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Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease. Patients with relapsing–remitting MS (RRMS) and secondary progressive MS (SPMS) differ in their responses to treatment; therefore, the correct diagnosis of the particular type of MS is crucial, and biomarkers that can differentiate between the forms of MS need to be identified. The aim of this study was to compare the levels of inflammatory parameters in serum samples from patients with RRMS and SPMS. The study group consisted of 60 patients with diagnosed MS. The patients were divided into RRMS and SPMS groups. In the RRMS patients, the usage of disease-modifying treatment was included in our analysis. The serum levels of inflammatory parameters were evaluated. The serum levels of BAFF, gp130 and osteopontin were significantly higher in SPMS patients than in RRMS patients. The serum levels of BAFF correlated with age in both RRMS and SPMS patients. The serum levels of MMP-2 were significantly higher in RRMS patients than in SPMS patients and correlated with the number of past relapses. The serum levels of IL-32 were significantly higher in RRMS treatment-naïve patients than in RRMS patients treated with disease-modifying therapy. Significant differences were found in BAFF, gp130, MMP-2 and osteopontin levels between RRMS and SPMS patients. Serum IL-32 levels were statistically lower in RRMS patients treated with disease-modifying therapy than in treatment-naïve patients. [ABSTRACT FROM AUTHOR]

Background Nintedanib is a tyrosine kinase inhibitor with efficacy in bevacizumab-resistant colorectal cancer models. This phase I/II study evaluated the recommended phase II dose and efficacy of nintedanib and capecitabine in refractory metastatic colorectal cancer. Methods Key eligibility criteria included refractory metastatic colorectal cancer and ECOG performance status of 1 or lower. The primary endpoint was 18-week progression-free survival (PFS). A 1-sided binomial test (at α = .1) compared the observed 18-week PFS with a historic control of.25. Results Forty-two patients were enrolled, including 39 at the recommended phase II dose. The recommended phase II dose was established to be nintedanib 200 mg by mouth twice daily and capecitabine 1000 mg/m2 by mouth twice daily. The protocol was evaluated for efficacy in 36 patients. The 18-week PFS was 42% (15/36 patients; P  = .0209). Median PFS was 3.4 mo. Median overall survival was 8.9 mo. Sixteen (44%) patients experienced a grade 3/4 adverse event, most commonly fatigue (8%), palmoplantar erythrodysesthesia (8%), aspartate aminotransferase elevation (6%), asthenia (6%), pulmonary embolus (6%), and dehydration (6%). Osteopontin levels at cycle 1, day 1 and cycle 3, day 1 as well as ΔCCL2 levels correlated to disease control at 18 weeks. Conclusions The combination of nintedanib and capecitabine is well tolerated. Clinical efficacy appears to be superior to regorafenib or tipiracil hydrochloride monotherapy. Further investigation of similar combinations is warranted. ClinicalTrials.gov identifier NCT02393755 [ABSTRACT FROM AUTHOR]

IL-33 is one of the novel IL-1 family members which are secreted in many tissues. Osteopontin (OPN) is a highly phosphorylated and glycosylated sialoprotein synthesized primarily in bone tissue, which the major role is to participate in biomineralization. Both IL-33 and OPN are mentioned associated with inflammatory disorders. Diabetes Mellitus Type 2 (T2DM) is a metabolic disorder in glucose homeostasis, which its pathophysiology involves a low-grade chronic inflammation. The aim of this study is to evaluate the IL-33 and OPN levels in well and poorly regulated T2DM patients. Three group were determined as; T2DM with HbA1c level below 8% as Group HbA1c <8, T2DM with HbA1c level of 8% and above as Group HbA1c ≥8, and control group consisting of healthy individuals respectively. Each group included 50 participant (n=50). Age, fasting plasma glucose, HbA1c and lipid parameters (total cholesterol, triglyceride, LDL, HDL), IL-33 and OPN values were examined. There was a significant statistical difference between the fasting plasma glucose, HbA1c, triglyceride, and HDL levels of the groups (p<0.001). OPN levels of the groups were not found statistically different but IL-33 levels were found to be significantly higher in the HbA1c <8 group compared to the control group (p=0.0108). IL-33 and OPN levels do not differ in terms of well or poorly regulation in T2DM patients and HbA1c level alone, is insufficient to be a predictor of OPN and IL-33 activity [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is one of the most frequent and severe childhood muscle diseases. Its pathophysiology is multifaceted and still incompletely understood, but we and others have previously shown that oxidative stress plays an important role. In particular, we have demonstrated that inhibition of mitochondrial monoamine oxidases could improve some functional and biohumoral markers of the pathology. In the present study we report the use of dystrophic mdx mice to evaluate the efficacy of a dual monoamine oxidase B (MAO-B)/semicarbazide-sensitive amine oxidase (SSAO) inhibitor, PXS-5131, in reducing inflammation and fibrosis and improving muscle function. We found that a one-month treatment starting at three months of age was able to decrease reactive oxygen species (ROS) production, fibrosis, and inflammatory infiltrate in the tibialis anterior (TA) and diaphragm muscles. Importantly, we also observed a marked improvement in the capacity of the gastrocnemius muscle to maintain its force when challenged with eccentric contractions. Upon performing a bulk RNA-seq analysis, PXS-5131 treatment affected the expression of genes involved in inflammatory processes and tissue remodeling. We also studied the effect of prolonged treatment in older dystrophic mice, and found that a three-month administration of PXS-5131 was able to greatly reduce the progression of fibrosis not only in the diaphragm but also in the heart. Taken together, these results suggest that PXS-5131 is an effective inhibitor of fibrosis and inflammation in dystrophic muscles, a finding that could open a new therapeutic avenue for DMD patients. [ABSTRACT FROM AUTHOR]

Niche signals maintain stem cells in a prolonged quiescence or transiently activate them for proper regeneration1. Altering balanced niche signalling can lead to regenerative disorders. Melanocytic skin nevi in human often display excessive hair growth, suggesting hair stem cell hyperactivity. Here, using genetic mouse models of nevi2,3, we show that dermal clusters of senescent melanocytes drive epithelial hair stem cells to exit quiescence and change their transcriptome and composition, potently enhancing hair renewal. Nevus melanocytes activate a distinct secretome, enriched for signalling factors. Osteopontin, the leading nevus signalling factor, is both necessary and sufficient to induce hair growth. Injection of osteopontin or its genetic overexpression is sufficient to induce robust hair growth in mice, whereas germline and conditional deletions of either osteopontin or CD44, its cognate receptor on epithelial hair cells, rescue enhanced hair growth induced by dermal nevus melanocytes. Osteopontin is overexpressed in human hairy nevi, and it stimulates new growth of human hair follicles. Although broad accumulation of senescent cells, such as upon ageing or genotoxic stress, is detrimental for the regenerative capacity of tissue4, we show that signalling by senescent cell clusters can potently enhance the activity of adjacent intact stem cells and stimulate tissue renewal. This finding identifies senescent cells and their secretome as an attractive therapeutic target in regenerative disorders.

Abstract Reconstruction of the neurovascular unit is essential for the repair of spinal cord injury (SCI). Nonetheless, detailed documentation of specific vascular changes following SCI and targeted interventions for vascular treatment remains limited. This study demonstrates that traumatic pathological vascular remodeling occurs during the chronic phase of injury, characterized by enlarged vessel diameter, disruption of blood‐spinal cord barrier, endothelial‐to‐mesenchymal transition (EndoMT), and heightened extracellular matrix deposition. After SCI, osteopontin (OPN), a critical factor secreted by immune cells, is indispensable for early vascular regeneration but also contributes to traumatic pathological vascular remodeling. This work further elucidates the mechanism by which OPN influences spinal cord microvascular endothelial cells, involving Akt‐mediated Foxo1 phosphorylation. This process facilitates the extranuclear transport of Foxo1 and decreases Smad7 expression, leading to excessive activation of the TGF‐β signaling pathway, which ultimately results in EndoMT and fibrosis. Targeted inhibition of Foxo1 phosphorylation through an endothelium‐specific aptamer‐liposome small molecule delivery system significantly mitigates vascular remodeling, thereby enhancing axon regeneration and neurological function recovery following SCI. The findings offer a novel perspective for drug therapies aimed at specifically targeting pathological vasculature after SCI.

Osteopontin (OPN) is a pro-inflammatory protein that influences bone remodelling, wound healing, angiogenesis, allergic inflammation, and skin diseases such as psoriasis, contact dermatitis and skin cancer. However, the role of OPN in the skin remains unclear. Therefore, this study aimed to investigate the role of OPN in the skin, particularly in the context of ultraviolet (UV) irradiation-induced inflammation. OPN expression and its effects on inflammatory modulators were assessed in human skin, in a mouse model and in vitro, using a UV source emitting both UVB and UVA radiation, which collectively contribute to UV-induced skin inflammation. OPN expression increased in human and mouse skin after UV irradiation. Compared with wild-type mice, UV irradiation-induced skin phenotypes, such as erythema and skin thickening, were alleviated in OPN−/− mice. In addition, the number of immune cells recruited to the skin after UV irradiation and the expression of inflammatory cytokines and matrix metalloproteinases (MMPs) were observed to be decreased in the skin of OPN−/− mice compared with that of wild-type mice. By contrast, the degree of skin inflammation was higher in the hOPN KI mice than in wild-type mice. Treatment with recombinant OPN increased the expression of MMP-1 and inflammatory cytokines in human dermal fibroblasts and epidermal keratinocytes in vitro. Our results suggest that OPN may play a regulatory role in UV-induced skin inflammation.

Summary: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a spectrum of disease states ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), which can eventually lead to the development of cirrhosis and hepatocellular carcinoma. Macrophages have long been implicated in driving the progression from steatosis to end-stage disease, yet we still know relatively little about the precise involvement of these cells in MASLD progression and/or regression. Rather, there are a considerable number of conflicting reports regarding the precise roles of these cells. This confusion stems from the fact that, until recently, macrophages in the liver were considered a homogenous population. However, thanks to recent technological advances including multi-parameter flow cytometry, single-cell RNA sequencing and spatial proteogenomics, we now know that this is not the case. Rather hepatic macrophages, even in the healthy liver, are heterogenous, existing in multiple subsets with distinct transcriptional profiles and hence likely functions. This heterogeneity is even more prominent in MASLD, where the macrophage pool consists of multiple different subsets of resident and recruited cells. To probe the unique functions of these cells and determine if targeting macrophages may be a viable therapeutic strategy in MASLD, we first need to unravel this complexity and decipher which populations and/or activation states are present and what functions each of these may play in driving MASLD progression. In this review, we summarise recent advances in the field, highlighting what is currently known about the hepatic macrophage landscape in MASLD and the questions that remain to be tackled.

Introduction: Psoriasis is a chronic inflammatory disease affecting 2%-3% of the global population via immune-mediated mechanisms. Osteopontin plays a crucial role in T-helper 1 and T-helper 17-mediated illnesses, including psoriasis. Ocular complications in psoriasis have been reported and their assessment is of importance. Osteopontin is normally expressed constitutively in ocular structures and is linked to ocular homeostasis. Objective: This study aimed to clarify the role of osteopontin (OPN) in psoriasis (PS) and its correlation with disease severity and ocular manifestations. Methods: A case-control study involving 40 psoriatic patients and an equal number of age and sex-matched healthy subjects was conducted. We used the psoriasis area severity index (PASI) to assess disease severity and performed a comprehensive ophthalmological examination. Additionally, we measured serum osteopontin levels using Enzyme-Linked Immunosorbent Assay (ELISA) in both groups. Results: A significant elevation in serum OPN levels in psoriatic patients compared to controls was found (P=0.00). Furthermore, there was a highly significant positive correlation between serum OPN levels and patient age, disease duration, and PASI scores. Notably, a higher prevalence of ocular complications, including blepharitis, corneal affection, conjunctivitis, keratoconjunctivitis sicca, and cataract, in psoriatic patients compared to controls was observed. Importantly, significant associations between serum OPN levels and the presence of cataracts and intraocular pressure (IOP) were identified. Additionally, significant correlations between serum OPN levels and measures of visual acuity and ocular surface health were found. Conclusions: Osteopontin is considered a marker of psoriasis severity and is associated with ocular comorbidities in psoriasis.

Abstract Osteopontin (OPN) is a multi‐functional glycoprotein that coordinates the innate immune response, prevents nanocrystal formation in renal tubule fluid, and is a biomarker for kidney injury. OPN expression is markedly increased in cystic epithelial cells of polycystic kidney disease (PKD) kidneys; however, its role in PKD progression remains unclear. We investigated the in vitro effects of recombinant OPN on the proliferation of tubular epithelial cells from PKD and normal human kidneys and in vivo effects of OPN deletion on kidney cyst formation, fibrosis, and mineral metabolism in pcy/pcy mice, a non‐orthologous model of autosomal‐dominant PKD. In vitro studies revealed that OPN enhanced the proliferation of PKD cells but had no effect on normal kidney cells. Deletion of OPN in pcy/pcy mice significantly reduced kidney cyst burden; however, this was accompanied by increased fibrosis and no change in kidney function. The loss of OPN had no effect on kidney macrophage numbers, cyst epithelial cell proliferation, or apoptosis. Furthermore, there was no difference in kidney mineral deposition or mineral metabolism parameters between pcy/pcy mice with and without OPN expression. Global deletion of OPN reduced kidney cyst burden, while paradoxically exacerbating kidney fibrosis in mice with cystic kidney disease.

Objective: To investigate the relationship between serum osteopontin (OPN), high mobility group protein B1 (HMGB1) and T cell subsets and chemotherapy efficacy in patients with multidrug-resistant pulmonary tuberculosis (MDR-TB). Methods: 147 MDR-TB patients (MDR-TB group) admitted to Xuzhou Infectious Disease Hospital from March 2018 to September 2021 were selected, and 109 non-MDR-TB patients (control group) admitted to Xuzhou Infectious Disease Hospital during the same period were selected. The correlation between serum OPN, HMGB1 and peripheral blood T cell subsets in MDR-TB group was analyzed by Pearson correlation analysis. The factors of unsuccessful MDR-TB treatment were analyzed by multivariate Logistic regression analysis. Results: Serum OPN and HMGB1 in MDR-TB group were positively correlated with peripheral blood CD8+ count (P<0.05), and negatively correlated with peripheral blood CD3+ count, CD4+ count and CD4+ /CD8+ ratio (P<0.05). Multivariate Logistic regression analysis showed that cavity, high OPN and high HMGB1 were risk factors for unsuccessful MDR-TB treatment (P<0.05). Conclusion: The levels of serum OPN and HMGB1 in MDR-TB patients are significantly increase, which are relate to the abnormality of T cell subsets and the failure of chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract Background Perihematomal edema (PHE) after post-intracerebral hemorrhage (ICH) has complex pathophysiological mechanisms that are poorly understood. The complicated immune response in the post-ICH brain constitutes a crucial component of PHE pathophysiology. In this study, we aimed to characterize the transcriptional profiles of immune cell populations in human PHE tissue and explore the microscopic differences between different types of immune cells. Methods 9 patients with basal ganglia intracerebral hemorrhage (hematoma volume 50-100 ml) were enrolled in this study. A multi-stage profile was developed, comprising Group1 (n = 3, 0–6 h post-ICH, G1), Group2 (n = 3, 6–24 h post-ICH, G2), and Group3 (n = 3, 24–48 h post-ICH, G3). A minimal quantity of edematous tissue surrounding the hematoma was preserved during hematoma evacuation. Single cell RNA sequencing (scRNA-seq) was used to map immune cell populations within comprehensively resected PHE samples collected from patients at different stages after ICH. Results We established, for the first time, a comprehensive landscape of diverse immune cell populations in human PHE tissue at a single-cell level. Our study identified 12 microglia subsets and 5 neutrophil subsets in human PHE tissue. What’s more, we discovered that the secreted phosphoprotein-1 (SPP1) pathway served as the basis for self-communication between microglia subclusters during the progression of PHE. Additionally, we traced the trajectory branches of different neutrophil subtypes. Finally, we also demonstrated that microglia-produced osteopontin (OPN) could regulate the immune environment in PHE tissue by interacting with CD44-positive cells. Conclusions As a result of our research, we have gained valuable insight into the immune-microenvironment within PHE tissue, which could potentially be used to develop novel treatment modalities for ICH.

Abstract Background This study aims to explore the potential of utilizing the expression levels of cannabinoid receptor 2 (CB2), μ-opioid receptor (MOR), MCP-1, IL-17, IFN-γ, and osteopontin as predictors for the severity of SARS-CoV-2 infection. The overarching goal is to delineate the pathogenic mechanisms associated with SARS-CoV-2. Methods Using quantitative Real-time PCR, we analyzed the gene expression levels of CB2 and MOR in nasopharynx specimens obtained from patients diagnosed with SARS-CoV-2 infection, with 46 individuals classified as having severe symptoms and 46 as non-severe. Additionally, we measured the circulating levels of MCP-1, IL-17, IFN-γ, and osteopontin using an ELISA assay. We examined the predictive capabilities of these variables and explored their correlations across all patient groups. Results Our results demonstrated a significant increase in MOR gene expression in the epithelium of patients with severe infection. The expression of CB2 receptor was also elevated in both male and female patients with severe symptoms. Furthermore, we observed concurrent rises in MCP-1, IL-17, IFN-γ, and osteopontin levels in patients, which were linked to disease severity. CB2, MOR, MCP-1, IL-17, IFN-γ, and osteopontin showed strong predictive abilities in distinguishing between patients with varying degrees of SARS-CoV-2 severity. Moreover, we identified a significant correlation between CB2 expression and the levels of MOR, MCP-1, osteopontin, and IFN-γ. Conclusions These results underline the interconnected nature of molecular mediators in a sequential manner, suggesting that their overexpression may play a role in the development of SARS-CoV-2 infections. Graphical Abstract

Background: Diabetic foot is a major complication of diabetes. The bone transverse transport method could be applied in clinics for treatment, which could improve the metabolism of the tissues via lasting distraction forces. However, the process’ specific regulating mechanism is still unknown. Methods: Based on the notion that the healing of bones involves the recruitment of calcium ions, in this study, we established the model of tibial cortex transverse transport (TTT) on rats and then used tissue immunologic detection, such as the double fluorescent staining to explore the expression of the calcium channels’ calcium release-activated calcium modulator 1 (Orai1)/stromal interaction molecule 1 (STIM1), which belong to the store-operated calcium entry (SOCE) signaling pathways on the tissues around the bone transport area. By using the laser capture microdissection (LCM) tool, we acquired samples of tissues around the bone and endeavored to identify pivotal protein molecules. Subsequently, we validated the functions of key protein molecules through in vitro and in vivo experiments. Results: After protein profile analysis, we found the differentially expressed key protein osteopontin (OPN). The in vitro experiments verified that, being stimulated by OPN, the migration, proliferation, and angiogenesis of human umbilical vein endothelial cells (HUVEC) were observed to be enhanced. The activation of Orai1/STIM1 might increase the activity of endothelial nitric oxide synthase (eNOS) and its effect on releasing nitric oxide (NO). Subsequently, the migration and proliferation of the HUVECs are improved, which ultimately accelerates wound healing. These signaling pathway was also observed in the OPN-stimulated healing process of the skin wound surface of diabetic mice. Conclusion: This study identifies the molecular biological mechanism of OPN-benefited the migration and proliferation of the HUVECs and provides ideas for searching for new therapeutic targets for drugs that repair diabetes-induced wounds to replace invasive treatment methods. The translational potential of this article: The OPN is highly expressed in the tissues surrounding the TTT bone transfer area, which may possibly stimulate the activation of eNOS to increase NO release through the SOCE pathway mediated by Orai1/STIM1. This mechanism may play a significant role in the angiogenesis of diabetic foot's wounds promoted by TTT, providing new therapeutic strategies for the non-surgical treatment for this disease.

Abstract Background First-degree relatives (FDRs) of rheumatoid arthritis (RA) patients are known to have increased risk of developing the disease. The detection of altered bone metabolism in FDRs could be a predictor of the disease. Musculoskeletal ultrasound (MSUS) is known for its ability to detect subclinical joint inflammation in RA, but changes in FDRs are not yet described. We aimed to study serum Osteopontin (OPN) and Osteoprotegerin (OPG) levels in FDRs of RA patients as markers of altered bone metabolism in relation to clinical, laboratory and musculoskeletal ultrasound (MSUS) findings. Methods Fifty-five individuals were included, 20 had definite RA, 25 were first degree relatives (FDRs) of RA patients, and 10 healthy controls. Clinical evaluation for joint swelling/tenderness was performed for all. ESR, CRP, rheumatoid factor (RF), anti-citrullinated antibodies (ACPA), OPN, OPG, and Musculoskeletal ultrasound (MSUS) by the US7 score were evaluated. Results Osteoprotegerin was significantly higher in RA (143.89 pg/ml ± 365.47) than in FDRs (22.23 pg/ml ± 65.73; p = 0.009) and controls (6.20 pg/ml ± 12.43; p = 0.003). OPN was also higher in RA (3.66 ng/ml ± 4.20) than in FDRs (1.97 ng/ml ± 1.04) and controls (2.81 ng/ml ± 1.31), though not significant (p = 0.102). Eight of 25 FDRs (32%) had arthralgia without clinical arthritis and 17/25 (68%) were asymptomatic. FDRs with arthralgia had significantly higher ESR and CRP levels than asymptomatic FDRs (9.82 mm/h ± 4.13; p = 0.003, and 3.93 mg/l ± 3.58; p = 0.003). Osteoprotegerin was higher in FDRs than in controls, and also in those with arthralgia (51.55 pg/ml ± 114.68) than in those without (8.44 pg/ml ± 9.67), though without significant difference. OPN was higher in FDRs with arthralgia (2.09 ng/ml ± 1.19) than in asymptomatic (1.70 ng/ml ± 0.55), also without significant difference. Pathologic findings by US7 were detected in 10/25 (40%) FDRs, of which three (12%) had arthralgia and seven (28%) were asymptomatic. Conclusions The raised OPG and lower OPN in FDRs than in controls reflect an altered bone metabolism which could precede clinical disease phase. OPN and OPG could serve as markers of altered preclinical bone metabolism in FDRs of RA. US7 score might be a useful screening tool to identify ‘at-risk’ individuals.

Osteopontin (OPN), a bioactive milk protein in breast milk, has diverse applications in food and medicine. OPN is predominantly extracted from fresh bovine milk; however, the concentration of OPN in bovine milk is exceedingly low. To address these issues, in the present study, we used Komagataella phaffii for the recombinant expression of human OPN (hOPN). The results of host cell screening revealed that X33 cells were more suitable than other K. phaffii hosts for hOPN expression, yielding a titer of 340.5 μg/L. Subsequently, it was observed that the extracellular production of hOPN significantly increased to 8.02 mg/L from strain XPSA01 using the PAOX1 promoter and the hybrid signal peptide PROSCW10-α. Meanwhile, the co-expression of transcription factors, translation factors, and molecular chaperones resulted in a 2.94-fold enhancement in extracellular hOPN production compared with that in XPSA01, resulting in a titer of 23.6 mg/L. Finally, the above strategies were combined to obtain the recombinant strain XPSA01-CP, which achieved titers of 35.6 and 128.5 mg/L hOPN in shake-flask fermentation and 3-L bioreactor, respectively. To the best of our knowledge, this is the highest extracellular yield of hOPN ever reported.

Osteopontin (OPN) is a ubiquitously expressed protein with a wide range of physiological functions, including roles in bone mineralization, immune regulation, and wound healing. OPN has been implicated in the pathogenesis of several forms of chronic kidney disease (CKD) where it promotes inflammation and fibrosis and regulates calcium and phosphate metabolism. OPN expression is increased in the kidneys, blood, and urine of patients with CKD, particularly in those with diabetic kidney disease and glomerulonephritis. The full-length OPN protein is cleaved by various proteases, including thrombin, matrix metalloproteinase (MMP)-3, MMP-7, cathepsin-D, and plasmin, producing N-terminal OPN (ntOPN), which may have more detrimental effects in CKD. Studies suggest that OPN may serve as a biomarker in CKD, and while more research is needed to fully evaluate and validate OPN and ntOPN as CKD biomarkers, the available evidence suggests that they are promising candidates for further investigation. Targeting OPN may be a potential treatment strategy. Several studies show that inhibition of OPN expression or activity can attenuate kidney injury and improve kidney function. In addition to its effects on kidney function, OPN has been linked to cardiovascular disease, which is a major cause of morbidity and mortality in patients with CKD.

Background: Perihematomal edema (PHE) after post-intracerebral hemorrhage (ICH) has complex pathophysiological mechanisms that are poorly understood. The complicated immune response in the post-ICH brain constitutes a crucial component of PHE pathophysiology. In this study, we aimed to characterize the transcriptional profiles of immune cell populations in human PHE tissue and explore the microscopic differences between different types of immune cells. Methods: 9 patients with basal ganglia intracerebral hemorrhage (hematoma volume 50-100 ml) were enrolled in this study. A multi-stage profile was developed, comprising Group1 (n = 3, 0–6 h post-ICH, G1), Group2 (n = 3, 6–24 h post-ICH, G2), and Group3 (n = 3, 24–48 h post-ICH, G3). A minimal quantity of edematous tissue surrounding the hematoma was preserved during hematoma evacuation. Single cell RNA sequencing (scRNA-seq) was used to map immune cell populations within comprehensively resected PHE samples collected from patients at different stages after ICH. Results: We established, for the first time, a comprehensive landscape of diverse immune cell populations in human PHE tissue at a single-cell level. Our study identified 12 microglia subsets and 5 neutrophil subsets in human PHE tissue. What's more, we discovered that the secreted phosphoprotein-1 (SPP1) pathway served as the basis for self-communication between microglia subclusters during the progression of PHE. Additionally, we traced the trajectory branches of different neutrophil subtypes. Finally, we also demonstrated that microglia-produced osteopontin (OPN) could regulate the immune environment in PHE tissue by interacting with CD44-positive cells. Conclusions: As a result of our research, we have gained valuable insight into the immune-microenvironment within PHE tissue, which could potentially be used to develop novel treatment modalities for ICH. [ABSTRACT FROM AUTHOR]

Study Design. Basic science study using a hemisection spinal cord injury (SCI) model. Objective. We sought to assess the effect of blocking osteopontin (OPN) upregulation on motor function recovery and pain behavior after SCI and to further investigate the possible downstream target of OPN in the injured spinal cord. Summary of Background Data. OPN is a noncollagenous extracellular matrix protein widely expressed across different tissues. Its expression substantially increases following SCI. A previous study suggested that this protein might contribute to locomotor function recovery after SCI. However, its neuroprotective potential was not fully explored, nor were the underlying mechanisms. Materials and Methods. We constructed a SCI mouse model and analyzed the expression of OPN at different time points and the particular cell distribution in the injured spinal cord. Then, we blocked OPN upregulation with lentivirus-delivering siRNA targeting OPN specifically and examined its effect on motor function impairment and neuropathic pain after SCI. The underlying mechanisms were explored in the OPN-knockdown mice model and cultured vascular endothelial cells. Results. The proteome study revealed that OPN was the most dramatically increased protein following SCI. OPN in the spinal cord was significantly increased three weeks after SCI. Suppressing OPN upregulation through siRNA exacerbated motor function impairment and neuropathic pain. In addition, SCI resulted in an increase in vascular endothelial growth factor (VEGF), AKT phosphorylation, and angiogenesis within the spinal cord, all of which were curbed by OPN reduction. Similarly, OPN knockdown suppressed VEGF expression, AKT phosphorylation, cell migration, invasion, and angiogenesis in cultured vascular endothelial cells. Conclusion. OPN demonstrates a protective influence against motor function impairment and neuropathic pain following SCI. This phenomenon may result from the proangiogenetic effect of OPN, possibly due to activation of the VEGF and/or AKT pathways. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a hypertensive disorder in pregnancy associated with significant fetal and maternal complications. Antiphospholipid syndrome (APS) is an acquired form of thrombophilia characterized by recurrent venous or arterial thrombosis and obstetric complications that significantly increases morbidity and mortality rates. While preeclampsia may not be the most prevalent obstetric complication in APS, it significantly impacts the long-term health of both mother and child. The treatment of preeclampsia in antiphospholipid syndrome is different from the treatment of preeclampsia as an independent disease. Despite current treatments involving anticoagulants, antiplatelet agents, and antihypertensive drugs, obstetric complications may persist, underscoring the need for cohesive management and effective treatments. The objective of our review is to briefly present knowledge about the physiopathology of preeclampsia and the role of antiphospholipid antibodies in this process. Based on the existing literature, our review aims to identify future directions in molecular pathology toward the discovery of biomarkers and targeted treatments. The application of multidisciplinary approaches and prognostic models, including new biomarkers, could be beneficial in the prediction of PE. [ABSTRACT FROM AUTHOR]

Chronic immune activation in tuberculosis (TB) associated with human immunodeficiency virus (HIV) infection (HIV/TB) modifies their clinical course. We prospectively measured osteopontin (OPN), full-length galectin-9 (FL-Gal9), and total-Gal9 (T-Gal9) levels in 32 patients with HIV/TB coinfection treated with anti-tuberculosis and antiretroviral therapies over 6–18 months to determine the amelioration of inflammatory conditions in response to the therapies. We observed a significant time-dependent decrease in FL-Gal9 in both pulmonary TB (PTB, n = 20) and extrapulmonary TB (EPTB, n = 12) patients. The levels of T-Gal9, OPN, and CRP decreased significantly after treatment in only PTB patients. We calculated the inflammatory score (INS) indicating immunologic recovery based on the decline in OPN, FL-Gal9, T-Gal9, and CRP levels. Baseline levels of T-Gal9 and OPN positively correlated with INS in all TB and only PTB patients, respectively, indicating that their levels predict better recovery. In contrast, FL-Gal9 levels at the second visit negatively correlated with INS in EPTB patients. The decrease rate in OPN levels at the second visit also correlated positively with INS in PTB patients. Women showed a higher INS and lower levels of FL-Gal9 than men. The patients with moderate grade severity on chest X-ray had higher CD4 cell numbers than those with limited grade severity. Monitoring these markers will help to predict and assess the response to therapy as well as to devise strategies to reduce the complications caused by chronic immune activation in patients with HIV/TB coinfection. [ABSTRACT FROM AUTHOR]

The regenerative function of stem cells is compromised when the proportion of senescent stem cells increases with ageing advance. Therefore, combating stem cell senescence is of great importance for stem cell-based tissue engineering in the elderly, but remains largely unexplored. Osteopontin (OPN), a glycosylated phosphoprotein, is one of the key extracellular matrix molecules in bone tissue. OPN activates various signalling pathways and modulates cellular activities, including cell senescence. However, the role of OPN in stem cell senescence remains largely unknown. This study aims to investigate if OPN modulates cell senescence and bone regenerative function in human adipose-derived mesenchymal stem cells (ASCs), and to determine the underlying mechanisms. We first developed a senescent ASC model using serial passaging until passage 10 (P10), in which senescent cells were characterised by reduced proliferation and osteogenic differentiation capacity compared to P4 ASCs. The conditioned medium from P10 ASCs exhibited a diminished trophic effect on human osteoblasts (HOBs), compared to that from P4 ASCs. P10 ASCs on OPN-coated surface showed rejuvenated phenotype and enhanced osteogenic differentiation. The conditioned medium from P10 ASCs on OPN-coating improved trophic effects on HOBs. OPN regulated the morphology of senescent ASCs, transforming them from a more rounded and flattened cell shape to an elongated shape with a smaller area. These findings demonstrated the effects of OPN in restoring senescent ASCs functions, possibly through a mechanism that involves the modulation of cell morphology, indicating that OPN might hold a great potential for rejuvenating senescent stem cells and could potentially open a new venue for regenerating bone tissue in age-related diseases. [ABSTRACT FROM AUTHOR]

STUDY QUESTION How does osteopontin (OPN) in endometriosis ectopic stromal cells (EESCs) participate in the pathogenesis of endometriosis and achieve non-invasive detection in vitro ? SUMMARY ANSWER Targeted OPN regulates endometriosis's necroptosis and inflammatory state by inhibiting the RhoA/reactive oxygen species (ROS) axis, thereby alleviating endometriosis and enabling non-invasive detection of menstrual blood in vitro. WHAT IS KNOWN ALREADY Endometriosis is a chronic inflammatory disease. Recent studies have shown that OPN plays an important role in disease progression by regulating cell death and inflammation. STUDY DESIGN, SIZE, DURATION The study included 20 patients diagnosed with endometriosis (confirmed by laparoscopy and histology) and 10 controls without endometriosis. Endometriotic stromal cells were isolated from endometrial samples, while menstrual blood endometrial cells (MESCs) were isolated from menstrual blood. These cells were then cultured in vitro and utilized in subsequent experiments. PARTICIPANTS/MATERIALS, SETTING, METHODS OPN expression in EESCs was assessed using inflammatory factor sequencing, immunohistochemical staining (IHC), quantitative real-time PCR (qRT–PCR) analysis, and Western blotting (WB). The biological behavior of OPN and its effects on inflammatory factors were examined using EdU, wound-healing, Transwell, and ELISA assays. Necroptosis in EESCs and its impact on inflammatory factors were detected through qRT–PCR, WB, and Calcein-AM/PI fluorescence assays. The examination of mitochondrial stress in EESCs involved the use of the Mitochondrial Membrane Potential (ΔΨm) Assay, ROS detection, and Calcein-AM Loading/cobalt chloride Quenching. qRT–PCR, WB, and other experiments were conducted to verify the regulation of necroptosis and inflammatory factor levels in EESCs by OPN through the RhoA/ROS axis. Knockdown of OPN and its inhibitory effect on endometriosis lesion size were confirmed using AAV9 virus, IHC, qRT–PCR, WB, and other experiments. Additionally, OPN expression in MESCs was detected using transcriptome sequencing, RT-PCR, WB, and other experiments. MAIN RESULTS AND THE ROLE OF CHANCE In vitro assays demonstrated a significant upregulation of OPN in EESCs, and the knockdown of OPN effectively inhibited necroptosis and the release of inflammatory factors. OPN inhibited necroptosis and inflammatory factor release by mediating RhoA-dependent ROS production and blocking mixed lineage kinase domain-like protein phosphorylation at the cell membrane. In vivo , targeting of OPN can inhibit the growth of endometriosis lesions. Clinically, OPN was also significantly upregulated in the menstrual blood of patients with endometriosis. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Due to limitations in obtaining surgical specimens, our study primarily involved collecting endometriosis tissues from women during the proliferative and secretory phases of the menstrual cycle. We observed a significant overexpression of OPN in the samples used for our investigation. However, the expression of OPN in endometriosis tissues during the intermenstrual phase remains unknown. WIDER IMPLICATIONS OF THE FINDINGS Our findings highlight the pivotal role of the OPN/RhoA/ROS axis in the regulation of necroptosis and the release of inflammatory factors. OPN knockdown exerts a therapeutic effect in vivo , and the high expression detection of OPN in menstrual blood in vitro. In summary, targeting OPN provides possibilities for the treatment and detection of endometriosis. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the National Natural Science Foundation of China (82071626), the Zhejiang Province Public Welfare Technology Application Research Project (LGF21H040010), and the Clinical Research project of the Second Affiliated Hospital of Wenzhou Medical University (1010293). The authors have no conflicts of interest. [ABSTRACT FROM AUTHOR]

Importance: Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis characterized by inflammation within the central nervous system. However, inflammation in non-neuronal tissues, including the lungs, has not been fully evaluated. Objective: This study evaluated the inflammatory response in lungs of EAE mice by immunohistochemistry and histochemistry. Methods: Eight adult C57BL/6 mice were injected with myelin oligodendrocyte glycoprotein35-55 to induce the EAE. Lungs and spinal cords were sampled from the experimental mice at the time of sacrifice and used for the western blotting, histochemistry, and immunohistochemistry. Results: Histopathological examination revealed inflammatory lesions in the lungs of EAE mice, characterized by infiltration of myeloperoxidase (MPO)- and galectin-3-positive cells, as determined by immunohistochemistry. Increased numbers of collagen fibers in the lungs of EAE mice were confirmed by histopathological analysis. Western blotting revealed significantly elevated level of osteopontin (OPN), cluster of differentiation 44 (CD44), MPO and galectin-3 in the lungs of EAE mice compared with normal controls (p < 0.05). Immunohistochemical analysis revealed both OPN and CD44 in ionized calcium-binding adapter molecule 1-positive macrophages within the lungs of EAE mice. Conclusions and Relevance: Taken together, these findings suggest that the increased OPN level in lungs of EAE mice led to inflammation; concurrent increases in proinflammatory factors (OPN and galectin-3) caused pulmonary impairment. [ABSTRACT FROM AUTHOR]

Osteopontin (OPN) is a glycoprotein involved in Th1 and Th17 differentiation, and inflammation and tissue remodeling. OPN is a biomarker of disease activity in patients with autoimmune inflammatory conditions. This study aimed to assess the diagnostic and prognostic value of OPN in interstitial lung diseases (ILDs). Between May 2016 and October 2019, 344 patients with ILD were recruited at the Hospital Universitario Marqués de Valdecilla (Spain) and were prospectively followed-up. This study involved the determination of OPN serum levels by ELISA and OPN RNA expression quantified using qPCR. Six genetic polymorphisms in OPN (rs28357094, rs2853749, rs2853750, rs11728697, rs7695531, and rs1126616) were genotyped using TaqMan assays. OPN serum levels were also assessed in 140 healthy controls. OPN serum levels (median [interquartile range]) were significantly higher in ILD patients than in controls (1.05 [0.75–1.51] ng/mL versus 0.81 [0.65–0.98] ng/mL in healthy controls; p < 0.01). OPN serum levels were inversely correlated with the forced vital capacity. OPN serum levels were also higher in ILD patients who died or underwent lung transplantation when compared with the remaining ILD patients (1.15 [0.80–1.72] ng/mL versus 0.99 [0.66–1.32] ng/mL; p = 0.05). Survival worsened in ILD patients with OPN > 1.03 ng/mL at 1, 3, and 5 years. No statistically significant differences in the genetic frequencies of OPN polymorphisms or the RNA expression were found among the different ILD groups. Elevated levels of OPN in the serum may be a useful indicator in identifying patients with ILD who are more likely to experience poor outcomes. [ABSTRACT FROM AUTHOR]

Osteopontin (OPN) is a multifunctional protein that plays diverse roles in physiological and pathological processes. It acts as a molecular bridge between cells and their extracellular environment, interacting with various cell surface receptors and participating in cellular processes such as adhesion, migration, inflammation, and signaling pathways. OPN exists in different isoforms and undergoes post-translational modifications that can alter its properties and functions. In physiological contexts, OPN contributes to tissue maintenance, wound healing, immune system regulation, and stress response mechanisms. However, it is also involved in the pathogenesis of conditions such as atherosclerosis, cancer, autoimmune disorders, chronic inflammation, and sepsis. OPN can serve as a diagnostic and prognostic biomarker for these disorders, and certain OPN gene polymorphisms are associated with disease susceptibility or progression. This Special Issue of Biomedicines explores the multifaceted roles of OPN in health and disease through eight papers, including studies on its role as a biomarker for glomerulopathies, coronary artery disease, melanoma metastasis, and dental biofilm formation. The issue also includes reviews on OPN's involvement in the central nervous system, thyroid cancer, and infectious diseases. Overall, OPN plays a central role in various biological activities and continues to be a subject of ongoing research to further understand its significance in different contexts. [Extracted from the article]

Background and Objectives: Systemic inflammatory response syndrome (SIRS) is one of the most significant complications after on-pump heart surgery procedures. High cytokine levels have been shown after open-heart surgeries and a genetic predisposition seems to be an important underlying modulatory characteristic for SIRS. To investigate the association between interleukin 18 -607 C/A, interleukin 18 -137 G/C and osteopontin 9250 C/T genetic polymorphisms and SIRS in on-pump CABG patients. Materials and Methods: Two hundred consecutive elective on-pump CABG patients were recruited prospectively to the study. Genomic DNA was extracted from whole blood and genotyping was determined by sequence specific PCR or PCR-RFLP methods for related polymorphisms. Results: SIRS incidence was 60.2%, 38.1%, 18.9% on postoperative day 1, 2 and 3, respectively, in the whole study population. The SIRS rate on the second postoperative day was 13% and 43.4%, respectively, in osteopontin 9250 C/T T allele non-carriers and carriers (p = 0.004). WBC (White Blood Cell) counts were higher on day 2 and 3 in osteopontin 9250 C/T T allele carriers compared to non-carriers (day 2; 12.7 ± 4 vs. 10.5 ± 2.4 (p = 0.015), day 3; 11.8 ± 4 vs. 9.1 ± 4.7 (p = 0.035)). The average ICU stay was 3.1 ± 7.4, 1.28 ± 0.97 for IL 18-137 G/C C allele carriers and non-carriers, respectively (p = 0.003), and in the IL 18-137 G/C C allele carriers, SIRS developed in 42.2% by the second postoperative day whereas the rate was 57.8% in non-carriers (p = 0.025). Conclusions: The current research revealed a possible link between osteopontin 9250 C/T and IL18-137 G/C genetic polymorphism and SIRS and morbidity in on-pump CABG patients. [ABSTRACT FROM AUTHOR]

Objective To observe the promotional effects of psoralen on proliferation and osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs), and to explore their mechanism. Methods The third-generation hPDLSCs were divided into six groups: the control group and 5, 10, 25, 50 and 100 μmol/L psoralen groups, respectively. HPDLSCs in the 5, 10, 25, 50 and 100 μmol/L psoralen groups were treated with 5, 10, 25, 50 and 100 μmol/L psoralen, and hPDLSCs in the control group were cultured normally. Cell proliferation capacity was measured by CCK-8 assay, alkaline phosphatase (ALP) activity by colorimetric method, and mineralization nodules by alizarin red staining. Another third-generation hPDLSCs were divided into two groups: the control group and 25 μmol/L psoralen group. Cells in the 25 μmol/L psoralen group were treated with 25 μmol/L psoralen, while cells in the control group were cultured normally. Transcription factor 2 (Runx 2) and osteopontin (OPN) mRNA were detected by RT-PCR. Results Compared with the control group, cell proliferation capacity and ALP activity increased in the 5, 10, 25, 50 and 100 μmol/L psoralen groups, and mineralization nodules increased in the 25 μmol/L psoralen group (all P<0. 05) . Compared with the 5 μmol/L psoralen group, cell proliferative capacity increased in the 25, 50 and 100 μmol/L psoralen groups, ALP activity increased in the 10 and 25 μmol/L psoralen groups, and mineralization nodules increased in the 25 μmol/L psoralen group (all P<0. 05) . Compared with the 10 μmol/L psoralen group, cell proliferation capacity increased in the 25, 50 and 100 μmol/L psoralen groups (all P<0. 05) . Compared with the 25 μmol/L group, ALP activity decreased in the 50 and 100 μmol/L psoralen groups (all P<0. 05) . Compared with the control group, relative expression levels of Runx 2 and OPN mRNA increased in the 25 μmol/L psoralen group (all P<0. 05) . Conclusions Psoralen of 5-100 μmol/L promotes the proliferation and osteogenic differentiation of hPDLSCs. It shows a dose-dependent enhancement at 5 to 25 μmol/L, and there is no obvious change at 50 to 100 μmol/L. The mechanism of psoralen promoting the proliferation and osteogenic differentiation of hPDLSCs may be related to the regulation of Runx 2 signaling pathway. [ABSTRACT FROM AUTHOR]

Background: This study aims to explore the potential of utilizing the expression levels of cannabinoid receptor 2 (CB2), μ-opioid receptor (MOR), MCP-1, IL-17, IFN-γ, and osteopontin as predictors for the severity of SARS-CoV-2 infection. The overarching goal is to delineate the pathogenic mechanisms associated with SARS-CoV-2. Methods: Using quantitative Real-time PCR, we analyzed the gene expression levels of CB2 and MOR in nasopharynx specimens obtained from patients diagnosed with SARS-CoV-2 infection, with 46 individuals classified as having severe symptoms and 46 as non-severe. Additionally, we measured the circulating levels of MCP-1, IL-17, IFN-γ, and osteopontin using an ELISA assay. We examined the predictive capabilities of these variables and explored their correlations across all patient groups. Results: Our results demonstrated a significant increase in MOR gene expression in the epithelium of patients with severe infection. The expression of CB2 receptor was also elevated in both male and female patients with severe symptoms. Furthermore, we observed concurrent rises in MCP-1, IL-17, IFN-γ, and osteopontin levels in patients, which were linked to disease severity. CB2, MOR, MCP-1, IL-17, IFN-γ, and osteopontin showed strong predictive abilities in distinguishing between patients with varying degrees of SARS-CoV-2 severity. Moreover, we identified a significant correlation between CB2 expression and the levels of MOR, MCP-1, osteopontin, and IFN-γ. Conclusions: These results underline the interconnected nature of molecular mediators in a sequential manner, suggesting that their overexpression may play a role in the development of SARS-CoV-2 infections. [ABSTRACT FROM AUTHOR]

This article explores the relationship between osteopontin (OPN) and neutrophil extracellular trap (NET) formation in elderly patients with severe sepsis. The study found that levels of NETs and OPN were correlated and increased with markers of patient frailty. Higher levels of NETs were associated with increased mortality in elderly septic patients. The findings suggest that NETs and OPN could potentially be used as biomarkers to predict poor outcomes in sepsis. The article also discusses the role of OPN in sepsis and its influence on immune functions. Further research is needed to understand the signaling pathway between OPN and NET formation and how the septic environment affects neutrophil activation. [Extracted from the article]

Aim: To investigate novel diagnostic markers for pulpitis and validate by clinical samples from normal and inflamed pulp. To explore the relationship between diagnostic markers and immune cells or their phenotypes during pulp inflammation. Methodology: Two microarray datasets, GSE77459 and GSE92681, and identified differential expression genes were integrated. To understand immune features, gene functions, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Disease Ontology (DO) and ImmuneSigDB Gene Set Enrichment Analysis (GSEA) were analysed. For predictive purposes, machine learning techniques were applied to detect diagnostic markers. Immune infiltration in inflamed pulp was studied using CIBERSORT. The relationship between diagnostic markers and immune cells was investigated and validated their gene expression in clinical samples from the normal or inflamed pulp by qRT‐PCR. Finally, the correlation between one marker, secreted phosphoprotein 1 (SPP1), encoding osteopontin (OPN), and dendritic cells (DCs)/macrophages was identified via HE staining and multiplex immunohistochemistry. An in vitro inflammatory dental pulp microenvironment model of THP‐1 macrophages cocultured with dental pulp cells derived conditioned media (DPCs‐CM) to investigate OPN production and macrophage phenotypes was established. Results: Analysis revealed unique immunologic features in inflamed pulp. Three diagnostic markers for pulpitis: endothelin‐1 (EDN1), SPP1, and purine nucleoside phosphorylase (PNP), and validated them using qRT‐PCR were predicted. Multiplex immunohistochemistry demonstrated OPN co‐localized with activated DCs and M2 macrophages during pulp inflammation. In vitro experiments showed that THP‐1 macrophages produced the highest levels of OPN when stimulated with DPCs‐CM derived from the 20 μg/mL LPS pre‐conditioned group, suggesting an M2b‐like phenotype by increasing surface marker CD86 and expression of IL6, TNFα, IL10, and CCL1 but not CCL17 and MerTK. Levels of CCL1 and IL10 elevated significantly in the macrophages' supernatant from the 20 μg/mL LPS pre‐conditioned CM group. OPN was proven co‐localizing with CD86 in the inflamed pulp by immunofluorescence. Conclusions: The current findings suggest that OPN can serve as a promising biomarker for pulpitis, correlated with DCs and macrophages. OPN+ macrophages in the inflamed pulp are associated with M2b‐like phenotypes. These insights offer the potential for improved diagnosis and targeted therapy. [ABSTRACT FROM AUTHOR]

Purpose: Pembrolizumab-based regimens are conditioned by the expression of PD-L1, but durable response rate is limited by innate and acquired resistance mechanisms. Here, we focus on osteopontin (OPN), an upfront biomarker of senescence, which closely associated with natural history of non-small cell lung cancer (NSCLC). Methods: Seventy-nine patients eligible to pembrolizumab regimens—alone or in combination with chemotherapy—as first-line treatment of advanced NSCLC were enrolled. Predictive value of OPN toward iRECIST progression disease (PD) was set as first outcome. Secondary ones included performance status (ECOG) at baseline, early (first and best) responses, and overall survival (OS). Results: High Serum OPN characterized patients with worse ECOG-PS (p = 0.015) at baseline and subjects experienced PD/death at first (OR 1.17 [1.02 to 1.35]; p = 0.030) and best responses (0.04 [0.00 to 0.81]; p = 0.035). OPN was associated with time-to-progression (B -2.74 [−4.46 to −1.01]) and time-to death (−0.13 [−0.20 to −0.05]). Cox regression models unveil a predictive value for iRECIST-PD (HR 1.01 [1.00 to 1.02]; p = −0.005), RECIST-PD (HR 1.01 [1.00 to 1.02]; p = 0.017), and OS (HR 1.02 [1.01 to 1.03]; p = 0.001). These models were internally validated through bootstrap resampling and characterized by relevant discrimination ability at ROC curve analyses. Conclusion: Baseline levels of serum OPN is closely associated with performance status and short/long term outcomes in patients with advanced NSCLC, which are candidate to pembrolizumab-based regimens. As upfront biomarker of senescence, OPN may pave the way for future studies focusing on senescence patterns in NSCLC. [ABSTRACT FROM AUTHOR]

Osteopontin (OPN) and osteoprotegerin (OPG) are glycoproteins that participate in the regulation of tissue biomineralization. The aim of the project is to verify the hypothesis that the content of OPN and OPG in the aorta walls increases with the development of atherosclerosis and that these proteins are quantitatively related to the main proteins in the extracellular arteries matrix. Quantitative and qualitative analyses of the OPN and OPG content in 101 aorta sections have been conducted. Additionally, an enzyme-linked immunosorbent assay (ELISA) test has been performed to determine the collagen types I–IV and elastin content in the tissues. Correlations between the biochemical data and patients' age/sex, atherosclerosis stages, and calcification occurrences in the tissue have been established. We are the first to report correlations between OPN or OPG and various types of collagen and elastin content (OPG/type I collagen correlation: r = 0.37, p = 0.004; OPG/type II collagen: r = 0.34, p = 0.007; OPG/type III collagen: r = 0.39, p = 0.002, OPG/type IV collagen: r = 0.27, p = 0.03; OPG/elastin: r = 0.42, p = 0.001; OPN/collagen type I: r = 0.34, p = 0.007; OPN/collagen type II: r = 0.52, p = 0.000; OPN/elastin: r = 0.61, p = 0.001). OPN overexpression accompanies calcium deposit (CA) formation with the protein localized in the calcium deposit, whereas OPG is located outside the CA. Although OPN and OPG seem to play a similar function (inhibiting calcification), these glycoproteins have different tissue localizations and independent expression regulation. The independent expression regulation presumably depends on the factors responsible for stimulating the synthesis of collagens and elastin. [ABSTRACT FROM AUTHOR]

Endometrial epidermal growth factor (EGF) shows a cyclic change with two peaks on days 2–4 and days 13–14 of the estrous cycle. In repeat breeder cows, loss of the peaks has been associated with reduced fertility. By infusing seminal plasma (SP) and osteopontin (OPN) derived from SP and milk into the vagina, their EGF profile and fertility are restored. However, SP is difficult to obtain, and both SP and OPN can transmit infectious diseases. While OPN can be sourced from recombinant protein without this risk, recombinant bovine OPN (rOPN) expressed in Escherichia coli should be examined for its effects on the EGF profile, since it does not undergo posttranslational modification, which is important for its biological activity. In study 1, PBS, SP (0.5 mL), and rOPN (0.3 mg) were infused into the vagina at estrus (day 0) in 74, 37, and 105 repeat breeder Holstein cows, respectively, with an altered EGF profile. The endometrial EGF concentrations were measured on day 3. Some cows (n = 58, 20, and 83, respectively) were inseminated immediately before the infusion and then diagnosed for pregnancy between days 30 and 35. The normalization rate of the EGF profile and conception rate in the rOPN group (58.1 % and 47.0 %, respectively) were not significantly different from those in the SP group (62.2 % and 45.0 %, respectively) but higher than those in PBS group (29.7 % and 28.1 %, respectively) (P < 0.05). In study 2, repeat breeder cows with an altered EGF profile were infused with PBS (n = 18) and rOPN (n = 17), while fertile controls with a normal EGF profile (n = 18) were infused with PBS. Two or three embryos were transferred into cows on day 7 and then recovered on day 14. Embryo recovery rates of the rOPN and fertile groups were comparable (58.7 % vs. 58.3 %) but higher than that of the PBS group (58.7 % vs. 32.0 %) (P < 0.05). The embryo recovery rate of cows with normalized EGF profile was higher than that of cows with unnormalized EGF profile (64.4 % vs. 16.7 %) (P < 0.05). The embryo sizes of cows in the rOPN and fertile groups were comparable but larger than those in the PBS group (P < 0.05). However, the embryo size was not correlated to the corresponding endometrial EGF concentrations. In conclusion, rOPN without posttranslational modifications normalized the EGF profile in repeat breeder cows. Improved fertility by normalization of the EGF profile could be attributed partly to the increased embryo viability up to day 14. • The infusion of recombinant osteopontin (rOPN) expressed in Escherichia coli into the vagina at estrus restores the normal endometrial epidermal growth factor (EGF) profile and fertility to the similar extent as seminal plasma in repeat breeder dairy cows. • The normalization of the endometrial EGF profile by rOPN infusion increases embryo survival to day 14 in repeat breeder dairy cows. • Osteopontin infused to the vagina does not require the post-translational modification for these reproductive functions. [ABSTRACT FROM AUTHOR]

Background: First-degree relatives (FDRs) of rheumatoid arthritis (RA) patients are known to have increased risk of developing the disease. The detection of altered bone metabolism in FDRs could be a predictor of the disease. Musculoskeletal ultrasound (MSUS) is known for its ability to detect subclinical joint inflammation in RA, but changes in FDRs are not yet described. We aimed to study serum Osteopontin (OPN) and Osteoprotegerin (OPG) levels in FDRs of RA patients as markers of altered bone metabolism in relation to clinical, laboratory and musculoskeletal ultrasound (MSUS) findings. Methods: Fifty-five individuals were included, 20 had definite RA, 25 were first degree relatives (FDRs) of RA patients, and 10 healthy controls. Clinical evaluation for joint swelling/tenderness was performed for all. ESR, CRP, rheumatoid factor (RF), anti-citrullinated antibodies (ACPA), OPN, OPG, and Musculoskeletal ultrasound (MSUS) by the US7 score were evaluated. Results: Osteoprotegerin was significantly higher in RA (143.89 pg/ml ± 365.47) than in FDRs (22.23 pg/ml ± 65.73; p = 0.009) and controls (6.20 pg/ml ± 12.43; p = 0.003). OPN was also higher in RA (3.66 ng/ml ± 4.20) than in FDRs (1.97 ng/ml ± 1.04) and controls (2.81 ng/ml ± 1.31), though not significant (p = 0.102). Eight of 25 FDRs (32%) had arthralgia without clinical arthritis and 17/25 (68%) were asymptomatic. FDRs with arthralgia had significantly higher ESR and CRP levels than asymptomatic FDRs (9.82 mm/h ± 4.13; p = 0.003, and 3.93 mg/l ± 3.58; p = 0.003). Osteoprotegerin was higher in FDRs than in controls, and also in those with arthralgia (51.55 pg/ml ± 114.68) than in those without (8.44 pg/ml ± 9.67), though without significant difference. OPN was higher in FDRs with arthralgia (2.09 ng/ml ± 1.19) than in asymptomatic (1.70 ng/ml ± 0.55), also without significant difference. Pathologic findings by US7 were detected in 10/25 (40%) FDRs, of which three (12%) had arthralgia and seven (28%) were asymptomatic. Conclusions: The raised OPG and lower OPN in FDRs than in controls reflect an altered bone metabolism which could precede clinical disease phase. OPN and OPG could serve as markers of altered preclinical bone metabolism in FDRs of RA. US7 score might be a useful screening tool to identify 'at-risk' individuals. [ABSTRACT FROM AUTHOR]

Senescent cells compromise tissue structure and function in older organisms. We recently identified senescent fibroadipogenic progenitors (FAPs) with activated chemokine signaling pathways in the skeletal muscle of old mice, and hypothesized these cells may contribute to the age‐associated accumulation of immune cells in skeletal muscle. In this study, through cell–cell communication analysis of skeletal muscle single‐cell RNA‐sequencing data, we identified unique interactions between senescent FAPs and macrophages, including those mediated by Ccl2 and Spp1. Using mouse primary FAPs in vitro, we verified increased expression of Ccl2 and Spp1 and secretion of their respective proteins in the context of both irradiation‐ and etoposide‐induced senescence. Compared to non‐senescent FAPs, the medium of senescent FAPs markedly increased the recruitment of macrophages in an in vitro migration assay, an effect that was mitigated by preincubation with antibodies to either CCL2 or osteopontin (encoded by Spp1). Further studies demonstrated that the secretome of senescent FAPs promotes polarization of macrophages toward an M2 subtype. These data suggest the unique secretome of senescent FAPs may compromise skeletal muscle homeostasis by recruiting and directing the behavior of macrophages. [ABSTRACT FROM AUTHOR]

Objective: To investigate the correlation of serum osteopontin levels with disease severity and prognosis in patients with acute cerebral infarction. Methods: This retrospective analysis included forty patients with acute cerebral infarction (ACI) admitted to the Department of Neurology of Baoding Children's Hospital from May, 2019 to May, 2022 within 24 hours of onset were selected as the observation group, while 40 healthy subjects in our hospital during the same period were selected as the control group. The correlation between serum Osteopontin (OPN) levels and risk factors on one day, seven days and 14 days was analyzed. Patients in the observation group were subdivided into the good prognosis group and the poor prognosis group according to mRS score, and the serum OPN levels of the two groups were compared. The correlation between serum OPN and disease severity and prognosis of patients with ACI was analyzed. Results: The serum OPN levels in the observation group were significantly higher than those in control group (P< 0.05), and its level was positively correlated with NIHSS score and infarct size. The proportion of patients with hyperlipidemia, smoking, drinking, hypertension and OPN level on seven day in the poor prognosis group were higher than those in the good prognosis group (P<0.05). The OPN level > 8.720 ng/ml on seven days was an independent risk factor for poor prognosis of cerebral infarction. Conclusion: OPN is involved in the entire pathophysiological process of ACI, and its level can predict the severity of the disease in patients with ACI, and can be used as an important indicator for evaluating their clinical prognosis. [ABSTRACT FROM AUTHOR]

Although Osteopontin (OPN) has been reported to be associated with many different human cancers, the data on non-small cell lung cancer (NSCLC) are not definitive. This study aimed to explore the prognostic effect of OPN expression and clinicopathological characteristics in patients with NSCLC. This study followed all aspects of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) report. PubMed, Embase and the Cochrane Library were searched to identify the relative studies. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to estimate the prognostic value of the OPN in patients with NSCLC. The odds ratio (OR) was calculated to represent the relationship between OPN expression and clinicopathological parameters. A total of fifteen studies with 2173 participants were finally included. The results revealed that high expression of OPN was significantly associated with poorer overall survival (OS) (HR = 1.89; 95%CI = 1.68–2.11; p < 0.001). Moreover, a significant correlation was observed between increased OPN expression and poorly differentiated (well and moderately differentiated vs. poorly differentiated; pooled OR = 0.38; 95% CI = 0.23–0.64; p < 0.001), lymph node metastasis (absence vs. presence; pooled OR = 0.49; 95%CI = 0.32–0.74; p < 0.001), and distant metastasis (absence vs. presence; pooled OR = 0.18; 95%CI = 0.11–0.29; p < 0.001). This meta-analysis implies that OPN might be a valuable biomarker for a poor prognosis and poor clinicopathological outcomes for patients with NSCLC. Our findings suggest that osteopontin is an important biomarker for poor prognosis and poor clinicopathological outcome in Non-small cell lung cancer (NSCLC) patients. Increased expression of osteopontin in NSCLC patients is associated not only with poorer survival but also with tumor differentiation, lymph node metastasis, and distant metastasis. This may be due to that osteopontin promotes multiple pathological processes including cancer cell proliferation, invasion, tumor progression, and metastasis in NSCLC. [ABSTRACT FROM AUTHOR]

Aims Abdominal aortic aneurysm (AAA) is a highly lethal disease with progressive dilatation of the abdominal aorta accompanied by degradation and remodelling of the vessel wall due to chronic inflammation. Platelets play an important role in cardiovascular diseases, but their role in AAA is poorly understood. Methods and results The present study revealed that platelets play a crucial role in promoting AAA through modulation of inflammation and degradation of the extracellular matrix (ECM). They are responsible for the up-regulation of SPP1 (osteopontin, OPN) gene expression in macrophages and aortic tissue, which triggers inflammation and remodelling and also platelet adhesion and migration into the abdominal aortic wall and the intraluminal thrombus (ILT). Further, enhanced platelet activation and pro-coagulant activity result in elevated gene expression of various cytokines, Mmp9 and Col1a1 in macrophages and Il-6 and Mmp9 in fibroblasts. Enhanced platelet activation and pro-coagulant activity were also detected in AAA patients. Further, we detected platelets and OPN in the vessel wall and in the ILT of patients who underwent open repair of AAA. Platelet depletion in experimental murine AAA reduced inflammation and ECM remodelling, with reduced elastin fragmentation and aortic diameter expansion. Of note, OPN co-localized with platelets, suggesting a potential role of OPN for the recruitment of platelets into the ILT and the aortic wall. Conclusion In conclusion, our data strongly support the potential relevance of anti-platelet therapy to reduce AAA progression and rupture in AAA patients. [ABSTRACT FROM AUTHOR]

Introduction: Triple-negative breast cancer (TNBC) is associated with lack of expression of estrogen and progesterone receptors and HER2 and is the subgroup of breast cancers with the worst prognosis. Osteopontin is a phosphorylated glycoprotein whose overexpression may occur in pathological states such as cancers. The main purpose of our study was to evaluate the immunohistochemical expression of osteopontin in connection with the analysis of recognized clinical and pathological prognostic factors in primary sites of TNBC with and without lymph node metastases. Material and methods: The immunohistochemical evaluation of osteopontin expression in 35 women with TNBC, chosen from a group of 726 patients, was performed. The material came from the excisional biopsies of primary breast cancers and total mastectomies. Results: All patients showed expression of osteopontin, in most cases the expression of osteopontin rated at [+] (57.1%) and [++] (42.9%). Our study analyzed the relationship between the expression of osteopontin and traditional prognostic markers, such as the tumor grade, size, and lymph node involvement. We found a strong relationship only between the expression of osteopontin and the presence of lymph node metastases (p ≤ 0.0001). 93% of patients for whom the expression of osteopontin was determined at [++] had metastasis to lymph nodes and, for comparison, only 15% of women for whom the expression of osteopontin was rated at [+] showed the presence of metastases in the lymphatic nodes. Conclusions: There is a correlation between osteopontin expression and the presence of lymph node metastases in TNBC, suggesting that osteopontin plays an important role in the invasiveness of TNBC. [ABSTRACT FROM AUTHOR]

Purpose: Triple-negative breast cancer (TNBC) features high aggressiveness, metastasis rate, drug resistance as well as poor prognosis. Osteopontin (OPN) is a key protein in the process of osteogenesis and has emerged as a new tumor marker in recent years. Methods: Cell viability was tested with the CCK-8 kit. Transwell and wound healing were adopted to test cell invasive and migratory abilities. Tumor sphere formation was detected by tumor sphere formation assay. Human umbilical vein endothelial cell (HUVEC) tube formation assay was used to measure the angiogenesis of tumor cells. Western blot was applied for the estimation of the expression of cancer stem cell markers, angiogenesis-, signaling pathway-related proteins as well as OPN. Bioinformatics tools predicted OPN expression in breast cancer tissues. The levels of oxidative stress-related markers were assessed with ELISA. Following the overexpression of OPN in MD-MB-436 cells and the addition of the PI3K/AKT/mTOR pathway inhibitor LY294002, the aforementioned functional experiments were implemented again to investigate the mechanism. Finally, in vivo experiments of tumor-bearing mice were performed for further verification. Results: The proliferative, invasive, migratory and tumor sphere formation capabilities as well as angiogenesis of TNBC cells were conspicuously increased in contrast to non-TNBC cell lines. OPN expression in TNBC tissues and cells was dramatically enhanced. OPN upregulation significantly elevated cell proliferative, invasive and migratory capabilities as well as tumor sphere formation and angiogenesis. The mechanism might be achieved by activating PI3K/AKT/mTOR signaling to regulate glutathione peroxidase 4 (GPX4)-mediated anti-lipid peroxidation. Conclusion: OPN promoted tumor sphere formation and angiogenesis in TNBC by activating the PI3K/AKT/mTOR pathway to regulate GPX4-mediated anti-lipid peroxidation levels. [ABSTRACT FROM AUTHOR]

Cholesteatoma is a common disease of the middle ear. Currently, surgical removal is the only treatment option and patients face a high risk of relapse. The molecular basis of cholesteatoma remains largely unknown. Here, we show that Osteopontin (OPN), a predominantly secreted protein, plays a crucial role in the development of middle ear cholesteatoma. Global transcriptome analysis revealed the loss of epithelial features and an enhanced immune response in human cholesteatoma tissues. Quantitative RT-PCR and immunohistochemical staining of middle ear cholesteatoma validated the reduced expression of epithelial markers, as well as the elevated expression of mesenchymal markers including Vimentin and Fibronectin, but not N-Cadherin, α-smooth muscle actin (α-SMA) or ferroptosis suppressor protein 1 (FSP1), indicating a partial epithelial-mesenchymal transition (EMT) state. Besides, the expression of OPN was significantly elevated in human cholesteatoma tissues. Treatment with OPN promoted cell proliferation, survival and migration and led to a partial EMT in immortalized human keratinocyte cells. Importantly, blockade of OPN signaling could remarkably improve the cholesteatoma-like symptoms in SD rats. Our mechanistic study demonstrated that the AKT-zinc finger E-box binding homeobox 2 (ZEB2) axis mediated the effects of OPN. Overall, these findings suggest that targeting the OPN signaling represents a promising strategy for the treatment of middle ear cholesteatoma. [ABSTRACT FROM AUTHOR]

Endometriosis is a disease affecting mainly women of childbearing age, where ectopic endometrial lesions occur outside the uterine cavity. Its main symptoms are chronic pain, infertility and dysmenorrhea. These symptoms significantly reduce the quality of life of patients suffering from this disease. Despite advanced research, the exact etiopathogenesis of endometriosis is still unknown and various theories explaining its origin are postulated in the course of research. Osteopontin is a protein originally discovered in the bone matrix and then in various tissues and organs of the body such as the kidneys, lungs, reproductive organs, vascular epithelial cells or some cancer cells. It is involved in processes such as cell adhesion and migration, angiogenesis and the promotion of tumor cell metastasis. These processes play a role in the pathogenesis of endometriosis, hence intensive research on the role of osteopontin in the development of this disease is an interesting research direction. [ABSTRACT FROM AUTHOR]

To reveal the changes in the flavor quality of chicken osteopontin (CO) before and after enzymatic hydrolysis and a thermal reaction, the present study was carried out to evaluate the volatile compounds and non-volatile compounds in CO. The results show that the chicken boneset enzymatic solution (CBES) presented a notably richer aroma after the enzymatic hydrolysis treatment. At the same time, the concentrations of the total free amino acids (FAAs) and 5′-nucleotides in the CBES increased dramatically. The ERP (enzymatic reaction paste) scores and the ORC (osteopontin reactive cream) scores were exceptionally high in terms of the umami and salty flavor profiles. As precursors, FAAs and 5′-nucleotides also boosted the Maillard reaction, leading to the generation of wide volatile compounds. Compared to CO, CBES, and ORC, the sensory evaluation showed that ERP scored the highest. In summary, the enzymatic hydrolysis treatment coupled with the Maillard reaction significantly enhanced the flavor profile of CO. These findings offer valuable insights into the high-value utilization of bone by-products, making a significant advancement in the field. [ABSTRACT FROM AUTHOR]

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Purpose: Previous evidence shows that lithium chloride (LiCl), a suppressor of glycogen synthase kinase-3β (GSK-3β), may enhance bone formation in several medical and dental conditions. Thus, the purpose of the current study was to assess the effects of LiCl on extraction socket repair in rats. Methods: Thirty rats were randomly assigned into a control group (administration of water; n = 15) or a LiCl group (administration of 150 mg/kg of LiCl; n = 15). LiCl and water were given every other day, starting at 7 days before the extraction of upper first molars until the end of each experiment period. Histological sections from five rats per group were obtained at 10, 20, and 30 days post-extractions. Histometrical analysis of newly formed bone (NB) and the levels of tartrate-resistant acid phosphatase (TRAP)-stained cells were evaluated at 10, 20, and 30 days post-extractions. Immunohistochemical staining for receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoprotegerin (OPG), bone sialoprotein (BSP), osteocalcin (OCN), and osteopontin (OPN) was assessed at 10 days post-extractions. Results: The LiCl group had a greater proportion of NB than the control group at 20 days (P < 0.05). At 30 days, the rate of TRAP-stained cells was lower in the LiCl group than in the control group (P < 0.05). At 10 days, the LiCl group presented stronger staining for OPG, BSP, OPN, and OCN, when compared to the control group (P < 0.05). Conclusion: Systemic LiCl enhanced extraction socket repair, stimulated an overall increase in bone formation markers, and restricted the levels of TRAP in rats. [ABSTRACT FROM AUTHOR]