Organellophagy regulates cell death:A potential therapeutic target for inflammatory diseases.

BACKGROUND: Dysregulated alterations in organelle structure and function have a significant connection with cell death, as well as the occurrence and development of inflammatory diseases. Maintaining cell viability and inhibiting the release of inflammatory cytokines are essential measures to treat inflammatory diseases. Recently, many studies have showed that autophagy selectively targets dysfunctional organelles, thereby sustaining the functional stability of organelles, alleviating the release of multiple cytokines, and maintaining organismal homeostasis. Organellophagy dysfunction is critically engaged in different kinds of cell death and inflammatory diseases. AIM OF REVIEW: We summarized the current knowledge of organellophagy (e.g., mitophagy, reticulophagy, golgiphagy, lysophagy, pexophagy, nucleophagy, and ribophagy) and the underlying mechanisms by which organellophagy regulates cell death. KEY SCIENTIFIC CONCEPTS OF REVIEW: We outlined the potential role of organellophagy in the modulation of cell fate during the inflammatory response to develop an intervention strategy for the organelle quality control in inflammatory diseases.

Interferon-α stimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis.

BACKGROUND: Liver ischemia/reperfusion (I/R) injury is usually caused by hepatic inflow occlusion during liver surgery, and is frequently observed during war wounds and trauma. Hepatocyte ferroptosis plays a critical role in liver I/R injury, however, it remains unclear whether this process is controlled or regulated by members of the DEAD/DExH-box helicase (DDX/DHX) family. METHODS: The expression of DDX/DHX family members during liver I/R injury was screened using transcriptome analysis. Hepatocyte-specific Dhx58 knockout mice were constructed, and a partial liver I/R operation was performed. Single-cell RNA sequencing (scRNA-seq) in the liver post I/R suggested enhanced ferroptosis by Dhx58hep-/-. The mRNAs and proteins associated with DExH-box helicase 58 (DHX58) were screened using RNA immunoprecipitation-sequencing (RIP-seq) and IP-mass spectrometry (IP-MS). RESULTS: Excessive production of reactive oxygen species (ROS) decreased the expression of the IFN-stimulated gene Dhx58 in hepatocytes and promoted hepatic ferroptosis, while treatment using IFN-α increased DHX58 expression and prevented ferroptosis during liver I/R injury. Mechanistically, DHX58 with RNA-binding activity constitutively associates with the mRNA of glutathione peroxidase 4 (GPX4), a central ferroptosis suppressor, and recruits the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in an m6A-dependent manner, thus enhancing GPX4 protein levels and preventing hepatic ferroptosis. CONCLUSIONS: This study provides mechanistic evidence that IFN-α stimulates DHX58 to promote the translation of m6A-modified Gpx4 mRNA, suggesting the potential clinical application of IFN-α in the prevention of hepatic ferroptosis during liver I/R injury.

The crosstalk between mitochondrial quality control and metal-dependent cell death.

Mitochondria are the centers of energy and material metabolism, and they also serve as the storage and dispatch hubs of metal ions. Damage to mitochondrial structure and function can cause abnormal levels and distribution of metal ions, leading to cell dysfunction and even death. For a long time, mitochondrial quality control pathways such as mitochondrial dynamics and mitophagy have been considered to inhibit metal-induced cell death. However, with the discovery of new metal-dependent cell death including ferroptosis and cuproptosis, increasing evidence shows that there is a complex relationship between mitochondrial quality control and metal-dependent cell death. This article reviews the latest research results and mechanisms of crosstalk between mitochondrial quality control and metal-dependent cell death in recent years, as well as their involvement in neurodegenerative diseases, tumors and other diseases, in order to provide new ideas for the research and treatment of related diseases.

Ferritinophagy: A novel insight into the double-edged sword in ferritinophagy-ferroptosis axis and human diseases.

Nuclear receptor coactive 4 (NCOA4), which functions as a selective cargo receptor, is a critical regulator of the particularly autophagic degradation of ferritin, a process known as ferritinophagy. Mechanistically, NCOA4-mediated ferritinophagy performs an increasingly vital role in the maintenance of intracellular iron homeostasis by promoting ferritin transport and iron release as needed. Ferritinophagy is not only involved in iron-dependent responses but also in the pathogenesis and progression of various human diseases, including metabolism-related, neurodegenerative, cardiovascular and infectious diseases. Therefore, ferritinophagy is of great importance in maintaining cell viability and function and represents a potential therapeutic target. Recent studies indicated that ferritinophagy regulates the signalling pathway associated with ferroptosis, a newly discovered type of cell death characterised by iron-dependent lipid peroxidation. Although accumulating evidence clearly demonstrates the importance of the interplay between dysfunction in iron metabolism and ferroptosis, a deeper understanding of the double-edged sword effect of ferritinophagy in ferroptosis has remained elusive. Details of the mechanisms underlying the ferritinophagy-ferroptosis axis in regulating relevant human diseases remain to be elucidated. In this review, we discuss the latest research findings regarding the mechanisms that regulate the biological function of NCOA4-mediated ferritinophagy and its contribution to the pathophysiology of ferroptosis. The important role of the ferritinophagy-ferroptosis axis in human diseases will be discussed in detail, highlighting the great potential of targeting ferritinophagy in the treatment of diseases.

Pharmacologically significant constituents collectively responsible for anti-sepsis action of XueBiJing, a Chinese herb-based intravenous formulation.

Sepsis, a life-threatening health issue, lacks effective medicine targeting the septic response. In China, treatment combining the intravenous herbal medicine XueBiJing with conventional procedures reduces the 28-day mortality of critically ill patients by modulating septic response. In this study, we identified the combined active constituents that are responsible for the XueBiJing's anti-sepsis action. Sepsis was induced in rats by cecal ligation and puncture (CLP). The compounds were identified based on their systemic exposure levels and anti-sepsis activities in CLP rats that were given an intravenous bolus dose of XueBiJing. Furthermore, the identified compounds in combination were assessed, by comparing with XueBiJing, for levels of primary therapeutic outcome, pharmacokinetic equivalence, and pharmacokinetic compatibility. We showed that a total of 12 XueBiJing compounds, unchanged or metabolized, circulated with significant systemic exposure in CLP rats that received XueBiJing. Among these compounds, hydroxysafflor yellow A, paeoniflorin, oxypaeoniflorin, albiflorin, senkyunolide I, and tanshinol displayed significant anti-sepsis activities, which involved regulating immune responses, inhibiting excessive inflammation, modulating hemostasis, and improving organ function. A combination of the six compounds, with the same respective doses as in XueBiJing, displayed percentage survival and systemic exposure in CLP rats similar to those by XueBiJing. Both the combination and XueBiJing showed high degrees of pharmacokinetic compatibility regarding interactions among the six active compounds and influences of other circulating XueBiJing compounds. The identification of XueBiJing's pharmacologically significant constituents supports the medicine's anti-sepsis use and provides insights into a polypharmacology-based approach to develop medicines for effective sepsis management.

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.

Single-cell transcriptome profiling of sepsis identifies HLA-DRlowS100Ahigh monocytes with immunosuppressive function.

BACKGROUND: Sustained yet intractable immunosuppression is commonly observed in septic patients, resulting in aggravated clinical outcomes. However, due to the substantial heterogeneity within septic patients, precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking. METHODS: We adopted cross-species, single-cell RNA sequencing (scRNA-seq) analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis. Flow cytometry, laser scanning confocal microscopy (LSCM) imaging and Western blotting were applied to identify the presence of S100A9+ monocytes at protein level. To interrogate the immunosuppressive function of this subset, splenic monocytes isolated from septic wild-type or S100a9-/- mice were co-cultured with naïve CD4+ T cells, followed by proliferative assay. Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage. RESULTS: ScRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis, for which distinct monocyte subsets were enriched in disparate subclusters of septic patients. We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR (HLA-DR), which were prominently enriched in septic patients and might exert immunosuppressive function. By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments, we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice, corresponding to HLA-DRlowS100Ahigh monocytes in human sepsis. Moreover, we found that S100A9+ monocytes exhibited profound immunosuppressive function on CD4+ T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression. CONCLUSIONS: This study identifies HLA-DRlowS100Ahigh monocytes correlated with immunosuppressive state upon septic challenge, inhibition of which can markedly mitigate sepsis-induced immune depression, thereby providing a novel therapeutic strategy for the management of sepsis.

Nuclear fragile X mental retardation-interacting protein 1-mediated ribophagy protects T lymphocytes against apoptosis in sepsis.

Background: Ribophagy is a selective autophagic process that specifically degrades dysfunctional or superfluous ribosomes to maintain cellular homeostasis. Whether ribophagy can ameliorate the immunosuppression in sepsis similar to endoplasmic reticulum autophagy (ERphagy) and mitophagy remains unclear. This study was conducted to investigate the activity and regulation of ribophagy in sepsis and to further explore the potential mechanism underlying the involvement of ribophagy in T-lymphocyte apoptosis. Methods: The activity and regulation of nuclear fragile X mental retardation-interacting protein 1 (NUFIP1)-mediated ribophagy in T lymphocytes during sepsis were first investigated by western blotting, laser confocal microscopy and transmission electron microscopy. Then, we constructed lentivirally transfected cells and gene-defective mouse models to observe the impact of NUFIP1 deletion on T-lymphocyte apoptosis and finally explored the signaling pathway associated with T-cell mediated immune response following septic challenge. Results: Both cecal ligation and perforation-induced sepsis and lipopolysaccharide stimulation significantly induced the occurrence of ribophagy, which peaked at 24 h. When NUFIP1 was knocked down, T-lymphocyte apoptosis was noticeably increased. Conversely, the overexpression of NUFIP1 exerted a significant protective impact on T-lymphocyte apoptosis. Consistently, the apoptosis and immunosuppression of T lymphocytes and 1-week mortality rate in NUFIP1 gene-deficient mice were significantly increased compared with those in wild-type mice. In addition, the protective effect of NUFIP1-mediated ribophagy on T lymphocytes was identified to be closely related to the endoplasmic reticulum stress apoptosis pathway, and PERK-ATF4-CHOP signaling was obviously involved in downregulating T-lymphocyte apoptosis in the setting of sepsis. Conclusions: NUFIP1-mediated ribophagy can be significantly activated to alleviate T lymphocyte apoptosis through the PERK-ATF4-CHOP pathway in the context of sepsis. Thus, targeting NUFIP1-mediated ribophagy might be of importance in reversing the immunosuppression associated with septic complications.

Expert consensus on the monitoring and treatment of sepsis-induced immunosuppression.

Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis. To provide clinical practice recommendations on the immune function in sepsis, an expert consensus focusing on the monitoring and treatment of sepsis-induced immunosuppression was developed. Literature related to the immune monitoring and treatment of sepsis were retrieved from PubMed, Web of Science, and Chinese National Knowledge Infrastructure to design items and expert opinions were collected through an online questionnaire. Then, the Delphi method was used to form consensus opinions, and RAND appropriateness method was developed to provide consistency evaluation and recommendation levels for consensus opinions. This consensus achieved satisfactory results through two rounds of questionnaire survey, with 2 statements rated as perfect consistency, 13 as very good consistency, and 9 as good consistency. After summarizing the results, a total of 14 strong recommended opinions, 8 weak recommended opinions and 2 non-recommended opinions were produced. Finally, a face-to-face discussion of the consensus opinions was performed through an online meeting, and all judges unanimously agreed on the content of this consensus. In summary, this expert consensus provides a preliminary guidance for the monitoring and treatment of immunosuppression in patients with sepsis.

Worldwide productivity and research trend of publications concerning glioma-associated macrophage/microglia: A bibliometric study.

Glioma-associated macrophage/microglia (GAM) represents a key player in shaping a unique glioma ecosystem to facilitate tumor progression and therapeutic resistance. Numerous studies have been published concerning GAM, but no relevant bibliometric study has been performed yet. Our bibliometric study aimed to comprehensively summarize and analyze the global scientific output, research hotspots, and trendy topics of publications on GAM over time. Data on publications on GAM were collected using the Web of Science (WoS). The search date was 16 January 2022, and the publications were collected from 2002 to 2021. Totally, 1,224 articles and reviews were incorporated and analyzed in the current study. It showed that the annual publications concerning GAM kept increasing over the past 20 years. The United States had the largest number of publications and total citations. Holland, Kettenmann, and Gutmann were the top three authors in terms of citation frequency. Neuro-oncology represented the most influential journal in GAM studies, with the highest H-index, total citations, and publication numbers. The paper published by Hambardzumyan in 2016 had the highest local citations. Additionally, the analysis of keywords implied that "prognosis," "tumor microenvironment," and "immunotherapy" might become research hotspots. Furthermore, trendy topics in GAM studies suggested that "immune infiltration," "immune microenvironment," "bioinformatics," "prognosis," and "immunotherapy" deserved additional attention. In conclusion, this bibliometric study comprehensively analyzed the publication trend of GAM studies for the past 20 years, in which the research hotspots and trendy topics were also uncovered. This information offered scholars critical references for conducting in-depth studies on GAM in the future.

Publication trends of research on sepsis and programmed cell death during 2002-2022: A 20-year bibliometric analysis.

Background: Sepsis is considered an intractable dysfunction that results from the disordered host immune response to uncontrolled infection. Even though the precise mechanism of sepsis remains unclear, scientific advances have highlighted the key role of various programmed cell death processes in the pathophysiology of sepsis. The current study aims to explore the worldwide research trend on programmed cell death in the setting of sepsis and assesses the achievements of publications from various countries, institutions, journals, and authors globally. Material and methods: Associated publications during 2002-2022 with the topical subject of sepsis and programmed cell death were extracted from the Web of Science. VOSviewer was utilized to evaluate and map the published trend in the relevant fields. Results: All 2,037 relevant manuscripts with a total citation of 71,575 times were screened out by the end of 1 January 2022. China accounted for the largest number of publications (45.07%) and was accompanied by corporate citations (11,037) and H-index (48), which ranked second globally. The United States has been ranked first place with the highest citations (30,775) and H-index (88), despite a low publication number (29.95%), which was subsequent to China. The journal Shock accounted for the largest number of publications in this area. R. S. Hotchkiss, affiliated with Washington University, was considered to have published the most papers in the relevant fields (57) and achieved the highest citation frequencies (9,523). The primary keywords on the topic of programmed cell death in sepsis remarkably focused on "inflammation" "immunosuppression", and "oxidative stress", which were recognized as the core mechanisms of sepsis, eventually attributing to programmed cell death. The involved research on programmed cell death induced by immune dysregulation of sepsis was undoubtedly the hotspot in the pertinent areas. Conclusions: The United States has been academically outstanding in sepsis-related research. There appears to be an incompatible performance between publications and quantity with China. Frontier advances may be consulted in the journal Shock. The leading-edge research on the scope of programmed cell death in sepsis should preferably focus on immune dissonance-related studies in the future.

Publication trends of research on COVID-19 and host immune response: A bibliometric analysis.

Introduction: As the first bibliometric analysis of COVID-19 and immune responses, this study will provide a comprehensive overview of the latest research advances. We attempt to summarize the scientific productivity and cooperation across countries and institutions using the bibliometric methodology. Meanwhile, using clustering analysis of keywords, we revealed the evolution of research hotspots and predicted future research focuses, thereby providing valuable information for the follow-up studies. Methods: We selected publications on COVID-19 and immune response using our pre-designed search strategy. Web of Science was applied to screen the eligible publications for subsequent bibliometric analyses. GraphPad Prism 8.0, VOSviewer, and CiteSpace were applied to analyze the research trends and compared the contributions of countries, authors, institutions, and journals to the global publications in this field. Results: We identified 2,200 publications on COVID-19 and immune response published between December 1, 2019, and April 25, 2022, with a total of 3,154 citations. The United States (611), China (353), and Germany (209) ranked the top three in terms of the number of publications, accounting for 53.3% of the total articles. Among the top 15 institutions publishing articles in this area, four were from France, four were from the United States, and three were from China. The journal Frontiers in Immunology published the most articles (178) related to COVID-19 and immune response. Alessandro Sette (31 publications) from the United States were the most productive and influential scholar in this field, whose publications with the most citation frequency (3,633). Furthermore, the development and evaluation of vaccines might become a hotspot in relevant scope. Conclusions: The United States makes the most indispensable contribution in this field in terms of publication numbers, total citations, and H-index. Although publications from China also take the lead regarding quality and quantity, their international cooperation and preclinical research need to be further strengthened. Regarding the citation frequency and the total number of published articles, the latest research progress might be tracked in the top-ranking journals in this field. By analyzing the chronological order of the appearance of retrieved keywords, we speculated that vaccine-related research might be the novel focus in this field.

Application Status and Prospects of Artificial Intelligence in Peptic Ulcers.

Peptic ulcer (PU) is a common and frequently occurring disease. Although PU seriously threatens the lives and health of global residents, the applications of artificial intelligence (AI) have strongly promoted diversification and modernization in the diagnosis and treatment of PU. This minireview elaborates on the research progress of AI in the field of PU, from PU's pathogenic factor Helicobacter pylori (Hp) infection, diagnosis and differential diagnosis, to its management and complications (bleeding, obstruction, perforation and canceration). Finally, the challenges and prospects of AI application in PU are prospected and expounded. With the in-depth understanding of modern medical technology, AI remains a promising option in the management of PU patients and plays a more indispensable role. How to realize the robustness, versatility and diversity of multifunctional AI systems in PU and conduct multicenter prospective clinical research as soon as possible are the top priorities in the future.

Single-cell transcriptome profiling of the immune space-time landscape reveals dendritic cell regulatory program in polymicrobial sepsis.

Rationale: Evident immunosuppression has been commonly seen among septic patients, and it is demonstrated to be a major driver of morbidity. Nevertheless, a comprehensive view of the host immune response to sepsis is lacking as the majority of studies on immunosuppression have focused on a specific type of immune cells. Methods: We applied multi-compartment, single-cell RNA sequencing (scRNA-seq) to dissect heterogeneity within immune cell subsets during sepsis progression on cecal ligation and puncture (CLP) mouse model. Flow cytometry and multiplex immunofluorescence tissue staining were adopted to identify the presence of 'mature DCs enriched in immunoregulatory molecules' (mregDC) upon septic challenge. To explore the function of mregDC, sorted mregDC were co-cultured with naïve CD4+ T cells. Intracellular signaling pathways that drove mregDC program were determined by integrating scRNA-seq and bulk-seq data, combined with inhibitory experiments. Results: ScRNA-seq analysis revealed that sepsis induction was associated with substantial alterations and heterogeneity of canonical immune cell types, including T, B, natural killer (NK), and myeloid cells, across three immune-relevant tissue sites. We found a unique subcluster of conventional dendritic cells (cDCs) that was characterized by specific expression of maturation- and migration-related genes, along with upregulation of immunoregulatory molecules, corresponding to the previously described 'mregDCs' in cancer. Flow cytometry and in stiu immunofluorescence staining confirmed the presence of sepsis-induced mregDC at protein level. Functional experiments showed that sepsis-induced mregDCs potently activated naive CD4+ T cells, while promoted CD4+ T cell conversion to regulatory T cells. Further observations indicated that the mregDC program was initiated via TNFRSF-NF-κB- and IFNGR2-JAK-STAT3-dependent pathways within 24 h of septic challenge. Additionally, we confirmed the detection of mregDC in human sepsis using publicly available data from a recently published single-cell study of COVID-19 patients. Conclusions: Our study generates a comprehensive single-cell immune landscape for polymicrobial sepsis, in which we identify the significant alterations and heterogeneity in immune cell subsets that take place during sepsis. Moreover, we find a conserved and potentially targetable immunoregulatory program within DCs that associates with hyperinflammation and organ dysfunction early following sepsis induction.

Advances in Immune Monitoring Approaches for Sepsis-Induced Immunosuppression.

Sepsis represents a life-threatening organ dysfunction due to an aberrant host response. Of note is that majority of patients have experienced a severe immune depression during and after sepsis, which is significantly correlated with the occurrence of nosocomial infection and higher risk of in-hospital death. Nevertheless, the clinical sign of sepsis-induced immune paralysis remains highly indetectable and ambiguous. Given that, specific yet robust biomarkers for monitoring the immune functional status of septic patients are of prominent significance in clinical practice. In turn, the stratification of a subgroup of septic patients with an immunosuppressive state will greatly contribute to the implementation of personalized adjuvant immunotherapy. In this review, we comprehensively summarize the mechanism of sepsis-associated immunosuppression at the cellular level and highlight the recent advances in immune monitoring approaches targeting the functional status of both innate and adaptive immune responses.

Eukaryotic ribosome quality control system: a potential therapeutic target for human diseases.

Protein homeostasis is well accepted as the prerequisite for proper operation of various life activities. As the main apparatus of protein translation, ribosomes play an indispensable role in the maintenance of protein homeostasis. Nevertheless, upon stimulation of various internal and external factors, malfunction of ribosomes may be evident with the excessive production of aberrant proteins, accumulation of which can result in deleterious effects on cellular fate and even cell death. Ribosomopathies are characterized as a series of diseases caused by abnormalities of ribosomal compositions and functions. Correspondingly, cell evolves several ribosome quality control mechanisms in maintaining the quantity and quality of intracellular ribosomes, namely ribosome quality control system (RQCS). Of note, RQCS can tightly monitor the entire process from ribosome biogenesis to its degradation, with the capacity of coping with ribosomal dysfunction, including misassembled ribosomes and incorrectly synthesized ribosomal proteins. In the current literature review, we mainly introduce the RQCS and elaborate on the underlying pathogenesis of several ribosomopathies. With the in-depth understanding of ribosomal dysfunction and molecular basis of RQCS, therapeutic strategy by specifically targeting RQCS remains a promising option in treating patients with ribosomopathies and other ribosome-associated human diseases.

Global Research Status of Multiple Organ Dysfunction Syndrome During 2001-2021: A 20-Year Bibliometric Analysis.

Background: Multiple Organ Dysfunction Syndrome (MODS) is a major cause of high morbidity and mortality among patients in intensive care units (ICU). Although numerous basic and clinical researches on MODS have been conducted, there is still a long way to go to prevent patients from entering this stage. To our knowledge, no bibliometric analyses of MODS have been reported, this study, therefore, was conducted to reveal MODS research status and trends during 2001-2021. Methods: All relevant literature covering MODS during 2001-2021 were extracted from Web of Science. An online analysis platform of literature metrology was used to analyze the publication trends. VOSviewer software was used to collect and analyze the keywords and research hotspots related to MODS. Results: As of July 31, 2021, a total of 994 MODS-related articles from 2001 to 2021 were identified. The United States accounted for the largest number of publications (31.1%), followed by China and Germany, with 186 and 75 publications, respectively. Among all the institutions, the University of Pittsburgh published the most papers related to MODS (21). Critical Care Medicine published the most papers in this field (106). Professor Moore EE, who had the most citation frequency (1847), made great achievements in MODS research. Moreover, analysis of the keywords identified three MODS research hotspot clusters: "mechanism-related research," "clinical research," and "diagnostic research." Conclusions: The United States maintained a top position worldwide and made the most outstanding contribution in the MODS field. In terms of publication, China was next only to the United States, but there was a disproportion between the quantity of publications and citation frequency. The institution University of Pittsburgh and journal Critical Care Medicine represent the highest level of research in this field. During the 20 years from 2001 to 2021, basic MODS research has been in-depth yet progressed relatively slowly recently, but the outbreak of COVID-19 has to some extent set off an upsurge of clinical research in MODS field.

Sepsis-Associated Coagulopathy Predicts Hospital Mortality in Critically Ill Patients With Postoperative Sepsis.

BACKGROUND: The incidence of coagulopathy, which was responsible for poor outcomes, was commonly seen among patients with sepsis. In the current study, we aim to determine whether the presence of sepsis-associated coagulopathy (SAC) predicts the clinical outcomes among critically ill patients with postoperative sepsis. METHODS: We conducted a single-center retrospective cohort study by including patients with sepsis admitted to surgical ICU of Chinese PLA General Hospital from January 1, 2014 to December 31, 2018. Baseline characteristics and clinical outcomes were compared with respect to the presence of SAC. Kaplan-Meier analysis was applied to calculate survival rate, and Log-rank test was carried out to compare the differences between two groups. Furthermore, multivariable Cox and logistic and linear regression analysis were performed to assess the relationship between SAC and clinical outcomes, including hospital mortality, development of septic shock, and length of hospital stay (LOS), respectively. Additionally, both sensitivity and subgroup analyses were performed to further testify the robustness of our findings. RESULTS: A total of 175 patients were included in the current study. Among all included patients, 41.1% (72/175) ICU patients were identified as having SAC. In-hospital mortality rates were significantly higher in the SAC group when compared to that of the No SAC group (37.5% vs. 11.7%; p < 0.001). By performing univariable and multivariable regression analyses, presence of SAC was demonstrated to significantly correlate with an increased in-hospital mortality for patients with sepsis in surgical ICU [Hazard ratio (HR), 3.75; 95% Confidence interval (CI), 1.90-7.40; p < 0.001]. Meanwhile, a complication of SAC was found to be the independent predictor of the development of septic shock [Odds ratio (OR), 4.11; 95% CI, 1.81-9.32; p = 0.001], whereas it was not significantly associated with prolonged hospital LOS (OR, 0.97; 95% CI, 0.83-1.14; p = 0.743). CONCLUSION: The presence of SAC was significantly associated with increased risk of in-hospital death and septic shock among postoperative patients with sepsis admitted to ICU. Moreover, there was no statistical difference of hospital LOS between the SAC and no SAC groups.

Combination of transcriptional biomarkers and clinical parameters for early prediction of sepsis indued acute respiratory distress syndrome.

Objective: As a common yet intractable complication of severe sepsis, acute respiratory distress syndrome (ARDS) is closely associated with poor clinical outcomes and elevated medical expenses. The aim of the current study is to generate a model combining transcriptional biomarkers and clinical parameters to alarm the development of ARDS in septic patients. Methods: Gene expression profile (GSE66890) was downloaded from the Gene Expression Omnibus database and clinical data were extracted. Differentially expressed genes (DEGs) from whole blood leukocytes were identified between patients with sepsis alone and septic patients who develop ARDS. ARDS prediction model was constructed using backward stepwise regression and Akaike Information Criterion (AIC). Meanwhile, a nomogram based on this model was established, with subsequent internal validation. Results: A total of 57 severe septic patients were enrolled in this study, and 28 (49.1%) developed ARDS. Based on the differential expression analysis, six DEGs (BPI, OLFM4, LCN2, CD24, MMP8 and MME) were screened. According to the outcome prediction model, six valuable risk factors (direct lung injury, shock, tumor, BPI, MME and MMP8) were incorporated into a nomogram, which was used to predict the onset of ARDS in septic patients. The calibration curves of the nomogram showed good consistency between the probabilities and observed values. The decision curve analysis also revealed the potential clinical usefulness of the nomogram. The area under the receiver operating characteristic (AUROC) for the prediction of ARDS occurrence in septic patients by the nomogram was 0.86 (95% CI = 0.767-0.952). A sensitivity analysis showed that the AUROC for the prediction of ARDS development in septic patients without direct lung injury was 0.967 (95% CI = 0.896-1.0). Conclusions: The nomogram based on transcriptional biomarkers and clinical parameters showed a good performance for the prediction of ARDS occurrence in septic patients.

A Novel Insight Into the Fate of Cardiomyocytes in Ischemia-Reperfusion Injury: From Iron Metabolism to Ferroptosis.

Ischemia-reperfusion injury (IRI), critically involved in the pathology of reperfusion therapy for myocardial infarction, is closely related to oxidative stress the inflammatory response, and disturbances in energy metabolism. Emerging evidence shows that metabolic imbalances of iron participate in the pathophysiological process of cardiomyocyte IRI [also termed as myocardial ischemia-reperfusion injury (MIRI)]. Iron is an essential mineral required for vital physiological functions, including cellular respiration, lipid and oxygen metabolism, and protein synthesis. Nevertheless, cardiomyocyte homeostasis and viability are inclined to be jeopardized by iron-induced toxicity under pathological conditions, which is defined as ferroptosis. Upon the occurrence of IRI, excessive iron is transported into cells that drive cardiomyocytes more vulnerable to ferroptosis by the accumulation of reactive oxygen species (ROS) through Fenton reaction and Haber-Weiss reaction. The increased ROS production in ferroptosis correspondingly leads cardiomyocytes to become more sensitive to oxidative stress under the exposure of excess iron. Therefore, ferroptosis might play an important role in the pathogenic progression of MIRI, and precisely targeting ferroptosis mechanisms may be a promising therapeutic option to revert myocardial remodeling. Notably, targeting inhibitors are expected to prevent MIRI deterioration by suppressing cardiomyocyte ferroptosis. Here, we review the pathophysiological alterations from iron homeostasis to ferroptosis together with potential pathways regarding ferroptosis secondary to cardiovascular IRI. We also provide a comprehensive analysis of ferroptosis inhibitors and initiators, as well as regulatory genes involved in the setting of MIRI.