Search Results (23)

Oxidative stress, caused by excessive reactive oxygen species (ROS) accumulation, is a major factor in muscle cell damage and muscle atrophy-related disorders. Although Stanniocalcin 2 (STC2) is involved in cellular stress and exhibits cytoprotective effects in various cell types, its role in skeletal muscle cells during oxidative stress is unclear. This study investigated the effects of STC2 overexpression in quail muscle (QM7) cells exposed to H₂O₂-induced oxidative stress. STC2 expression was upregulated in non-transfected QM7 cells following H₂O₂ treatment. Stable STC2-overexpressing cells were differentiated for 4 days, and then assessed for cell viability, ROS accumulation, cell death, and myotube morphology following H₂O₂ treatment. Compared with control cells, STC2-overexpressing cells exhibited higher cell viability, reduced ROS accumulation, and decreased cell death. STC2 overexpression also attenuated the H₂O₂-induced reduction in MyHC protein expression. Antioxidant-related genes, including Superoxide Dismutase 1, Glutathione Peroxidase 1, Heme Oxygenase 1, and NAD(P)H Quinone Dehydrogenase 1, were significantly upregulated in STC2-overexpressing cells. Compared with the control cells, nuclear factor erythroid 2-related factor 2 protein levels were not increased in STC2-overexpressing cells under oxidative stress conditions. These findings suggest that STC2 overexpression alleviates oxidative stress-induced cellular damage and may contribute to protective antioxidant responses in muscle cells. Full article

STC2 (stanniocalcin 2) controls calcium (Ca²⁺) homeostasis in human platelets and other cell lines. The regulation of intracellular Ca²⁺ homeostasis is crucial for platelet activation; thus, the alteration in intracellular Ca²⁺ concentration or the mechanism involved in its regulation has been proposed to underlie some thrombotic disorders. Our previous studies evidenced that the knockdown of STC2 altered murine platelet activation; furthermore, a reduction in STC2 expression resulted in enhanced Ca²⁺ homeostasis in diabetic patients and, therefore, would contribute to the prothrombotic condition as a hallmark of diabetes mellitus type 2 (DM2). In this study, we examine a possible link between the expression of stanniocalcins (STCs) and different thrombotic events in humans. The expression of STCs was determined by Western blotting (WB); meanwhile, the analysis of protein interaction and phosphorylation was performed by completing a previous immunoprecipitation protocol (IP) of the proteins of interest. Thus, our results from patients with stroke/ictus presented a clear reduction in STC2 expression in their platelets, finding less STC2 content in the youngest thrombotic patients. Furthermore, acetyl-salicylic acid (ASA) administration reversed the decrease in the expression of STC2 in patients who did not suffer additional thrombotic episodes, as evidenced by the longitudinal analysis of up to 10 years of follow-up. Additionally, the increase in STC2 phosphorylation at the serine residues revealed increased activity of STC2 in thrombotic patients. Finally, we suggest that store-operated Ca²⁺ entry (SOCE) is over-activated in patients suffering from stroke/ictus, as revealed by the increase in the STIM1/Orai1 interaction found under resting conditions and, further, because MEG-01 cells transfected with siRNA STC2 to evoke artificial reduction in the STC2 expression presented an increased SOCE with respect to the control cells transfected with siRNA A. Conversely, the expression of the non-capacitative Ca²⁺ channels, Orai3 and TRPC6, was found to be reduced in patients with stroke. Altogether, our data allow us to conclude that STC2 represents a promising marker of stroke/ictus in thrombotic patients. Full article

Background: Breast cancer is the most commonly diagnosed cancer among women, and resistance to chemotherapy presents a significant challenge in its treatment. Stanniocalcin-2 (STC2), a glycoprotein involved in calcium homeostasis and cellular stress responses, is frequently overexpressed in various human cancers. Despite its critical role in cellular adaptation to stress, the potential of STC2 as a biomarker for predicting chemotherapy response has not been evaluated. This study aimed to assess the potential of STC2 as a predictive biomarker of response to chemotherapy in breast cancer. Methods: We utilized publicly available databases to characterize STC2 expression in breast cancer patients and its role in predicting relapse-free survival (RFS). Moreover, we evaluated the treatment responses of patients subjected to chemotherapy, correlating their outcomes with STC2 expression levels to determine its potential as a predictive biomarker. Finally, we evaluated the STC2 expression levels in breast cancer cell lines following exposure to doxorubicin (Dox), the primary anthracycline used in chemotherapy, and they were contrasted with the publicly available dataset. Results: The analysis showed that STC2 is significantly overexpressed in luminal A breast cancer, where it is linked to genetic amplifications. High STC2 expression was associated with improved RFS in ER-positive patients but correlated with worse outcomes in ER-negative cases. Furthermore, in grade II ER-positive patients, higher STC2 expression is linked to better chemotherapy response, while in grade II ER-negative patients, it was associated with poorer response. Finally, STC2 downregulation was observed in response to Dox treatment. Conclusions: These findings suggest that STC2 expression serves as a predictive biomarker for chemotherapy response in grade II breast cancer patients. Full article

Platelet-rich fibrin (PRF) is prepared by spontaneous coagulation of fractionated blood. When squeezed between two plates, PRF is separated into solid PRF membranes and a liquid exudate, the PRF serum. The question arises regarding how much the overall activity remains in the PRF membranes and what is discarded into the PRF serum. To this end, we have exposed gingival fibroblasts to lysates prepared from PRF membranes and PRF serum, followed by bulk RNA sequencing. A total of 268 up- and 136 down-regulated genes in gingival fibroblasts exposed to PRF membrane lysates were significantly regulated under the premise of a minimum log2 with 2.5-fold change and a minus log10 significance level of two, respectively. PRF serum only caused 62 up- and 32 down-regulated genes under these conditions. Among the 46 commonly up-regulated genes were CXCL1, CXCL5, CXCL6, CXCL8, IL33, IL6, and PTGS2/COX2, stanniocalcin-1—all linked to an inflammatory response. PRF membrane lysates further increased chemokines CCL2, CCL7, CXCL2, CXCL3, and IL1R1, IL1RL1, and IL1RN, as well as the paracrine factors IL11, LIF, IGF1, BMP2, BMP6, FGF2, and CCN2/CTGF, and all hyaluronan synthases. On the other hand, PRF serum increased DKK1. The genes commonly down-regulated by PRF membrane lysates and PRF serum included interferon-induced protein with tetratricopeptide repeats (IFIT1, IFIT2, IFIT3) and odd-skipped-related transcription factors (OSR1 and OSR2), as well as FGF18 and GDF15, respectively. Taken together, PRF membrane lysates, compared to PRF serum, cause a more complex response in gingival fibroblasts, but each increased chemokine expression in gingival fibroblasts. Full article

Gingival fibroblasts are a significant source of paracrine signals required to maintain periodontal homeostasis and to mediate pathological events linked to periodontitis and oral squamous cell carcinomas. Among the potential paracrine signals are stanniocalcin-1 (STC1), involved in oxidative stress and cellular survival; amphiregulin (AREG), a growth factor that mediates the cross-talk between immune cells and epithelial cells; chromosome 11 open reading frame 96 (C11orf96) with an unclear biologic function; and the inflammation-associated prostaglandin E synthase (PTGES). Gingival fibroblasts increasingly express these genes in response to bone allografts containing remnants of injured cells. Thus, the gene expression might be caused by the local release of damage-associated molecular patterns arising from injured cells. The aim of this study is consequently to use the established gene panel as a bioassay to measure the damage-associated activity of oral cell lysates. To this aim, we have exposed gingival fibroblasts to lysates prepared from the squamous carcinoma cell lines TR146 and HSC2, oral epithelial cells, and gingival fibroblasts. We report here that all lysates significantly increased the transcription of the entire gene panel, supported for STC1 at the protein level. Blocking TGF-β receptor 1 kinase with SB431542 only partially reduced the forced expression of STC1, AREG, and C11orf96. SB431542 even increased the PTGES expression. Together, these findings suggest that the damage signals originating from oral cells can change the paracrine activity of gingival fibroblasts. Moreover, the expression panel of genes can serve as a bioassay for testing the biocompatibility of materials for oral application. Full article

Pregnancy-associated plasma protein-A (PAPP-A) and PAPP-A2 modulate insulin-like growth factor (IGF) action and are inhibited by the stanniocalcins (STC1 and STC2). We previously demonstrated increased PAPP-A and IGF activity in ascites from women with ovarian carcinomas. In this prospective, longitudinal study of 107 women with ovarian cancer and ascites accumulation, we determined corresponding serum and ascites levels of IGF-1, IGF-2, PAPP-A, PAPP-A2, STC1, and STC2 and assessed their relationship with mortality. As compared to serum, we found highly increased ascites levels of PAPP-A (51-fold) and PAPP-A2 (4-fold). Elevated levels were also observed for IGF-1 (12%), STC1 (90%) and STC2 (68%). In contrast, IGF-2 was reduced by 29% in ascites. Patients were followed for a median of 38.4 months (range: 45 days to 8.9 years), during which 73 patients (68.2%) died. Overall survival was longer for patients with high serum IGF-1 (hazard ratio (HR) per doubling in protein concentration: 0.60, 95% CI: 0.40–0.90). However, patients with high ascites levels of IGF-1 showed a poorer prognosis (HR: 2.00 (1.26–3.27)). High serum and ascites IGF-2 levels were associated with increased risk of mortality (HR: 2.01 (1.22–3.30) and HR: 1.78 (1.24–2.54), respectively). Similarly, serum PAPP-A2 was associated with mortality (HR: 1.26 (1.08–1.48)). Our findings demonstrate the presence and activity of the IGF system in the local tumor ecosystem, which is likely a characteristic feature of malignant disease and plays a role in its peritoneal dissemination. The potential clinical implications are supported by our finding that serum levels of the proteins are associated with patient prognosis. Full article

Stanniocalcin 2 (STC2) is a secreted glycoprotein involved in multiple biological processes. To systemically study the biological role of STC2 in chickens, phylogenetic tree analysis and conservation analysis were conducted. Association analysis between variations in the STC2 gene and the economic traits of Gushi-Anka F2 was conducted. The tissue expression patterns of STC2 expression in different chicken tissues and liver at different stages were detected. The biological role of STC2 in chicken liver was investigated through overexpression and interfering methods in the LMH cell line. Correlation analyses between STC2 expression and lipid components were conducted. (1) The phylogenetic tree displayed that chicken STC2 is most closely related with Japanese quail and most distantly related with Xenopus tropicalis. STC2 has the same identical conserved motifs as other species. (2) rs9949205 (T > C) found in STC2 intron was highly significantly correlated with chicken body weight at 0, 2, 4, 6, 8, 10 and 12 weeks (p < 0.01). Extremely significant correlations of rs9949205 with semi-evisceration weight (SEW), evisceration weight (EW), breast muscle weight (BMW), leg muscle weight (LMW), liver weight and abdominal fat weight (AFW) were revealed (p < 0.01). Significant associations between rs9949205 and abdominal fat percentage, liver weight rate, breast muscle weight rate and leg muscle weight rate were also found (p < 0.05). Individuals with TT or TC genotypes had significantly lower abdominal fat percentage and liver weight rate compared to those with the CC genotype, while their body weight and other carcass traits were higher. (3) STC2 showed a high expression level in chicken liver tissue, which significantly increased with the progression of age (p < 0.05). STC2 was observed to inhibit the content of lipid droplets, triglycerides (TG) and cholesterol (TC), as well the expression level of genes related to lipid metabolism in LMH cells. (4) Correlation analysis showed that the STC2 gene was significantly correlated with 176 lipids in the breast muscle (p < 0.05) and mainly enriched in omega-3 and omega-6 unsaturated fatty acids. In conclusion, the STC2 gene in chicken might potentially play a crucial role in chicken growth and development, as well as liver lipid metabolism and muscle lipid deposition. This study provides a scientific foundation for further investigation into the regulatory mechanism of the STC2 gene on lipid metabolism and deposition in chicken liver. Full article

Prostate cancer is one of the most prevalent tumors in men, accounting for about 7.3% of cancer deaths. Although there are several strategies for diagnosing prostate cancer, these are only accurate when the tumor is already at a very advanced stage, so early diagnosis is essential. Stanniocalcin 1 (STC1) is a secreted glycoprotein, which has been suggested as a tumor marker as its increased expression is associated with the development and/or progression of different types of malignant tumors. In this work, an electronic tongue (ET) prototype, based on a set of four sensors prepared from thin films that included STC1 antibodies for detecting prostate cancer, was developed. In the preparation of the thin films, polyelectrolytes of polyallylamine hydrochloride, polystyrene sulfonate of sodium and polyethyleneimine, and the biomolecules chitosan, protein A, and STC1 antibody were used. These films were deposited on quartz lamellae and on solid supports using layer-on-layer and self-assembly techniques. The deposition of the films was analyzed by ultraviolet-visible spectroscopy, and the detection of STC1 in aqueous solutions of PBS was analyzed by impedance spectroscopy. The impedance data were statistically analyzed using principal component analysis. The ETs formed by the four sensors and the three best sensors could detect the antigen at concentrations in the range from 5 × 10⁻¹¹ to 5 × 10⁻⁴ M. They showed a linear dependence with the logarithm of the antigen concentration and a sensitivity of 5371 ± 820 and 4863 ± 634 per decade of concentration, respectively. Finally, the results allow us to conclude that this prototype can advance to the calibration phase with patient samples. Full article

Cancer stem cells (CSCs) are closely associated with metastasis and epithelial mesenchymal transition (EMT). We previously reported that extracellular ATP (eATP) induces and regulates EMT in cancer cells. We recently found that the gene stanniocalcin 1 (STC1) is significantly upregulated by eATP in human non-small lung cancer (NSCLC) A549 cells; however, the relationships among eATP, CSCs, and STC1 were largely unknown. In this study, we performed gene knockdown and knockout, and a wide variety of functional assays to determine if and how eATP and STC1 induce CSCs in NSCLC A549 and H1299 cells. Our data show that, in both cultured cells and tumors, eATP increased the number of CSCs in the cancer cell population and upregulated CSC-related genes and protein markers. STC1 deletion led to drastically slower cell and tumor growth, reduced intracellular ATP levels and CSC markers, and metabolically shifted STC1-deficient cells from an energetic state to a quiescent state. These findings indicate that eATP induces and regulates CSCs at transcriptional, translational, and metabolic levels, and these activities are mediated through STC1 via mitochondria-associated ATP synthesis. These novel findings offer insights into eATP-induced CSCs and identify new targets for inhibiting CSCs. Full article

Background: Hepatocellular carcinoma (HCC) originates from the hepatocytes and accounts for 90% of liver cancer. The study intends to identify novel prognostic biomarkers for predicting the prognosis of HCC patients based on TCGA and GSE14520 cohorts. Methods: Differential analysis was employed to obtain the DEGs (Differentially Expressed Genes) of the TCGA-LIHC-TPM cohort. The lasso regression analysis was applied to build the prognosis model through using the TCGA cohort as the training group and the GSE14520 cohort as the testing group. Next, based on the prognosis model, we performed the following analyses: the survival analysis, the independent prognosis analysis, the clinical feature analysis, the mutation analysis, the immune cell infiltration analysis, the tumor microenvironment analysis, and the drug sensitivity analysis. Finally, the survival time of HCC patients was predicted by constructing nomograms. Results: Through the lasso regression analysis, we obtained a prognosis model of ten genes including BIRC5 (baculoviral IAP repeat containing 5), CDK4 (cyclin-dependent kinase 4), DCK (deoxycytidine kinase), HSPA4 (heat shock protein family A member 4), HSP90AA1 (heat shock protein 90 α family class A member 1), PSMD2 (Proteasome 26S Subunit Ubiquitin Receptor, Non-ATPase 2), IL1RN (interleukin 1 receptor antagonist), PGF (placental growth factor), SPP1 (secreted phosphoprotein 1), and STC2 (stanniocalcin 2). First, we found that the risk score is an independent prognosis factor and is related to the clinical features of HCC patients, covering AFP (α-fetoprotein) and stage. Second, we observed that the p53 mutation was the most obvious mutation between the high-risk and low-risk groups. Third, we also discovered that the risk score is related to some immune cells, covering B cells, T cells, dendritic, macrophages, neutrophils, etc. Fourth, the high-risk group possesses a lower TIDE score, a higher expression of immune checkpoints, and higher ESTIMATE score. Finally, nomograms include the clinical features and risk signatures, displaying the clinical utility of the signature in the survival prediction of HCC patients. Conclusions: Through the comprehensive analysis, we constructed an immune-related prognosis model to predict the survival of HCC patients. In addition to predicting the survival time of HCC patients, this model significantly correlates with the tumor microenvironment. Furthermore, we concluded that these ten immune-related genes (BIRC5, CDK4, DCK, HSPA4, HSP90AA1, PSMD2, IL1RN, PGF, SPP1, and STC2) serve as novel targets for antitumor immunity. Therefore, this study plays a significant role in exploring the clinical application of immune-related genes. Full article

The plasma protein histidine-rich glycoprotein (HRG) is implicated in the polarization of macrophages to an M1 antitumoral phenotype. The broadly expressed secreted protein stanniocalcin 2 (STC2), also implicated in tumor inflammation, is an HRG interaction partner. With the aim to biochemically characterize the HRG and STC2 complex, binding of recombinant HRG and STC2 preparations to each other and to cells was explored using the quartz crystal microbalance (QCM) methodology. The functionality of recombinant proteins was tested in a phagocytosis assay, where HRG increased phagocytosis by monocytic U937 cells while STC2 suppressed HRG-induced phagocytosis. The binding of HRG to STC2, measured using QCM, showed an affinity between the proteins in the nanomolar range, and both HRG and STC2 bound individually and in combination to vitamin D3-treated, differentiated U937 monocytes. HRG, but not STC2, also bound to formaldehyde-fixed U937 cells irrespective of their differentiation stage in part through the interaction with heparan sulfate. These data show that HRG and STC2 bind to each other as well as to U937 monocytes with high affinity, supporting the relevance of these interactions in monocyte/macrophage polarity. Full article

Increasing evidence links chronic neurodegenerative diseases with neuroinflammation; it is known that neuroprotective agents are capable of modulating the inflammatory processes, that occur with the onset of neurodegeneration pathologies. Here, with the intention of providing a means for active compounds’ screening, a dysregulation of neuronal inflammatory marker genes was induced and subjected to neuroprotective active principles, with the aim of selecting a set of inflammatory marker genes linked to neurodegenerative diseases. Considering the important role of microglia in neurodegeneration, a murine co-culture of hippocampal cells and inflamed microglia cells was set up. The evaluation of differentially expressed genes and subsequent in silico analysis showed the main dysregulated genes in both cells and the principal inflammatory processes involved in the model. Among the identified genes, a well-defined set was chosen, selecting those in which a role in human neurodegenerative progression in vivo was already defined in literature, matched with the rate of prediction derived from the Principal Component Analysis (PCA) of in vitro treatment-affected genes variation. The obtained panel of dysregulated target genes, including Cxcl9 (Chemokine (C-X-C motif) ligand 9), C4b (Complement Component 4B), Stc1 (Stanniocalcin 1), Abcb1a (ATP Binding Cassette Subfamily B Member 1), Hp (Haptoglobin) and Adm (Adrenomedullin), can be considered an in vitro tool to select old and new active compounds directed to neuroinflammation. Full article

Calcium balance is of paramount importance for vertebrates. In fish, the endocrine modulators of calcium homeostasis include the stanniocalcin (STC), and some members of the parathyroid hormone (PTH) family, such as the PTH-related protein (PTHrP), acting as antagonists. STC is ubiquitously expressed in higher vertebrates. In turn, bony fish exhibit specific STC-producing glands named the corpuscles of Stannius (CS). Previous studies pointed to a calcium-sensing receptor (CaSR) involvement in the secretion of STC, but little is known of the involvement of other putative regulators. The CS provides a unique model to deepen the study of STC secretion. We developed an ex vivo assay to culture CS of fish and a competitive ELISA method to measure STC concentrations. As expected, STC released from the CS responds to CaSR stimulation by calcium, calcimimetics, and calcilytic drugs. Moreover, we uncover the presence (by PCR) of two PTHrP receptors in the CS, e.g., PTH1R and PTH3R. Thus, ex vivo incubations revealed a dose-response inhibition of STC secretion in response to PTHrP at basal Ca²⁺ concentrations. This inhibition is achieved through specific and reversible second messenger pathways (transmembrane adenylyl cyclases and phospholipase C), as the use of specific inhibitors highlights. Together, these results provide evidence for endocrine modulation between two antagonist hormones, STC and PTHrP. Full article

Metabolic syndrome increases the risk for cardiovascular disease including metabolic cardiomyopathy that may progress to heart failure. The decline in mitochondrial metabolism is considered a critical pathogenic mechanism that drives this progression. Considering its cardiac specificity, we hypothesized that miR 208a regulates the bioenergetic metabolism in human cardiomyocytes exposed to metabolic challenges. We screened in silico for potential miR 208a targets focusing on mitochondrial outcomes, and we found that mRNA species for mediator complex subunit 7, mitochondrial ribosomal protein 28, stanniocalcin 1, and Sortin nexin 10 are rescued by the CRISPR deletion of miR 208a in human SV40 cardiomyocytes exposed to metabolic challenges (high glucose and high albumin-bound palmitate). These mRNAs translate into proteins that are involved in nuclear transcription, mitochondrial translation, mitochondrial integrity, and protein trafficking. MiR 208a suppression prevented the decrease in myosin heavy chain α isoform induced by the metabolic stress suggesting protection against a decrease in cardiac contractility. MiR 208a deficiency opposed the decrease in the mitochondrial biogenesis signaling pathway, mtDNA, mitochondrial markers, and respiratory properties induced by metabolic challenges. The benefit of miR 208a suppression on mitochondrial function was canceled by the reinsertion of miR 208a. In summary, miR 208a regulates mitochondrial biogenesis and function in cardiomyocytes exposed to diabetic conditions. MiR 208a may be a therapeutic target to promote mitochondrial biogenesis in chronic diseases associated with mitochondrial defects. Full article

The insulin-like growth factor (IGF) system is responsible for growth, but also affects metabolism and brain function throughout life. New IGF family members (i.e., pappalysins and stanniocalcins) control the availability/activity of IGFs and are implicated in growth. However, how diet and obesity modify this system has been poorly studied. We explored how intake of a high-fat diet (HFD) or commercial control diet (CCD) affects the IGF system in the circulation, visceral adipose tissue (VAT) and hypothalamus. Male and female C57/BL6J mice received HFD (60% fat, 5.1 kcal/g), CCD (10% fat, 3.7 kcal/g) or chow (3.1 % fat, 3.4 kcal/g) for 8 weeks. After 7 weeks of HFD intake, males had decreased glucose tolerance (p < 0.01) and at sacrifice increased plasma insulin (p < 0.05) and leptin (p < 0.01). Circulating free IGF1 (p < 0.001), total IGF1 (p < 0.001), IGF2 (p < 0.05) and IGFBP3 (p < 0.01) were higher after HFD in both sexes, with CCD increasing IGFBP2 in males (p < 0.001). In VAT, HFD reduced mRNA levels of IGF2 (p < 0.05), PAPP-A (p < 0.001) and stanniocalcin (STC)-1 (p < 0.001) in males. HFD increased hypothalamic IGF1 (p < 0.01), IGF2 (p < 0.05) and IGFBP5 (p < 0.01) mRNA levels, with these changes more apparent in females. Our results show that diet-induced changes in the IGF system are tissue-, sex- and diet-dependent. Full article