Search Results (1,376)

Background: Local analgesia administered through a wound catheter is widely used for postoperative pain control, yet its effects on wound healing remain incompletely understood. This study examined how levobupivacaine alone or combined with meloxicam or buprenorphine influences inflammatory markers, angiogenesis, apoptosis, and transforming growth factor β1 (TGF-β1) expression during wound healing in rats. Methods: Thirty Sprague Dawley rats were assigned to five groups: control, saline, levobupivacaine (L), levobupivacaine/meloxicam (L/MEL), and levobupivacaine/buprenorphine (L/BUP). Treatments were administered via a wound catheter for three days. Blood and skin samples were collected before surgery and on days 3, 10, and 21. Results: Levobupivacaine combined with meloxicam or buprenorphine caused fluctuations in white blood cell counts, while albumin levels remained stable. Angiogenesis in the L/MEL group was markedly increased compared with the control, saline, and levobupivacaine-only groups, but the newly formed vessels exhibited consistently narrow lumina during the early healing phase. Caspase-3–positive cells were most numerous in L/MEL during inflammatory and proliferative phases, whereas delayed caspase-3 activation was observed in L/BUP. TGF-β1 expression peaked in both adjuvant groups on days 3 and 10. Conclusions: Meloxicam and buprenorphine increased TGF-β1 expression, but their vascular effects differed considerably. Meloxicam induced a marked increase in angiogenesis, but the newly formed vessels were structurally immature, displaying uniformly narrow lumina and poor architectural organisation, which led to their subsequent regression. In contrast, buprenorphine supported the formation of more mature vascular structures, characterised by wider vessel lumina and a more organised vascular network. These findings demonstrate that adjuvants used with levobupivacaine can significantly modify angiogenic and apoptotic responses and should be carefully considered when selecting multimodal local analgesia strategies after surgery. Full article

In this study, an innovative bioreactor, named BioAxFlow, particularly suitable for tissue engineering applications, is tested. Unlike traditional bioreactors, it does not rely on mechanical components to agitate the culture medium, but on the unique fluid-dynamics behaviour induced by the geometry of the culture chamber, which ensures continuous movement of the medium, promoting the constant exposure of the cells to nutrients and growth factors. Using the human osteosarcoma cell line SAOS-2, the bioreactor’s ability to enhance cell adhesion and proliferation on polylactic acid (PLA) scaffolds, mimicking bone matrix architecture, is investigated. Cells cultured in the bioreactor showed significant improvement in cell growth and adhesion, compared to static cultures, and a more homogeneous cell distribution upon the scaffold surfaces, which is crucial for the development of functional tissue constructs. The bioreactor also preserves the osteogenic potential of SAOS-2 cells as assessed by the expression of key osteogenic markers. Additionally, it retains the tumorigenic characteristics of SAOS-2 cells, including the expression of pro-angiogenic factors and apoptosis-related genes. These results indicate that the BioAxFlow bioreactor could be an effective platform for tissue engineering and cancer research, offering a promising tool for both regenerative medicine applications and drug testing. Full article

Background: Peripheral artery disease (PAD) represents a major global cause of mortality and disability. A primary therapeutic strategy involves promoting angiogenesis in ischemic limbs. The Xuefu Zhuyu Capsule (XFZYC) is widely used in China for treating PAD and demonstrates therapeutic potential; however, the mechanism underlying its pro-angiogenic effect remains unclear. Methods: The components of XFZYC were identified via TCMSP and HERB databases, with network pharmacology and molecular docking predicting its potential targets and pathways. For in vitro validation, drug-containing serum and blank control serum were prepared. Human Microvascular Endothelial Cells (HMEC-1) cells were treated with 1.25%, 2.5%, or 5% serum to determine the optimal concentration using tube formation assays and Western blot (WB) analysis of HIF-1α, HK2, and PFKFB3. The efficacy of XFZYC was further assessed through CCK-8, scratch wound healing, cell adhesion, and tube formation assays. Glycolytic metabolite levels and enzyme activities were measured by colorimetric assays and WB. Results: Network pharmacology screening identified 167 active components in XFZYC and 2967 potential targets. GO functional and KEGG pathway enrichment analyses suggested that XFZYC likely promotes the glycolytic pathway via the HIF-1 signaling pathway, specifically mediated by HK2 and PFKFB3. In vitro experiments confirmed that XFZYC enhanced HMEC-1 cell viability, migration, adhesion, and tube formation. Concurrently, it augmented the glycolytic capacity of HMEC-1 cells, manifested by increased glucose consumption, lactate production, enhanced activity of key glycolytic enzymes (HK, PFK, and PK), and upregulated protein expression of PFKFB3. Treatment with 3PO, a glycolytic inhibitor, significantly suppressed these drug-induced effects. Conclusions: XFZYC promotes angiogenesis in endothelial cells by modulating the glycolytic pathway, an effect primarily mediated through the upregulation of PFKFB3 expression. This study offers a preliminary exploration of the underlying mechanisms by which XFZYC may act in the treatment of PAD, thereby providing a new scientific perspective for further understanding its therapeutic effects. Full article

Two endogenous peptides, β-alanyl-L-histidine, named carnosine (Car), and glycyl-L-histidyl-L-lysine (GHK), derived from the matricellular protein Secreted Protein Acidic and Rich in Cysteine (SPARC), share many beneficial functions. The hydrolytic enzyme carnosinase for Car and the low stability for GHK can put into question their antioxidant, antiaggregating, and anti-inflammatory properties. The glycoconjugates of Car with a di- (trehalose, Tre) or polysaccharide (hyaluronan, HA) inhibit carnosinase, while the synthesis of HAGHK derivatives increases the tripeptide stability and protects/delays the biopolymer degradation. A synergic effect between the two components of the glycoconjugates is evident in their consequently preserved protective features. TreCar, HACar, and HAGHK maintain the copper-binding ability of the peptides alone, and the saccharides potentiate the Cu,Zn-superoxide dismutase-like ability of the copper(II) complexes with the glycoconjugates. These peptide derivatives behave as copper ionophores, utilizing Cu²⁺ present in the culture medium; also, an increase in the metal intracellular level occurs with a consequent stimulation of the copper-driven signaling pathways that produce the expression/release of trophic (Brain-Derived Neurotrophic Factor, BDNF, and Bone Morphogenetic Protein 2, BMP-2) and angiogenic (Vascular Endothelial Growth Factor, VEGF) proteins. Copper chaperons for SOD1, CCS, and Antioxidant 1 (Atox-1) are the copper chaperones that act as transcription factors. Full article

Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality worldwide, with most patients, especially those with microsatellite-stable disease, having limited treatment options. Oncolytic viruses (OVs) have emerged as a promising therapeutic modality due to their ability to selectively replicate in malignant cells and mediate antitumor effects through direct oncolysis, immune activation, and modulation of tumor angiogenesis. This review analyzed 101 primary studies that reported the use of OV in CRC. The extracted data, including virus type, study design, model system, mechanistic pathways, and therapeutic strategies, were organized as standalone therapy, combination therapy, or enhancer-based approaches. Across studies, OV monotherapy consistently induced selective tumor cell lysis and, in some models, also exhibited additional immunogenic and anti-angiogenic effects. Combination strategies, particularly those with immune checkpoint inhibitors, demonstrated synergistic activity, enhancing T-cell infiltration, cytokine production, and tumor control even in resistant CRC settings. Enhancer approaches, including mesenchymal stem cell delivery systems and tumor-specific promoters, have improved viral selectivity, tumor penetration, and reduced immune clearance. Despite promising findings, progress is hindered by heterogeneous models and the scarcity of advanced clinical trials. Translation into well-designed clinical studies is now warranted to optimize therapeutic outcomes. Full article

In this study, the neurorehabilitation potential of combined and isolated intermittent hypercapnia and hypoxia exposure was evaluated following photochemically induced cerebral thrombosis in rats. Particular attention was given to the roles of possible neuroplasticity mechanisms mediated by VEGF and BDNF, as well as the potential of hypercapnic–hypoxic interventions to synergistically amplify the therapeutic effects of pharmacological neuroprotectants during recovery. A total of 50 male Wistar rats were randomly assigned to five equal groups (n = 10 per group), each undergoing a course of respiratory interventions lasting 30 min per day for 15 sessions. The groups included (1) a normobaric hypoxia (PO₂ ≈ 90 mmHg) group, (2) a permissive hypercapnia (PCO₂ ≈ 50 mmHg) group, (3) a combined hypercapnic hypoxia (PO₂ ≈ 90 mmHg, PCO₂ ≈ 50 mmHg) group, (4) a control group, and (5) a sham-operated group. Following the rehabilitation protocol, animals exposed to hypercapnic hypoxia exhibited a two-fold reduction in stroke volume compared with controls, significant improvement in motor coordination (as assessed via the rotarod test), and marked upregulation of VEGF and BDNF expression within the ischemic brain region. Notably, only the HH group showed a decrease in serum neuron-specific enolase (NSE) levels. These findings indicate that hypercapnic hypoxia exerts a possible neurorehabilitative effect after focal ischemic injury, superior to that of isolated hypoxia or hypercapnia. Possible mechanisms underlying this outcome may involve activation of neurotrophic (BDNF) and angiogenic (VEGF) signaling pathways. Full article

In the developing lung, oxidative stress caused by relative hyperoxia constitutes a central pathogenic mechanism of neonatal lung injury resulting in bronchopulmonary dysplasia (BPD). The immature postnatal lung is highly susceptible to oxidative damage due to incomplete antioxidant defenses and ongoing alveolar and vascular maturation. In a postnatal high-oxygen-induced rat model of BPD-associated lung injury, three or five days of exposure to 80% oxygen was found to disrupt developmental signaling pathways, downregulating genes essential for alveolarization and angiogenesis while inducing profibrotic mediators and collagen expression (Sirius Red staining). These changes resulted in simplified alveolar architecture, as quantified by toluidine blue staining and mean linear intercept analysis of normalized volumes of parenchyma, non-parenchyma, airspaces, septa, and edema. Acting as a multifunctional antioxidant with antifibrotic activity, caffeine mitigated structural lung damage and normalized the transcription of angiogenic and fibrotic genes. It counteracted TGF-β/CTGF-driven fibrogenic signaling and promoted recovery of normal lung morphology following hyperoxic injury. Under normoxic conditions, however, caffeine transiently upregulated profibrotic mediators. Overall, caffeine mitigates hyperoxia-induced lung injury and may actively promote physiological lung maturation, warranting future studies to define optimal dosing windows, clarify context-dependent fibrotic signaling, and translate gene-level effects into long-term clinical outcomes. Full article

Background/Objectives: Neovascular age-related macular degeneration (nAMD) poses a serious threat to the eyesight of older adults, representing a leading cause of irreversible vision loss. Anti-vascular endothelial growth factor (anti-VEGF) treatments are effective but require repeated intraocular injections and show poor responses in some patients. CGK012 is a novel derivative of decursin that inhibits the Wnt/β-catenin pathway. This study aimed to elucidate the mode of action of CGK012 and examine its therapeutic effects. Methods: We performed in vitro cellular studies in a retinal pigment epithelial (RPE) cell line (ARPE-19) and human umbilical vein endothelial cells (HUVECs). We examined the in vivo efficacy of CGK012-loaded implants in laser-induced choroidal neovascularization (CNV) rabbit models. We also determined the implants’ in vitro dissolution, intraocular release, and disposition characteristics. Results: CGK012 decreased angiogenic/proinflammatory factor expression and suppressed the epithelial–mesenchymal transition (EMT) in RPE cells by promoting intracellular β-catenin degradation. Additionally, it repressed the expression of cyclin D1 and c-myc, downstream target genes of β-catenin, and inhibited HUVEC capillary tube formation. CGK012-loaded poly (lactic-co-glycolic acid) (PLGA) intravitreal implants significantly reduced vascular leakage in a laser-induced CNV rabbit model. Notably, CGK012 released from the implant was highly permeable to retina/choroid tissue and downregulated β-catenin, angiogenic/inflammatory factors, and vimentin in the rabbit model. The CGK012 concentration reached a plateau at 28–42 days in the vitreous humor and decayed with a half-life of 14 days without systemic exposure. Conclusions: Our findings demonstrate that CGK012 implants prevent choroidal neovascularization through the Wnt/β-catenin pathway suppression and produce high concentrations of CGK012 in the posterior eye segment with prolonged release. Thus, these implants provide more therapeutic choices for nAMD treatment. Full article

Preserving dental pulp vitality is a key goal in minimally invasive dentistry. Conventional materials such as calcium hydroxide and mineral trioxide aggregate (MTA) are effective but limited in bioactivity and mechanical strength. This systematic review evaluated the biological efficacy of chitosan-based nanoparticles and biomaterials for pulp capping and regeneration. Following PRISMA 2020 guidelines, electronic searches were conducted across five databases up to April 2025. Controlled in vitro and animal studies using chitosan-based nanoparticles, hydrogels, or composite scaffolds were included. Risk of bias was assessed using SYRCLE (animal) and ToxRTool (in vitro), and certainty of evidence was rated via the GRADE-Preclinical framework. Due to methodological heterogeneity, data were synthesized using direction-of-effect coding and visualized through Albatross and heatmap plots. Sixteen studies met the criteria, consistently demonstrating enhanced cell viability, mineralization, and upregulation of odontogenic and angiogenic markers (BMP-2, TGF-β₁, VEGF, DSPP) compared with MTA or calcium hydroxide. Animal models confirmed improved angiogenesis, reparative dentin formation, and pulp vitality preservation. Despite uniformly positive biological outcomes, the overall certainty was rated Low to Very Low owing to small samples and unclear randomization. Chitosan-based biomaterials show promising regenerative potential, warranting well-designed preclinical and clinical studies for translational validation. Full article

Background and Objectives: Endometrial carcinoma is among the most common gynecological malignancies, with recurrence and chemoresistance remaining major clinical challenges. This study aimed to evaluate the combined effects of Boswellic acid (BA), a natural pentacyclic triterpene, and Gemcitabine (GEM), a nucleoside analog chemotherapeutic, on hypoxia, angiogenesis, and apoptosis in human endometrial cancer cells. Materials and Methods: ECC-1 cells were treated with BA, GEM, or their combination under normoxic and hypoxic conditions. Cell viability (MTT assay); nuclear morphology (NucBlue staining); cell cycle distribution (PI flow cytometry); angiogenesis (VEGF ELISA expression); apoptosis (Caspase-3/7 activity; Bax; Bcl-2 expression); inflammatory cytokines (IL-1β; IL-6; TNF-α); and gene ontology enrichment were analyzed. Results: Both BA and GEM reduced cell viability in a dose- and time-dependent manner, with the combination producing synergistic cytotoxicity and lower IC₅₀ values. Hypoxia enhanced drug sensitivity, particularly in combination therapy. BA and GEM significantly suppressed HIF-1α and VEGF expression, with maximal inhibition observed in the combination group. Apoptotic induction was confirmed by increased Bax and Caspase-3 and decreased Bcl-2 expression, together with elevated Caspase-3/7, -8, and -9 activity. Pro-inflammatory cytokine levels were markedly reduced, and gene ontology analysis revealed enrichment of apoptotic, anti-proliferative, and anti-angiogenic pathways. Conclusions: BA + GEM combination synergistically suppresses hypoxia-driven angiogenesis and promotes apoptosis in endometrial cancer cells. These findings support its potential as an adjuvant therapeutic approach, warranting further preclinical and clinical validation. Full article

The increasing prevalence of multidrug-resistant bacteria necessitates alternative therapeutic strategies that combine antimicrobial efficacy with immunomodulatory properties. Here, we report the immunostimulatory activity and antibacterial potential of the amino-functionalized metal–organic framework MIL-101(Al)-NH₂ as a carrier for penicillin (PEN) and hypericin (Hyp), a photodynamically active compound. Structural and physicochemical characterization confirmed successful encapsulation of PEN, Hyp, and their combination within MIL-101(Al)-NH₂, with distinct effects on porosity, release kinetics, and thermal stability. Drug release studies revealed rapid Hyp liberation triggered by serum components, whereas PEN exhibited a biphasic, diffusion-controlled profile. Using a quail chorioallantoic membrane (CAM) model, we demonstrated that MIL-101(Al)-NH₂ enhances interferon-α expression, indicating intrinsic immunostimulatory activity, and that Hyp-loaded systems promote angiogenic responses. In a bacterial infection CAM model, MIL-101(Al)-NH₂ carriers loaded with Hyp or Hyp/PEN induced immunomodulatory changes and, upon photodynamic activation, inhibited bacterial growth. While Gram-negative Escherichia coli remained resistant, Gram-positive Staphylococcus epidermidis was effectively suppressed by photodynamic therapy (PDT), and Hyp/PEN co-delivery overcame bacterial resistance to PEN. These results highlight MIL-101(Al)-NH₂ as a multifunctional nanoplatform with immunostimulatory capacity and PDT-enhanced antibacterial activity, offering a promising strategy to combat antibiotic resistance and infections associated with medical implants. Full article

Background: Hypoxia and ageing both involve impaired oxygen delivery, leading to oxidative damage, and endothelial cell (EC) dysfunction. In the presence of chronic hyperglycemia, these effects are amplified, accelerating EC senescence and vascular impairment. Methods: We assessed key mediators of inflammatory signalling and senescence, as well as transcriptional regulators responsive to oxidative stress in ECs exposed to high glucose (30.5 mmol/L) for 72 h under either normoxia (21% O₂) or prolonged (16 h) hypoxia (2% O₂) followed by 2 h of reoxygenation. Results: ECs exposed to high glucose and hypoxia developed a senescent phenotype, as indicated by increased expression of p21 and p16, and elevated β-galactosidase staining. Interestingly, hypoxia-induced senescence did not coincide with the classical senescence-associated secretory phenotype (SASP). Compared to normoxia, ECs exposed to hypoxia, particularly under high-glucose conditions, showed reduced NF-κB-driven proinflammatory secretome (MCP-1, IL-6, IL-8), downregulation of the NF-κB p50 subunit, and simultaneous upregulation of the angiogenic factor VEGF-A with downregulation of YAP-1, a key regulator of cell survival. Notably, we observed a strong upregulation of A20 and TNIP-3, two well-characterized negative regulators of NF-κB signalling. Conclusions: Hypoxia-induced senescence did not trigger a typical inflammatory SASP. Although ECs enter a senescent state, they activate an anti-inflammatory response, suppressing NF-κB signalling and increasing the expression of its inhibitors, A20 and TNIP-3. This may reflect a non-canonical senescence response whose functional significance remains to be determined. Full article

Background: Chemoresistance, particularly to cisplatin, remains a significant challenge in treating high-risk neuroblastoma, resulting in a mere 20% five-year overall survival rate. Tumour-derived small extracellular vesicles (sEVs) have been implicated in cancer progression by promoting angiogenesis, invasion, and proliferation in recipient cells. This study investigated alterations in the protein cargo of sEVs secreted by cisplatin-sensitive and resistant neuroblastoma cells and their impact on reprogramming non-cancerous recipient cells. Methods: sEVs from cisplatin-resistant (KellyCis83) and its cisplatin-sensitive parental cell line (Kelly) were isolated and characterised, followed by proteomic profiling and Gene Set Enrichment Analysis. Functional assays using human umbilical vein endothelial cells (HUVECs) evaluated the effects of sEVs on proliferation, migration, tube formation, and metabolism. The clinical relevance of the shortlisted sEV glycolytic proteins was evaluated using the R2 Genomics Analysis and Visualisation Platform. Results: Proteomic analysis revealed dysregulated metabolic pathways in KellyCis83 sEVs. While Kelly’s and KellyCis83’s sEV-induced aerobic glycolytic rates were similar, oxidative phosphorylation (OXPHOS) was significantly reduced in HUVECs treated with Kelly’s sEVs compared to KellyCis83’s sEVs, which might have been due to an altered balance of glycolytic enzymes in sEVs. Under angiogenic-factor-deprived conditions, the uptake of sEVs by HUVECs reduced their proliferation and increased anchorage-dependent differentiation. Our study demonstrated the enrichment of the MYCN oncogene and clinically relevant glycolytic proteins in neuroblastoma cell-derived sEVs. Conclusions: This study reports a potential mechanism by which sEVs derived from cisplatin-resistant neuroblastoma cells modulate endothelial cell function through alterations in metabolic pathways and provides an opportunity to explore exosomal MYCN and glycolytic proteins as circulating biomarkers for progression and treatment response signatures, using less invasive methods and enabling personalised treatment approaches for neuroblastoma patients. Full article

Ovarian cancer is the sixth leading cause of cancer-related deaths among women in the United States. This complex disease arises from tissues such as the ovarian surface epithelium, fallopian tube epithelium, endometrium, or ectopic Müllerian components and is characterized by diverse histological and molecular traits. Standard treatments like surgery, chemotherapy, and radiation have limited effectiveness and high toxicity. Targeted therapies, including poly (ADP-ribose) polymerase PARP inhibitors, anti-angiogenics, and immune checkpoint inhibitors (ICIs), face obstacles such as adaptive resistance and microenvironmental barriers that affect drug delivery and immune responses. Factors in the tumor microenvironment, such as dense stroma, hypoxia, immune suppression, cancer stem cells (CSCs), and angiogenesis, can reduce drug efficacy, worsen prognosis, and increase the risk of recurrence. Research highlights impaired immune function in ovarian cancer patients as a contributor to recurrence, emphasizing the importance of immunotherapies to target tumors and restore immune function. Preclinical studies and early clinical trials found that natural killer (NK) cell-based therapies have great potential to tackle ovarian tumors. This review explores the challenges and opportunities in treating ovarian cancer, focusing on how NK cells could help overcome these obstacles. Recent findings reveal that engineered NK cells, unlike their primary NK cells, can destroy both stem-like and differentiated ovarian tumors, pointing to their ability to target diverse tumor types. Animal studies on NK cell therapies for solid cancers have shown smaller tumor sizes, tumor differentiation in vivo, recruitment of NK and T cells in the tumor environment and peripheral tissues, restored immune function, and fewer tumor-related systemic effects—suggesting a lower chance of recurrence. NK cells clinical trials in ovarian cancer patients have also shown encouraging results, and future directions include combining NK cell therapies with standard treatments to potentially boost effectiveness. Full article

Background: The epithelial-to-mesenchymal transition (EMT) process is necessary for metastasis as it enables tumor cells’ migration and invasion. In the remote organ, tumor cells can develop into metastatic lesions or arrest their proliferation and become dormant, thus suspending metastatic development. EMMPRIN is a membrane glycoprotein, implicated in cell–cell interactions, proliferation, angiogenesis, and EMT. We asked whether neutralizing EMMPRIN with the new anti-EMMPRIN monoclonal antibody hMR18-mAb can inhibit EMT. Methods: We co-cultured tumor cell lines (breast carcinoma MCF-7, MDA-MB-231, or oral squamous cell carcinoma SCC-40) together with U937 monocytic-like cells, with or without hMR18-mAb or its negative control rabbit IgG. Results: We demonstrate that depending on the initial state of the cells along the epithelial–mesenchymal axis (E/M axis), co-culture enhanced the EMT process, whereas hMR18-mAb reversed this effect. The co-culture increased EMT-inducer cytokines in all cell lines (by 2.5-fold), while hMR18-mAb reduced them (by ~55–70% in the breast cancer cells and by 81% in the SCC-40 cells). The co-culture reduced E-cadherin (by 2-fold in MCF-7 and SCC-40 cells) and increased vimentin expression (by 2–3-fold in MDA-MB-231 and SCC-40), while hMR18-mAb reverted this effect. Co-culture enhanced proliferation, migration, and angiogenic potential of the tumor cells, while hMR18-mAb reduced these by ~20%, 30–44% and ~60–80%, respectively. Co-culture reduced the standard markers of dormancy (NR2F1, p21, p27) and stemness (SOX2, Nanog) (by 30–60% in MCF-7 and SCC-40), while hMR18-mAb elevated gene expression of these markers (by 1.5–3.5-fold) in all cell lines, pushing the cells towards dormancy. Conclusions: We conclude that EMMPRIN is a gatekeeper that prevents cells from entering dormancy, and that hMR18-mAb disrupts this effect. As it is the first antibody shown to induce dormancy in tumor cells and stop the development of metastases, this could become a new therapeutic strategy to prevent and treat metastasis. Full article