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Journal of the Canadian Association of... Feb 2024Crohn's disease (CD), a chronic inflammatory condition of the digestive tract, poses significant challenges in terms of disease prognosis and treatment selection.... (Review)
Review
Crohn's disease (CD), a chronic inflammatory condition of the digestive tract, poses significant challenges in terms of disease prognosis and treatment selection. Biomarkers have the potential to predict CD outcomes and guide clinical decision-making. This review aims to summarize the current literature on promising biomarkers associated with CD outcomes and their potential clinical implications. The identification of reliable biomarkers for CD outcomes is of paramount importance in tailoring treatment strategies, monitoring disease activity, and predicting the risk of complications. Clinical prognostic factors traditionally used to assess disease severity, and the likelihood of complications have limitations in accuracy and predictive value. Thus, there is a need for more precise biomarkers, particularly in newly diagnosed and treatment-naive patients. Pharmacogenomic markers, such as TPMT and NUDT15 polymorphisms, have been utilized to identify patients at risk of adverse events with thiopurine therapy. Several biomarkers, including HLA haplotypes, oncostatin M expression, and transcriptomic profiles, have shown associations with response to anti-TNF therapy. Confocal laser endomicroscopy and single-cell analyses hold promise in predicting treatment response to specific therapies. The identification of biomarkers associated with post-operative recurrence in CD is crucial, as it could lead to changes in management algorithms. Several promising microbiome signatures and proteomic profiles have been identified. In conclusion, biomarkers have the potential to revolutionize the management of CD by providing valuable prognostic information and guiding treatment decisions. However, further research and validation are necessary to establish their clinical utility and integration into routine practice.
PubMed: 38314176
DOI: 10.1093/jcag/gwad024 -
The Journal of Clinical Investigation Jan 2024Cancer cell plasticity contributes to therapy resistance and metastasis, which represent the main causes of cancer-related death, including in breast cancer. The tumor...
Cancer cell plasticity contributes to therapy resistance and metastasis, which represent the main causes of cancer-related death, including in breast cancer. The tumor microenvironment drives cancer cell plasticity and metastasis, and unraveling the underlying cues may provide novel strategies for managing metastatic disease. Using breast cancer experimental models and transcriptomic analyses, we show that stem cell antigen-1 positive (SCA1+) murine breast cancer cells enriched during tumor progression and metastasis had higher in vitro cancer stem cell-like properties, enhanced in vivo metastatic ability, and generated tumors rich in Gr1hiLy6G+CD11b+ cells. In turn, tumor-educated Gr1+CD11b+ (Tu-Gr1+CD11b+) cells rapidly and transiently converted low metastatic SCA1- cells into highly metastatic SCA1+ cells via secreted oncostatin M (OSM) and IL-6. JAK inhibition prevented OSM/IL-6-induced SCA1+ population enrichment, while OSM/IL-6 depletion suppressed Tu-Gr1+CD11b+-induced SCA1+ population enrichment in vitro and metastasis in vivo. Moreover, chemotherapy-selected highly metastatic 4T1 cells maintained high SCA1+ positivity through autocrine IL-6 production, and in vitro JAK inhibition blunted SCA1 positivity and metastatic capacity. Importantly, Tu-Gr1+CD11b+ cells invoked a gene signature in tumor cells predicting shorter overall survival (OS), relapse-free survival (RFS), and lung metastasis in breast cancer patients. Collectively, our data identified OSM/IL-6/JAK as a clinically relevant paracrine/autocrine axis instigating breast cancer cell plasticity and triggering metastasis.
Topics: Humans; Mice; Animals; Female; Breast Neoplasms; Interleukin-6; Oncostatin M; Cell Plasticity; Cell Line, Tumor; Neoplasm Recurrence, Local; Lung Neoplasms; Neoplasms, Second Primary; Spinocerebellar Ataxias; Neoplasm Metastasis; Tumor Microenvironment
PubMed: 38236642
DOI: 10.1172/JCI166847 -
JOR Spine Mar 2024M1 macrophages (Mφs) are involved in osteogenic differentiation of ligamentum flavum (LF) cells and play an important role in heterotopic ossification. However, the...
BACKGROUND
M1 macrophages (Mφs) are involved in osteogenic differentiation of ligamentum flavum (LF) cells and play an important role in heterotopic ossification. However, the mechanism by which M1 Mφs influence osteogenic differentiation of LF cells has not been studied.
METHODS
The effect of conditioned medium including secretions of M1 Mφs (CM-M1) on LF cells was analyzed by GeneChip profiling and ingenuity pathway analysis (IPA). THP-1 cells were polarized into M1 Mφs and CM-M1 was used to induce LF cells. In addition, LF cells were induced by CM-M1 in the presence of cyclooxygenase 2 (COX-2) inhibitors or oncostatin M (OSM)-neutralizing antibodies. Based on the presence of OSM, knockout of OSMR or GP130 receptors, or addition of the Janus kinase 2 (JAK2) inhibitor AZD1480 or signal transducer and activator of transcription 3 (STAT3) inhibitor Stattic were examined for effects on osteogenic differentiation of LF cells. OSM secretion was quantified by ELISA, while qPCR and western blot were used to evaluate expression of osteogenic genes and receptor and signaling pathway-related proteins, respectively.
RESULTS
GeneChip and IPA results indicate that the OSM signaling pathway and its downstream signaling molecules JAK2 and STAT3 are significantly activated. ELISA results indicate that OSM is highly expressed in cells treated with CM-M1 and lowly expressed in cells treated with CM-M1 and a COX-2 inhibitor. Besides, CM-M1 induces osteogenic differentiation of LF cells, which is weakened when COX-2 inhibitors or OSM-neutralizing antibody are added to it. Recombinant OSM could induce osteogenic differentiation of LF cells and upregulate expression of OSMR, GP130, phosphorylated (P)-JAK2, and P-STAT3. Upon knockdown of OSMR or GP130, or the addition of AZD1480 or Stattic, P-JAK2 and P-STAT3 expression were decreased and osteogenic differentiation was reduced.
CONCLUSION
M1 Mφ-derived OSM induces osteogenic differentiation of LF cells and the JAK2/STAT3 signaling pathway plays an important role.
PubMed: 38222812
DOI: 10.1002/jsp2.1290 -
Cureus Dec 2023The expression of oncostatin M (OSM) has been studied in various diseases related to inflammatory response, but its implementation in acute ischemic stroke (AIS) remains...
BACKGROUND
The expression of oncostatin M (OSM) has been studied in various diseases related to inflammatory response, but its implementation in acute ischemic stroke (AIS) remains to be explored. Objective: The objective of this study is to assess the correlation between serum OSM expression and various aspects of AIS in a clinical setting.
MATERIALS AND METHOD
A single-centered case-control study was performed in the First Affiliate Hospital of Chongqing Medical University from October 2020 to March 2021. A total of 134 patients were enrolled in the AIS group and 34 healthy individuals were enrolled in the control group. Physical examinations were performed and venous blood samples were collected. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum OSM. Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, National Institutes of Health Stroke Scale (NIHSS) score, magnetic resonance imaging (MRI) scan, and modified Rankin scale (mRS) were used to assess the classification, etiology, severity, and prognosis of the AIS group. Assessments were done to analyze serum OSM expression based on sensitivity, etiology, severity, prognosis, and several risk factors of AIS. Regression models, correlation, and sensitivity tests were performed to explore the correlation of OSM expression with various aspects of AIS.
RESULTS
There was a statistically significant elevation of serum OSM expression in the AIS group (P<0.001). All AIS subgroups showed elevation in OSM level and statistically significant results were reflected in three subgroups. The area under the curve to differentiate AIS patients and control by serum OSM level was 0.747 (P<0.001), with the optimal cut-off value showing sensitivity at 58.82% and specificity at 75.37%. The elevation of serum OSM expression was proportional with severity, not proportional to the volume of infarct, and less elevated in the favorable outcome group. Serum OSM correlation with several risk factors of AIS was statistically significant in age, low-density lipoprotein, non-high-density lipoprotein, prothrombin time, and systolic blood pressure.
CONCLUSION
Serum OSM was expressed differently in correlation with various aspects of AIS. Our findings supported the initial hypothesis that OSM is correlated with various aspects of AIS in humans.
PubMed: 38205475
DOI: 10.7759/cureus.50297 -
Current Osteoporosis Reports Feb 2024The bone and hematopoietic tissues coemerge during development and are functionally intertwined throughout mammalian life. Oncostatin M (OSM) is an inflammatory cytokine... (Review)
Review
PURPOSE OF THE REVIEW
The bone and hematopoietic tissues coemerge during development and are functionally intertwined throughout mammalian life. Oncostatin M (OSM) is an inflammatory cytokine of the interleukin-6 family produced by osteoblasts, bone marrow macrophages, and neutrophils. OSM acts via two heterodimeric receptors comprising GP130 with either an OSM receptor (OSMR) or a leukemia inhibitory factor receptor (LIFR). OSMR is expressed on osteoblasts, mesenchymal, and endothelial cells and mice deficient for the Osm or Osmr genes have both bone and blood phenotypes illustrating the importance of OSM and OSMR in regulating these two intertwined tissues.
RECENT FINDINGS
OSM regulates bone mass through signaling via OSMR, adaptor protein SHC1, and transducer STAT3 to both stimulate osteoclast formation and promote osteoblast commitment; the effect on bone formation is also supported by action through LIFR. OSM produced by macrophages is an important inducer of neurogenic heterotopic ossifications in peri-articular muscles following spinal cord injury. OSM produced by neutrophils in the bone marrow induces hematopoietic stem and progenitor cell proliferation in an indirect manner via OSMR expressed by bone marrow stromal and endothelial cells that form hematopoietic stem cell niches. OSM acts as a brake to therapeutic hematopoietic stem cell mobilization in response to G-CSF and CXCR4 antagonist plerixafor. Excessive OSM production by macrophages in the bone marrow is a key contributor to poor hematopoietic stem cell mobilization (mobilopathy) in people with diabetes. OSM and OSMR may also play important roles in the progression of several cancers. It is increasingly clear that OSM plays unique roles in regulating the maintenance and regeneration of bone, hematopoietic stem and progenitor cells, inflammation, and skeletal muscles. Dysregulated OSM production can lead to bone pathologies, defective muscle repair and formation of heterotopic ossifications in injured muscles, suboptimal mobilization of hematopoietic stem cells, exacerbated inflammatory responses, and anti-tumoral immunity. Ongoing research will establish whether neutralizing antibodies or cytokine traps may be useful to correct pathologies associated with excessive OSM production.
Topics: Animals; Humans; Mice; Endothelial Cells; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Heterocyclic Compounds; Mammals; Oncostatin M; Ossification, Heterotopic
PubMed: 38198032
DOI: 10.1007/s11914-023-00837-z -
Investigative Ophthalmology & Visual... Jan 2024Continuous vision loss due to vasoproliferative eye disease still represents an unsolved issue despite anti-vascular endothelial growth factor (VEGF) therapy. The impact...
PURPOSE
Continuous vision loss due to vasoproliferative eye disease still represents an unsolved issue despite anti-vascular endothelial growth factor (VEGF) therapy. The impact of signal transducer and activator of transcription 3 (STAT3) signaling on retinal angiogenesis and its potential use as a therapeutic target remain controversial. In vitro, oncostatin M (OSM), as a strong STAT3 activator, possesses robust proangiogenic activity. This study investigated to what extent the proangiogenic effects of OSM translate to the in vivo setting of vasoproliferative eye disease.
METHODS
The in vitro effect of OSM on endothelial cells was investigated in the spheroid sprouting assay and through RNA sequencing. The mouse model for oxygen-induced retinopathy (OIR) was used to evaluate the impact of OSM in vivo. Signaling patterns were measured by western blot and retinal cryosections. Primary Müller cell cultures were used to evaluate the effect of OSM on the Müller cell secretome. Murine retinal vascular endothelial cells were isolated from OIR retinas using fluorescence-activated cell sorting (FACS) and were used for RNA sequencing.
RESULTS
Although OSM induced pro-angiogenic responses in vitro, in the OIR model intravitreal injection of OSM reduced retinal neovascularization by 65.2% and vaso-obliteration by 45.5% in Müller cells. Injecting OSM into the vitreous activated the STAT3 signaling pathway in multiple retinal cell types, including Müller cells. In vitro, OSM treatment increased CXCL10 secretion. RNA sequencing of sorted vascular endothelial cells at OIR P17 following OSM treatment indicated downregulation of angiogenesis- and mitosis-associated genes.
CONCLUSIONS
In vivo, OSM reveals a beneficial angiomodulatory effect by activating Müller cells and changing their secretome. The data highlight contradictions between cytokine-induced effects in vitro and in vivo depending on the cell types mediating the effect.
Topics: Animals; Mice; Endothelial Cells; Ependymoglial Cells; Neovascularization, Pathologic; Oncostatin M; Retina; Retinal Diseases
PubMed: 38190125
DOI: 10.1167/iovs.65.1.22 -
BioRxiv : the Preprint Server For... Dec 2023Antiviral immune mediators, including interferons and their downstream effectors, are critical for host defense yet can become detrimental when uncontrolled. Here, we...
Antiviral immune mediators, including interferons and their downstream effectors, are critical for host defense yet can become detrimental when uncontrolled. Here, we identify a macrophage-mediated anti-inflammatory mechanism that limits type I interferon (IFN-I) responses. Specifically, we found that cellular stress and pathogen recognition induce Oncostatin M (OSM) production by macrophages. OSM-deficient mice succumbed to challenge with influenza or a viral mimic due to heightened IFN-I activation. Macrophage-derived OSM restricted excessive IFN-I production by lung epithelial cells following viral stimulation. Furthermore, reconstitution of OSM in the respiratory tract was sufficient to protect mice lacking macrophage-derived OSM against morbidity, indicating the importance of local OSM production. This work reveals a host strategy to dampen inflammation in the lung through the negative regulation of IFN-I by macrophages.
PubMed: 38168230
DOI: 10.1101/2023.12.16.572019 -
Cell Reports. Medicine Jan 2024The discovery of exercise-regulated circulatory factors has fueled interest in organ crosstalk, especially between skeletal muscle and adipose tissue, and the role in...
The discovery of exercise-regulated circulatory factors has fueled interest in organ crosstalk, especially between skeletal muscle and adipose tissue, and the role in mediating beneficial effects of exercise. We studied the adipose tissue transcriptome in men and women with normal glucose tolerance or type 2 diabetes following an acute exercise bout, revealing substantial exercise- and time-dependent changes, with sustained increase in inflammatory genes in type 2 diabetes. We identify oncostatin-M as one of the most upregulated adipose-tissue-secreted factors post-exercise. In cultured human adipocytes, oncostatin-M enhances MAPK signaling and regulates lipolysis. Oncostatin-M expression arises predominantly from adipose tissue immune cell fractions, while the corresponding receptors are expressed in adipocytes. Oncostatin-M expression increases in cultured human Thp1 macrophages following exercise-like stimuli. Our results suggest that immune cells, via secreted factors such as oncostatin-M, mediate a crosstalk between skeletal muscle and adipose tissue during exercise to regulate adipocyte metabolism and adaptation.
Topics: Female; Humans; Male; Adipocytes; Adipose Tissue; Cells, Cultured; Diabetes Mellitus, Type 2; Lipolysis
PubMed: 38151020
DOI: 10.1016/j.xcrm.2023.101348 -
Journal of Inflammation Research 2023The aim of this study was to investigate the level of serum tumor suppressor factor (Oncostatin-M, OSM) in patients with community-acquired pneumonia (CAP) and evaluate...
PURPOSE
The aim of this study was to investigate the level of serum tumor suppressor factor (Oncostatin-M, OSM) in patients with community-acquired pneumonia (CAP) and evaluate its predictive value for the severity and prognosis of pneumonia, so as to improve the ability to identify the risk of death in CAP patients.
PATIENTS AND METHODS
A total of 110 patients with CAP admitted to the hospital from November 2020 to November 2021 were enrolled in this prospective study. Clinical data of all patients were collected. According to the 2016 edition of "Guidelines for the Diagnosis and Treatment of Community-acquired Pneumonia in Chinese Adults", the patients were divided into non-severe CAP (NSCAP)(n=55) and severe CAP (SCAP)(n=55). At the same time, they were divided into a survival group (n=96) and a death group (n=14) by tracking the survival of patients in the hospital. The OSM concentration of CAP patients on the first day after admission was determined by enzyme-linked immunosorbent assay. All clinical data were statistically and graphed using SPSS V23.0 and Grahpad Prim 8.
RESULTS
Compared with NSCAP, patients with SCAP had higher serum OSM concentration on the day of admission, which was negatively correlated with LYM and positively correlated with WBC, NEU, CRP, IL-6, IL-8, IL-10, CURB-65 score, and PSI score. The level of OSM in the dead patient group was significantly higher than that in the surviving patient group. OSM and PSI scores were independent risk factors for in-hospital mortality in CAP patients. Kaplan-Meier survival curve showed that OSM≥76pg/mL was more advantageous in predicting mortality in patients with CAP.
CONCLUSION
The level of the OSM is closely related to the severity and prognosis of CAP and may be a new biomarker for the prognosis of CAP patients.
PubMed: 38146322
DOI: 10.2147/JIR.S445484 -
Journal of Personalized Medicine Nov 2023The objective of our study was to evaluate the concentrations of pro-inflammatory biomarkers in patients with acute myocardial infarction with non-obstructive coronary...
UNLABELLED
The objective of our study was to evaluate the concentrations of pro-inflammatory biomarkers in patients with acute myocardial infarction with non-obstructive coronary arteries (MINOCA) compared to patients with acute myocardial infarction with obstructive coronary arteries (MI-CAD) in the early post-infarction period and after 1 year and to perform a comparative analysis of the relationship between laboratory biomarkers and atherosclerosis progression in patients with MINOCA and MI-CAD.
METHODS
Samples of peripheral venous blood were collected upon admission and on days 2, 4, and 7 of hospitalization and after 1 year. An extended multiplex analysis was performed in blood serum. Multidetector-computed tomography coronary angiography was performed on day 7 and 1 year after acute myocardial infarction to assess the progression of atherosclerosis.
RESULTS
The level of high-sensitive C-reactive protein (hsCRP) was elevated upon admission in MINOCA patients compared to MI-CAD patients ( = 0.05), but it was comparable in two groups at other time points and did not exceed the reference range after 1 year. Despite comparable levels of cytokines CXCL-6, LIGHT, CCL-8, and endocan-1 in patients in both groups, MINOCA patients had a greater increase in pro-inflammatory cytokines PlGF, oncostatin M, IL-20, and CCL-15 sVCAM-1 in the early post-infarction period and in CCL-21, sVCAM-1, oncostatin M, and PlGF after 1 year. We observed significant differences in the dynamics of the following biomarkers between patients with MI-CAD and MINOCA: the dynamics of concentrations of CCL21 ( = 0.002), LIGHT ( = 0.03), and endocan-1 ( = 0.03) after 1 year compared to day 1 in MI-CAD and MINOCA patients was opposite, while the dynamics of CXCL6 ( = 0.04) and endocan-1 ( = 0.02) differed between groups when evaluated after 1 year compared to day 7 of the early post-infarction period. In the MINOCA group, factors associated with atherosclerosis progression were concentrations of sVCAM-1 and CCL-21, while in the MI-CAD group, concentrations of CCL-8 and CXCL6 were the main determinants of atherosclerosis progression.
CONCLUSIONS
This small study showed that MINOCA and MI-CAD patients exhibited differences in a pro-inflammatory biomarker profile in the early post-infarction period and after 1-year follow-up, which implies distinct inflammatory pathways involved in atherogenesis during MINOCA. The key factors that were associated with atherosclerosis progression in MINOCA patients are sVCAM-1 and CCL-21, which may suggest a complex genesis of atherosclerosis progression due to structurally altered plaques and changes in the microcirculatory bed. In MI-CAD patients, CCL-8 and CXCL-6 were the key biomarkers associated with atherosclerosis progression. Further large-scale studies are required to confirm our data.
PubMed: 38138896
DOI: 10.3390/jpm13121669