Search Results (633)

Obesity is characterized by chronic low-grade inflammation and oxidative stress, conditions that disrupt metabolic homeostasis and promote vascular endothelial growth factor (VEGF) expression. While hypoxia and fatty acid-induced oxidative stress are known regulators of VEGF, the contribution of endoplasmic reticulum (ER) stress in monocytic cells remains unclear. In this study, we investigated the interplay between ER stress and metabolic stress in regulating VEGF expression using THP-1 monocytic cells. Metabolic stress was induced by palmitic acid (PA) and ER stress by thapsigargin (TG). Co-treatment with PA and TG significantly increased VEGF mRNA and protein levels compared to PA alone. This effect was accompanied by enhanced reactive oxygen species (ROS) production and upregulation of ER stress markers, including CHOP, ATF6, and IRE1. Pretreatment with the antioxidant curcumin markedly reduced VEGF expression and ROS levels, indicating a ROS-dependent mechanism. Additionally, PA+TG co-treatment elevated transcripts of antioxidant defense genes such as SOD2 and NRF2, suggesting a compensatory cellular response to oxidative stress. These findings demonstrate that ER stress amplifies VEGF induction in monocytic cells under lipotoxic conditions through ROS-mediated pathways, highlighting a potential mechanism linking metabolic stress, inflammation, and angiogenesis in obesity-related disorders. Full article

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that influence cancer progression via extracellular matrix (ECM) remodeling and secretion of growth factors and cytokines. Endothelial-to-mesenchymal transition (EndMT) is emerging as an important axis among the heterogeneous origins of CAFs. This review introduces the diverse methods used to induce EndMT in cancer—mouse tumor models, conditioned-medium treatment, co-culture, targeted gene perturbation, ligand stimulation, exosome exposure, irradiation, viral infection, and three-dimensional (3D) culture systems—and summarizes EndMT cell-type evidence uncovered using transcriptomic and proteomic technologies. Hallmark EndMT features include spindle-like morphology, increased motility, impaired angiogenesis and barrier function, decreased endothelial markers (CD31, VE-cadherin), and increased mesenchymal markers (α-SMA, FN1). Reported mechanisms include signaling via TGF-β, cytoskeletal/mechanical stress, reactive oxygen species, osteopontin, PAI-1, IL-1β, GSK-3β, HSP90α, Tie1, TNF-α, HSBP1, and NOTCH. Cancer-induced EndMT affects tumors and surrounding TME—promoting tumor growth and metastasis, expanding cancer stem cell-like cells, driving macrophage differentiation, and redistributing pericytes—and is closely associated with poor survival and therapy resistance. Finally, we indicate each study’s stance: some frame cancer-induced EndMT as a source of CAFs, whereas others, from an endothelial perspective, emphasize barrier weakening and promotion of metastasis. Full article

Background: p73, a member of the p53 family of transcription factors, plays important roles in DNA repair, cell proliferation, angiogenesis, invasion, metastasis, immune evasion, and cytotoxic therapy response. The clinicopathological significance of p73 in breast cancer, particularly in the context of TP53 mutation, remains largely unknown. Methods: Clinicopathological significance of p73 and p53 protein expression was evaluated in 1369 invasive BC and 317 ductal carcinomas in situ (DCIS), including in p53 wild-type or p53 mutant tumours. p73 transcripts and splice variants were investigated in breast cancer genomes (TCGA). Results: High cytoplasmic p73 was significantly associated with high tumour grades, high pleomorphism scores, high mitotic scores, high risk Nottingham prognostic index, negative expression of oestrogen receptors (ERs), triple negative phenotypes (all p values ≤ 0.01), and poor breast cancer specific survival (BCSS) (p = 0.013). In TP53 mutant breast cancers, high p73 was significantly associated with aggressive histopathological features (all p ≤ 0.001) and poor BCSS (p = 0.001) but not in p53 wild-type tumours. Conclusions: Cytoplasmic p73 may be a marker of aggressive phenotype and worse prognosis, particularly in p53 mutant breast cancer. p73, in conjunction with altered p53 expression, may be involved in breast cancer pathogenesis. Full article

Background/Objectives: Osteoporosis is a prevalent and debilitating skeletal disease characterized by a progressive loss of bone mass and deterioration of bone microarchitecture. Probiotics have emerged as a potential therapeutic tool for treating osteoporosis through modulation of the gut microbiota. In this study, we aimed to examine the effects of live Lacticaseibacillus rhamnosus AC1 (LR-AC1), isolated from a fecal sample from a newborn in Hong Kong, on deoxycorticosterone acetate (DOCA)-induced bone loss in a rat model. Methods: Bone mass and microarchitecture were assessed using micro-computed tomography (micro-CT). Immunostaining for CD31⁺ and osterix, markers of endothelial cells and osteoblast precursors, respectively, was performed. Gut microbiota composition was analyzed via 16S rRNA sequencing. The effects of an LR-AC1 cell-free conditioned supernatant (CCS) on osteoclastogenesis, angiogenesis, and migration of bone marrow mesenchymal stem cells (BMSCs) were evaluated in vitro using RT-qPCR and wound healing assays. Results: LR-AC1 administration did not induce adverse effects in healthy rats; however, it exacerbated bone loss in rats with DOCA-salt-induced osteoporosis. Correspondingly, the number of CD31-positive endothelial cells and osterix-positive osteoprogenitors decreased with bone loss. In vitro, LR-AC1 CCS promoted osteoclastogenesis and angiogenesis, while in the presence of DOCA, LR-AC1 CCS inhibited BMSC migration. Gut microbiota analysis revealed that the relative abundances of the genera g_RF39 and g_Clostridia_UCG-014 correlated with the severity of bone loss. Conclusions: While several studies suggest that probiotics can prevent and treat osteoporosis, our findings indicate that in a male rat model of DOCA-salt-induced osteoporosis, live LR-AC1 aggravated bone loss. This effect is associated with alterations in gut microbiota and disruption of the coupling process in bone remodeling. Full article

Bioactive agents can stimulate osteogenesis, angiogenesis, and cell proliferation; therefore, their application in bone regeneration offers significant therapeutic potential. The aim of this systematic review was to evaluate strategies for applying chitosan-based scaffolds with growth factors in bone regeneration. A structured literature search was conducted in July 2025 across the PubMed, Scopus, and Web of Science databases. Search terms included combinations of (chitosan scaffold) AND (growth factor OR BMP-2 OR VEGF OR FGF OR TGF-beta OR periostin OR PDGF OR IGF-1 OR EGF OR ANG-1 OR ANG-2 OR GDF-5 OR SDF-1 OR osteopontin). The study selection process followed PRISMA 2020 guidelines and the PICO framework. Out of 367 records, 226 were screened, and 17 studies met the eligibility criteria for qualitative analysis. BMP-2 was the most frequently investigated growth factor, studied in both in vitro and in vivo models, with rats and rabbits as the most common animal models. Scaffold compositions varied, incorporating hydroxyapatite, heparin, polyethylene glycol diacrylate, octacalcium phosphate-mineralized graphene, silk fibroin, and aloe vera. Growth factors were introduced using diverse methods, including microspheres, chemical grafting, covalent coupling, protein carriers, and nanohydroxyapatite mesopores. Most studies reported enhanced bone regeneration, although differences in models, scaffold composition, and delivery methods preclude definitive conclusions. The addition of growth factors generally improved osteoblast proliferation, angiogenesis, bone density, and expression of osteogenic markers (RunX2, COL1, OPN, OCN). Combining two bioactive agents further amplified osteoinduction and vascularization. Sustained-release systems, particularly those using heparin or hydroxyapatite, prolonged biological activity and improved regenerative outcomes. In conclusion, functionalization of chitosan-based scaffolds with growth factors shows promising potential for bone regeneration. Controlled-release systems and combinations of different bioactive molecules may offer synergistic effects on osteogenesis and angiogenesis. Further research should focus on optimizing scaffold compositions and delivery methods to tailor bioactive agent release for specific clinical applications. Full article

Cytoskeleton-associated protein 4 (CKAP4) has emerged as a critical player in gastrointestinal (GI) cancer progression, diagnosis, and therapy. This comprehensive review synthesizes current knowledge on CKAP4′s multifaceted roles across GI malignancies, providing novel insights into its mechanisms of action and clinical potential. Its interaction with DKK1 and subsequent activation of the PI3K/AKT pathway underscores its role in promoting tumor growth. This review also highlights novel insights into CKAP4′s mechanisms of action beyond the well-established DKK1-CKAP4 axis, including its interaction with integrin β1 and involvement in angiogenesis through the FMNL2/EGFL6/CKAP4/ERK pathway. CKAP4′s impact on tumor microenvironment and immune evasion is elucidated, offering a new perspective on its contribution to cancer progression. In addition, CKAP4 arises as a promising serum biomarker for early detection and prognosis across multiple GI cancers, emphasizing its potential superiority over traditional markers. The therapeutic potential of targeting CKAP4 is extensively explored, including novel approaches like anti-CKAP4 antibodies and aptamers, and their synergistic effects with existing treatments. By integrating findings from esophageal, gastric, pancreatic, and colorectal cancers, this review provides a unique, comprehensive overview of CKAP4 in GI oncology, underscoring CKAP4′s potential to revolutionize GI cancer diagnosis and treatment and paving the way for future translational research. Full article

Wound healing is impaired under diabetic conditions due to reduced angiogenesis, thereby increasing the risk of wound-healing complications. Studies have shown that inhibition of α- and β-adrenoceptors delays wound healing. This study investigates the effects of topical salbutamol (TS) on STZ-induced diabetic wound healing in rats. The rats were divided into two initial groups: non-diabetic and diabetic. Diabetes mellitus was induced in the second group with STZ (65 mg/kg). Excision wounds were inflicted on the dorsal thoracic region, 1–1.5 cm away from the vertebral column on either side, following anesthesia on all groups. Group 2 was subdivided into untreated diabetic wounds, low-dose-TS-treated diabetic wounds (6.25 mg/mL), medium-dose-TS-treated diabetic wounds (12.5 mg/mL), and high-dose-TS-treated diabetic wounds (25 mg/mL), and were monitored for 14 days. Percentage wound contraction and the time required for complete wound closure were observed and recorded. In addition, oxidative stress and inflammatory markers such as NO, CRP, MPO, TGF-β1, TNF-α, IL-6, IL-1β, NO, and hexosamine were estimated in wound exudates and tissue over 14 days. TS treatment resulted in 100% wound contraction in all treated wounds within 14 days compared to untreated non-diabetic and diabetic wounds. Increased NO, TGF-β1, and hexosamine activity was observed in TS-treated wounds when compared to untreated diabetic wounds. In addition, TS treatment decreased the activity of IL-1β, TNF-α, IL-6, CRP, and MPO, all of which were elevated in the untreated diabetic wounds. The current study shows that the application of TS significantly improved diabetic wound contraction and aided the healing process. Angiogenic markers, such as TGF-β1 and NO, were prominently increased, supporting the role of sympathetic nerve stimulation in angiogenesis. Full article

The development of dressing materials mainly protects the wound, prevents infection, and assists in wound healing. Apart from the most common gauze on the market, different dressing materials can accelerate wound healing. Bacterial cellulose (BC) dressings have had many related studies and applications so far, and other natural or artificial compounds that are beneficial to tissue repair may also be added during the manufacturing process. This study compared the wound healing efficacies of BC dry membrane developed by our team, gauze, commercially available “Tegaderm^TM Hydrocolloid Dressing”, and “AQUACEL^® EXTRA Hydrofiber Dressing”. This study used rats as experimental animals and injured them by scalding. Moreover, Staphylococcus aureus was used to infect wounds to compare the effects on wound healing. We first used NIH-3T3 cells for an in vitro model to confirm that the BC membrane is not harmful to cells. In the animal experiment, wounds were created by scalding and then treated with different dressing materials and doses of S. aureus. After 10 days of treatment, the wound recovery in the BC membrane and AQUACEL^® groups was the most obvious, including angiogenesis in the dermal layer and regeneration of the epidermis layer. Especially without S. aureus infection, inflammatory markers such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression levels were reduced to those of healthy tissue. In conclusion, we confirmed that the BC dry membrane can accelerate wound healing. In the future, it may provide high-efficiency and less expensive options in the dressing market. Full article

Background: Periodontitis is a chronic inflammatory disease that leads to tooth loosening and ultimately tooth loss. Regenerative approaches employing bioactive substances aim to restore lost tissues. Platelet-rich fibrin (PRF) is a simple and cost-effective option, but its effects on periodontal ligament (PDL) cells under inflammatory conditions remain unclear. Objectives: This study investigated the stimulating effects of platelet-rich fibrin on molecules crucial for periodontal wound healing and tissue remodelling in periodontal ligament (PDL) cells, under normal and inflammatory conditions mimicked by TNF-α. Methods The stimulating effects of different concentrations of PRF on the gene expression of VEGF, BMP2, COX2, TNF-α, and SPP1 were analysed by real-time PCR and ELISA. In addition, the possible modulating effects of TNF-α, a pro-inflammatory cytokine associated with periodontitis, on PRF-induced effects were studied. Furthermore, cell viability, proliferation, and migration were investigated. Results: A 2–3-fold dose-dependent increase in the expression of all the aforementioned genes by PRF was observed at 24 h and 48 h. Additional incubation with TNF-α did not lead to any significant modulation of PRF-induced expression patterns, indicating that the effects of PRF were not compromised in an inflammatory environment. Functionally, PRF caused a significant 35% increase in cell migration between 24 h and 48 h, which was again not affected by a pro-inflammatory condition. Cell viability and proliferation remained largely unaffected by PRF, irrespective of the presence of TNF-α or not. Conclusions: The results suggest that PRF can promote initial periodontal wound healing even in an inflammatory environment by stimulating the expression of cytokines, growth factors and markers of osteogenic differentiation such as VEGF, BMP2 and SPP1, which are involved in angiogenesis, tissue remodelling, and/or cell migration. Full article

Collagens make up the main components of the extracellular matrix (ECM), and, in cancer, are often aberrantly secreted by both tumor cells and stromal cells in the tumor microenvironment (TME). Collagen prolyl 4-hydroxylase (C-P4H), an enzyme that hydroxylates proline into 4-hydroxyproline at the Y position of the collagen -X-Y-Gly- triplet motif, is essential for the stability of the mature collagen trimer and collagen secretion. In this review, we summarize the research on the structure and function of C-P4H, the regulation of C-P4H enzyme activity, and the role of overexpression of its α-subunit, P4HA1, in promoting cancer progression as well as its potential as a prognostic marker and therapeutic target. Overexpression of P4HA1 is displayed in almost all solid cancers, including breast, colorectal, and lung cancer, and is associated with cancer progression, worse response to therapy, and poorer patient survival. Characterization of P4HA1 overexpression has demonstrated links to key hallmarks of cancer, not only in the canonical collagen deposition role, but also in non-canonical functions, such as cell stemness, hypoxic response, glucose metabolism, angiogenesis, and modulation of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment. P4HA1 is thus an attractive target for developing novel targeted therapies to improve treatment response in many cancer types. Full article

During pregnancy, the maternal hemostatic system undergoes significant changes to support placental angiogenesis, maintain fetal blood flow, and ensure safe delivery. This study investigates the dysregulation of hemostasis in placental insufficiency and explores potential markers for diagnosing and managing this gestational complication. Thromboelastography, coagulation and fibrinolysis functional assays, ELISA, and immunoblotting were employed to assess hemostasis dysregulation in placental dysfunction of two cohorts of pregnant women with placental dysfunction and healthy controls. Thromboelastographic analysis revealed no significant differences in clot lysis indices between the control and placental dysfunction groups, with values remaining within normal ranges, suggesting this method’s limitations for assessing fibrinolysis in pregnancy. The placental dysfunction group demonstrated moderately increased fibrinogen levels and platelet sensitivity to ADP, indicating hemostasis reactiveness. Significantly lower D-dimer levels, decreased plasminogen activator inhibitor activity (total PAI-1 + PAI-2), and increased plasminogen activator activity, driven primarily by uPA in the placental dysfunction group, indicated abnormal fibrinolysis. Immunoblotting confirmed elevated uPA/uPA-PAI complexes and reduced tPA/tPA-PAI complexes, indicating that shutdown of tPA-mediated fibrinolysis and induction of uPA-driven vessel-wall-associated proteolysis are linked to placental dysfunction. Placental dysfunction involves fibrinolytic system dysregulation, marked by decreased PAI and tPA, uPA overproduction, and hypofibrinolysis, contributing to thrombotic risks, impaired placental flow, and complications like fetal growth retardation. PAI/PA ratio and D-dimer levels have diagnostic potential for placental-dysfunction-associated complications. Full article

This study aimed to evaluate the regenerative effects of various microcurrent waveforms in cast-induced gastrocnemius muscle atrophy in rabbits, integrating both in vitro and in vivo analyses. After two weeks of enforced hindlimb immobilization via casting, twenty-four rabbits were divided into four groups and treated for two weeks: Group-1 (control) received sham microcurrent, Group-2 was treated with a square waveform microcurrent, Group-3 with a sine waveform, and Group-4 with a triangular waveform. Treatments were administered daily for one hour. Calf circumference, muscle thickness (via ultrasound), tibial nerve CMAP, muscle fiber CSA, and protein expression (via Western blot analysis) were assessed. Among the groups, the sine waveform microcurrent resulted in significantly enhanced recovery across all measured parameters (p < 0.05), showing superior improvements in muscle thickness, CMAP amplitude, and fiber CSA. Immunohistochemical analysis revealed increased expression of proliferation and angiogenesis markers, including BrdU, PCNA, VEGF, and PECAM-1, while Western blotting demonstrated robust upregulation of myogenic regulatory factors such as MyoD and myogenin. Furthermore, levels of inflammatory and apoptotic markers, including TNF-α, NF-κB, and cleaved caspase-3, and stress response proteins, including p-CHK1 and p-CHK2, were markedly reduced. Collectively, these findings indicate that sine waveform microcurrent stimulation most effectively promotes muscle regeneration in both dexamethasone-induced C2C12 myoblasts and cast-induced muscle atrophy, underscoring its therapeutic potential and warranting further studies to optimize clinical application parameters. Full article

Liquid biopsy, which analyzes tumor secretomes in biological fluids, allows us to not only diagnose cancer, but also evaluate the effectiveness of antitumor therapy, predict the prognosis of the disease, and select targeted therapy. One of the promising sources for identifying tumor markers using liquid biopsy is exosomes—small extracellular vesicles (sEVs) (30–150 nm in size) that are secreted by all types of cells, including tumor cells, to exchange information. It is known that during the maturation process, mainly biologically active proteins and non-coding RNA are packaged into exosomes, and tumor cells secrete significantly more exosomes than normal cells. Taking into account the involvement of microRNAs in the mechanisms of carcinogenesis, their high stability in EVs, and ease of detection, exosomal microRNAs are the most promising tumor markers for creating panels that can serve as a guide both for clarifying diagnostics and for making therapeutic decisions on effective cancer treatment, including breast cancer (BC). The purpose of this review is to summarize information on the shortcomings of modern methods for diagnosing early BC, the involvement of exosomal microRNAs in BC dissemination (impact on the immune system, epithelial–mesenchymal transition, proliferation, invasion, migration, angiogenesis, and metastasis), and the high diagnostic potential of exosomal microRNAs for detecting early BC. Full article

The interaction between tumor cells and stroma in urological malignancies is governed by secreted and damage-associated factors that promote angiogenesis, immune modulation, and metastasis. This review synthesizes current evidence on six biomarkers—GDF15, VEGF, TGF-β1, HSP90, HMGB1, and S100A9—detailing their biological functions and clinical implications. We discuss GDF15’s roles in metabolic stress and immune regulation, VEGF’s central role in neovascularization, and TGF-β1’s dualistic tumor-suppressive and promotive effects. We then examine damage-associated molecular patterns, highlighting HSP90’s extracellular immunomodulation, HMGB1’s signaling via pattern-recognition receptors, and S100A9’s pro-inflammatory activity through RAGE and Toll-like receptors. Comparative analyses across renal cell carcinoma and bladder cancer cohorts elucidate each marker’s diagnostic accuracy, prognostic value, and predictive capacity for targeted therapies. Notably, GDF15 and HSP90 correlate with ferroptosis susceptibility in RCC and urinary VEGF with HMGB1 increases the chances of non-invasive bladder cancer detection. We suggest that multiplexed biomarker panels could enhance early detection, risk stratification, and personalized treatment in urological oncology. We advocate for prospective studies to validate thresholds, clarify interactions, and improve clinical integration. Full article

Proteins and peptides play a pivotal role in key pathological processes, including cancer growth, immune evasion, angiogenesis, and metastasis. Consequently, they are gaining attention as significant biomolecules in the diagnosis and treatment of various diseases. This review provides a comprehensive overview of the latest research trends and technological advancements in protein- and peptide-based cancer diagnostic and therapeutic strategies. It covers the clinical application of major diagnostic markers such as PSA, CA125, HER2, and AFP, as well as therapeutic strategies including monoclonal antibodies, immune checkpoint inhibitors, and anticancer peptides. Additionally, it introduces quantitative analysis techniques such as ELISA, mass spectrometry, and CyTOF, as well as advancements in delivery systems based on nanoparticle–peptide complexes. Peptides offer advantages for precision therapy due to their high target specificity and structural modifiability. However, they also have limitations such as stability, enzymatic degradation, and delivery efficiency. Emerging technologies such as synthetic biology, computational design, and omics-integrated analysis are being developed to address these challenges, and rapid advancements in this field are enhancing the potential for clinical application. This review underscores the potential of protein- and peptide-based strategies for precision cancer diagnosis and personalized therapy and proposes future research directions in this field. Full article