CXCL10 Levels Research Articles

CXCL5 inhibition ameliorates acute kidney injury and prevents the progression from acute kidney injury to chronic kidney disease.

Acute kidney injury (AKI) increases the risk of chronic kidney disease (CKD). CXCL5 is upregulated in kidney diseases. We aimed to investigate the direct effect of CXCL5 on the pathology of AKI. Serum and renal expression of CXCL5 were increased in animals with renal ischemia-reperfusion injury or unilateral ureteral obstruction. CXCL5-knockout mice exhibited reduced systemic oxidative stress and preserved renal function in the acute and chronic phases of AKI, as evidenced by reductions in serum BUN and creatinine levels, the urinary albumin-to-creatinine ratio, and the kidney-to-body weight ratio. CXCL5-knockout mice improved AKI-induced tubular injury and fibrosis, reduced renal macrophage infiltration, and reduced expression of NADPH oxidase and inflammatory and fibrotic proteins. CXCL5 activated p47 to upregulate ROS generation and induce cellular damages through CXCR2. CXCL5 knockdown exerted antioxidative, anti-inflammatory, anti-fibrotic, and anti-apoptotic effects on hypoxia-reoxygenation-stimulated renal proximal tubular epithelial cells. Clinical data indicated elevated circulating and renal CXCL5 in CKD patients, and renal CXCL5 was correlated with increased renal fibrosis and decreased estimated glomerular filtration rate. Altogether, CXCL5 levels increased in experimental AKI and clinical CKD, and in vivo and in vitro CXCL5 inhibition may reduce acute tubular injury and prevent the subsequent progression from AKI to CKD.

Causal relationship between inflammatory cytokines and polycystic ovary syndrome: a bidirectional mendelian randomization study.

Polycystic ovary syndrome (PCOS) is defined as a chronic low-grade inflammatory reproductive endocrine disorder. PCOS can induce various metabolic disorders, which are associated with a state of mild and slow-acting inflammation. Nevertheless, the causal relationship between polycystic ovary syndrome and inflammatory factors is uncertain. The causality between inflammatory cytokines and PCOS was analyzed by bidirectional Mendelian randomization (MR) in this current probe. We performed an interactive MR study to assess the causal relationships between 91 inflammatory cytokines and PCOS using Genome Wide Association Study (GWAS) data. We underwent dual-sample MR analysis with inverse variance weights (IVW) as the predominant MR methodology with multiple validity and heterogeneity analyses. MR-Egger, weighted median, simple mode, weighted mode and MR-PRESSO were analyzed as multiple likelihood sensitivity analyses to enhance the final results.The results came out interleukin-1-alpha (IL-1A) levels (odds ratio [OR] = 1.051, 95% fiducial interval [95% CI] = 1.009-1.095, P = 0.02) and oncostatin-M (OSM) levels ( [OR] = 1.041, [95% CI] = 1.001-1.082, P = 0.04) were positively associated with the development of PCOS. Moreover, interleukin-7 (IL-7) levels ([OR] = 0.935, [95% CI] = 0.884-0.989, P = 0.02); interleukin-15 receptor subunit alpha (IL15RA) levels ([OR] = 0.959, [95% CI] = 0.929-0.99, P = 0.01); and C-X-C motif chemokine 11 (CXCL11) levels ([OR] = 0.959, [95% CI] = 0.922-0.996. P = 0.03) were strongly negatively associated with PCOS. However, we did not find any strong positive results in the reverse analysis, suggesting that although inflammatory factors contribute to the pathogenesis of PCOS, PCOS itself does not trigger inflammatory factor production.Our study provides genetic evidence for the connection between systemic inflammatory regulators and PCOS. Treatments targeting specific inflammatory factors may help to mitigate the risk of PCOS. The levels of five of the 91 inflammatory factors included in this study, namely, IL1A and OSM, were associated with PCOS. IL1A and OSM contribute to the progression of PCOS while IL-7, IL15RA, and CXCL11 levels are negatively correlated with the development of PCOS.

Induced collagen type-I secretion by hepatocytes of the melanoma liver metastasis is associated with a reduction in tumour-infiltrating lymphocytes.

Overall patients with melanoma liver metastasis (MLiM) have a dismal prognosis and poor responses to the standard of care treatment. Understanding the role of the tumour microenvironment (TME) is critical for discovering better strategies to overcome intrinsic therapy resistance in MLiM. The aim was to understand the crosstalk signalling pathways between hepatocytes and metastatic melanoma cells in the TME of MLiM. Hepatocytes and melanoma tumour cells of MLiM were assessed using transcriptomic NanoString GeoMx digital spatial profiling (NGDSP) assay. Functional assays were performed using normal hepatocytes and MLiM-derived cell lines. Validation was performed using multiplex immunofluorescence. In NGDSP analysis adjacent normal hepatocytes (ANH) had higher CXCR4 and COL1A1/2 levels than distant normal hepatocytes (DNH), while melanoma cells had higher TNF-α levels. In vitro, MLiM cell lines released TNF-α which upregulated CXCR4 and CXCL12 levels in ANH. CXCL12 activated CXCR4, which triggered AKT and NFκB signalling pathways. Consequently, AKT signalling induced the upregulation of collagen type I. MLiM were significantly encircled by a shield of collagen, whereas other liver metastases showed reduced levels of collagen. Of all the liver metastasis analyzed, the presence of collagen in melanoma liver metastasis was associated with a reduction in tumour-infiltrating lymphocytes. MLiM modified ANH to increase collagen production and created a physical barrier. The collagen barrier was associated with a reduction of immune cell infiltration which could potentially deter MLiM immune surveillance and treatment responses. Spatial analyses of melanoma liver metastasis show that adjacent normal hepatocytes have increased collagen-type I levels. Melanoma liver metastases tumour cells secrete enhanced levels of TNF-α to stimulate CXCR4/CXCL12 upregulation in adjacent normal hepatocytes. Activation of CXCR4 promotes AKT and NF-κB signalling pathways to promote collagen-type I secretion in adjacent normal hepatocytes. Elevated collagen levels were associated with reduced tumour-infiltrating lymphocytes.

An inflammatory cytokine signature predicts IgA nephropathy severity and progression.

IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis, resulting in end-stage renal disease and increased mortality rates. Prognostic biomarkers reflecting molecular mechanisms for effective IgAN management are urgently needed. Analysis of kidney single-cell transcriptomic sequencing data demonstrated that IgAN expressed high-expression levels of inflammatory cytokines TNFSF10, TNFSF12, CCL2, CXCL1, and CXCL12 than healthy controls (HCs). We also measured the urine proteins in 120 IgAN (57 stable and 63 progressive) and 32 HCs using the proximity extension assay (PEA), and the multivariable and least absolute shrinkage and selection operator (LASSO) logistic regression analysis both revealed that CXCL12, MCP1 were the prognostic significant variables to predict IgAN progression severity. These two proteins exhibited negative correlation with the estimated glomerular filtration rate (eGFR) and patients with higher expression levels of these two proteins had a higher probability to have poorer renal outcome. We further developed a risk index model utilizing CXCL12, MCP1, and baseline clinical indicators, which achieved an impressive area under the curve (AUC) of 0.896 for prediction of IgAN progression severity. Our study highlights the significance of the inflammatory protein biomarkers for noninvasive prediction of IgAN severity and progression, offering valuable insights for clinical management.

Integrated respiratory toxicity of municipal wastewater to human bronchial epithelial cells and 3D bronchospheres

Respiratory symptoms have been reported in wastewater treatment workers and residents living close to sewage treatment plant. However, toxicological research about the respiratory hazards of municipal wastewater is scarce. The present study aims to gain insight into the comprehensive respiratory hazards induced by the contaminant mixtures in municipal wastewater. The integrated respiratory hazards of effluents from four secondary wastewater treatment plants (SWTPs), a tertiary wastewater treatment plant (TTP), and a constructed wetland (CW) were evaluated using normal human bronchial epithelial cells (NHBE) bioassay, and toxicity reduction efficiency of various treatment techniques was analyzed. Effluents caused cytotoxicity, oxidative damage, inflammation response with the increased levels of IL-6 and CXCL8, and impaired barrier integrity with decreased expressions of ZO-1 and occludin in NHBE. Further, the effluents inhibited the development of 3D bronchospheres, increased irregular surface and cell debris, and suppressed the formation of luminal structures. TTP E effluent significantly increased the expression of MUC5AC in bronchospheres. The integrated biomarker response (IBR) of the influent was removed by 40.2% at SWTPs, 18.2% at TTP, and 36.6% at CW, respectively. The IBR of the final effluents from SWTPs, TTP, and CW were 7.2, 7.7, and 7.7, respectively. Significant correlation with toxicity biomarkers was frequently observed for stearyl alcohol, o-cresol, phenanthrene, butylated hydroxytoluene, and dimethyl phthalate. The present study provided human relevant evidence concerning the adverse respiratory effects associated with discharge. The necessity for deep water treatment, performance optimization, and the potential means were suggested for improving water quality and protecting respiratory health.

High serum levels of CXCL13 predict lower response to csDMARDs in both ACPA-positive and ACPA-negative early rheumatoid arthritis.

Increased circulating levels of CXCL13 reflect synovial production and indicate immune dysregulation in patients with rheumatoid arthritis (RA). Here we tested whether CXCL13 predicts response to first-line treatment with methotrexate (MTX) in patients with early RA, independently and in association with anti-citrullinated protein antibodies (ACPA) and IgM-rheumatoid factor (RF). A prospective cohort of 243 early RA patients undergoing treat-to-target with MTX was evaluated. CXCL13, ACPA and IgM-RF were determined on baseline sera. Short-term variations of CXCL13 were measured after 2 months. The association of high CXCL13 (≥100 pg/ml) with disease remission after 6 months and escalation to second-line therapies within year 2 was evaluated in the total population and in ACPA-subgroups separately. High levels of CXCL13 were found in 53.6% of ACPA-positive and 31.5% of ACPA-negative patients, with minimal association with disease activity and RF. Serum CXCL13 remained stable after 2 months. High baseline CXCL13 independently predicted failure to achieve remission and more frequent requirement of second-line treatment in ACPA-positive patients, with adjusted ORs in the range of 0.17-0.49 for remission and 6.75 for second-line treatment. In ACPA-negative patients with high CXCL13, remission occurred at the expense of higher doses of MTX, and levels of CXCL13 predicted MTX escalations with an adjusted OR (95% CI) of 2.69 (1.35-5.34). High serum levels of CXCL13 identify a subgroup of RA patients who are more refractory to first-line treatment with MTX. CXCL13 appears a promising biomarker of response to MTX in both ACPA-positive and -negative early RA.

Toll-Like Receptor 2 Attenuates the Formation and Progression of Angiotensin II-Induced Abdominal Aortic Aneurysm in ApoE−/− Mice

Introduction: We demonstrated Toll-like receptor (TLR) 4 in the pathogenesis of angiotensin II (AngII)-mediated abdominal aortic aneurysm (AAA) formation. Here, we study TLR2 in the AAA formation. Methods: Male ApoE−/− and ApoE−/−TLR2−/− mice were treated with AngII. Mice were injected with the TLR2 agonist Pam3CSK4. The incidence and severity of AAA were determined. MCP-1, MCP-5, RANTES, CXCL10, CCR5, and CXCR3 were analyzed. M1 and M2 macrophages in the aorta were detected by flow cytometry. Results: These studies demonstrated an increase in AAA formation in TLR2−/− mice and a decrease by Pam3CSK4. Pam3CSK4 decreased the ratio of M1/M2 and the levels of RANTES, CXCL10, CCR5, and CXCR3. Furthermore, Pam3CSK4 treatment 1 week following AngII retarded the progression of AAA. Conclusion: These data demonstrated a protective effect of TLR2 signaling on AAA in association with a decrease in the ratio of M1 to M2 macrophages and the expression of chemokines and their receptors. Furthermore, the treatment of Pam3CSK4 after AngII demonstrated a marked retardation of lesion progression. Given the fact that most AAA patients are detected late in the disease process, these findings suggest that TLR2 stimulation may play a therapeutic role in retarding disease progression.

Metformin Exhibits Anti-Inflammatory Effects by Regulating microRNA-451/CXCL16 and B Cell Leukemia/Lymphoma 2 in Patients With Osteoarthritis.

Osteoarthritis (OA) is the most common cause of chronic disability in joints among older individuals. The primary goal of OA treatment is pain relief to improve the quality of life. Inflammation and aging are involved in the pathogenesis of pain in OA. In this study, we evaluated the ability of metformin to regulate microRNAs, such as miR-451 and miR-15b, and their target proteins, CXCL16 and B cell leukemia/lymphoma 2 (BCL-2), involved in inflammation and apoptosis. In this double-blind placebo-controlled clinical trial, patients were randomly divided into two groups: one receiving metformin and the other receiving a placebo for four months (starting at 0.5 g/day for the first week, increasing to 1 g/day for the second week, and increasing to 1.5 g/day for the remaining period). In addition to evaluating the clinical response using the Knee Injury and Osteoarthritis Outcome Score questionnaire, miR-451 and miR-15b expression levels were detected using real-time polymerase chain reaction. The serum levels of CXCL16 and BCL-2 were evaluated using enzyme-linked immunosorbent assay kits before (time zero) and after treatment (month four). Metformin increased miR-451 expression levels simultaneously with pain reduction, whereas miR-15b expression did not change significantly after four months of treatment. Also, metformin decreased the serum levels of BCL-2 and CXCL16 in patients with OA. The effects of metformin in reducing pain can be attributed to many factors, including its anti-inflammatory and antiaging effects. Our findings suggest that metformin may reduce pain and inflammation in patients with OA through the regulation of miR-451/CXCL16 and BCL-2.

Increased expression of CXCL10 and CCL3 salivary gland chemokines in primary Sjögren's syndrome detected and systematically quantified using novel RNAscope® in situ hybridisation.

Primary Sjogren's syndrome is a chronic inflammatory disease characterised by the destruction of exocrine glands. We have previously shown significantly upregulated levels of CXCL10 and CCL3 chemokines in saliva from Sjogren's syndrome patients. In this study, we examined the expression pattern and localisation of these chemokines at the site of inflammation in patients' minor salivary glands using novel RNAscope® in situ hybridisation. Minor salivary glands from 33 primary Sjogren's syndrome patients and 22 non-Sjogren's syndrome sicca controls were included. The biopsies were formalin- fixed, paraffin-embedded and histopathologically evaluated. The CXCL10 and CCL3 mRNA expression in the glandular tissue was investigated using reverse transcription quantitative real-time polymerase chain reaction followed by RNAscope® in situ hybridisation. The mRNA expression of CXCL10 was higher than CCL3 in all patients. Significantly elevated expression of CXCL10 and CCL3 was detected in patients that also expressed autoantibody positivity and a positive biopsy for mononuclear cell infiltrates when compared to controls. CXCL10 was localised as clusters within focal infiltrates as well as adjacent to acinar and ductal epithelium, while CCL3 was expressed as scattered single mRNA molecules in focal infiltrates and in acinar cells. Our findings suggest CXCL10 as a possible disease biomarker in primary Sjogren's syndrome due to its upregulated expression in both saliva and minor salivary glands of patients and the localisation in the tissue. This should be re-assessed in a larger primary Sjogren's syndrome patient cohort, followed by additional functional studies to further validate its potential as a disease biomarker.

Acute and chronic impact of interleukin-33 stimulation on chemokines and growth factors in human cord blood-derived mast cells.

Mast cells (MCs) are multifaceted immune cells that are capable of recognizing and responding to various stimuli by releasing an array of cytokines. We aimed to use human cord blood-derived mast cells (hCBMCs) as a model to evaluate different conditions under which chemokines and growth factors are expressed and secreted as mediators upon stimulation with the alarmin interleukin-33 (IL-33). hCBMCs were stimulated with 10 ng/mL or 20 ng/mL of recombinant human IL-33 (rhIL-33) for 6 h (acute) or 24 h (chronic). The mRNA expression of chemokines and growth factors was analyzed using microarrays, and the mediators released in the supernatant were evaluated using a multiplex assay. The mRNA expression levels of C-C chemokine ligands (CCL) CCL1, CCL5, granulocyte macrophage colony-stimulating factor (GM-CSF), and macrophage inflammatory protein (MIP)-4/CCL18 were upregulated under all conditions. In contrast, C-X-C motif chemokine ligand (CXCL) CXCL8 and CCL24 levels increased only under acute (6 h) and prolonged (24 h) conditions, respectively. Moreover, high levels of CXCL8, MIP-1α, and MIP-1β were secreted during acute inflammation, whereas the release of GM-CSF and CXCL9 proteins increased under all four conditions. This study highlights the sentinel role of MCs in mounting a specific immune response against a pathogenic-like stimulus in a timely and dose-dependent manner and is relevant for improving inflammatory treatment options.

TMT-based quantitative proteomics unveils the protective mechanism of Polygonatum sibiricum polysaccharides on septic acute liver injury

Polygonatum sibiricum polysaccharides (PSP) has been shown to possess multiple pharmacological functions. Our previous study found that PSP could protect against acute liver injury during sepsis via inhibiting inflammatory response. However, the underlying molecular mechanism by which PSP alleviates septic acute liver injury (SALI) remains unknown. Herein, TMT-based quantitative proteomics was utilized to explore the essential pathways and proteins involved in the protective effects of PSP on SALI. The results revealed that 632 and 176 differentially expressed proteins (DEPs) were identified in Model_vs_Control and PSP_vs_Model, respectively. GO annotation showed similar trends, suggesting that these DEPs were primarily involved in the cellular anatomical entity in Cellular Component, the cellular processe and the biological regulation in Biological Process, the binding and the catalytic activity in Molecular Function. Meanwhile, KEGG enrichment analysis implied that four common pathways, including the NF-κB signaling pathway, the IL-17 signaling pathway, the TNF signaling pathway and the Toll-like receptor signaling pathway, were closely associated with the pathogenesis of sepsis among the top 20 remarkably enriched pathways in Model_vs_Control_up and PSP_vs_Model_down. Moreover, the levels of several common DEPs, including TLR2, IKKi, JunB and CXCL9, were validated by WB, which was in line with the results of proteomics. Therefore, the protective effects of PSP on SALI might exert via blocking the above-mentioned inflammation pathways.Significance: PSP, recognized as a key component of Polygonatum sibiricum, exhibits a range of pharmacological functions. Our previous study found that PSP could protect against SALI, yet failing to clarify the mechanism of action. To reveal the underlying molecular mechanism involved in the protective effects of PSP on SALI, a TMT-based quantitative proteomic analysis was performed to detect and analyse the DEPs in liver tissue among the control group, the model group and the PSP group in this study. The results provide theoretical references for exploring the action mechanism of drugs and facilitate the comprehensive utilization of PSP. SignificancePSP have been identified as the most crucial components of Polygonatum sibiricum with various pharmacological functions. Our previous study found that PSP could protect against SALI, but the mechanism of action remains unknown. To reveal the underlying molecular mechanism involved in the protective effects of PSP on SALI, a TMT-based quantitative proteomic analysis was performed to detect and analyse the DEPs in liver tissue among the control group, the model group and the PSP group in this study. The results provide theoretical references for exploring the action mechanism of drugs and facilitate the comprehensive utilization of PSP.

Causal Relationship Between Sjögren's Syndrome and Gut Microbiota: A Two-Sample Mendelian Randomization Study.

Background: Gut microbiota have been previously reported to be related to a variety of immune diseases. However, the causal connection between Sjögren's syndrome (SS) and gut microbiota has yet to be clarified. Methods: We employed a two-sample Mendelian randomization (MR) analysis to evaluate the causal connection between gut microbiota and SS, utilizing summary statistics from genome-wide association studies (GWASs) obtained from the MiBioGen and FinnGen consortia. The inverse variance weighted (IVW) approach represents the primary method of Mendelian randomization (MR) analysis. Sensitivity analysis was used to eliminate instrumental variables heterogeneity and horizontal pleiotropy. In addition, we performed an analysis using independent GWAS summary statistics for SS from the European Bioinformatics Institute (EBI) dataset for further verify our results. Results: IVW results demonstrated that the phylum Lentisphaerae (OR = 0.79, 95% CI: 0.63-0.99, p = 0.037), class Deltaproteobacteria (OR = 0.67, 95% CI: 0.47-0.96, p = 0.030), family Porphyromonadaceae (OR = 0.60, 95% CI: 0.38-0.94, p = 0.026), genus Eubacterium coprostanoligenes group (OR = 0.61, 95% CI: 0.4-0.93, p = 0.021), genus Blautia (OR = 0.62, 95% CI: 0.43-0.90, p = 0.012), genus Butyricicoccus (OR = 0.61, 95% CI: 0.42-0.90, p = 0.012), genus Escherichia.Shigella (OR = 0.7, 95% CI: 0.49-0.99, p = 0.045) and genus Subdoligranulum (OR = 0.61, 95% CI: 0.44-0.86, p = 0.005) exhibited protective effects on SS. Relevant heterogeneity of horizontal pleiotropy or instrumental variables was not detected. Furthermore, repeating our results with an independent cohort provided by the EBI dataset, only the genus Eubacterium coprostanoligenes group remained significantly associated with the protective effect on SS (OR = 0.41, 95% CI: 0.18-0.91, p = 0.029). Two-step MR analysis further revealed that genus Eubacterium coprostanoligenes group exerts its protective effect by reducing CXCL6 levels in SS (OR, 0.87; 95% CI = 0.76-0.99, p = 0.033). Conclusions: Our study using two-sample MR analysis identified a causal association between multiple genera and SS. A two-step MR result calculated that genus Eubacterium coprostanoligenes group mediated its protective effect by reducing CXCL6 levels in SS. However, the datasets available from the MiBioGen and FinnGen consortia do not provide sufficient information or comprehensive demographic data for subgroup analyses. Additional validation using various omics technologies is necessary to comprehend the development of SS in the intricate interplay between genes and the environment over a period of time.

OS10.4.A CXCL1 MEDIATES LEPTOMENINGEAL METASTASIS GROWTH

Abstract BACKGROUND Leptomeningeal metastasis (LM) is a fatal neurological complication of cancer characterized by the entry of metastatic cancer cells originated from solid or hematologic tumors into the cerebrospinal fluid (CSF)-filled leptomeningeal compartment encasing the brain and the spinal cord. LM occurs in 5-20% in patients with solid tumors, especially those with breast cancer, lung cancer, melanoma. Untreated LM patients succumb within 4-6 weeks after diagnosis, or 2-5 months when they are treated with the current available therapies. To date, the only efficacious life-prolonging intervention was the application of proton craniospinal irradiation (pCSI) as demonstrated in the recent clinical trial, NCT04343573, with an average overall survival of 9 months. While a cohort of pCSI-treated patients survived over 18 months (responders), another cohort did not respond to pCSI and succumbed to the disease within 3 months post-treatment (non-responders). In this project, we aimed to characterize the molecular basis of pCSI response to turn the non-responders into responders. MATERIAL AND METHODS We performed proteomic analyses on serially collected CSF from LM patients at baseline (before pCSI), and multiple time points post-treatment. We further established syngeneic mouse models of LM-CSI to define the molecular basis of pCSI resistance. RESULTS We found that pCSI resulted in a significant drop in the levels of the chemokine CXCL1, a CXC-motif chemokine with elevated baseline levels after the onset of LM. Patients with significantly higher CSF CXCL1 levels prior to pCSI had worse central nervous system (CNS) progression-free survival. Using our preclinical LM mouse models, we found that both the cancer and host cells, namely macrophages, choroid plexus epithelial cells, and leptomeningeal fibroblasts, were a source of CXCL1. Genetic manipulation of Cxcl1expression in cancer cells or host revealed that the CXCL1 produced by the cancer cells was an essential factor for their growth in the leptomeninges. Moreover, we found that a subset of cancer cells expressed a receptor for CXCL1 - CXCR2 - and transcriptomic profiling of this rare population revealed an enrichment in pathways associated with cell cycle progression. Finally, intrathecally delivered CXCR2 antagonist hampered the LM growth. CONCLUSION Our results indicate that CXCL1/CXCR2 signaling axis regulates LM growth and suggests interruption of this signaling axis as a possible actionable therapeutic intervention to halt LM progression.

Effects of Chitosan and N-Succinyl Chitosan on Metabolic Disorders Caused by Oral Administration of Olanzapine in Mice.

The issue of human mental health is gaining more and more attention nowadays. However, most mental disorders are treated with antipsychotic drugs that cause weight gain and metabolic disorders, which include olanzapine (OLZ). The search for and development of natural compounds for the prevention of obesity when taking antipsychotic drugs is an urgent task. The biopolymer chitosan (Chi) and its derivatives have lipid-lowering and anti-diabetic properties, which makes them potential therapeutic substances for use in the treatment of metabolic disorders. The purpose of this work was to analyze the effect of the natural biopolymer Chi, its derivative N-succinyl chitosan (SuChi), and Orlistat (ORL) as a control on the effects caused by the intake of OLZ in a mouse model. Mice were fed with pearl barley porridge mixed with OLZ or combinations OLZ + Chi, OLZ + SuChi, or OLZ + ORL for 2 months. The weight, lipid profile, blood chemokines, expression of genes associated with appetite regulation, and behavior of the mice were analyzed in dynamics. For the first time, data were obtained on the effects of Chi and SuChi on metabolic changes during the co-administration of antipsychotics. Oral OLZ increased body weight, food and water intake, and glucose, triglyceride, and cholesterol levels in blood. ORL and SuChi better normalized lipid metabolism than Chi, decreasing triglyceride and cholesterol levels. OLZ decreased the production of all chemokines tested at the 4th week of treatment and increased CXCL1, CXCL13, and CCL22 chemokine levels at the 7th week. All of the supplements corrected the level of CXCL1, CXCL13, and CCL22 chemokines but did not recover suppressed chemokines. SuChi and ORL stimulated the expression of satiety associated proopiomelanocortin (POMC) and suppressed the appetite-stimulating Agouti-related protein (AgRP) genes. All supplements improved the locomotion of mice. Taken collectively, we found that SuChi more than Chi possessed an activity close to that of ORL, preventing metabolic disorders in mice fed with OLZ. As OLZ carries positive charge and SuChi is negatively charged, we hypothesized that SuChi's protective effect can be explained by electrostatic interaction between OLZ byproducts and SuChi in the gastrointestinal tract.

Role of AhR-Hsp90-MDM2-mediated VDR ubiquitination in PM2.5-induced renal toxicity

Background and objectivesThe kidney is a primary target for the accumulation of particulate matter (PM2.5). This study aimed to investigate PM2.5-induced renal toxicity mechanisms, focusing on the aryl hydrocarbon receptor (AhR)-Hsp90-MDM2 axis and its impact on vitamin D receptor (VDR) ubiquitination. MethodsPM2.5's role in activating the AhR and its downstream pathways was investigated using in vitro and in vivo models. Renal damage and therapeutic effects in PM2.5-exposed and paricalcitol-treated mice were evaluated using weight measurements, histopathology, and scanning electron microscopy. AhR, Hsp90, and VDR localization and expression in renal cells were assessed using FISH and Western blot. Protein interactions were examined using co-immunoprecipitation. Differentially expressed gene (DEG) analysis of GEO datasets was used to identify related proteins and genes. ResultsPM2.5 exposure caused significant renal damage in mice, including increased serum creatinine, albuminuria, and histopathological deterioration, which were alleviated by paricalcitol. PM2.5 induced the nuclear translocation of AhR and Hsp90 and reduced nuclear VDR expression; paricalcitol reversed these effects. Immunohistochemistry confirmed these findings. PM2.5 upregulated the NLRP3/caspase-1/IL-1β/IL-18 axis, which was reversed by paricalcitol treatment. Inhibition of Hsp90 increased nuclear VDR expression through MDM2 mediation. DEG analysis identified VDR-regulated genes; PM2.5 increased the mRNA levels of IL-6, IL-2, and CXCL8, which were downregulated by Hsp90 and MDM2 inhibitors, with VDR agonists further decreasing these levels. ConclusionThis study reveals a novel mechanism of PM2.5-induced renal toxicity through the AhR-Hsp90-MDM2 axis, promoting VDR ubiquitination and degradation and increasing inflammation. These findings provide a foundation for future studies and lay the groundwork for developing targeted interventions to mitigate the public health impact of PM2.5 exposure.

Increased Cytokine Levels in Seronegative Myositis: Potential Th17 Immune Response Implications

Th17 cells are known for producing IL-17 and their role in the pathogenesis of various autoimmune diseases, including myositis. Likewise, the participation of the IL-23/IL-17 pathway in autoimmunity has been confirmed. In this study, we aimed to evaluate the behavior of cytokines in myositis, focusing on the autoantibodies profile and the myositis core set measures. Twenty-five myositis patients were enrolled in this cross-sectional study. An expert rheumatologist evaluated the myositis core set measures. Serum levels of cytokines and chemokines were quantified using the LEGENDplex Multi-Analyte Flow Assay Kit from BioLegend. The autoantibodies detection was carried out using the line-blot assay kit Euroline: Autoimmune Inflammatory Myopathies from EUROIMMUN. We found higher serum levels of IL-33, CXCL8, IL-6, IL-23, and IL-12p70 in seronegative patients. A multiple linear regression analysis revealed that MYOACT scores could be predicted by the increment of IL-23 and the decrement of CCL2, IL-10, and CXCL8 serum levels. These findings suggest that the immune response in seronegative myositis patients exhibits an IL-23-driven Th17 immune response. The relevance of this discovery lies in its potential therapeutic implications. Insights into the IL-23-driven Th17 immune response in seronegative patients highlight the potential for targeted therapies aimed at modulating Th17 activity.

TGFβ1-TNFα regulated secretion of neutrophil chemokines is independent of epithelial-mesenchymal transitions in breast tumor cells.

Neutrophils have tumor-promoting roles in breast cancer and are detected in higher numbers in aggressive breast tumors. How aggressive breast tumors recruit neutrophils remains undefined. Here, we investigated the roles of TGF-β1 and TNF-α in the regulation of neutrophil recruitment by breast cancer cells. TGF-β1 and TNF-α are pro-inflammatory factors upregulated in breast tumors and induce epithelial to mesenchymal transitions (EMT), a process linked to cancer cell aggressiveness. We report that, as expected, dual treatment with TGF-β1 and TNF-α induces EMT signatures in premalignant M2 cells, which are part of the MCF10A breast cancer progression model. Conditioned media (CM) harvested from M2 cells treated with TGF-β1/TNF-α gives rise to amplified neutrophil chemotaxis compared to CM from control M2 cells. This response correlates with higher levels of the neutrophil chemokines CXCL1, CXCL2, and CXCL8 and is significantly attenuated in the presence of a CXCL8-neutralizing antibody. Furthermore, we found that secretion of CXCL1 and CXCL8 from treated M2 cells depends on p38MAPK activity. By combining gene editing, immunological and biochemical approaches, we show that the regulation of neutrophil recruitment and EMT signatures are not mechanistically linked in treated M2 cells. Finally, analysis of publicly available cancer cell line transcriptomic databases revealed a significant correlation between CXCL8 and TGF-β1/TNF-α-regulated or effector genes in breast cancer. Together, our findings establish a novel role for the TGF-β1/TNF-α/p38 MAPK signaling axis in regulating neutrophil recruitment in breast cancer, independent of TGF-β1/TNF-α regulated EMT.

Unveiling the role of CXCL8/CXCR2 in intervertebral disc degeneration: A path to promising therapeutic strategies

BackgroundIntervertebral disc degeneration(IVDD) is the primary etiology of low back pain and radicular pain. Recent studies have found that chemokines play a role in IVDD, but the underlying mechanism is largely unclear. MethodsBioinformatics analysis was employed to screen CXCL8 as the target gene. The expression levels of CXCL8 and CXCR2 were quantified using RT-qPCR, western blot(WB), immunohistochemistry(IHC), and enzyme-linked immuno-sorbent assay(ELISA). In the IVDD mouse model, X-ray images, Safranin O-fast green staining(SO-FG), IHC, and WB were conducted to assess the therapeutic effects of CXCL8 on IVDD. Reactive oxygen species (ROS) production, apoptosis of nucleus pulposus cells (NPCs), and the involvement of the NF-κB pathway were evaluated through WB, flow cytometry, immunofluorescence(IF), and Tunnel assay. ResultsIn our study, we observed that CXCL8 emerged as one of the chemokines that were up-regulated in IVDD. The mitigation of extracellular matrix degradation (ECM) and the severity of IVDD were significantly achieved by neutralizing CXCL8 or its receptor CXCR2(SB225002, CXCR2 antagonist). The release of CXCL8 from infiltrated macrophages within intervertebral discs (IVDs) was predominantly observed upon stimulation. CXCL8 exerted its effects on NPCs by inducing apoptosis and ECM degradation through the activation of CXCR2. Specifically, the formation of the CXCL8/CXCR2 complex triggered the NF-κB signaling pathway, resulting in an abnormal increase in intracellular ROS levels and ultimately contributing to the development of IVDD. ConclusionOur findings suggest that macrophage-derived CXCL8 and subsequent CXCR2 signaling play crucial roles in mediating inflammation, oxidative stress, and apoptosis in IVDD. Targeting the CXCL8/CXCR2 axis may offer promising therapeutic strategies to ameliorate IVDD. The translational potential of this articleThis study indicates that CXCL8 can effectively exacerbate the excessive apoptosis and oxidative stress of NPCs through activating the NF-κB pathway. This study may provide new potential targets for preventing and reversing IVDD.

Cytokine profiles and their correlation with clinical and blood parameters in rheumatoid arthritis and systemic lupus erythematosus.

The abnormal biological activity of cytokines and their imbalance are implicated in developing rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Cytokine levels were measured in RA and SLE patients and compared to healthy controls using the Wilcoxon rank sum test and Kruskal-Wallis test. The relationship between cytokine levels and blood and clinical parameters was assessed using Spearman's correlation test. Compared to healthy controls, both RA and SLE patients exhibited elevated levels of GM-CSF, CX3CL1, IFN-α2, IL-12p70, IL-17A, TNF-α, IL-1β, and IFN-γ, which is evidence of their shared inflammatory signature. IL-2 levels were elevated exclusively in RA patients, while MCP-1 and IL-10 were uniquely increased in SLE patients. Notably, TNF-α showed the most significant increase in SLE patients. IL-4 was elevated in SLE patients with nephritis, correlating with IL-6, IL-10, sCD40L, and IL-8, suggesting B cell involvement in lupus nephritis. The negative correlation between CX3CL1 and TNF-α with HDL in RA and SLE respectively, highlights the potential association of these inflammatory markers with cardiovascular risk. These findings underscore the complex cytokine interplay in RA and SLE. CX3CL1 emerges as a potential therapeutic target for RA, while TNF-α and IL-4 show promise as therapeutic targets for SLE.

Erlotinib regulates short-term memory, tau/Aβ pathology, and astrogliosis in mouse models of AD.

Erlotinib is an epidermal growth factor receptor (EGFR) inhibitor that is approved by the FDA to treat non-small cell lung cancer (NSCLC). Several membrane receptors, including EGFR, interact with amyloid β (Aβ), raising the possibility that erlotinib could have therapeutic effects on Alzheimer's disease (AD). However, the effects of erlotinib on Aβ/tau-related pathology and cognitive function in mouse models of AD and its mechanisms of action have not been examined in detail. To investigate the effects of erlotinib on cognitive function and AD pathology, 3 to 6-month-old PS19 mice and 3 to 3.5-month-old 5xFAD mice and WT mice were injected with vehicle (5% DMSO + 10% PEG + 20% Tween80 + 65% D.W.) or erlotinib (20 mg/kg, i.p.) daily for 14 or 21 days. Then, behavioral tests, Golgi staining, immunofluorescence staining, western blotting ELISA, and real-time PCR were conducted. We found that erlotinib significantly enhanced short-term spatial memory and dendritic spine formation in 6-month-old P301S tau transgenic (PS19) mice. Importantly, erlotinib administration reduced tau phosphorylation at Ser202/Thr205 (AT8) and Thr231 (AT180) and further aggregation of tau into paired helical fragments (PHFs) and neurofibrillary tangles (NFTs) in 3-month-old and/or 6-month-old PS19 mice by suppressing the expression of the tau kinase DYRK1A. Moreover, erlotinib treatment decreased astrogliosis in 6-month-old PS19 mice and reduced proinflammatory responses in primary astrocytes (PACs) from PS19 mice. In 3- to 3.5-month-old 5xFAD mice, erlotinib treatment improved short-term spatial memory and hippocampal dendritic spine number and diminished Aβ plaque deposition and tau hyperphosphorylation. Furthermore, erlotinib-treated 5xFAD mice exhibited significant downregulation of astrocyte activation, and treating PACs from 5xFAD mice with erlotinib markedly reduced cxcl10 (reactive astrocyte marker) and gbp2 (A1 astrocyte marker) mRNA levels and proinflammatory cytokine mRNA and protein levels. Taken together, our results suggest that erlotinib regulates tau/Aβ-induced AD pathology, cognitive function, and Aβ/tau-evoked astrogliosis and therefore could be a potent therapeutic drug for ameliorating AD symptoms.