Beyond prediction: unveiling the prognostic power of µ-opioid and cannabinoid receptors, alongside immune mediators, in assessing the severity of SARS-CoV-2 infection.

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.

The expression changes of PD-L1 and immune response mediators are related to the severity of primary bone tumors.

The expression pattern, diagnostic value, and association of PD-L1, IFN-γ and TGF-ß with bone tumor type, severity, and relapse are determined in this study. 300 human samples from patients with osteosarcoma, Ewing sarcoma, and GCT were enrolled. The PD-L1 gene and protein expression were assessed by qRT-PCR and immunohistochemistry, respectively. ELISA and flow cytometry was used to detect cytokines and CD4/CD8 T cell percentages, respectively. A considerable increase in PD-L1 level was detected in bone tumor tissues at both gene and protein levels that was considerable in osteosarcoma and Ewing sarcoma. A positive correlation was detected regarding the PD-L1 and tumor metastasis and recurrence in osteosarcoma and Ewing sarcoma. The increased IFN-γ level was detected in patients with metastatic, and recurrent osteosarcoma tumors that were in accordance with the level of TGF-ß in these samples. The simultaneous elevation of IFN-γ and TGF-ß was detected in Ewing sarcoma and GCT, also the CD4 + /CD8 + ratio was decreased significantly in patients with osteosarcoma compared to GCT tumors. The elevated levels of PD-L1, TGF- ß, and IFN-γ were associated with bone tumor severity that can provide insights into the possible role of this axis in promoting immune system escape, suppression, and tumor invasion.

15-lipoxygenase and cyclooxygenase expression profile and their related modulators in COVID-19 infection.

BACKGROUND: The role of the lipoxygenase (LOX) and cyclooxygenase (COX) enzymes in maintaining cellular homeostasis and regulating immune responses promoted us in this study to analyze the pattern of changes in 15-lipoxygenase and cyclooxygenase isoforms and their related cytokines in SARS-CoV-2 infection. METHODS: 15-LOX-1, 15-LOX-2, COX-1 and COX-2 gene expression levels were determined using qRT-PCR in nasopharynx specimens from patients with severe [N = 40] and non-severe [N = 40] confirmed SARS-CoV-2 infections and healthy controls. Circulating levels of lL-6, lL-10, PGE2, and IFN-γ were measured in patients and healthy controls using ELISA assay. The associations between the measured variables and the patient's clinic-pathological characteristics were assessed for all groups. RESULTS: The expression level of 15-LOX-1 was elevated significantly in male patients with severe infection; although female patients showed a different expression profile. 15-LOX-2 expression level was considerably increased in male patients with severe infection; while changes in its expression remained inconclusive in female patients. The relationship between 15-LOX expression and the male gender was prominent. Both COX isoforms expression showed elevation in male and female patients that were correlated with disease severity. The simultaneous increase in lL-6, PGE2 and IFN-γ levels also decrease in lL-10 in patients with severe infection indicating the possible regulatory network related to the COX and 15-LOX enzymes in the output of the SARS-CoV-2 infection. CONCLUSION: The results of this study determined the pattern of possible changes in key enzymes of prostaglandin and eicosanoids synthesis pathway and their mediators, which can be helpful in mapping the SARS-CoV-2 pathogenicity and pharmaceutical approaches.

Up-regulation of matrix metalloproteinase-9 in primary bone tumors and its association with tumor aggressiveness.

BACKGROUND: Understanding the molecular mechanism underlying the pathophysiology of primary skeletal tumors is crucial due to the tumor-related complications, incidence at a young age, and tumor recurrence. METHODS AND RESULTS: The local expression pattern of MMP-9 as an active matrix-degrading protease was detected in 180 bone tissues, including 90 tumors and 90 noncancerous tissues, utilizing real-time qRT-PCR at the mRNA level and immunohistochemistry at the protein level. The correlation of the MMP-9 expression level with the patient's clinical pathological characteristics and the aggressiveness of the tumor was evaluated. The diagnostic significance of MMP-9 and the model of association of variables and MMP-9 expression and their predictive values were determined. Mean mRNA expression was higher in all types of primary bone tumors than their paired non-cancerous tissues. Osteosarcoma and Ewing's sarcoma expressed higher levels of MMP-9 compared to benign giant cell tumors, and the MMP-9 expression level was significantly correlated with the size, metastasis, and recurrence of the malignant tumor. A consistent expression pattern was demonstrated for MMP-9 protein levels in tissues. In addition, the MMP-9 gene and protein levels significantly discriminate between bone tumors and normal tissue, as well as benign and malignant tumors, and could predict potentially malignant traits such as tumor grade and metastasis. CONCLUSIONS: The data propose that MMP-9 may be involved in the proliferation and invasion of primary bone tumors and has the potential to monitor and treat the progression of malignant tumors.

Evaluation of the expression pattern and diagnostic value of PPARγ in malignant and benign primary bone tumors.

PURPOSE: The quantifiable description of PPARγ expression pattern beside mechanistic in-vitro evidence will provide insights into the involvement of this mediator in tumor pathogenesis. This study is focused on illuminating the PPARγ gene and protein expression pattern, its association with tumor deterioration and its diagnostic value in different types of primary bone tumors. METHODS: The expression pattern of PPARγ was investigated in the 180 bone tissues including 90 bone tumor tissues and 90 non-cancerous bone tissues. The local PPARγ expression level was assessed using real-time qRT-PCR and the PPARγ protein expression pattern was measured using immunohistochemistry. The correlation of PPARγ expression level with patients' clinic-pathological features, also the value of the variables in predicting PPARγ expression level in tumors and the value of PPARγ to discriminate tumor subtypes were assessed. RESULTS: The mean PPARγ mRNA expression was significantly higher in bone tumors compared to healthy bone tissues, also the malignant tumors including osteosarcoma and Ewing sarcoma had the elevated level of PPARγ mRNA compared to GCT tumors. Consistently, the protein expression of PPARγ in the tumor site was significantly higher in the bone tumors and malignant tumors compared to non-cancerous and benign tumors, respectively. The PPARγ protein could predict malignant tumor features including tumor grade, metastasis and recurrence significantly. Moreover, PPARγ could potentially discriminate the patients from the controls also malignant tumors from benign tumors with significant sensitivity and specificity. CONCLUSIONS: PPARγ might be involved in primary bone tumor pathogenesis and determining its molecular mechanism regarding bone cancer pathogenesis is of grave importance.

Functional and pathological role of 15-Lipoxygenase and its metabolites in pregnancy and pregnancy-associated complications.

Maternal lipid metabolism status during pregnancy may have pivotal effects on a healthy pregnancy, the progression of labor, and childbirth. Based on evidence, changes in maternal lipid profile and metabolism is related to various alterations in fetal metabolic status, fat mass, birth weight and can result in serious maternal and fetal complications. 15-lipoxygenase accounts as a key enzyme in metabolizing polyunsaturated fatty acids that generate various inflammatory lipid metabolites. The possible involvement of 15- lipoxygenase and its metabolites in the inflammatory process, cell proliferation and death, and immune response has been postulated. The indicative role of the 15- lipoxygenase enzymatic pathway in the implantation process, stages of pregnancy, embryogenesis, organogenesis, progression of labor, pregnancy period, and pregnancy-associated complications is remarkable. Accordingly, this study will review the research conducted on the role of 15- lipoxygenase in different reproductive tissues, and its pathological role in pregnancy-related diseases to provide more insight regarding the emerging role of 15-lipoxygenase in normal pregnancy.

Evaluating the local expression pattern of IGF-1R in tumor tissues and the circulating levels of IGF-1, IGFBP-1, and IGFBP-3 in the blood of patients with different primary bone tumors.

Introduction: The present study tried to provide insights into the expression pattern and diagnostic significance of the IGF-1 axis main mediators in three main primary bone tumor types with different degrees of severity. Methods: The real-time qRT-PCR (to analyze IGF-1R gene expression), the immunohistochemistry (to measure IGF-1R protein), and the ELISA assay (to assess the circulating level of IGF-1, IGFBP-1, and IGFBP-3) were applied to confirm this hypothesis. A total number of 180 bone tissues (90 tumors and 90 noncancerous adjacent tissues) and 120 blood samples drained from 90 patients with bone tumors and 30 healthy controls were enrolled in the study. The association of insulin-like growth factor (IGF)-1 axis expression pattern with the patient's clinical pathological characteristics and tumor aggressive features, the diagnostic and predictive values were assessed for all tumor groups. Results: A significantly elevated level of IGF-1R gene and protein was detected in bone tumors compared to the noncancerous bone tissues that were prominent in osteosarcoma and Ewing sarcoma compared to the GCT group. The positive association of the IGF-1R gene and protein level with tumor grade, metastasis, and recurrence was detected in the osteosarcoma and Ewing sarcoma groups. The circulating level of IGF-1, IGFPB-1, and IGFBP-3 were increased in osteosarcoma and Ewing sarcoma and GCT groups that were correlated significantly to the tumor severity. The ability of the IGF-1 axis to discriminate between bone tumors also malignant and benign tumors was considerable. Discussion: In summary, our data suggested that IGF-1R, IGF-1, IGFBP-1, and IGFBP-3 levels are associated with bone tumor malignancy, metastasis, and recurrence that might serve as biomarkers for osteosarcoma and Ewing sarcoma recurrence.

15-Lipoxygenase and its metabolites in the pathogenesis of breast cancer: A double-edged sword.

15-lipoxygenase is one of the key enzymes for the metabolism of unsaturated fatty acids that its manipulation has been proposed recently as a new molecular target for regulating cancer cell growth. Aberrant expression of 15-lipoxygenase enzyme seems to play an indicative role in the pathology of different cancer types, tumor progression, metastasis, or apoptosis. Based on the fact that breast cancer is one of the most common cancers that imposes a burden of mortality in women also, on the other hand, evidence in experimental models and human studies indicate the emerging role of the 15-lipoxygenase pathway in breast cancer pathogenesis, we present a review of recent findings related to the role of 15- lipoxygenase enzyme and metabolites in breast cancer growth, apoptosis, metastasis, and invasion as well as their local and circulating expression pattern in patients with breast cancer. Our review supports the emerging role of 15- lipoxygenase in molecular and cellular processes regulating breast tumor cell fate with both positive and negative effects.