Search Results (19)

Dermal papilla (DP) cells orchestrate hair follicle growth and cycling by secreting signaling molecules that stimulate follicular epithelial stem cells. The signal peptide CUB-EGF-like domain-containing protein 3 (SCUBE3) was recently identified as a potent anagen stimulator secreted by DP cells. Ageratum houstonianum ethanolic extract (AHE) and its active constituent agerarin exhibit anti-inflammatory properties; however, their effects on hair follicle growth remain unclear. This study aimed to investigate the effects of AHE and agerarin on SCUBE3 expression in primary human DP cells and to elucidate the underlying molecular signaling pathway. Cell viability was assessed by measuring cell confluency. Ex vivo hair growth was analyzed using organ cultures of human hair follicles. Gene and protein expression were determined using reverse transcription-PCR, immunoblot analysis, immunofluorescent staining, tyramide signal amplification-based multiplex immunohistochemistry, and gene promoter-reporter assay in primary human follicle DP cells. In a hair follicle organ culture model, both AHE and agerarin increased the population of the anagen phase and promoted hair shaft elongation. AHE and agerarin significantly upregulated SCUBE3 expression at both the mRNA and protein levels. Mechanistically, AHE and agerarin induced activator protein-1 (AP-1) expression by activating mitogen-activated protein kinase signaling pathways, thereby increasing SCUBE3 gene promoter activity. AHE and agerarin promoted hair follicle growth by upregulating SCUBE3 expression via activation of the MAPK–AP-1 signaling axis. In conclusion, AHE and agerarin may serve as potential therapeutic agents for the prevention and treatment of alopecia (hair loss). Full article

Background: The signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) is a secretory protein that plays a role in cancer, cardiovascular, and immune disorders. SCUBE1, SCUBE2, and SCUBE3 belong to the SCUBE family. They contain multiple copies of EGF-like repeats at the amino acid terminal, a spacer region, three cysteine-rich motifs, and a CUB domain at the carboxyl terminus. The SCUBE family members are multifunctional proteins that act primarily as extracellular ligands or co-receptors in various cells. Methods: In this study, we examined the expression pattern and role of SCUBE3 in various cancers, as well as other diseases such as cardiovascular disease and immune disorders, and its impact on growth and development. Results: SCUBE3 expression is upregulated and secreted by the cells of lung cancer, hepatocellular carcinoma (HCC), melanoma, osteosarcoma, ovarian cancer, glioma, and breast cancer. Extracellular SCUBE3 protein often binds to TGFβRII or acts as a co-receptor for TGFβ and BMP2/BMP4 in regulating cellular signaling. Through the TGFβRII signaling, SCUBE3 activities promote tumor growth, metastasis, invasion, angiogenesis, and poor clinical outcomes. Conversely, in renal cell carcinoma, SCUBE3 expression suppresses growth. Altered SCUBE3 activity is associated with cardiovascular diseases, immune disorders, and hair growth. Conclusions: The review presents mechanistic evidence that SCUBE3 plays a crucial regulatory role in multiple cancers and other diseases. The evidence suggests the SCUBE3 protein could serve as a potential molecular target for various diseases and highlights its usefulness as a minimally invasive diagnostic marker, as it is a secreted protein. Full article

Background/Objectives: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to pose a significant global health challenge due to its high transmissibility and potential for severe clinical outcomes. Early identification of patients at risk of hospitalization is essential for effective triage in emergency departments and for the optimal allocation of healthcare resources. Methods: This prospective study included 84 patients aged over 18 years who presented to the emergency department on 23 December 2020, with suspected SARS-CoV-2 infection. Initially, 100 patients were evaluated, and 16 were excluded based on predefined exclusion criteria. The mean age of the participants was 53.65 ± 13.62 years, and 39 (46.4%) were women. Results: At admission, the mean signal peptide, CUB domain, EGF (SCUBE-1) level among SARS-CoV-2 patients was 0.16 ± 0.08 ng/mL. There was no significant difference in SCUBE-1 levels between patient and control groups (n = 59 vs. 25), but levels differed significantly between hospitalized and home-treated patients (n = 37 vs. 22; p = 0.001). Neutrophil count (p = 0.001) and NLR (p = 0.010) were higher in patients than controls and also higher in hospitalized than home-treated patients (p = 0.003 and p = 0.015). ROC analysis revealed that SCUBE-1 predicted hospitalization with 84.6% sensitivity and 88.9% specificity. A positive correlation was observed between SCUBE-1 levels and length of hospital stay (p = 0.007, r = 0.554), with a median stay of 9.0 (5.0–11.0) days. Conclusions: SCUBE-1 levels were significantly associated with disease severity in SARS-CoV-2 patients and may serve as a promising biomarker to support clinical decision-making for hospitalization versus home-based management. Full article

Background/Objective: Fetal growth restriction (FGR) is a condition in which the fetus fails to grow as expected for gestational age, and its growth is restricted. This study aimed to investigate the role of SCUBE-1, a new ischemia marker, in the diagnosis of late-onset FGR and its contribution to its pathophysiology. Methods: The data of 33 cases with late-onset fetal growth restriction were compared with the data of 33 cases without any pregnancy complications. Only cases beyond 32nd weeks of gestation were included. Fetal sonography and maternal/fetal vascular Doppler parameters were recorded. Maternal serum SCUBE-1 and ischemia-modified albumin (IMA) levels were measured. Results: The mean maternal was 29.82 ± 5.66 years old in the study group and 30.15 ± 4.85 years old in the control group. The gestational ages in both groups were comparable. Maternal serum IMA levels were found to be similar in the late-onset FGR and control groups. However, serum SCUBE-1 levels were found to be statistically significantly higher in the study group than in the control group. In cases where the SCUBE-1 level was above 1.64, the sensitivity for predicting late-onset FGR was 93.9% and the specificity was 60.6% (AUC 0.891, p < 0.001, 95% CI 0.811–0.970). Conclusions: This study reported a significant increase in SCUBE-1, which may be important in determining oxidative stress in late-onset FGR cases. SCUBE-1 was an effective and highly sensitive marker that could provide results in a maternal blood sample within an average of one hour and may be useful in the biochemical diagnosis of late-onset FGR. It may also be a useful serum marker for timing and planning delivery. Full article

Objective: This study aimed to investigate the structural, vascular, and biochemical alterations in patients with pseudoexfoliation syndrome (PES) and pseudoexfoliative glaucoma (PXG) and to evaluate the associations between serum biomarkers, the retinal nerve fiber layer (RNFL), choroidal thickness (CT), and vessel density (VD) in these groups. Methods: All subjects underwent spectral-domain optical coherence tomography (SD-OCT) and OCT angiography (OCTA) to assess RNFL thickness, CT, and VD. Serum levels of inflammatory and oxidative stress biomarkers—including malondialdehyde (MDA), glutathione (GSH), interleukin-6 (IL-6), nitric oxide (NO), inducible NO synthase (iNOS), galectin-3, and SCUBE-1—were analyzed, and regression and ROC curve analyses were performed to evaluate predictive value and diagnostic performance. Results: A total of 80 patients were included and are listed as follows: 25 controls, 30 with PES, and 25 with PXG. There were no significant differences among groups in terms of age or gender. RNFL thickness, CT, and VD were significantly reduced in the PXG group compared to the PES and control groups (p < 0.001). PXG patients showed the most pronounced reductions in both peripapillary and macular CT, as well as superficial and deep VD. Serum iNOS, SCUBE-1, galectin-3, and MDA levels were significantly elevated in PXG, while GSH levels were lower (p < 0.001); NO levels showed no significant differences. In the PES and PXG groups, several ocular parameters correlated significantly with serum biomarkers, particularly iNOS, MDA, and GSH. Regression analysis in PXG patients identified iNOS and MDA as significant predictors of RNFL thickness and VD. ROC analysis demonstrated that MDA and GSH exhibited the highest diagnostic accuracy among the tested biomarkers for distinguishing PXG patients from controls. Conclusions: PXG is associated with significant structural, vascular, and biochemical alterations, including reduced RNFL thickness, choroidal thinning, and decreased VD. Altered serum levels of MDA and GSH were significantly associated with these ocular changes and demonstrated the highest diagnostic accuracy among the biomarkers evaluated. These findings support their potential utility as non-invasive biomarkers for distinguishing PXG from PES and healthy controls and for monitoring disease progression. Full article

The genetic mechanisms underlying the formation of defects, such as bumps and growths on the hock joints in pigs, remain poorly understood. Therefore, the aim of this study was to investigate the relationship between runs of homozygosity (ROH) and the formation of hock joint bumps, with the goal of identifying associated SNPs and candidate genes involved in these defects. The study was conducted on a population of Large White breed pigs (n = 568) using runs of homozygosity (ROH) analysis and genome-wide association studies (GWAS). The results suggested that the predisposition to hock joint bumps in pigs may have arisen due to recent selective breeding pressure. Using GWAS, 27 SNPs were identified at the suggestive significance level, with one SNP (rs325478346) reaching genome-wide significance. These markers are localized in genes associated with various biological processes, including lipid metabolism (VIPR2 and CFTR), inflammatory processes (MTURN and ADCY2), connective tissue structural integrity (COL27A1), muscle regeneration (PAMR1), and ion exchange and cellular homeostasis (KCNIP4 and NALCN), as well as regulation of cell growth, extracellular matrix remodeling, and fibroblast differentiation (CEP120 and SCUBE3). Further research utilizing omics technologies will provide deeper insights into the pathogenesis of hock joint bumps and contribute to the development of strategies for the prevention and potential treatment of this defect. Full article

Background: This study aims to identify circulating biomarkers by using proteomic analysis associated with sac shrinkage or expansion in patients undergoing endovascular aneurysm repair (EVAR) for abdominal aortic aneurysms (AAAs). Methods: Plasma samples were analysed from 32 patients treated with EVAR between 10/2009 and 10/2020. Patients were divided into two groups based on postoperative sac behaviour: sac shrinkage (≥5 mm reduction) and no shrinkage (stabilisation or expansion). Proteomic analysis was performed using high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS), with abundant protein depletion to enhance the detection of low-abundant proteins. Results: Of the 32 patients, 20 exhibited sac shrinkage, and 12 showed no shrinkage. Proteomic analysis identified 632 proteins, with significant differential abundance observed after adjusting for relevant clinical parameters. Notably, neurogranin (NRGN) levels were significantly associated with hypertension and smoking, while casein alpha S1 (CSN1S1) levels varied with statin use. Differentially abundant proteins related to aortic diameter included calpastatin, SCUBE3, and ubiquitin-conjugating enzyme E2, among others. Conclusions: Proteomic profiling revealed distinct biomarker patterns associated with sac behaviour in EVAR-treated AAA patients. These findings suggest potential therapeutic targets for enhancing EVAR outcomes and underscore the need for further investigation into the biological mechanisms underlying aneurysm sac shrinkage and stability. Full article

Background: SCUBE-1 (Signal peptide-CUB (complement C1r/C1s, Uegf, and Bmp1)-EGF (epidermal growth factor)-domain-containing protein 1) is a novel marker of ischemia, which is a cell surface-secreted protein in the platelets and endothelial cells. The aim of the study is to measure serum SCUBE-1 levels and investigate their association with uteroplacental blood flow in patients with preeclampsia. Methods: The study was conducted on patients with preeclampsia. Maternal serum SCUBE1 and IMA levels were the main outcomes. The control group consisted of gestational-age-matched pregnant women. Fetal umbilical artery (UA) pulsatility index (PI), middle cerebral artery PI, cerebroplacental ratio (CPR), and maternal uterine artery (UtA)-PI were also examined, and correlation analysis was performed to reveal the association between maternal serum SCUBE1 levels and Doppler findings. Results: The study group consisted of thirty-two preeclamptic patients, and the control group consisted of thirty-two uncomplicated singleton pregnancies. Maternal serum SCUBE1 and IMA levels were significantly higher in preeclamptic women compared to the control group (p < 0.000, p < 0.004, respectively). Mean UtA-PI values and fetal UA-PI values were significantly higher in preeclamptic pregnant women compared to the control group (p < 0.05, p < 0.05, respectively). However, the average CPR was significantly lower in pregnant women with preeclampsia (p < 0.05). While no significant correlation was found between maternal serum SCUBE1 levels and UA-PI and CPR (p > 0.05, p > 0.05, respectively), a significant correlation was found between right and left UtA-PI (p < 0.004, p < 0.006, respectively). Conclusions: The maternal serum SCUBE1 level is increased in patients with preeclampsia, and this increase is significantly correlated with the maternal uterine artery pulsatility index. Full article

Ovarian torsion (OT) is a rare gynaecological emergency that requires a prompt diagnosis for optimal patient management. To determine whether there were any biomarkers suitable for the non-invasive detection of OT, two independent reviewers performed systematic searches of five literature databases (PubMed, Medline, Scopus, Cochrane, and CINAHL) from inception until October 1st, 2023. Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, the search included patients with OT that had quantified biomarker expression with no age, geographical location, publication date, language, or setting restrictions. Articles were excluded if OT was found incidentally, was based on qualitative analyses, or were not primary research articles. Full texts of 23 selected articles were assessed for risk of bias and quality assurance using a modified Newcastle–Ottawa Scale (NOS) for clinical studies and SYRCLE’s risk of bias tool for the assessment of pre-clinical (animal) studies. A total of 11 articles described studies on animals and all described serum biomarkers comparing results between OT versus a sham operation, a control group, or readings before and after OT. Ischaemia-modified albumhumin (IMA), serum D-dimer (s-DD), heat shock protein-70 (hsp-70), Pentraxin-3 (PTX3), and c-reactive protein (CRP) each showed the most promise, with p-values for the difference between OT and control groups achieving ≤ 0.001. In studies of humans, the biomarkers ranged from 16.4 to 92.3% sensitivity and 77–100% specificity. The most promising biomarkers for the early prediction of OT in patients included s-DD, interleukin-6 (IL-6), IMA, and tumour necrosis factor-alpha (TNF-α). Signal peptide, CUB domain, and EGF-like domain-containing 1 (SCUBE1) had a high specificity at 93.3%, second only to s-DD and a positive likelihood ratio (LR) > 10. IMA was the only other biomarker that also had a positive LR > 10, making it a promising diagnostic biomarker. The studies identified by this systematic literature review each analysed small patient groups but IMA, DD, and SCUBE1 nevertheless showed promise as serum biomarkers with a pooled LR > 10. However, further well-designed studies are needed to identify and evaluate individual markers or diagnostic panels to help clinicians manage this important organ-threatening condition. Full article

The number of thoracic vertebrae (NTV) in pigs is an important economic trait that significantly influences pork production. While the Licha black pig is a well-known Chinese pig breed with multiple thoracic vertebrae, the genetic mechanism is still unknown. Here, we performed a selective signal analysis on the genome of Licha black pigs, comparing individuals with 15 NTV versus those with 16 NTV to better understand functional genes associated with NTV. A total of 2265 selection signal regions were detected across the genome, including 527 genes and 1073 QTL that overlapped with the selection signal regions. Functional enrichment analysis revealed that LRP5 and SP5 genes were involved in biological processes such as bone morphogenesis and Wnt protein binding. Furthermore, three genes, LRP8, DEF6, and SCUBE3, associated with osteoblast differentiation and bone formation, were located within or close to the QTL related to bone development and vertebrae number. These five genes were hypothesized to be potential candidates for regulating the NTV trait in Licha black pigs. Our findings revealed several candidate genes that play crucial roles in NTV regulation and provide a theoretical foundation to understand the genetic mechanism of the NTV trait in pig breeding. Full article

During their biosynthesis, Sonic hedgehog (Shh) morphogens are covalently modified by cholesterol at the C-terminus and palmitate at the N-terminus. Although both lipids initially anchor Shh to the plasma membrane of producing cells, it later translocates to the extracellular compartment to direct developmental fates in cells expressing the Patched (Ptch) receptor. Possible release mechanisms for dually lipidated Hh/Shh into the extracellular compartment are currently under intense debate. In this paper, we describe the serum-dependent conversion of the dually lipidated cellular precursor into a soluble cholesteroylated variant (Shh^C) during its release. Although Shh^C is formed in a Dispatched- and Scube2-dependent manner, suggesting the physiological relevance of the protein, the depalmitoylation of Shh^C during release is inconsistent with the previously postulated function of N-palmitate in Ptch receptor binding and signaling. Therefore, we analyzed the potency of Shh^C to induce Ptch-controlled target cell transcription and differentiation in Hh-sensitive reporter cells and in the Drosophila eye. In both experimental systems, we found that Shh^C was highly bioactive despite the absence of the N-palmitate. We also found that the artificial removal of N-terminal peptides longer than eight amino acids inactivated the depalmitoylated soluble proteins in vitro and in the developing Drosophila eye. These results demonstrate that N-depalmitoylated Shh^C requires an N-peptide of a defined minimum length for its signaling function to Ptch. Full article

Aim: Method: This research presents a model combining machine learning (ML) techniques and eXplainable artificial intelligence (XAI) to predict breast cancer (BC) metastasis and reveal important genomic biomarkers in metastasis patients. Method: A total of 98 primary BC samples was analyzed, comprising 34 samples from patients who developed distant metastases within a 5-year follow-up period and 44 samples from patients who remained disease-free for at least 5 years after diagnosis. Genomic data were then subjected to biostatistical analysis, followed by the application of the elastic net feature selection method. This technique identified a restricted number of genomic biomarkers associated with BC metastasis. A light gradient boosting machine (LightGBM), categorical boosting (CatBoost), Extreme Gradient Boosting (XGBoost), Gradient Boosting Trees (GBT), and Ada boosting (AdaBoost) algorithms were utilized for prediction. To assess the models’ predictive abilities, the accuracy, F1 score, precision, recall, area under the ROC curve (AUC), and Brier score were calculated as performance evaluation metrics. To promote interpretability and overcome the “black box” problem of ML models, a SHapley Additive exPlanations (SHAP) method was employed. Results: The LightGBM model outperformed other models, yielding remarkable accuracy of 96% and an AUC of 99.3%. In addition to biostatistical evaluation, in XAI-based SHAP results, increased expression levels of TSPYL5, ATP5E, CA9, NUP210, SLC37A1, ARIH1, PSMD7, UBQLN1, PRAME, and UBE2T (p ≤ 0.05) were found to be associated with an increased incidence of BC metastasis. Finally, decreased levels of expression of CACTIN, TGFB3, SCUBE2, ARL4D, OR1F1, ALDH4A1, PHF1, and CROCC (p ≤ 0.05) genes were also determined to increase the risk of metastasis in BC. Conclusion: The findings of this study may prevent disease progression and metastases and potentially improve clinical outcomes by recommending customized treatment approaches for BC patients. Full article

The anthelmintic resistance of gastrointestinal nematodes (GINs) poses a significant threat to sheep worldwide, but genomic selection can serve as an alternative to the use of chemical treatment as a solution for parasitic infection. The objective of this study is to conduct genome-wide association studies (GWASs) to identify single nucleotide polymorphisms (SNPs) in Rambouillet (RA) and Dorper × White Dorper (DWD) lambs associated with the biological response to a GIN infection. All lambs were genotyped with a medium-density genomic panel with 40,598 markers used for analysis. Separate GWASs were conducted using fecal egg counts (FECs) from lambs (<1 year of age) that acquired their artificial infections via an oral inoculation of 10,000 Haemonchus contortus larvae (n = 145) or naturally while grazing on pasture (n = 184). A GWAS was also performed for packed cell volume (PCV) in artificially GIN-challenged lambs. A total of 26 SNPs exceeded significance and 21 SNPs were in or within 20 kb of genes such as SCUBE1, GALNT6, IGF1R, CAPZB and PTK2B. The ontology analysis of candidate genes signifies the importance of immune cell development, mucin production and cellular signaling for coagulation and wound healing following epithelial damage in the abomasal gastric pits via H. contortus during GIN infection in lambs. These results add to a growing body of the literature that promotes the use of genomic selection for increased sheep resistance to GINs. Full article

Signal peptide, CUB, and EGF-like domain-containing proteins (SCUBE) are secretory cell surface glycoproteins that play key roles in the developmental process. SCUBE proteins participate in the progression of several diseases, including cancer, and are recognized for their oncogenic and tumor suppressor functions depending on the cellular context. SCUBE proteins promote cancer cell proliferation, angiogenesis, invasion, or metastasis, stemness or self-renewal, and drug resistance. The association of SCUBE with other proteins alters the expression of signaling pathways, including Hedgehog, Notch, TGF-β/Smad2/3, and β-catenin. Further, SCUBE proteins function as potential prognostic and diagnostic biomarkers for breast cancer, renal cell carcinoma, endometrial carcinoma, and nasopharyngeal carcinoma. This review presents key features of SCUBE family members, and their structure and functions, and highlights their contribution in the development and progression of cancer. A comprehensive understanding of the role of SCUBE family members offers novel strategies for cancer therapy. Full article

Molecular factors that drive metastasis in premenopausal patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−), early breast cancer (EBC) are largely unknown. To identify markers/signatures contributing to metastasis, we analyzed molecular changes in tumors from premenopausal patients who developed metastasis (M1) and who did not (M0). Ninety-seven premenopausal patients with HR+/HER2− EBC were included (M1, n = 48, median distant metastasis-free survival (DMFS): 54 (7–184) months; M0, n = 49, median follow-up: 149 (121–191) months). Gene expression profiling on tumor RNA (Breast Cancer 360^TM panel, Nanostring) was performed, followed by comprehensive bioinformatic and statistical analyses. Significantly enhanced ROR (risk of recurrence) scores and reduced signature scores of PGR (progesterone receptor), claudin-low, and mammary stemness were determined in M1. These differences were significantly associated with shorter DMFS in univariate survival analyses. Gene set enrichment analysis showed an enriched mTORC1 pathway in M1. Moreover, a metastasis signature of 19 differentially expressed genes (DEGs) that were DMFS-related was defined. Multivariate analysis including the four signatures, 19 DEGs, pN, and pT status, identified LRP2, IBSP, and SCUBE2 as independent prognostic factors. We identified prognostic gene signatures and single-gene markers for distant metastasis in premenopausal HR+/HER2− EBC potentially applicable in future clinical practice. Full article