Bibliometric and visual analysis of single-cell multiomics in neurodegenerative disease arrest studies.

Background: Neurodegenerative diseases are progressive disorders that severely diminish the quality of life of patients. However, research on neurodegenerative diseases needs to be refined and deepened. Single-cell polyomics is a technique for obtaining transcriptomic, proteomic, and other information from a single cell. In recent years, the heat of single-cell multiomics as an emerging research tool for brain science has gradually increased. Therefore, the aim of this study was to analyze the current status and trends of studies related to the application of single-cell multiomics in neurodegenerative diseases through bibliometrics. Result: A total of 596 publications were included in the bibliometric analysis. Between 2015 and 2022, the number of publications increased annually, with the total number of citations increasing significantly, exhibiting the fastest rate of growth between 2019 and 2022. The country/region collaboration map shows that the United States has the most publications and cumulative citations, and that China and the United States have the most collaborations. The institutions that produced the greatest number of articles were Harvard Medical School, Skupin, Alexander, and Wiendl. Among the authors, Heinz had the highest output. Mathys, H accumulated the most citations and was the authoritative author in the field. The journal Nature Communications has published the most literature in this field. A keyword analysis reveals that neurodegenerative diseases and lesions (e.g., Alzheimer's disease, amyloid beta) are the core and foundation of the field. Conversely, single-cell multiomics related research (e.g., single-cell RNA sequencing, bioinformatics) and brain nerve cells (e.g., microglia, astrocytes, neural stem cells) are the hot frontiers of this specialty. Among the references, the article "Single-cell transcriptomic analysis of Alzheimer's disease" is the most frequently cited (1,146 citations), and the article "Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq" was the most cited article in the field. Conclusion: The objective of this study is to employ bibliometric methods to visualize studies related to single-cell multiomics in neurodegenerative diseases. This will enable us to summarize the current state of research and to reveal key trends and emerging hotspots in the field.

Effects of wearing myopia glasses on eye movement and scleral blood supply.

The present study examined the effect of wearing myopia glasses on eye movement and scleral blood supply. For this purpose, a total of 30 individuals were recruited for the present self-control study. Under the same fixation distance, the individuals wore 0.00 D and -10.00 D glasses. The amount of eye movement generated when shifting from gazing at a central point to a point light source located at the left or right was measured and compared between the two glasses. The results revealed that the range of eye movement was significantly reduced after wearing -10.00 D glasses. When gazing at the right point light source from the central point, the difference between the rotation distances of the right eye when wearing the 0.00 D glasses and the -10.0 D glasses was 0.73±0.45 mm (t=8.93, P<0.01) and that of the left eye was 0.73±0.43 mm (t=9.34, P<0.01). Similar results were obtained when the left point light source was viewed from a shift in gaze from the central point. On the whole, the present study demonstrates that wearing concave lenses limits eyeball movement. Restricted eyeball movement can affect vascular changes within the extraocular muscles and blood flow, thereby affecting the blood supply to the anterior segment and sclera of the eye, potentially accelerating the development of myopia.

Current trends and research topics regarding organoids: A bibliometric analysis of global research from 2000 to 2023.

The use of animal models for biological experiments is no longer sufficient for research related to human life and disease. The development of organ tissues has replaced animal models by mimicking the structure, function, development and homeostasis of natural organs. This provides more opportunities to study human diseases such as cancer, infectious diseases and genetic disorders. In this study, bibliometric methods were used to analyze organoid-related articles published over the last 20+ years to identify emerging trends and frontiers in organoid research. A total of 13,143 articles from 4125 institutions in 86 countries or regions were included in the analysis. The number of papers increased steadily over the 20-year period. The United States was the leading country in terms of number of papers and citations. Harvard Medical School had the highest number of papers published. Keyword analysis revealed research trends and focus areas such as organ tissues, stem cells, 3D culture and tissue engineering. In conclusion, this study used bibliometric and visualization methods to explore the field of organoid research and found that organ tissues are receiving increasing attention in areas such as cancer, drug discovery, personalized medicine, genetic disease modelling and gene repair, making them a current research hotspot and a future research trend.

Exploring the oncogenic potential of circSOD2 in clear cell renal cell carcinoma: a novel positive feedback loop.

BACKGROUND: Existing studies have found that circular RNAs (circRNAs) act as sponges for micro RNAs (miRNAs) to control downstream genes. However, the specific functionalities and mechanisms of circRNAs in human clear cell renal cell carcinoma (ccRCC) have yet to be thoroughly investigated. METHODS: Patient cohorts from online databases were used to screen candidate circRNAs, while another cohort from our hospital was obtained for validation. CircSOD2 was identified as a potential oncogenic target, and its relevant characteristics were investigated during ccRCC progression through various assays. A positive feedback loop containing downstream miRNA and its target gene were identified using bioinformatics and validated by luciferase reporter assays, RNA pull-down, and high-throughput sequencing. RESULTS: CircSOD2 expression was elevated in tumor samples and significantly correlated with overall survival (OS) and the tumor stage of ccRCC patients, which appeared in the enhanced proliferation, invasion, and migration of tumor cells. Through competitive binding to circSOD2, miR-532-3p can promote the expression of PAX5 and the progression of ccRCC, and such regulation can be salvaged by miR-532-3p inhibitor. CONCLUSION: A novel positive feedback loop, PAX5/circSOD2/miR-532-3p/PAX5 was identified in the study, indicating that the loop may play an important role in the diagnosis and prognostic prediction in ccRCC patients.

Research Hotspots and Frontiers of Alzheimer's Disease and Gut Microbiota: A Knowledge Mapping and Text Mining Analysis.

Gut microbiota has been confirmed to be closely related to Alzheimer's disease (AD). Research on gut microbiota and AD has also increased significantly. This study aimed to conduct a bibliometric and visual analysis of published studies related to gut microbiota and AD. Based on the Web of Science Core Collection SCI-Expanded database, we utilize Excel 2019 and visualization analysis tools VOSviewer, Co-Occurrence13.2 (COOC13.2), Citespace, HistCite, and Bibliometrix (R-Tool of R-Studio) for analysis. A total of 1093 related kinds of literature were included, and the number of papers presented an overall increasing trend. The country/region with the most publications is China, the institution is Zhejiang University, the author is Walter J Lukiw from the USA, and the journal is the Journal of Alzheimer's Disease. Hotspot research areas include the relationship between gut microbiota metabolism and AD, AD treatments related to the gut microbiota, and diseases related to AD and gut microbiota. The future research direction may be T cells, NLRP3 inflammasome, and Porphyromonas gingivalis. Studies on AD and gut microbiota have grown rapidly in recent years. Our research results may provide valuable references for readers and help researchers better find new research directions in the future.

LRP1 induces anti-PD-1 resistance by modulating the DLL4-NOTCH2-CCL2 axis and redirecting M2-like macrophage polarisation in bladder cancer.

The tumour microenvironment (TME) drives bladder cancer (BLCA) progression. Targeting the TME has emerged as a promising strategy for BLCA treatment in recent years. Furthermore, checkpoint blockade therapies are only beneficial for a minority of patients with BLCA, and drug resistance is a barrier to achieving significant clinical effects of anti-programmed cell death protein-1 (PD-1)/programmed death protein ligand-1 (PD-L1) therapy. In this study, higher low-density lipoprotein receptor-related protein 1 (LRP1) levels were related to a poorer prognosis for patients with various cancers, including those with higher grades and later stages of BLCA. Enrichment analysis demonstrated that LRP1 plays a role in the epithelial-mesenchymal transition (EMT), NOTCH signalling pathway, and ubiquitination. LRP1 knockdown in BLCA cells delayed BLCA progression both in vivo and in vitro. Furthermore, LRP1 knockdown suppressed EMT, reduced DLL4-NOTCH2 signalling activity, and downregulated M2-like macrophage polarisation. Patients with BLCA and higher LRP1 levels responded weakly to anti-PD-1 therapy in the IMvigor210 cohort. Moreover, LRP1 knockdown enhanced the therapeutic effects of anti-PD-1 in mice. Taken together, our findings suggest that LRP1 is a potential target for improving the efficacy of anti-PD-1/PD-L1 therapy by preventing EMT and M2-like macrophage polarisation by blocking the DLL4-NOTCH2 axis.

Current Status and Future Direction of Albumin-Bilirubin in Hepatocellular Carcinoma: A Bibliometric Analysis.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a common malignant tumor, so we need a convenient and objective way to diagnose and treat HCC. We discuss the current situation, progress, hotspots, and existing problems of Albumin-Bilirubin (ALBI) in HCC, which can provide new ideas for the prevention, diagnosis, and treatment of HCC. METHODS: We adopt Excel 2019 software and visual analysis tools based on Web of Science database search. This manuscript uses VOSviewer, Co-Occurrence13.3 (COOC13.3) software to conduct overall trend analysis, synonym merging, frequency of countries, journals, institutions, funds, dissimilarity matrices, co-occurrence matrices, bimodal matrices, coupling matrices, cluster analysis of topic evolution time zone graphs. RESULTS: A total of 610 papers were included, and the number of papers output showed an overall upward trend. ALBI has been valued by the industry in HCC and plays an important role in diagnosing and treating HCC, even better than the classic Child-Pugh (C-P) grade. At the same time, hot spots in the treatment of HCC and other applications of ALBI were discovered. CONCLUSION: ALBI score is a convenient and objective liver function evaluation index, which plays an important role in the prediction of patient survival rate and prognosis. Promoting the ALBI score in HCC can help doctors judge the patient's condition and improve the diagnosis and precise treatment effect.

Bibliometric and visual analysis of intraoperative hypotension from 2004 to 2022.

Background: Intraoperative hypotension (IOH) is a common complication occurring in surgical practice. This study aims to comprehensively review the collaboration and impact of countries, institutions, authors, journals, keywords, and critical papers on intraoperative hypotension from the perspective of bibliometric, and to evaluate the evolution of knowledge structure clustering and identify research hotspots and emerging topics. Methods: Articles and reviews related to IOH published from 2004 to 2022 were retrieved from the Web of Science Core Collection. Bibliometric analyses and visualization were conducted on Excel, CiteSpace, VOSviewer, and Bibliometrix (R-Tool of R-Studio). Results: A total of 1,784 articles and reviews were included from 2004 to 2022. The number of articles on IOH gradually increased in the past few years, and peaked in 2021. These publications were chiefly from 1,938 institutions in 40 countries, led by America and China in publications. Sessler Daniel I published the most papers and enjoyed the highest number of citations. Analysis of the journals with the most outputs showed that most journals concentrated on perioperative medicine and clinical anesthesiology. Delirium, acute kidney injury and vasoconstrictor agents are the current and developing research hotspots. The keywords "Acute kidney injury", "postoperative complication", "machine learning", "risk factors" and "hemodynamic instability" may also become new trends and focuses of the near future research. Conclusion: This study uses bibliometrics and visualization methods to comprehensively review the research on intraoperative hypotension, which is helpful for scholars to better understand the dynamic evolution of IOH and provide directions for future research.

Knowledge mapping of COVID-19 and autoimmune diseases: a visual and bibliometric analysis.

BACKGROUND: Many studies have shown an association between COVID-19 and autoimmune diseases (ADs). Studies on COVID-19 and ADs have also increased significantly, but there is no bibliometric analysis to summarize the association between COVID-19 and ADs. The purpose of this study was to perform a bibliometric and visual analysis of published studies related to COVID-19 and ADs. METHODS: Based on the Web of Science Core Collection SCI-Expanded database, we utilize Excel 2019 and visualization analysis tools Co-Occurrence13.2 (COOC13.2), VOSviewer, CiteSpace, and HistCite for analysis. RESULTS: A total of 1736 related kinds of papers were included, and the number of papers presented an overall increasing trend. The country/region with the most publications is the USA, the institution is the Harvard Medical School, the author is Yehuda Shoenfeld from Israel, and the journal is Frontiers in Immunology. Research hotspots include immune responses (such as cytokines storm), multisystem ADs (such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis), treatment modalities (such as hydroxychloroquine, rituximab), vaccination and autoimmune mechanisms (such as autoantibodies, molecular mimicry). The future research direction may be the mechanisms and treatment ideas of the association between ADs and COVID-19 (such as NF-κB, hyperinflammation, antiphospholipid antibodies, neutrophil extracellular traps, granulocyte-macrophage colony-stimulating factor), other cross-diseases of COVID-19 and ADs (such as inflammatory bowel disease, chronic mucocutaneous candidiasis, acute respiratory distress syndrome). CONCLUSION: The growth rate of publications regarding ADs and COVID-19 has risen sharply. Our research results can help researchers grasp the current status of ADs and COVID-19 research and find new research directions in the future.

Advances in gut microbiome in metabonomics perspective: based on bibliometrics methods and visualization analysis.

Background and aims: Gastrointestinal microbial metabolomics is closely related to the state of the organism and has significant interaction with the pathogenesis of many diseases. Based on the publications in Web of Science Core Collection(WoSCC) from 2004 to 2022, this study conducted a bibliometric analysis of this field, aiming to understand its development trend and frontier, and provide basic information and potential points for in-depth exploration of this field. Methods: All articles on gastrointestinal flora and metabolism published from 2004 to 2022 were collected and identified in WoCSS. CiteSpace v.6.1 and VOSviewer v.1.6.15.0 were used to calculate bibliometric indicators, including number of publications and citations, study categories, countries/institutions, authors/co-cited authors, journals/co-cited journals, co-cited references, and keywords. A map was drawn to visualize the data based on the analysis results for a more intuitive view. Results: There were 3811 articles in WoSCC that met our criteria. Analysis results show that the number of publications and citations in this field are increasing year by year. China is the country with the highest number of publications and USA owns the highest total link strength and citations. Chinese Acad Sci rank first for the number of institutional publications and total link strength. Journal of Proteome Research has the most publications. Nicholson, Jeremy K. is one of the most important scholars in this field. The most cited reference is "Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease". Burst detection indicates that Urine, spectroscopy, metabonomic and gut microflora are long-standing hot topics in this field, while autism spectrum disorder and omics are likely to be at the forefront of research. The study of related metabolic small molecules and the application of gastrointestinal microbiome metabolomics in various diseases are currently emerging research directions and frontier in this field. Conclusion: This study is the first to make a bibliometric analysis of the studies related to gastrointestinal microbial metabolomics and reveal the development trends and current research hotspots in this field. This can contribute to the development of the field by providing relevant scholars with valuable and effective information about the current state of the field.

Identification and validation of a DNA methylation-driven gene-based prognostic model for clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a malignant tumor with heterogeneous morphology and poor prognosis. This study aimed to establish a DNA methylation (DNAm)-driven gene-based prognostic model for ccRCC. METHODS: Reduced representation bisulfite sequencing (RRBS) was performed on the DNA extracts from ccRCC patients. We analyzed the RRBS data from 10 pairs of patient samples to screen the candidate CpG sites, then trained and validated an 18-CpG site model, and integrated the clinical characters to establish a Nomogram model for the prognosis or risk evaluation of ccRCC. RESULTS: We identified 2261 DMRs in the promoter region. After DMR selection, 578 candidates were screened, and was correspondence with 408 CpG dinucleotides in the 450 K array. We collected the DNAm profiles of 478 ccRCC samples from TCGA dataset. Using the training set with 319 samples, a prognostic panel of 18 CpGs was determined by univariate Cox regression, LASSO regression, and multivariate Cox proportional hazards regression analyses. We constructed a prognostic model by combining the clinical signatures. In the test set (159 samples) and whole set (478 samples), the Kaplan-Meier plot showed significant differences; and the ROC curve and survival analyses showed AUC greater than 0.7. The Nomogram integrated with clinicopathological characters and methylation risk score had better performance, and the decision curve analyses also showed a beneficial effect. CONCLUSIONS: This work provides insight into the role of hypermethylation in ccRCC. The targets identified might serve as biomarkers for early ccRCC diagnosis and prognosis biomarkers for ccRCC. We believe our findings have implications for better risk stratification and personalized management of this disease.

Integrated single-nucleus sequencing and spatial architecture analysis identified distinct injured-proximal tubular types in calculi rats.

BACKGROUND: Urolithiasis with high prevalence and recurrence rate, has impacts on kidney injury in patients, becomes a socioeconomic and healthcare problem in worldwide. However, the biology of kidney with crystal formation and proximal tubular injury remains essentially unclear. The present study aims to evaluate the cell biology and immune-communications in urolithiasis mediated kidney injury, to provide new insights in the kidney stone treatment and prevention. RESULTS: We identified 3 distinct injured-proximal tubular cell types based on the differentially expression injury markers (Havcr1 and lcn2) and functional solute carriers (slc34a3, slc22a8, slc38a3 and slc7a13), and characterized 4 main immune cell types in kidney and one undefined cell population, where F13a1+/high/CD163+/high monocyte & macrophage and Sirpa/Fcgr1a/Fcgr2a+/high granulocyte were the most enriched. We performed intercellular crosstalk analysis based on the snRNA-seq data and explored the potential immunomodulation of calculi stone formation, and founded that the interaction between ligand Gas6 and its receptors (Gas6-Axl, Gas6-Mertk) was specifically observed in the injured-PT1 cells, but not injured-PT2 and -PT3 cells. The interaction of Ptn-Plxnb2 was only observed between the injured-PT3 cells and its receptor enriched cells. CONCLUSIONS: Present study comprehensively characterized the gene expression profile in the calculi rat kidney at single nucleus level, identified novel marker genes for all cell types of rat kidney, and determined 3 distinct sub-population of injured-PT clusters, as well as intercellular communication between injured-PTs and immune cells. Our collection of data provides a reliable resource and reference for studies on renal cell biology and kidney disease.

Identification of a pyroptosis-related prognostic signature in breast cancer.

BACKGROUND: The relationship between pyroptosis and cancer is complex. It is controversial that whether pyroptosis represses or promotes tumor development. This study aimed to explore prognostic molecular characteristics to predict the prognosis of breast cancer (BRCA) based on a comprehensive analysis of pyroptosis-related gene expression data. METHODS: RNA-sequcing data of BRCA were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Ominibus (GEO) datasets. First, pyroptosis-related differentially expressed genes (DEGs) between normal and tumor tissues were identified from the TCGA database. Based on the DEGs, 1053 BRCA patients were divided into two clusters. Second, DEGs between the two clusters were used to construct a signature by a least absolute shrinkage and selection operator (LASSO) Cox regression model, and the GEO cohort was used to validate the signature. Various statistical methods were applied to assess this gene signature. Finally, Single-sample gene set enrichment analysis (ssGSEA) was employed to compare the enrichment scores of 16 types of immune cells and 13 immune-related pathways between the low- and high-risk groups. We calculated the tumor mutational burden (TMB) of TCGA cohort and evaluated the correlations between the TMB and riskscores of the TCGA cohort. We also compared the TMB between the low- and high-risk groups. RESULTS: A total of 39 pyroptosis-related DEGs were identified from the TCGA-breast cancer dataset. A prognostic signature comprising 16 genes in the two clusters of DEGs was developed to divide patients into high-risk and low-risk groups, and its prognostic performance was excellent in two independent patient cohorts. The high-risk group generally had lower levels of immune cell infiltration and lower activity of immune pathway activity than did the low-risk group, and different risk groups revealed different proportions of immune subtypes. The TMB is higher in high-risk group compared with low-risk group. OS of low-TMB group is better than that of high-TMB group. CONCLUSION: A 16-gene signature comprising pyroptosis-related genes was constructed to assess the prognosis of breast cancer patients and its prognostic performance was excellent in two independent patient cohorts. The signature was found closely associated with the tumor immune microenvironment and the potential correlation could provide some clues for further studies. The signature was also correlated with TMB and the mechanisms are still warranted.

16S rRNA gene sequencing reveals altered composition of gut microbiota in postoperative individuals with renal stones.

Renal stones are a common urological disease with high prevalence and recurrence rates. Characterizing gut microbiome profiles of first-onset renal calculi patients, both before and after surgery, may provide valuable insights and identify potential biomarkers for the disease. In this study, we explored the associations between the gut microbiome and renal stone formation using 16S ribosomal RNA (rRNA) gene sequencing. In brief, 20 patients were recruited, and information on health and eating habits within the previous 1-3 months was collected upon admission. A total of 493 operational taxonomic units (OTUs) were detected in 40 specimens, with an average of 67,888 ± 827 reads per sample. The results of OTU-based partial least squares discriminant analysis (PLS-DA) analysis showed differences between RS1 (fecal specimen before surgery) and RS2 (one month later after surgery) groups, with a significantly higher level of OTU7 in the RS2 group. Taxonomy-based comparisons of the gut microbiome showed differences in the flora composition, with the prevalence of Enterobacteriales, Enterobacteriaceae, Gammaproteobacteria and Escherichia being higher in the RS2 group and the prevalence of Pseudomonadaceae, Pseudomonadales and Pseudomonas being higher in the RS1 group. Correlation analysis showed that an increased prevalence of Enterobacteriaceae, Gammaproteobacteria and Escherichia associated with a decreased level of urea, and a decreased creatinine level was correlated with an increased prevalence of Escherichia. These data strongly suggest that the gut microbiome plays an important role in kidney stone formation, and these findings may provide new insights for the prevention, diagnosis, and treatment of renal stones.

High expression of RNF169 is associated with poor prognosis in pancreatic adenocarcinoma by regulating tumour immune infiltration.

Background: Pancreatic adenocarcinoma (PAAD) is a highly deadly and aggressive tumour with a poor prognosis. However, the prognostic value of RNF169 and its related mechanisms in PAAD have not been elucidated. In this study, we aimed to explore prognosis-related genes, especially RNF169 in PAAD and to identify novel potential prognostic predictors of PAAD. Methods: The GEPIA and UALCAN databases were used to investigate the expression and prognostic value of RNF169 in PAAD. The correlation between RNF169 expression and immune infiltration was determined by using TIMER and TISIDB. Correlation analysis with starBase was performed to identify a potential regulatory axis of lncRNA-miRNA-RNF169. Results: The data showed that the level of RNF169 mRNA expression in PAAD tissues was higher than that in normal tissues. High RNF169 expression was correlated with poor prognosis in PAAD. In addition, analysis with the TISIDB and TIMER databases revealed that RNF169 expression was positively correlated with tumour immune infiltration in PAAD. Correlation analysis suggested that the long non-coding RNA (lncRNA) AL049555.1 and the microRNA (miRNA) hsa-miR-324-5p were involved in the expression of RNF169, composing a potential regulatory axis to control the progression of PAAD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that RNF169 plays a role in PAAD through pathways such as TNF, Hippo, JAK-STAT and Toll-like receptor signaling. Conclusion: In summary, the upregulation of RNF169 expression mediated by ncRNAs might influence immune cell infiltration in the microenvironment; thus, it can be used as a prognostic biomarker and a potential therapeutic target in PAAD.

Hypervalent Iodine(III)-Promoted Radical Oxidative C-H Annulation of Arylamines with α-Keto Acids.

A novel catalyst-free radical oxidative C-H annulation reaction of arylamines with α-keto acids toward benzoxazin-2-ones synthesis under mild conditions was developed. This hypervalent iodine(III)-promoted process eliminated the use of a metal catalyst or additive with high levels of functional group tolerance. Hypervalent iodine(III) was both an oxidant and a radical initiator for this reaction. The synthetic utility of this method was confirmed by the synthesis of the natural product cephalandole A.

Proteasome inhibition induces macrophage apoptosis via mitochondrial dysfunction.

Dysfunction of the ubiquitin-proteasome system has been linked to the pathogenesis of a variety of diseases. Proteasome inhibition not only exerts antitumor effects but also affects inflammatory signaling pathways. MG132, a proteasome inhibitor, has been shown to induce tumor cell apoptosis. However, its role in the induction of macrophage apoptosis remains unknown. In our study, we investigated the mechanism of the proapoptotic effects of MG132 in macrophages. Our data showed that MG132 treatment induced mitochondrial reactive oxygen species (ROS) generation and loss of mitochondrial membrane potential in macrophages. We found that proteasome inhibition induced a significant increase in the apoptosis rate, as evidenced by cleavage of caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). Moreover, (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenyl-phosphonium chloride (Mito-TEMPO) attenuated MG132-induced apoptosis. In conclusion, proteasome inhibition by MG132 can induce macrophage apoptosis by promoting the production of ROS and mitochondrial dysfunction.

TBK1/IKKε Negatively Regulate LPS-Induced Neutrophil Necroptosis and Lung Inflammation.

ABSTRACT: Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that controls cell release of inflammatory mediators from innate immune cells, such as polymorphonuclear neutrophils (PMNs), and critically regulates the progress of inflammation. Cell necroptosis features receptor-interacting protein (RIPK) 1 activation and necroptosome formation. This leads to loss of plasma membrane integrity, the release of cell contents into the extracellular space, and subsequent increased inflammation. Here, we report an intra-PMN mechanism of negative regulation of necroptosis mediated through TBK1/IKKε. Using an in vivo mouse model of intratracheal injection (i.t.) of LPS and in vitro LPS stimulation of mouse PMN, we found that LPS-TLR4 signaling in PMNs activates and phosphorylates TBK1 and IKKε, which in turn suppress LPS-induced formation of the RIPK1-RIPK3-MLKL (necrosome) complex. TBK1 dysfunction by knockdown or inhibitor significantly increases the phosphorylation of RIPK1 (∼67%), RIPK3 (∼68%), and MLKL (∼50%) and promotes RIPK1-RIPK3 and RIPK3-MLKL interactions and increases PMN necroptosis (∼83%) in response to LPS, with subsequent augmented lung inflammation. These findings suggest that the LPS-TLR4-TBK1 axis serves as a negative regulator for PMN necroptosis and might be a therapeutic target for modulating PMN death and inflammation.

RAGE-induced ILC2 expansion in acute lung injury due to haemorrhagic shock.

BACKGROUND: Type 2 immune dysfunction contributes to acute lung injury and lethality following haemorrhagic shock (HS) and trauma. Group 2 innate lymphoid cells (ILC2s) play a significant role in the regulation of type 2 immune responses. However, the role of ILC2 in post-HS acute lung injury and the underlying mechanism has not yet been elucidated. OBJECTIVE: To investigate the regulatory role of ILC2s in HS-induced acute lung injury and the underlying mechanism in patients and animal model. METHODS: Circulating markers of type 2 immune responses in patients with HS and healthy controls were characterised. Using a murine model of HS, the role of high-mobility group box 1 (HMGB1)-receptor for advanced glycation end products (RAGE) signalling in regulation of ILC2 proliferation, survival and function was determined. And the role of ILC2 in inducing type 2 immune dysfunction was assessed as well. RESULTS: The number of ILC2s was significantly increased in the circulation of patients with HS that was correlated with the increase in the markers of type 2 immune responses in the patients. Animal studies showed that HMGB1 acted via RAGE to induce ILC2 accumulation in the lungs by promoting ILC2 proliferation and decreasing ILC2 death. The expansion of ILC2s resulted in type 2 cytokines secretion and eosinophil infiltration in the lungs, both of which contributed to lung injury after HS. CONCLUSIONS: These results indicate that HMGB1-RAGE signalling plays a critical role in regulating ILC2 biological function that aggravates type 2 lung inflammation following HS.

Enteric dysbiosis-linked gut barrier disruption triggers early renal injury induced by chronic high salt feeding in mice.

Chronic high-salt diet-associated renal injury is a key risk factor for the development of hypertension. However, the mechanism by which salt triggers kidney damage is poorly understood. Our study investigated how high salt (HS) intake triggers early renal injury by considering the 'gut-kidney axis'. We fed mice 2% NaCl in drinking water continuously for 8 weeks to induce early renal injury. We found that the 'quantitative' and 'qualitative' levels of the intestinal microflora were significantly altered after chronic HS feeding, which indicated the occurrence of enteric dysbiosis. In addition, intestinal immunological gene expression was impaired in mice with HS intake. Gut permeability elevation and enteric bacterial translocation into the kidney were detected after chronic HS feeding. Gut bacteria depletion by non-absorbable antibiotic administration restored HS loading-induced gut leakiness, renal injury and systolic blood pressure elevation. The fecal microbiota from mice fed chronic HS could independently cause gut leakiness and renal injury. Our current work provides a novel insight into the mechanism of HS-induced renal injury by investigating the role of the intestine with enteric bacteria and gut permeability and clearly illustrates that chronic HS loading elicited renal injury and dysfunction that was dependent on the intestine.