Association between lactate dehydrogenase to albumin ratio and acute kidney injury in patients with sepsis: a retrospective cohort study.

BACKGROUND: Serum lactate dehydrogenase to albumin ratio (LAR) is associated with poor outcomes in malignancy and pneumonia. However, there are few studies suggesting that LAR is associated with the occurrence of acute kidney injury (AKI) in patients with sepsis, which was investigated in this study. METHODS: We conducted a retrospective cohort study based on the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary outcome was the occurrence of AKI within 2 days and 7 days. Multivariable logistic regression models were used to calculate odds ratios to validate the association between LAR and AKI, in-hospital mortality, RRT use, and recovery of renal function, respectively. RESULTS: A total of 4010 participants were included in this study. The median age of the participants was 63.5 years and the median LAR was 10.5. After adjusting for confounding variables, patients in the highest LAR quartile had a higher risk of AKI than those in the lowest LAR quartile within 2 days and 7 days, with odds ratios of 1.37 (95% confidence interval [CI]: 1.23-1.52) and 1.95 (95% CI: 1.72-2.22), respectively. The adjusted odds of AKI within 2 and 7 days were 1.16 (95% CI: 1.12-1.20) and 1.29 (95% CI: 1.24-1.35) for each 1 unit increase in LAR(log2), respectively. CONCLUSION: This study demonstrated that elevated LAR was associated with poor prognosis in patients with sepsis. The risk of AKI and in-hospital mortality increased, the need for RRT increased, and the chance of recovery of renal function decreased with the increase of LAR.

Mild hypothermia alleviates oxygen-glucose deprivation/reperfusion-induced apoptosis by inhibiting ROS generation, improving mitochondrial dysfunction and regulating DNA damage repair pathway in PC12 cells.

The brain ischemia/reperfusion (I/R) injury has a great impact on human life and property safety. As far as we know, mild hypothermia (MH) is an effective measure to reduce neuronal injury after I/R. However, the precise mechanism is not extremely clear. The purpose of this study was to investigate whether mild therapeutic hypothermia can play a protective role in nerve cells dealing with brain I/R injury and explore its specific mechanism in vitro. A flow cytometer, cell counting kit-8 (CCK-8) assay and lactate dehydrogenase (LDH) release assay were performed to detect apoptotic rate of cells, cell viability and cytotoxicity, respectively, reactive oxygen species (ROS) assay kit, JC-1 fluorescent methods, immunofluorescence and western blot were used to explore ROS, mitochondrial transmembrane potential (Δψm), mitochondrial permeability transition pore (MPTP) and protein expression, respectively. The result indicated that the cell activity was decreased, while the cytotoxicity and apoptosis rate were increased after treating with oxygen-glucose deprivation/reperfusion (OGD/R) in PC12 cells. However, MH could antagonize this phenomenon. Interestingly, treating with OGD/R increased the release of ROS and the transfer of Cytochrome C (Cyt-C) from mitochondria to cytoplasm. In addition, it up-regulated the expression of γH2AX, Bax and Clv-caspase3, down-regulated the expression of PCNA, Rad51 and Bcl-2, and inhibited the function of mitochondria in PC12 cells. Excitingly, the opposite trend was observed after MH treatment. Therefore, our results suggest that MH protects PC12 cells against OGD/R-induced injury with the mechanism of inhibiting cell apoptosis by reducing ROS production, improving mitochondrial function, reducing DNA damage, and enhancing DNA repair.

Polydatin relieves paraquat-induced human MRC-5 fibroblast injury through inhibiting the activation of the NLRP3 inflammasome.

BACKGROUND: Paraquat (PQ) is a herbicide that is highly toxic to the lungs and kidneys. When it enters the body, it will disrupt the balance of the microenvironment in the body, induce a large number of inflammatory factors and cause cell damage. Polydatin (PD), resveratrol glycoside, has multiple pharmacological effects. However, the protective effect of PD on human embryo lung fibroblast damage caused by PQ poisoning has not been reported. The purpose of this study was to investigate the regulatory effect of PD on human embryo lung fibroblast damage caused by PQ poisoning. METHOD: The optimal experimental concentration of PQ for human embryonic lung fibroblast MRC-5 was 100 µmol/L, and then the cells of 100 µmol/L PQ group were treated with different concentrations of PD for 24 h. MTT assay to detect MRC-5 cell viability and flow cytometry to detect apoptosis. The corresponding kit was used to detect the contents of glutathione peroxidase (GSH-PX), malondialdehyde (MDA) and superoxide dismutase (SOD). Enzyme-linked immunosorbent assay (ELISA) to detect the levels of related inflammatory factors tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-ß), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6). Western blot detection of NLRP3 inflammatory body activation-related protein expression. RESULTS: Compared with the PQ group, cell activity, GSH-Px content, and SOD content in PD intervention group were significantly increased, while apoptosis, MDA content, inflammatory factor level, and activation-related proteins of the NLRP3 inflammasome were significantly reduced and were dose-dependent. CONCLUSIONS: PD can relieve PQ-induced human MRC-5 fibroblasts injury by reducing the inflammatory response, improving the antioxidant stress capacity, and inhibiting the activation of the NLRP3 inflammasome.

The inhibitor of interleukin-3 receptor protects against sepsis in a rat model of cecal ligation and puncture.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. There are multiple cytokines involved in the process of sepsis. As an important upstream cytokine in inflammation, Interleukin-3 (IL-3) plays a crucial role during sepsis, however, its exact role is unclear. The purpose of this study is to discuss the role of IL-3 and its receptor in cecal ligation and puncture (CLP)-induced sepsis in a rat model. The Cluster of Differentiation 123 (CD123, IL-3 receptor alpha chain, IL-3Rac) antibody (anti-CD123) was used to directly target IL-3's receptor and alleviate the effect of IL-3 in the CLP + anti-CD123 group during the early stage of sepsis. CLP was performed in the CLP and CLP + anti-CD123 groups. The time points of observation included 12 h, 24 h, and 5d after the operation. The results showed that the rats in the CLP + anti-CD123 group had lower levels of lactate, serum tumor necrosis factor-α (TNF-α), Interleukin-1ß (IL-1ß), and Interleukin-6 (IL-6), and also exhibited a higher core temperature, mean arterial pressure (MAP), Oxygenation Index (PO2/FiO2), and end-tidal carbon dioxide (ETCO2) and serum Interleukin-10 (IL-10) levels after CLP than those in the CLP group. Additionally, administration of anti-CD123 led to a stable down-regulation of tyrosine phosphorylation of the IL-3 receptor, a decline in phosphorylation of the Janus kinase 2 (JAK2) protein, and the signal transduction and activation of transcription 5 (STAT5) proteins in lung tissues. Meanwhile, the study revealed that treatment of anti-CD123 can markedly attenuate histological damages in lung and kidney tissues, improve sublingual microcirculation, and prolong survival post sepsis. In conclusion, anti-CD123 reduces mortality and alleviates organ dysfunction by restraining the JAK2-STAT5 signaling pathway and reduces serum cytokines in the development of early sepsis in a rat model induced by CLP.

LDK378 improves micro- and macro-circulation via alleviating STING-mediated inflammatory injury in a Sepsis rat model induced by Cecal ligation and puncture.

BACKGROUND: Sepsis is a systemic inflammatory response syndrome caused by severe infections. LDK378, a second-generation ALK inhibitor, exhibits a potential anti-inflammatory function against sepsis. Micro- and macro-circulatory dysfunctions are pivotal elements of the pathogenesis of severe sepsis and septic shock. We hypothesized that LDK378 can improve micro- and macro-circulation of septic rats, therefore improving the outcome of survival via blocking the ALK-STING pathway to attenuate inflammatory injuries. METHODS: A septic rat model was established by the cecal ligation and puncture (CLP) method. A total of 60 rats were randomized into three groups: a sham group, CLP group, and CLP + LDK378 group (n = 20 in each group). Five rats were randomly selected from each group for the mechanism study; the remaining 15 rats in each group were involved in a survival curve examination. A sidestream dark field video microscope was used to record sublingual microcirculation and mean arterial pressure (MAP) and levels of inflammatory cytokine secretion were examined at 6 h, 30 h, and 54 h after CLP surgery. Expressions of TANK binding kinase 1 (TBK1) and its downstream targets were determined, and histological alterations to the heart, lungs, and kidneys were examined at 54 h after CLP surgery. RESULTS: We found the group that received LDK378 treatment showed increased MAP levels compared to the CLP group at 30 h and 54 h. Meanwhile, LDK378 ameliorated the perfused small vessel density and microvascular flow index, decreased the expression of TNF-a and IL-6, and upregulated the expression of IL-10 in comparison with the CLP group. LDK378 injections also downregulated the expression of TBK1 and its downstream targets. Furthermore, LDK378 treatment significantly reduced sepsis-induced organ injuries, therefore improving survival rates. CONCLUSIONS: These findings demonstrate that LDK378 treatment can improve microcirculation and reduce organ injuries in CLP-induced septic rats via the regulation of inflammatory cytokine secretion and the downstream signaling components of the ALK-STING pathway.