Search Results (132)

Background: Osteodysplastic syndromes comprise a very diverse group of clinically and genetically heterogeneous disorders characterized by defects in bone and connective tissue development, as well as in bone density. Here, we report the case of a 48-year-old female with a complex medical history characterized by bone dysplasia, hyperostosis, and partial tooth agenesis. Methods: Genetic testing was performed using WES analysis and Sanger sequencing. Molecular modeling analysis and dynamics simulation explored the impact of detected pathogenic variants. Results: The genetic analysis detected multiple pathogenic variants in genes CREB3L1, SLCO2A1, SFRP4, LRP5, and LRP6, each of which has been associated with rare osteodysplastic syndromes. The patient was homozygous for the same rare alleles associated with three of the identified autosomal recessive disorders osteogenesis imperfecta type XVI, primary hypertrophic osteoarthropathy, and metaphyseal dysplasia Pyle type. She also had a variant linked to autosomal dominant endosteal hyperostosis and a variant previously associated with increased risk of osteoporosis and bone fractures. Two of the detected variants are predicted to cause abnormal splicing, while molecular modeling and dynamics simulations analysis suggest that the other three variants probably confer altered local secondary structure and flexibility that may have functionally devastating consequences. Conclusions: Our case highlights the rare coexistence of multiple osteodysplastic syndromes in a single patient that may complicate differential diagnosis. Furthermore, this case emphasizes the necessity for early genetic investigation of such complex cases with overlying phenotypic traits, followed by genetic counseling, facilitating orchestration of clinical interventions and allowing prevention and/or prompt management of manifestations. Full article

Background: Prostate cancer is a common malignancy among men worldwide, with various histopathologic features that influence its progression and prognosis. One such feature is perineural invasion (PNI), which has been associated with aggressive disease. In this retrospective study, we analyzed genomic alterations associated with PNI in patients who underwent radical prostatectomy. Methods: A total of 421 prostate cancer patients who underwent radical prostatectomy without neoadjuvant therapy were identified from The Cancer Genome Atlas. PNI was present in 378 patients (89.8%) and absent in 43 (10.2%). Differentially expressed genes were identified, and mRNA expression levels of key genes were analyzed. The prognostic significance of these genes was evaluated using log-rank tests and Cox proportional hazards models to estimate hazard ratios and 95% confidence intervals. Results: Levels of COL9A3, ASPN, ESR1, MUC1, PIP, SFRP4, KRT19, CLDN1, and COMP were significantly higher in the tumor tissues of patients in the PNI group compared to those in the non-PNI group (q < 0.05), and RYR2, MME, and AZGP1 expression levels were significantly higher in the non-PNI group (q < 0.05). A high mRNA expression level of AZGP1 was associated with longer disease-free survival, whereas high mRNA expressions of ASPN, COMP, RYR2, and SFRP4 were associated with shorter disease-free survival. Conclusions: Prostate cancer patients with genomic alterations associated with PNI may face a higher risk of disease progression after prostatectomy, highlighting the need for further prospective studies to validate these findings. Full article

IMF (intramuscular fat, IMF), as a key index for evaluating meat quality traits (shear force and cooking loss, etc.), and its deposition process are jointly regulated by nutritional and genetic factors. In this study, we analyzed the molecular regulation mechanism of IMF deposition in the LD (longissimus dorsal muscle, LD) by dietary energy level in Pamir yaks. Meat quality assessment showed that the meat quality of the High-energy diet group (1.53 MJ/Kg, G) and the Medium-energy diet group (1.38 MJ/Kg, Z) were significantly improved compared with that of the Low-energy diet group (0.75 MJ/Kg, C), in which IMF content in the LD of yaks in G group was significantly higher (p < 0.05) compared with Z and C groups. Further analysis by combined transcriptomics and lipid metabolomics revealed that the differences in IMF deposition mainly originated from the metabolism of lipids, such as TG (triglycerides, TG), PS (phosphatidylserine, PS), and LPC (lysophosphatidylcholine, LPC), and were influenced by SFRP4, FABP4, GADD45A, PDGFRA, RBP4, and DGAT2 genes, further confirming the importance of lipid–gene interactions in IMF deposition. This study reveals the energy-dependent epigenetic regulatory mechanism of IMF deposition in plateau ruminants, which provides molecular targets for optimizing yak nutritional strategies and quality meat production, while having important theoretical and practical value for the sustainable development of livestock husbandry on the Tibetan Plateau. Full article

Mitochondrial DNA (mtDNA) damage in trabecular meshwork (TM) cells occurs in open-angle glaucoma (OAG). However, current in vitro models for OAG-like changes in TM cells do not explicitly incorporate mtDNA damage. This work validated two methods of mtDNA damage in immortalized TM cells and assessed OAG-associated expression changes. mtDNA was depleted in TM-1 cells via both ethidium bromide (EtBr) treatment and doxycycline (Dox) induction of a mutant (Y147A) version of Uracil DNA Glycosylase 1 (UNG1) in TM-1 cells (TM-1^{rtTAadv-TRE-UNG1Y147A}). Levels of mitochondrial proteins (ATP5F1A, COXII, and COXIV) were measured via western blot. mtDNA levels and mRNA for OAG-associated transcripts (CTGF, FN1, PAI1, and SFRP1) were measured by qPCR. There was a statistically significant decrease in mtDNA levels per cell at all treatment times in both EtBr-treated TM-1 cells and induced TM-1^{rtTAadv-TRE-UNG1Y147A} cells. Protein levels of ATP5F1A were not significantly changed; COXII and COXIV showed significant decreases after both EtBr and Dox induction. Both models resulted in upregulation of CTGF, FN1, and PAI1; additionally, EtBr treatment but not Dox induction resulted in SFRP1 upregulation. In conclusion, two models of mitochondrial depletion were demonstrated in immortalized TM cells; damage was associated with increases in OAG-associated transcripts, supporting a link between mitochondrial damage and glaucoma phenotypes. Full article

The mechanical properties of additive manufactured (AM) short-fibre reinforced polymer (SFRP) composites are significantly influenced by infill patterns, fibre orientation, and fibre-matrix interactions. While previous studies have explored the role of process parameters in optimising AM components, the impact of infill geometry on anisotropy and mechanical performance remains underexplored, particularly in the context of machine learning (ML). This study develops an ML-driven framework to predict the tensile and flexural properties of AM SFRP composites with different infill patterns, including triangular, hexagonal, and rectangular. AM structures were fabricated and subjected to tensile and flexural tests, with the data used to train ML models, including LightGBM, XGBoost, and artificial neural networks (ANN). The results showed that the triangular infill pattern had the highest tensile strength and stiffness, the hexagonal infill had the lowest flexural properties, and the rectangular infill exhibited performance levels that fell between those of the triangular and hexagonal patterns. The ML models demonstrated high prediction accuracy, with R-squared values exceeding 0.95. XGBoost performed best for predicting tensile properties of hexagonal infill, while ANN excelled with triangular and rectangular configurations. This study demonstrates the potential of machine learning to enhance the mechanical performance of additively manufactured SFRP composites by capturing the complex interplay between infill geometry and fibre-matrix interactions. Thus, providing additional data for the design of high-performance materials in applications such as biomedical devices. Full article

The establishment of cell fate and boundaries between cell types is an essential step in development and organogenesis. In the mammalian cochlea, a distinct boundary exists between a medial region of non-sensory cells and a lateral region of sensory cells. We report that Wnt4 and sFRP2 act in combination to modulate the sensory cell differentiation of the organ of Corti. The hair cell inhibitory effects of Wnt4 in the inner ear are mediated through the activation of the non-canonical Wnt/Calcium/PKC pathway. We show that Wnt4 stimulates the activation of PKC in the cochlea, and that the inhibition of PKC rescues the ectopic Wnt4 activity phenotype. Finally, we demonstrate that modification at a PKC target site on Atoh1 diminishes its ability to induce hair cell formation. Ultimately, we identify a new Wnt/Calcium/PKC non-canonical signaling pathway that is involved in proper hair cell and organ of Corti formation in the developing mammalian cochlea. Full article

Secreted Frizzled-related protein 4 (SFRP4) has been identified as a patient-level biomarker of the stem-like subtype of gastric cancer (GC), which is associated with poor prognosis and resistance to chemotherapy. Although multiple studies have documented the clinical significance of SFRP4 in GC, its mechanistic role in the stem-like subtype remains incompletely understood. In this study, we elucidate how phosphorylation of SFRP4 by protein kinase A (PKA) converts it into a Wnt signaling agonist. We began with a phosphoproteomic database search to identify candidate kinases that phosphorylate SFRP4. Co-immunoprecipitation assays revealed a direct interaction between PKA and SFRP4, and in vitro kinase assays confirmed that PKA phosphorylates SFRP4 at key threonine residues. Phosphorylated SFRP4 then associates with β-catenin, augmenting Wnt-driven transcriptional activity. Importantly, pharmacological inhibition of PKA significantly reduced SFRP4 phosphorylation and suppressed stemness-associated phenotypes, such as sphere formation, migratory capacity, and chemoresistance, in gastric cancer cells. Collectively, our data demonstrate that PKA-mediated phosphorylation of SFRP4 enhances cancer stemness-related properties in GC through Wnt signaling. Furthermore, these results highlight the PKA–SFRP4 axis as a promising therapeutic target in the stem-like subtype of GC. Full article

Antlers, as the only fully regenerable bone tissue in mammals, serve as an exceptional model for investigating bone growth, mineralization, articular cartilage repair, and the pathophysiology of osteoporosis. Nevertheless, the exact molecular mechanisms governing osteogenesis, particularly the dynamic cellular interactions and signaling pathways coordinating these processes, remain poorly characterized. This study used single-cell RNA sequencing (scRNA-seq) on the 10× Genomics Chromium platform, combined with bulk-RNA sequencing results, to comprehensively analyze molecular regulatory mechanisms in rapid antler osteogenesis. The results showed that eight cell types were identified in sika deer antler during the growth and ossification stages: mesenchymal, chondrocyte, osteoblast, pericyte, endothelial, monocyte/macrophage, osteoclast, and NK cells. Chondrocytes were predominantly found during the growth stage, while osteoblasts were more abundant during the ossification stage. Mesenchymal cells were subclassified into three subcategories: MSC_1 (VCAN and SFRP2), MSC_2 (TOP2A, MKI67), and MSC_3 (LYVE1 and TNN). MSC_3 was predominantly present during the growth stage. During the growth stage, MSC_1 and MSC_2 upregulated genes related to vasculature development (COL8A1, NRP1) and cell differentiation (PTN, SFRP2). During the ossification stage, these subcategories upregulated genes involved in the positive regulation of p53 class mediator signal transduction (RPL37, RPL23, RPS20, and RPL26), osteoblast differentiation (SPP1, IBSP, BGLAP), and proton-motive ATP synthesis (NDUFA7, NDUFB3, NDUFA3, NDUFB1). Endothelial cells were categorized into five subpopulations: Enc_1 (SPARCL1, VWF), Enc_2 (MCM5), Enc_3 (ASPM, MKI67), Enc_4 (SAT1, CXCL12), and Enc_5 (ZFHX4, COL6A3). Combined scRNA-seq and bulk RNA-seq analysis revealed that the ossification stage’s upregulation genes included osteoclast- and endothelial cell-specific genes, while the growth stage’s upregulation genes were mainly linked to collagen organization, osteoblast differentiation, mitotic cell cycle, and chondrocyte differentiation. Overall, this study offers a detailed single-cell analysis of gene expression patterns in antlers during the growth and ossification stages, providing insights into the molecular mechanisms driving rapid osteogenesis. Full article

Highland animals have unique hair growth mechanisms to allow them to adapt to harsh living environments. Compared with other species, their hair cycle growth is affected by more environmental factors. Yaks, as highland animals, have obvious periodic hair growth characteristics in a year; this biological process is regulated by numerous proteins, but the specific molecular regulatory mechanism is still unclear. Here we analyzed the histological characteristics of yak hair follicles (HFs) at each stage and conducted TMT proteomics research. The protein expression network of yak hair at each stage and the mechanism of the yak HF growth cycle were systematically explored, and the candidate proteins Sfrp1 and Ppard were verified. A total of 3176 proteins were quantifiable and 1142 differentially expressed proteins (DEPs) were obtained at five stages of the yak hair cycle. DEPs enriched in complement activation change, tissue development, lipid metabolism, WNT pathway, VEGF pathway, JAK-STAT pathway, and PPAR pathway may promote the growth of yak hair follicles, such as Serpinf1, Ppard, and Stat3. DEPs enriched in complement system, coagulation, cell adhesion, lipid metabolic process, proliferation of epidermal cells, and estrogen pathway may promote the degeneration of yak hair, such as Sfrp1, Eppk1, and Egfr. Using Protein-Protein Interaction (PPI) analysis, we found that core nodes of DEP networks in yak skin are significantly different at three critical time points in hair follicle development, and lipid metabolism proteins are common core DEP nodes during yak HF growth and degeneration. The expression of Sfrp1 and Ppard in yak hair follicles at different periods showed they are related to yak hair cycle control. This study showed that the protein regulatory network of the yak HF growth cycle is complex and dynamically changing and revealed key candidate proteins that may affect yak hair follicle development. These findings provided detailed data for further understanding of the plateau adaptation mechanism of the yak, which is of great significance to make better use of the yak livestock resources and enhance their economic value. Full article

Background: Among the various forms of root resorption, External Apical Root Resorption (EARR) has garnered particular attention due to its prevalence and potential complications associated with orthodontic interventions. Methods: An electronic search of literature was performed between September 2024 and December 2024 to identify all articles investigating the Role of Genetic Polymorphisms in External Apical Root Resorption Among Orthodontic Patients: Implications for Treatment Outcomes. The search was conducted using MEDLINE (National Library of Medicine)-PubMed with restrictions concerning the date of publication. In particular, we focused on the period 2014–2024 using the following keywords: gene polymorphisms AND orthodontic treatment AND apical root resorption OR external apical root resorption. This was followed by a manual search, and references were used to identify relevant articles. Results: The review showed that certain variations of the following genes may be positively associated with OIEARR: Osteopontin gene, P2RX7, IL-1β, IL-6, IL1RN, OPG, RANK, STAG2, RP1-30E17.2, SSP1, SFRP2, TNFSF11, TNFRSF11A, TNFRSF11B, VDR, CYP27B1, ACT3N, TSC2, WNT3A, LRP1, LRP6. Conversely, the IRAK1 gene has a protective function against the development of OIEARR. Conclusions: Despite these advancements, it is still not feasible to establish new guidelines and clinical protocols based on the existing research findings. The integration of genetic considerations into orthodontic practice has the potential to revolutionize treatment strategies, ensuring that they are not only effective but also respectful of each patient’s unique biological landscape. Full article

Introduction: Neuroendocrine tumors are a diverse group of tumors predominantly found in the gastrointestinal tract or respiratory system. Methods: This retrospective study aimed to measure the serum concentrations of LRP6 (low-density lipoprotein receptor-related protein 6), SFRP3 (secreted frizzled-related protein 3), and DVL1 (segment polarity protein dishevelled homolog) using the ELISA method in patients with NETs (N = 80) and a control group (N = 62). We evaluated the results against various demographic, clinicopathological, and biochemical characteristics. Results: Our analyses revealed that the concentration of SFRP3 in patients with neuroendocrine tumors was significantly elevated (p < 0.001) compared to the control group. Additionally, DVL1 concentrations were significantly higher (p < 0.01) in patients with BP-NETs compared to GEP-NETs. Furthermore, DVL1 analysis showed a moderate negative correlation with chromogranin A (p < 0.001) and weak negative correlations with serotonin (p < 0.05) and 5-HIAA (p < 0.05). Significant negative correlations were also observed between DVL1 and age in the control group (p < 0.01), and between LRP6 and Ki-67 in the study group. Conclusions: These results suggest that changes in the SFRP3 and DVL1 pathways play a key role in NET development. Elevated levels of these proteins highlight their importance in tumor biology, with SFRP3 and DVL1 potentially being crucial in NET molecular mechanisms. Further research is needed to explore their roles and potential in diagnosis and treatment. Full article

In the current work, we aimed to evaluate the association of clinical data of Cushing’s disease (CD) patients with USP8 mutation status and to study USP8-related molecular mechanisms connected to the regulation of corticotropinoma growth and activity. 35 CD patients were enrolled; the sequencing of exon 14 in USP8 revealed variants in eighteen adenomas, two of which were described for the first time in CD. USP8 variants were more common in women (94% vs. 76%; p = 0.001), and microadenomas and tumor recurrence were prevalent in the USP8-mutant group (44% vs. 29%; p = 0.04 and 44% vs. 22%; p = 0.0015). Preoperative ACTH and serum cortisol did not differ in the USP8-WT and USP8-mutant patients. All USP8-mutant adenomas were SST5-positive, and 73% of them were double-positive (SST5+/SST2+). A total of 50% of USP8-WT adenomas were double-negative (SST5−/SST2−), and 40% of them were SST5-positive. Analysis of transcriptome was performed for nine USP8-mutant and six USP8-WT adenomas and revealed the that the bidirectional dysregulation of Wnt signaling, including both the agonist RSPO2 and antagonist SFRP1, in the USP8-mutant corticotropinomas was downregulated. These alterations may indicate the existence of regulatory connections between USP8 enzyme activity, Wnt signaling, EGFR signaling and somatostatin receptors’ trafficking, which can explain, at least in part, the clinical manifestations of CD in patients with corticotropinomas harboring USP8 variants. Full article

Background: Melanin overproduction leads to pigmented skin diseases. Brown algae polyphenols, non-toxic secondary metabolites, exhibit potential bioactivities. Sargassum fusiforme, an edible seaweed, has been underexplored in the field of beauty despite its polyphenol richness. Methods: Polyphenols from S. fusiforme were extracted using macroporous resin (SFRP) and ethyl acetate (SFEP). Their antioxidant and anti-aging properties, tyrosinase inhibitory activities, and mechanisms were assessed. The melanogenesis inhibition effect and mechanism by SFRP was examined in B16F10 melanoma cells. Results: Both SFRP and SFEP demonstrated scavenging activities against DPPH, superoxide anion, and hydroxyl radicals. SFRP showed stronger anti-collagenase and anti-elastase effects. They dose-dependently inhibited mushroom tyrosinase, with IC50 values of 9.89 μg/mL for SFRP and 0.99 μg/mL for SFEP. SFRP reversibly inhibited tyrosinase, while SFEP showed irreversible inhibition. SFRP also suppressed melanin content and intracellular tyrosinase activity in B16F10 cells, downregulating the expression of microphthalmia-associated transcription factor, tyrosinase, and tyrosinase-related protein 1 and 2 expression through the PI3K/Akt and MAPK/ERK signal pathways. Conclusions: S. fusiforme polyphenols, especially SFRP, exhibit promising antioxidant, anti-aging, and melanogenesis inhibitory properties, highlighting their potential application as novel anti-melanogenic agents in cosmetics and the food industry. Full article

Background/Objective: Secreted frizzled-related protein 5 (Sfrp5) is an anti-inflammatory adipokine that has been implicated in the pathophysiology of obesity and its metabolic complications. Despite the fact that numerous studies have been carried out in adults, limited data on Sfrp5 exist for youth, especially in relation to overweight and obesity. Methods: In our study, we assessed the concentrations of Sfrp5, total oxidative (TOS) and antioxidative (TAS) status, high-sensitivity C-reactive protein (hs-CRP), and several cytokines (IL-1α, IL-1β, IL-2, IL-6, IL-8, IL-12, TNF-α) in 120 children and adolescents (mean age ± SE: 11.48 ± 0.25 years; 48 prepubertal, 72 pubertal; 74 males and 46 females) before and 1 year after the implementation of a personalized, structured, lifestyle intervention program of healthy diet, sleep, and physical exercise. Results: Based on the body mass index (BMI), participants were categorized as having morbid obesity (n = 63, 52.5%), obesity (n = 21, 17.5%), overweight (n = 22, 18.33%), or normal BMIs (n = 14, 11.67%), based on the International Obesity Task Force (IOTF) cut-off points. Following the 1-year lifestyle intervention program, a significant improvement in anthropometric measurements (BMI, BMI-z score, diastolic blood pressure, WHR, and WHtR), body-composition parameters, hepatic enzymes, lipid profile, inflammation markers, and the insulin-sensitivity profile (HbA1C, HOMA index) was observed in all subjects. Sfrp5 decreased in subjects with obesity (p < 0.01); however, it increased significantly (p < 0.05) in patients with morbid obesity. Linear regression analysis indicates that TNF-α and systolic blood pressure were the best positive predictors and hs-CRP was the best negative predictor for Sfpr5 concentration at initial assessment and glucose concentration for ΔSfrp5, while TNF-α and TAS were the best positive predictors for Sfpr5 concentration at annual assessment. Conclusions: These results indicate that Sfrp5 is associated with severe obesity and is increased following weight loss in children and adolescents with morbid obesity. It is also related to metabolic homeostasis, as well as inflammation and oxidative status. Full article

Avian primordial germ cells (PGCs) are essential in avian transgenic research, germplasm conservation, and disease resistance breeding. However, cultured PGCs are prone to fragmentation and apoptosis, regulated at transcriptional and translational levels, with N6-methyladenosine (m6A) being the most common mRNA modification. Resveratrol (RSV) is known for its antioxidant and anti-apoptotic properties, but its effects on PGCs and the underlying mechanisms are not well understood. This study shows that RSV supplementation in cultured PGCs improves cell morphology, significantly enhances total antioxidant capacity (p < 0.01), reduces malondialdehyde levels (p < 0.05), increases anti-apoptotic BCL2 expression, and decreases Caspase-9 expression (p < 0.05). Additionally, RSV upregulates the expression of m6A reader proteins YTHDF1 and YTHDF3 (p < 0.05). m6A methylation sequencing revealed changes in mRNA m6A levels after RSV treatment, identifying 6245 methylation sites, with 1223 unique to the control group and 798 unique to the RSV group. Combined analysis of m6A peaks and mRNA expression identified 65 mRNAs with significantly altered methylation and expression levels. Sixteen candidate genes were selected, and four were randomly chosen for RT-qPCR validation, showing results consistent with the transcriptome data. Notably, FAM129A and SFRP1 are closely related to apoptosis, indicating potential research value. Overall, our study reveals the protective effects and potential mechanisms of RSV on chicken PGCs, providing new insight into its use as a supplement in reproductive stem cell culture. Full article