Long noncoding RNA MCM3AP-AS1 attenuates sepsis-induced cardiomyopathy by improving inflammation, oxidative stress, and mitochondrial function through mediating the miR-501-3p/CADM1/STAT3 axis.

Oxidative stress and inflammation are highly important for sepsis-mediated myocardial damage. The long noncoding RNA (lncRNA) MCM3AP-AS1 is involved in inflammatory diseases, but its function in acute myocardial injury during sepsis has not been fully elucidated. LPS and cecal ligation and puncture (CLP) were used to construct in vitro and in vivo sepsis-induced myocardial damage models, respectively. qRT-PCR was used to evaluate alterations in MCM3AP-AS1 and miR-501-3p alterations. After the MCM3AP-AS1 and miR-501-3p knockdown or overexpression models were established, the viability, apoptosis, inflammation, oxidative stress, and mitochondrial function of the myocardial cells were examined. Dual luciferase activity assay, RNA immunoprecipitation, and fluorescence in situ hybridization (FISH) confirmed the correlation among MCM3AP-AS1, miR-501-3p, and CADM1. Previous studies revealed that MCM3AP-AS1 was downregulated in sepsis patients, myocardial cells treated with LPS, and in the CLP mouse sepsis model, whereas miR-501-3p expression was increased. MCM3AP-AS1 overexpression hampered myocardial damage mediated by LPS and abated inflammation, oxidative stress, and mitochondrial dysfunction in myocardial cells and THP-1 cells. In contrast, MCM3AP-AS1 knockdown or miR-501-3p overexpression promoted all the effects of LPS. In vivo, MCM3AP-AS1 overexpression increased the survival rate of CLP mice; ameliorated myocardial injury; decreased the levels of TNF-α, IL-1ß, IL-6, iNOS, COX2, ICAM1, VCAM1, PGE2, and MDA; and increased the levels of SOD, GSH-PX, Nrf2, and HO-1. Mechanistic studies demonstrated that MCM3AP-AS1 acted as a competitive endogenous RNA to repress miR-501-3p, enhance CADM1 expression, and dampen STAT3/nuclear factor-kappaB (NF-κB) activation. MCM3AP-AS1 suppresses myocardial injury elicited by sepsis by mediating the miR-501-3p/CADM1/STAT3/NF-κB axis.

Bone marrow mesenchymal stem cells-derived exosomes ameliorate LPS-induced acute lung injury by miR-223-regulated alveolar macrophage M2 polarization.

Numerous studies have shown that the M2 polarization of alveolar macrophages (AM) plays a protective role in acute lung injury (ALI). Mesenchymal stem cells (MSCs) secreted exosomes have been reported to be involved in inflammatory diseases by the effects of polarized M1/M2 macrophage populations. However, whether bone marrow mesenchymal stem cells (BMMSCs) derived exosomes could protect from ALI and its mechanisms are still unclear. Here, we explored the role of exosomes from BMMSC in rat AM polarization and the lipopolysaccharide- (LPS-) induced ALI rat model. Furthermore, the levels of exosomal miR-223 in BMMSCs were measured by RT-qPCR. Additionally, miR-223 mimics and its inhibitors were used to verify the vital role of miR-223 of BMMSCs-derived exosomes in the polarization of M2 macrophages. The results showed that BMMSCs-derived exosomes were taken up by the AM. Exosomes derived from BMMSCs promoted M2 polarization of AM in vitro. BMMSCs exosomes effectively mitigated pathological injuries, lung edema, and the inflammation of rats from LPS-induced ALI, accompanied by an increase of M2 polarization of AM in lung tissue. Interestingly, we also found that miR-223 was enriched in BMMSCs-derived exosomes, and overexpression of miR-223 in BMMSCs-derived exosomes promoted M2 polarization of AM while depressing miR-223 showed opposite effects in AM. The present study demonstrated that BMMSCs-derived exosomes triggered alveolar M2 polarization to improve inflammation by transferring miR-223, which may provide new therapeutic strategies in ALI.

Effect of combined sedation using multiple drugs on inflammatory cytokines in patients with acute respiratory distress syndrome

Abstract he innate immune response plays an important role in the pathophysiology of acute respiratory distress syndrome (ARDS); however, no drug has been proven to be beneficial in the management of ARDS. Therefore, the aim of this study was to investigate the effects of using combined sedatives on systemic inflammatory responses in patients with ARDS. A total of 90 patients with ARDS and an intubation time of > 120 h were randomly divided into the propofol group (group P), midazolam group (group M), and combined sedation group (group U). Patients in groups P and M were sedated with propofol and midazolam, respectively, whereas patients in group U were sedated with a combination of propofol, midazolam, and dexmedetomidine. The dosage of sedatives and vasoactive drugs, duration of mechanical ventilation, and incidence of sedative adverse reactions were documented. The dosage of sedatives and vasoactive drugs, as well as the incidence of sedative adverse reactions in group U, was significantly lower than those in groups P and M. Similarly, the duration of mechanical ventilation in group U was significantly shorter than that in groups P and M. Hence, inducing sedation through a combination of multiple drugs can significantly reduce their adverse effects, improve their sedative effect, inhibit systemic inflammatory responses, and improve oxygenation in patients with ARDS

Effect of Transradial Artery Catheterization on Shock Patients.

Objective: This study aimed to investigate the clinical effect of ultrasound-guided transradial catheterization (TRC) for ICU patients with shock. Methods: 120 shock patients registered in the ICU of our hospital from January 2019 to June 2022 were selected for prospective study. The control group (60 patients) were treated with palpation-guided TRC. The observation group was treated with ultrasound-guided TRC and was divided into the internal puncture group (internal TRC) and external puncture group (external TRC), with 30 cases in each. The first attempt success rate, total success rate, operation duration, complication, measurement of radial artery, and VAS scores were compared in these groups. Results: The success rate was higher in the observation group than in the control group (P < 0.05), and higher in the internal puncture group than in the external puncture group (P < 0.05). The first attempt success rate was significantly higher in the observation group than in the control group (P < 0.05), with no significant difference in between (P > 0.05). The number of attempts and operation duration were lower in the observation group than in the control group (P < 0.05), with significantly more operation duration in the internal puncture group than in the external puncture group (P < 0.05) and no significant difference in the number of attempts (both P > 0.05). The complication rate was significantly lower in the observation group than in the control group (P < 0.05) and there was no significant difference in between (P > 0.05). The radial artery diameter, cross-sectional area, and depth from the skin in the observation group were larger than those in the control group (P < 0.05) and there was no significant difference in between (P > 0.05). At 1, 6, 24, and 48 h after the surgery, the observation group showed lower VAS scores than the control group (P < 0.05). Conclusion: The ultrasound-guided TRC reduced the number of attempts, the complication rates, and the operation duration. For patients with shock, if Doppler ultrasound cannot detect blood flow, the success rate in the observation group was higher than that in the control group, and its advantage is worthy of promotion in severe patients.

MicroRNA-23a-3p ameliorates acute kidney injury by targeting FKBP5 and NF-κB signaling in sepsis.

Low miR-23a-3p expression in patients with acute kidney injury (AKI) or sepsis has been revealed. However, the specific role of miR-23a-3p in AKI remains unclear. Our study aimed to determine the function of miR-23a-3p in AKI. Exposure to lipopolysaccharide (LPS) was used to induce cell injury in vitro. Cecal ligation and puncture (CLP) surgery was used to establish an animal model of septic AKI. Bioinformatics analysis and a wide range of experiments, including RT-qPCR, luciferase reporter, western blot, ELISA, TUNEL, hematoxylin and eosin staining, and immunofluorescence assays were conducted. The experimental results revealed that LPS exposure induced the significant apoptosis and inflammatory response of HK-2 cells, and miR-23a-3p exhibited a low expression in LPS-exposed HK-2 cells. Functionally, miR-23a-3p overexpression inhibited cell apoptosis and release of inflammatory cytokines including interleukin (IL)-1ß, IL-6 and IL-8. Mechanistically, miR-23a-3p bound to the FKBP prolyl isomerase 5 (FKBP5) 3' untranslated region and negatively regulated its expression at mRNA and protein levels. Rescue assays indicated that FKBP5 overexpression reversed the influence of miR-23a-3p mimics on cell apoptosis and inflammatory response. Furthermore, miR-23a-3p overexpression attenuated the sepsis-induced impairment of renal function and the inflammatory response in mice with AKI. Finally, the knockdown of FKBP5 inactivated the nuclear factor kappaB (NF-κB) signaling by inactivating NF-κB nuclear translocation, and thereby inhibited the release of proinflammatory cytokines. Overall, our study demonstrates that miR-23a-3p ameliorates sepsis induced AKI by targeting FKBP5 and inactivating the NF-κB signaling, implying a potential therapeutic or diagnostic target for AKI.

Infusion of esmolol attenuates lipopolysaccharide-induced myocardial dysfunction.

BACKGROUND: Myocardial depression, as a well-recognized manifestation of cardiac dysfunction, often accompanies severe sepsis and septic shock. Inflammation-induced myocardial apoptosis is key to the development of sepsis-induced cardiac dysfunction. Increasing evidence suggests the anti-inflammatory role of ß1-adrenergic blocker, esmolol, during lethal endotoxemia. However, the direct protective effect of esmolol on cardiomyocyte viability during sepsis is still not clear. Here, we aimed to study whether infusion of esmolol can directly inhibit myocardial apoptosis during lipopolysaccharide (LPS)-triggered inflammatory insult. METHODS: C57BL/6 mice were randomized into four groups as follows: control; esmolol infusion; LPS insult; and esmolol infusion + LPS insult. Function of left ventricle was assessed by invasive hemodynamics at 6 h after LPS insult. Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining, caspase-3 expression level, and the Bcl-2/Bax ratio were used to evaluate myocardial apoptosis at 6 h after LPS insult or esmolol infusion. RESULTS: Administration of LPS resulted in significant decrease in left ventricular end-systolic pressure, reduced maximal rate of change of left ventricular pressure, and the increase in left ventricular end-diastolic pressure. Esmolol infusion reversed LPS-induced impairment of cardiac function and reduced LPS-induced myocardial apoptosis that is associated with c-Jun N-terminal kinase (JNK) and p38 activation. CONCLUSIONS: These data demonstrate that cardioprotection provided by esmolol infusion during LPS insult is associated with antiapoptotic effects and regulation of JNK and p38 activations.

Combination therapy with milrinone and esmolol for heart protection in patients with severe sepsis: a prospective, randomized trial.

BACKGROUND AND OBJECTIVE: As a ß-adrenoceptor antagonist (ß-blocker), esmolol can reduce cardiac output and the phosphodiesterase III inhibitor milrinone has been shown to improve heart contractility in patients with septic shock. This study was performed to assess the effects of esmolol combined with milrinone in patients with severe sepsis. METHODS: This prospective randomized study was conducted in patients with severe sepsis in the intensive care unit of the Jiangxi Provincial People's Hospital (Nanchang, Jiangsu, China) between June 2013 and June 2014. Patients were randomly divided into control (C), milrinone (M), and milrinone-esmolol (ME) groups. The primary outcome was the rate of controlling the heart rate (HR) to achieve target levels. Secondary outcomes included the 28-day survival rate and changes in hemodynamic variables, organ function variables, myocardial injury markers, and the serum levels of proinflammatory factors. RESULT: A total of 90 patients with severe sepsis were included in this study (30 per group). The HR in the ME group was lower than in the M and C groups after 12 h. The rate of successful HR control during the first 96 h was significantly higher in the ME group (60.0 vs. 33.3 % in the M group, vs. 26.7 % in the C group). Also, patients in the ME group had higher 28-day overall survival compared with the M (Log rank statistic = 5.452; P = 0.020) and C groups (Log rank statistic = 10.206; P = 0.001). Additionally, several variables showed significant improvement in the ME group 96 h after treatment compared with the M and C groups (P < 0.05). CONCLUSION: Combination therapy with milrinone and esmolol could improve cardiac function and the 28-day survival rate in patients with severe sepsis.