Volume 13, Issue 4

Sepsis, a potentially fatal illness marked by an abnormal host immune response to an infection, continues to be a major global health issue. This study explores the role of pyroptosis and neutrophil extracellular traps (NETs) and their complex interactions, two dominant immune cell death, in the setting of sepsis. The review begins by explaining sepsis and its strong dependence on the immune system. It then delves into the basic mechanisms of neutrophil extracellular trap associated death (NETosis) and pyroptosis, examining their functions in inflammation and host defense. Going further, it looks at the dysregulated immune response in sepsis, with a focus on neutrophils and other immune cells and their critical role. We analyze in detail two types of cell death: pyroptosis and NETosis, both of which are closely examined for their roles in the development of sepsis, particularly the escalation of pathophysiology. Additionally, the study looks into the complex interactions between pyroptosis and NETosis, illuminating possible mechanisms for control as well as their cooperative effects. The report concludes with a summary of the major findings and recommendations for future therapy approaches and research prospects. This review adds to our knowledge of the pathophysiology of sepsis by thoroughly analyzing the roles of NETosis and pyroptosis in sepsis and providing possible directions for therapeutic intervention. Graphical Abstract

Argonaute 2 (Ago2), the core component of the microRNA-induced silencing complex (miRNA-RISC), is a pivotal protein with a well-established and potent role in gene expression regulation. Traditionally, Ago2 functions at the post-transcriptional level by binding to non-coding RNAs in the cytoplasm, facilitating gene expression via cleavage, deadenylation, or repression of target messenger RNA (mRNA) translation. Emerging evidence indicates that Ago2 can be transported from the cytoplasm to the nucleus or mitochondria, where it performs its critical functions. We observed that nuclear and mitochondrial Ago2 have been increasingly implicated in the pathogenesis of various cardiovascular diseases, such as hypertension, diabetic cardiomyopathy, and heart failure. These findings suggest a potential novel therapeutic strategy for targeting Ago2 in cardiovascular conditions. In this review, we aim to provide a comprehensive overview of recent studies elucidating the transport mechanisms of mammalian Ago2 into various subcellular organelles and summarise the functional roles and molecular mechanisms of subcellular Ago2 in cardiovascular diseases, offering a theoretical framework for Ago2-related therapeutic strategies.

Background and Objectives Periodontitis is a chronic multifactorial inflammatory disease caused by the excessive host immune response to bacterial infection, leading to periodontal tissue destruction. Owing to their plasticity, macrophages are key players in this process, and B10 cells, with their immunosuppressive efects, are vital for periodontal immunity. We propose that, in periodontitis, B10 cells transmit immunosuppressive signals via programmed cell death ligand-1 (PD-L1) /programmed cell death protein 1 (PD-1) signalling, stimulating macrophage diferentiation, alleviating inflammation, restoring homeostasis, and reducing alveolar bone resorption. The aim of this study was to investigate the efect of B10 cells on the polarization of macrophages in the context of periodontitis and the related molecular mechanism. Methods B10 cells were cocultured with RAW264.7 cells in the presence or absence of a Transwell insert. The M2 macrophage proportion and PD-1 expression in macrophages were assessed by flow cytometry and quantitative polymerase chain reaction (qPCR). PD-L1 knockout (KO) B10 cells and wild-type B10 cells were subsequently cocultured with macrophages separately. For in vivo experiments, we injected phosphate-buffered saline (PBS), B10 cells, or PD-L1 KO B10 cells into periodontitis model mice. We evaluated outcomes via microcomputed tomography, histological analysis, and tartrate-resistant acid phosphatase (TRAP) staining and measured the messenger ribonucleic acid (mRNA) expression levels of tumor necrosis factor-α (TNF-α), receptor activator of nuclear factor kappa-B ligand (RANKL), interferon-γ (IFN-γ), interleukin 10 (IL-10), and osteoprotegerin (OPG) in gingival tissue surrounding the maxillary second molar via qPCR. Results Compared with the indirect coculture, the direct coculture of macrophages with B10 cells led to a greater proportion of M2 macrophages and increased PD-1 expression levels in macrophages. Coculturing macrophages with PD-L1 KO B10 cells confirmed that B10 cells induced the M2 polarization of macrophages and upregulated PD-L1 expression in macrophages via PD-L1/PD-1 signalling. Compared with the groups injected with PBS or PD-L1 KO B10 cells, the B10 cell group exhibited significant decreases in local inflammatory factor levels, alveolar bone resorption, and the number of bone-resorbed cells within the alveolar bone area in vivo . Conclusion B10 cells can regulate macrophage polarization via the PD-L1/PD-1 signalling pathway, thereby suppressing the inflammatory response and reducing alveolar bone resorption during periodontitis. This novel concept can guide future treatment strategies for periodontitis.

Background and Objectives Oligomenorrhea and hypomenorrhea were common conditions in outpatient visit which affected child-bearing aged women, and the conventional progesterone treatment has been related to several side effect and contradiction, and this study aimed to evaluate the effectiveness and safety of traditional Chinese medicine (TCM), progesterone capsules, and their combination in treating oligomenorrhea and hypomenorrhea via both clinical and metabolomic approach. Methods A prospective, randomized, multi-center trial has been conducted, and a total of 239 oligomenorrhea and hypomenorrhea were randomly assigned to receive TCM, progesterone capsules (PG), or the combined Chinese and Western medicine (COM) and treated from 3 months, respectively. Scores were recorded at 1 st and 3 rd month of treatment, while the seral samples for sex hormone and safety parameters were taken before and after management, with adverse events recorded. A post-hoc metabolomic research was further conducted, in which a total of 84 patients' blood sample collected before and after 3-month treatment were screened via liquid chromatography-tandem mass spectrometry (LC-MS) and the results were analyzed with machine learning models to identify the differential metabolites, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database and Interactive pathways explore (iPath) database were applied to unveil the potential pathway involved in the treatment. Results A total of 220 participants completed the trial treatment, with dropout rate of 11.6%. The Traditional Chinese Medicine Syndrome Scale (TCMSS) scores of each group were significantly lower than those before treatment after 1 month of treatment and after 3 months of treatment. After 3 months of treatment, the COM group had the highest total effective rate (61.54%). The pictorial blood loss assessment chart (PBAC) scores in the TCM group were significantly higher than those before treatment after 1 month of treatment and 3 months after treatment, whereas no difference before and after treatment was observed within PG group. In COM group, the score after 3 months of treatment was significantly higher than that before treatment. In the post-hoc study with metabolomic approach with KEGG pathway enrichment and topological analyses, glycerophospholipid (GPL) metabolism were found significantly altered in all 3 groups. while TCM could potentially improve the clinical symptom via tryptophan metabolism. Conclusion From the perspective of TCMSS scores, the effect of COM group is more significant. In terms of PBAC scores, sex hormone level, endometrium and the improvement of ovarian function in patients with low ovarian function, the TCM group had a better response. In a comprehensive evaluation, the regimen of TCM alone or COM can significantly improve menstrual flow and treat oligomenorrhea and hypomenorrhea patients. With KEGG pathway enrichment and topological analyses, GPL metabolism were found significantly altered in all 3 groups, and TCM could potentially improve the clinical symptom via tryptophan metabolism. Whereas unique pathways influenced under combo treatment suggested a synergetic effect of combination TCM with western medicine in management of oligomenorrhea and hypomenorrhea.

Background and Objectives Few studies have provided real-world data on the biochemical response, risk assessment, and prognosis of patients with primary biliary cholangitis (PBC)-related decompensated cirrhosis undergoing ursodeoxycholic acid therapy. The objective of this study is to define recompensation in this patient population based on the BAVENO VII criteria. Methods This retrospective analysis included 170 patients with cirrhosis who presented with ascites, hepatic encephalopathy, and/or variceal bleeding as their initial decompensating events at Xijing Hospital from 2006 to 2023. Events of further decompensation, liver transplantation, and liver-related death were recorded. Results Alkaline phosphatase (ALP) had complex prognostic value in patients with PBC-related decompensated cirrhosis receiving ursodeoxycholic acid therapy. In patients with normal total bilirubin (TBIL) at the 1-year follow-up, elevated ALP was associated with poor prognosis (hazard ratio [HR]: 2.57, 95% confidence interval [CI]: 1.12-5.87, P = 0.025), whereas in those with elevated TBIL, decreased ALP was associated with poor prognosis (HR: 0.53, 95% CI: 0.26-1.08, P = 0.082). A Model for End-Stage Liver Disease score < 10 and the absence of decompensating events from the last decompensated state over the next 12 months were used to assess PBC recompensation. During follow-up, 26% (45/170) of patients experienced at least one episode of recompensation. Compared with observations in the non-recompensation group, the recompensation group exhibited a longer liver transplantation-free survival (HR: 16.48, 95% CI: 2.23-121.57, P = 0.006), lower rates of further decompensation (22% vs . 63%, P < 0.001), a significant reduction in high-risk patients ( P < 0.05, all), and notable improvements in serum indicators (platelet count, TBIL, albumin, and international normalized ratio). Baseline platelet and TBIL levels, the 1-year Rotterdam criteria, and severe interface hepatitis were associated with recompensation. Conclusions We defined PBC recompensation as a Model for End-Stage Liver Disease score < 10 and the absence of decompensating events from the last decompensated state for the next 12 months, aligned with the requirements of BAVENO VII for patients with PBC-related decompensated cirrhosis.

Background and Objectives Acute myeloid leukaemia (AML) with the translocation of chromosome (6;9)(p23;q34) forms the DEK-NUP214 fusion mRNA, which is a rare subtype (~1%). Owing to the paucity of this AML subtype, comprehensive studies analysing allogeneic haematopoietic stem cell transplantation (allo-HSCT) outcomes are lacking. Methods We aimed to evaluate the dynamic evolution of DEK-NUP214 transcripts before and after allo-HSCT as well as the impact of pretransplant DEK-NUP214 status on posttransplant outcomes in AML patients in a retrospective, multicentre study ( n = 14). Results Intermediate- or high-risk AML patients without DEK-NUP214 transcripts receiving allo-HSCT during the same time period were enrolled as controls. Ten (71.4%) patients showed DEK-NUP214 positivity before allo-HSCT. Except for one patient who died early after allo-HSCT, 7 out of the other 9 patients (77.8%) achieved DEK-NUP214 negativity after allo-HSCT. The 2-year probabilities of relapse, non-relapse mortality (NRM), leukaemia-free survival (LFS), and overall survival (OS) were 14.3% (95% CI, 0%–33.6%), 35.7% (95% CI, 9.3%–62.1%), 50.0% (95% CI, 29.6%–84.4%), and 50.0% (95% CI, 29.6%–84.4%), respectively. The incidence of relapse was comparable between AML patients with and without DEK-NUP214 transcript, but the incidence of NRM, LFS, and OS of patients with DEK-NUP214 was poorer compared with those without DEK-NUP214 transcript. Conclusions Thus, this study observed that allo-HSCT could overcome the poor prognosis of persistent DEK-NUP214 positivity after chemotherapy; however, new therapies should be further identified to improve the outcomes of AML patients with DEK-NUP214 . Graphical Abstract