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BACKGROUND: Compared to midazolam, remimazolam has a faster onset and offset of hypnotic effect, as well as cardiorespiratory stability, this study aims to determine the 90% effective dose (ED90) of remimazolam to inhibit responses to insertion of a duodenoscope during endoscopic retrograde cholangiopancreatography (ERCP). METHODS: A dose-response study was carried out undergoing ERCP who received remimazolam-alfentanil anesthesia using 10 µg/kg of alfentanil between September 2021 and November 2021. The initial dose of remimazolam was 0.2 mg/kg. The dose was then decided based on the responses of earlier patients by exploiting the sequential ascend and descend according to a 9: 1 biased coin design. Upon failure, the dose of remimazolam was increased by 0.025 mg/kg in the next patient. When the insertion was successful, the succeeding patient was randomized to an identical dose or a dose that was lower by 0.025 mg/kg.The ED90 of remimazolam for inhibiting responses to the insertion of a duodenoscope during ERCP was calculated. Adverse events and complications of remimazolam were recorded. RESULTS: A total of 55 elderly patients (age > 65) were included in the study. 45 successfully anesthetized patients, and 10 unsuccessfully. The ED90 of remimazolam was 0.300 mg/kg (95% CI = 0.287-0.320). ED95 was 0.315 (95% CI = 0.312-0.323) and ED99 was 0.323 (95% CI = 0.323-0.325). Among the patients, 9 patients developed hypotension, 2 patients developed bradycardia and 1 patient developed tachycardia, and hypoxia occurred in 2 patients. CONCLUSIONS: A loading dose of 0.300 mg / kg of remimazolam for elderly patients undergoing ERCP can safely, effectively, and quickly induce patients to fall asleep and inhibit responses to the insertion of a duodenoscope. TRIAL REGISTRATION: The study protocol was registered at the website ClinicalTrials.gov on 22/09/2021(NCT05053763).
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Colangiopancreatografia Retrógrada Endoscópica , Relación Dosis-Respuesta a Droga , Duodenoscopios , Hipnóticos y Sedantes , Humanos , Colangiopancreatografia Retrógrada Endoscópica/métodos , Masculino , Femenino , Hipnóticos y Sedantes/administración & dosificación , Anciano , Alfentanilo/administración & dosificación , Persona de Mediana Edad , Benzodiazepinas/administración & dosificaciónRESUMEN
Renal ischemia-reperfusion injury (IRI) is a common clinical complication of multiple severe diseases. Owing to its high mortality and the lack of effective treatment, renal IRI is still an intractable problem for clinicians. Itaconate, which is a metabolite of cis-aconitate, can exert anti-inflammatory and antioxidant roles in many diseases. As a derivative of itaconate with high cell membrane permeability, 4-octyl itaconate (4-OI) could provide a protective effect for various diseases. However, the role of 4-OI in renal IRI is still unclear. Herein, we examined whether 4-OI afforded kidney protection through attenuating endoplasmic reticulum stress (ERS) via nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. To observe the effects of 4-OI on alleviating renal pathologic injury, improving renal dysfunction, decreasing inflammatory cytokines, and reducing oxidative stress, we utilized C57BL/6J mice with bilateral renal pedicle clamped and HK-2 cells with hypoxia/reoxygenation (H/R) exposure in our study. In addition, through western blot assay, we found 4-OI ameliorated renal IRI-induced ERS, and activated Nrf2 pathway. Moreover, Nrf2-knockout (KO) mice and Nrf2 knockdown HK-2 cells were used to validate the role of Nrf2 signaling pathway in 4-OI-mediated alleviation of ERS caused by renal IRI. We demonstrated that 4-OI relieved renal injury and suppressed ERS in wild-type mice, while the therapeutic role was not shown in Nrf2-KO mice. Similarly, 4-OI could exert cytoprotective effect and inhibit ERS in HK-2 cells after H/R, but not in Nrf2 knockdown cells. Our in vivo and in vitro studies revealed that 4-OI protected renal IRI through attenuating ERS via Nrf2 pathway.
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Factor 2 Relacionado con NF-E2 , Daño por Reperfusión , Succinatos , Ratones , Animales , Factor 2 Relacionado con NF-E2/metabolismo , Ratones Endogámicos C57BL , Riñón/patología , Estrés Oxidativo , Daño por Reperfusión/metabolismo , Estrés del Retículo Endoplásmico , ApoptosisRESUMEN
BACKGROUND: Delirium is a common and disturbing postoperative complication that might be ameliorated by propofol-based anaesthesia. We therefore tested the primary hypothesis that there is less delirium after propofol-based than after sevoflurane-based anaesthesia within 7 days of major cancer surgery. METHODS: This multicentre randomised trial was conducted in 14 tertiary care hospitals in China. Patients aged 65-90 yr undergoing major cancer surgery were randomised to either propofol-based anaesthesia or to sevoflurane-based anaesthesia. The primary endpoint was the incidence of delirium within 7 postoperative days. RESULTS: A total of 1228 subjects were enrolled and randomised, with 1195 subjects included in the modified intention-to-treat analysis (mean age 71 yr; 422 [35%] women); one subject died before delirium assessment. Delirium occurred in 8.4% (50/597) of subjects given propofol-based anaesthesia vs 12.4% (74/597) of subjects given sevoflurane-based anaesthesia (relative risk 0.68 [95% confidence interval {CI}: 0.48-0.95]; P=0.023; adjusted relative risk 0.59 [95% CI: 0.39-0.90]; P=0.014). Delirium reduction mainly occurred on the first day after surgery, with a prevalence of 5.4% (32/597) with propofol anaesthesia vs 10.7% (64/597) with sevoflurane anaesthesia (relative risk 0.50 [95% CI: 0.33-0.75]; P=0.001). Secondary endpoints, including ICU admission, postoperative duration of hospitalisation, major complications within 30 days, cognitive function at 30 days and 3 yr, and safety outcomes, did not differ significantly between groups. CONCLUSIONS: Delirium was a third less common after propofol than sevoflurane anaesthesia in older patients having major cancer surgery. Clinicians might therefore reasonably select propofol-based anaesthesia in patients at high risk of postoperative delirium. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-IPR-15006209) and ClinicalTrials.gov (NCT02662257).
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Anestésicos por Inhalación , Delirio del Despertar , Neoplasias , Propofol , Humanos , Femenino , Anciano , Masculino , Propofol/efectos adversos , Sevoflurano/efectos adversos , Anestésicos por Inhalación/efectos adversos , Estudios de Seguimiento , Anestesia General/efectos adversos , Delirio del Despertar/inducido químicamente , Neoplasias/cirugíaRESUMEN
BACKGROUND: Experimental evidence indicates that i.v. anaesthesia might reduce cancer recurrence compared with volatile anaesthesia, but clinical information is observational only. We therefore tested the primary hypothesis that propofol-based anaesthesia improves survival over 3 or more years after potentially curative major cancer surgery. METHODS: This was a long-term follow-up of a multicentre randomised trial in 14 tertiary hospitals in China. We enrolled 1228 patients aged 65-90 yr who were scheduled for major cancer surgery. They were randomised to either propofol-based i.v. anaesthesia or to sevoflurane-based inhalational anaesthesia. The primary endpoint was overall survival after surgery. Secondary endpoints included recurrence-free and event-free survival. RESULTS: Amongst subjects randomised, 1195 (mean age 72 yr; 773 [65%] male) were included in the modified intention-to-treat analysis. At the end of follow-up (median 43 months), there were 188 deaths amongst 598 patients (31%) assigned to propofol-based anaesthesia compared with 175 deaths amongst 597 patients (29%) assigned to sevoflurane-based anaesthesia; adjusted hazard ratio 1.02; 95% confidence interval (CI): 0.83-1.26; P=0.834. Recurrence-free survival was 223/598 (37%) in patients given propofol anaesthesia vs 206/597 (35%) given sevoflurane anaesthesia; adjusted hazard ratio 1.07; 95% CI: 0.89-1.30; P=0.465. Event-free survival was 294/598 (49%) in patients given propofol anaesthesia vs 274/597 (46%) given sevoflurane anaesthesia; adjusted hazard ratio 1.09; 95% CI 0.93 to 1.29; P=0.298. CONCLUSIONS: Long-term survival after major cancer surgery was similar with i.v. and volatile anaesthesia. Propofol-based iv. anaesthesia should not be used for cancer surgery with the expectation that it will improve overall or cancer-specific survival. CLINICAL TRIAL REGISTRATIONS: ChiCTR-IPR-15006209; NCT02660411.
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Neoplasias , Propofol , Sevoflurano , Propofol/efectos adversos , Sevoflurano/efectos adversos , Neoplasias/cirugía , Humanos , Masculino , Femenino , Anciano , Estudios de Seguimiento , Anestésicos Intravenosos , Anestesia por Inhalación , Supervivientes de CáncerRESUMEN
Endotoxin-induced acute kidney injury (AKI) is commonly observed in clinical practice. Renal tubular epithelial cell (RTEC) pyroptosis is one of the main factors leading to the development of endotoxin-induced AKI. Mitochondrial dysfunction can lead to pyroptosis. However, the biological pathways involved in the potential lipopolysaccharide (LPS)-induced pyroptosis of RTECs, notably those associated with mitochondrial dysfunction, are poorly understood. Previous studies have demonstrated that heme oxygenase (HO)-1 confers cell protection via the induction of PTEN-induced putative kinase 1 (PINK1) expression through PTEN to regulate mitochondrial fusion/fission during endotoxin-induced AKI in vivo. Therefore, the present study investigated the role of HO-1/PINK1 in maintaining mitochondrial function and inhibiting the pyroptosis of RTECs exposed to LPS. Primary cultures of RTECs were obtained from wild-type (WT) and PINK1-knockout (PINK1KO) rats. An in vitro model of endotoxin-associated RTEC injury was established following treatment of the cells with LPS. The WT RTECs were divided into the control, LPS, Znpp + LPS and Hemin + LPS groups, and the PINK1KO RTECs were divided into the control, LPS and Hemin + LPS groups. RTECs were exposed to LPS for 6 h to assess cell viability, inflammation, pyroptosis and mitochondrial function. In the LPS-treated RTECs, the mRNA and protein expression levels of HO-1 and PINK1 were upregulated. Cell viability, adenosine triphosphate (ATP) levels and the mitochondrial oxygen consumption rate were decreased, whereas the inflammatory response, pyroptosis and mitochondrial reactive oxygen species (ROS) levels were increased. The cell inflammatory response and the induction of pyroptosis were inhibited, whereas the levels of mitochondrial ROS were decreased. In addition, the cell viability and ATP levels were increased in the WT RTECs following the upregulation of HO-1 expression. These effects were reversed by the downregulation of HO-1 expression. However, no statistically significant differences were noted between the LPS and the Hemin + LPS groups in the PINK1KO RTECs. Collectively, the findings of the present study indicate that HO-1 inhibits inflammation and regulates mitochondrial function by inhibiting the pyroptosis of LPS-exposed RTECs via PINK1.
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STUDY OBJECTIVE: In many countries, the combination of propofol and opioid is used as the preferred sedative regime during ERCP. However, the most serious risks of propofol sedation are oxygen deficiency and hypotension. Compared to midazolam, remimazolam has a faster onset and offset of hypnotic effect, as well as cardiorespiratory stability, and to achieve widespread acceptance for procedural sedation, remimazolam must replace propofol which is the most commonly used for procedural sedation. The objective of this study was to compare the safety and efficacy profiles of the remimazolam and propofol when combined with alfentanil for sedation during ERCP procedures. DESIGN: A randomized, controlled, single-center trial. SETTING: The Endoscopic Centre of Tianjin Nankai Hospital, China. PATIENTS: 518 patients undergoing elective ERCP under deep sedation. INTERVENTIONS: Patients scheduled for ERCP were randomly assigned to be sedated with either a combination of remimazolam-alfentanil or propofol-alfentanil. MEASUREMENTS: The primary outcome was the prevalence of hypoxia, which was defined as SpO2 < 90% for >10 s. Other outcomes were the need for airway maneuver, procedure, and sedation-related outcomes and side effects (e.g., nausea, vomiting, and cardiovascular adverse events). MAIN RESULTS: A total of 518 patients underwent randomization. Of these, 250 were assigned to the remimazolam group and 255 to the propofol group. During ERCP, 9.6% of patients in the remimazolam group showed hypoxia, while in the propofol group, 15.7% showed hypoxia (p = 0.04). The need for airway maneuvering due to hypoxia was significantly greater in the propofol group (p = 0.04). Furthermore, patients sedated with remimazolam had a lower percentage of hypotension than patients sedated with propofol (p < 0.001). Patients receiving remimazolam sedation expressed higher satisfaction scores and were recommended the same sedation for the next ERCP. The procedure time in the remimazolam group was much longer than in the propofol group due to the complexity of the patient's disease, which resulted in a longer sedation time. CONCLUSION: During elective ERCP, patients administered with remimazolam showed fewer respiratory depression events under deep sedation with hemodynamic advantages over propofol when administered in combination with alfentanil.
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Hipotensión , Propofol , Humanos , Propofol/efectos adversos , Alfentanilo/efectos adversos , Colangiopancreatografia Retrógrada Endoscópica/efectos adversos , Hipnóticos y Sedantes/efectos adversos , Hipoxia/inducido químicamente , Hipoxia/epidemiología , Hipotensión/inducido químicamente , Hipotensión/epidemiología , Sedación Consciente/efectos adversos , Sedación Consciente/métodosRESUMEN
BACKGROUND: Facilitating the recurrence of spontaneous voiding is considered to be a way to prevent urinary retention after surgery, which is of great importance in cholecystectomy. This study aimed to assess the effect of transcutaneous electrical acupoint stimulation (TEAS) on spontaneous voiding recovery after laparoscopic cholecystectom. METHODS: Participants who underwent elective laparoscopic cholecystectomy were randomly assigned to either the TEAS group or the sham group. Active TEAS or sham TEAS at specific acupuncture points was conducted intraoperatively and postoperatively. The primary outcome was the recovery speed of spontaneous voiding ability after surgery and secondary outcomes included postoperative urinary retention (POUR), voiding dysfunction, pain, anxiety and depression, and early recovery after surgery. RESULTS: A total of 1,948 participants were recruited and randomized to TEAS (n = 975) or sham (n = 973) between August 2018 and June 2020. TEAS shortens the time delay of the first spontaneous voiding after laparoscopic cholecystectomy (5.6 h [IQR, 3.7-8.1 h] in the TEAS group vs 7.0 h [IQR, 4.7-9.7 h] in the sham group) (p < 0.001). The TEAS group experienced less POUR (p = 0.020), less voiding difficulty (p < 0.001), less anxiety and depression (p < 0.001), reduced pain (p = 0.007), and earlier ambulation (p = 0.01) than the sham group. CONCLUSIONS: Our results showed that TEAS is an effective approach to accelerate the recovery of spontaneous voiding and reduce POUR which facilitates recovery for patients after laparoscopic cholecystectomy.
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Colecistectomía Laparoscópica , Estimulación Eléctrica Transcutánea del Nervio , Retención Urinaria , Humanos , Colecistectomía Laparoscópica/efectos adversos , Estimulación Eléctrica Transcutánea del Nervio/métodos , Retención Urinaria/etiología , Retención Urinaria/terapia , Puntos de Acupuntura , Complicaciones Posoperatorias , DolorRESUMEN
BACKGROUND: Intestinal barrier integrity in the pathogenesis of sepsis is critical. Despite an abundance of evidence, the molecular mechanism of the intestinal barrier in sepsis pathology remains unclear. Here, we report a protective role of polo-like kinase 1 (PLK1) in intestinal barrier integrity during sepsis. METHODS: Mice with PLK1 overexpression (CAG-PLK1 mice) or PLK1 inhibition (BI2536-treated mice) underwent caecal ligation and puncture (CLP) to establish a sepsis model. The intestinal barrier function, apoptosis in the intestinal epithelium, mitochondrial function and NF-κB signalling activity were evaluated. To suppress the activation of NF-κB signalling, the NF-κB inhibitor PDTC, was administered. The Caco-2 cell line was chosen to establish an intestinal epithelial injury model in vitro. RESULTS: Sepsis destroyed intestinal barrier function, induced excessive apoptosis in the intestinal epithelium, and disrupted the balance of mitochondrial dynamics in wild-type mice. PLK1 overexpression alleviated sepsis-induced damage to the intestinal epithelium by inhibiting the activation of NF-κB signalling. PLK1 colocalized and interacted with TANK in Caco-2 cells. Transfecting Caco-2 cells with TANK-SiRNA suppressed NF-κB signalling and ameliorated mitochondrial dysfunction, apoptosis and the high permeability of cells induced by lipopolysaccharide (LPS). Furthermore, TANK overexpression impaired the protective effect of PLK1 on LPS-induced injuries in Caco-2 cells. CONCLUSION: Our findings reveal that the PLK1/TANK/NF-κB axis plays a crucial role in sepsis-induced intestinal barrier dysfunction by regulating mitochondrial dynamics and apoptosis in the intestinal epithelium and might be a potential therapeutic target in the clinic.
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Enfermedades Intestinales , Sepsis , Humanos , Ratones , Animales , FN-kappa B/metabolismo , Células CACO-2 , Lipopolisacáridos , Dinámicas Mitocondriales , Enfermedades Intestinales/etiología , Sepsis/metabolismo , Quinasa Tipo Polo 1RESUMEN
BACKGROUND: Ophthalmic segment artery aneurysms (OSAs) are difficult to clip; therefore, improvement of the surgical method is of great significance to the prevention of complications, and the classification of the aneurysms is essential to formulate a reasonable surgical plan. OBJECTIVE: To explore the strategies and effects of surgery for OSAs using a modified subdural Dolenc approach. METHODS: The clinical data of 38 patients (12 men and 26 women, aged 48-73 years) with OSA were analyzed retrospectively. A total of 44 aneurysms were identified, 40 of which were OSAs. The 40 aneurysms were divided into types Ia1 (n = 2), Ia2 (n = 2), Ib (n = 6), IIa (n = 4), IIb (n = 4), IIIa (n = 0), IIIb (n = 4), IIIc (n = 16), and IV (n = 2) based on preoperative images. Thirty-nine OSAs were operated successfully through pterional craniotomy combined with the modified subdural Dolenc approach, and 1 aneurysm was clipped through the contralateral approach. Clinical outcomes were evaluated using the Glasgow Outcome Scale (GOS). RESULTS: Thirty-nine OSAs were clipped, and one was wrapped. Visual dysfunction, headache, and dizziness improved after the operation in 18 patients. One patient had new visual impairment, and there were no deaths. At discharge, the GOS score was 5 in 36 cases, 4 in 1 case, and 3 in 1 case. Thirty-seven patients had a GOS score of 5, and 1 patient had a score of 3 at 6 months after the operation. CONCLUSION: The modified subdural Dolenc approach (Zheng approach) for clipping OSAs may be associated with less trauma and good postoperative outcomes.
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Aneurisma Intracraneal , Femenino , Humanos , Masculino , Craneotomía/métodos , Aneurisma Intracraneal/diagnóstico por imagen , Aneurisma Intracraneal/cirugía , Arteria Oftálmica , Estudios RetrospectivosRESUMEN
Mitochondria need to interact with the nucleus under homeostasis and stress to maintain cellular demands and nuclear transcriptional programs. Disrupted mitonuclear interaction is involved in many disease processes. However, the role of mitonuclear signaling regulators in endotoxin-induced acute lung injury (ALI) remains unknown. Nicotinamide adenine dinucleotide (NAD+) is closely related to mitonuclear interaction with its central role in mitochondrial metabolism. In the current study, C57BL/6J mice were administrated with lipopolysaccharide 15 mg/kg to induce endotoxin-induced ALI and investigated whether the NAD+ precursor nicotinamide mononucleotide (NMN) could preserve mitonuclear interaction and alleviate ALI. After pretreatment with NMN for 7 days, NAD+ levels in the mitochondrial, nucleus, and total intracellular were significantly increased in endotoxemia mice. Moreover, supplementation of NMN alleviated lung pathologic injury, reduced ROS levels, increased MnSOD activities, mitigated mitochondrial dysfunction, ameliorated the defects in the nucleus morphology, and these cytoprotective effects were accompanied by preserving mitonuclear interaction (including mitonuclear protein imbalance and the mitochondrial unfolded protein response, UPRmt). Furthermore, NAD+-mediated mitonuclear protein imbalance and UPRmt are probably regulated by deacetylase Sirtuin1 (SIRT1). Taken together, our results indicated that NMN pretreatment ameliorated ALI by inducing mitonuclear protein imbalance and activating the UPRmt in an SIRT1-dependent manner.
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Lesión Pulmonar Aguda , Mononucleótido de Nicotinamida , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Animales , Endotoxinas , Ratones , Ratones Endogámicos C57BL , NAD/metabolismo , Mononucleótido de Nicotinamida/metabolismo , Mononucleótido de Nicotinamida/farmacología , Sirtuina 1RESUMEN
INTRODUCTION: Electroacupuncture (EA) treatment has been demonstrated to have the potential to prevent sepsis-induced hippocampal injury; however, the mechanisms underlying the protective effects of EA against such injury remain unclear. Herein, to elucidate these mechanisms, we constructed a mouse model of lipopolysaccharide (LPS)-induced hippocampal injury to investigate the protection mechanism of EA and to determine whether heme oxygenase-1 (HO-1)-mediated mitochondrial function is involved in the protective effect of EA. MATERIALS AND METHODS: The sepsis model of hippocampal injury was induced by administering LPS. The Zusanli and Baihui acupoints were stimulated using EA for 30 min once a day, for 5 d before LPS exposure and the first day after administering LPS. Hippocampal injury was investigated by hematoxylin and eosin staining and Nissl staining. HO-1 levels were measured using Western blotting. Mitochondrial metabolism was validated by assessing adenosine triphosphate, superoxide dismutase, malondialdehyde levels, reactive oxygen species production, and mitochondrial respiratory chain activity. Mitochondrial morphology was analyzed by transmission electron microscopy. RESULTS: EA treatment alleviated neuronal injury, impeded oxidative stress, and improved mitochondrial respiratory function, energy metabolism, and mitochondrial morphology in LPS-exposed mice. In addition, HO-1 knockout aggravated LPS-induced hippocampal injury, aggravated oxidative stress, and reduced mitochondrial respiratory function and aggravated mitochondrial swelling, crest relaxation, and vacuole degeneration. Moreover, EA was unable to reverse the hippocampal damage and mitochondrial dysfunction caused by LPS exposure after HO-1 knockout. CONCLUSIONS: EA improves LPS-induced hippocampal injury by regulating HO-1-mediated mitochondrial function. Furthermore, HO-1 plays a critical role in maintaining mitochondrial function and resisting oxidative injury.
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Electroacupuntura , Sepsis , Animales , Hemo-Oxigenasa 1/metabolismo , Hipocampo/metabolismo , Lipopolisacáridos , Ratones , Mitocondrias/metabolismo , Estrés Oxidativo , Sepsis/metabolismo , Sepsis/terapiaRESUMEN
Sepsis and sepsis-induced skeletal muscle atrophy are common in patients in intensive care units with high mortality, while the mechanisms are controversial and complicated. In the present study, the atrophy of skeletal muscle was evaluated in sepsis mouse model as well as the apoptosis of muscle fibres. Sepsis induced atrophy of skeletal muscle and apoptosis of myofibres in vivo and in vitro. In cell-based in vitro experiments, lipopolysaccharide (LPS) stimulation also inhibited the proliferation of myoblasts. At the molecular level, the expression of polo-like kinase 1 (PLK1) and phosphorylated protein kinase B (p-AKT) was decreased. Overexpression of PLK1 partly rescued LPS-induced apoptosis, proliferation suppression and atrophy in C2C12 cells. Furthermore, inhibiting the AKT pathway deteriorated LPS-induced atrophy in PLK1-overexpressing C2C12 myotubes. PLK1 was found to participate in regulating apoptosis and E3 ubiquitin ligase activity in C2C12 cells. Taken together, these results indicate that sepsis induces skeletal muscle atrophy by promoting apoptosis of muscle fibres and inhibiting proliferation of myoblasts via regulation of the PLK1-AKT pathway. These findings enhance understanding of the mechanism of sepsis-induced skeletal muscle atrophy.
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Apoptosis , Proteínas de Ciclo Celular/metabolismo , Atrofia Muscular/etiología , Atrofia Muscular/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Sepsis/complicaciones , Animales , Biomarcadores , Línea Celular , Supervivencia Celular , Modelos Animales de Enfermedad , Inmunohistoquímica , Inmunofenotipificación , Masculino , Ratones , Modelos Biológicos , Atrofia Muscular/diagnóstico , Mioblastos/metabolismo , Mioblastos/patología , ARN Interferente Pequeño , Transducción de Señal , Ubiquitina-Proteína Ligasas/metabolismo , Quinasa Tipo Polo 1RESUMEN
Various pharmacological agents and protective methods have been shown to reverse pneumoperitoneum-related lung injury, but identifying the best strategy is challenging. Herein, we employed lung tissues and blood samples from C57BL/6 mice with pneumoperitoneum-induced lung injury and blood samples from patients who received laparoscopic gynecological surgery to investigate the therapeutic role of hydromorphone in pneumoperitoneum-induced lung injury along with the underlying mechanism. We found that pretreatment with hydromorphone alleviated lung injury in mice that underwent CO2 insufflation, decreased the levels of myeloperoxidase (MPO), total oxidant status (TOS), and oxidative stress index (OSI), and increased total antioxidant status (TAS). In addition, after pretreatment with hydromorphone, upregulated HO-1 protein expression, reduced mitochondrial DNA content, and improved mitochondrial morphology and dynamics were observed in mice subjected to pneumoperitoneum. Immunohistochemical staining also verified that hydromorphone could increase the expression of HO-1 in lung tissues in mice subjected to CO2 pneumoperitoneum. Notably, in mice treated with HO-1-siRNA, the protective effects of hydromorphone against pneumoperitoneum-induced lung injury were abolished, and hydromorphone did not have additional protective effects on mitochondria. Additionally, in clinical patients who received laparoscopic gynecological surgery, pretreatment with hydromorphone resulted in lower serum levels of club cell secretory protein-16 (CC-16) and intercellular adhesion molecule-1 (ICAM-1), a lower prooxidant-antioxidant balance (PAB), and higher heme oxygenase-1 (HO-1) activity than morphine pretreatment. Collectively, our results suggest that hydromorphone protects against CO2 pneumoperitoneum-induced lung injury via HO-1-regulated mitochondrial dynamics and may be a promising strategy to treat CO2 pneumoperitoneum-induced lung injury.
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Lesión Pulmonar Aguda/etiología , Dióxido de Carbono/efectos adversos , Hemo-Oxigenasa 1/metabolismo , Hidromorfona/uso terapéutico , Dinámicas Mitocondriales/genética , Neumoperitoneo/complicaciones , Lesión Pulmonar Aguda/fisiopatología , Animales , Hidromorfona/farmacología , Masculino , RatonesRESUMEN
Traumatic brain injury (TBI) is an increasingly common emergency disease that usually leads to prolonged physical and cognitive impairments. In this study, we investigated if sevoflurane could induce cognitive improvement in TBI rats. Rats were subjected to head trauma induced by a fluid percussion device. A two-hour exposure to 3% sevoflurane was performed in a chamber immediately after TBI. Sevoflurane inhalation reduced the neurological and cognitive deficits induced by TBI with ameliorated synaptic injuries in the hippocampus. Moreover, after sevoflurane treatment, the expression of nuclear factor erythroid-2-related factor-2 (Nrf-2) and hemeoxygenase-1 (HO-1) in the hippocampus was enhanced 1 d after TBI and maintained at high levels 14 days later, and oxidative stress induced by TBI was inhibited. However, the HO-1 inhibitor, Zinc protoporphyrin (ZnPP), used to demonstrate the involvement of HO-1, suppressed the protective effect of sevoflurane. These results indicate that sevoflurane administered immediately after TBI may protect against TBI-induced synaptic and cognitive impairments by promoting the antioxidant Nrf-2/HO-1 pathway. Sevoflurane may be a promising anesthetic for patients with TBI.
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Anestésicos por Inhalación/farmacología , Lesiones Traumáticas del Encéfalo/complicaciones , Disfunción Cognitiva/tratamiento farmacológico , Hemo Oxigenasa (Desciclizante)/efectos de los fármacos , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Sevoflurano/farmacología , Transducción de Señal/efectos de los fármacos , Anestésicos por Inhalación/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Disfunción Cognitiva/etiología , Modelos Animales de Enfermedad , Masculino , Fármacos Neuroprotectores/administración & dosificación , Ratas , Ratas Sprague-Dawley , Sevoflurano/administración & dosificaciónRESUMEN
BACKGROUND: Endotoxin-associated acute kidney injury (AKI), a disease characterized by marked oxidative stress and inflammation disease, is a major cause of mortality in critically ill patients. Mitochondrial fission and pyroptosis often occur in AKI. However, the underlying biological pathways involved in endotoxin AKI remain poorly understood, especially those related to mitochondrial dynamics equilibrium disregulation and pyroptosis. Previous studies suggest that heme oxygenase- (HO-) 1 confers cytoprotection against AKI during endotoxic shock, and PTEN-induced putative kinase 1 (PINK1) takes part in mitochondrial dysfunction. Thus, in this study, we examine the roles of HO-1/PINK1 in maintaining the dynamic process of mitochondrial fusion/fission to inhibit pyroptosis and mitigate acute kidney injury in rats exposed to endotoxin. METHODS: An endotoxin-associated AKI model induced by lipopolysaccharide (LPS) was used in our study. Wild-type (WT) rats and PINK1 knockout (PINK1KO) rats, respectively, were divided into four groups: the control, LPS, Znpp+LPS, and Hemin+LPS groups. Rats were sacrificed 6 h after intraperitoneal injecting LPS to assess renal function, oxidative stress, and inflammation by plasma. Mitochondrial dynamics, morphology, and pyroptosis were evaluated by histological examinations. RESULTS: In the rats with LPS-induced endotoxemia, the expression of HO-1 and PINK1 were upregulated at both mRNA and protein levels. These rats also exhibited inflammatory response, oxidative stress, mitochondrial fission, pyroptosis, and decreased renal function. After upregulating HO-1 in normal rats, pyroptosis was inhibited; mitochondrial fission and inflammatory response to oxidative stress were decreased; and the renal function was improved. The effects were reversed by adding Znpp (a type of HO-1 inhibitor). Finally, after PINK1 knockout, there is no statistical difference in the LPS-treated group and Hemin or Znpp pretreated group. CONCLUSIONS: HO-1 inhibits inflammation response and oxidative stress and regulates mitochondria fusion/fission to inhibit pyroptosis, which can alleviate endotoxin-induced AKI by PINK1.
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Lesión Renal Aguda/genética , Hemo Oxigenasa (Desciclizante)/genética , Dinámicas Mitocondriales/genética , Proteínas Quinasas/genética , Piroptosis/genética , Choque Séptico/genética , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/enzimología , Lesión Renal Aguda/patología , Animales , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/enzimología , Células Epiteliales/patología , Regulación de la Expresión Génica , Técnicas de Inactivación de Genes , Hemo Oxigenasa (Desciclizante)/antagonistas & inhibidores , Hemo Oxigenasa (Desciclizante)/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Riñón/efectos de los fármacos , Riñón/enzimología , Riñón/patología , Lipocalina 2/genética , Lipocalina 2/metabolismo , Lipopolisacáridos/administración & dosificación , Masculino , Dinámicas Mitocondriales/efectos de los fármacos , Estrés Oxidativo , Proteínas Quinasas/deficiencia , Protoporfirinas/farmacología , Piroptosis/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Choque Séptico/inducido químicamente , Choque Séptico/enzimología , Choque Séptico/patología , Transducción de Señal , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Sepsis-associated encephalopathy (SAE) is a common complication of sepsis. Although sepsis is effectively managed with the administration of antibiotics and source control, which may include surgical intervention, SAE usually leads to prolonged cognitive dysfunction affecting the quality of life of the patients. In this study, we investigated the possible effect of electroacupuncture (EA) on cognition in a model of SAE induced by cecal ligation and puncture (CLP). MATERIALS AND METHODS: The rats were randomly divided into four groups: the control group, the CLP group, the CLP with EA treatment group (CLP + EA), and the CLP with sham EA treatment group (CLP + sham EA). EA at DU20, LI11, and ST36 or sham EA was performed 30 min daily for 10 consecutive days starting from 2 days before CLP. Then cognitive function was examined by the Morris water maze test. On day 14 after CLP surgery, the synaptic injury, neuron loss, and oxidative stress were studied. RESULTS: Rats with EA treatment showed improved survival rate, spatial learning, and memory abilities. The dendritic spine density, the synaptic proteins, and the hippocampal neuron number were also increased after EA treatment. Furthermore, EA suppressed oxidative stress through regulating the level of malondialdehyde and superoxide dismutase and enhanced the expression of antioxidant nuclear factor erythroid-2-related factor-2 and hemeoxygenase-1. But sham EA did not have the same effect. CONCLUSIONS: EA may protect against SAE-induced cognitive dysfunction by inhibiting synaptic injury, neuronal loss, and oxidative stress, and the nuclear factor erythroid-2-related factor-2/hemeoxygenase-1 signaling pathway may be involved in this effect.
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Disfunción Cognitiva/terapia , Electroacupuntura , Encefalopatía Asociada a la Sepsis/terapia , Sepsis/complicaciones , Animales , Cognición/fisiología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Modelos Animales de Enfermedad , Hemo Oxigenasa (Desciclizante)/metabolismo , Humanos , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Neuronas/patología , Estrés Oxidativo/fisiología , Ratas , Sepsis/terapia , Encefalopatía Asociada a la Sepsis/diagnóstico , Encefalopatía Asociada a la Sepsis/etiología , Encefalopatía Asociada a la Sepsis/patología , Transducción de Señal/fisiología , Sinapsis/patologíaRESUMEN
BACKGROUND Our previous studies have shown that electroacupuncture (EA) can alleviate lung injury induced by limb ischemia-reperfusion, but the specific mechanism is still unclear. MATERIAL AND METHODS The animals were randomly divided into sham operation group (Sham), model group (IR), electroacupuncture group (EA), sham electroacupuncture group (SEA), and EA+luzindole group (EA+luzindole). The limb ischemia-reperfusion model was established according to previously described, the rabbits in the EA and EA+luzindole groups were given EA at ST36 and BL13 for 7 days before the model preparation and during the model implementation, however, sham EA was mainly used to stimulate the rabbits in the SEA group with shallow needling at the points 0.5 cm near ST36 and BL13. Then, 30 mg/kg of luzindole was intraperitoneally injected 30 minutes before the model preparation in the EA+luzindole group. RESULTS The wet weight/dry weight (W/D) ratio, lung injury score, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1ß, IL-6, and malondialdehyde (MDA) contents in the EA group at 4 hours after reperfusion were significantly lower than those in the IR, SEA, and EA+luzindole groups. The levels of serum melatonin at T0 in the EA and EA+luzindole groups were significantly higher than those in the Sham group. The levels of serum melatonin at T1 and T2 in the IR group were significantly lower than those in the Sham group. There was no significant difference in the expression levels of melatonin receptor 1 (MR-1) and MR-2 in lung tissues among the 5 groups. CONCLUSIONS EA could alleviate the lung injury induced by limb ischemia-reperfusion by promoting the secretion of melatonin, while having no effect on the expression of melatonin receptor in lung tissues.
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Electroacupuntura/métodos , Melatonina/farmacología , Daño por Reperfusión/terapia , Animales , Modelos Animales de Enfermedad , Lesión Pulmonar/terapia , Melatonina/metabolismo , Conejos , Reperfusión , Daño por Reperfusión/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Adipose tissue-derived mesenchymal stem cells (ADSCs) are multipotent cells that can differentiate into various cell types. This study aimed to investigate the effect of ghrelin on the neural differentiation of rat ADSCs and underlying molecular mechanisms. Rat ADSCs were isolated and third-passage ADSCs were used in this study. The isolated ADSCs were characterized by flow cytometry analysis for MSCs' surface expression markers as evidenced by positive for CD90, CD44, and CD29 and negative for CD34, CD45, and CD11b/2f/c. The multilineage differentiation of ADSCs was confirmed by adipogenic, osteogenic, and neural differentiation. After induction of neurogenesis, the differentiated cells were identified by development of neuron-like morphology and expression of neural markers including glial fibrillary acidic protein, Nestin, MAP2, and ß-Tubulin III using immunofluorescence and western blot. Ghrelin concentration dependently elevated the proportion of neural-like cells and branching dendrites, as well as upregulated the expression of neural markers. Further, the expression of nuclear ß-catenin, p-GSK-3ß, p-AKT, and p-mTOR was increased by ghrelin, indicating an activation of ß-catenin and AKT/mTOR signaling after the ghrelin treatment. Importantly, inhibition of ß-catenin or AKT/mTOR signaling suppressed ghrelin-induced neurogenesis. Therefore, we demonstrate that ghrelin promotes neural differentiation of ADSCs through the activation of ß-catenin and AKT/mTOR signaling pathways.
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Adipocitos/efectos de los fármacos , Ghrelina/farmacología , Células Madre Mesenquimatosas/efectos de los fármacos , Neuronas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/genética , Serina-Treonina Quinasas TOR/genética , beta Catenina/genética , Adipocitos/citología , Adipocitos/metabolismo , Tejido Adiposo/citología , Tejido Adiposo/metabolismo , Animales , Anticuerpos Heterófilos/farmacología , Diferenciación Celular/efectos de los fármacos , Regulación de la Expresión Génica , Ghrelina/genética , Ghrelina/metabolismo , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Compuestos Heterocíclicos con 3 Anillos/farmacología , Receptores de Hialuranos/genética , Receptores de Hialuranos/metabolismo , Integrina beta1/genética , Integrina beta1/metabolismo , Masculino , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Nestina/genética , Nestina/metabolismo , Neuronas/citología , Neuronas/metabolismo , Cultivo Primario de Células , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Antígenos Thy-1/genética , Antígenos Thy-1/metabolismo , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , beta Catenina/antagonistas & inhibidores , beta Catenina/metabolismoRESUMEN
The bioengineered luciferase reporter has been widely used for monitoring of a variety of molecular events in living cells because of their ability to provide highly sensitive quantitation with broad linearity. In the present study, we made a cyclin A2-luciferase (CYCA-Luc) fusion protein and examined the utility of this optical reporter for monitoring G2-phase cell cycle arrest in living animals. In vitro luciferase assay and in vivo bioluminescence imaging assay showed that the lithium chloride (LiCl), G2-phase-specific drug, induced G2-phase arrest of cell cycle and increased the activity of this reporter under in vitro or in vivo conditions, and this reporter can also be potentially used in high-throughput screening efforts aimed at discovering novel anti-cancer drugs that will cause cell cycle arrest at the G2-phase in cultivated cell lines and animal models.
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Ciclina A2/genética , Puntos de Control de la Fase G2 del Ciclo Celular , Genes Reporteros , Luciferasas/genética , Imagen Óptica , Neoplasias del Cuello Uterino/patología , Animales , Ciclina A2/biosíntesis , Femenino , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células HeLa , Ensayos Analíticos de Alto Rendimiento , Humanos , Cloruro de Litio/farmacología , Luciferasas/biosíntesis , Mediciones Luminiscentes , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/genética , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Electroacupuncture has been reported to protect the body from organ damages, but its mechanisms remain to be explored. This research was designed to investigate the function of electroacupuncture in lung injury resulted from hind limb ischemia-reperfusion (LIR) and whether p38 mitogen-activated protein kinase (p38 MAPK)-mediated nuclear factor erythroid-2-related factor-2 (Nrf2)/heme oxygenase (HO)-1 pathway contributes to the protective effect of electroacupuncture on LIR-originated lung damage. MATERIALS AND METHODS: Rabbits were subjected to occluding femoral artery for 2 h. Then they received reperfusion for 4 h to establish lung injury model. Electroacupuncture stimulation was performed bilaterally at Feishu and Zusanli acupoints for 15 min once a day for 5 d before the experiment and throughout the hind LIR model performing in the experimental day. Blood samples and lung tissues were collected to examine the role of electroacupuncture treatment in inflammatory response, oxidative stress, and lung injury. Both the protein expression and the messenger RNA level of Nrf2 and HO-1 were detected. RESULTS: The results showed that electroacupuncture treatment remarkably alleviated lung injury, decreased inflammatory cytokines secretion, attenuated lung oxidative stress, increased the amount of Nrf2 and HO-1, and increased the ratio of phospho-p38 MAPK to p38 MAPK after LIR. However, the protective effects exerted by electroacupuncture were reversed to some extent by the preconditioning with SB203580, a p38 MAPK-specific inhibitor. CONCLUSIONS: These results suggested that electroacupuncture could attenuate lung injury in rabbits subjected to LIR by inhibition of proinflammatory cytokine response and oxidative stress through activating p38 MAPK-mediated Nrf2/HO-1 pathway.