Epithelial cells derived exosomal miR-203a-3p facilitates stromal inflammation of type IIIA chronic prostatitis/chronic pelvic pain syndrome by targeting DUSP5 and increasing MCP-1 generation.

Increased proinflammatory cytokines and infiltration of inflammatory cells in the stroma are important pathological features of type IIIA chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS-A), and the interaction between stromal cells and other cells in the inflammatory microenvironment is closely related to the inflammatory process of CP/CPPS-A. However, the interaction between stromal and epithelial cells remains unclear. In this study, inflammatory prostate epithelial cells (PECs) released miR-203a-3p-rich exosomes and facilitated prostate stromal cells (PSCs) inflammation by upregulating MCP-1 expression. Mechanistically, DUSP5 was identified as a novel target gene of miR-203a-3p and regulated PSCs inflammation through the ERK1/2/MCP-1 signaling pathway. Meanwhile, the effect of exosomes derived from prostatic fluids of CP/CPPS-A patients was consistent with that of exosomes derived from inflammatory PECs. Importantly, we demonstrated that miR-203a-3p antagomirs-loaded exosomes derived from PECs targeted the prostate and alleviated prostatitis by inhibiting the DUSP5-ERK1/2 pathway. Collectively, our findings provide new insights into underlying the interaction between PECs and PSCs in CP/CPPS-A, providing a promising therapeutic strategy for CP/CPPS-A.

Identification of the new molecular subtypes related to inflammation in breast cancer.

Breast cancer is a prevalent ailment among women, and the inflammatory response plays a crucial role in the management and prediction of breast cancer (BRCA). However, the new subtypes based on inflammation in BRCA research are still undefined. The databases including The Cancer Genome Atlas and gene expression omnibus were utilized to gather clinical data and somatic mutation information for approximately 1069 BRCA patients. Through Consensus Clustering, novel subtypes linked to inflammation were identified. A comparative analysis was conducted on the prognosis, and immune cell infiltration, and somatic mutation of the new subtypes. Additionally, an investigation into drug therapy and immunotherapy was conducted to distinguish high-risk individuals from low-risk ones. The findings of this investigation proposed the categorization of BRCA into innovative subtypes predicated on the inflammatory response and 6 key genes were a meaningful approach. Specifically, the low-, medium-, and high-inflammation subtypes exhibited varying degrees of association with clinicopathological features, tumor microenvironment, and prognosis. Notably, the high-inflammation subtype was characterized by a strong correlation with immunosuppressive microenvironments and a higher frequency of somatic mutations, which was an indication of poorer health. This study revealed that a brand-new classification could throw new light on the effective prognosis. The integration of multiple key genes was a new characterization that could promote more immunotherapy strategies and contribute to predicting the efficacy of the chemotherapeutic drugs.

Interactions between circulating inflammatory factors and autism spectrum disorder: a bidirectional Mendelian randomization study in European population.

Background: Extensive observational studies have reported an association between inflammatory factors and autism spectrum disorder (ASD), but their causal relationships remain unclear. This study aims to offer deeper insight into causal relationships between circulating inflammatory factors and ASD. Methods: Two-sample bidirectional Mendelian randomization (MR) analysis method was used in this study. The genetic variation of 91 circulating inflammatory factors was obtained from the genome-wide association study (GWAS) database of European ancestry. The germline GWAS summary data for ASD were also obtained (18,381 ASD cases and 27,969 controls). Single nucleotide polymorphisms robustly associated with the 91 inflammatory factors were used as instrumental variables. The random-effects inverse-variance weighted method was used as the primary analysis, and the Bonferroni correction for multiple comparisons was applied. Sensitivity tests were carried out to assess the validity of the causal relationship. Results: The forward MR analysis results suggest that levels of sulfotransferase 1A1, natural killer cell receptor 2B4, T-cell surface glycoprotein CD5, Fms-related tyrosine kinase 3 ligand, and tumor necrosis factor-related apoptosis-inducing ligand are positively associated with the occurrence of ASD, while levels of interleukin-7, interleukin-2 receptor subunit beta, and interleukin-2 are inversely associated with the occurrence of ASD. In addition, matrix metalloproteinase-10, caspase 8, tumor necrosis factor-related activation-induced cytokine, and C-C motif chemokine 19 were considered downstream consequences of ASD. Conclusion: This MR study identified additional inflammatory factors in patients with ASD relative to previous studies, and raised a possibility of ASD-caused immune abnormalities. These identified inflammatory factors may be potential biomarkers of immunologic dysfunction in ASD.

E4BP4 in macrophages induces an anti-inflammatory phenotype that ameliorates the severity of colitis.

Macrophages are versatile cells of the innate immune system that work by altering their pro- or anti-inflammatory features. Their dysregulation leads to inflammatory disorders such as inflammatory bowel disease. We show that macrophage-specific upregulation of the clock output gene and transcription factor E4BP4 reduces the severity of colitis in mice. RNA-sequencing and single-cell analyses of macrophages revealed that increased expression of E4BP4 leads to an overall increase in expression of anti-inflammatory genes including Il4ra with a concomitant reduction in pro-inflammatory gene expression. In contrast, knockout of E4BP4 in macrophages leads to increased proinflammatory gene expression and decreased expression of anti-inflammatory genes. ChIP-seq and ATAC-seq analyses further identified Il4ra as a target of E4BP4, which drives anti-inflammatory polarization in macrophages. Together, these results reveal a critical role for E4BP4 in regulating macrophage inflammatory phenotypes and resolving inflammatory bowel diseases.

Comprehensive pan-cancer analysis of inflammatory age-clock-related genes as prognostic and immunity markers based on multi-omics data.

Inflammatory age (iAge) is a vital concept for understanding the intricate interplay between chronic inflammation and aging in the context of cancer. However, the importance of iAge-clock-related genes (iAge-CRGs) across cancers remains unexplored. This study aimed to explore the mechanisms and applications of these genes across diverse cancer types. We analyzed profiling data from over 10,000 individuals, covering 33 cancer types, 750 small molecule drugs, and 24 immune cell types. We focused on DCBLD2's function at the single-cell level and computed an iAge-CRG score using GSVA. This score was correlated with cancer pathways, immune infiltration, and survival. A signature was then derived using univariate Cox and LASSO regression, followed by ROC curve analysis, nomogram construction, decision curve analysis, and immunocytochemistry. Our comprehensive analysis revealed epigenetic, genomic, and immunogenomic alterations in iAge-CRGs, especially DCBLD2, leading to abnormal expression. Aberrant DCBLD2 expression strongly correlated with cancer-associated fibroblast infiltration and prognosis in multiple cancers. Based on GSVA results, we developed a risk model using five iAge-CRGs, which proved to be an independent prognostic index for uveal melanoma (UVM) patients. We also systematically evaluated the correlation between the iAge-related signature risk score and immune cell infiltration. iAge-CRGs, particularly DCBLD2, emerge as potential targets for enhancing immunotherapy outcomes. The strong correlation between abnormal DCBLD2 expression, cancer-associated fibroblast infiltration, and patient survival across various cancers underscores their significance. Our five-gene risk signature offers an independent prognostic tool for UVM patients, highlighting the crucial role of these genes in suppressing the immune response in UVM.Kindly check and confirm whether the corresponding affiliation is correctly identified.I identified the affiliation is correctly.thank you.Per style, a structured abstract is not allowed so we have changed the structured abstract to an unstructured abstract. Please check and confirm.I confirm the abstract is correctly ,thank you.

A case study of a liver transplant-treated patient with glycogen storage disease type Ia presenting with multiple inflammatory hepatic adenomas: an analysis of clinicopathologic and genetic data.

BACKGROUND: Glycogen storage disease (GSD) is a disease caused by excessive deposition of glycogen in tissues due to genetic disorders in glycogen metabolism. Glycogen storage disease type I (GSD-I) is also known as VonGeirk disease and glucose-6-phosphatase deficiency. This disease is inherited in an autosomal recessive manner, and both sexes can be affected. The main symptoms include hypoglycaemia, hepatomegaly, acidosis, hyperlipidaemia, hyperuricaemia, hyperlactataemia, coagulopathy and developmental delay. CASE PRESENTATION: Here, we present the case of a 13-year-old female patient with GSD Ia complicated with multiple inflammatory hepatic adenomas. She presented to the hospital with hepatomegaly, hypoglycaemia, and epistaxis. By clinical manifestations and imaging and laboratory examinations, we suspected that the patient suffered from GSD I. Finally, the diagnosis was confirmed by liver pathology and whole-exome sequencing (WES). WES revealed a synonymous mutation, c.648 G > T (p.L216 = , NM_000151.4), in exon 5 and a frameshift mutation, c.262delG (p.Val88Phefs*14, NM_000151.4), in exon 2 of the G6PC gene. According to the pedigree analysis results of first-generation sequencing, heterozygous mutations of c.648 G > T and c.262delG were obtained from the patient's father and mother. Liver pathology revealed that the solid nodules were hepatocellular hyperplastic lesions, and immunohistochemical (IHC) results revealed positive expression of CD34 (incomplete vascularization), liver fatty acid binding protein (L-FABP) and C-reactive protein (CRP) in nodule hepatocytes and negative expression of ß-catenin and glutamine synthetase (GS). These findings suggest multiple inflammatory hepatocellular adenomas. PAS-stained peripheral hepatocytes that were mostly digested by PAS-D were strongly positive. This patient was finally diagnosed with GSD-Ia complicated with multiple inflammatory hepatic adenomas, briefly treated with nutritional therapy after diagnosis and then underwent living-donor liver allotransplantation. After 14 months of follow-up, the patient recovered well, liver function and blood glucose levels remained normal, and no complications occurred. CONCLUSION: The patient was diagnosed with GSD-Ia combined with multiple inflammatory hepatic adenomas and received liver transplant treatment. For childhood patients who present with hepatomegaly, growth retardation, and laboratory test abnormalities, including hypoglycaemia, hyperuricaemia, and hyperlipidaemia, a diagnosis of GSD should be considered. Gene sequencing and liver pathology play important roles in the diagnosis and typing of GSD.

The role of proinflammatory cytokines and CXC chemokines (CXCL1-CXCL16) in the progression of prostate cancer: insights on their therapeutic management.

Reproductive cancers are malignancies that develop in the reproductive organs. One of the leading cancers affecting the male reproductive system on a global scale is prostate cancer (PCa). The negative consequences of PCa metastases endure and are severe, significantly affecting mortality and life quality for those who are affected. The association between inflammation and PCa has captured interest for a while. Inflammatory cells, cytokines, CXC chemokines, signaling pathways, and other elements make up the tumor microenvironment (TME), which is characterized by inflammation. Inflammatory cytokines and CXC chemokines are especially crucial for PCa development and prognosis. Cytokines (interleukins) and CXC chemokines such as IL-1, IL-6, IL-7, IL-17, TGF-ß, TNF-α, CXCL1-CXCL6, and CXCL8-CXCL16 are thought to be responsible for the pleiotropic effects of PCa, which include inflammation, progression, angiogenesis, leukocyte infiltration in advanced PCa, and therapeutic resistance. The inflammatory cytokine and CXC chemokines systems are also promising candidates for PCa suppression and immunotherapy. Therefore, the purpose of this work is to provide insight on how the spectra of inflammatory cytokines and CXC chemokines evolve as PCa develops and spreads. We also discussed recent developments in our awareness of the diverse molecular signaling pathways of these circulating cytokines and CXC chemokines, as well as their associated receptors, which may one day serve as PCa-targeted therapies. Moreover, the current status and potential of theranostic PCa therapies based on cytokines, CXC chemokines, and CXC receptors (CXCRs) are examined.

[Heme oxygenase-1 (HO-1) gene knockout affects the balance of lung immune cell composition and aggravates inflammatory injury in lung tissues of LPS-induced acute lung injury (ALI) mice].

Objective To evaluate the effects of heme oxygenase-1 (HO-1) gene deletion on immune cell composition and inflammatory injury in lung tissues of mice with lipopolysaccharide (LPS)-induced acute lung injury (ALI). Methods C57BL/6 wild-type (WT) mice and HO-1 conditional-knockout (HO-1-/-) mice on the same background were randomly divided into four groups (n=5 in every group): WT control group, LPS-treated WT group, HO-1-/- control group and LPS-treated HO-1-/- group. LPS-treated WT and HO-1-/- groups were injected with LPS (15 mg/kg) through the tail vein to establish ALI model, while WT control group and HO-1-/- control group were injected with an equivalent volume of normal saline through the tail vein, respectively. Twelve hours later, the mice were sacrificed and lung tissues from each group were collected for analysis. Histopathological alterations of lung tissues were assessed by HE staining. The levels of mRNA expression of tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and IL-6 were determined by PCR. The percentages of neutrophils (CD45+CD11b+Ly6G+Ly6C-), total monocytes (CD45+CD11b+Ly6Chi), pro-inflammatory monocyte subsets (CD45+CD11b+Ly6ChiCCR2hi) and total macrophages (CD45+CD11b+F4/80+), M1 macrophage (CD45+CD11b+F4/80+CD86+), M2 macrophage (CD45+CD11b+F4/80+CD206+), total T cells (CD45+CD3+), CD3+CD4+ T cells, CD3+CD8+ T cells and myeloid suppressor cells (MDSCs, CD45+CD11b+Gr1+) were detected by flow cytometry. Results Compared with the corresponding control groups, HE staining exhibited increased inflammation in the lung tissues of both LPS-treated WT and HO-1-/- model mice; mRNA expression levels of TNF-α, IL-1ß and IL-6 were up-regulated; the proportions of neutrophils, total monocytes, pro-inflammatory monocyte subsets, MDSCs and total macrophages increased significantly. The percentage of CD3+, CD3+CD4+ and CD3+CD8+ T cells decreased significantly. Under resting-state, compared with WT control mice, the proportion of neutrophils, monocytes and pro-inflammatory monocyte subset increased in lung tissues of HO-1-/- control mice, while the proportion of CD3+ and CD3+CD8+ T cells decreased. Compared with LPS-treated WT mice, the mRNA expression levels of TNF-α and IL-1ß were up-regulated in lung tissues of LPS-treated HO-1-/- mice; the proportion of total monocytes, pro-inflammatory monocyte subsets, M1 macrophages and M1/M2 ratio increased greatly; the percentage of CD3+CD8+ T cells decreased significantly. Conclusion The deletion of HO-1 affects the function of the lung immune system and aggravates the inflammatory injury after LPS stimulation in ALI mice.

MicroRNA-671-5p regulates the inflammatory response of periodontal ligament stem cells via the DUSP8/p38 MAPK pathway.

BACKGROUND: MicroRNAs are differentially expressed in periodontitis tissues. They are involved in cellular responses to inflammation and can be used as markers for diagnosing periodontitis. Microarray analysis showed that the expression level of microRNA-671-5p in periodontal tissues of patients with periodontitis was increased. In this study, we investigated the mechanism of action of microRNA-671-5p in human periodontal ligament stem cells (hPDLSCs) under inflammatory conditions. METHODS AND RESULTS: HPDLSCs were treated with lipopolysaccharide (LPS) to establish an inflammation model. The cell survival rate was determined using the cell counting kit-8 (CCK8). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analyses were used to detect the expression of microRNA-671-5p and dual-specificity phosphatase (DUSP) 8 proteins, respectively, Interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α were detected using qRT-PCR and Enzyme-linked immunosorbent assay (ELISA). A dual-luciferase reporter system was employed to determine the relationship between micoRNA-671-5p and DUSP8 expression. Activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway was confirmed using western blot analysis. Following the treatment of hPDLSCs with LPS, the expression levels of microRNA-671-5p in hPDLSCs were increased, cell viability decreased, and the expression of inflammatory factors displayed an increasing trend. MicroRNA-671-5p targets and binds to DUSP8. Silencing microRNA-671-5p or overexpressing DUSP8 can improve cell survival rate and reduce inflammatory responses. When DUSP8 was overexpressed, the expression of p-p38 was reduced. CONCLUSIONS: microRNA-671-5p targets DUSP8/p38 MAPK pathway to regulate LPS-induced proliferation and inflammation in hPDLSCs.

miR-200b-3p relieved inflammation in patients with heart failure by regulating ZEB1 expression.

BACKGROUND: MicroRNA-200b-3p (miR-200b-3p) plays a pivotal role in inflammatory responses and is implicated in various inflammatory disorders. In this study, we aim to explore the role of miR-200b-3p in the inflammatory response in heart failure (HF). METHODS: Patients diagnosed with heart failure and age-matched healthy controls were studied. Peripheral blood samples from participants were collected for RNA-seq analysis to explore the expression profile of miR-200b-3p. The predictive value of miR-200b-3p and ZEB1 in the prognosis of heart failure was evaluated by analyzing the receiver operating characteristic (ROC) curve. Bioinformatics analysis and double luciferase reporter gene analysis were used to confirm the interaction between miR-200b-3p and ZEB1. Real-time quantitative polymerase chain reaction (QRT-PCR) was used to detect the expression levels of miR-200b-3p and ZEB1 in cardiopulmonary bypass. Additionally, the effects of miR-200b-3p on myocardial cell line (H9c2) injury were evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS: In the extracardiac circulation of HF patients, miR-200b-3p expression was significantly reduced, while ZEB1 levels were notably elevated. Analysis of the ROC curve revealed that miR-200b-3p and ZEB1 have predictive value in the prognosis of HF patients. The double luciferase reporter experiment demonstrated that miR-200b-3p binds to ZEB1 and inhibits its expression. Overexpression of miR-200b-3p demonstrated a remarkable ability to alleviate inflammation and inhibit the damage to myocardial cells in vivo. CONCLUSION: MiR-200b-3p can target and inhibit ZEB1, reducing the inflammatory reaction of myocardial cells. The miR-200b-3p/ZEB1 network may be helpful in preventing and treating HF.

KLF5-mediated pyroptosis of airway epithelial cells leads to airway inflammation in asthmatic mice through the miR-182-5p/TLR4 axis.

Asthma is viewed as an airway disease and an inflammatory condition. This study aims to reveal the role of Kruppel-like factor 5 (KLF5)-mediated pyroptosis of airway epithelial cells in airway inflammation in asthma. The asthmatic mouse model was established. The mice were infected with the lentivirus containing sh-KLF5, antagomiR-182-5p, and pc-Toll-like receptor 4 (TLR4). Airway hyperresponsiveness was measured, and the cells in bronchoalveolar lavage fluid (BALF) were sorted and counted. The expression levels of interleukin (IL)-4/IL-13/IL-6/IL-18/IL-1ß/NOD-like receptor family pyrin domain containing 3 (NLRP3)/N-gasdermin D (GSDMD-N)/cleaved caspase-1 were detected. The pathological changes in lung tissue were observed. The enrichment of KLF5 in the miR-182-5p promoter region was measured. The binding relationship among KLF5, miR-182-5p, and TLR4 were analyzed. KLF5 was highly expressed in asthmatic mice. Silencing KLF5 improved airway resistance and lung dynamic compliance, reduced the cells in BALF and the expression of IL-4/IL-13/IL-6/NLRP3/GSDMD-N/cleaved caspase-1/IL-18/IL-1ß, and alleviated the pathological changes. Mechanistically, KLF5 bonded to the miR-182-5p promoter to inhibit miR-182-5p expression, and miR-182-5p inhibited TLR4. Silencing miR-182-5p or TLR4 overexpression reversed the improvement of silencing KLF5 on airway inflammation and pyroptosis in asthmatic mice. In conclusion, KLF5 inhibited miR-182-5p to promote TLR4 expression, thus aggravating pyroptosis and airway inflammation in asthmatic mice.

Rocaglamide regulates iron homeostasis by suppressing hepcidin expression.

The anemia of inflammation (AI) is characterized by the presence of inflammation and abnormal elevation of hepcidin. Accumulating evidence has proved that Rocaglamide (RocA) was involved in inflammation regulation. Nevertheless, the role of RocA in AI, especially in iron metabolism, has not been investigated, and its underlying mechanism remains elusive. Here, we demonstrated that RocA dramatically suppressed the elevation of hepcidin and ferritin in LPS-treated mice cell line RAW264.7 and peritoneal macrophages. In vivo study showed that RocA can restrain the depletion of serum iron (SI) and transferrin (Tf) saturation caused by LPS. Further investigation showed that RocA suppressed the upregulation of hepcidin mRNA and downregulation of Fpn1 protein expression in the spleen and liver of LPS-treated mice. Mechanistically, this effect was attributed to RocA's ability to inhibit the IL-6/STAT3 pathway, resulting in the suppression of hepcidin mRNA and subsequent increase in Fpn1 and TfR1 expression in LPS-treated macrophages. Moreover, RocA inhibited the elevation of the cellular labile iron pool (LIP) and reactive oxygen species (ROS) induced by LPS in RAW264.7 cells. These findings reveal a pivotal mechanism underlying the roles of RocA in modulating iron homeostasis and also provide a candidate natural product on alleviating AI.

Kreotoxin A administration inhibits hyperproliferation and inflammation of human ear keloid tissue and keloid-derived fibroblasts by downregulating HIF-1α expression.

Keloids represent a prevalent dermal fibroproliferative disorder. They only affect humans and exhibit several tumor characteristics, such as excessive extracellular matrix (ECM) deposition, which usually occurs after skin injury. Kreotoxin type A (KTA) can inhibit the release of acetylcholine, and thereby inhibit the proliferation of keloid fibroblasts and reducing the formation of scars. Thus, KTA could be used as a therapeutic agent for keloids. However, the mechanisms of action of KTA in keloid treatment remain unclear. In this study, we aimed to explore the underlying mechanisms of action of KTA in human keloid treatment using human tissue and a cell-based model. Integrative microarray analysis revealed that hypoxia-inducible factor 1-alpha (HIF-1α) expression was frequently upregulated in hypertrophic scar and keloid tissues, whereas it was downregulated in the KTA-treated samples. Furthermore, KTA addition to keloid-derived fibroblasts (KDFs) reduced the growth rate and viability, induced apoptosis, and decreased inflammation and oxidative stress in KDFs. However, overexpression of HIF-1α restored cell number and survival, decreased apoptosis, and promoted inflammation and oxidative stress in KTA-treated KDFs. Furthermore, KTA treatment reduced the expression of ECM proteins, including vascular endothelial growth factor (VEGF), collagen I and III, whereas HIF-1α overexpression abolished the effects of KTA on KDFs. In conclusion, our findings provide novel insights into the mechanisms of action of KTA as a potential therapeutic agent for keloids via modulating HIF-1α expression.

Effects of miR-129-5p on inflammation and nucleus pulposus cell apoptosis in rats with intervertebral disc degeneration through JNK signaling pathway.

This study aimed to explore the effects of miR-129-5p on inflammation and nucleus pulposus (NP) cell apoptosis in rats with intervertebral disc degeneration (IVDD) through the c-Jun N-terminal kinase (JNK) signaling pathway. A total of 20 rats were randomly divided into control group (n=10) or IVDD group (n=10). The mRNA expressions of miR-129-5p and apoptosis index Fas in IVDD tissues were determined using RT-PCR. NP cell apoptosis rate was detected via TUNEL assay. NP cells were extracted from IVDD tissues for primary culture. Subsequently, the cells were transfected with miR-129-5p inhibitor or mimic to inhibit or overexpress miR-129-5p, respectively. Furthermore, the changes in the JNK pathway indexes and apoptosis indexes were detected using Western blotting. In IVDD group, the expression of miR-129-5p was significantly down-regulated, while the transcriptional level of Fas was up-regulated compared with those in control group. Pearson correlation analysis revealed a negative correlation between the expressions of miR-129-5p and Fas mRNA (r=-0.75, P<0.05). IVDD group exhibited significantly higher levels of serum TNF-α, IL-6 and IL-1 than control group. Subsequent TUNEL assay indicated that the apoptosis rate was evidently higher in IVDD group (60.6%) than control group (2.5%). The results of Western blotting showed that the protein expressions of JNK1, JNK2 and Fas remarkably rose in IVDD group compared with those in control group. However, they declined remarkably in miR-129-5p mimic group compared with those in control group. Furthermore, such trends were significantly reversed in miR-129-5p inhibitor group. MiR-129-5p was significantly down-regulated in IVDD, whose overexpression has anti-inflammatory and anti-apoptotic effects.

MiR-4454 in Combined Allergic Rhinitis and Asthma Syndrome (CARAS): Clinical significance and mechanistic insights into airway inflammation.

Abnormal expression of non-coding microRNA is associated with the development of combined allergic rhinitis and asthma syndrome (CARAS). However, the function of miR-4454 in CARAS is unknown. Our study aimed to reveal the clinical significance and related mechanism of miR-4454 in CARAS. Blood samples from 38 cases of CARAS and 43 cases of healthy subjects were collected to detect the expression of miR-4454. House dust mite (HDM) sensitization and challenge-induced bronchial epithelial cells to simulate the asthma state model in vitro, miR-4454 mimics and inhibitor transfection to detect the expression level of pro-inflammatory cytokines, cell survival rate and migration ability, flow cytometry and western blot (WB) Detection of cell cycle, apoptosis and inflammation-related protein levels. Compared with healthy controls, the expression of miR-4454 in the blood of CARAS patients was significantly up-regulated, and IL-6 and IL-8 were significantly up-regulated in the HDM treatment group, indicating that the model induction was successful. After overexpression of miR-4454, cell proliferation and migration in the HDM-treated group were significantly inhibited, and the levels of early apoptosis and inflammation-related proteins (IL-17, IL-17RD, TNF-α, GCSF and NF-κB) were increased High; after inhibiting miR-4454, cell proliferation and migration were significantly enhanced, and the levels of apoptosis and inflammation-related proteins were decreased. This study found that inhibiting the expression of miR-4454 can improve HDM-induced cell injury, which may be related to miR-4454 regulating the activation of IL-17/NF-кB inflammatory axis.

Bioinformatics-based discovery of biomarkers and immunoinflammatory targets in children with cerebral palsy: An observational study.

Cerebral palsy (CP) is the most common disabling disease in children, and motor dysfunction is the core symptom of CP. Although relevant risk factors have been found to be closely associated with CP: congenital malformations, multiple gestation, prematurity, intrauterine inflammation and infection, birth asphyxia, thrombophilia, and perinatal stroke. Its important pathophysiological mechanism is amniotic fluid infection and intraamniotic inflammation leading to fetal developing brain damage, which may last for many years. However, the molecular mechanism of CP is still not well explained. This study aimed to use bioinformatics to identify key biomarker-related signaling pathways in CP. The expression profile of children with CP was selected from the Gene Expression Comprehensive Database, and the CP disease gene data set was obtained from GeneCards. A protein-protein interaction network was established and functional enrichment analysis was performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. A total of 144 differential key intersection genes and 10 hub genes were identified through molecular biology. Gene Ontology functional enrichment analysis results show that differentially expressed genes are mainly concentrated in biological processes, such as immune response and neurogenesis. The cellular components involved mainly include axons, postsynaptic membranes, etc, and their molecular functions mainly involve proteoglycan binding, collagen binding, etc. Kyoto Encyclopedia of Genes and Genomes analysis shows that the intersection genes are mainly in signaling pathways related to the immune system, inflammatory response, and nervous system, such as Th17 cell differentiation, Toll-like receptor signaling pathway, tumor necrosis factor signaling pathway, NF-κB signaling pathway, axon guidance, PI3K-Akt signaling pathway, HIF-1 signaling pathway, gap junction, etc. Jak-STAT signaling pathway, mTOR signaling pathway, and related hub genes regulate immune cells and inflammatory factors and play an important role in the development and progression of CP.

[Identification of Osteoarthritis Inflamm-Aging Biomarkers by Integrating Bioinformatic Analysis and Machine Learning Strategies and the Clinical Validation]. / ç”Ÿç‰©ä¿¡æ¯å­¦å’Œæœºå™¨å­¦ä¹ ç­–ç•¥è¯†åˆ«éª¨å ³èŠ‚ç‚Žç‚Žæ€§è¡°è€ç”Ÿç‰©æ ‡å¿—ç‰©ä¸Žä¸´åºŠéªŒè¯.

Objective: To identify inflamm-aging related biomarkers in osteoarthritis (OA). Methods: Microarray gene profiles of young and aging OA patients were obtained from the Gene Expression Omnibus (GEO) database and aging-related genes (ARGs) were obtained from the Human Aging Genome Resource (HAGR) database. The differentially expressed genes of young OA and older OA patients were screened and then intersected with ARGs to obtain the aging-related genes of OA. Enrichment analysis was performed to reveal the potential mechanisms of aging-related markers in OA. Three machine learning methods were used to identify core senescence markers of OA and the receiver operating characteristic (ROC) curve was used to assess their diagnostic performance. Peripheral blood mononuclear cells were collected from clinical OA patients to verify the expression of senescence-associated secretory phenotype (SASP) factors and senescence markers. Results: A total of 45 senescence-related markers were obtained, which were mainly involved in the regulation of cellular senescence, the cell cycle, inflammatory response, etc. Through the screening with the three machine learning methods, 5 core senescence biomarkers, including FOXO3, MCL1, SIRT3, STAG1, and S100A13, were obtained. A total of 20 cases of normal controls and 40 cases of OA patients, including 20 cases in the young patient group and 20 in the elderly patient group, were enrolled. Compared with those of the young patient group, C-reactive protein (CRP), interleukin (IL)-6, and IL-1ß levels increased and IL-4 levels decreased in the elderly OA patient group (P<0.01); FOXO3, MCL1, and SIRT3 mRNA expression decreased and STAG1 and S100A13 mRNA expression increased (P<0.01). Pearson correlation analysis demonstrated that the selected markers were associated with some indicators, including erythrocyte sedimentation rate (ESR), IL-1ß, IL-4, CRP, and IL-6. The area under the ROC curve of the 5 core aging genes was always greater than 0.8 and the C-index of the calibration curve in the nomogram prediction model was 0.755, which suggested the good calibration ability of the model. Conclusion: FOXO3, MCL1, SIRT3, STAG1, and S100A13 may serve as novel diagnostic biomolecular markers and potential therapeutic targets for OA inflamm-aging.

A 15-Inflammation-Related Gene Signature Predicts the Prognosis of Patients With Pancreatic Ductal Adenocarcinoma.

Chronic inflammation promotes the development of pancreatic ductal adenocarcinoma (PDAC) and PDAC-related inflammatory tumor microenvironment facilitates tumor growth and metastasis. Thus, we aimed to study the association between inflammatory response and prognosis in patients with PDAC. We conducted the whole transcriptomic sequencing using tissue samples collected from patients diagnosed with PDAC (n = 106) recruited from Shandong Cancer Hospital. We first constructed a prognostic signature using 15 inflammation-related genes in The Cancer Genome Atlas (TCGA) cohort (n = 177) and further validated it in an independent International Cancer Genome Consortium (ICGC) cohort (n = 90) and our in-house cohort. PDAC patients with a higher risk score had poorer overall survival (OS) (P < 0.001; HR, 3.02; 95% CI, 1.94-4.70). The association between the prognostic signature and OS remained significant in the multivariable Cox regression adjusting for age, sex, alcohol exposure, diabetes, and stage (P < 0.001; HR, 2.91; 95% CI, 1.73-4.89). This gene signature also robustly predicted prognosis in the ICGC cohort (P = 0.01; HR, 1.94; 95% CI, 1.14-3.30) and our cohort (P < 0.001; HR, 2.40; 95% CI, 1.45-3.97). Immune subtype C3 (inflammatory) was enriched and CD8+ T cells were higher in patients with a lower risk score (P < 0.05). Furthermore, PDAC patients with higher risk scores were more sensitive to chemotherapy, immunotherapy, and PARP inhibitors (P < 0.05). In sum, we identified a novel gene signature that was associated with inflammatory response for risk stratification, prognosis prediction, and therapy guidance in PDAC patients. Future studies are warranted to validate the clinical utility of the signature.

LRRK2 G2019S Promotes Colon Cancer Potentially via LRRK2-GSDMD Axis-Mediated Gut Inflammation.

Leucine-rich repeat kinase 2 (LRRK2) is a serine-threonine protein kinase belonging to the ROCO protein family. Within the kinase domain of LRRK2, a point mutation known as LRRK2 G2019S has emerged as the most prevalent variant associated with Parkinson's disease. Recent clinical studies have indicated that G2019S carriers have an elevated risk of cancers, including colon cancer. Despite this observation, the underlying mechanisms linking LRRK2 G2019S to colon cancer remain elusive. In this study, employing a colitis-associated cancer (CAC) model and LRRK2 G2019S knock-in (KI) mouse model, we demonstrate that LRRK2 G2019S promotes the pathogenesis of colon cancer, characterized by increased tumor number and size in KI mice. Furthermore, LRRK2 G2019S enhances intestinal epithelial cell proliferation and inflammation within the tumor microenvironment. Mechanistically, KI mice exhibit heightened susceptibility to DSS-induced colitis, with inhibition of LRRK2 kinase activity ameliorating colitis severity and CAC progression. Our investigation also reveals that LRRK2 G2019S promotes inflammasome activation and exacerbates gut epithelium necrosis in the colitis model. Notably, GSDMD inhibitors attenuate colitis in LRRK2 G2019S KI mice. Taken together, our findings offer experimental evidence indicating that the gain-of-kinase activity in LRRK2 promotes colorectal tumorigenesis, suggesting LRRK2 as a potential therapeutic target in colon cancer patients exhibiting hyper LRRK2 kinase activity.

Targeting epigenetic and post-translational modifications regulating pyroptosis for the treatment of inflammatory diseases.

Inflammatory diseases, including infectious diseases, diabetes-related diseases, arthritis-related diseases, neurological diseases, digestive diseases, and tumor, continue to threaten human health and impose a significant financial burden despite advancements in clinical treatment. Pyroptosis, a pro-inflammatory programmed cell death pathway, plays an important role in the regulation of inflammation. Moderate pyroptosis contributes to the activation of native immunity, whereas excessive pyroptosis is associated with the occurrence and progression of inflammation. Pyroptosis is complicated and tightly controlled by various factors. Accumulating evidence has confirmed that epigenetic modifications and post-translational modifications (PTMs) play vital roles in the regulation of pyroptosis. Epigenetic modifications, which include DNA methylation and histone modifications (such as methylation and acetylation), and post-translational modifications (such as ubiquitination, phosphorylation, and acetylation) precisely manipulate gene expression and protein functions at the transcriptional and post-translational levels, respectively. In this review, we summarize the major pathways of pyroptosis and focus on the regulatory roles and mechanisms of epigenetic and post-translational modifications of pyroptotic components. We also illustrate these within pyroptosis-associated inflammatory diseases. In addition, we discuss the effects of novel therapeutic strategies targeting epigenetic and post-translational modifications on pyroptosis, and provide prospective insight into the regulation of pyroptosis for the treatment of inflammatory diseases.