Search Results (1,487)

Oral mucosal wound healing is a rapid, precisely regulated process distinct from cutaneous repair due to the specialized anatomical, microbial, and physiological features of the oral cavity. This review outlines the sequential healing phases—hemostasis, inflammation, proliferation, and remodeling—and examines the coordinated roles of keratinocytes, fibroblasts, endothelial cells, and immune cell subsets in tissue restoration. Central molecular pathways, including PI3K/Akt, JAK/STAT, Ras/MAPK, TGF-β/SMAD, and Wnt/β-catenin, along with growth factors such as TGF-β, FGF, EGF, and VEGF, are discussed in relation to their regulatory influence on cell behavior and extracellular matrix dynamics. Unique intraoral factors—namely saliva-derived histatins and a distinct resident microbiota—promote accelerated re-epithelialization and attenuated fibrosis. Systemic conditions such as diabetes, aging, and tobacco exposure are identified as key modulators that compromise repair efficiency. Emerging therapeutic strategies, including stem-cell-based interventions, microbiota modulation, bioengineered scaffolds, and photobiomodulation, offer translational potential to enhance clinical outcomes in oral tissue regeneration. Full article

Malware analytics suffer from scarce, delayed, and privacy-constrained labels, limiting fully supervised detection and hampering responsiveness to zero-day threats. We propose SMAD, a Semi-supervised Android Malicious App Detector that integrates a segmentation-oriented backbone—to extract pixel-level, multi-scale features from APK imagery—with a dual-branch consistency objective that enforces predictive agreement between two parallel branches on the same image. We evaluate SMAD on CICMalDroid2020 under label budgets of 0.5, 0.25, and 0.125 and show that it achieves higher accuracy, macro-precision, macro-recall, and macro-F1 with smoother learning curves than supervised training, a recursive pseudo-labeling baseline, a FixMatch baseline, and a confidence-thresholded consistency ablation. A backbone ablation (replacing the dense encoder with WideResNet) indicates that pixel-level, multi-scale features under agreement contribute substantially to these gains. We observe a coverage–precision trade-off: hard confidence gating filters noise but lowers early-training performance, whereas enforcing consistency on dense, pixel-level representations yields sustained label-efficiency gains for image-based malware detection. Consequently, SMAD offers a practical path to high-utility detection under tight labeling budgets—a setting common in real-world security applications. Full article

Background/Objectives: A comparative study of silver (Ag), titanium nitride (TiN), zirconium nitride (ZrN), and copper (Cu) coatings on titanium (Ti) disks, considering the specifications of a microporous skin- and bone-integrated titanium pylon (SBIP), was performed to assess their biocompatibility, osseointegration, and mechanical properties. Methods: To assess cytotoxicity and biocompatibility, Ti disks with various metal coatings were co-cultured with FetMSCs and MG-63 cells for 1, 3, 7, and 14 days and subsequently evaluated using a cell viability assay, as supported by SEM and confocal microscopy studies. The antimicrobial activity of the selected four materials coating the implants was tested against S. aureus by mounting Ti disks onto the surface of LB agar dishes spread with a bacterial suspension and measuring the diameter of the growth inhibition zones. Quantitative Real-Time Polymerase Chain Reaction (RT-PCR) analysis of the relative gene expression of biomarkers that are associated with extracellular matrix components (fibronectin, vitronectin, type I collagen) and cell adhesion (α2, α5, αV integrins), as well as of osteogenic markers (osteopontin, osteonectin, TGF-β1, SMAD), was performed during the 14-day follow-up period. Additionally, the activity of matrix metalloproteinases (MMP-1, -2, -8, -9) was assessed. Results: All samples with metal coatings, except the copper coating, demonstrated a good cytotoxicity profile, as evidenced by the presence of a cellular monolayer on the sample surface on the 14th day of the follow-up period (as shown by SEM and inverted confocal microscopy). All metal coatings enhanced MMP activity, as well as cellular adhesion and osteogenic marker expression; however, TiN showed the highest values of these parameters. Significant inhibition of bacterial growth was observed only in the Ag-coated Ti disks, and it persisted for over 35 days. Conclusions: The silver-based coating, due to its high antibacterial activity, low cytotoxicity, and biointegrative capacity, can be recommended as the coating of choice for microporous titanium implants for further preclinical studies. Full article

Brain arteriovenous malformations (bAVMs) consist of a tangled nidus of abnormal dilated vessels characterized by direct connections between arteries and veins that lack an intervening capillary bed, creating a high-to-low flow pressure system that is predisposed to spontaneous hemorrhage with significant associated neurologic morbidity and mortality. Treatment options for bAVMs include the following: surgical resection, intravascular embolization to obliterate blood flow through the AVM, and radiosurgery. Understanding the molecular mechanisms of bAVM formation and factors that predispose it to hemorrhage can lead to novel treatments that can improve the prognosis for patients. This review summarizes emerging insights into the complex and dynamic molecular mechanisms of bAVMs. Dysregulation in key VEGF, TGF-β/BMP9/10–ENG–ALK1–SMAD4, Notch, and MAPK/ERK signaling pathways drive abnormal angiogenesis in both syndromic and sporadic forms, with KRAS/BRAF/MAPK21 mutations specifically linked to the latter. Advances in bAVM-induced animal models have corroborated many of the genetic profiles found in humans, and they continue to provide novel insights into bAVM mechanisms. Collectively, these mechanistic findings are guiding translational advances, with targeted therapies and liquid biopsy approaches emerging as avenues for precision treatment and improved patient outcomes. Full article

Background/Objectives: The optimal healing process following root canal treatment involves biological apical sealing through new cementum formation. Bone morphogenetic protein 7 (BMP-7) has recently gained attention as a potential regulator of cementoblast differentiation and periodontal regeneration. However, its effects on periodontal ligament fibroblasts (PDLFs) and the underlying mechanisms remain incompletely understood. This study aimed to investigate whether BMP-7 induces cementoblast-like differentiation of PDLFs both in vivo and in vitro via the BMP-SMAD signaling pathway. Methods: In a rat pulpectomy model, root canals were treated with or without BMP-7 and examined histologically and immunohistochemically for F-spondin (Spon1) expression. In vitro, human PDLFs were stimulated with BMP-7, and analyses of mineralization, cementoblast marker expression, alkaline phosphatase activity, and SMAD-1/5/9 phosphorylation were conducted. Results: Immunohistochemical analysis revealed that Spon1-positive regions increased around the apical area following BMP-7 treatment, suggesting the induction of cementoblast-like differentiation. In vitro, BMP-7 enhanced the expression of cementoblast-associated genes and mineral deposition while activating SMAD-1/5/9 signaling. Phosphorylation was suppressed by the BMP receptor inhibitor LDN-193189, indicating canonical BMP-SMAD pathway involvement. Conclusions: Although the specific concentration range of maximal activity remains to be determined, the findings collectively suggest that BMP-7 can promote cementoblast-like differentiation of PDLFs and may contribute to apical healing through cementum-related mechanisms. These results provide mechanistic and biological insights that support the potential of BMP-7 as a modulator for biologically favorable periapical tissue regeneration following root canal therapy. Full article

Diabetic nephropathy (DN) remains the leading cause of end-stage renal disease worldwide, with proximal tubular epithelial cells (PTECs) playing a central role in its pathogenesis. Under hyperglycemic conditions, PTECs drive a pathological triad of inflammation, apoptosis, and fibrosis. Recent advances reveal that these processes interact synergistically to form a self-perpetuating vicious cycle, rather than operating in isolation. This review systematically elucidates the molecular mechanisms underlying this crosstalk in PTECs. Hyperglycemia induces reactive oxygen species (ROS) overproduction, advanced glycation end products (AGEs) accumulation, and endoplasmic reticulum stress (ERS), which collectively activate key inflammatory pathways (NF-κB, NLRP3, cGAS-STING). The resulting inflammatory milieu triggers apoptosis via death receptor and mitochondrial pathways, while apoptotic cells release damage-associated molecular patterns (DAMPs) that further amplify inflammation. Concurrently, fibrogenic signaling (TGF-β1/Smad, Hippo-YAP/TAZ) promotes epithelial–mesenchymal transition (EMT) and extracellular matrix (ECM) deposition. Crucially, the resulting fibrotic microenvironment reciprocally exacerbates inflammation and apoptosis through mechanical stress and hypoxia. Quantitative data from preclinical and clinical studies are integrated to underscore the magnitude of these effects. Current therapeutic strategies are evolving toward multi-target interventions against this pathological network. We contrast the paradigm of monotargeted agents (e.g., Finerenone, SGLT2 inhibitors), which offer high specificity, with that of multi-targeted natural product-based formulations (e.g., Huangkui capsule, Astragaloside IV), which provide synergistic multi-pathway modulation. Emerging approaches (metabolic reprogramming, epigenetic regulation, mechanobiological signaling) hold promise for reversing fibrosis. Future directions include leveraging single-cell technologies to decipher PTEC heterogeneity and developing kidney-targeted drug delivery systems. We conclude that disrupting the inflammation–apoptosis–fibrosis vicious cycle in PTECs is central to developing next-generation therapies for DN. Full article

Background: In patients aged 65 years and older who experience severe trauma, their underlying health status significantly influences overall mortality. This study aimed to determine whether computed tomography (CT) evaluation of skeletal muscle quality could serve as an effective risk stratification tool in the emergency department (ED) for this population. Methods: Retrospective observational study conducted between January 2018 and September 2021, including consecutive patients ≥65 years admitted to the ED for a major trauma (defined as having an Injury Severity Score > 15). Muscle quality analysis was made by specific software (Slice-O-Matic v5.0, Tomovision^®, Montreal, QC, Canada) on a CT-scan slice at the level of the third lumbar vertebra (L3). Results: A total of 263 patients were included (72.2% males, median age 76 (71–82)), of whom 88 (33.5%) died during hospitalization. The deceased patients had a significantly lower skeletal muscle area density (SMAd) compared with survivors. The multivariate Cox regression analysis confirmed that SMAd <38 at the ED admission was an independent risk for death (adjusted HR 1.68 [1.1–2.7]). The analysis also revealed that, among the survivors after the first week of hospitalization, the patients with low SMAd had an increased risk of death (adjusted HR 3.12 [1.2–7.9]). Conclusions: Skeletal muscle density assessed by a CT scan at ED admission may represent a valuable prognostic marker for risk stratification patients ≥65 years with major trauma. In patients with SMAd <38 HU the in-hospital mortality risk could be particularly increased after the first week of hospitalization. Full article

We evaluated the effects of fenofibrate (FF) in a SU5416/hypoxia model of pulmonary arterial hypertension (PAH) with a specific focus on its influence on the renin–angiotensin system (RAS). We assessed right ventricular systolic pressure (RVSP), mean pulmonary artery pressure (mPAP), medial pulmonary artery wall thickening, right ventricular (RV) hypertrophy, systolic pulmonary artery pressure (SPAP), pulmonary artery effective elastance (PAEa), RV diastolic pressure (RVDP), RV developed pressure (RVDevP), right ventricular–pulmonary arterial coupling index (RVPAC), RV dp/dt max and dp/dt min. Levels of angiotensin II, angiotensin (1–7), angiotensin-converting enzyme 2 (ACE2), Bmpr2, Smad5 and nitrite (NO₂⁻) and nitrate (NO₃⁻) in the lung and RV were evaluated. The expression of AT1R, MAS receptors, and ACE2 in lung tissue was assessed. FF prevented the increase in RVSP, mPAP, RV hypertrophy, reduced pulmonary arterioles remodeling, and attenuated the rise in SPAP, mPAP, and PAEa. In the RV, it reduced RVDevP and prevented the decrease in dp/dt min, without affecting RVDP. RVPAC showed partial improvement. In lung tissue, FF decreased angiotensin II levels, the Ang II/Ang-(1–7) ratio, and reduced angiotensin II receptor type 1 (AT1R) expression, while preserving the receptor for the angiotensin-(1–7) (MAS) and ACE2. FF tended to restore Bmpr2/Smad5 expression. NO₂⁻ levels were preserved and tended to preserve (NO₃⁻) levels. In the RV, Ang-(1–7) increased, ACE2 was preserved, and NO₂⁻ and NO₃ levels were maintained. FF exerts protective effects in Su/Hx-induced PAH. Full article

Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for degenerative diseases due to their ability to modulate disease progression through paracrine mechanisms. Among various MSC sources, placenta-derived MSCs (PD-MSCs) offer significant advantages, including high proliferation capacity, reduced senescence, and low immunogenicity, making them ideal for allogeneic applications. In this study, we investigated the therapeutic effects of PD-MSC transplantation in an estrogen-deficiency-induced osteoporosis mouse model. Mice were divided into three groups: a normal control group, a non-transplanted osteoporosis group, and a PD-MSC-transplanted group. Our findings demonstrated that PD-MSC transplantation significantly improved osteoporosis-related parameters, including increased femur weight, bone volume, bone mineral density, and calcium deposition. Additionally, estrogen levels were elevated, bone formation markers were upregulated, and bone resorption markers were downregulated. PD-MSCs also reduced inflammatory cytokine levels while enhancing anti-inflammatory factors. Notably, the BMP/SMAD signaling pathway, crucial for bone formation, was significantly upregulated. These results suggest that PD-MSC transplantation effectively restores bone homeostasis by inhibiting osteoclast activity, promoting osteogenesis, and modulating inflammation. This study provides strong evidence supporting the potential of PD-MSCs as a novel therapeutic strategy for osteoporosis, offering a regenerative and anti-inflammatory approach to bone disease management. Full article

MicroRNAs (miRNAs) are critical regulators of gene expression in cancer biology and cardiovascular disease. miR-106b-5p, a member of the miR-106b-25 cluster, has been widely studied for its oncogenic activity in various malignancies. However, its role as a direct molecular driver of anthracycline-induced cardiotoxicity has only recently been uncovered. This finding highlights new therapeutic possibilities at the intersection of oncology and cardiovascular medicine. This review outlines the dual role of miR-106b-5p as a key modulator in both tumor progression and chemotherapy-induced cardiac dysfunction. miR-106b-5p is upregulated in numerous cancers—including breast, prostate, lung, gastric, colorectal, hepatocellular, and esophageal—and promotes tumorigenesis via suppression of tumor suppressors such as PTEN, BTG3, p21, and SMAD7, leading to activation of oncogenic pathways like PI3K/AKT and TGF-β. Importantly, we present the first evidence that miR-106b-5p is significantly upregulated in the myocardium in response to doxorubicin treatment, where it drives left ventricular dysfunction by targeting PR55α, a key regulator of PP2A activity. This pathway results in cytoplasmic HDAC4 accumulation, aberrant activation of the YY1 transcription factor, and upregulation of sST2, a biomarker linked to adverse cardiac remodeling and poor prognosis. In response, we developed AM106, a novel locked nucleic acid antagomir that silences miR-106 b-5p. Preclinical studies demonstrate that AM106 restores PR55α/PP2A activity, reduces sST2 expression, and prevents structural and functional cardiac damage without compromising anti-tumor efficacy. In parallel, artificial intelligence (AI) tools could be leveraged in the future—based on established AI applications in miRNA cancer research—to accelerate the identification of miR-106b-5p-related biomarkers and guide personalized therapy selection. Our findings position miR-106b-5p as a previously unrecognized molecular bridge between cancer and doxorubicin-induced cardiotoxicity. The development of the AM106 antagomir represents a promising approach with potential clinical applicability in cardio-oncology, offering dual benefits: tumor control and cardioprotection. Coupling this innovation with AI-driven analysis of patient data may enable precision risk stratification, early intervention, and improved outcomes. miR-106b-5p thus emerges as a central therapeutic target and biomarker candidate for transforming the clinical management of cancer patients at risk for heart failure. Full article

Orthodontic tooth movement (OTM) arises from force-induced mechanotransduction within the periodontal ligament (PDL), which coordinates osteoblast and osteoclast activity with immune responses to remodel the PDL and alveolar bone. This review integrates contemporary biological insights on OTM and assesses photobiomodulation (PBM) as an adjunctive therapy. We propose that mechanical and photonic inputs may interact and potentiate signaling through the Ca²⁺-NFAT, MAPK (ERK, p38, JNK), PI3K–Akt–mTOR, NF-kB, TGF-β/Smad, and Wnt/β-catenin pathways. Such interaction could influence processes such as cell proliferation, differentiation, specific cellular functions, apoptosis, autophagy, and communication between stromal and immune cells. This convergence establishes a solid foundation for understanding the context-dependent effects of PBM in OTM. In principle, PBM appears most effective as a phase-tuned adjunct, promoting early inflammatory recruitment of osteoclasts and subsequently facilitating late-phase remodeling through immunomodulatory and reparative mechanisms. However, inconsistent irradiation parameters, small sample sizes, trial heterogeneity, and the absence of mechanistic endpoints undermine current conclusions. Furthermore, the lack of integrated PBM–OTM models limits mechanistic understanding, as much of the available evidence is derived from non-OTM contexts. Overall, PBM remains a promising adjunct in orthodontics, with the potential to integrate mechanical and photonic signals in a phase-dependent manner, though its application is not yet standardized. Full article

Background/Objectives: Appendiceal cancer (AC) is a rare and understudied malignancy with limited genomic data available to guide clinical interventions. Historically treated as a subtype of colorectal cancer, AC is now recognized as a distinct disease with unique histologic subtypes and molecular features. This review aims to consolidate current genomic data across AC subtypes and explore the clinical relevance of recurrent mutations. Methods: A systematic literature review was performed in accordance with general Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines. Using search engines such as PubMed and Web of Science, we selected studies based on relevance to AC genomics using search terms such as “appendix cancer”, “appendiceal cancer”, “pseudomyxoma peritonei”, “sequencing”, “mutation”, and “genotype”. Results: AC comprises five major histologic subtypes—appendiceal neuroendocrine neoplasms (ANENs), mucinous appendiceal neoplasms (MANs), goblet cell adenocarcinomas (GCAs), colonic-type adenocarcinomas (CTAs) and signet ring cell adenocarcinomas (SRCs)—each with unique clinical behaviors and mutational profiles. Low-grade tumors, such as ANENs and MANs, frequently harbor KRAS and GNAS mutations, while high-grade subtypes, such as CTAs and SRCs, are enriched for TP53, APC, and SMAD gene alterations. GCA tumors exhibit a distinct mutational spectrum involving chromatin remodeling genes such as ARID1A and KMT2D. Compared to colorectal cancer, AC demonstrates lower frequencies of APC and TP53 mutations and a higher prevalence of GNAS mutations, consistent with a pathological divergence from CRC. Conclusions: The genomic heterogeneity of AC is commensurate with its histological complexity and has important implications for diagnosis, prognosis and treatment. While certain actionable mutations are present in a subset of tumors, large-scale genomic characterization efforts and development of subtype-specific models will be essential for advancing precision medicine in AC. Full article

Background/Objectives: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive loss of lung function and poor prognosis. Cryptotanshinone (CTS), a small-molecule compound extracted from Salvia miltiorrhiza, possesses diverse pharmacological activities but suffers from poor oral bioavailability, which restricts its clinical development, particularly in pulmonary fibrosis. DST-3, a newly synthesized derivative of CTS, was designed to overcome these limitations. Methods: The antifibrotic effects of DST-3 were investigated in a bleomycin-induced pulmonary fibrosis model in C57BL/6 mice through lung function assessment, histopathological evaluation, hydroxyproline quantification, and cytokine profiling. In vitro, TGF-β1-stimulated MRC5 fibroblasts were employed to explore the mechanism of action, focusing on STAT3/Smad signaling via Western blotting and molecular binding assays. Furthermore, a validated HPLC–MS/MS method was developed for DST-3, and its pharmacokinetic profile was characterized in Sprague–Dawley rats and compared with that of CTS. Results: DST-3 markedly attenuated pulmonary fibrosis in vivo, as evidenced by improved lung function, reduced collagen deposition, and decreased proinflammatory cytokine levels. In vitro, DST-3 inhibited TGF-β1-induced fibroblast activation by directly binding to STAT3 and suppressing STAT3/Smad signaling. Pharmacokinetic analysis demonstrated that, compared with CTS, DST-3 exhibited more rapid absorption, a higher peak plasma concentration, a greater area under the curve (AUC), improved hepatic metabolic stability, and enhanced lung tissue exposure. Conclusions: Our study demonstrates that DST-3 exerts potent antifibrotic effects in vivo and in vitro, primarily through STAT3 pathway inhibition. Its improved pharmacokinetic characteristics further support its potential as a promising candidate for the treatment of pulmonary fibrosis. Full article

(1) Background: The present study investigated the effects of extracellular vesicles (EVs), derived from adipose tissue stem cells (ADSCs) and bone marrow mesenchymal stem cells (BMMSCs), on atherosclerosis-associated cardiac hypertrophy. (2) Methodology: The experiments were performed on hamsters divided into the following groups: control (C) fed with a standard diet; hypertensive–hyperlipidemic (HH) generated by combining a diet enriched with 3% cholesterol, 15% butter, and by gavage with 8% NaCl on a daily basis; HH groups injected with EVs (ADSCs) or EVs (BMMSCs), either transfected with Smad2/3 siRNAs or not (HH-EVs (ADSCs), HH-EVs (BMMSCs), HH-EVs (ADSCs) + Smad2/3siRNA, HH-EVs (BMMSCs) + Smad2/3siRNA); and HH group injected with Smad2/3 siRNAs (HH-Smad2/3siRNA). (3) Results: In comparison with the HH group, the findings demonstrated that treatment using EVs (ADSCs or BMMSCs), either with or without Smad2/3 siRNAs, resulted in several significant improvements in the following aspects: the plasma levels of cholesterol, LDL, triglycerides, TGF-β1, and Ang II were decreased; the left ventricular structure and function were recovered; inflammatory markers, ROS, COL1A, α-SMA, Cx43, MIF, ANF, and M1/M2 macrophages, were reduced; the level of key protein NF-κB p50 was diminished. (4) Conclusions: These findings underscore the therapeutic potential of mesenchymal stem cell-derived EVs in atherosclerosis-associated cardiac hypertrophy. Full article

Background: Ultraviolet B (UVB) radiation accelerates skin aging by inducing oxidative stress, collagen degradation, and cellular senescence. Although Petasites japonicus is known for its antioxidant properties, its anti-photoaging potential remains underexplored. This research explored the protective properties of a hot water extract from P. japonicus leaves (KP-1) against photoaging caused by UVB exposure. Methods: Hairless mice were exposed to UVB three times per week and orally administered KP-1 for 13 weeks. Wrinkle formation, epidermal thickness, skin hydration, and collagen content were assessed. Protein expression related to MAPK/AP-1, TGF-β/Smad2/3, and p53/p21 pathways was analyzed by Western blotting. Results: KP-1 significantly reduced UVB-induced wrinkle area, epidermal and dermal thickening, and transepidermal water loss while restoring collagen density and skin hydration. KP-1 inhibited MMP-1 expression, enhanced COL1A1 levels, suppressed MAPK/AP-1 activation, and activated TGF-β/Smad2/3 signaling. It also balanced p53/p21 expression and restored cyclin D1 and CDK4 levels, thereby preventing UVB-induced senescence. Conclusions: The findings of this research revealed that KP-1 can serve as a promising natural substance for safeguarding the skin from damage and aging caused by UVB exposure. Full article