CXC Ligand Research Articles

Enhanced Expression of TRIM46 in Ovarian Cancer Cells Induced by Tumor-Associated Macrophages Promotes Invasion via the Wnt/β-Catenin Pathway

Metastasis presents significant challenges in ovarian cancer treatment. Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) facilitate metastasis through epithelial-mesenchymal transition, yet the molecular underlying mechanisms are not fully understood. Here, we identified that tripartite motif-containing 46 (TRIM46) is significantly upregulated in ovarian cancer cells treated with a conditioned medium derived from macrophages stimulated by ovarian cancer cells (OC-MQs). Furthermore, TRIM46 was highly expressed in late-stage ovarian cancer patients and was associated with poor prognosis. Silencing of TRIM46 suppressed cancer cell invasion stimulated by OC-MQ and mesenchymal marker expression without affecting cell viability. Gene set enrichment analysis showed that the Wnt/β-catenin pathway is enriched in the high-TRIM46 expression group. Importantly, the inhibition of TRIM46-mediated β-catenin nuclear translocation and ovarian cancer cell invasion was reversed by CHIR99021, a Wnt/β-catenin activator. Additionally, C-X-C motif chemokine ligand 8 (CXCL8) was identified as being highly expressed in peritoneal MQs from the ascites of ovarian cancer patients and was positively correlated with C-X-C chemokine receptor 1/2 (CXCR1/2) expression in tumor cells. Notably, pre-treatment with reparixin, a CXCR1/2 inhibitor, blocked OC-MQ-induced TRIM46 expression and cell invasion. These results suggest that CXCL8 derived from TAMs promotes human ovarian cancer cell invasion via the Wnt/β-catenin pathway by upregulating TRIM46.

Effects of endometrial embryokines on the preimplantation bovine embryo to create a gene expression signature consistent with a high competence phenotype†.

Optimal embryonic development depends upon cell-signaling molecules released by the maternal reproductive tract called embryokines. Identity of specific embryokines that enhance competence of the embryo for sustained survival is largely lacking. The current objective was to evaluate effects of three putative embryokines in cattle on embryonic development to the blastocyst stage. The molecules tested were vascular endothelial growth factor A (VEGFA), C-X-C motif chemokine ligand 12 (CXCL12), and interleukin-6 (IL6). Molecules were added from day 4 to 7.5 of culture at 50ng/mL (VEGFA and CXCL12) or 100ng/mL (IL6). Endpoints were development to the blastocyst stage, and transcript abundance for 94 specific genes involved in lineage commitment, epigenetic regulation, and other functions. Among the genes examined were eight whose transcript abundance have been related to embryo competence for survival after embryo transfer. None of the molecules increased the proportion of putative zygotes or cleaved embryos becoming blastocyst at day 7.5 of development. An embryo competence index based on a Bayesian multiple regression formula to weigh transcript abundance of the eight biomarker genes was not affected by treatment with VEGFA but was increased by both CXCL12 and IL6. Transcript abundance of five genes were modified by VEGFA, 19 by CXCL12 and 19 by IL6. A total of 11 genes were modified in a similar manner by CXCL12 and IL6. Most differentially-expressed genes for CXCL12 and IL6 were downregulated, suggesting that the embryokines may promote a less energetically-demanding metabolic state than would be the case in their absence.

Angiotensin 1-7 Attenuates the Development of Ischemia-Reperfusion-Induced Arrhythmia in Rats: Electrophysiology, Molecular, and Immunohistochemical Study.

Arrhythmia is a common and serious global health problem, contributing to cardiovascular morbidity and mortality. The cardiac muscle is susceptible to ischemia-reperfusion (I/R) injury, which can lead to fatal arrhythmias during open-heart surgery. We investigated the potential prophylactic effect of angiotensin 1-7 (Ang 1-7) using an invivo rat model of I/R injury and examined the underlying mechanisms. Rats were treated with Ang 1-7 (1 mg/kg, IP) 30 min before the surgical procedures. Twenty-four rats were equally divided into four groups: sham control, sham-treated with Ang 1-7, I/R injury group, and I/R injury group treated with Ang 1-7. Invivo I/R injury was induced by clamping the left coronary artery for 30 min, followed by 1 hour of reperfusion. The I/R group showed abnormal electrophysiological changes and arrhythmic episodes during electrocardiography (ECG) recording, increased oxidative stress, downregulation of peroxisome proliferator-activated receptor gamma (PPAR-γ), and upregulation of C-X-C motif chemokine ligand 16 (CXCL16) expression in cardiac tissue, which increased cardiac NF-kB expression and IL-17 levels. Moreover, I/R injury caused significant histological disruption and increased cyclooxygenase 2 (COX-2) and heat shock protein 90 (HSP90) immunoreactions, correlating with the extent of cardiac damage. However, preoperative Ang 1-7 administration significantly improved the electrophysiological, biochemical, and histopathological changes induced by I/R injury. This study demonstrated that Ang 1-7 exerted protective anti-arrhythmic, anti-inflammatory, and pro-healing effects by upregulating PPAR-γ and downregulating CXCL16, IL-17, and NF-kB pathways, suggesting it is a promising cardioprotective agent for preventing arrhythmias induced by I/R injury.

Role of CXCL10 released from osteocytes in response to TNF-α stimulation on osteoclasts

Tumor necrosis factor-alpha (TNF-α) is a significant cytokine that regulates bone resorption under inflammatory conditions. However, its mechanism of action in osteocytes remains unclear. In this study, highly purified osteocytes were isolated from dentin matrix protein 1 (DMP1)-Topaz mice using cell sorter. RNA sequencing (RNA-seq) revealed that TNF-α stimulation increased C-X-C motif chemokine ligand 10 (CXCL10) gene expression in osteocytes. Although CXCL10 did not affect osteoclast differentiation in vitro, it enhanced the migration of osteoclast precursors. Additionally, in the transwell co-culture system, TNF-α induced the migration of osteoclast precursors. However, this effect was attenuated by a CXCL10-neutralizing antibody. In vivo, mice were administered supracalvarial injections of TNF-α with or without the CXCL10-neutralizing antibody for 5 days. The percentage of CXCL10-positive osteocytes increased after TNF-α administration. Additionally, osteoclast formation and bone resorption were assessed. CXCL10-neutralizing antibody-treated calvariae exhibited a significantly lower number of osteoclasts and bone resorption than those treated with TNF-α alone. These results indicated that TNF-α-induced CXCL10, which affects the migration of osteocyte-derived osteoclast precursors, may enhance TNF-α-triggered osteoclast formation and bone resorption in vivo.

The role of inflammatory factors in mediating the causal effects of type 1 diabetes mellitus on idiopathic pulmonary fibrosis: A two-step Mendelian randomization study.

While recent studies suggested a potential causal link between type 1 diabetes mellitus (T1DM) but not type 2 diabetes mellitus (T2DM) and idiopathic pulmonary fibrosis (IPF), the involved mechanism remains unclear. Here, using a Mendelian randomization (MR) approach, we verified the causal relationship between the two types of diabetes mellitus and IPF and investigated the possible role of inflammation in the association between diabetes mellitus and IPF. Based on genome-wide association study (GWAS) summary data of T1DM, T2DM, and IPF, the univariable MR, multivariable MR (MVMR), and mediation MR were successively used to analyze the causal relationship. Inverse variance weighted was used as the main method to infer the causal effect, together with a series of sensitivity analyses. The univariable MR showed that only T1DM increased the risk of IPF, and there was no significant causal relationship between T2DM and IPF. The MVMR further verified that there was an independent direct causal effect of T1DM on IPF. Further mediation analysis showed that this effect was partly mediated by increasing C-X-C motif chemokine ligand 10 (CXCL10) and interleukin-12 subunit beta (IL-12B). In conclusion, T1DM is related to an increased risk of IPF. Notably, the causal effect was partially mediated by CXCL10 and IL-12B. Hence, monitoring T1DM patients may help in the early detection and prevention of IPF.

P0252 Mild Crohn’s disease is associated with altered sphingolipid metabolism and reduced neutrophilic inflammation

Abstract Background Around 20-30% of patients with Crohn's disease (CD) experience a mild disease course. However, identifying patients likely to maintain a mild course is challenging. This study aimed to identify molecular features of mild CD by exploring biological datasets from two large patient cohorts. Methods Patients with mild CD were analysed from two longitudinal cohorts: the Mount Sinai Crohn's and Colitis Registry (MSSCR) observational cohort and the Ocean State Crohn’s and Colitis Registry (OSCCAR) inception cohort. Baseline assessments in both cohorts included biological/immunomodulator use, history of IBD-related surgeries, and complications (stricturing, penetrating, and perianal CD). Mild CD was defined by the absence of these variables at baseline and after five years of follow-up (Fig. 1A). The remaining patients were mild at baseline but progressed during follow-up. Patients with mild CD and those who progressed after being mild at baseline were evaluated for potential molecular biomarkers including circulating metabolites (metabolomics), immune cell profiles (multiparametric flow cytometry), serum proteomics, and intestinal transcriptomics. Results In total, 100 (MSSCR) and 152 (OSCCAR) patients were characterized, with 55 (55.0%) and 74 (48.7%) classified as mild CD, respectively. Intestinal transcriptomic analysis revealed downregulation of genes associated with neutrophilic inflammation and innate immunity, including SAA, DUOXA2, FCGR3B, LCN2, S100A8, and AQP9 (Fig. 1B). Flow cytometry showed lower frequencies of neutrophils (CD16+), lower neutrophil-to-lymphocyte ratios (NLR), and higher counts of NK and total B cells in mild CD (Fig. 1C). Metabolomic analysis identified ceramide- and sphingomyelin compounds (particularly acyl-CoA chain lengths C14-16 and C22-26) as positively associated with mild CD (odds ratios [OR] >2.0), whereas primary and secondary bile acids and amino acid derivatives from lysine, tyrosine, and proline metabolism were inversely associated (Fig. 1D). Proteomic analysis in OSCCAR demonstrated associations between C-X-C motif chemokine ligand 9 (CXCL9), macrophage colony stimulating factor (CSF-1), and TGF-β1 latency-associated peptide (LAP-TGF-β), and an inverse association for Delta and Notch-like epidermal growth factor-related receptor (DNER) with mild CD (adjusted P<0.05) (Fig. 1E). Conclusion This study provides multi-omics-based biomarker signatures of mild CD, which primarily relate to altered ceramide- and sphingomyelin metabolites and lower systemic neutrophilic inflammation. Future studies focusing on the biological significance and potential clinical impact on disease monitoring and therapeutic strategies are warranted.

Prognostic values of intracellular cell-related genes in esophageal cancer and their regulatory mechanisms

Esophageal cancer is a grave malignant condition. While radiotherapy, often in conjunction with chemotherapy, serves as a cornerstone in the management of locally advanced or metastatic cases, patient tolerance and treatment resistance frequently hinder its efficacy. Cell-in-cell structures, prevalent in various tumors, have been linked to prognosis. Hence, investigating the prognostic significance and regulatory mechanisms of genes related to these intracellular structures in esophageal cancer is imperative. The Cancer Genome Atlas (TCGA) Esophageal Cancer (ESCA) dataset served as the training set for the analysis. Differentially expressed genes (DEGs) in ESCA samples were identified, with those related to intercellular structures designated cell-in-cell-related differential expression genes (CIC-related DEGs). Cox regression analysis was employed to identify prognostic genes, categorizing samples into high- and low-risk groups based on median risk scores. Validation was conducted using the GSE53624 risk model. Established methodologies included morphological mapping, enrichment analysis, immune infiltration analysis, prognostic gene expression validation, molecular docking, and Reverse Transcription Polymerase Chain Reaction (RT-PCR) validation. Thirty-eight intersecting genes were identified between the disease and normal groups in ESCA samples. Stepwise multivariate Cox analysis pinpointed three prognostic genes: androgen receptor (AR), C-X-C motif chemokine ligand 8 (CXCL8), and epidermal growth factor receptor (EGFR). The risk model’s applicability was confirmed in the GSE53624 dataset, revealing eight significantly different immune-related gene sets. Prognostic gene expression validation demonstrated significant differences between the disease and normal groups in both datasets. The proteins corresponding to the three prognostic genes interacted with gefitinib and osimertinib. RT-PCR results corroborated the differential expression of prognostic genes in esophageal cancer tissues. This study identified AR, CXCL8, and EGFR as prognostic genes and demonstrated their molecular interactions with gefitinib and osimertinib, providing a foundation for ESCA diagnosis and treatment.

Identifying novel inflammatory protein biomarkers and drug targets of inflammatory bowel disease by integrating Mendelian randomization, bioinformatics, and druggability analysis.

Inflammatory proteins have the potential to be used as therapeutic targets for inflammatory bowel disease (IBD). We conducted Mendelian randomization (MR) analysis to probe causal associations between 91 circulating inflammatory proteins and IBD in the discovery and replication cohorts. Subsequently, we conducted meta-analysis of results from two cohorts. We further conducted protein-protein interaction (PPI), enrichment analysis, and druggability evaluation to elucidate our results and prioritize potential therapeutic targets. By integrating data from two cohorts, we demonstrated that genetically predicted CD40 (odds ratio [OR] = 0.878, 95% confidence interval [CI] = 0.838-0.919) and C-X-C motif chemokine ligand (CXCL)5 (OR = 0.884, 95%CI = 0.841-0.930) decreased IBD risk. However, genetically predicted CXCL9 (OR = 1.184, 95%CI = 1.084-1.294), Interleukin (IL)-18 (OR = 1.140, 95%CI = 1.076-1.208), CD6 (OR = 1.096, 95%CI = 1.045-1.150), and 4E-binding protein 1 (4E-BP1) (OR = 1.154, 95%CI = 1.070-1.244) increased IBD risk. Moreover, genetically predicted CD40 (OR = 0.855, 95%CI = 0.801-0.912) decreased Crohn's disease (CD) risk. Genetically predicted fibroblast growth factor 21 (FGF21) (OR = 1.259, 95%CI = 1.135-1.397) and 4E-BP1 (OR = 1.202, 95%CI = 1.088-1.327) increased CD risk. We found no inflammatory protein associated with ulcerative colitis. Additionally, CD was significantly associated with elevated levels of three circulating inflammatory proteins, which are suggested to be the consequences of CD. PPI analysis demonstrated interactions between CXCL5, CXCL9, IL-18, CD40, and FGF21. Enrichment analysis indicated these identified proteins significantly enriched in inflammation-related signaling pathways, including interleukin signaling, cytokine signaling, and NF-κB pathway. Three proteins (CD40, IL-18, 4E-BP1) have been targeted for drug development on cancers and immune-related diseases, with potentials of therapeutic targets for IBD. Our results provide new biomarkers and drug targets for CD. Moreover, we further demonstrate critical roles of inflammation and immunity in the occurrence and development of IBD.

Fecal microbiota transplantation combined with inulin promotes the development and function of early immune organs in chicks.

Modern management of chicks hinders the vertical transmission of intestinal microbiota, which is closely related to immunity. Inulin is a substrate that can be utilized by the microbiota. This study aimed to determine whether fecal microbiota transplantation (FMT) combined with inulin played a "1 + 1 > 2" role in enhancing the development and function of immune organs. Chicks were treated with 1 % inulin and/or fecal microbiota suspension on days 1-6. The growth performance, immune organ development, and immune indicators were evaluated on days 7, 14, and 21. Results showed that the combination of FMT and inulin significantly increased the immune organ index on day 7 and promoted the morphological structure and the expression of proliferating cell nuclear antigen (PCNA) in immune organs on days 7, 14, and 21. Each treatment increased the gene expression of interferon-gamma (IFN-γ), interleukin-4 (IL-4), interleukin-2 (IL-2), B cell-activating factor receptor (BAFFR), B cell linker (BLNK), C-X-C Motif Chemokine Ligand 12 (CXCL12), C-X-C Motif Chemokine Receptor 4 (CXCR4), and Biotin (Bu-1) to varying degrees. FMT combined with inulin significantly increased the expression of IgA-positive cells on days 7 and 14. In conclusion, the synergistic effect of FMT and inulin had beneficial impacts on the development and function of immune organs.

Analysis of changes in the chemokine CXC ligand 13 in serum and cerebrospinal fluid of patients with neuromyelitis optica

To determine correlation between the Extended Disability Status Scale(EDSS) grade and the progression of neuromyelitis optica(NMO) patients’ levels of the chemokine CXC ligand 13 (CXCL13) in their serum and cerebrospinal fluid. This research included forty-one patients diagnosed with neuromyelitis optica(NMO) and forty-three patients diagnosed with multiple sclerosis(MS). The control group consisted of forty-three non-inflammatory neurological disease(NND) patients. The patients’ serum and cerebrospinal fluid CXCL13 levels were measured. Patients in NMO group and MS group had serum and cerebrospinal fluid with CXCL13 levels that were substantially greater than those in the NND group. When comparing the CXCL13 levels of blood and cerebrospinal fluid between patients in the EDSS ≥ 3.5 group and the EDSS<3.5 group, with the EDSS ≥ 3.5 group’s CXCL13 levels being greater(P<0.05). There was a positive correlation between the serum CXCL13 and the EDSS grades of both the NMO and MS groups(r = 0.884, P < 0.001); The cerebrospinal fluid CXCL13 of the NMO and MS groups showed a positive correlation with their EDSS grades(r = 0.681, P < 0.001). EDSS scores of NMO patients were positively correlated with their serum BLC-1 (r = 0.896, P < 0.001); EDSS scores of NMO patients were positively correlated with their cerebrospinal fluid BLC-1 (r = 0.678, P < 0.001).EDSS scores of MS patients were positively correlated with their serum BLC-1 (r = 0.852, P < 0.001); EDSS scores of MS patients were positively correlated with their cerebrospinal fluid BLC-1 (r = 0.613, P < 0.001). Serum and cerebrospinal fluid levels of CXCL13 may serve as an important biomarker for the presumptive assessment of the degree of disability in NMO and MS disease, providing a basis for the treatment and control of the disease.

Cepharanthine relieves nonalcoholic steatohepatitis through inhibiting STAT1/CXCL10 axis-mediated lipogenesis and inflammatory responses.

Stephania rotunda Lour., a medicinal herb, has been utilized in both Traditional Chinese Medicine (TCM) and Traditional Indian Medicine to treat conditions such as fever, dysentery, and inflammation. Cepharanthine (CEP), a primary active ingredient of Stephania rotunda Lour., has demonstrated a range of pharmacological activities, including anti-oxidative, anti-inflammatory, anti-cancer, anti-viral and anti-parasitic properties. However, the effects and underlying mechanisms of CEP on improving nonalcoholic steatohepatitis (NASH) remain unclear. This study aimed to investigate the effects of CEP on mitigating diet-induced NASH and explore its underlying mechanisms. A High-Fat Diet (HFD) and the high levels of free fatty acids (FFA) were used to establish in vivo and in vitro NASH models to evaluate the intervention effect of CEP. Subsequently, RNA-sequencing, western blotting, quantitative real-time PCR (qRT-PCR) and siRNA transfection were employed to investigate its underlying mechanisms. Our findings indicated that CEP significantly reduced lipogenesis and inflammatory responses in both HFD-fed rats and FFA-induced hepatic cells (including HepG2, L02 and AML12 cell lines), as is evidenced by the reduction of triglyceride (TG), lipid accumulation, and the release of inflammatory cytokines such as TNF-α, IL-6 and IL-1β. Mechanistically, CEP significantly inhibits CXC motif chemokine ligand 10 (CXCL10) expression both in vivo and in vitro. It also regulates sterol regulatory element binding protein-1c (SREBP1c)-induced lipogenic gene expression and CXCL10-mediated nuclear factor kappa B (NFκB) activation. Notably, knockdown of CXCL10 mimics the ability of CEP to reduce lipid accumulation and inflammatory responses, which is also observed following the blockade of signal transducer and activator of transcription 1 (STAT1) in HepG2 cells. CEP alleviates NASH by inhibiting lipogenesis and inflammatory responses in a STAT1/CXCL10 axis-dependent manner.

Ethyl Acetate Extract of Cichorium glandulosum Activates the P21/Nrf2/HO-1 Pathway to Alleviate Oxidative Stress in a Mouse Model of Alcoholic Liver Disease.

Alcoholic liver disease (ALD) is a significant global health concern, primarily resulting from chronic alcohol consumption, with oxidative stress as a key driver. The ethyl acetate extract of Cichorium glandulosum (CGE) exhibits antioxidant and hepatoprotective properties, but its detailed mechanism of action against ALD remains unclear. This study investigates the effects and mechanisms of CGE in alleviating alcohol-induced oxidative stress and liver injury. Ultra-Performance Liquid Chromatography coupled with Quadrupole-Orbitrap Mass Spectrometry (UPLC-Q-Orbitrap-MS) was used to identify CGE components. A C57BL/6J mouse model of ALD was established via daily oral ethanol (56%) for six weeks, with CGE treatment at low (100 mg/kg) and high doses (200 mg/kg). Silibinin (100 mg/kg) served as a positive control. Liver function markers, oxidative stress indicators, and inflammatory markers were assessed. Transcriptomic and network pharmacology analyses identified key genes and pathways, validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting. UPLC-Q-Orbitrap-MS identified 81 CGE compounds, mainly including terpenoids, flavonoids, and phenylpropanoids. CGE significantly ameliorated liver injury by reducing alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) levels and enhancing antioxidative markers such as total antioxidant capacity (T-AOC) and total superoxide dismutase (T-SOD) while lowering hepatic malondialdehyde (MDA) levels. Inflammation was mitigated through reduced levels of Tumor Necrosis Factor Alpha (TNF-α), Interleukin-1 Beta (IL-1β), and C-X-C Motif Chemokine Ligand 10 (CXCL-10). Transcriptomic and network pharmacology analysis revealed seven key antioxidant-related genes, including HMOX1, RSAD2, BCL6, CDKN1A, THBD, SLC2A4, and TGFβ3, validated by RT-qPCR. CGE activated the P21/Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1) signaling axis, increasing P21, Nrf2, and HO-1 protein levels while suppressing Kelch-like ECH-associated Protein 1 (Keap1) expression. CGE mitigates oxidative stress and liver injury by activating the P21/Nrf2/HO-1 pathway and regulating antioxidant genes. Its hepatoprotective effects and multi-target mechanisms highlight CGE's potential as a promising therapeutic candidate for ALD treatment.

Protocatechuic aldehyde ameliorates psoriasis-like skin inflammation and represses keratinocyte-derived IL-1α and CXCL9 via inhibiting STAT3 activation.

Psoriasis is a chronic inflammatory skin disease. Consistent activation of Signal Transducer and Activator of Transcription 3 (STAT3) in epidermal keratinocyte transactivates various keratinocyte-derived pro-inflammatory cytokines and elicits spontaneous psoriasis-like skin inflammation. In the current study, we first report that topical application of protocatechuic aldehyde (PA), the bioactive compound from Salvia miltiorrhiza (Danshen), significantly improved psoriasis-like skin symptoms and reduced immune cell infiltration in psoriatic lesions. Further molecular mechanism studies demonstrated that PA inactivated STAT3 and inhibited STAT3-mediated transactivation of interleukin-1α (IL-1α) and C-X-C motif chemokine ligand 9 (CXCL9) in epidermal keratinocyte both in vivo and in vitro. Knockdown of STAT3 attenuated the repression effect on IL-1α and CXCL9 by PA. Our results suggested that PA repressed the transactivation of IL-1α and CXCL9 through inhibiting STAT3 in keratinocyte. PA could be potentially used for psoriasis topical treatment or be as a lead compound for drug development.

Integrated Analysis and Validation of Ferroptosis-Related Genes Associated with Ischemia/Reperfusion Injury in Lung Transplantation.

Lung transplantation is the only effective therapeutic option for patients with end-stage lung disease. However, ischemia/reperfusion injury (IRI) during transplantation is a leading cause of primary graft dysfunction (PGD). Ferroptosis, a form of iron-dependent cell death driven by lipid peroxidation, has been implicated in IRI across various organs. This study aims to explore the role of ferroptosis in lung transplantation-related ischemia/reperfusion injury and to identify its potential molecular mechanisms through bioinformatics analysis. Transcriptome data from lung transplant patients were obtained from the Gene Expression Omnibus (GEO) database. Ferroptosis-related differentially expressed genes (FRGs) were identified by analyzing gene expression profiles before and after reperfusion. Weighted gene co-expression network analysis (WGCNA) was used to identify module genes, and overlapping genes were further analyzed using two machine learning algorithms. The CIBERSORT algorithm was applied to assess immune cell infiltration, while Mendelian randomization (MR) analysis was used to investigate causal relationships between candidate genes and PGD. Finally, Consensus clustering based on FRGs was performed to identify subtypes. We identified four candidate genes associated with ferroptosis during lung reperfusion: tumor necrosis factor alpha-induced protein 3 (TNFAIP3), C-X-C motif chemokine ligand 2 (CXCL2), neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L), and sestrin 2 (SESN2). These genes were closely associated with immune cell infiltration. MR analysis suggested that SESN2 might play a protective role against PGD. Additionally, consensus clustering revealed distinct immune infiltration patterns across subtypes, providing insights for personalized therapeutic approaches to lung ischemia/reperfusion injury (LIRI). This study highlights TNFAIP3, CXCL2, NEDD4L, and SESN2 as candidate genes associated with ferroptosis during LIRI, with SESN2 potentially protecting against PGD. These findings offer promising therapeutic targets for preventing LIRI and improving outcomes in lung transplantation.

Regulation of macrophage polarization by metformin through inhibition of TLR4/NF-κB pathway to improve pre-eclampsia.

Pre-eclampsia (PE) is a pregnancy complication featuring hypertension and proteinuria. Metformin exerts clinically preventive effects on PE with an unspecified mechanism. Placental tissues from PE patients and normal pregnant (NP) women were collected. Twenty-four pregnant mice were divided into control, PE (40μg/kg lipopolysaccharides (LPS)-induced modeling), aspirin, and metformin groups. After acquisition of bone marrow-derived macrophages (BMDM) and THP-1cells, cells were categorized into control, LPS (100ng/mL), metformin, and metformin+toll-like receptor 4 (TLR4) agonist RS 09 groups. Inflammatory factors and macrophage polarization were detected by ELISA, flow cytometry, immunofluorescence, immunohistochemistry, and qRT-PCR methods. TLR4/Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway protein expression was examined using Western blot. Both PE patients and PE-like mice enhanced inducible nitric oxide synthase (iNOS), TLR4, p-NF-κB/NF-κB, and p-inhibitor of NF-κB (IκBα)/IκBα expression, and lower arginase 1 (Arg-1) expression. Moreover, metformin treatment in PE-like mice increased fetal number and weight and reduced hypertension, proteinuria, insulin resistance, tumor necrosis factor-α (TNF-α), IL-6, IL-1β, chemokine ligand 4 (CCL4), C-X-C motif chemokine ligand 2 (CXCL2) expression and M1 macrophage polarization, with similar inhibition to aspirin. In LPS-induced cells, metformin had the same effects mentioned above. Decreased TLR4, p-NF-κB/NF-κB, and p-IκBα/IκBα protein expression was caused by metformin both in vivo and in vitro. In vitro, RS 09 intervention inhibited anti-inflammatory and pro-M2 polarizing effects of metformin, activating TLR4/NF-κB pathway. Metformin may ameliorate PE by promoting M2 macrophage polarization through up-regulating TLR4/NF-κB pathway, laying theoretical basis for metformin clinical application in PE.

SLC25A21 correlates with the prognosis of adult acute myeloid leukemia through inhibiting the growth of leukemia cells via downregulating CXCL8

In recent years, targeting mitochondrial apoptosis has emerged as a promising therapeutic strategy for Acute Myeloid Leukemia (AML). The SLC25 family of mitochondrial carriers plays a critical role in maintaining mitochondrial function and regulating apoptosis. However, the role of SLC25A21, an oxodicarboxylate carrier, in AML progression and its potential as a prognostic biomarker remain underexplored. This study aimed to further investigate the role, molecular mechanism, and potential clinical value of SLC25A21 in AML progression. The transcript levels of SLC25A21 in bone marrow specimens were analyzed using real-time quantitative polymerase chain reaction. The correlation between SLC25A21 expression and the prognosis of AML was assessed through survival analysis. Findings revealed that SLC25A21 was downregulated in adult AML, and the low expression of SLC25A21 was correlated with worse prognosis for AML patients. Furthermore, overexpression of SLC25A21 inhibited cell proliferation and cell cycle progression, and was correlated with apoptosis through mitochondrial apoptosis signaling pathway. C-X-C motif chemokine ligand 8 (CXCL8) was identified as a downstream target of SLC25A21. These functions of SLC25A21 could be rescued by the overexpression of CXCL8. Moreover, SLC25A21 overexpression significantly suppressed the growth of xenograft tumors. In conclusion, the low SLC25A21 expression is correlated with poor clinical outcome. The overexpression of SLC25A21 inhibited the AML cell survival and proliferation by dysregulating the expression of CXCL8. SLC25A21 might be a potential prognostic marker and a treatment target for AML.

Umbilical cord-derived mesenchymal stem cells preferentially modulate macrophages to alleviate pulmonary fibrosis

BackgroundIdiopathic Pulmonary Fibrosis (IPF) is a type of interstitial lung disease characterized by chronic inflammation due to persistent lung damage. Mesenchymal stem cells (MSCs), including those derived from the umbilical cord (UCMSCs) and placenta (PLMSCs), have been utilized in clinical trials for IPF treatment. However, the varying therapeutic effectiveness between these two MSC types remains unclear.MethodsIn this study, we examined the therapeutic differences between UCMSCs and PLMSCs in treating lung damage using a bleomycin (BLM)-induced pulmonary injury mouse model.ResultsWe showed that UCMSCs had a superior therapeutic impact on lung damage compared to PLMSCs. Upon cytokine stimulation, UCMSCs expressed higher levels of inflammation-related genes and more effectively directed macrophage polarization towards the M2 phenotype than PLMSCs, both in vitro and in vivo. Furthermore, UCMSCs showed a preference for expressing CC motif ligation 2 (CCL2) and C-X-C motif chemokine ligand 1 (CXCL1) compared to PLMSCs. The expression of secreted phosphoprotein 1 (SPP1), triggering receptor expressed on myeloid cells 2 (Trem2), and CCAAT enhancer binding protein beta (Cebpb) in macrophages from mice with the disease treated with UCMSCs was significantly reduced compared to those treated with PLMSCs. Conclusions: Therefore, UCMSCs demonstrated superior anti-fibrotic abilities in treating lung damage, potentially through inducing a more robust M2 polarization of macrophages than PLMSCs.

Inflammatory mediator contributes to leptin resistance and obesity in craniopharyngioma.

Obesity presents a significant challenge in managing patients with craniopharyngioma (CP). Cyst fluid (CF), rich in inflammatory mediators, is implicated in CP-related obesity, though the precise mechanism remains unclear. This study investigated the impact of CF or C-X-C motif chemokine ligand-1 (CXCL1) injections on body weight, Lee index, plasma lipid profiles, hepatic lipid accumulation, leptin levels, NF-κB pathway, the suppressor of cytokine signaling 3 (SOCS3) expression, and leptin sensitivity in rats. Bioinformatics was employed to identify differentially expressed genes (DEGs) between CF/CXCL1-treated and control SY5Y cells, as well as to confirm enriched pathways. Western blotting was used for experimental validation, including the effects of sodium salicylate (SS) on leptin sensitivity in SY5Y cells. Injecting CF or CXCL1 into the brain, without hypothalamic damage, led to increased body weight, Lee index, and hepatic lipid accumulation in rats, alongside elevated fasting blood glucose, triglycerides, and total cholesterol, while high-density lipoprotein cholesterol levels decreased. Additionally, CF and CXCL1 could induce elevated leptin levels, a higher leptin-to-body weight ratio, and resistance to exogenous leptin by activating the NF-κB pathway and upregulating the expression of SOCS3 in rats. Further validation confirmed that CF and CXCL1 suppress leptin signaling by activating the NF-κB pathway and upregulating SOCS3. Moreover, SS mitigated the inhibitory effects of CF or CXCL1 on leptin signaling, preserving leptin sensitivity in SY5Y cells. These results highlight the obesogenic role of CF and CXCL1, offering insights into the development of morbid obesity through inflammatory factor-mediated leptin resistance, independent of hypothalamic damage. SS may serve as a promising therapeutic approach for CP-associated obesity, though additional clinical studies are necessary to confirm its efficacy.

The C-X-C Motif Chemokine Ligand 5, Which Exerts an Antioxidant Role by Inducing HO-1 Expression, Is C-X-C Motif Chemokine Receptor 2-Dependent in Human Prostate Stroma and Cancer Cells.

While the C-X-C motif chemokine ligand 5 (CXCL5) is recognized as an inflammatory mediator and a potent attractant for immune cells, its functions within the human prostate remain unclear. This study explored the expression, functions, and regulatory mechanisms of CXCL5 in prostate stroma and cancer cells. CXCL5 secreted from prostate cancer cells enhanced neutrophil migration. CXCL5 induced cell proliferation and invasion of prostate cancer cells in vitro and tumorigenesis in a xenograft animal model. C-X-C motif chemokine receptor 2 (CXCR2) has been identified on the surface of prostate fibroblasts and cancer cells. The supernatant of LNCaP cells or CXCL5 overexpression enhanced the migration and contraction of prostate myofibroblast WPMY-1 cells; however, pretreatment with SB225002, a CXCR2 inhibitor, can reverse these effects. CXCL5 evinces antioxidant properties by upregulating heme oxygenase-1 (HO-1) to counteract H2O2-induced reactive oxygen species (ROS) in a CXCR2-dependent manner in WPMY-1 and prostate cancer cells. Our findings illustrate that CXCL5, through HO-1, plays a role in antioxidation, and determine that the CXCL5/CXCR2/HO-1 pathway facilitates antioxidative communication between fibroblasts and cancer cells in the prostate. Therefore, targeting the CXCL5/CXCR2 signaling pathway could provide a new strategy for managing oxidative stress within the prostate.

Construction of a prognostic survival model with tumor immune-related genes for breast cancer.

Numerous studies have demonstrated that immune cell infiltration is a significant predictor in the prognosis of those with breast cancer. This study aimed to develop a prognostic model for undifferentiated breast cancer using immune-related markers. Differentially expressed genes (DEGs) and prognostic factors were identified from The Cancer Genome Atlas (TCGA) database. Cancer immune-associated genes were filtered using the GeneCards database. Least absolute shrinkage and selection operator (LASSO) and Cox proportional hazards regression were employed to select prognostic indicators. The single-sample gene set enrichment analysis (ssGSEA) algorithm and the CIBERSORT algorithm were used to analyze the correlation of prognostic indicators with immune cells in breast cancer. We identified six tumor immune-related genes, including zic family member 2 (ZIC2), solute carrier family 7 member 5 (SLC7A5), forkhead box J1 (FOXJ1), C-X-C motif chemokine ligand 9 (CXCL9), tumor necrosis factor receptor superfamily member 18 (TNFRSF18), and serine protease 2 (PRSS2), for the development of a prognostic model for patients with breast cancer. Notably, the results of the correlation analysis indicated that CXCL9 was associated with antitumor immune cells, including CD8+ T cells, cytotoxic cells, M1 macrophages, and activated memory CD4 T cells, and with the enrichment of natural killer (NK) CD56dim cells. Furthermore, CXCL9 exhibited a significant negative association with the tumor-promoting M2 macrophage phenotype. Our study established a six-gene model for predicting breast cancer prognosis. Furthermore, we unexpectedly discovered that CXCL9 is integral to immune infiltration in breast cancer and may serve as a critical biomarker for evaluating immune response and therapeutic efficacy in breast cancer treatment.