability and AHN impairment in Hspa12a-/- mice. Further analyses revealed that HSPA12A was necessary for sustaining cerebral lactate homeostasis, which could be mediated by inhibiting GSK3ß in hippocampal neurons, to maintain AHN and mood stabilization. Taken together, HSPA12A is defined as a novel regulator of mood stability and exerts therapeutic potential for mood disorder. Our findings establish a framework for determining mood disorder and AHN relevance of cerebral lactate homeostasis. HSPA12A is a novel mood stabilizer through inhibiting GSK3ß in hippocampal neurons, thereby sustaining glycolysis-generated lactate to maintain cerebral lactate homeostasis, which ultimately leading to maintenance of hippocampal neurogenesis and mood stabilization.
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Afecto , Proteínas HSP70 de Choque Térmico , Neurogénesis , Animales , Ratones , Trastorno Depresivo Mayor/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hipocampo/metabolismo , Ácido Láctico/metabolismo , Ratones Noqueados , Proteínas HSP70 de Choque Térmico/metabolismoRESUMEN
Rationale: Liver ischemia-reperfusion (LI/R) injury is characterized by two interconnected phases: local ischemia that causes hepatic cell damage to release damage-associated molecular pattern (DAMPs), and DAMPs that recruit immune cells to elicit inflammatory cascade for further injury of hepatocytes. High-mobility group box 1 (HMGB1) is a representative DAMP. Studies in macrophages demonstrated that HMGB1 is secreted after lactylation during sepsis. However, whether lactylation mediates HMGB1 secretion from hepatocytes after LI/R is known. Heat shock protein A12A (HSPA12A) is an atypical member of HSP70 family. Methods: Gene expression was examined by microarray analysis and immunoblotting. The hepatic injury was analyzed using released ALT and AST activities assays. Hepatic macrophage chemotaxis was evaluated by Transwell chemotaxis assays. Inflammatory mediators were evaluated by immunoblotting. HMGB1 secretion was examined in exosomes or serum. HMGB1 lactylation was determined using immunoprecipitation and immunoblotting. Results: Here, we report that LI/R decreased HSPA12A expression in hepatocytes, while hepatocyte-specific HSPA12A overexpression attenuated LI/R-induced hepatic dysfunction and mortality of mice. We also noticed that hepatocyte HSPA12A overexpression suppressed macrophage chemotaxis to LI/R-exposed livers in vivo and to hypoxia/reoxygenation (H/R)-exposed hepatocytes in vitro. The LI/R-increased serum HMGB1 levels of mice and the H/R-increased HMGB1 lactylation and secretion levels of hepatocytes were also inhibited by hepatocyte HSPA12A overexpression. By contrast, HSPA12A knockout in hepatocytes promoted not only H/R-induced HMGB1 lactylation and secretion of hepatocytes but also the effects of H/R-hepatocytes on macrophage chemotaxis and inflammatory activation, while all these deleterious effects of HSPA12A knockout were reversed following hepatocyte HMGB1 knockdown. Further molecular analyses showed that HSPA12A overexpression reduced glycolysis-generated lactate, thus decreasing HMGB1 lactylation and secretion from hepatocytes, thereby inhibiting not only macrophage chemotaxis but also the subsequent inflammatory cascade, which ultimately protecting against LI/R injury. Conclusion: Taken together, these findings suggest that hepatocyte HSPA12A is a novel regulator that protects livers from LI/R injury by suppressing glycolysis-mediated HMGB1 lactylation and secretion from hepatocytes to inhibit macrophage chemotaxis and inflammatory activation. Therefore, targeting hepatocyte HSPA12A may have therapeutic potential in the management of LI/R injury in patients.
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Proteína HMGB1 , Hepatopatías , Daño por Reperfusión , Animales , Ratones , Proteínas de Choque Térmico/metabolismo , Proteína HMGB1/metabolismo , Quimiotaxis , Hígado/metabolismo , Hepatocitos/metabolismo , Macrófagos/metabolismo , Glucólisis , Daño por Reperfusión/metabolismo , Ratones Endogámicos C57BLRESUMEN
Angiogenesis plays a critical role in wound healing postmyocardial infarction (MI). However, there is still a lack of ideal angiogenic therapeutics for rescuing ischemic hearts clinically, suggesting that a more understanding regarding angiogenesis regulation is urgently needed. Heat shock protein A12A (HSPA12A) is an atypical member of the HSP70 family. Here, we demonstrated that HSPA12A was upregulated during endothelial tube formation, a characteristic of in vitro angiogenesis. Intriguingly, overexpression of HSPA12A promoted in vitro angiogenic characteristics including proliferation, migration, and tube formation of endothelial cells. By contrast, deficiency of HSPA12A impaired myocardial angiogenesis and worsened cardiac dysfunction post-MI in mice. The expression of genes related to angiogenesis (VEGF, VEGFR2, and Ang-1) was decreased by HSPA12A deficiency in MI hearts of mice, whereas their expression was increased by HSPA12A overexpression in endothelial cells. HSPA12A overexpression in endothelial cells increased phosphorylation levels and nuclear localization of AP-1, a transcription factor dominating angiogenic gene expression. Also, HSPA12A increased p38 and ERK phosphorylation levels, whereas inhibition of p38 or ERKs diminished the HSPA12A-promoted AP-1 phosphorylation and nuclear localization, as well as VEGF and VEGFR2 expression in endothelial cells. Notably, inhibition of either p38 or ERKs diminished the HSPA12A-promoted in vitro angiogenesis characteristics. The findings identified HSPA12A as a novel angiogenesis activator, and HSPA12A might represent a viable strategy for the management of myocardial healing in patients with ischemic heart diseases.
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Proteínas HSP70 de Choque Térmico/metabolismo , Infarto del Miocardio , Factor de Transcripción AP-1 , Animales , Células Endoteliales/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteínas de Choque Térmico/genética , Ratones , Infarto del Miocardio/metabolismo , Neovascularización Patológica , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Metastasis is responsible for most of the hepatocellular carcinoma (HCC)-associated death. However, its underlying mechanism has yet to be fully elucidated. Glycolysis-derived lactate has been shown to be a powerful regulator of cancer metastasis. Heat shock protein A12A (HSPA12A) encodes a novel member of HSP70 family. We have recently demonstrated that heat shock protein A12A (HSPA12A) inhibited renal cancer cell migration by suppressing lactate output and glycolytic activity, which were mediated by unstabilizing CD147 and promoting its degradation. By striking contrast, here we demonstrated that HSPA12A promoted migration of human HCC cells. Extracellular acidification, lactate export, and glycolytic activity in HCC cells were also promoted following HSPA12A overexpression. Further analysis revealed that HSPA12A interacted with MCT4 and increased its membrane localization, thereby promoting export of lactate generated from glycolysis; this led, ultimately, to HCC cell migration. Our results revealed the opposite effect of HSPA12A on migration of renal cancer cells and that of HCC cells. Of note, in contrast to the inhibitory effect on CD147 expression in renal cancer cells, we found that HSPA12A increased CD147 expression in HCC cells, indicating that the expression of CD147 might exist heterogeneity in different cancer cell types. Taken together, we identified HSPA12A as an activator of HCC migration, a role opposite to that of renal cancer cells. Inhibiting HSPA12A might be a potential therapeutic intervention for HCC metastasis.
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Carcinoma Hepatocelular , Proteínas HSP70 de Choque Térmico/metabolismo , Neoplasias Renales , Neoplasias Hepáticas , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Femenino , Proteínas de Choque Térmico , Humanos , Lactatos , Neoplasias Hepáticas/metabolismo , MasculinoRESUMEN
Local anesthetics (LAs) are widely used for intraoperative anesthesia and postoperative analgesia. However, LAs (e.g. Bupivacaine) can evoke myotoxicity that closely associated to mitochondrial damage. PGC1a is a mast co-factor for mitochondrial quality control. We have recently demonstrated that PGC1a can be activated by HSPA12A in hepatocytes, suggesting a possibility that HSPA12A protects from LAs myotoxicity through activating PGC1α-mediated mitochondrial integrity. Here, we reported that HSPA12A was downregulated during Bupivacaine-induced myotoxicity in skeletal muscles of mice in vivo and C2c12 myoblast cultures in vitro. Intriguingly, overexpression of HSPA12A attenuated the Bupivacaine-induced C2c12 cell death. We also noticed that the Bupivacaine-induced decrease of glucose consumption and ATP production was improved by HSPA12A overexpression. Moreover, overexpression of HSPA12A in C2c12 cells attenuated the Bupivacaine-induced decrease of mitochondrial contents and increase of mitochondrial fragmentation. The Bupivacaine-induced reduction of PGC1α expression and nuclear localization was markedly attenuated by HSPA12A overexpression. Importantly, pretreatment with a selective PGC1α inhibitor (SR-18292) abolished the protection of HSPA12A from Bupivacaine-induced death and mitochondrial loss in C2c12 cells. Altogether, the findings indicate that downregulation of HSPA12A underlies myotoxicity of Local anesthetic agent Bupivacaine through inhibiting PGC1α-mediated Mitochondrial Integrity. Thus, HSPA12A might represent a viable strategy for preventing myotoxicity of LAs.
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Bupivacaína/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Enfermedades Musculares/inducido químicamente , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Anestésicos Locales/toxicidad , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Proteínas HSP70 de Choque Térmico , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Enfermedades Musculares/metabolismo , Enfermedades Musculares/patología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genéticaRESUMEN
Acute lung injury (ALI) is a critical manifestation of sepsis/septic shock. Disruption of endothelial barrier function is critical for ALI pathogenesis; however, the regulation of endothelial barrier integrity remains largely unclear. Heat shock protein A12A (HSPA12A) is an atypical member of HSP70 family. We have recently demonstrated that hepatocyte HSPA12A attenuated the bacteria endotoxin (lipopolysaccharide, LPS)-induced liver injury. However, the role of HSPA12A in endothelial barrier function and ALI is unknown. Here in this study, HSPA12A showed upregulation in lungs of mice during bacteria endotoxin (lipopolysaccharide, LPS)-induced lung injury in vivo and in primary human umbilical vein endothelial cells (HUVECs) during LPS-induced barrier disruption in vitro. Knockout of HSPA12A in mice exacerbated LPS-induced ALI. Intriguingly, overexpression of HSPA12A in HUVECs attenuated the LPS-induced endothelial hyperpermeability. In line with this, HSPA12A overexpression increased VE-cadherin and decreased VEGF expression following LPS treatment in HUVECs. Also, knockout of HSPA12A enhanced the LPS-evoked pulmonary endothelial cell apoptosis in mice whereas overexpression of HSPA12A inhibited the LPS-induced death of HUVECs. The levels of ERKs and Akt phosphorylation in HUVECs were promoted by HSPA12A overexpression when cells exposed to LPS. Importantly, inhibition of either ERKs or Akt diminished the HSPA12A-induced protection from LPS-induced endothelial hyperpermeability and death. Taken together, these findings indicated that HSPA12A is a novel regulator of endothelial barrier function through both ERKs and Akt-mediated signaling. HSPA12A might represent a viable strategy for the pulmonary protection against endotoxemia challenge.
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Lesión Pulmonar Aguda/metabolismo , Endotelio Vascular/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Animales , Apoptosis , Supervivencia Celular/efectos de los fármacos , Células Endoteliales/metabolismo , Endotoxemia/inducido químicamente , Proteínas HSP70 de Choque Térmico/deficiencia , Proteínas HSP70 de Choque Térmico/genética , Células Endoteliales de la Vena Umbilical Humana , Humanos , Lipopolisacáridos/farmacología , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de SeñalRESUMEN
BACKGROUND: Pulmonary aspiration (PA) of gastric contents is a rare but serious perioperative complication. Recent studies focused on pediatric patients, but over a decade has passed since the latest incidence and outcome in adult population have been reported. Patients who experienced regurgitation without aspiration were rarely mentioned. Besides, our department proposed a modified rapid sequence induction (RSI) protocol in 2018 and its preventive effect remained to be examined. METHODS: A total of 166,491 anesthesia records from March 2015-October 2020 were reviewed. Outcomes from regurgitation events were classified as PA or regurgitation without aspiration following strict criteria. Available information including demographics, anesthetic managements, surgical procedures, and other medical records were reviewed for analysis. RESULTS: Among the 166,491 anesthesia records, 20 patients had PA (1:8,325), and 20 had regurgitation without aspiration (1:8,325). The morbidity of PA was 1:16,649, and the mortality was 1:55,497. During anesthesia induction, 76.0% of regurgitation events developed aspiration, and the remaining 24.0% had regurgitation without aspiration. But prior to anesthesia induction, only 10.0% regurgitation events developed aspiration. Emergency procedures were associated with serious risks of PA (OR: 27.1, 95% CI: 10.8-68.0) and regurgitation without aspiration (OR: 83.0, 95% CI: 24.3-283.1) compared with elective procedures. The highest incidence of pulmonary aspiration was observed in bronchoscopy procedures (2/1,747). The modified RSI reduced the incidence of regurgitation events during induction in emergency procedures but did not show significant advantages over classic protocol (0:1,055 versus 12:4,469, P=0.139) possibly due to insufficient sample size. The sample size required for future study was estimated based on the current data. CONCLUSIONS: The incidence of pulmonary aspiration and regurgitation without aspiration was low, especially in elective cases. Regurgitation during anesthesia induction had mostly developed aspiration. Further evaluation of the effect of modified RSI protocol needs a large sample size.
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Neumonía por Aspiración , Adulto , Anestesia General , Niño , Humanos , Incidencia , Neumonía por Aspiración/prevención & control , Estudios Retrospectivos , VómitosRESUMEN
BACKGROUND: Bronchoscopy treatments of central airway obstruction (CAO) under general anesthesia are high-risky procedures, and posing a giant challenge to the anesthesiologists. We summarized and analyzed our clinical experience in patients with CAO undergoing flexible or rigid bronchoscopy, to estimate the safety of skeletal muscle relaxants application and the traditional Low-frequency ventilation. METHODS: Clinical data of 375 patients with CAO who underwent urgent endoscopic treatments in general anesthesia from January 2016 to October 2019 were retrospectively reviewed. The use ratio of skeletal muscle relaxants, dose of skeletal muscle relaxants used, the incidence of perioperative adverse events, adequacy of ventilation and gas exchange, post-operative recovery between rigid bronchoscopy and flexible bronchoscopy therapy, and risk factors for postoperative ICU admission were evaluated. RESULTS: Of the 375 patients with CAO, 204 patients were treated with flexible bronchoscopy and 171 patients were treated with rigid bronchoscopy. Muscle relaxants were used in 362 of 375 patients (including 313 cisatracurium, 45 rocuronium, 4 atracurium, and 13 unrecorded). The usage rate of muscle relaxants (96.5% in total) was very high in patients with CAO who underwent either flexible bronchoscopy (96.6%) or rigid bronchoscopy (96.5%) therapy. The dosage of skeletal muscle relaxants (Cisatracium) used was higher in rigid bronchoscopy compared with flexible bronchoscopy therapy (10.8 ± 3.8 VS 11.6 ± 3.6 mg, respectively, p < 0.05). No patient suffered the failure of ventilation, bronchospasm and intraoperative cough either in flexible or rigid bronchoscopy therapy. Hypoxemia was occurred in 13 patients (8 in flexible, 5 in rigid bronchoscopy) during the procedure, and reintubation after extubation happened in 2 patients with flexible bronchoscopy. Sufficient ventilation was successfully established using the traditional Low-frequency ventilation with no significant carbon dioxide accumulation and hypoxemia occurred both in flexible and rigid bronchoscopy group (p > 0.05). Three patients (1 in flexible and 2 in rigid) died, during the post-operative recovery, and the higher grade of American Society of Anesthesiologists (ASA) and obvious dyspnea or orthopnea were the independent risk factors for postoperative ICU admission. CONCLUSION: The muscle relaxants and low-frequency traditional ventilation can be safely used both in flexible and rigid bronchoscopy treatments in patients with CAO. These results may provide strong clinical evidence for optimizing the anesthesia management of bronchoscopy for these patients.
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Obstrucción de las Vías Aéreas/terapia , Broncoscopía/métodos , Máscaras Laríngeas , Relajantes Musculares Centrales/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anestesia General , Femenino , Humanos , Hipoxia/etiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVE: This study compared the continuity equation-based effective orifice area (EOA) of prosthetic mitral valves between two-dimensional (2D) and 3D transesophageal echocardiography (TEE). METHODS: Thirty-four patients without major aortic valve abnormalities underwent mitral valve replacement surgery. The EOAs of prosthetic mitral valves were calculated using the continuity equation with 2D and 3D TEE. For 18/34 patients using a biological valve prosthesis, the EOA of the prosthesis was obtained from commercial records. RESULTS: The EOA of prosthetic mitral valves significantly varied between the 2D and 3D methods (2.22 ± 0.71 vs 2.35 ± 0.70 cm2, n = 34). The area of the diameter of the left ventricular outflow tract as determined by the 3D method was significantly higher than that by the 2D method (mean difference: -0.14 ± 0.20 cm2), with 95% coherence boundaries of -0.53 and 0.25 cm2. The regression equation for the EOA by 3D and 2D TEE was y = 0.27 + 0.94x, with a good correlation. CONCLUSIONS: The EOA of prosthetic mitral valves is underestimated using the 2D TEE method compared with the 3D TEE method. The 3D-TEE method has the advantage of higher precision over the 2D TEE method, and it may be helpful for better assessment of prosthetic mitral valves intraoperatively.
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Ecocardiografía Tridimensional , Prótesis Valvulares Cardíacas , Válvula Aórtica/diagnóstico por imagen , Ecocardiografía Transesofágica , Humanos , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/cirugíaRESUMEN
BACKGROUND: Postoperative nausea and vomiting (PONV) is one of the most frequent complications following strabismus surgery. Penehyclidine, an anticholinergic agent, is widely used as premedication. This study investigated the effect of preoperative penehyclidine on PONV in patients undergoing strabismus surgery. METHODS: In this prospective, randomized, double-blind study, patients scheduled for strabismus surgery under general anesthesia were randomly assigned to either penehyclidine (n = 114) or normal saline (n = 104) group. Penehyclidine was administrated immediately after anesthesia induction, and normal saline was substituted as control. PONV was investigated from 0 to 48 h after surgery. Intraoperative oculocardiac reflex (OCR) was also recorded. RESULTS: Compared with normal saline, penehyclidine significantly reduced PONV incidence (30.7% vs. 54.8%, P < 0.01) and mitigated PONV severity as indicated by severity scoring (P < 0.01). Compared with normal saline, penehyclidine also significantly reduced OCR incidence (57.9% vs. 77.9%, P < 0.01) and mitigated OCR severity, as indicated by the requirement for atropine rescue (77.3% vs. 90.1%, P < 0.05) and the maximum decrease of heart rate during OCR (23.1 ± 9.4 bpm vs. 27.3 ± 12.4 bpm, P < 0.05). The recovery course did not differ between groups. CONCLUSIONS: Penehyclidine administrated after anesthesia induction significantly reduced the incidence of PONV and alleviated intraoperative OCR in patients undergoing strabismus surgery. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT04054479 ). Retrospectively registered August 13, 2019.
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Complicaciones Intraoperatorias/prevención & control , Náusea y Vómito Posoperatorios/prevención & control , Quinuclidinas/farmacología , Reflejo Oculocardíaco/efectos de los fármacos , Estrabismo/cirugía , Adolescente , Adulto , Anciano , Niño , Preescolar , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Postoperative cognitive dysfunction (POCD) is a common postoperative central nervous system complication, especially in the elderly. It has been consistently reported that the pathological process of this clinical syndrome is related to neuroinflammation and microglial proliferation. Glycogen synthase kinase 3ß (GSK-3ß) is a widely expressed kinase with distinct functions in different types of cells. The role of GSK-3ß in regulating innate immune activation has been well documented, but as far as we know, its role in POCD has not been fully elucidated. Lithium chloride (LiCl) is a widely used inhibitor of GSK-3ß, and it is also the main drug for the treatment of bipolar disorder. Prophylactic administration of lithium chloride (2 mM/kg) can inhibit the expression of proinflammatory mediators in the hippocampus, reduce the hippocampal expression of NF-κB, and increase both the downregulation of M1 microglial-related genes (inducible nitric oxide synthase and CD86) and upregulation of M2 microglial-related genes (IL-10 and CD206), to alleviate the cognitive impairment caused by orthopedic surgery. In vitro, LiCl reversed LPS-induced production of proinflammatory mediators and M1 polarization of microglia. To sum up these results, GSK-3ß is a key contributor to POCD and a potential target of neuroprotective strategies.
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Glucógeno Sintasa Quinasa 3 beta/fisiología , Microglía/fisiología , Complicaciones Cognitivas Postoperatorias/etiología , Animales , Movimiento Celular , Polaridad Celular , Células Cultivadas , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Interleucina-1beta/biosíntesis , Lipopolisacáridos/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
OBJECTIVE: To investigate the effect of intraoperative lithotomy position (LP) with a head-down tilt (HDT) on the absorption of intraoperative irrigation fluid in patients undergoing bipolar plasmakinetic resection of the prostate (PKRP). METHODS: Eighty BPH patients underwent PKRP, 40 in a conventional 0-degree position (0° LP) and the other 40 in a ï¼10-degree HDT position (ï¼10° LP), with 0.9% saline containing 1% ethanol as intraoperative irrigation fluid. We determined the alcohol concentration in the exhaled breath of the patients with a digital alcohol detector at the start of the operation and every 10 minutes afterwards. Meanwhile we recorded the operation time, the volume of intraoperative intravenous crystalloid infusion and the weight of the resected prostatic tissue, monitored the mean arterial pressure (MAP) and heart rate (HR) at 5 minutes before surgery, 30 minutes after the start of surgery and the end of surgery, and measured the concentrations of Na+, K+, Clï¼ and Ca2+ with an arterial blood gas analyzer at 5 minutes before surgery and 1 hour after the start of surgery. RESULTS: There were no statistically significant differences in age, height, body weight and prostate volume, or in intraoperative MAP and HR between the 0° LP and ï¼10° LP groups. Compared with the baseline, at 1 hour after the start of PKRP, the patients in the 0° LP group showed significantly decreased concentrations of K+ (ï¼»3.64 ± 0.29ï¼½ vs ï¼»3.49 ± 0.22ï¼½ mmol/L, P = 0.002) and Ca2+ (ï¼»1.16 ± 0.03ï¼½ vs ï¼»1.13 ± 0.04ï¼½ mmol/L, P = 0.001), increased concentration of Clï¼ (ï¼»106.9 ± 2.2ï¼½ vs ï¼»108.7 ± 2.3ï¼½ mmol/L, P = 0.006), but no significant difference in the concentration of Na+ (ï¼»139.7 ± 1.5ï¼½ vs ï¼»139.4 ± 1.6ï¼½ mmol/L, P = 0.231), while those in the ï¼10° LP group exhibited remarkably decreased concentration of Ca2+ (ï¼»1.14 ± 0.04ï¼½ vs ï¼»1.13 ± 0.04ï¼½ mmol/L, P = 0.016) but no statistically significant differences in the concentrations of Na+ (ï¼»140.3 ± 1.8ï¼½ vs ï¼»140.0 ± 2.0ï¼½ mmol/L, P = 0.156), K+ (ï¼»3.49 ± 0.36ï¼½ vs ï¼»3.47 ± 0.34ï¼½ mmol/L, P = 0.506) and Clï¼ (ï¼»108.2 ± 2.6ï¼½ vs ï¼»109.1 ± 2.5ï¼½ mmol/L, P = 0.071). Over 1 500 ml of intraoperative irrigation fluid absorption was observed in 6 cases (15%) in the 0° LP group as compared with 4 cases (10%) in the ï¼10°LP group, with no significant difference between the two groups. CONCLUSIONS: Lithotomy position with a 10-degree head-down tilt can reduce PKRP-induced decrease in the concentration of K+ and increase in that of Clï¼ without affecting the levels of the other electrolytes.
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Inclinación de Cabeza , Posicionamiento del Paciente , Hiperplasia Prostática , Resección Transuretral de la Próstata , Humanos , Masculino , Tempo Operativo , Hiperplasia Prostática/cirugía , Irrigación TerapéuticaRESUMEN
Background: Metastasis accounts for 90% of cancer-associated mortality in patients with renal cell carcinoma (RCC). However, the clinical management of RCC metastasis is challenging. Lactate export is known to play an important role in cancer cell migration. This study investigated the role of heat shock protein A12A (HSPA12A) in RCC migration. Methods: HSPA12A expression was examined in 82 pairs of matched RCC tumors and corresponding normal kidney tissues from patients by immunoblotting and immunofluorescence analyses. The proliferation of RCC cells was analyzed using MTT and EdU incorporation assays. The migration of RCC cells was evaluated by wound healing and Transwell migration assays. Extracellular acidification was examined using Seahorse technology. Protein stability was determined following treatment with protein synthesis inhibitor cycloheximide and proteasome inhibitor MG132. Mass spectrometry, immunoprecipitation, and immunoblotting were employed to examine protein-protein interactions. Results: RCC tumors from patients showed downregulation of HSPA12A, which was associated with advanced tumor node metastasis stage. Intriguingly, overexpression of HSPA12A in RCC cells inhibited migration, whereas HSPA12A knockdown had the opposite effect. Lactate export, glycolysis rate, and CD147 protein abundance were also inhibited by HSPA12A overexpression but promoted by HSPA12A knockdown. An interaction of HSPA12A with HRD1 ubiquitin E3 ligase was detected in RCC cells. Further studies demonstrated that CD147 ubiquitination and proteasomal degradation were promoted by HSPA12A overexpression whereas inhibited by HSPA12A knockdown. Notably, the HSPA12A overexpression-induced inhibition of lactate export and migration were abolished by CD147 overexpression. Conclusion: Human RCC shows downregulation of HSPA12A. Overexpression of HSPA12A in RCC cells unstabilizes CD147 through increasing its ubiquitin-proteasome degradation, thereby inhibits lactate export and glycolysis, and ultimately suppresses RCC cell migration. Our results demonstrate that overexpression of HSPA12A might represent a viable strategy for managing RCC metastasis.
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Basigina/metabolismo , Carcinoma de Células Renales/patología , Regulación hacia Abajo , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Neoplasias Renales/patología , Ácido Láctico/metabolismo , Transporte Biológico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Glucólisis , Células Hep G2 , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Pronóstico , Estabilidad Proteica , Análisis de SupervivenciaRESUMEN
OBJECTIVE: In this study, we aimed to assess the feasibility of fiberoptic intubation (FOI), using a new, self-designed, "tongue root holder" device, in combination with the jaw thrust maneuver. METHODS: Three hundred patients undergoing elective surgery requiring orotracheal intubation were enrolled. Patients presented at least one or more risk factors for difficult airway. The patients were randomly allocated at a 1:1 ratio to one of two groups: group L, FOI with tongue root holder, or group C, standard FOI. Orotracheal FOI was performed after commencement of anesthesia. The jaw thrust maneuver was applied in both groups to facilitate advancement of the fiberoptic bronchoscope. The primary endpoint was the feasibility of FOI. The secondary endpoints were number of attempts, time to intubation, and airway clearance at the soft palate and epiglottis levels. RESULTS: The FOI was achieved in all 150 patients in group L, significantly higher than that in group C (100% vs 95.3%; P = 0.015). Less attempts of intubation were made in group L (P = 0.039). Mean time to successful intubation on the first attempt was shorter in group L (P < 0.001). The mean times to view the vocal cord and carina were also shorter in group L (P = 0.011 and P < 0.001, respectively). Airway clearance was better in group L at both the soft palate and the glottis levels (P = 0.010 and P = 0.038, respectively). CONCLUSIONS: This study shows that FOI is feasible with the newly introduced, self-designed, "tongue root holder" device, when combined with the jaw thrust maneuver in patients with risk factors for difficult airway. The device also provides better airway clearance, less intubation attempts, and shorter time to intubation at first attempt. CLINICAL RELEVANCE: Fiberoptic bronchoscope has been the gold standard for routine management of difficult airway. A technique to open the airway is introduced to reduce the incidence rate of upper airway obstruction.