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Pharmacophore hybridization is a well-established strategy for developing novel anticancer agents with improved biological profiles. In this study, a new series of (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamide derivatives has been rationally designed by hybridizing key structural features of sorafenib with cinnamide pharmacophores and subsequently synthesized. The antiproliferative activities of the synthesized compounds were evaluated against a panel of human cancer cell lines, including A549 (lung), DU-145 (prostate), SKOV3 (ovarian), and HepG2 (liver), along with non-cancerous Hek293T cells. In comparison with the standard drug sorafenib, most of the (E)-4-(4-acrylamidophenoxy)-N-methylpicolinamides demonstrated significant antiproliferative activity, with specificity toward the HepG2 (liver cancer) cell line, and no effect on the noncancerous cells (Hek293T). Among them, compound 5f, the derivative containing a trifluoromethyl-substituted cinnamoyl moiety was identified as the lead candidate, exhibiting an IC50 of 5.3 µM towards HepG2 (liver) cancer cells, comparable to the reference drug sorafenib. Enzyme inhibition studies showed that compound 5f inhibited both b-Raf and VEGFR-2 with IC50 values of 1.45 and 0.37 µM, respectively. Furthermore, compound 5f suppressed angiogenesis in vitro and in vivo, as evidenced by the tube formation assay using HUVECs and in transgenic zebrafish Tg(fli1a:EGFP) models, respectively. Mechanistic studies indicated that compound 5f induced apoptosis in HepG2 cells through mitochondrial membrane depolarization and increased ROS generation. Molecular docking studies supported experimental findings and showed that 5f can interact with catalytically active residues via hydrogen-bonding interactions. Overall, these results highlight the potential of compound 5f as a promising dual target therapeutic lead with dual direct anticancer and antiangiogenic properties.

Bone-related defects present a key challenge in orthopaedics. The current gold standard, autografts, poses significant limitations, such as donor site morbidity, limited supply, and poor morphological adaptability. This study investigates the potential of scaffold geometry to induce osteogenic differentiation of human adipose-derived stem cells (hADSCs) through mechanotransduction, without the use of chemical inducers. Four distinct poly-(L)-lactic acid (PLA) scaffold architectures—Traditional Cross (Tc), Triangle (T), Diamond (D), and Gyroid (G)—were fabricated using fused filament fabrication (FFF) 3D printing. hADSCs were cultured on these scaffolds, and their response was evaluated utilising an alkaline phosphatase (ALP) assay, immunofluorescence, and extensive proteomic analyses. The results showed the D scaffold to have the highest ALP activity, followed by Tc. Proteomics results showed that more than 1200 proteins were identified in each scaffold with unique proteins expressed in each scaffold, respectively Tc—204, T—194, D—244, and G—216. Bioinformatics analysis revealed structures with complex curvature to have an increased expression of proteins involved in mid- to late-stage osteogenesis signalling and differentiation pathways, while the Tc scaffold induced an increased expression of signalling and differentiation pathways pertaining to angiogenesis and early osteogenesis.

This review explores the pivotal role of angiogenesis in breast cancer progression and treatment. It covers biomarkers, imaging techniques, therapeutic approaches, resistance mechanisms, and clinical implications. Key topics include Vascular Endothelial Growth Factors, angiopoietins, microRNA signatures, and circulating endothelial cells as biomarkers, along with Magnetic Resonance Imaging, Computed Tomography Angiography, Ultrasound, and Positron Emission Tomography for imaging. Therapeutic strategies targeting VEGF, tyrosine kinase inhibitors, and the intersection of angiogenesis with immunotherapy are discussed. Challenges such as resistance mechanisms and personalized medicine approaches are addressed. Clinical implications, prognostic value, and the future direction of angiogenesis-targeted therapies are highlighted. The article concludes with reflections on the transformative potential of understanding angiogenesis.

The subcutaneous space offers an attractive and accessible site for cell transplantation. However, its clinical utility is often hindered by insufficient vascularization. This study evaluated the vascularization potential of three hydrogels; human collagen type I, human fibrin, and alginate implanted subcutaneously in Sprague-Dawley rats. Polylactide-co-glycolide (PLG) scaffolds used as positive controls for foreign body response. Sequential injections were performed at 1, 2, and 4 weeks, and tissues were retrieved for histopathological examination. Human collagen type I and fibrin induced robust neovascularization compared to controls, with peak vessel density at week 1 (2.79-fold and 3.18-fold; P  < 0.001) and sustained increases through week 4 (1.94-fold and 2.3-fold, respectively). No significant differences were observed between human collagen type I and fibrin at any time point. Both biomaterials were well tolerated without evident of fibrosis or foreign body reaction. Alginate produced the strongest early angiogenic effect (3.96-fold at week 1; P  < 0.001) but was associated with marked inflammation and fibrosis by week 4. PLG scaffolds induced modest vascularization but consistently provoked inflammatory reactions and fibrosis. Human-derived hydrogels thus combine rapid and durable vascularization with excellent biocompatibility, providing a minimally invasive strategy to enhance subcutaneous cell transplantation outcomes.

Background Replicating the endogenous electromechanical microenvironment of bone remains a significant challenge in regenerative medicine. This study aims to develop a promising scaffold by integrating piezoelectric K 0.5 Na 0.5 NbO 3 /poly (KNN) nanoparticles into poly (L-lactic acid) (PLLA) nanofibers to promote bone healing. Methods KNN/PLLA nanofibers were electrospun and verified via X-ray diffraction (XRD). Scanning Electron Microscope (SEM) was used to characterize morphology and assess biocompatibility on 9 wt% KNN/PLLA. The distribution of KNN was analyzed via energy dispersive spectroscopy (EDS). The mechanical properties were evaluated through Universal Testing Machine (UTM). Piezoelectric properties were quantified using an electrostatic voltmeter and Piezoresponse Force Microscopy (PFM), while Niobium (Nb) ion release was measured via inductively coupled plasma (ICP) analysis. Osteogenic differentiation was evaluated through cell proliferation, quantitative real-time PCR (qRT-PCR) for osteogenic markers osteocalcin (OCN) and runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP) and Alizarin Red S (ARS) assays for osteogenesis, and tube formation for angiogenesis. Results XRD confirmed successful KNN loading. Tensile tests showed that KNN incorporation enhanced mechanical properties. ICP analysis detected Nb release, reflecting the degradation. Increasing KNN content reduced fiber diameter and enhanced piezoelectricity. SEM verified biocompatibility via cell growth on 9 wt% KNN. Notably, KNN loading dose dependently upregulated OCN and RUNX2 expression, enhanced ALP activity and ARS staining, and promoted angiogenesis. Conclusion The 9 wt% KNN/PLLA nanofibers exhibited superior physicochemical and mechanical properties, a sevenfold increase in piezoelectric output. The nanofibers significantly enhanced bone regeneration, evidenced by upregulated osteogenic markers (OCN/RUNX2) and markedly improved ALP activity (60%) and ARS mineralization (70%). Coupled with favorable degradation and enhanced angiogenesis, the nanofibers demonstrate high potential for functional bone tissue engineering.

Skin wound healing is a complex and highly coordinated biological process involving inflammation, cell migration and proliferation, angiogenesis, extracellular matrix remodeling and tissue regeneration. While the zebrafish-derived antimicrobial peptide AP10W exhibits broad-spectrum antimicrobial properties, its potential in tissue repair remains unexplored. Herein, we demonstrate that AP10W possesses intrinsic wound-healing capabilities, providing a preliminary investigation into its underlying mechanisms. In this study, using a full-thickness murine wound model and in vitro cell-based assays to evaluate the effects of AP10W on fibroblasts, keratinocytes, endothelial cells, and macrophages, we found that AP10W significantly promoted fibroblast and keratinocyte migration and proliferation. Furthermore, it enhanced endothelial cell motility, survival, and tube formation, while upregulating key pro-angiogenic factors, including Vascular endothelial growth factor A (VEGFA), Platelet-derived growth factor (PDGF), and Fibroblast growth factor 2 (FGF2). Concurrently, AP10W drove macrophage reprogramming from a pro-inflammatory M1 phenotype toward a pro-healing M2 state, as evidenced by upregulated Arginase-1 (Arg-1) and Interleukin-10 (Il-10) expression, alongside attenuated Tumor necrosis factor-alpha (Tnf-α), Interleukin-1 beta (Il-1β), Interleukin-6 (Il-6), and Inducible nitric oxide synthase (iNOS) levels. In vivo, the topical application of AP10W accelerated wound closure, markedly improving re-epithelialization, collagen deposition, vascularization, tissue perfusion, and skin appendage regeneration. Preliminary mechanistic studies revealed that AP10W increased YAP expression and nuclear translocation; conversely, the pharmacological inhibition of YAP significantly abrogated these pro-healing effects. Collectively, our findings identify AP10W as a multifunctional peptide with potent wound-healing properties, positioning it as a promising candidate for wound therapy.

Background Kidney organoids derived from human pluripotent stem cells (HiPSCs) hold huge applications for drug screening, disease modeling, and cell transplanting therapy. However, these applications are limited since kidney organoid cannot maintain complete morphology and function like human kidney. Kidney organoids are not well differentiated since the core of the organoid lacked oxygen, nutrition, and vasculature, which creates essential niches. Hypoxia-inducible factor-1 α (HIF-1α) serves as a critical regulator in vascularization and cell survival under hypoxia environment. Less is known about the role of HIF-1α in kidney organoids in this regard. This study tried to investigate the effect of HIF-1α in kidney organoid vascularization and related disease modeling. Methods For the vascularization study, kidney organoids were generated from human induced pluripotent stem cells. We overexpressed HIF-1α via plasmid transfection or treated DMOG (Dimethyloxallyl Glycine, an agent for HIF-1α stabilization and accumulation) in kidney progenitor cells to detect the endothelium. For the disease modeling study, we treated kidney organoid with cisplatin under hypoxia environment, with additional HIF-1α transfection. Result HIF-1α overexpression elicited kidney organoid vascularization. The endothelial cells and angiotool analysis parameters were increased in HIF-1α plasmid-transfected and DMOG-treated organoids. These angiogenesis processes were partially blocked by VEGFR inhibitors, semaxanib or axitinib. Cisplatin-induced kidney injury (Cleaved caspase 3) was protected by HIF-1α through the upregulation of CD31 and SOD2. Conclusion We demonstrated that HIF-1α elicited the process of kidney organoid vascularization and protected against cisplatin-induced kidney organoid injury in hypoxia environment.

Background Magnesium (Mg) and its alloys, as biodegradable metallic materials, possess numerous advantageous properties compared to traditional biomaterials. Furthermore, magnesium ions (Mg²⁺) are the second most abundant intracellular cations, participating in over 300 enzymatic reactions and serving as essential trace elements for various physiological processes. The release of Mg²⁺ is believed to promote osteogenic differentiation and angiogenesis, both of which are crucial for bone regeneration. However, the mechanisms underlying Mg²⁺-mediated promotion of osteogenesis and angiogenesis are not yet fully elucidated. Methods We treated Bone marrow mesenchymal stem cells (BMSCs) with Mg²⁺ and performed transcriptome sequencing on both control and experimental groups. Bioinformatics analysis was conducted using the sequencing data, including principal component analysis, differential expression analysis, enrichment analysis, and protein-protein interaction analysis. Pathway proteins were assessed by Western blot. The osteogenic capacity of BMSCs was directly evaluated using ALP and ARS staining. Immunofluorescence staining was used to detect the expression of osteogenesis-related proteins RUNX2 and OPN. Tube formation assays were employed to evaluate the effect of magnesium ions on angiogenesis capability, while Western blotting and quantitative PCR were used to assess changes in FGF2 and CD31 expression levels. Concurrently, the functional impact of Mg²⁺ on BMSCs was assessed using Transwell and CCK8 assays. Finally, we established a bone defect model in rats and implanted magnesium alloy scaffolds to verify the conclusions drawn from the in vitro experiments. Result Through bioinformatics analysis, we identified the PI3K-AKT-mTOR pathway as a potential key pathway through which Mg²⁺ promotes osteogenesis and angiogenesis in BMSCs. Magnesium ion treatment enhanced the activity of pPI3K, pAKT, and pmTOR, elevated the expression of osteogenic and angiogenic proteins, increased ALP activity and mineralized nodule formation, and promoted tube-like structure formation. Additionally, the migratory ability, cell viability, and osteogenic activity of BMSCs were significantly elevated. Conversely, intervention with the activation of PI3K and mTOR directly affected the aforementioned outcomes, In vivo experiments also confirmed the above findings. Conclusion This study confirms that Mg²⁺ synergistically promotes osteogenic differentiation, migration of BMSCs, and angiogenesis of vascular endothelial cells by activating the PI3K-AKT-mTOR pathway. By adopting the “activation-inhibition-reversal” experimental framework and conducting in vitro and in vivo validations, the critical upstream role of PI3K and the downstream effector function of mTOR were established. These findings reveal a unified mechanism by which Mg²⁺ coordinates bone regeneration via a single signaling pathway, providing a theoretical foundation for developing smart Mg-based bone repair materials targeting this pathway.

Background: Gastrointestinal (GI) mucosal injury is a frequent complication of long-term nonsteroidal anti-inflammatory drug (NSAID) use. Effective mucosal healing requires coordinated epithelial migration, proliferation, and angiogenesis, which may be influenced by focal adhesion kinase (FAK). This study aimed to determine whether our newly developed FAK activators promote intestinal mucosal healing by enhancing angiogenesis and whether FAK activation increases resistance to reinjury. Methods: Ischemic jejunal ulcers were induced in C57BL/6 mice. After 24 h, mice received intraperitoneal injections of the FAK activator ZINC40099027 (ZN27, 900 µg/kg every 6 h) or vehicle for 2, 4, or 14 days. Ulcer areas were quantified, and liver and kidney function were assessed. Ulcer and adjacent tissues were analyzed by immunofluorescence staining for angiogenesis and proliferation markers. In vitro, human umbilical vein endothelial cells (HUVECs) were treated with ZN27 to evaluate proliferation, migration, angiogenesis, and intracellular signaling. In a reinjury model, male C57BL/6J mice received continuous infusion of the FAK activator M64HCl (25 mg/kg/day) or vehicle for 7 days, with a single subcutaneous injection of indomethacin (10 mg/kg) on day 1 to induce GI injury. Fourteen days after the first dose of indomethacin, the mice received a second indomethacin challenge, and one day later, total ulcer areas in the pyloric opening and small intestine were quantified. Results: Ulcer areas were significantly smaller in ZN27-treated mice compared with vehicle-treated controls at 3 and 5 days, accompanied by increased expression of angiogenesis and proliferation markers. In vitro, ZN27 enhanced HUVEC migration via FAK activation in an ERK1/2-dependent manner and increased the number of angiogenic sprouts. In the reinjury model, treatment with M64HCl during the initial indomethacin-induced injury resulted in significantly smaller ulcer areas in both the pyloric opening and small intestine after the second indomethacin challenge compared with controls. Conclusions: FAK activation accelerates ischemic ulcer healing, in part by enhancing angiogenesis. Moreover, FAK activation during an initial injury reduces susceptibility to recurrent NSAID-induced intestinal injury, perhaps because it promotes initial higher-quality ulcer repair.

Background: Aging, especially after menopause, reduces the quantity and function of adult stem cells. Estrogen deficiency impairs proliferation, differentiation, and regenerative capacity. This study evaluated whether estrogen enhances endothelial differentiation of adipose-derived stromal cells (ADSCs) and improves therapeutic efficacy in critical limb ischemia (CLI). Methods: Male-derived ADSCs were assessed in vitro for endothelial differentiation using flow cytometry, biochemical assays, and angiogenesis analyses. Therapeutic effects were tested in a rat CLI model using endothelial-differentiated ADSCs (ED-ADSCs) with or without 17β-estradiol (E2). An ovariectomized (OVX) model examined estrogen deficiency and supplementation in vivo. Results: E2 promoted endothelial differentiation, increasing ERα/ERβ expression and activating PI3K/Akt/eNOS and MAPK signaling. This led to elevated VEGF expression, enhanced tube formation, and increased CD34+, KDR+, and CD31+ cell populations. In vivo, E2-pretreated ED-ADSCs significantly improved blood flow recovery. Estrogen deficiency reduced endothelial progenitor populations, which were restored by E2 supplementation. Conclusions: Estrogen modulates endothelial-associated characteristics and angiogenesis-related responses of ADSCs via ER-associated signaling, and may contribute to improved functional outcomes in ischemic conditions. E2 preconditioning may represent a potential strategy for stem cell-based therapy in estrogen-deficient settings.