Causal associations of immune cells with benign prostatic hyperplasia: insights from a Mendelian randomization study.

BACKGROUND: Previous research has focused on the association between immune cells and the development of benign prostatic hyperplasia (BPH). Nevertheless, the causal relationships in this context remain uncertain. METHODS: This study employed a comprehensive and systematic two-sample Mendelian randomization (MR) analysis to determine the causal relationships between immunophenotypes and BPH. We examined the causal associations between 731 immunophenotypes and the risk of BPH by utilizing publicly available genetic data. Integrated sensitivity analyses were performed to validate the robustness, assess heterogeneity, and examine horizontal pleiotropy in the results. RESULTS: We discovered that 38 immunophenotypes have a causal effect on BPH. Subsequently, four of these immunophenotypes underwent verification using weighted median, weighted mode, and inverse variance weighted (IVW) algorithms, which included CD19 on CD24+ CD27+, CD19 on naive-mature B cell, HLA DR on CD14- CD16+ and HLA DR+ T cell%lymphocyte. Furthermore, BPH exhibited a significant association with three immunophenotypes: CD19 on IgD+ CD38dim (ß = -0.152, 95% CI = 0.746-0.989, P = 0.034), CD19 on IgD+ (ß = -0.167, 95% CI = 0.737-0.973, P = 0.019), and CD19 on naive-mature B cell (ß = -0.166, 95% CI = 0.737-0.972, P = 0.018). CONCLUSIONS: Our study provides valuable insights for future clinical investigations by establishing a significant association between immune cells and BPH.

Normalized circulating Tfh and Th17 associates with improvement in myasthenia gravis treated with ofatumumab.

Objective: To assess the effect of B cell depletion therapy (BCDT) on circulating T follicular helper (cTfh) and circulating T helper 17 (cTh17) cells and its relation to clinical improvement in patients with myasthenia gravis (MG). Methods: 28 anti-AchR positive MG patients treated with ofatumumab and 28 healthy controls (HCs) were included. Frequencies of cTfh and cTh17 cells were monitored by flow cytometry at baseline and 4, and 12 weeks after the initial dose ofatumumab. Serum cytokines associated with cTfh and cTh17, including IL-6, IL-21, and IL-17, were also analyzed. Results: The frequency of cTfh and cTh17 significantly increased in MG patients compared with HCs. Additionally, elevated levels of both T-cell subsets correlated with MG severity. During the follow-up, cTfh and cTh17 return to normal after BCDT. Furthermore, the decrease in cTfh and cTh17 was associated with MG scores improvement over time. Notably, cTfh- and cTh17-related cytokines, including IL-6, IL-21, and IL-17, exhibited a marked decrease following ofatumumab therapy. Conclusions: Abnormal expansion of cTfh and cTh17 cells may be key features in the immunopathology of MG. Their levels returned to normal after BCDT, which was closely correlated with clinical amelioration. This result suggests that these two T-cell subsets may be targets for BCDT treatment of MG.

Structured postoperative handover protocol improves efficiency and quality of interdisciplinary communication and nursing care in surgical intensive care unit: a randomized controlled trial.

This study aimed to evaluate the effectiveness of a structured postoperative handover protocol for postoperative transfer to the SICU. This study was a randomized controlled trial conducted in a comprehensive teaching hospital in China. Patients who were transferred to the SICU after surgery were randomly divided into two groups. The intervention group underwent postoperative structured handover protocol, and the control group still applied conventional oral handover. A total of 101 postoperative patients and 50 clinicians were enrolled. Although the intervention group did not shorten the handover duration (6.18 ± 1.66 vs 5.94 ± 1.91; P = 0.505), the handover integrity was significantly improved, mainly reflected in fewer information omissions (1.44 ± 0.97 vs 0.67 ± 0.62; P < 0.001), fewer additional questions raised by ICU physicians (1.06 ± 1.04 vs 0.24 ± 0.43; P < 0.001) and fewer additional handovers via phone call (16% vs 3.9%; P = 0.042). The total score of satisfaction of the intervention group was significantly higher than that of the control group (76.44 ± 7.32 vs 81.24 ± 6.95; P = 0.001). With respect to critical care, the incidence of stage I pressure sore within 24 h was lower in the intervention group than in the control group (20% vs 3.9%, P = 0.029). Structured postoperative handover protocol improves the efficiency and quality of interdisciplinary communication and clinical care in SICU.Trial registration This study was registered in China on January 8th, 2022 at Chinese Clinical Trial Registry (ChiCTR2200055400).

Aldehyde dehydrogenase 2 deficiency reinforces formaldehyde-potentiated pro-inflammatory responses and glycolysis in macrophages.

Aldehyde dehydrogenase 2 (ALDH2) deficiency caused by   genetic variant is present in more than 560 million people of East Asian descent, which can be identified by apparent facial flushing from acetaldehyde accumulation after consuming alcohol. Recent findings indicated that ALDH2 also played a critical role in detoxification of formaldehyde (FA). Our previous studies showed that FA could enhance macrophagic inflammatory responses through the induction of HIF-1α-dependent glycolysis. In the present study, pro-inflammatory responses and glycolysis promoted by 0.5 mg/m3 FA were found in mice with Aldh2 gene knockout, which was confirmed in the primary macrophages isolated from Aldh2 gene knockout mice treated with 50 µM FA. FA at 50 and 100 µM also induced stronger dose-dependent increases of pro-inflammatory responses and glycolysis in RAW264.7 murine macrophages with knock-down of ALDH2, and the enhanced effects induced by 50 µM FA was alleviated by inhibition of HIF-1α in RAW264.7 macrophages with ALDH2 knock-down. Collectively, these results clearly demonstrated that ALDH2 deficiency reinforced pro-inflammatory responses and glycolysis in macrophages potentiated by environmentally relevant concentration of FA, which may increase the susceptibility to inflammation and immunotoxicity induced by environmental FA exposure.

circELP2 reverse-splicing biogenesis and function as a pro-fibrogenic factor by targeting mitochondrial quality control pathway.

Idiopathic pulmonary fibrosis (IPF) is considered as a chronic, fibrosing interstitial pneumonia with unknown mechanism. The present work aimed to explore the function, biogenesis and regulatory mechanism of circELP2 in pulmonary fibrosis and evaluate the value of blocking circELP2-medicated signal pathway for IPF treatment. The results showed that heterogeneous nuclear ribonucleoprotein L initiated reverse splicing of circELP2 resulting in the increase of circELP2 generation. The biogenetic circELP2 activated the abnormal proliferation and migration of fibroblast and extracellular matrix deposition to promote pulmonary fibrogenesis. Mechanistic studies demonstrated that cytoplasmic circELP2 sponged miR-630 to increase transcriptional co-activators Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ). Then, YAP1/TAZ bound to the promoter regions of their target genes, such as mTOR, Raptor and mLST8, which in turn activated or inhibited the genes expression in mitochondrial quality control pathway. Finally, the overexpressed circELP2 and miR-630 mimic were packaged into adenovirus vector for spraying into the mice lung to evaluate therapeutic effect of blocking circELP2-miR-630-YAP1/TAZ-mitochondrial quality control pathway in vivo. In conclusion, blocking circELP2-medicated pathway can alleviate pulmonary fibrosis, and circELP2 may be a potential target to treat lung fibrosis.

Proteomic analysis reveals the aging-related pathways contribute to pulmonary fibrogenesis.

Aging usually causes lung-function decline and susceptibility to chronic lung diseases, such as pulmonary fibrosis. However, how aging affects the lung-fibrosis pathways and leads to the occurrence of pulmonary fibrosis is not completely understood. Here, mass spectrometry-based proteomics was used to chart the lung proteome of young and old mice. Micro computed tomography imaging, RNA immunoprecipitation, dual-fluorescence mRFP-GFP-LC3 adenovirus monitoring, transmission electron microscopy, and other experiments were performed to explore the screened differentially expressed proteins related to abnormal ferroptosis, autophagy, mitochondria, and mechanical force in vivo, in vitro, and in healthy people. Combined with our previous studies on pulmonary fibrosis, we further demonstrated that these biological processes and underlying molecular players were also involved in the aging process. Our work depicted a comprehensive cellular and molecular atlas of the aging lung and attempted to explain why aging is a risk factor for pulmonary fibrosis and the role that aging plays in the progression of pulmonary fibrosis. The abnormalities of aging triggered an increase in mechanical force and ferroptosis, autophagy blockade, and mitochondrial dysfunction, which often appear during pulmonary fibrogenesis. We hope that the elucidation of these anomalies will help to enhance our understanding of senescence-inducing pulmonary fibrosis, thereby guiding the use of anti-senescence as an entry point for early intervention in pulmonary fibrosis and age-related diseases.

Identification and validation of a prognostic-related mutant gene DNAH5 for hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide and has a poor prognosis. Thus, there is a need for an effective biomarker to improve and predict the prognosis of HCC. Methods: RNA sequencing data, simple nucleotide variation data, and clinical data of HCC patients from The Cancer Genome Atlas (TCGA) to identify mutant genes, simple nucleotide variation data, and clinical data of HCC patients from the International Cancer Genome Consortium (ICGC) to validate the prognostic value of mutant genes were the data sources of the present study. To identify the overall survival (OS)-related mutant genes, a Kaplan-Meier (KM) analysis was conducted. We carried out univariate Cox and multivariate Cox regression analyses to identify the independent prognostic factors. We also conducted a correlation analysis of immune cells and mutant genes. To explore the molecular mechanisms of mutant genes, we conducted a gene set enrichment analysis (GSEA). A nomogram was constructed to help predict the prognosis of HCC. In addition, we explored the expression profile of mutant genes in HCC based on a TCGA dataset, an ICGC dataset, and our own HCC tissue samples. Results: We identified and validated a mutant gene, dynein axonemal heavy chain 5 (DNAH5), which was negatively related to the OS of HCC patients. Univariate Cox and multivariate Cox regression analyses revealed that the mutant gene DNAH5 could act as an independent prognostic factor for HCC. Most pathways of the mutant gene DNAH5 were involved in cancer development and progression based on GSEA analysis. The mutant gene DNAH5 was negatively correlated with monocytes, naive CD4 T cells, activated dendritic cells, and activated mast cells. In addition, the mRNA and protein levels of DNAH5 had a significantly higher level of expression in the tissue samples of patients with HCC. A nomogram consisting of the pathological stage, DNAH5, and tumor mutation burden (TMB) performed well. Conclusion: The mutant gene DNAH5 had a significantly higher level of expression in the tissue samples of patients with HCC, could act as an independent prognostic factor for HCC, and is a potential new immunotherapy target for HCC.

Study of the Intersegmental Veins Between S5 and S8 Based on 3D Reconstruction.

BACKGROUND: Anatomic resection (AR) is a surgical method for treating hepatocellular carcinoma, and identifying intersegmental planes between segments 5 (S5) and 8 (S8) remains challenging. This study aims to find reliable intersegmental veins (IVs) between them as anatomical landmarks using 3D reconstruction analysis. METHODS: We retrospectively evaluated 57 patients who underwent multidetector-row CT scans from September 2021 to January 2023. The portal vein watershed of S5 and S8 and hepatic veins were reconstructed using 3D reconstruction analysis software. We counted and analyzed the IVs running within the intersegmental plane between S5 and S8, examined their features, and analyzed the location of the junctions between IVs and middle hepatic veins (MHVs). RESULTS: Among the 57 patients, 43 patients (75.4%) had IVs between S5 and S8. Most patients (81.4%) had a single IV joining the MHV, while 13.9% had two IVs, one joining the MHV and the other joining the right hepatic vein (RHV). The majority of IV-MHV junctions were found in the lower part of the MHVs. The most clearly identifiable junctions between the IVs and MHVs occurred slightly below the midpoint of the horizontal planes of the second hepatic portal and the center of the gallbladder bed. CONCLUSION: Our study identified IVs between S5 and S8 in the liver as potential anatomical landmarks during AR for hepatocellular carcinoma surgery. We found three types of IVs and provided insights on how to locate their junctions with MHVs for easier surgical navigation. However, individual anatomical variations must be considered, and preoperative 3D reconstruction and personalized surgical planning are crucial for success. More research with larger sample sizes is needed to validate our findings and establish the clinical significance of these IVs as landmarks for AR.

hucMSCs Treatment Ameliorated Pulmonary Fibrosis via Downregulating the circFOXP1-HuR-EZH2/STAT1/FOXK1 Autophagic Axis.

This study was performed to determine the effect of human umbilical cord mesenchymal stem cells (hucMSCs) treatment on pulmonary fibrosis and investigate the circFOXP1-mediated autophagic mechanism of hucMSCs treatment. Pulmonary fibrosis models were established by spraying bleomycin in mice and TGF-ß1 treatment of MRC-5 cells. Results showed that hucMSCs were retained in lung and hucMSCs treatment alleviated pulmonary fibrosis. Morphological staining indicated that hucMSCs-treated mice had thinner alveolar walls, effectively improved alveolar structure, significantly reduced alveolar inflammation, and decreased collagen deposition than control mice. Fibrotic proteins, including vimentin, α-SMA, collagens I and III, and the differentiation-related protein S100 calcium-binding protein A4 was reduced considerably in the hucMSCs-treated group. The mechanistic study revealed that the inhibition of hucMSCs treatment on pulmonary fibrogenesis depended on downregulating circFOXP1, in which hucMSCs treatment promoted circFOXP1-mediated autophagy process via blocking the nuclear human antigen R (HuR) translocation and promoting the HuR degradation, leading to a marked decrease in autophagy negative regulators EZH2, STAT1, and FOXK1. In conclusion, hucMSCs treatment significantly improved pulmonary fibrosis by downregulating the circFOXP1-HuR-EZH2/STAT1/FOXK1 autophagic axis. hucMSCs can act as an effective treatment for pulmonary fibrosis.

Prevalence, risk factors, and prognosis of central nervous system manifestations in antiphospholipid syndrome.

The central nervous system (CNS) is considered as one of the most frequently affected organs in antiphospholipid syndrome (APS). This study investigated the prevalence of CNS manifestations in APS and associated risk factors and evaluated stroke recurrence. We carried out this retrospective study from 2009 to 2021 at Peking University People's Hospital, which enrolled 342 APS patients, and 174 neurologic events were suffered by 119 patients (34.8%). Patients with and without CNS involvement were compared regarding demographics and laboratory parameters. The analysis showed that older age, livedo reticularis, and dyslipidaemia were significant related factors for CNS manifestations (P = 0.047, 0.038, and 0.030 respectively). The use of anticoagulants (P = 0.004), and/or hydroxychloroquine (P = 0.016) appeared to associated with a lower incidence of CNS manifestations. During a median follow-up of 4.1 years, 10 individuals developed new episodes of stroke in APS patients with previous ischemic strokes. Livedo reticularis, smoking and male gender may predict the risk of recurrent stroke (P = 0.020, 0.006, and 0.026 respectively). Collectively, our results indicated the protective and risk factors for CNS manifestations, as well as demonstrated that APS patients appeared at high risk of stroke recurrence despite current therapy.

hucMSCs treatment prevents pulmonary fibrosis by reducing circANKRD42-YAP1-mediated mechanical stiffness.

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia of unknown cause. The most typical characteristic of IPF is gradual weakening of pulmonary elasticity and increase in hardness/rigidity with aging. This study aims to identify a novel treatment approach for IPF and explore mechanism of mechanical stiffness underlying human umbilical cord mesenchymal stem cells (hucMSCs) therapy. Target ability of hucMSCs was examined by labeling with cell membrane dye Dil. Anti-pulmonary fibrosis effect of hucMSCs therapy by reducing mechanical stiffness was evaluated by lung function analysis and MicroCT imaging system and atomic force microscope in vivo and in vitro. Results showed that stiff environment of fibrogenesis caused cells to establish a mechanical connection between cytoplasm and nucleus, initiating expression of related mechanical genes such as Myo1c and F-actin. HucMSCs treatment blocked force transmission and reduced mechanical force. For further exploration of mechanism, ATGGAG was mutated to CTTGCG (the binding site of miR-136-5p) in the full-length sequence of circANKRD42. Wildtype and mutant plasmids of circANKRD42 were packaged into adenovirus vectors and sprayed into lungs of mice. Mechanistic dissection revealed that hucMSCs treatment repressed circANKRD42 reverse splicing biogenesis by inhibiting hnRNP L, which in turn promoted miR-136-5p binds to 3'-Untranslated Region (3'-UTR) of YAP1 mRNA directly, thus inhibiting translation of YAP1 and reducing YAP1 protein entering nucleus. The condition repressed expression of related mechanical genes to block force transmission and reduce mechanical forces. The mechanosensing mechanism mediated directly by circANKRD42-YAP1 axis in hucMSCs treatment, which has potential general applicability in IPF treatment.

Identification and validation of cancer-associated fibroblast-related subtypes and the prognosis model of biochemical recurrence in prostate cancer based on single-cell and bulk RNA sequencing.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are an essential component of the tumor immune microenvironment that are involved in extracellular matrix (ECM) remodeling. We aim to investigate the characteristics of CAFs in prostate cancer and develop a biochemical recurrence (BCR)-related CAF signature for predicting the prognosis of PCa patients. METHODS: The bulk RNA-seq and relevant clinical information were obtained from the TCGA and GEO databases, respectively. The infiltration scores of CAFs in prostate cancer patients were calculated using the MCP counter and EPIC algorithms. The single-cell RNA sequencing (scRNA-seq) was downloaded from the GEO database. Subsequently, univariate Cox regression analysis was employed to identify prognostic genes associated with CAFs. We identified two subtypes (C1 and C2) of prostate cancer that were associated with CAFs via non-negative matrix factorization (NMF) clustering. In addition, the BCR-related CAF signatures were constructed using Lasso regression analysis. Finally, a nomogram model was established based on the risk score and clinical characteristics of the patients. RESULTS: Initially, we found that patients with high CAF infiltration scores had shorter biochemical recurrence-free survival (BCRFS) times. Subsequently, CAFs in four pairs of tumors and paracancerous tissues were identified. We discovered 253 significantly differentially expressed genes, of which 13 had prognostic significance. Using NMF clustering, we divided PCa patients into C1 and C2 subgroups, with the C1 subgroup having a worse prognosis and substantially enriched cell cycle, homologous recombination, and mismatch repair pathways. Furthermore, a BCR-related CAFs signature was established. Multivariate COX regression analysis confirmed that the BCR-related CAFs signature was an independent prognostic factor for BCR in PCa. In addition, the nomogram was based on the clinical characteristics and risk scores of the patient and demonstrated high accuracy and reliability for predicting BCR. Lastly, our findings indicate that the risk score may be a useful tool for predicting PCa patients' sensitivity to immunotherapy and drug treatment. CONCLUSION: NMF clustering based on CAF-related genes revealed distinct TME immune characteristics between groups. The BCR-related CAF signature accurately predicted prognosis and immunotherapy response in prostate cancer patients, offering a promising new approach to cancer treatment.

G protein-coupled receptor GPR68 inhibits lymphocyte infiltration and contributes to gender-dependent melanoma growth.

Introduction: Melanoma is a common and aggressive type of skin cancer with rising incidence rate globally. Gender is one of the determining factors, and overall males have a higher risk of developing melanoma as well as worse prognosis. Emerging evidence show that GPR68, a G protein-coupled receptor that is sensitive to acid and mechanical stimulations for cellular microenvironment, plays an important role in tumor biology. However, whether GPR68 is involved in gender-dependent regulation of tumor growth is unclear. Methods: We established a syngeneic melanoma model in Gpr68-deficient mice and investigated tumor growth in males and females. The GPR68 activation-induced cellular responses of melanocytes, including intracellular calcium dynamics, proliferation and migration were measured. The landscape of tumor-infiltrating immune cells were analyzed by flow cytometry and the expression various cytokines were checked by qRT-PCR. Results: GPR68 is required for melanoma growth in males but dispensable in females. GPR68 is expressed and functional in B16-F10 melanocytes, but the activity of the receptor does not directly contribute to proliferation and migration of the cells. GPR68 inhibits infiltration of CD45+ lymphocytes, CD8+ T cells and NK cells in melanoma in male mice, but has no apparent effect in females. Furthermore, GPR68 functionally inhibits the expression of IFNγ in the tumor infiltrating CD8+ T cells and NK cells as well as the inflammatory cytokine expression in the spleen in male mice but not in females. Our results show the gender-dependent modulatory effect of GPR68 on tumor-infiltrating immune cells and their tumor-killing capacity. Discussion: GPR68 is sensor for acid and mechanical stimulations, which are two important factors in the microenvironment associated with tumor growth and metastasis. Our results suggest a prominent role of the receptor molecules in tumor biology in a gender-dependent manner. Since GPCRs are more feasible to develop small molecule drugs compared to transcription factors, our study demonstrates the potential of GPR68 as a novel druggable therapeutic target for melanoma in male patients.

The effect of exogenous estrogen on depressive mood in women: A systematic review and meta-analysis of randomized controlled trials.

Sex differences exist in the prevalence of major depressive disorder (MDD). Comparing with males, females are at a higher risk of depression, especially in some reproductive statuses with significant changes in sex hormones. Based on the positive effect on menopausal symptoms in human and on depression-like behaviors in animals, exogenous estrogen was considered as a potential therapeutic approach to the treatment of female depression, however, with inconsistent conclusions in previous studies. In the present systematic review and meta-analysis, 14 eligible randomized controlled trials (RCTs) were included to investigate the effect of exogenous estrogen on depressive mood in women. The results indicated that exogenous estrogens were superior to the control group either alone or in combination with progesterone or antidepressants. Female individuals in perimenopause are more sensitive to estrogen than those in other reproductive statuses, which might be the reason that depressive mood during this stage is more associated with estrogen fluctuations, and exogenous estrogen supplementation can moderate these drastic changes. The finding of meta-regressions that the effect of exogenous estrogen was associated with age in perimenopause and post-menopause rather than the dose or administration of exogenous estrogen, showed again that a stable level of estrogen is more beneficial than a high serum level. This study provides strong evidence of the important role of estrogen fluctuations but not estrogen levels in female depression.

Association between pre-stroke sarcopenia risk and stroke-associated infection in older people with acute ischemic stroke.

Background: Stroke-associated infection (SAI) is a common complication after a stroke. The incidence of infection was higher in people with sarcopenia than in the general population. However, the relationship between pre-stroke sarcopenia risk and SAI in older patients has not been confirmed. This study aimed to investigate the association between pre-stroke sarcopenia risk and SAI in older patients with acute ischemic stroke (AIS). Methods: This retrospective study was conducted by the Peking University People's Hospital. We evaluated the pre-stroke sarcopenia risk by applying the SARC-F questionnaire. Multivariate logistic regression was applied to explore the association between pre-stroke sarcopenia risk and SAI. Results: A total of 1,002 elder patients with AIS (592 men; 72.9 ± 8.6 years) were enrolled in our study. Pre-stroke sarcopenia risk was found in 29.1% of the cohort. The proportion of patients with pre-stroke sarcopenia risk was larger in the SAI group than in the non-SAI group (43.2 vs. 25.3%, p < 0.001). In multivariate logistic analysis, pre-stroke sarcopenia risk was shown to be independently associated with SAI (OR = 1.454, 95% CI: 1.008-2.097, p = 0.045) after adjusting for potential factors. This association remained consistent across the subgroups based on age, sex, body mass index, smoking status, drinking status, diabetes, hypertension, and dyslipidemia. Conclusion: Pre-stroke sarcopenia risk was independently associated with SAI in older patients with AIS. Our findings highlight the significance of pre-stroke sarcopenia identification in the prevention and management of SAI in this population.

Formaldehyde aggravates allergic contact dermatitis by facilitating NLRP3 inflammasome activation in macrophages.

Formaldehyde (FA) is known to be an environmental pollutant and contact sensitizer at 1 % or 2 % concentrations, which can induce inflammatory diseases such as allergic contact dermatitis (ACD). However, the aggravative effects of FA on ACD at legitimate low concentrations in cosmetics have not been studied. The activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome in ACD was recently identified, and the inflammatory responses were attenuated by NLRP3 inhibition. Since non-cytotoxic concentrations of FA at 50 and 100 µM were found to reinforce inflammatory responses in macrophages, the 0.05 % low concentration of FA was applied to ACD mice induced by 2,4-dinitro-1-fluorobenzene. FA significantly exacerbated inflammatory responses and NLRP3 inflammasome activation, which was confirmed in RAW264.7 macrophages treated with FA at 50 and 100 µM in vitro. Induction of mitochondrial reactive oxygen species, the common activation signal for NLRP3 inflammasome, was also observed in FA-treated macrophages. Inhibition of NLRP3 by MCC950 significantly attenuated the NLRP3 inflammasome activation induced by 100 µM FA in vitro and alleviated FA-enhanced inflammatory responses in ACD mice. These results not only demonstrated that FA was able to aggravate the inflammatory responses of ACD by facilitating NLRP3 inflammasome activation in macrophages, which was likely to play important roles in FA-related sensitization, but also indicated that NLRP3 could be targeted to relieve FA-induced inflammation.

Accumulation of Intracellular Ferrous Iron in Inflammatory-Activated Macrophages.

Macrophages are important innate immune cells which can be polarized into heterogeneous populations. The inflammatory-activated M1 cells are known to be involved in all kinds of inflammatory diseases, which were also found to be associated with dysregulation of iron metabolism. While iron overload is known to induce M1 polarization, the valence states of iron and its intracellular dynamics during macrophage inflammatory activation have not been identified. In this study, THP-1-derived macrophages were polarized into M1, M2a, M2b, M2c, and M2d cells, and intracellular ferrous iron (Fe(II)) was measured by our previously developed ultrasensitive Fe(II) fluorescent probe. Significant accumulation of Fe(II) was only observed in M1 cells, which was different from the alterations of total iron. Time-dependent change of intracellular Fe(II) during the inflammatory activation was also consistent with the expression shifts of transferrin receptor CD71, ferrireductase Steap3, and Fe(II) exporter Slc40a1. In addition, accumulation of Fe(II) was also found in the colon macrophages of mice with ulcerative colitis, which was positively correlated to inflammatory phenotypes, including the productions of NO, IL-1ß, TNF-α, and IL-6. Collectively, these results demonstrated the specific accumulation of Fe(II) in inflammatory-activated macrophages, which not only enriched our understanding of iron homeostasis in macrophages, but also indicated that Fe(II) could be further developed as a potential biomarker for inflammatory-activated macrophages.

A cuproptosis-related lncRNA signature identified prognosis and tumour immune microenvironment in kidney renal clear cell carcinoma.

Kidney renal clear cell carcinoma (KIRC) is a heterogeneous malignant tumor with high incidence, metastasis, and mortality. The imbalance of copper homeostasis can produce cytotoxicity and cause cell damage. At the same time, copper can also induce tumor cell death and inhibit tumor transformation. The latest research found that this copper-induced cell death is different from the known cell death pathway, so it is defined as cuproptosis. We included 539 KIRC samples and 72 normal tissues from the Cancer Genome Atlas (TCGA) in our study. After identifying long non-coding RNAs (lncRNAs) significantly associated with cuproptosis, we clustered 526 KIRC samples based on the prognostic lncRNAs and obtained two different patterns (Cuproptosis.C1 and C2). C1 indicated an obviously worse prognostic outcome and possessed a higher immune score and immune cell infiltration level. Moreover, a prognosis signature (CRGscore) was constructed to effectively and accurately evaluate the overall survival (OS) of KIRC patients. There were significant differences in tumor immune microenvironment (TIME) and tumor mutation burden (TMB) between CRGscore-defined groups. CRGscore also has the potential to predict medicine efficacy.

The neutrophil-to-lymphocyte ratio: A potential predictor of poor prognosis in adult patients with trauma and traumatic brain injury.

Purpose: This study aimed to determine the prognostic impact of the neutrophil-to-lymphocyte ratio (NLR) in critically ill trauma patients. Methods: This retrospective study involved adult trauma patients from 335 intensive care units (ICUs) at 208 hospitals stored in the eICU database. The primary outcome was ICU mortality. The lengths of ICU and hospital stay were calculated as the secondary outcomes. The multivariable logistic regression model was used to identify independent predictors of mortality. To identify the effect of the NLR on survival, a 15-day survival curve was used. Results: A total of 3,865 eligible subjects were enrolled in the study. Univariate analysis showed that patients in the group with a higher NLR were more likely to receive aggressive methods of care delivery: mechanical ventilation, vasopressor, and antibiotics ( P < 0.001 for all). The ICU, in-hospital, and 15-day mortality rates of the four groups increased in turn (P < 0.001 for all). The multivariable logistic Cox regression model indicated that a higher NLR was an independent risk factor of ICU mortality in trauma patients. ROC analysis showed that the NLR had better predictive capacity on the mortality of patients with traumatic brain injury (TBI) than those with trauma (AUC 0.725 vs. 0.681). An NLR > 7.44 was an independent risk factor for ICU death in patients with TBI (OR: 1.837, 95% CI: 1.045-3.229) and TBI victims whose NLR > 7.44 had a 15-day survival disadvantage (P = 0.005). Conclusion: A high NLR is associated with a poor prognosis in trauma patients, even worse in patients with TBI. An NLR > 7.44 is an independent risk factor for death in patients with TBI.

Myricetin alleviates the formaldehyde-enhanced Warburg effect in tumor cells through inhibition of HIF-1α.

Myricetin is a flavonoid widely-distributed in foods with many beneficial health effects, which has been marketed in health products. Formaldehyde is an environmental carcinogen which can enhance the Warburg effect through the induction of human hypoxia-inducible factor 1 subunit alpha (HIF-1α), the primary regulator of cellular glycolysis. HIF-1α was verified as an important target in lung and ovarian tumors, which was also identified as a receptor for myricetin via molecular docking. The reinforced HIF-1α signaling, the Warburg effect and T cell suppression induced by 50 µM formaldehyde in both A549 and Caov-3 cells were dose-dependently attenuated by myricetin from 20 to 100 µM, and the attenuative effects were diminished by the stabilization of HIF-1α with deferoxamine. Exposure to 2.0 mg/m3 formaldehyde also stimulated tumor growth and elevated HIF-1α expression in tumor tissues of A549 xenograft mice, which were also alleviated by oral administration of 100 mg/kg myricetin. These results demonstrated that myricetin alleviated formaldehyde-enhanced Warburg effect in tumor cells through HIF-1α inhibition, which could be further developed as a therapeutic or complementary agent for formaldehyde-induced carcinogenesis.