Search Results (352)

Focal adhesion kinase (FAK) is a crucial protein component of focal adhesions (FAs) and belongs to the cytoplasmic non-receptor protein tyrosine kinase family. FAK primarily regulates adhesion signaling and cell migration and is highly expressed in various tumors, including lung, liver, gastric, and colorectal cancers, as well as in conditions such as acute lung injury (ALI) and pulmonary fibrosis (PF). Recent research on FAK and its small-molecule inhibitors has revealed that targeting FAK provides a novel approach for treating various lung diseases. FAK inhibitors can obstruct signaling pathways, demonstrating anti-tumor, anti-inflammatory, and anti-fibrotic effects. In lung cancer, FAK inhibitors suppress tumor growth and metastasis; in ALI, they exert protective effects by alleviating inflammatory responses and oxidative stress; and in pulmonary fibrosis, FAK inhibitors reduce fibroblast activation and inhibit collagen deposition. The findings demonstrate promising efficacy and an acceptable safety profile in preclinical models. However, these early-stage results require further validation through clinical studies. Additionally, the underlying mechanisms, as well as the toxic effects and side effects, necessitate further in-depth investigation. Some have progressed to clinical trials (Defactinib (Phase II), PF-562271 (Phase I), CEP-37440 (Phase I), PND-1186 (Phase I), GSK-2256098 (Phase II), BI-853520 (Phase I)), offering potential therapeutic targets for lung diseases. Collectively, these findings establish a foundational basis for the advancement of FAK inhibitor discovery. Emerging methodologies, such as PROTAC degraders and combination regimens, demonstrate significant potential for future research. Based on a comprehensive analysis of the relevant literature from 2015 to the present, this review briefly introduces the structure and function of FAK and discusses recent research advancements regarding FAK and its inhibitors in the context of pulmonary diseases. Full article

Background/Objectives: Degenerative joint diseases (DJDs) involve intricate molecular disruptions within bone, cartilage, and synovial tissues, often preceding overt radiographic changes. These tissues exhibit complex biomolecular architectures and their degeneration leads to microstructural disorganization and inflammation that are challenging to detect with conventional imaging techniques. This review aims to synthesize recent advances in imaging, computational modeling, and sequencing technologies that enable high-resolution, non-invasive characterization of joint tissue health. Methods: We examined advanced modalities including high-resolution MRI (e.g., T1ρ, sodium MRI), quantitative and dual-energy CT (qCT, DECT), and ultrasound elastography, integrating them with radiomics, deep learning, and multi-scale modeling approaches. We also evaluated RNA-seq, spatial transcriptomics, and mass spectrometry-based proteomics for omics-guided imaging biomarker discovery. Results: Emerging technologies now permit detailed visualization of proteoglycan content, collagen integrity, mineralization patterns, and inflammatory microenvironments. Computational frameworks ranging from convolutional neural networks to finite element and agent-based models enhance diagnostic granularity. Multi-omics integration links imaging phenotypes to gene and protein expression, enabling predictive modeling of tissue remodeling, risk stratification, and personalized therapy planning. Conclusions: The convergence of imaging, AI, and molecular profiling is transforming musculoskeletal diagnostics. These synergistic platforms enable early detection, multi-parametric tissue assessment, and targeted intervention. Widespread clinical integration requires robust data infrastructure, regulatory compliance, and physician education, but offers a pathway toward precision musculoskeletal care. Full article

Peripheral nerve injury initiates a complex cascade of events coordinating immune responses, extracellular matrix (ECM) remodeling, and neuronal repair. While β2-microglobulin (B2M) is well known for its role in MHC class I-mediated antigen presentation and CD8⁺ T-cell differentiation, its potential contributions to non-immune processes remain underexplored. In this study, we investigated the role of B2M in peripheral nerve regeneration using a chronic constriction injury (CCI) model in wild-type and B2M-deficient (B2M-KO) mice. Flow cytometry, RNA sequencing (RNA-seq), and quantitative PCR (qPCR) were performed to assess T-cell subset dynamics and gene expression following injury. Flow cytometric analysis showed that CD3⁺CD4⁺ and CD3⁺CD8⁺ T-cell populations increased by day 7 post-injury. While CD3⁺CD4⁺ T-cell expansion occurred in both groups, a significant increase in CD3⁺CD8⁺ T cells was observed only in wild-type mice. RNA-seq analysis at 3 days post-injury—prior to substantial T-cell accumulation—revealed marked downregulation of ECM-related genes in B2M-KO mice, including collagens, matrix-associated proteins, and other key ECM components. KEGG analysis identified suppression of ECM–receptor interaction, PI3K-Akt, and TGF-β signaling pathways. qPCR confirmed reduced expression of Thbs1 in B2M-KO mice. These findings suggest that B2M plays a critical, CD8⁺ T-cell-independent role in regulating ECM dynamics and regenerative signaling during early nerve repair, expanding the conceptual framework of B2M’s function beyond classical immune roles. Full article

Background. Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than 30% of the world population. Progression to its inflammatory state, MASH, is associated with increasing liver fibrosis, leading to end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC). SW033291, an inhibitor of 15-PGDH (the PGE2 degradation enzyme), has been shown to increase in vivo regeneration of liver parenchyma, ameliorating oxidative stress and inflammation. We hypothesized that SW033291 abrogates MASH progression by inducing a paucity of the initial apoptotic switch and restoring physiological collagen’s microenvironment. Methods. The expression levels of the cell metabolic proteins FOXO1, mTOR, and SIRT7 were determined in a diet-induced MASH-mouse model at 16, 20, and 24 weeks. Non-targeted metabolomics in mouse plasma were measured by LC-MS/MS. Liver morphology and apoptotic activity were quantified by the NAS score and TUNEL assay, respectively. Statistical analyses between groups (NMC, HFD, and SW033291) were determined by ANOVA, t-test/Tukey’s post hoc test using GraphPad Prism. Metabolomics data were analyzed using R-lab. Results. The treated group showed significant decreases in total body fat, cellular oxidative stress, and inflammation and an increase in total lean mass with improved insulin resistance and favorable modulation of metabolic protein expressions (p < 0.05). SW033291 significantly decreased GS:SG, citric acid, and corticosterone, NAS scores (9.4 ± 0.2 vs. 6.2 ± 0.1, p < 0.05), liver fibrosis scores (1.3 ± 0.5 vs. 0.25 ± 0.1, p < 0.05), and apoptotic activity (43.9 ± 4.6 vs. 0.38 ± 0.1%, p < 0.05) compared with controls at 24W. Conclusions. The inhibition of 15-PGDH appears to normalize the metabolic and morphological disturbances during MASH progression with a paucity of the initial apoptotic switch, restoring normal collagen architecture. SW033291 warrants further investigation for its translation. Full article

Collagen II is a vital structural component in developing bones and mature cartilage. Mutations in this protein cause spondyloepiphyseal dysplasia, a disease characterized primarily by altered skeletal growth and manifesting with a range of phenotypes, from lethal to mild. This study examined transgenic mice harboring the R992C (p.R1124C) substitution in collagen II. Previous research demonstrated significant growth abnormalities and disorganized growth plate structure in these mice, and histological signs of osteoarthritic changes in the knee joints of 9-month-old mice with the R992C mutation. Our study focuses on detecting early structural changes in the articular cartilage that occur before histological signs become apparent. Through microscopic and spectroscopic analyses, we observed significant alterations in the distribution gradients of collagenous proteins and proteoglycans in the cartilage of R992C mutant mice. We propose that these early changes, eventually leading to articular cartilage degeneration in older mice, underscore the progressive nature of osteoarthritic changes linked to collagen II mutations. By identifying these early structural aberrations, our findings emphasize the importance of early detection of osteoarthritic changes, potentially facilitating timely, non-surgical interventions. Full article

Muscle dystrophies are a group of genetic disorders characterized by progressive muscle degeneration. Prednisone is a glucocorticoid drug widely used to prevent muscle weakness in these diseases. Despite its known beneficial role, the effect of intermittent delivery on monocytes’ polarization and on dystrophic muscle microenvironment has not yet been thoroughly investigated. In this study, our aim was to identify the phenotype of monocyte subsets in blood and the expression of fibrosis-related genes in dystrophic muscle biopsies in patients receiving intermittent prednisone therapy. We found an increased rate of classical monocytes and a decreased rate of non-classical monocytes that expressed anti-inflammatory marker CD206 in treated patients. In dystrophic muscles, 21 fibrosis-related genes were altered, among which we identified CCAAT/enhancer-binding protein beta CEBPB. Both classical monocytes and CEBPB are known for their roles in stimulating collagen 1 production, a probable marker hampering monocyte/macrophage function. Hence, in some patients with muscular dystrophy, intermittent prednisone treatment could shift the monocytes’ phenotype toward an M2, senescent-like profile. This seems to decrease the inflammatory infiltrate in muscle tissue, an observation that needs to be further confirmed. Full article

BYVET JOINT HEAL^TM (BJH) contains mucopolysaccharide protein, chondroitin sulfate, type II collagen, and omega-3 fatty acids, which protect and prevent osteoarthritis (OA)-associated tissue damage and degradation in dogs and cats. This study aimed to generate a novel dietary supplement and evaluate its prevention and therapeutic efficacy in an OA Sprague Dawley rat model induced using monosodium iodoacetate (MIA). Negative control, MIA-induced OA control (MIA), OA rats treated with BJH three weeks after (M+BJH3) and those treated two weeks before and three weeks after OA induction (BJH2+M+BJH3) groups were assigned. M+BJH3 and BJH2+M+BJH3 had similar mean body weight increases until 29 days. BJH2+M+BJH3 showed a significantly higher body weight than M+BJH3 and MIA on the final day. Interleukin-1β in BJH2+M+BJH3 was significantly lower than that in MIA. Tumor necrosis factor-α, aggrecan, matrix metalloproteinases13, and cyclooxygenase-2 levels in M+BJH3 and BJH2+M+BJH3 significantly differed compared to those in MIA. BJH administration before OA induction significantly decreased OA severity and functional recovery. Consuming a BJH supplement showed modifying and chondroprotective effects and significantly reduced cartilage degeneration and inflammation with no side effects. Hence, our findings demonstrate the potential of using BJH as a safe therapeutic and preventive supplement for OA and associated cartilage abnormalities. Also, 30 dogs diagnosed with OA by a veterinarian participated in the clinical trial, and BJH was provided for 8 weeks. Blood tests (CBC, serum chemistry) and joint assessment were performed before and after the feeding, and the effects of a BJH supplement were compared. BJH supplement was easy to administer, and no side effects were reported. Feeding BJH supplementation alone to dogs with arthritis had an overall positive effect on arthritis scores for 8 weeks without any other treatment, including non-steroidal drugs. Full article

Maternal overnutrition and targeted supplements during pregnancy strongly affect fetal development in beef cattle, influencing gene expression, tissue development, and productivity after birth. As modern feeding practices often result in cows receiving energy and protein above requirements, understanding the balance between adequate nutrition and overconditioning is critical for sustainable beef production. This review synthesizes findings from recent studies on maternal overnutrition and supplementation, focusing on macronutrients (energy, protein, methionine) and key micronutrients (e.g., selenium, zinc). It evaluates the timing and impact of supplementation during different gestational stages, with emphasis on fetal muscle and adipose tissue development, immune function, and metabolic programming. The role of epigenetic mechanisms, such as DNA methylation and non-coding RNAs, is also discussed in relation to maternal dietary inputs. Mid-gestation supplementation promotes muscle growth by activating muscle-specific genes, whereas late-gestation diets enhance marbling and carcass traits. However, maternal overnutrition may impair mitochondrial efficiency, encourage fat deposition over muscle, and promote collagen synthesis, reducing meat tenderness. Recent evidence highlights sex-specific fetal programming differences, the significant impact of maternal diets on offspring gut microbiomes, and breed-specific nutritional responses, and multi-OMICs integration reveals metabolic reprogramming mechanisms. Targeted trace mineral and methionine supplementation enhance antioxidant capacity, immune function, and reproductive performance. Precision feeding strategies aligned with gestational requirements improve feed efficiency and minimize overfeeding risks. Early interventions, including protein and vitamin supplementation, optimize placental function and fetal development, supporting stronger postnatal growth, immunity, and fertility. Balancing nutritional adequacy without excessive feeding supports animal welfare, profitability, and sustainability in beef cattle systems. Full article

Objective: This study explores the material basis and biological functions of meridian interstitial channels in mini-pigs proximal to the stomach meridian by analyzing differential proteomics between interstitial channels and adjacent non-interstitial channel tissues. Methods: Liquid chromatography–mass spectrometry (LC-MS) under data-dependent acquisition mode was employed to analyze and identify the proteome of subcutaneous connective tissues along the stomach meridian and adjacent tissues. SWATH MS^ALL method and omicsbean online analysis platforms were used for protein quantification and differential proteomic analysis. Differential proteins were subjected to Gene Ontology annotation and KEGG pathway analysis to understand their functions and biological processes. Combining traditional Chinese meridian theory with modern meridian research, proteins most relevant to meridian functions were selected, and their expression levels were assessed using Western blotting. Results: GO annotation and KEGG pathway analysis revealed differences in molecular functions, biological processes, and metabolic pathways among differential proteins. Most downregulated proteins were enzyme functional proteins involved in amino acid metabolism (GOT1), adenosine nucleotide balance conversion (AK1), and calcium ion-binding processes (ANXA6). Most upregulated proteins were structural proteins in the extracellular matrix—collagen proteins (COL3A1, COL6A1, COL6A3, COL6A6, COL12A1, COL14A1) and proteoglycans (DCN, BGN, FMOD)—involved in influencing and regulating collagen fiber generation and arrangement. Intriguingly, almost all differential proteins were associated with gastrointestinal diseases, implying a pathological correlation of differential proteins in the stomach meridian interstitial channel. Conclusions: The stomach meridian interstitial channels in mini-pigs show 72 differentially expressed proteins compared to adjacent tissues. These differences include the upregulation of structural proteins and downregulation of functional proteins, potentially forming the molecular biological basis for the structural and functional specificity of meridians. Full article

Mechanical stress is known to be a pivotal risk factor in the development of OA. However, the involvement of repetitive compressive loading in mitochondrial dysfunction in chondrocytes remains unclear. The aim of this study was to investigate whether physiologic levels of repetitive mechanical force affect the regulation of energy metabolism and activities of mitochondrial function regulators, sirtuin 1 and nicotinamide adenine dinucleotide (NAD) in chondrocytes, and to clarify any correlation with chondrocyte catabolic activity. Repetitive physiological mechanical stress was applied in a 3D chondrocyte-collagen scaffold construct, and the 3D cultured tissues were collected at different time points by collagenase treatment to collect cellular proteins. Changes in chondrocyte activity (cell proliferation, MMP-13 production), energy metabolism regulator levels (sirtuin 1), mitochondrial function (ATP production, NAD level), and the expression level of the osteogenic and hypertrophic chondrogenic transcription factor, runt-related transcription factor 2 (Runx2), were measured. Treatment with repetitive compressive loading resulted in no significant change in the cell viability of chondrocytes. In the repetitive mechanical loading group, there were statistically significant increases in MMP-13 production and expression of both sirtuin 1 and Runx2 in chondrocytes relative to the non-loading control group. Furthermore, ATP production and NAD activity in mitochondria decreased in the repetitive mechanical loading group. Our present study reveals that in chondrocytes, repetitive compressive loading accelerated sirtuin activation, which requires and consumes NAD within mitochondria, leading to a decrease of NAD and ultimately in reduced mitochondrial ATP production. Additionally, since sirtuin 1 is known to positively regulate Runx2 activity in chondrocytes, the activation of sirtuin 1 by repetitive load stimulation may induce an increase in the expression of Runx2, which promotes the expression of MMP-13, and subsequently enhances MMP-13 production. Our findings indicate that repetitive compression loading-mediated mitochondrial dysfunction plays a pivotal role in the progression of OA, primarily by driving the downregulation of ATP production and promoting the expression of the matrix-degrading enzyme MMP-13. Full article

Necrotic enteritis (NE), caused by pathogenic Clostridium perfringens, poses a significant threat to global poultry health, with estimated annual losses exceeding USD 6 billion. The rising incidence of NE has been associated with the reduced use of antibiotic growth promoters, underscoring the urgent need for alternative control measures such as vaccination. Collagen adhesin protein (CNA), a key virulence factor in NE pathogenesis, represents a promising vaccine target. The US Food and Drug Administration has begun phasing out animal testing requirements for biologics and monoclonal antibody drugs. In this study, a computational multi-epitope vaccine (MEV) targeting CNA was designed by integrating predicted Cluster of Differentiation (CD)4⁺ helper T lymphocyte (Th), CD8⁺ cytotoxic T lymphocyte (CTL), and B-cell epitopes. Bioinformatics tools were used to identify immunogenic, antigenic, and non-allergenic epitopes assembled into a 115-amino-acid peptide vaccine construct. The candidate demonstrated strong stability and solubility. In silico immune simulation predicted robust immune responses, including elevated IgG and IgM antibody levels, plasma cell proliferation, Th memory formation, and CTL activation, comparable to responses elicited by a full-length CNA. These findings support the potential of the designed peptide as one of the multiple effective NE vaccine components, offering a promising alternative to antibiotic-based approaches in poultry disease management. Full article

Chronic rhinosinusitis (CRS) is a persistent inflammatory condition of the sinus mucosa characterized by significant tissue remodeling. This study aimed to evaluate the gene expression of extracellular matrix (ECM) proteins, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) in post-operative tissues of CRS patients. A total of 30 patients diagnosed with CRS, divided into CRSwNP (with nasal polyps) and CRSsNP (without nasal polyps) groups, were compared with a control group of 10 individuals undergoing nasal surgeries for non-CRS conditions. Gene expression analysis was conducted using quantitative real-time PCR, and plasma cytokine levels were measured via ELISA. Results indicated significantly higher expression of collagen I, collagen III, fibronectin, vimentin, periostin, and tenascin C in CRS tissues, especially in CRSsNP patients. Conversely, elastin expression was markedly lower. MMP-2, MMP-9, TIMP-1, and TIMP-2 expression was significantly altered, with CRSsNP showing lower levels compared to CRSwNP and controls. TGF-β1 expression was elevated in both CRS groups, particularly in CRSsNP, highlighting its role in fibrosis and ECM remodeling. Additionally, increased plasma concentrations of TSLP and TGF-β1 suggest epithelial activation and immune dysregulation in CRS. These findings underscore distinct remodeling profiles in CRS endotypes, emphasizing the need for targeted therapeutic strategies based on molecular phenotyping. Understanding ECM dysregulation and inflammatory pathways in CRS may lead to improved, individualized treatment approaches. Full article

Sarcopenia and osteoporosis are age-related musculoskeletal pathologies that often develop in parallel, and numerous studies support the concept of a bone–muscle unit, where deep interaction between the two tissues takes place. In Mediterranean areas, the lowest incidence of osteoporosis within Europe is observed, so the Mediterranean diet was suggested to play an important role. Consequently, in this study, oleuropein, a phenolic compound found in olive oil, and polydatin, another natural polyphenol found in the Mediterranean diet, were evaluated to determine their beneficial effects on bone and muscle metabolism. In human osteoblasts and skeletal muscle myoblasts, the effects were examined, and, after analyzing the cytotoxic effect to find non-toxic doses, the modulation of bone and muscle differentiation markers was evaluated at the gene and protein levels using PCR, Western blot, and immunohistochemistry. Interestingly, the compounds increased markers involved in osteoblast differentiation, such as osteocalcin, type I collagen, and dentin-sialo-phosphoprotein, as well as markers involved in myoblast differentiation, such as myogenic regulatory factors and creatine kinase. These effects were most noticeable when the compounds were administered together. These results suggest a beneficial role for oleuropein–polydatin association on bone and muscle tissue pathologies simultaneously. Full article

Background: Skin photoaging caused by ultraviolet B (UV-B) irradiation leads to the formation of wrinkles. A method to lessen wrinkles is the application of Polydioxanone (PDO) lifting threads. HanDam (Twist) is a PDO lifting thread with a unique morphological twisted shape. Objective: The aim of this study was to evaluate the wrinkle improvement ability of HanDam (Twist) on UV-B irradiation-induced skin photoaging in a hairless mouse model. Methods: Wrinkles were induced by UV-B irradiation to the backs of female hairless mice for six weeks. After induction, the wrinkles were treated with threads, and the mice were monitored for six weeks post-treatment. Results: Our results showed that treatment with HanDam (Twist) effectively ameliorated UV-B irradiation-induced wrinkle depth and significantly increased collagen density by 13% compared to HanDam (non-Twist) in the histological analysis. In measuring protein expression related to collagen production, HanDam (Twist) significantly increased transforming growth factor beta (TGF-β) and collagen type 1 (COL1) by 46% and 67% compared to HanDam (non-Twist). Matrix metalloproteinase-1 (MMP-1) protein expression showed similar density and no significance compared to HanDam (non-Twist). Conclusions: These findings suggest that HanDam (Twist) improves the effectiveness of lifting threads for skin care compared to that of existing products. Full article

The purpose of this study was to evaluate in vitro whether the type of tooth preservation before treatment with the Tooth Transformer^® (TT) device affects the osteoinductive characteristics of the extracted tooth. Forty extracted teeth from healthy non-smoking patients were selected. All teeth were cleaned of caries, tartar, and filling material and then roughly sectioned and divided into four experimental groups according to storage type: room-temperature (RT) tooth samples, frozen tooth samples, RIPA tooth samples, and fresh tooth samples. Each sample was minced, demineralized, and disinfected using the TT device. The Enzyme-Linked ImmunoSorbent Assay (ELISA) test revealed the presence of bone morphogenetic protein-2 (BMP-2) and collagen type-I (COL-I) in all of the samples, demonstrating that the fresh teeth retained the most significant amount of osteoinductive protein. In contrast, the tooth samples stored at room temperature (RT) showed the most important loss of BMP-2 and COL-I. A Western Blot analysis demonstrated the presence of the Mineralization Protein LIM-1 (LMP-1) and Transforming Growth Factor-β (TGF-β) in all of the dental samples analyzed. The fresh and frozen dental samples showed significantly higher levels of LMP-1 than those in the other samples. In contrast, the levels of TGF-β were similar in all of the dental samples examined, regardless of the type of storage. These experimental results suggest that an extracted tooth should be treated with the TT device as soon as possible to maximize its osteoinductive potential in surgical bone preservation and regeneration procedures. Full article