The effects of antioxidant supplementation on short-term mortality in sepsis patients.

Background: The occurrence and development of sepsis are related to the excessive production of oxygen free radicals and the weakened natural clearance mechanism. Further dependable evidence is required to clarify the effectiveness of antioxidant therapy, especially its impact on short-term mortality. Objectives: The purpose of this systematic review and meta-analysis was to evaluate the effect of common antioxidant therapy on short-term mortality in patients with sepsis. Methods: According to PRISMA guidelines, a systematic literature search on antioxidants in adults sepsis patients was performed on PubMed/Medline, Embase, and the Cochrane Library from the establishment of the database to November 2023. Antioxidant supplements can be a single-drug or multi-drug combination: HAT (hydrocortisone, ascorbic acid, and thiamine), ascorbic acid, thiamine, N-acetylcysteine and selenium. The primary outcome was the effect of antioxidant treatment on short-term mortality, which included 28-day mortality, in-hospital mortality, intensive care unit mortality, and 30-day mortality. Subgroup analyses of short-term mortality were used to reduce statistical heterogeneity and publication bias. Results: Sixty studies of 130,986 sepsis patients fulfilled the predefined criteria and were quantified and meta-analyzed. Antioxidant therapy reduces the risk of short-term death in sepsis patients by multivariate meta-analysis of current data, including a reduction of in-hospital mortality (OR = 0.81, 95% CI 0.67 to 0.99; P = 0.040) and 28-day mortality (OR = 0.81, 95% CI 0.69 to 0.95]; P = 0.008). Particularly in subgroup analyses, ascorbic acid treatment can reduce in-hospital mortality (OR = 0.66, 95% CI 0.90 to 0.98; P = 0.006) and 28-day mortality (OR = 0.43, 95% CI 0.24 to 0.75; P = 0.003). However, the meta-analysis of RCTs found that antioxidant therapy drugs, especially ascorbic acid, did substantially reduce short-term mortality(OR = 0.78, 95% CI 0.62 to 0.98; P = 0.030; OR = 0.57, 95% CI 0.36 to 0.91; P = 0.020). Conclusions: According to current data of RCTs, antioxidant therapy, especially ascorbic acid, has a trend of improving short-term mortality in patients with sepsis, but the evidence remains to be further demonstrated.

S100A9 exacerbates sepsis-induced acute lung injury via the IL17-NFκB-caspase-3 signaling pathway.

BACKGROUND: Sepsis-induced acute lung injury (ALI) is associated with considerable morbidity and mortality in critically ill patients. S100A9, a key endothelial injury factor, is markedly upregulated in sepsis-induced ALI; however, its specific mechanism of action has not been fully elucidated. METHODS: The Gene Expression Omnibus database transcriptome data for sepsis-induced ALI were used to screen for key differentially expressed genes (DEGs). Using bioinformatics analysis methods such as Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction network analyses, the pathogenesis of sepsis-induced ALI was revealed. Intratracheal infusion of lipopolysaccharide (LPS, 10 mg/kg) induced ALI in wild-type (WT) and S100A9 knockout mice. Multiomics analyses (transcriptomics and proteomics) were performed to investigate the potential mechanisms by which S100A9 exacerbates acute lung damage. Hematoxylin-eosin, Giemsa, and TUNEL staining were used to evaluate lung injury and cell apoptosis. LPS (10 µg/mL)-induced murine lung epithelial MLE-12 cells were utilized to mimic ALI and were modulated by S100A9 lentiviral transfection. The impact of S100A9 on cell apoptosis and inflammatory responses were identified using flow cytometry and PCR. The expression of interleukin (IL)-17-nuclear factor kappa B (NFκB)-caspase-3 signaling components was identified using western blotting. RESULTS: Six common DEGs (S100A9, S100A8, IFITM6, SAA3, CD177, and MMP9) were identified in the six datasets related to ALI in sepsis. Compared to WT sepsis mice, S100A9 knockout significantly alleviated LPS-induced ALI in mice, with reduced lung structural damage and inflammatory exudation, decreased exfoliated cell and protein content in the lung lavage fluid, and reduced apoptosis and necrosis of pulmonary epithelial cells. Transcriptomic analysis revealed that knocking out S100A9 significantly affected 123 DEGs, which were enriched in immune responses, defense responses against bacteria or lipopolysaccharides, cytokine-cytokine receptor interactions, and the IL-17 signaling pathway. Proteomic analysis revealed that S100A9 knockout alleviated muscle contraction dysfunction and structural remodeling in sepsis-induced ALI. Multiomics analysis revealed that S100A9 may be closely related to interferon-induced proteins with tetratricopeptide repeats and oligoadenylate synthase-like proteins. LPS decreased MLE12 cell activity, accompanied by high expression of S100A9. The expression of IL-17RA, pNFκB, and cleaved-caspase-3 were increased by S100A9 overexpression and reduced by S100A9 knockdown in LPS-stimulated MLE12 cells. S100A9 knockdown decreases transcription of apoptosis-related markers Bax, Bcl and caspase-3, alleviating LPS-induced apoptosis. CONCLUSIONS: S100A9 as a key biomarker of sepsis-induced acute lung injury, and exacerbates lung damage and epithelial cell apoptosis induced by LPS via the IL-17-NFκB-caspase-3 signaling pathway.

Matrix metalloproteinase-8 regulates dendritic cell tolerance in late polymicrobial sepsis via the nuclear factor kappa-B p65/ß-catenin pathway.

Background: Tolerogenic dendritic cells (DCs) are associated with poor prognosis of sepsis. Matrix metalloproteinases (MMPs) have been shown to have immunomodulatory effects. However, whether MMPs are involved in the functional reprogramming of DCs is unknown. The study aims to investigate the role of MMPs in sepsis-induced DCs tolerance and the potential mechanisms. Methods: A murine model of late sepsis was induced by cecal ligation and puncture (CLP). The expression levels of members of the MMP family were detected in sepsis-induced tolerogenic DCs by using microarray assessment. The potential roles and mechanisms underlying MMP8 in the differentiation, maturation and functional reprogramming of DCs during late sepsis were assessed both in vitro and in vivo. Results: DCs from late septic mice expressed higher levels of MMP8, MMP9, MMP14, MMP19, MMP25 and MMP27, and MMP8 levels were the highest. MMP8 deficiency significantly alleviated sepsis-induced immune tolerance of DCs both in vivo and in vitro. Adoptive transfer of MMP8 knockdown post-septic bone marrow-derived DCs protected mice against sepsis-associated lethality and organ dysfunction, inhibited regulatory T-cell expansion and enhanced Th1 response. Furthermore, the effect of MMP8 on DC tolerance was found to be associated with the nuclear factor kappa-B p65/ß-catenin pathway. Conclusions: Increased MMP8 levels in septic DCs might serve as a negative feedback loop, thereby suppressing the proinflammatory response and inducing DC tolerance.

Risk model for predicting mortality in patients with necrotizing soft tissue infections in the intensive care unit.

BACKGROUND: The goal of this study is to look into the factors that lead to death in patients with necrotizing soft tissue infections（NSTIs） in the intensive care unit and create a mortality risk model. METHODS: The clinical data of 106 patients with necrotizing soft tissue infections admitted to intensive care unit(ICU) of the First Affiliated Hospital of Wenzhou Medical University between January 2008 and December 2021 were retrospectively analyzed. Univariate analysis and multivariate analysis were performed to evaluate the risk factors impacting patient mortality. The regression coefficient in binary logistic regression analysis was converted into the item score in the model, and then the model score of each patient was calculated. Finally, an ROC curve was constructed to evaluate the efficiency of the model for predicting mortality. Thirteen patients with NSTIs admitted to ICU between January 2022 and November 2022 were used to validate the model. RESULTS: The death group had 44 patients, while the survival group had 62 patients. The overall mortality was 41.5%. Binary logistic regression analysis showed that risk factors for mortality were age≥ 60 years(OR:4.419; 95%CI:1.093-17.862; P = 0.037), creatinine ≥ 132µmol/L(OR:11.166; 95%CI:2.234-55.816; P = 0.003), creatine kinase ≥ 1104 U/L(OR:4.019; 95%CI:1.134-14.250; P = 0.031), prothrombin time ≥ 24.4 s(OR:11.589; 95%CI:2.510-53.506; P = 0.002), and invasive mechanical ventilation (OR:17.404; 95%CI:4.586-66.052; P＜0.000). The AUC of the model for predicting mortality was 0.940 (95% CI:0.894-0.986). When the cut-off value for the model was 4 points, the sensitivity was 95.5% and the specificity was 83.9%. CONCLUSION: The death risk model in this study for NSTIs patients in the intensive care unit shows high sensitivity and specificity. Patients with a score of ≥ 4 points have a higher risk of mortality.

Mitochondrial reactive oxygen species initiate gasdermin D-mediated pyroptosis and contribute to paraquat-induced nephrotoxicity.

Paraquat (PQ)-induced acute kidney injury (AKI) progresses rapidly and is associated with high mortality rates; however, no specific antidote for PQ has been identified. Poor understanding of toxicological mechanisms underlying PQ has hindered the development of suitable treatments to combat PQ exposure. Gasdermin D (GSDMD), a key executor of pyroptosis, has recently been shown to enhance nephrotoxicity in drug-induced AKI. To explore the role of pyroptosis in PQ-induced AKI, the plasma membrane damage of the cells was detected by LDH release assay. Western blot was performed to detect the cleavage of GSDMD. RNA sequencing analysis was performed to explore the mechanism of PQ induced nephrotoxicity. Herein, we demonstrated that PQ could induce pyroptosis in HK-2 cells and nephridial tissues. Mechanistically, PQ initiated GSDMD cleavage, and GSDMD knockout attenuated PQ-induced nephrotoxicity in vivo. Further analysis revealed that the accumulation of mitochondrial reactive oxygen species (ROS) induced p38 activation, contributing to PQ-induced pyroptosis. Furthermore, mitoquinone, a mitochondria-targeted antioxidant, reduced mitochondrial ROS levels and inhibited pyroptosis. Collectively, these findings provide insights into the role of GSDMD-dependent pyroptosis as a novel mechanism of PQ-induced AKI.

Autophagy mediated FTH1 degradation activates gasdermin E dependent pyroptosis contributing to diquat induced kidney injury.

Acute kidney injury (AKI) induced by diquat (DQ) progresses rapidly, leading to high mortality, and there is no specific antidote for this chemical. Our limited knowledge of the pathogenic toxicological mechanisms of DQ has hindered the development of treatments against DQ poisoning. Pyroptosis is a form of programmed cell death and was recently identified as a novel molecular mechanism of drug-induced AKI. To explore the role of pyroptosis in HK-2 cells exposed to DQ, the plasma membrane damage of the cells was detected by LDH release assay. Western blot was performed to detect the cleavage of GSDME. Proteomics analysis was performed to explore the mechanism of DQ induced nephrotoxicity. FerroOrange probe was used to measure the intracellular Fe2+ levels. Herein, we show that DQ induces pyroptosis in HK-2 cells. Mechanistically, DQ induces the accumulation of mitochondrial ROS and initiates the cleavage of gasdermin E (GSDME) in an intrinsic mitochondrial pathway. Knockout of GSDME attenuated DQ-induced cell death. Further analysis revealed that loss of FTH1 induces Fe2+ accumulation, contributing to DQ-induced pyroptosis. Knockdown LC3B could help restore the expression of FTH1 and improve cell viability. Moreover, we found DFO, an iron chelator, could reduce cellular Fe2+ levels and inhibit pyroptosis. Collectively, these findings suggest an unrecognized mechanism for GSDME-dependent pyroptosis in DQ-induced AKI.

Abnormalities of serum lipid metabolism in patients with acute paraquat poisoning caused by ferroptosis.

As the mechanism of paraquat (PQ) poisoning is still not fully elucidated, and no specific treatment has been developed in medical practice, the management of PQ poisoning continues to present a medical challenge. In this study, the objective was to investigate the early metabolic changes in serum metabolism and identify the key metabolic pathways involved in patients with PQ poisoning. Quantitative analysis was conducted to determine the relevant metabolites. Additionally, experiments were carried out in both plasma and cell to elucidate the mechanisms underlying metabolic disorder and cell death in PQ poisoning. The study found that polyunsaturated fatty acids (PUFAs) and their metabolites, such as arachidonic acid (AA) and hydroxy eicosatetraenoic acids (HETEs), were significantly increased by non-enzymatic oxidative reaction. Reactive oxygen species (ROS) production increased rapidly at 2 h after PQ poisoning, followed by an increase in PUFAs at 12 h, and intracellular glutathione, cysteine (Cys), and Fe2+ at 24 h. However, at 36 h later, intracellular glutathione and Cys decreased, HETEs increased, and the expression of SLC7A11 and glutathione peroxidase 4 (GPX4) decreased. Ultrastructural examination revealed the absence of mitochondrial cristae. Deferoxamine was found to alleviate lipid oxidation, and increase the viability of PQ toxic cells in the low dose. In conclusion, unsaturated fatty acids metabolism was the key metabolic pathways in PQ poisoning. PQ caused cell death through the induction of ferroptosis. Inhibition of ferroptosis could be a novel strategy for the treatment of PQ poisoning.

Paraquat-induced ferroptosis suppression via NRF2 expression regulation.

Paraquat (PQ) is an environmentally friendly and efficient herbicide, but PQ misuse or intentional self-use can cause death through multiple organ damage and can cause acute lung injury. Existing clinical treatments alleviate symptoms but do not significantly improve the mortality rate. Ferroptosis is a type of necrosis that presents in a manner very similar to the cell damage induced by high doses of PQ, but the role of ferroptosis in paraquat-induced lung injury remains unclear. In this study, we aimed to explore the role of ferroptosis in PQ-induced A549 cell injury and identify the potential mechanisms and critical sites of protection against PQ-induced A549 injury by ferroptosis inhibitors. We found that the ferroptosis inhibitors Ferr-1 and Lip-1 inhibit ferroptosis by attenuating oxidative stress through the upregulation of NRF2 gene expression. The protective role of the ferroptosis inhibitor Dfo was most evident in paraquat-induced cell injury. Dfo inhibited ferroptosis by iron chelation and promoted NRF2 protein level reduction. NRF2 attenuated PQ-induced ferroptosis in A549 cells, mainly through the upregulation of SLC40A1 to encourage the movement of iron to the extracellular side to alleviate iron overload, and the upregulation of SLC7A11 to promote the expression of GPX4 to inhibit lipid peroxidation.

SUPPLEMENTATION WITH NICOTINAMIDE RIBOSIDE ATTENUATES T CELL EXHAUSTION AND IMPROVES SURVIVAL IN SEPSIS.

ABSTRACT: T cell exhaustion is the main cause of sepsis-induced immunosuppression and is associated with the poor prognosis. Nicotinamide adenine dinucleotide (NAD + ) is well known for its anti-aging effect, but its role in sepsis-induced T cell exhaustion remains to be elucidated. In the present study, using a classic septic animal model, we found that the levels of NAD + and its downstream molecule, which is sirtuins 1 (SIRT1), in T cells in sepsis were decreased. Supplementation with nicotinamide ribose (NR), the precursor of NAD + , right after cecal ligation and puncture significantly increased the levels of NAD + and SIRT1. Supplementation with NR alleviated the depletion of mononuclear cells and T lymphocytes in spleen in sepsis and increased the levels of CD3 + CD4 + and CD3 + CD8 + T cells. Interestingly, both Th1 and Th2 cells were expanded after NR treatment, but the balance of Th1/Th2 was partly restored. Nicotinamide ribose also inhibited the regulatory T cells expansion and programmed cell death 1 expression in CD4 + T cells in sepsis. In addition, the bacteria load, organ damage (lung, heart, liver, and kidney), and the mortality of septic mice were reduced after NR supplementation. In summary, these results demonstrate the beneficial effect of NR on sepsis and T cell exhaustion, which is associated with NAD + /SIRT1 pathway.

Administration of protopine prevents mitophagy and acute lung injury in sepsis.

Introduction: Sepsis is a severe life-threatening infection that induces a series of dysregulated physiologic responses and results in organ dysfunction. Acute lung injury (ALI), the primary cause of respiratory failure brought on by sepsis, does not have a specific therapy. Protopine (PTP) is an alkaloid with antiinflammatory and antioxidant properties. However, the function of PTP in septic ALI has not yet been documented. This work sought to investigate how PTP affected septic ALI and the mechanisms involved in septic lung damage, including inflammation, oxidative stress, apoptosis, and mitophagy. Methods: Here, we established a mouse model induced by cecal ligation and puncture (CLP) and a BEAS-2B cell model exposed to lipopolysaccharide (LPS). Results: PTP treatment significantly reduced mortality in CLP mice. PTP mitigated lung damage and reduced apoptosis. Western blot analysis showed that PTP dramatically reduced the expression of the apoptosis-associated protein (Cleaved Caspase-3, Cyto C) and increased Bcl-2/Bax. In addition, PTP decreased the production of inflammatory cytokines (IL-6, IL-1ß, TNF-α), increased glutathione (GSH) levels and superoxide dismutase (SOD) activity, and decreased malondialdehyde (MDA) levels. Meanwhile, PTP significantly reduced the expression of mitophagy-related proteins (PINK1, Parkin, LC-II), and downregulated mitophagy by transmission electron microscopy. Additionally, the cells were consistent with animal experiments. Discussion: PTP intervention reduced inflammatory responses, oxidative stress, and apoptosis, restored mitochondrial membrane potential, and downregulated mitophagy. The research shows that PTP prevents excessivemitophagy and ALI in sepsis, suggesting that PTP has a potential role in the therapy of sepsis.

Prediction of transport proteins from sequence information with the deep learning approach.

Transport proteins (TPs) are vital to the growth and life of all living things, especially in fields of microbial pathogenesis and drug resistance of tumor cells. Accurately identifying potential TPs remains an important challenge for the advancement of functional genomics. This study aimed to develop a tool for predicting TPs using the deep learning approach. Here, we proposed DeepTP, a convolutional neural network model that uses parallel subnetworks to extract features from protein sequences and uses fully connected layers for TP classification. To train and evaluate the performance of the developed model, datasets were collected from the UniProtKB/Swiss-Prot database. The test results revealed that the proposed model could successfully identify TPs with the AUCROC, accuracy, F-value, and Matthews correlation coefficient of 0.9719, 0.9513, 0.8982, and 0.8679, respectively. By further comparison, DeepTP achieved better performance than other commonly used methods. Analysis of the gradients of prediction score concerning input suggested that DeepTP makes predictions by recognizing the functional domains of TPs. We anticipate that DeepTP will serve as a useful tool for predicting TPs in large-scale genome projects, which will facilitate the discovery of novel TPs.

Mutual promotion of mitochondrial fission and oxidative stress contributes to mitochondrial-DNA-mediated inflammation and epithelial-mesenchymal transition in paraquat-induced pulmonary fibrosis.

BACKGROUND: Pulmonary fibrosis (PF) is one of the main causes of death in patients with paraquat (PQ) poisoning. This study aimed to evaluate the relationship between mitochondrial fission and oxidative stress in PQ-induced epithelial-mesenchymal transition (EMT) and PF. METHODS: C57BL/6 mice and MLE-12 cells were exposed to PQ to construct a PF model in vivo and in vitro. Histological changes in the lungs were examined by hematoxylin and eosin (H&E) staining. Mitochondrial morphology was detected by MitoTracker® Deep Red FM or transmission electron microscopy (TEM). Western blotting and immunofluorescence were used to determine the expression of protein. The migration ability of the cells was detected by the cell scratch test. Mitochondrial DNA (mtDNA) levels were assessed by real-time polymerase chain reaction (PCR). Enzyme-linked immunosorbent assay (ELISA) was applied to detect cytokine levels. Superoxide dismutase (SOD) activity and the levels of glutathione (GSH) and malondialdehyde (MDA) were detected by chemichromatometry. RESULTS: PQ exposure caused EMT and PF in vivo and in vitro. PQ destroyed mitochondrial structure and enhanced the expression of dynamin-related protein 1 (Drp1), which were accompanied by oxidative stress. Inhibiting mitochondrial fission using mitochondrial division inhibitor-1 (Mdivi-1), a selective inhibitor of Drp1, attenuated PQ-induced EMT and oxidative damage. Treatment with N-acetyl-L-cysteine (NAC), an antioxidant, reduced Drp1 expression, attenuated mitochondrial structure damage and inhibited PQ-induced EMT and PF. Both Mdivi-1 and NAC treatment markedly suppressed mtDNA release, the expression of Toll-like receptor 9 (TLR9) and phosphorylation (P)-NF-κB p65 as well as cytokines (interleukin 6 [IL-6], interleukin-1ß [IL-1ß], and tumor necrosis factor-α [TNF-α]) production. CONCLUSION: Mutual promotion of mitochondrial fission and oxidative stress contributes to EMT in PQ-induced PF, which is associated with the mtDNA/TLR9/NF-κB pathway.

Glabridin Therapy Reduces Chronic Allodynia, Spinal Microgliosis, and Dendritic Spine Generation by Inhibiting Fractalkine-CX3CR1 Signaling in a Mouse Model of Tibial Fractures.

Patients undergoing bone fractures frequently suffer from irritating chronic pain after orthopedic repairs. Chemokine-mediated interactions between neurons and microglia are important steps for neuroinflammation and excitatory synaptic plasticity during the spinal transmission of pathological pain. Recently, glabridin, the main bioactive component of licorice, has been shown to exhibit anti-nociceptive and neuroprotective properties for inflammatory pain. This present study evaluated the therapeutic potential of glabridin and its analgesic mechanisms using a mouse model of tibial fracture-associated chronic pain. Repetitive injections of glabridin were delivered spinally daily for 4 continuous days from days 3 to 6 after the fractures. Herein, we discovered that repeated administrations of glabridin (10 and 50 µg, but not 1 µg) could prevent prolonged cold allodynia and mechanical allodynia following bone fractures. A single intrathecal intervention with glabridin (50 µg) relieved an existing chronic allodynia two weeks following the fracture surgeries. Systemic therapies with glabridin (intraperitoneal; 50 mg kg-1) were protective against long-lasting allodynia caused by fractures. Furthermore, glabridin restricted the fracture-caused spinal overexpressions of the chemokine fractalkine and its receptor CX3CR1, as well as the elevated number of microglial cells and dendritic spines. Strikingly, glabridin induced the inhibition of pain behaviors, microgliosis, and spine generation, which were abolished with the co-administration of exogenous fractalkine. Meanwhile, the exogenous fractalkine-evoked acute pain was compensated after microglia inhibition. Additionally, spinal neutralization of fractalkine/CX3CR1 signaling alleviated the intensity of postoperative allodynia after tibial fractures. These key findings identify that glabridin therapies confer protection against inducing and sustaining fracture-elicited chronic allodynia by suppressing fractalkine/CX3CR1-dependent spinal microgliosis and spine morphogenesis, suggesting that glabridin is a promising candidate in the translational development of chronic fracture pain control.

Berberine Alleviates Acute Lung Injury in Septic Mice by Modulating Treg/Th17 Homeostasis and Downregulating NF-κB Signaling.

Purpose: A common complication of sepsis is acute lung injury (ALI), which is associated with an acute onset, rapid disease changes, and high mortality. Regulatory T (Treg) and T helper 17 (Th17) cells comprise CD4+ T cell subsets, which strongly influence inflammation during ALI. In this study, we investigated the effect of berberine (BBR), an antioxidant, anti-inflammatory, and immunomodulatory drug, on the inflammatory response and immune state in mice with sepsis. Methods: A mouse model of cecal ligation and puncture (CLP) was established. The mice were intragastrically administered 50 mg/kg BBR. We used histological techniques to evaluate inflammatory tissue injury and flow cytometry for analyzing Treg/Th17 levels. We also assessed NF-κB signaling pathways by Western blotting assays and immunofluorescence staining. Enzyme-linked immunosorbent assay (ELISA) was performed to measure the content of cytokines. Results: Treatment with BBR considerably mitigated lung injury while improving survival, post-cecal ligation, and puncture (CLP). Treatment with BBR ameliorated pulmonary edema and hypoxemia in septic mice and inhibited the NF-κB signaling pathway. BBR also increased Treg cells and decreased Th17 proportions in the spleen and lung tissue of CLP-treated mice. Blocking Treg cells weakened the protective effect of BBR on sepsis-associated lung injury. Conclusion: Overall, these results suggested that BBR is a potential therapeutic agent for sepsis.

A new criteria for acute on preexisting kidney dysfunction in critically ill patients.

Critically ill patients with preexisting kidney dysfunction (PKD) are at high risk for acute kidney injury (AKI). Nevertheless, there is no criteria for screening and classifying AKI in patients with PKD. In this study, after assessing relationship between the change in SCr from baseline and in-hospital mortality, a new criteria, named APKD, for identifying AKI in PKD was proposed. APKD defined AKI in critically ill patients with PKD as an absolute increase of ≥ 0.2 mg/dL in SCr within 48 h or an increase in SCr ≥ 1.1 times over baseline within 7 d. APKD detected more AKI among PKD patients compared with the other criteria. Additionally, the AKI patients identified by APKD but missed by the other criteria had higher mortality than those without AKI. APKD shows higher sensitivities than KDIGO criteria in predicating in-hospital mortality. APKD, but not the KDIGO, is effective for staging the severity of AKI in patients with PKD. In conclusion, APKD is more effective in screening and classifying AKI in critically ill patients with PKD compared with the earlier criteria, and it may helpful in guiding clinical treatment and predicting prognosis.

A fuzzy-set qualitative comparative analysis exploration of multiple paths to users' continuous use behavior of diabetes self-management apps.

BACKGROUND: Despite the obvious potential benefits of diabetes self-management apps, users' continuous use of diabetes self-management apps is still not widespread. Influential factors coexisted in information ecologies are likely to have a synthetic effect on users' continuous use behavior. However, it is less clear how factors in information ecologies combine to influence users' continuous use behavior. OBJECTIVE: The objectives of this study are to explore combinations of factors (perceived severity, information quality, service quality, system quality, and social influence) in information ecologies that lead to users' continuous use behavior of diabetes self-management apps and which combination is the most important. METHODS: Purpose sampling was used to recruit diabetes self-management app users from July 1, 2021 to January 31, 2022. Fuzzy-set qualitative comparative analysis (fsQCA) was then employed by conducting necessity and sufficiency analysis. RESULTS: In total 280 diabetes self-management app users participated. The necessity analysis indicated that no single factor was necessary to cause users' continuous use behavior, and the sufficiency analysis identified five different combinations of factors that lead to users' continuous use behavior. Of these five, the combination of high information quality, high service quality, and high social influence was found to be the most important path. CONCLUSIONS: Users' continuous use behavior of diabetes self-management apps results from the synergistic effects of factors in information ecologies. The five paths that directly contribute to users' continuous use, as well as the four user types preliminarily identified in this study may provide a reference for healthcare providers and app developers.

Prevalence and predictors in self-neglect: A cross-sectional study of domestic migrant older adults in China.

Insufficient information is available on the prevalence and predictors of self-neglect among Chinese domestic migrant older adults resulting from rapid aging and mass population migration. This cross-sectional study was conducted on 597 older adults in four districts of Wenzhou from May to November 2020. A self-neglect scale was used to assess the prevalence of self-neglect among such adults. Sixteen potential predictors were considered in the domains of sociodemographic, health condition, socioeconomic, social isolation, intergenerational relationship, and filial piety. The prevalence of self-neglect within this population was 72.7%. Social isolation (OR = 0.823; 95%CI 0.684-0.990), physical health (OR = 0.966; 95%CI 0.941-0.992), intergenerational ambivalence (OR = 1.240; 95%CI 1.013-1.519), and affective-cognitive solidarity (OR = 0.796; 95%CI 0.719-0.880) were found to be independent predictors of self-neglect in this population. We suggest that community health service organizations should prioritize migrant older adults with a poor health status and those with intergenerational ambivalence to reduce self-neglect in migrant older adults. Such older adults should also be encouraged to participate in community activities for more social integration.

PINK1 protects against dendritic cell dysfunction during sepsis through the regulation of mitochondrial quality control.

BACKGROUND: Dendritic cell (DC) dysfunction plays a central role in sepsis-induced immunosuppression. Recent research has indicated that collective mitochondrial fragmentation contributes to the dysfunction of immune cells observed during sepsis. PTEN-induced putative kinase 1 (PINK1) has been characterized as a guide for impaired mitochondria that can keep mitochondrial homeostasis. However, its role in the function of DCs during sepsis and the related mechanisms remain obscure. In our study, we elucidated the effect of PINK1 on DC function during sepsis and its underlying mechanism of action. METHODS: Cecal ligation and puncture (CLP) surgery and lipopolysaccharide (LPS) treatment were used as in vivo and in vitro sepsis models, respectively. RESULTS: We found that changes in mitochondrial PINK1 expression of DCs paralleled changes in DC function during sepsis. The ratio of DCs expressing MHC-II, CD86, and CD80, the mRNAs level of dendritic cells expressing TNF-α and IL-12, and the level of DC-mediated T-cell proliferation were all decreased, both in vivo and in vitro during sepsis, when PINK1 was knocked out. This suggested that PINK1 knockout prevented the function of DCs during sepsis. Furthermore, PINK1 knockout inhibited Parkin RBR E3 ubiquitin protein (Parkin)-dependent mitophagy and enhanced dynamin-related protein 1 (Drp1)-related mitochondrial fission, and the negative effects of PINK1 knockout on DC function following LPS treatment were reversed by Parkin activation and Drp1 inhibitor. Knockout of PINK1 also increased apoptosis of DCs and the mortality of CLP mice. CONCLUSION: Our results indicated that PINK1 protected against DC dysfunction during sepsis through the regulation of mitochondrial quality control.

A novel mechanism of Dimethyl ester of Alpha-ketoglutarate in suppressing Paraquat-induced BEAS-2B cell injury by alleviating GSDME dependent pyroptosis.

BACKGROUND: Acute lung injury (ALI) induced by paraquat (PQ) progresses rapidly, leading to high mortality; however, there is no specific antidote. Our limited knowledge of the pathogenic toxicological mechanisms of PQ has hindered the development of treatments against PQ exposure. PURPOSE: Pyroptosis is a form of programmed cell death recently identified as a novel molecular mechanism adopted by chemotherapeutic drugs for cancer therapy. However, the involvement of pyroptosis in PQ-induced lung injury has not been reported. Therefore, we investigated the effects of PQ on the lung tissues to elucidate the molecular mechanisms underlying its toxicity, especially its ability to induce pyroptosis. METHODS: To observe the morphological changes of BEAS-2B cells exposed to PQ, the plasma membrane damage of the cells was detected by LDH release assay, mitochondrial function and cell metabolism were detected by energy metabolism analysis. Western blotting was used to detect the protein levels of GSDMD, C-GSDMD, GSDME and N-GSDME in BEAS-2B cells. Metabolites of TCA cycle were detected by metabolomics, and the changes of TCA cycle metabolic enzymes in cells were detected by Western blotting. RESULTS: We observed that PQ induced proteolytic cleavage of gasdermin E (GSDME) with concomitant cleavage of caspase 3 in BEAS-2B cells. Knockout of GSDME attenuated PQ-induced cell death. Additionally, PQ induced ROS accumulation, mitochondrial depolarisation, and mitochondrial dysfunction in these cells. PQ activated the caspase 3/GSDME pathway and damaged the cytoplasmic membrane in cells, leading to pyroptosis. We demonstrated that DMK suppressed PQ-induced pyroptosis by blocking PQ-induced caspase 3/GSDME pathway activation, reducing cellular ROS levels, and improving mitochondrial function. CONCLUSION: These findings provide novel insights into the previously unrecognized mechanism of GSDME-dependent pyroptosis in PQ poisoning.

Orai1 overexpression improves sepsis-induced T-lymphocyte immunosuppression and acute organ dysfunction in mice.

Immune paralysis induced by sepsis, especially dysfunction of CD4+ T cells, leads to an increased risk of infection. In sepsis, abnormal differentiation of T lymphocytes is associated with multiorgan dysfunction syndrome. In T lymphocytes, the Orai1/nuclear factor of activated T Cells (NFAT) pathway is a critical mediator of infection, inflammation, and autoimmunity. In this study, we confirmed immunosuppression of splenic CD4+ T cells and abnormal differentiation of T lymphocytes in septic mice. Furthermore, we found that the Orai1/NFAT signaling pathway was inhibited in septic mice; however, the overexpression of Orai1 not only improved immune function of T cells in sepsis but also reduced the mortality and organ damage in septic mice. Moreover, the overexpression of Orai1 could reverse the increases in the numbers of T regulatory and T helper 17 cells in septic mice. These data suggest that the Orai1-mediated NFAT signaling pathway can improve sepsis-induced T-lymphocyte immunosuppression and acute organ dysfunction.