Neutrophil asthma is a severe, corticosteroid-resistant subtype characterized by airway neutrophilia and declining lung function. Su et al. identify a sirtuin 6-lactate dehydrogenase A-histone lactylation axis that links macrophage glycolysis to epigenetic chemokine regulation, offering mechanistic insight into neutrophil recruitment and highlighting potential therapeutic targets.

Abstract Microplastics (MPLs) are pervasive environmental pollutants increasingly linked to adverse human health outcomes, including atherosclerosis. However, the underlying mechanisms remain poorly understood. Human aortic endothelial cells (HAECs), which line the inner surface of blood vessels, play a critical role in maintaining vascular homeostasis and in the development of atherosclerosis. This study demonstrates that polystyrene microplastics enter HAECs through clathrin-mediated endocytosis and macropinocytosis and subsequently co-localize with mitochondria and lysosomes. Exposure to MPLs induced coordinated transcriptional, epitranscriptomic, and metabolomic reprogramming in HAECs. Transcriptomic analysis revealed disruption of mitochondrial genes and activation of inflammatory pathways with the response of the NF-κB pathway being particularly prominent. Mass spectrometry analysis of RNA modification further identified significant remodeling of the epitranscriptomic landscape, highlighted by increased 1-methyladenosine (m1A) modification and reciprocal regulation of its associated enzymes ( TRMT61A upregulation and ALKBH3 suppression), along with alterations in other RNA modifications such as m3C, pseudouridine (Ψ), m5C, and m7G. Comparative analysis of transcriptomic profiles from human atherosclerotic plaques revealed shared dysregulated pathways in vascular regulation and cellular signaling. Metabolomic profiling further showed extensive remodeling of lipid metabolic networks associated with oxidative stress and inflammation. Together, these findings suggest that MPLs exposure may disrupt endothelial function and pose a potential risk to human cardiovascular health. Graphical Abstract

INTRODUCTION:The epithelial cells of the airway mucosa, as the initiating factors of airway inflammation, regulate the occurrence of innate and acquired immune responses. According to the same airway theory and the latest research results on pericytes in the lower respiratory tract, there may also be interactions or information transmission between the epithelial cells and pericytes of the airway mucosa in the upper respiratory tract. METHODS:In this study, primary mucosal epithelial cells of nasal polyps (NP) were first isolated and cultured to establish a stimulation system of house dust mite (HDM) extract. Then, a coculture system of primary mucosal epithelial cells of NP and human microvascular pericytes was established using transwell chambers. The migration of pericytes in each group after coculture was determined by using the plate scratch test. Transcriptomics was applied to study the differences in gene expression of pericytes in each group after coculture. The expression of cytokines and chemokines in the culture supernatants of each group was detected by ELISA. Finally, the protein expression of the related pathways after coculture was detected by the WB method. RESULTS:The results of this study show that the pericytes migration in the eosinophilic coculture group is significantly higher than that in the other groups. Compared with the model group, the coculture group increased the cell viability of human nasal mucosal epithelial cells stimulated by HDM. The migration ability of human nasal mucosal epithelial cells decreased after HDM stimulation, and the migration ability was restored after coculture. The results indicated that in the coculture group, POSTN, VCAM-1, and CCL-5 expressed by pericytes were the most numerous. The WB detection results revealed that the PDGF pathway in pericytes was activated, and the expressions of related proteins all changed accordingly. CONCLUSION:This study indicates that in the coculture model of mucosal epithelial cells of NP and pericytes, the stimulated epithelial cells can upregulate the expression of factors such as POSTN, VCAM-1, and CCL-5 in pericytes. There exists a PDGF/PI3K/AKT/NF-κB signaling pathway between mucosal epithelial cells of NP and pericytes.

Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent and limiting side effect of paclitaxel treatment in patients with cancer. CIPN affects sensory neurons through neuroinflammatory mechanisms, but how immune cells sense and interpret systemic paclitaxel exposure during treatment is unclear. Here, we found that paclitaxel administration activated the endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) in circulating and dorsal root ganglion-resident myeloid cells, engendering an inflammatory milieu that promotes CIPN. Mechanistically, paclitaxel induced the overproduction of mitochondria-derived reactive oxygen species (ROS) that provoked ER stress and IRE1α hyperactivation in macrophages. This process reprogrammed macrophages toward an inflammatory state characterized by IRE1α-dependent production of TNF-α, IL-1β, PGE2, IL-6, IL-5, GM-CSF, MCP-1, and MIP-2. Ablation of IRE1α in leukocytes, or treatment with a selective IRE1α pharmacological inhibitor, prevented dorsal root ganglion neuroinflammation and CIPN-related pain behaviors in mice. Furthermore, the development and severity of CIPN in patients with gynecological cancer were associated with the status of IRE1α activation in their circulating leukocytes. Our study uncovers leukocyte-intrinsic IRE1α as a key mediator of CIPN and suggests that targeting its dysregulated activation could help mitigate CIPN in patients with cancer who are receiving paclitaxel.

The genetic causes of hereditary hearing loss have not been fully clarified, although more than 120 loci related to deafness have been identified. The traditional single-algorithm approach may miss the key complex gene interactions that cause hearing impairment. Conventional genetic verification techniques (such as Sanger sequencing or microarrays) are time-consuming, costly and require complex laboratory environments, which limits their application in rapid clinical transformation. Electrochemical sensors have become a promising alternative to on-site genetic testing due to their high sensitivity, portability and cost-effectiveness. This study aims to identify new genes related to deafness through comprehensive transcriptome analysis, combined with machine learning and electrochemical sensor verification, providing new targets for the diagnosis and treatment of hereditary hearing loss. Gene expression data were obtained from the GEO database, including 43 samples, which were divided into three groups: deafness patients, healthy controls, and heterozygous carriers. After quality control and preprocessing of the data, multiple machine learning algorithms (including random forest, LASSO regression, XGBoost, etc.) were used for analysis, and key genes were identified through integrated methods. The application of electrochemical sensors provides a rapid, sensitive and cost-effective method for gene verification. The combination with machine learning algorithms further enhances the accuracy and reliability of gene detection. The research successfully identified new candidate genes that may be involved in the pathogenesis of deafness through a multi-algorithm bioinformatics framework. These genes are ideal targets for subsequent verification using electrochemical sensors. This comprehensive approach combines computational prediction with scalable clinical verification, paving the way for the use of electrochemical sensors for gene detection in resource-limited environments. It is expected to promote the early diagnosis and treatment of hereditary hearing loss.

AbstractSkeletal muscle dysfunction in critical illnesses leaves survivors weak and functionally impaired. Macrophages infiltrate muscles; however, their functional role is unclear. We aim to examine muscle leukocyte composition and the effect of macrophages on muscle mass and function in the murine acute lung injury (ALI)‐associated skeletal muscle wasting model. We performed flow cytometry of hindlimb muscle to identify myeloid cells pre‐injury and time points up to 29 days after intratracheal lipopolysaccharide ALI. We evaluated muscle force and morphometrics after systemic and intramuscular clodronate‐induced macrophage depletions between peak lung injury and recovery (day 5–6) versus vehicle control. Our results show muscle leukocytes changed over ALI course with day 3 neutrophil infiltration (130.5 ± 95.6cells/mg control to 236.3 ± 70.6cells/mg day 3) and increased day 10 monocyte abundance (5.0 ± 3.4%CD45+CD11b+ day 3 to 14.0 ± 2.6%CD45+CD11b+ day 10, p = 0.005). Although macrophage count did not significantly change, pro‐inflammatory (27.0 ± 7.2% day 3 to 7.2 ± 3.8% day 10, p = 0.02) and anti‐inflammatory (30.5 ± 11.1% day 3 to 52.7 ± 9.7% day 10, p = 0.09) surface marker expression changed over the course of ALI. Macrophage depletion following peak lung injury increased muscle mass and force generation. These data suggest muscle macrophages beyond peak lung injury limit or delay muscle recovery. Targeting macrophages could augment muscle recovery following lung injury.

BACKGROUND:Chronic rhinosinusitis (CRS) may be caused by increased vascular permeability and inflammatory cell leakage in the subepithelial tissue. AIMS/OBJECTIVES:The aim of this study is to clarify the role of pericytes in tissue edema, microvessel dysfunction and vascular remodeling mechanisms in patients of CRS with nasal polyps (CRSwNP). MATERIAL AND METHODS:A total of 63 tissue samples were collected, including 42 CRSwNP samples (22 eosinophilic CRSwNP (eCRSwNP) and 20 non-eosinophilic CRSwNP (non-eCRSwNP) samples) and 21 samples of CRS without nasal polyps (CRSsNP). The samples were stained by immunofluorescence to measure microvessel density (MVD) and microvessel pericyte coverage index (MPI). RESULTS:We found that the albumin expression in the eCRSwNP group was significantly increased (p < .05). The MPI was significantly decreased (p <.05). There was a significant negative correlation between the MPI and the plasma albumin level (r=-0.82, p < .05). The MPI was negatively correlated with eosinophilic count (r=-0.77, p < .05). In the eCRSwNP group, the expressions of IL-4, Ang-1 and Ang-2 were increased compared with those in the control group. CONCLUSIONS AND SIGNIFICANCE:Pericyte loss may induce microvessel dysfunction, affect the development of interstitial edema and eosinophilic exosmosis in eCRSwNP, and contribute to the formation and maintenance of nasal polyps.

Laryngopharyngeal reflux disease (LPRD) is an inflammatory condition in the laryngopharynx and upper aerodigestive tract mucosa caused by reflux of stomach contents beyond the esophagus. LPRD commonly presents with sym-ptoms such as hoarseness, cough, sore throat, a feeling of throat obstruction, excessive throat mucus. This complex condition is thought to involve both reflux and reflex mechanisms, but a clear understanding of its molecular mechanisms is still lacking. Currently, there is no standardized diagnosis or treatment protocol. Therapeutic strategies for LPRD mainly include lifestyle modifications, proton pump inhibitors and endoscopic surgery. This paper seeks to provide a comprehensive overview of the existing literature regarding the mechanisms, patho-physiology and treatment of LPRD. We also provide an in-depth exploration of the association between LPRD and gastroesophageal reflux disease.

EDITORIAL article Front. Cardiovasc. Med., 01 November 2023Sec. Lipids in Cardiovascular Disease Volume 10 - 2023 | https://doi.org/10.3389/fcvm.2023.1293249

Activating the macrophage NLRP3 inflammasome can promote excessive inflammation with severe cell and tissue damage and organ dysfunction. Here, we show that pharmacological or genetic inhibition of pyruvate dehydrogenase kinase (PDHK) significantly attenuates NLRP3 inflammasome activation in murine and human macrophages and septic mice by lowering caspase-1 cleavage and interleukin-1β (IL-1β) secretion. Inhibiting PDHK reverses NLRP3 inflammasome-induced metabolic reprogramming, enhances autophagy, promotes mitochondrial fusion over fission, preserves crista ultrastructure, and attenuates mitochondrial reactive oxygen species (ROS) production. The suppressive effect of PDHK inhibition on the NLRP3 inflammasome is independent of its canonical role as a pyruvate dehydrogenase regulator. Our study suggests a non-canonical role of mitochondrial PDHK in promoting mitochondrial stress and supporting NLRP3 inflammasome activation during acute inflammation.

听力障碍是发病率最高的疾病之一,发病人群于不同年龄层段广泛存在,严重影响人们交往和社会发展.耳蜗毛细胞是耳蜗中最敏感而精细的元素之一,也是听力障碍发生的关键部位.本文从内耳干细胞角度,在分析内耳干细胞定位及分化的基础上,从相关细胞因子及信号传导通路等方面分析内耳干细胞分化成毛细胞从而治疗听力障碍的可能,为进一步及时终止听力损害或恢复已经损害的听力提出解决思路和方法.

Objective: The spread of the novel SARS-Cov-2 variant Omicron created a challenging public health situa-tion in a number of countries. In March 2022, Omicron emerged in Changchun, China, and the number of patients infected rapidly increased. The prevalence of Omicron infection symptoms differs from that of Delta, with more upper airway clinical symptoms apparent. This study aimed to investigate the clinical and upper airway characteristics of the Omicron variant.Materials and methods: In this retrospective study, we collected data from participants in Changchun who had tested positive for Omicron with quantitative polymerase chain reaction between 10 March and 30 May 2022 using telephone interviews. The questionnaire was designed by the research team based on the number of upper airway symptoms using the visual analogue scale. We also considered age, sex, vaccination status, general symptoms, and cure period.Results: A total of 3715 patients (2056 males and 1659 females) with mild COVID-19 from the Omicron variant were included. The patients had a mean age of 38.63 ( +/- 13.97) years (range 2-86 years). The vaccine uptake rate was 91.33 % (8.66 %, 4.58 %, 65.33 %, and 21.43 % had received zero, one, two, and three doses, respectively). The incidence of upper airway symptoms, including throat and nasal symptoms, was 54.21 %. Throat symptoms were the most common during Omicron infection (49.12 %). Nasal symptoms were also common (20.08 %). The incidence of lower airway symptoms was 25.60 %, and gastrointestinal symptoms was 10.87 %. The incidence of general symptoms was 55.26 %. The cure period ranged from three to 37 days, with a mean of 10.24 +/- 4.69 days. We compared the upper airway symptom severity for Omicron among different vaccination statuses and found no differences.Conclusions: The main clinical characteristics of the SARS-Cov-2 Omicron variant are upper airway symp-toms and general symptoms. Fever remains the most common symptom, followed by mild dry cough. There was no association between Omicron infection and COVID-19 vaccines, and the vaccination status might have been ineffective against upper airway symptom severity by Omicron.(c) 2023 Published by Elsevier Ltd on behalf of King Saud Bin Abdulaziz University for Health Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by localized inflammation of the upper airways. CRS includes two main phenotypes, namely, CRS with nasal polyps and CRS without nasal polyps. The phenotype-based classification method cannot reflect the pathological mechanism. The endotype-based classification method has been paid more and more attention by researchers. It is mainly divided into type 2 and non-type 2 endotypes. The mechanism driving the pathogenesis of non-type 2 inflammation is currently unknown. In this review, the PubMed and Web of Science databases were searched to conduct a critical analysis of representative literature works on the pathogenesis of non-type 2 inflammation in CRS published in the past decade. This review summarizes the latest evidence that may lead to the pathogenesis of non-type 2 inflammation. It is the main method that analyzing the pathogenesis from the perspective of immunology. Genomics and proteomics technique provide new approaches to the study of the pathogenesis. Due to differences in race, environment, geography, and living habits, there are differences in the occurrence of non-type 2 inflammation, which increase the difficulty of understanding the pathogenesis of non-type 2 inflammation in CRS. Studies have confirmed that non-type 2 endotype is more common in Asian patients. The emergence of overlap and unclassified endotypes has promoted the study of heterogeneity in CRS. In addition, as the source of inflammatory cells and the initiation site of the inflammatory response, microvessels and microlymphatic vessels in the nasal mucosal subepithelial tissue participate in the inflammatory response and tissue remodeling. It is uncertain whether CRS patients affect the risk of infection with SARS-CoV-2. In addition, the pathophysiological mechanism of non-type 2 CRS combined with COVID-19 remains to be further studied, and it is worth considering how to select the befitting biologics for CRS patients with non-type 2 inflammation.

In Hawaii, the plants P. albidus, P. forbesii, P. kauaiensis, and P. ruber are collectively known as māmaki in ethnomedicine, where P. albidus predominates. Farmed māmaki is becoming increasingly popular in Hawaii and the United States. Māmaki teas (such as bottled Shaka tea) are the dominant product. Historically, māmaki has been utilized for its medicinal properties, promoting well-being and good health through consuming tea made from its leaves, ingesting its fruit, and incorporating it into ointments. Māmaki holds cultural significance among Native Hawaiians and is widely used in ethnic medicine, having been incorporated into traditional practices for centuries. However, the scientific mechanisms behind its effects remain unclear. This review consolidates current knowledge of māmaki, shedding light on its potential therapeutic properties, physical properties, nutritional and mineral composition, and active phytochemicals. We also highlight recent research advances in māmaki’s antibacterial, anti-viral, chemopreventive, anti-inflammatory, and antioxidant activities. Additionally, we discuss future prospects in this field.

Subunit or inactivated vaccines comprise the majority of vaccines used against viral and bacterial pathogens. However, compared to their live/attenuated counterparts, these vaccines often demonstrate reduced immunogenicity, requiring multiple boosters and or adjuvants to elicit protective immune responses. For this reason, studies of adjuvants and the mechanism through which they can improve inactivated vaccine responses are critical for the development of vaccines with increased efficacy. Studies have shown that the direct conjugation of adjuvant to antigen promotes vaccine immunogenicity, with the advantage of both the adjuvant and antigen targeting the same cell. Using this strategy of direct linkage, we developed an inactivated influenza A (IAV) vaccine that is directly conjugated with the Toll-like receptor 7/8 agonist resiquimod (R848) through a heterobifunctional crosslinker. Previously, we showed that this vaccine resulted in improved protection and viral clearance in newborn nonhuman primates compared to a non-adjuvanted vaccine. We subsequently discovered that the choice of linker used to conjugate R848 to the virus alters the stimulatory activity of the vaccine, promoting increased maturation and proinflammatory cytokine production from DC differentiated in vitro. With this knowledge, we explored how the choice of crosslinker impacts the stimulatory activity of these vaccines. We found that the linker choice alters signaling through the NF-κB pathway in human monocyte-derived dendritic cells (moDCs). Further, we extended our analyses to in vivo differentiated APC present in human peripheral blood, replicating the linker-dependent differences found in in vitro differentiated cells. Finally, we demonstrated in a mouse model that the choice of linker impacts the amount of IAV-specific IgG antibody produced in response to vaccination. These data enhance our understanding of conjugation approaches for improving vaccine immunogenicity.

目的 研究采用小干扰RNA(si-RNA)沉默高迁移率族蛋白1(HMGB1)对人鼻黏膜上皮细胞(HNECs)Toll样受体4(TLR4)及其下游信号通路的影响.方法 体外培养人鼻黏膜上皮细胞,分为空白对照组、si-HMGB1组、脂多糖(LPS)组和LPS+si-HMGB1组.RT-PCR检测HNECs中HMGB1 mRNA的表达.Western blot检测4组细胞HMGB1、TLR4表达以及通路下游核因子-κB(NF-κB)和白介素1β(IL-1β)的表达水平.观察siRNA干扰HMGB1蛋白表达后鼻黏膜上皮细胞的相应变化.结果 RT-PCR结果显示,LPS组细胞中HMGB1的转录水平显著高于空白对照组(P<0.05).LPS+si-HMGB1组HMGB1的mRNA转录水平显著低于LPS组(P<0.05).Western blot检测结果显示,LPS+si-HMGB1组的TLR4,HMGB1蛋白表达水平明显低于LPS组,结果具有统计学意义(P<0.05).LPS+si-HMGB1组细胞的NF-κB以及IL-1β水平明显低于LPS组(P<0.05).结论 鼻黏膜上皮细胞表达HMGB1蛋白,通过siRNA沉默手段可以下调HMGB1的表达.LPS可以激活炎症性的HMGB1,TLR4,通路下游信号NF-κB及IL-1β.siRNA可以下调HMGB1蛋白表达水平,进而抑制TLR4-NF-κB以及IL-1β信号传导通路.

Interleukin; ventricle; ventricle; Systolic hypertensive ABSTRACT Hypertension affects 1 in 3 adults in the United States and leads to left ventricular (LV) concentric hypertrophy, interstitial fibrosis, and increased stiffness. The treatment of cardiac fibrosis remains challenging and empiric. Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid that is highly effective in reducing cardiovascular events in patients and cardiac fibrosis and hypertrophy in animals when administered before pressure overload by promoting the increase of anti-inflammatory M1 macrophages. In this study, we investigated whether EPA mitigates the exacerbation of cardiac remodeling and fibrosis induced by established hypertension, a situation that closely recapitulates a clinical scenario. Twelve-week-old spontaneously hypertensive rats (SHR) were randomized to eat an EPA-enriched or control diet for 20 weeks. We report that rats eating the EPA-enriched diet exhibited a reduction of interstitial cardiac fibrosis and ameliorated LV diastolic dysfunction despite the continuous increase in blood pressure. However, we found that EPA did not have an impact on cardiac hypertrophy. Interestingly, the EPA diet increased mRNA expression of M2 macrophage marker Mrc1 and interleukin (IL)-10 in cardiac tissue. These findings indicated that the anti-fibrotic effects of EPA are mediated in part by phenotypic polarization of macrophages toward anti-inflammatory M2 macrophages and increases of the anti-inflammatory cytokine, IL-10. In summary, EPA prevents the exacerbation of cardiac fibrosis and LV diastolic dysfunction during sustained pressure overload. EPA could represent a novel treatment strategy for hypertensive cardiomyopathy. Further studies in humans are needed to identify the translational value of our finding.

Hypertension affects 1 in 3 adults in the United States and leads to left ventricular (LV) concentric hypertrophy, interstitial fibrosis, and increased stiffness. The treatment of cardiac fibrosis remains challenging and empiric. Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid that is highly effective in reducing cardiovascular events in patients and cardiac fibrosis and hypertrophy in animals when administered before pressure overload by promoting the increase of anti-inflammatory M1 macrophages. In this study, we investigated whether EPA mitigates the exacerbation of cardiac remodeling and fibrosis induced by established hypertension, a situation that closely recapitulates a clinical scenario. Twelve-week-old spontaneously hypertensive rats were randomized to eat an EPA-enriched or control diet for 20 weeks. We report that rats eating the EPA-enriched diet exhibited a reduction of interstitial cardiac fibrosis and ameliorated LV diastolic dysfunction despite the continuous increase in blood pressure. However, we found that EPA did not have an impact on cardiac hypertrophy. Interestingly, the EPA diet increased mRNA expression of M2 macrophage marker Mrc1 and interleukin-10 in cardiac tissue. These findings indicated that the antifibrotic effects of EPA are mediated in part by phenotypic polarization of macrophages toward anti-inflammatory M2 macrophages and increases of the anti-inflammatory cytokine, interleukin-10. In summary, EPA prevents the exacerbation of cardiac fibrosis and LV diastolic dysfunction during sustained pressure overload. EPA could represent a novel treatment strategy for hypertensive cardiomyopathy.

Unravelling the regulatory programs from single-cell multi-omics data has long been one of the major challenges in genomics, especially in the current emerging single-cell field. Currently there is a huge gap between fast-growing single-cell multi-omics data and effective methods for the integrative analysis of these inherent sparse and heterogeneous data. In this study, we have developed a novel method, Single-cell Multi-omics Gene co-Regulatory algorithm (SMGR), to detect coherent functional regulatory signals and target genes from the joint single-cell RNA-sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) data obtained from different samples. Given that scRNA-seq and scATAC-seq data can be captured by zero-inflated Negative Binomial distribution, we utilize a generalized linear regression model to identify the latent representation of consistently expressed genes and peaks, thus enables the identification of co-regulatory programs and the elucidation of regulating mechanisms. Results from both simulation and experimental data demonstrate that SMGR outperforms the existing methods with considerably improved accuracy. To illustrate the biological insights of SMGR, we apply SMGR to mixed-phenotype acute leukemia (MPAL) and identify the MPAL-specific regulatory program with significant peak-gene links, which greatly enhance our understanding of the regulatory mechanisms and potential targets of this complex tumor.