Background: Dysbiosis of the nasal microbiome is considered to be related to the acute exacerbation of chronic rhinosinusitis (AECRS). The microbiota in the nasal cavity of AECRS patients and its association with disease severity has rarely been studied. This study aimed to characterize nasal dysbiosis in a prospective cohort of patients with AECRS.
Methods: We performed a cross-sectional study of 28 patients with AECRS, 20 patients with chronic rhinosinusitis (CRS) without acute exacerbation (AE), and 29 healthy controls using 16S rRNA gene sequencing. Subjective and objective assessments of CRS disease severity during AE were also collected.
Results: Compared to healthy controls and patients with CRS without AE, AECRS presented with a substantial decrease of the Corynebacterium_1 and a significant increase of Ralstonia and Acinetobacter at the genus level (LDA score > 2.0 [P < 0.05]). Furthermore, genera with a mean relative abundance (MRA) of less than 1% were defined as rare components based on published studies, then 29 genera with a substantial alteration in AECRS were rare constituents of the microbiome, of which 18 rare genera were highly associated with subjective and objective disease severity. Moreover, a combination of 15 genera could differentiate patients with AECRS with an area under the curve of 0.870 (95% CI = 0.784-0.955). Prediction of microbial functional pathways involved significantly enhanced lipopolysaccharide biosynthesis pathways and significantly decreased folate biosynthesis, sulfur relay system, and cysteine and methionine metabolism pathways in patients with AECRS.
Conclusions: The rare nasal microbiota (MRA < 1%) correlated with disease status and disease severity in patients with AECRS. The knowledge about the pattern of the nasal microbiome and its metabolomic pathway may contribute to the fundamental understanding of AECRS pathophysiology.
Background: Adenosine, an ATP degradation product, is a sleep pressure factor. The adenosine 1 receptor (A1R) reports sleep need. Histaminergic neurons (HN) of the tuberomamillary nucleus (TMN) fire exclusively during wakefulness and promote arousal. All of them express GABAA receptors and are inhibited by GABA. Does adenosine contribute to their silencing?
Subjects and treatment: Responses to adenosine were studied in mouse brain slices and primary dissociated cultures. For HN identification single-cell (sc)RT-PCR, reporter protein and pharmacology were used. Hippocampal Dentate Gyrus granular layer cells (DGgc) were studied in parallel.
Methods: Firing frequency was recorded in patch-clamp configuration or by microelectrode arrays. A1R-expression was studied by scRT-PCR and semiquantitative PCR.
Results: Most DGgc were inhibited through A1R, detected with scRT-PCR in 7 out of 10 PDZd2-positive DGgc; all HN were A1R negative. One HN out of 25 was inhibited by adenosine. The A1R mRNA level in the hippocampus was 6 times higher than in the caudal (posterior) hypothalamus. Response to adenosine was weaker in hypothalamic compared to hippocampal cultures.
Conclusions: Most HN are not inhibited by adenosine.
Acute pancreatitis (AP) represents a severe inflammatory condition of the exocrine pancreas, precipitating systemic organ dysfunction and potential failure. The global prevalence of acute pancreatitis is on an ascending trajectory. The condition carries a significant mortality rate during acute episodes. This underscores the imperative to elucidate the etiopathogenic pathways of acute pancreatitis, enhance comprehension of the disease's intricacies, and identify precise molecular targets coupled with efficacious therapeutic interventions. The pathobiology of acute pancreatitis encompasses not only the ectopic activation of trypsinogen but also extends to disturbances in calcium homeostasis, mitochondrial impairment, autophagic disruption, and endoplasmic reticulum stress responses. Notably, the realm of epigenetic regulation has garnered extensive attention and rigorous investigation in acute pancreatitis research over recent years. One of these modifications, lysine acetylation, is a reversible post-translational modification of proteins that affects enzyme activity, DNA binding, and protein stability by changing the charge on lysine residues and altering protein structure. Numerous studies have revealed the importance of acetylation modification in acute pancreatitis, and that it is a favorable target for the design of new drugs for this disease. This review centers on lysine acetylation, examining the strides made in acute pancreatitis research with a focus on the contributory role of acetylomic alterations in the pathophysiological landscape of acute pancreatitis, thereby aiming to delineate novel therapeutic targets and advance the development of more efficacious treatment modalities.
Objective: Fibroblast-like synoviocytes (FLS) are key players in rheumatoid arthritis (RA) by resisting apoptosis via increased autophagy. Elevated synovial aquaporin 1 (AQP1) affects RA FLS behaviors, but its relationship with FLS autophagy is unclear. We aim to clarify that silencing AQP1 inhibits autophagy to exert its anti-RA effects.
Methods: We studied the effects and mechanisms of AQP1 silencing on autophagy in TNF-α-induced RA FLS and examined the crucial role of autophagy inhibition in its impacts on RA FLS pathogenic behaviors. We explored whether silencing synovial AQP1 relieved rat adjuvant-induced arthritis (AIA) by reducing synovial autophagy.
Results: TNF-α stimulation increased AQP1 expression and autophagy levels in RA FLS, with a positive correlation between them. AQP1 silencing inhibited autophagy in TNF-α-stimulated RA FLS, along with suppressing proliferation, promoting apoptosis, and mitigating inflammation. Notably, the inhibitory effects of AQP1 silencing on RA FLS pathogenic behaviors were cancelled by autophagy activation with rapamycin (Rapa) but enhanced by autophagy inhibition using 3-Methyladenine. Mechanistically, silencing AQP1 enhanced the binding of Bcl-2 to Beclin1 by decreasing Beclin1-K63 ubiquitination, thus inhibiting RA FLS autophagy. In vivo, silencing synovial AQP1 relieved the severity and development of rat AIA, alongside reducing Ki67 expression, promoting apoptosis, and decreasing autophagy within AIA rat synovium. Expectedly, the Rapa co-administration nullified the anti-AIA effects of silencing synovial AQP1.
Conclusion: These findings reveal that silencing AQP1 inhibits RA FLS pathogenic behaviors and attenuates rat AIA through autophagy inhibition. This study may help clarify the pathogenic role of AQP1 in enhancing autophagy during RA development.
Background: Mitochondrial dysfunction and damage can result in the release of mitochondrial DNA (mtDNA) into the cytoplasm, which subsequently activates the cGAS-STING pathway, promoting the onset of inflammatory diseases. Various factors, such as oxidative stress, viral infection, and drug toxicity, have been identified as inducers of mitochondrial damage. This study aims to investigate the role of mtDNA as a critical inflammatory mediator in the pathogenesis of ketamine (KET)-induced cystitis (KC) through the cGAS-STING pathway.
Methods: To investigate the role of the cGAS-STING pathway in KET-induced cystitis, we assessed the expression of cGAS and STING in rats with KET cystitis. Additionally, we evaluated STING expression in conditionally deficient Simian Virus-transformed Human Uroepithelial Cell Line 1 (SV-HUC-1) cells in vitro. Morphological changes in mitochondria were examined using transmission electron microscopy. We measured intracellular reactive oxygen species (ROS) production through flow cytometry and immunofluorescence techniques. Furthermore, alterations in associated inflammatory factors and cytokines were quantified using real-time quantitative PCR with fluorescence detection.
Results: We observed up-regulation of cGAS and STING expressions in the bladder tissue of rats in the KET group, stimulation with KET also led to increased cGAS and STING levels in SV-HUC-1 cells. Notably, the knockdown of STING inhibited the nuclear translocation of NF-κB p65 and IRF3, resulting in a decrease in the expression of inflammatory cytokines, including IL-6, IL-8, and CXCL10. Additionally, KET induced damage to the mitochondria of SV-HUC-1 cells, facilitating the release of mtDNA into the cytoplasm. This significant depletion of mtDNA inhibited the activation of cGAS-STING pathway, subsequently affecting the expression of NF-κB p65 and IRF3. Importantly, the reintroduction of mtDNA after STING knockdown partially restored the inflammatory response.
Conclusion: Our findings confirmed the activation of the cGAS-STING pathway in KC rats and revealed mitochondrial damage in vitro. These results highlight the involvement of the cGAS-STING pathway in the pathogenesis of KC, suggesting its potential as a therapeutic target for intervention.
Objective: Arthritis is a class of diseases, characterized by joint and surrounding inflammation, accompanied by joint swelling, pain, dysfunction. According to different factors, arthritis can be divided into osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and so on. N6-methyladenosine (m6A) is the most common internal modification of eukaryotic mRNA and is involved in splicing, stabilization, output and degradation of RNA metabolism. This review systematically summarized current insights into the mechanism of m6A in arthritis.
Methods: The studies related to the involvement of m6A in the pathogenesis of arthritis reported in PubMed, Google scholar, and other open source literatures were investigated to evaluate the important roles of m6A in arhtritis, and the clinical relevances.
Results and conclusions: M6A methylation regulators play the roles of writers, erasers, and readers, are crucial for regulating gene expression, and play important roles in many biological processes such as virus replication and cell differentiation. In addition, more and more studies have shown that m6A is closely related to the development of arthritis. As a new therapeutic target for arthritis, m6A has a wide influence on the pathological mechanism of arthritis. However, further research is needed to determine how m6A affects arthritis pathology and its use in target therapy and diagnosis.
Allergic asthma is a chronic complex airway disease characterized by airway hyperresponsiveness, eosinophilic inflammation, excessive mucus secretion, and airway remodeling, with increasing mortality and incidence globally. The pathogenesis of allergic asthma is influenced by various factors including genetics, environment, and immune responses, making it complex and diverse. Recent studies have found that various cellular functions of mitochondria such as calcium regulation, adenosine triphosphate production, changes in redox potential, and free radical scavenging, are involved in regulating the pathogenesis of asthma. This review explores the involvement of mitochondrial functional changes in the pathogenesis of asthma, and investigate the potential of targeting cellular mitochondria as a therapeutic approach for asthma. Those insights can provide a novel theoretical foundations and treatment strategies for understanding and preventing asthma.
Background: Giant cell arteritis (GCA) is a prevalent artery and is strongly correlated with age. The role of CD4+ Memory T cells in giant cell arteritis has not been elucidated.
Method: Through single-cell analysis, we focused on the CD4+ Memory T cells in giant cell arteritis. eQTL analysis and mendelian randomization analysis identified the significant genes which have a causal effect on giant cell arteritis risk. CD4+ Memory T cells were subsequently divided into gene-positive and gene-negative groups, then further single-cell analysis was conducted. Mendelian randomization of plasma proteins, blood-urine biomarkers and metabolites were also performed. Eventually, the PMA induced Jurkat cell lines were used for biological experiments to explore the specific functions of significant causal genes in CD4+ Memory T cells.
Results: Similarity of CD4+ Memory T cells in GCA and old samples were explored. DDIT4 and ARHGAP15 were identified as significant risk genes via mendelian randomization. The CD4+ Memory T cells were then divided into DDIT4 ± or ARHGAP15 ± groups, and further single-cell analysis indicated the differences in aspects involving intercellular communication, functional pathways, protein activity, metabolism and drug sensitivity between positive and negative groups. In vitro experiments, including overexpression and knockdown, demonstrated that DDIT4 leading to a chronic, low-intensity inflammatory state in CD4+ Memory T cells, eventually promoting the development of GCA.
Conclusion: DDIT4 and ARHGAP15 have significant causal effects on giant cell arteritis risk. Specifically, DDIT4 exhibit pro-inflammatory effects on GCA via promotes chronic, low-intensity inflammatory in CD4+ Memory T cell.
Background: Traditional Chinese medicine (TCM) is a valuable resource for drug discovery and has demonstrated excellent efficacy in treating inflammatory diseases. This study aimed to develop a universal gene signature-based strategy for high-throughput discovery of anti-inflammatory drugs, especially Traditional Chinese medicine (TCM).
Methods: The disease gene signature of liposaccharide-stimulated THP-1 cells and drug gene signatures of 655 drug candidates were established via sequencing. Anti-inflammatory drugs were screened based on similarities between drug gene signatures and the reversed disease gene signature.
Results: Through screening, 83 potential anti-inflammatory drugs were identified. The efficacy of the TCM formula Biyun Powder, along with individual TCMs, Centipedea Herba, Kaempferiae Rhizoma, and Schizonepetae Spica Carbonisata, was verified in vitro or in vivo. Mechanistically, they exerted anti-inflammatory effects by inhibiting the nuclear factor-kappa B pathway. Kaempferol and luteolin were identified as bioactive IκB kinase-β inhibitors in Kaempferiae Rhizoma and Schizonepetae Spica Carbonisata, respectively.
Conclusion: We developed a universal gene signature-based approach for the high-throughput discovery of anti-inflammatory drugs that is applicable to compounds and to TCM herbs/formulae and established a workflow (screening, validation of efficacy, and identification of the mechanism of action and bioactive compounds) that can serve as a research template for high-throughput drug research.
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