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American Heart Journal Plus :... Nov 2023Oncostatin M (OSM) is an inflammatory cytokine belonging to the interleukin-6 family member, which plays an important role in various cardiovascular diseases. We...
OBJECTIVE
Oncostatin M (OSM) is an inflammatory cytokine belonging to the interleukin-6 family member, which plays an important role in various cardiovascular diseases. We recently reported increased serum OSM levels in patients with coronary artery disease. However, the specific role in HF with ischemic heart disease (IHD) remains unclear.
METHODS AND RESULTS
A total of 120 patients with HF and 48 control subjects were enrolled in this study. Serum OSM levels were measured using a sandwich technique immunoassay during the compensated state. The results revealed significantly higher serum OSM levels in HF patients compared to controls. Importantly, HF patients with IHD had higher OSM levels, and those with collateral flow showed the even higher levels, indicating a potential involvement in angiogenesis. Furthermore, a positive correlation was found between serum OSM levels and levels of vascular endothelial growth factor (VEGF). In vitro experiments demonstrated that recombinant OSM upregulated VEGF production in cultured human coronary artery endothelial cells. We additionally observed that endogenous OSM levels were enhanced through exercise. Lastly, we identified the potential of SGLT2 inhibitors to enhance OSM production.
CONCLUSIONS
Serum OSM levels were elevated in HF patients, particularly in those with IHD Our data indicated that endogenous OSM induces VEGF production in the heart, suggesting the activation of angiogenesis, which can be further enhanced by exercise or SGLT2 inhibitors.
PubMed: 38511182
DOI: 10.1016/j.ahjo.2023.100331 -
Advanced Science (Weinheim,... Jun 2024Intercellular communication often relies on exosomes as messengers and is critical for cancer metastasis in hypoxic tumor microenvironment. Some circular RNAs (circRNAs)...
Intercellular communication often relies on exosomes as messengers and is critical for cancer metastasis in hypoxic tumor microenvironment. Some circular RNAs (circRNAs) are enriched in cancer cell-derived exosomes, but little is known about their ability to regulate intercellular communication and cancer metastasis. Here, by systematically analyzing exosomes secreted by non-small cell lung cancer (NSCLC) cells, a hypoxia-induced exosomal circPLEKHM1 is identified that drives NSCLC metastasis through polarizing macrophages toward to M2 type. Mechanistically, exosomal circPLEKHM1 promoted PABPC1-eIF4G interaction to facilitate the translation of the oncostatin M receptor (OSMR), thereby promoting macrophage polarization for cancer metastasis. Importantly, circPLEKHM1-targeted therapy significantly reduces NSCLC metastasis in vivo. circPLEKHM1 serves as a prognostic biomarker for metastasis and poor survival in NSCLC patients. This study unveils a new circRNA-mediated mechanism underlying how cancer cells crosstalk with macrophages within the hypoxic tumor microenvironment to promote metastasis, highlighting the importance of exosomal circPLEKHM1 as a prognostic biomarker and therapeutic target for lung cancer metastasis.
Topics: Animals; Humans; Mice; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Disease Models, Animal; Exosomes; Lung Neoplasms; Macrophages; Neoplasm Metastasis; RNA, Circular; Tumor Microenvironment; Mice, Nude
PubMed: 38509870
DOI: 10.1002/advs.202309857 -
Clinical Pharmacology and Therapeutics Mar 2024Therapeutic neutralization of Oncostatin M (OSM) causes mechanism-driven anemia and thrombocytopenia, which narrows the therapeutic window complicating the selection of...
Therapeutic neutralization of Oncostatin M (OSM) causes mechanism-driven anemia and thrombocytopenia, which narrows the therapeutic window complicating the selection of doses (and dosing intervals) that optimize efficacy and safety. We utilized clinical data from studies of an anti-OSM monoclonal antibody (GSK2330811) in healthy volunteers (n = 49) and systemic sclerosis patients (n = 35), to quantitatively determine the link between OSM and alterations in red blood cell (RBC) and platelet production. Longitudinal changes in hematopoietic variables (including RBCs, reticulocytes, platelets, erythropoietin, and thrombopoietin) were linked in a physiology-based model, to capture the long-term effects and variability of therapeutic OSM neutralization on human hematopoiesis. Free serum OSM stimulated precursor cell production through sigmoidal relations, with higher maximum suppression (I ) and OSM concentration for 50% suppression (IC ) for platelets (89.1% [95% confidence interval: 83.4-93.0], 6.03 pg/mL [4.41-8.26]) than RBCs (57.0% [49.7-64.0], 2.93 pg/mL [2.55-3.36]). Reduction in hemoglobin and platelets increased erythro- and thrombopoietin, respectively, prompting reticulocytosis and (partially) alleviating OSM-restricted hematopoiesis. The physiology-based model was substantiated by preclinical data and utilized in exploration of once-weekly or every other week dosing regimens. Predictions revealed an (for the indication) unacceptable occurrence of grade 2 (67% [58-76], 29% [20-38]) and grade 3 (17% [10-25], 3% [0-7]) anemias, with limited thrombocytopenia. Individual extent of RBC precursor modulation was moderately correlated to skin mRNA gene expression changes. The physiological basis and consideration of interplay among hematopoietic variables makes the model generalizable to other drug and nondrug scenarios, with adaptations for patient populations, diseases, and therapeutics that modulate hematopoiesis or exhibit risk of anemia and/or thrombocytopenia.
PubMed: 38501358
DOI: 10.1002/cpt.3246 -
Stem Cell Reviews and Reports May 2024Macrophages are key regulators in bone repair and regeneration. Recent studies have shown that long-term epigenetic changes and metabolic shifts occur during specific...
Macrophages are key regulators in bone repair and regeneration. Recent studies have shown that long-term epigenetic changes and metabolic shifts occur during specific immune training of macrophages that affect their functional state, resulting in heightened (trained) or reduced (tolerant) responses upon exposure to a second stimulus. This is known as innate immune memory. Here, we study the impact of macrophages' memory trait on osteoblast differentiation of human mesenchymal stromal cells (hMSCs) and osteoclast differentiation. An in vitro trained immunity protocol of monocyte-derived macrophages was employed using inactivated Candida albicans and Bacillus Calmette-Guérin (BCG) to induce a 'trained' state and Pam3CSK4 (PAM) and Lipopolysaccharides (LPS) to induce a 'tolerance' state. Macrophages were subsequently cocultured with hMSCs undergoing osteogenic differentiation during either resting (unstimulated) or inflammatory conditions (restimulated with LPS). Alkaline phosphatase activity, mineralization, and cytokine levels (TNF, IL-6, oncostatin M and SDF-1α) were measured. In addition, macrophages underwent osteoclast differentiation. Our findings show that trained and tolerized macrophages induced opposing results. Under resting conditions, BCG-trained macrophages enhanced ALP levels (threefold), while under inflammatory conditions this was found in the LPS-tolerized macrophages (fourfold). Coculture of hMSCs with trained macrophages showed mineralization while tolerized macrophages inhibited the process under both resting and inflammatory conditions. While osteoclast differentiation was not affected in trained-macrophages, this ability was significantly loss in tolerized ones. This study further confirms the intricate cross talk between immune cells and bone cells, highlighting the need to consider this interaction in the development of personalized approaches for bone regenerative medicine.
Topics: Humans; Cell Differentiation; Osteoclasts; Osteoblasts; Macrophages; Immunity, Innate; Mesenchymal Stem Cells; Lipopolysaccharides; Coculture Techniques; Osteogenesis; Cells, Cultured; Cytokines; Candida albicans; Lipopeptides; Trained Immunity
PubMed: 38478316
DOI: 10.1007/s12015-024-10711-9 -
The Journal of Allergy and Clinical... Jun 2024
Topics: Humans; Prurigo; Antibodies, Monoclonal, Humanized
PubMed: 38460679
DOI: 10.1016/j.jaci.2024.02.016 -
Frontiers in Endocrinology 2024Axial spondyloarthritis (axSpA) is a heterogeneous disease that can be represented by radiographic axSpA (r-axSpA) and non-radiographic axSpA (nr-axSpA). This study...
INTRODUCTION
Axial spondyloarthritis (axSpA) is a heterogeneous disease that can be represented by radiographic axSpA (r-axSpA) and non-radiographic axSpA (nr-axSpA). This study aimed to evaluate the relationship between the markers of inflammation and bone turnover in r-axSpA patients and nr-axSpA patients.
METHODS
A cross-sectional study included 29 r-axSpA patients, 10 nr-axSpA patients, and 20 controls matched for age and sex. Plasma markers related to bone remodeling such as human procollagen type 1 N-terminal propeptide (P1NP), sclerostin, tartrate-resistant acid phosphatase 5b (TRACP5b), receptor activator of nuclear factor kappa B ligand (RANKL), and osteoprotegerin (OPG) were measured by an ELISA kit. A panel of 92 inflammatory molecules was analyzed by proximity extension assay.
RESULTS
R-axSpA patients had decreased plasma levels of P1NP, a marker of bone formation, compared to controls. In addition, r-axSpA patients exhibited decreased plasma levels of sclerostin, an anti-anabolic bone hormone, which would not explain the co-existence of decreased plasma P1NP concentration; however, sclerostin levels could also be influenced by inflammatory processes. Plasma markers of osteoclast activity were similar in all groups. Regarding inflammation-related molecules, nr-axSpA patients showed increased levels of serum interleukin 13 (IL13) as compared with both r-axSpA patients and controls, which may participate in the prevention of inflammation. On the other hand, r-axSpA patients had higher levels of pro-inflammatory molecules compared to controls (i.e., IL6, Oncostatin M, and TNF receptor superfamily member 9). Correlation analysis showed that sclerostin was inversely associated with IL6 and Oncostatin M among others.
CONCLUSION
Altogether, different inflammatory profiles may play a role in the development of the skeletal features in axSpA patients particularly related to decreased bone formation. The relationship between sclerostin and inflammation and the protective actions of IL13 could be of relevance in the axSpA pathology, which is a topic for further investigation.
Topics: Humans; Non-Radiographic Axial Spondyloarthritis; Oncostatin M; Cross-Sectional Studies; Interleukin-13; Interleukin-6; Inflammation; Biomarkers
PubMed: 38449853
DOI: 10.3389/fendo.2024.1227196 -
International Journal of Oral Science Feb 2024The immune-stromal cell interactions play a key role in health and diseases. In periodontitis, the most prevalent infectious disease in humans, immune cells accumulate...
The immune-stromal cell interactions play a key role in health and diseases. In periodontitis, the most prevalent infectious disease in humans, immune cells accumulate in the oral mucosa and promote bone destruction by inducing receptor activator of nuclear factor-κB ligand (RANKL) expression in osteogenic cells such as osteoblasts and periodontal ligament cells. However, the detailed mechanism underlying immune-bone cell interactions in periodontitis is not fully understood. Here, we performed single-cell RNA-sequencing analysis on mouse periodontal lesions and showed that neutrophil-osteogenic cell crosstalk is involved in periodontitis-induced bone loss. The periodontal lesions displayed marked infiltration of neutrophils, and in silico analyses suggested that the neutrophils interacted with osteogenic cells through cytokine production. Among the cytokines expressed in the periodontal neutrophils, oncostatin M (OSM) potently induced RANKL expression in the primary osteoblasts, and deletion of the OSM receptor in osteogenic cells significantly ameliorated periodontitis-induced bone loss. Epigenomic data analyses identified the OSM-regulated RANKL enhancer region in osteogenic cells, and mice lacking this enhancer showed decreased periodontal bone loss while maintaining physiological bone metabolism. These findings shed light on the role of neutrophils in bone regulation during bacterial infection, highlighting the novel mechanism underlying osteoimmune crosstalk.
Topics: Humans; Mice; Animals; Neutrophils; Periodontitis; Cytokines; Alveolar Bone Loss; Osteogenesis; RANK Ligand
PubMed: 38413562
DOI: 10.1038/s41368-023-00275-8 -
Nature Communications Feb 2024The response to programmed death-1 (PD-1) blockade varies in hepatocellular carcinoma (HCC). We utilize a panel of 16 serum factors to show that a circulating level of...
The response to programmed death-1 (PD-1) blockade varies in hepatocellular carcinoma (HCC). We utilize a panel of 16 serum factors to show that a circulating level of serum amyloid A (SAA) > 20.0 mg/L has the highest accuracy in predicting anti-PD-1 resistance in HCC. Further experiments show a correlation between peritumoral SAA expression and circulating SAA levels in patients with progressive disease after PD-1 inhibition. In vitro experiments demonstrate that SAA induces neutrophils to express PD-L1 through glycolytic activation via an LDHA/STAT3 pathway and to release oncostatin M, thereby attenuating cytotoxic T cell function. In vivo, genetic or pharmacological inhibition of STAT3 or SAA eliminates neutrophil-mediated immunosuppression and enhances antitumor efficacy of anti-PD-1 treatment. This study indicates that SAA may be a critical inflammatory cytokine implicated in anti-PD-1 resistance in HCC. Targeting SAA-induced PD-L1 neutrophils through STAT3 or SAA inhibition may present a potential approach for overcoming anti-PD1 resistance.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; B7-H1 Antigen; Neutrophils; Serum Amyloid A Protein; Programmed Cell Death 1 Receptor; Glycolysis
PubMed: 38409200
DOI: 10.1038/s41467-024-46118-w -
Biomedicines Feb 2024Oncostatin M, a novel adipokine, plays a role in oogenesis, lipogenesis, and inflammation and may contribute to polycystic ovary syndrome pathogenesis and related...
Oncostatin M, a novel adipokine, plays a role in oogenesis, lipogenesis, and inflammation and may contribute to polycystic ovary syndrome pathogenesis and related metabolic problems. Adipokines are believed to contribute to developing polycystic ovary syndrome and its accompanying metabolic parameters, such as dyslipidemia, insulin resistance, and cardiovascular diseases. In this case-control study, the patients were grouped in a 1:1 ratio into either the polycystic ovary syndrome ( 32) or the control group ( 32). Serum levels of fasting glucose, insulin, C-reactive protein, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, white blood cell count, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, total testosterone, prolactin, estradiol, homeostasis model assessment of insulin resistance, and oncostatin M were analyzed. Oncostatin M levels were significantly lower, but C-reactive protein levels were substantially higher in the polycystic ovary syndrome group than in the control group ( = 0.002, = 0.001, respectively). Oncostatin M was inversely correlated with total cholesterol, non-high-density lipoprotein cholesterol, fasting glucose, and the luteinizing hormone/follicle-stimulating hormone ratio (ρ = -0.329, =0.017; ρ = -0.386, = 0.005; ρ = -0.440, = 0.001; ρ = -0.316, = 0.023, respectively). Conversely, there was no correlation between oncostatin M and total testosterone level (ρ = 0.220; = 0.118). In the context of inflammation and metabolic parameters, oncostatin M was inversely correlated with C-reactive protein, homeostatic model assessment for insulin resistance score, and low-density lipoprotein cholesterol (ρ = -0.353, = 0.019; ρ = -0.275, = 0.048; ρ = -0.470, < 0.001, respectively). Plasma oncostatin M levels were considerably lower in patients with polycystic ovary syndrome than in the control group, and this was inversely correlated with the hormonal and metabolic parameters of polycystic ovary syndrome. Thus, oncostatin M may be a novel therapeutic target for polycystic ovary syndrome and its metabolic parameters.
PubMed: 38397957
DOI: 10.3390/biomedicines12020355 -
Biochemical Genetics Feb 2024Psoriasis is a kind of severe immune-mediated systemic skin disorder, becoming a worldwide public health concern. Daturataturin A (DTA), a withanolide compound, exerts...
Psoriasis is a kind of severe immune-mediated systemic skin disorder, becoming a worldwide public health concern. Daturataturin A (DTA), a withanolide compound, exerts excellent anti-inflammatory and anti-proliferative properties. The objective of this study is to elucidate the effect of DTA on psoriasis and its potential mechanism. We established psoriasis-like keratinocytes model by stimulating HaCaT cells with M5 cocktail cytokines including Interleukin (IL)-17A, IL-22, oncostatin M, IL-1α, and tumor necrosis factor-α (TNF-α), followed by intervention with DTA. The potential effects and mechanisms of DTA on psoriasis were evaluated in vitro. DTA was found to be able to inhibit hyperproliferation, promote apoptosis, decrease the release of pro-inflammatory cytokines, downregulate keratin expression, and improve lipid metabolism via regulating the peroxisome proliferator-activated receptor (PPAR) signaling pathway by M5 cocktail cytokines stimulation in HaCaT cells. DTA ameliorated lipid metabolism of psoriasis and exerted the potential anti-psoriasis effects by regulating PPAR pathway in vitro, suggesting that DTA may act as a new therapeutic agent for psoriasis.
PubMed: 38379039
DOI: 10.1007/s10528-024-10680-1