Search Results (1,197)

Healing large bone defects remains challenging. Gelatin scaffolds are biocompatible and biodegradable, but lack osteoinductive activity. Plant-derived exosomes carry miRNAs, growth factors, and proteins that modulate osteogenesis, but free exosomes suffer from poor stability, limited targeting, and low bioavailability in vivo. We developed a 3D GelMA hydrogel loaded with Epimedium-derived exosomes (“GelMA@Exo”) to improve exosome retention, stability, and sustained release. Its effects on MC3T3-E1 preosteoblasts—including proliferation, osteogenic differentiation, migration, and senescence—were evaluated via in vitro assays. Angiogenic potential was assessed using HUVECs. Underlying mechanisms were examined at transcriptomic and protein levels to elucidate GelMA@Exo’s therapeutic osteogenesis actions. GelMA@Exo exhibited sustained exosome release, enhancing exosome retention and cellular uptake. In vitro, GelMA@Exo markedly boosted MC3T3-E1 proliferation, migration, and mineralized nodule formation, while reducing senescence markers and promoting angiogenesis in HUVECs. Mechanistically, GelMA@Exo upregulated key osteogenic markers (RUNX2, TGF-β1, Osterix, COL1A1, ALPL) and activated the PI3K/Akt pathway. Transcriptomic data confirmed global upregulation of osteogenesis-related genes and bone-regeneration pathways. This study presents a GelMA hydrogel functionalized with plant-derived exosomes, which synergistically provides osteoinductive stimuli and structural support. The GelMA@Exo platform offers a versatile strategy for localized delivery of natural bioactive molecules and a promising approach for bone tissue engineering. Our findings provide strong experimental evidence for the translational potential of plant-derived exosomes in regenerative medicine. Full article

Various biomaterials are currently employed for dermal biostimulation and filling purposes, with hyaluronic acid (HA)-based fillers among those with the most favorable safety profile, albeit exhibiting a limited biostimulatory effect. This study suggests that hyaluronic acid and succinic acid (SA) can significantly induce beneficial effects on skin cells by targeting key aging hallmarks. Human dermal senescent fibroblasts and aged adipocytes were treated with HA + SA, and various aging characteristics were examined through gene expression analysis and microscopy staining. HA was found to stimulate autophagy gene expression, while SA modulated senescence-gene expression, and the combination of these compounds induced mitophagy in senescent fibroblasts. Additionally, the HA + SA promoted adipogenesis, increased IGF1, and decreased TNFA gene expression in aged adipocytes. Furthermore, the conditioned medium from adipocytes treated with HA + SA upregulated key dermal genes such as COL3A1 and EGF. The findings of this study suggest that HA and SA compounds can be used for the biostimulation of aged skin through the regulation of senescence-associated gene expression and cell communication between dermal fibroblasts and subcutaneous adipocytes. Full article

Background/Objectives: The increased risk of developing tendinopathies in athlete populations has led to investigations of several genes associated with tendon properties, suggesting that some individuals have a greater genetic predisposition for developing tendinopathies. The main purpose of this study was to investigate how the functional polymorphisms within the COL5A1, COL27A1 and TNC genes impact the risk of developing tendinopathies in high-level Croatian athletes. Methods: For this case–control genetic study, we recruited 63 high-level athletes with a diagnosis of tendinopathies and 92 healthy asymptomatic individuals as controls. All individuals were genotyped for three single-nucleotide polymorphisms (SNPs) within the COL5A1, COL27A1 and TNC genes using the pyrosequencing method. Results: TNC rs2104772 TT (p = 0.0089) and the T-T-T haplotype (p = 0.0234), constructed from rs12722, rs946053 and rs2104772, were significantly overrepresented in cases versus controls, implicating a predisposition for tendinopathies. COL27A1 rs946053 GG (p = 0.0118) and the G-A-C haplotype (p = 0.0424), constructed from rs12722, rs946053 and rs2104772, were significantly overrepresented in controls, implicating a protective role. Conclusions: These results further support associations between functional polymorphisms within the COL27A1 and TNC genes and the risk of tendinopathies in high-level athletes. Further research is needed to replicate these results in various populations and larger cohorts. Full article

Bassia scoparia (Syn. Kochia scoparia (L.) Schrad.) is a medicinal plant whose fruit, Kochiae Fructus, has been extensively studied for its dermatological applications. This study focused on extracts from the whole plant B. scoparia (WPBS), excluding fruits, to address the research gap regarding the medicinal properties of non-fruit parts. The diverse skin benefits of WPBS, including its anti-photoaging, moisturizing, wound healing, anti-inflammatory, and anti-angiogenic effects, were investigated. The WPBS extract enhanced the viability of keratinocytes (HaCaT) without inducing cytotoxic effects. WPBS significantly reduced matrix metalloproteinase-1 (MMP-1) levels and increased collagen type I alpha 1 (COL1A1) levels (p < 0.01) in fibroblasts exposed to ultraviolet B (UVB) radiation, indicating strong anti-photoaging effects. WPBS upregulated skin hydration markers such as aquaporin-3 (AQP3) and hyaluronan synthase-3 (HAS3) and effectively accelerated fibroblast wound closure compared to the positive control. Furthermore, WPBS substantially downregulated the expression of inflammatory (COX-2 and IL-1β) and angiogenic markers (VEGF). Transcriptome analysis (RNA-seq) confirmed that WPBS suppressed inflammation-related and UV-induced gene expression pathways. Overall, these findings expand the therapeutic scope of B. scoparia beyond its traditional fruit use and suggest that WPBS is a promising botanical ingredient for various skin applications. Full article

Inherited epidermolysis bullosa (EB) is a heterogeneous clinical entity that includes over 30 phenotypically and/or genotypically distinct inherited disorders, characterized by mechanical skin fragility and bullae formation. Junctional EB (JEB) is an autosomal recessive disease characterized by an intermediated cleavage level within the skin layers, commonly at the “lamina lucida”. Laryngo-onycho-cutaneous syndrome (LOC) is an extremely rare variant of JEB, characterized by granulation tissue formation in specific body sites (skin, larynx, and nails). Although most cases of JEB are caused by pathogenic variants occurring in the genes encoding for classical components of the lamina lucida, such as laminin 332 (LAMA3, LAMB3, LAMC2), integrin α6β4 (ITGA6, ITGB4), and collagen XVII (COL17A1), other variants have also been described. We report the case of a 4-month-old male infant who presented with recurrent bullous and erosive lesions from the first month of life. At the first dermatological evaluation, the patient was agitated and exhibited hoarse breathing, a clinical sign suggestive of laryngeal involvement. Multiple polygonal skin erosions were observed on the cheeks, along with similar isolated, roundish lesions on the scalp and legs. Notably, nail dystrophy and near-complete anonychia were evident on the left first and fifth toes. Due to the coexistence of skin erosions and nail dystrophy in such a young infant, a congenital bullous disorder was suspected, prompting molecular analysis of all potentially involved genes. In the patient’s DNA, clinical exome sequencing (CES) identified a pathogenic variant, apparently in homozygosity, in the exon 1 of the LAMA3 gene (18q11.2; NM_000227.6): c.47G > A;p.Trp16*. The presence of this variant was confirmed, in heterozygosity, in the genomic DNA of the patient’s mother, while it was absent in the father’s DNA. Subsequently, trio-based SNP array analysis was performed, revealing a paternally derived pathogenic microdeletion encompassing the LAMA3 locus (18q11.2). To our knowledge, this is the first reported case of JEB with a LOC-like phenotype caused by a maternally inherited monoallelic nonsense mutation in LAMA3, unmasked by an almost complete deletion of the paternal allele. The combined use of exome sequencing and SNP array is proving essential for elucidating autosomal recessive diseases with a discordant segregation. This is pivotal for providing accurate genetic counseling to parents regarding future pregnancies. Full article

Background: Hemiplegic migraine (HM) is a rare and severe subtype of migraine with a complex genetic basis. Although pathogenic variants in CACNA1A, ATP1A2, and SCN1A explain some familial cases, a significant proportion of patients remain genetically undiagnosed. Increasing evidence points to an overlap between migraine and cerebral small vessel disease (SVD), implicating vascular dysfunction in HM pathophysiology. Objective: This study aimed to identify rare or novel variants in genes associated with SVD in a cohort of patients clinically diagnosed with HM who tested negative for known familial hemiplegic migraine (FHM) pathogenic variants. Methods: We conducted a case-control association analysis of whole exome sequencing (WES) data from 184 unrelated HM patients. A targeted panel of 34 SVD-related genes was assessed. Variants were prioritised based on rarity (MAF ≤ 0.05), location (exonic/splice site), and predicted pathogenicity using in silico tools. Statistical comparisons to gnomAD’s Non-Finnish European population were made using chi-square tests. Results: Significant variants were identified in several SVD-related genes, including LRP1 (p.Thr4077Arg), COL4A1 (p.Pro54Leu), COL4A2 (p.Glu1123Gly), and TGFBR2 (p.Met148Leu and p.Ala51Pro). The LRP1 variant showed the strongest association (p < 0.001). All key variants demonstrated pathogenicity predictions in multiple computational models, implicating them in vascular dysfunction relevant to migraine mechanisms. Conclusions: This study provides new insights into the genetic architecture of hemiplegic migraine, identifying rare and potentially deleterious variants in SVD-related genes. These findings support the hypothesis that vascular and cellular maintenance pathways contribute to migraine susceptibility and may offer new targets for diagnosis and therapy. Full article

Background: Salmonella is a bacterium that causes foodborne infections. This study characterized two strains isolated from cheese and beef in Brazil using whole-genome sequencing (WGS). Objectives: We evaluated their antimicrobial resistance profiles, virulence factors, plasmid content, serotypes and phylogenetic relationships. Methods: DNA was extracted and sequenced on the NovaSeq 6000 platform; the pangenome was assembled using the Roary tool; and the phylogenetic tree was constructed via IQ-TREE. Results and Discussion: For contextualization and comparison, 3493 Salmonella genomes of Brazilian origin from NCBI were analyzed. In our isolates, both strains carried the aac(6′)-Iaa_1 gene, while only Schwarzengrund harbored the qnrB19_1 gene and the Col440I_1 plasmid. Cerro presented the islands SPI-1, SPI-2, SPI-3, SPI-4, SPI-5 and SPI-9, while Schwarzengrund also possessed SPI-13 and SPI-14. Upon comparison with other Brazilian genomes, we observed that Cerro and Schwarzengrund represented only 0.40% and 2.03% of the national database, respectively. Furthermore, they revealed that Schwarzengrund presented higher levels of antimicrobial resistance, a finding supported by the higher frequency of plasmids in this serovar. Furthermore, national data corroborated our findings that SPI-13 and SPI-14 were absent in Cerro. A virulence analysis revealed distinct profiles: the cdtB and pltABC genes were present in the Schwarzengrund isolates, while the sseK and tldE1 family genes were exclusive to Cerro. The results indicated that the sequenced strains have pathogenic potential but exhibit low levels of antimicrobial resistance compared to national data. The greater diversity of SPIs in Schwarzengrund explains their prevalence and higher virulence potential. Conclusions: Finally, the serovars exhibit distinct virulence profiles, which results in different clinical outcomes. Full article

Reparative tertiary dentinogenesis requires the recruitment and odontogenic differentiation of dental pulp stem cells (DPSCs). Extracellular vesicles (EVs) as bioactive molecules have gained attention in regenerative medicine for their ability to mediate tissue repair through intercellular communication, influencing cell recruitment, proliferation, and differentiation. This study aimed to evaluate the effects of EVs on DPSC homing and odontogenic differentiation for dentin regeneration. DPSC-derived EVs were cultured in either growth (EV-G) or odontogenic differentiation (EV-O) conditions and isolated using a modified precipitation method. EVs were characterized by nanoparticle tracking analysis, scanning electron microscopy, antibody array, and cellular uptake assay. Treatment with 5 × 10⁸ EVs/mL significantly enhanced DPSC chemotaxis and proliferation compared with a no-treatment control and a lower dosage of EV (5 × 10⁷ EVs/mL). Gene expression and biochemical analyses revealed that EV-O up-regulated odontogenic markers including collagen type 1A1 (COL1A1), runt-related transcription factor 2 (RUNX2), and alkaline phosphatase (ALP). EV-O enhanced dentin regeneration by approximately 55% over vehicle controls in a rabbit partial dentinotomy/pulpotomy model. We identified key microRNAs (miR-21-5p, miR-221-3p, and miR-708-3p) in EV-O involved in cell homing and odontogenesis. In conclusion, our EV-based cell homing and odontogenic differentiation strategy has significant therapeutic potential for dentin regeneration. Full article

Osteolforte, a compound with potential bone-regenerative properties, was investigated for its effects on human bone marrow stromal cells (hBMSCs). This study aimed to evaluate its impact on cell viability, osteogenic differentiation, and both gene and protein expression using a combination of assays, including CCK-8, Alizarin Red S staining, Quantitative Real-Time PCR (qRT-PCR), and Western blot analysis. The results demonstrated that Osteolforte significantly enhanced osteogenic differentiation in hBMSCs. Alizarin Red S staining revealed increased mineralization, indicating elevated calcium deposition. Gene expression analysis showed an upregulation of key osteogenic markers, including runt-related transcription factor-2 (RUNX-2), collagen type I (COL-1), and bone morphogenetic protein-2 (BMP-2), supporting the role of Osteolforte in promoting osteoblastic activity. In particular, the elevated expression of RUNX-2—a master transcription factor in osteoblast differentiation along with COL-1, a major bone matrix component, and BMP-2, a key bone morphogenetic protein—highlights the compound’s osteogenic potential. In conclusion, Osteolforte enhances early-stage osteogenesis and mineralization in hBMSCs and represents a promising candidate for bone regeneration. Full article

Auxin (IAA), a key natural signaling molecule, plays a pivotal role in regulating plant growth, development, and stress responses. Understanding its signal transduction mechanisms is crucial for improving crop yields. In this study, we conducted a comparative transcriptome analysis of wheat leaf and root tissues treated with different concentrations of IAA (0, 1, and 50 μM). Functional enrichment analysis revealed that differentially expressed genes (DEGs) exhibited tissue-specific regulatory patterns in response to auxin. Weighted Gene Co-expression Network Analysis (WGCNA) identified receptor-like kinase genes within the MEgreen module as highly correlated with auxin response, suggesting their involvement in both root and leaf regulation. Among them, TaPBL7-2B, a receptor-like kinase gene significantly upregulated under 50 μM IAA treatment, was selected for functional validation. Ectopic overexpression of TaPBL7-2B in Arabidopsis thaliana (Col-0) enhanced auxin sensitivity and inhibited plant growth by suppressing root development and leaf expansion. In contrast, knockout of the Arabidopsis homolog AtPBL7 reduced auxin sensitivity and promoted both root and leaf growth. Transcriptome analysis of Col-0, the TaPBL7-2B overexpression line, and the pbl7 mutant indicated that TaPBL7-2B primarily functions through the MAPK signaling pathway and plant hormone signal transduction pathway. Furthermore, qRT-PCR analysis of wheat varieties with differing auxin sensitivities confirmed a positive correlation between TaPBL7-2B expression and auxin response. In conclusion, TaPBL7-2B acts as a negative regulator of plant growth, affecting root development and leaf expansion in both Arabidopsis and wheat. These findings enhance our understanding of auxin signaling and provide new insights for optimizing crop architecture and productivity. Full article

Members of the genus Nemipterus are economically important fish species distributed in the tropical and subtropical Indo-West Pacific region. The majority of species in this genus inhabit waters with sandy–muddy substrates on the continental shelf, although different species are found at slightly varying water depths. In this study, we sequenced seven species within the genus Nemipterus after identifying the specimens using complementary morphological analysis and DNA barcoding. Each species yielded over 40,000,000 clean reads, totaling over 300,000,000 clean reads across the seven species. A total of 276,389 unigenes were obtained after de novo assembly and a total of 168,010 (60.79%) unigenes were annotated in the protein database. The comprehensive functional annotation based on the KOG, GO, and KEGG databases revealed that these unigenes are mainly associated with numerous physiological, metabolic, and molecular processes, and that the seven species exhibit similarity in these aspects. By constructing a phylogenetic tree and conducting divergence time analysis, we found that N. bathybius and N. virgatus diverged most recently, approximately during the Neogene Period (14.9 Mya). Compared with other species, N. bathybius and N. virgatus are distributed in deeper water layers. Therefore, we conducted selection pressure analysis using these two species as the foreground branches and identified several environmental-responsive genes. The results indicate that genes such as aqp1, arrdc3, ISP2, Hip, ndufa1, ndufa3, pcyt1a, ctsk, col6a2, casp2 exhibit faster evolutionary rates during long-term adaptation to deep-water environments. Specifically, these genes are considered to be associated with adaptation to aquatic osmoregulation, temperature fluctuations, and skeletal development. This comprehensive analysis provides valuable insights into the evolutionary biology and environmental adaptability of threadfin breams, contributing to the conservation and sustainable management of these species. 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

Autosomal recessive types of both syndromic and non-syndromic inherited myopia are common in Saudi Arabia (SA) because many people marry their relatives. The prevalence of syndromic myopathies in SA, like Stickler syndrome (SS), Knobloch syndrome (KS), and Marfan syndrome (MFS), further complicates the disease spectrum. The causative genes linked to the Knobloch, Marfan, and Pierson syndromes are COL18A1, FBN1, and LAMB2, respectively. Additionally, we found recessive types of non-syndromic high myopia that have a high chance of causing retinal detachment, like those linked to LRPAP1 and LEPREL1. In these cases, regular evaluation and early intervention, including prophylactic laser photocoagulation and pars plana vitrectomy, may improve the outcome. Advancements in genetic testing for diagnosis and prevention accelerate detection, facilitate early interventions, and provide genetic counseling. The utilization of artificial intelligence (AI), machine learning (ML), and the advancement of gene therapy offer promising avenues for personalized care. We place a high value on using genetic knowledge to create a national screening program and patient registry aimed at understanding the national burden of myopia, knowing that we have a high rate of consanguinity, which reflects pathogenic homozygous alleles and founder mutations. This initiative will incorporate genetic counseling and leverage innovative technologies, which are crucial for disease management, early identification, and prevention in Saudi Arabia’s healthcare system. Full article

An investigation into the biological mechanisms initiated in wounded skin following the application of mesenchymal stem cells (MSCs) and nanoparticles (NPs) (Ag, ZnO), either alone or combined, was performed in mice, with the aim of determining the optimal approach to accelerate the healing process. This combined treatment was hypothesized to be beneficial, as it is associated with the production of molecules supporting the healing process and antimicrobial activity. The samples were collected seven days after injury. When compared with untreated wounded animals (controls), the combined (MSCs+NPs) treatment induced the expression of Sprr2b, encoding small proline-rich protein 2B, which is involved in keratinocyte differentiation, the response to tissue injury, and inflammation. Pathways associated with keratinocyte differentiation were also affected. Ag NP treatment (alone or combined) modulated DNA methylation changes in genes involved in desmosome organization. The percentage of activated regulatory macrophages at the wound site was increased by MSC-alone and Ag-alone treatments, while the production of nitric oxide, an inflammatory marker, by stimulated macrophages was decreased by both MSC/Ag-alone and MSCs+Ag treatments. Ag induced the expression of Col1, encoding collagen-1, at the injury site. The results of the MSC and NP treatment of skin wounds (alone or combined) suggest an induction of processes accelerating the proliferative phase of healing. Thus, MSC-NP interactions are a key factor affecting global mRNA expression changes in the wound. Full article