Angiogenesis Capability Research Articles

Sema3A Alleviates the Malignant Behaviors of Gastric Cancer Cells by Inhibiting NRP-1.

Semaphorin3A (Sema3a) is lowly expressed in the peripheral blood of gastric cancer patients, suggesting Sema3a may be involved in the progression of gastric cancer. Nevertheless, the specific role and the potential regulatory mechanism of Sema3a in gastric cancer is still obscure. Neuropilin-1 (NRP-1) has been reported to interact with Sema3a; herein, we intended to reveal the role and regulatory mechanism of Sema3a/neuropilin-1 (NRP-1) in gastric cancer progression. Cell transfection was carried out to regulate gene expression. CCK-8 and colony formation assays were applied to estimate cell proliferation. Scratch assay and transwell assay were conducted to assess the cell migration and invasion abilities. Angiogenesis ability was assessed using a tubule-forming assay. The expression of corresponding genes and proteins were detected by RT-qPCR and western blot, respectively. Data showed that Sema3a was downregulated in gastric cancer cells and NRP-1 was upregulated. Sema3a overexpression repressed NRP-1 level in AGS cells. Overexpression of Sema3a inhibited cell proliferation, migration, and invasion abilities as well as epithelial-mesenchymal transition (EMT) of AGS cells. Overexpression of Sema3a inhibited tube formation and reduced the expression of VEGFA/VEGFR2 in AGS cells. However, the effects of Sema3a overexpression on the malignant behaviors in AGS cells were partly reversed by NRP-1 overexpression. Additionally, Sema3a overexpression enhanced the inhibitory effects of Ramucirumab, an anti-VEGFR2 agent, on the proliferative, migratory, and invasive capabilities as well as EMT in AGS cells. In conclusion, Sema3a alleviates the proliferation, migration, invasion, and angiogenesis capabilities of gastric cancer cells via repressing NRP-1. This finding may provide potential targets for gastric cancer therapy.

STC1 competitively binding βPIX enhances melanoma progression via YAP nuclear translocation and M2 macrophage recruitment through the YAP/CCL2/VEGFA/AKT feedback loop

This study investigates the role of Stanniocalcin-1 (STC1) in melanoma progression, with a focus on its impact on metastasis, angiogenesis, and immune evasion. Systematic bioinformatics analysis revealed the potential influence of STC1 dysregulation on prognosis, immune cell infiltration, response to immune therapy, and cellular functions. In vitro assays were conducted to assess the proliferation, invasion, migration, and angiogenesis capabilities of A375 cells. In vivo experiments utilizing C57BL/6 J mice established a lung metastasis model using B16-F10 cells to evaluate macrophage infiltration and M2 polarization. A Transwell co-culture system was employed to explore the crosstalk between melanoma and macrophages. Molecular interactions among STC1, YAP, βPIX, and CCL2 are investigated using mass spectrometry, Co-Immunoprecipitation, Dual-Luciferase Reporter Assay, and Chromatin Immunoprecipitation experiments. STC1 was found to enhance lung metastasis by promoting the recruitment and polarization of M2 macrophages, thereby fostering an immunosuppressive microenvironment. Mechanistically, STC1 competes with YAP for binding to βPIX within the KER domain in melanoma cells, leading to YAP activation and subsequent CCL2 upregulation. CCL2-induced M2 macrophages secrete VEGFA, which enhances tumor vascularization and increases STC1 expression via the AKT signaling pathway in melanoma cells, establishing a pro-metastatic feedback loop. Notably, STC1-induced YAP activation increases PD-L1 expression, promoting immune evasion. Silencing STC1 enhances the efficacy of PD-1 immune checkpoint therapy in mice. This research elucidates STC1's role in melanoma metastasis and its complex interactions with tumor-associated macrophages, proposing STC1 as a potential therapeutic target for countering melanoma metastasis and augmenting the efficacy of PD-1 immunotherapy.

On‐demand dissolvable hydrogel dressings for promoting wound healing

AbstractThe rapid and painless dressing change is a global challenge in wound management due to the traditional ways of dressing change often cause secondary damage on newly formed skin tissue. Recently, researchers have shown great interest in the development of on‐demand dissolvable hydrogel dressings that can be rapidly and safely dissolved under specific stimuli. These hydrogel dressings possess multifunctional properties, including injectability, self‐healing capacity, anti‐inflammation, antioxidation, and angiogenesis capabilities, which have successfully promoted healing for various types of wounds. In this review, we summarize current methods for fabricating on‐demand dissolvable hydrogels dressings, which include two strategies: (1) chemical stimuli, involving the introduction of external dissolving agents; (2) physical stimuli, where stimuli are applied without the use of dissolving agents. These approaches can decrease the density of cross‐links, resulting in the dissolution of hydrogel dressings. The advantages and drawbacks of these on‐demand dissolvable hydrogels dressings for promoting wound healing are discussed and addressed. The development and challenges for the clinical application of on‐demand dissolvable hydrogel dressings are prospected.

A Multifunctional, Tough, Stretchable, and Transparent Curcumin Hydrogel with Potent Antimicrobial, Antioxidative, Anti-inflammatory, and Angiogenesis Capabilities for Diabetic Wound Healing.

The treatment of diabetic chronic wounds is still faced with great challenges, mainly due to wound infection, excessive inflammation, and peripheral vascular disease in the wound area. Therefore, it is of great importance to develop a novel multifunctional hydrogel with high efficiency to accelerate diabetic wound healing. Curcumin (Cur), a Chinese herbal, has shown great potential in enhancing the healing of diabetic chronic wounds because of its immunomodulatory and pro-angiogenic properties. However, its low aqueous solubility, poor bioavailability, and chemical instability have limited its clinical applications. To address these current bottlenecks, novel poly(vinyl alcohol) (PVA)-chitosan (CS)/sodium alginate (SA)-Cur (PCSA) hydrogels were prepared for the first time, and they demonstrated all of the above intriguing performances by the Michael addition reaction of CS and Cur. PCSA hydrogels show multiple dynamic bonds, which possess strong mechanical properties (tensile stress: ∼0.980 MPa; toughness: ∼258.45 kJ/m3; and compressive strength: ∼7.38 MPa at strain of 80%). These intriguing performances provided an optimal microenvironment for cell migration and proliferation and also promoted the growth of blood vessels, leading to early angiogenesis. Importantly, the experimental results demonstrated that PCSA hydrogels can effectively transform pro-inflammatory M1 macrophages into anti-inflammatory M2 macrophages without the need for additional ingredients in vitro. Benefiting from these characteristics, a full-thickness diabetic wound in a rat model demonstrated that PCSA hydrogels can effectively accelerate wound healing via ROS-scavenging, downregulation of IL-1β, and upregulation of CD31 expression, resulting in angiogenesis and collagen deposition. This strategy not only provides a simple and safe Cur-based hydrogel for diabetic wound healing but also highlights the significant potential for the development of high-performance biomaterials for promoting diabetic wound healing using traditional Chinese medicine.

A multifunctional composite nanoparticle with antibacterial activities, anti-inflammatory, and angiogenesis for diabetic wound healing

The treatment of chronic diabetic wounds remains challenging due to the rapid bacterial infection, severe inflammation, and insufficient angiogenesis. To address these challenges, a novel multifunctional composite nanoparticle is developed by co-assembling antisolvent-induced co-assembling silk-fibroin ε-poly-l-Lysine nanoparticles (nSF-EPL) and further assembling nSF-EPL with polydeoxyribonucleotide (PDRN) and exosome derived from human umbilical mesenchymal stem cells (Exo). Owing to the modification of EPL, PDRN and Exo, composite nanoparticles exhibited synergistic antibacterial action, anti-inflammatory and angiogenesis, which can significantly benefit for promoting wound healing. Release results show that the composite nanoparticles exhibit long-term sustained PDRN and Exo release profiles as well as outstanding release efficiency. Furthermore, in vitro studies show that the composite nanoparticles exhibit effective antibacterial activity, thus inducing an anti-inflammatory M2 macrophages phenotype and promoting angiogenesis. In vivo research results of investigations pertaining to diabetic wound healing show that the composite nanoparticles have good anti-inflammatory and angiogenesis capabilities, which can promote granulation tissue formation, collagen deposition, wound tissue epithelialization, and significantly accelerate skin healing. This study presents a promising strategy for the clinical treatment of chronic diabetic wounds.

Injectable Microparticle-containing hydrogel with controlled release of bioactive molecules for facial rejuvenation

The skin is the largest organ and a crucial barrier for protection against various intrinsic and extrinsic factors. As we age, the skin's components become more vulnerable to damage, forming wrinkles. Among different procedures, hyaluronic acid-based hydrogel has been extensively utilized for skin regeneration and reducing wrinkles. However, it has limitations like low retention and weak mechanical properties. In this study, we suggested the poly(l-lactic acid) (PLLA) microparticles containing alkaline magnesium hydroxide and nitric oxide-generating zinc oxide and rejuvenative hyaluronic acid (HA) hydrogels including these functional microparticles and asiaticoside, creating a novel delivery system for skin rejuvenation and regeneration. The fabricated rejuvenative hydrogels have exhibited enhanced biocompatibility, pH neutralization, reactive oxygen species scavenging, collagen biosynthesis, and angiogenesis capabilities in vitro and in vivo. Additionally, an excellent volume retention ability was demonstrated due to the numerous hydrogen bonds that formed between hyaluronic acid and asiaticoside. Overall, our advanced injectable hydrogel containing functional microparticles, with controlled release of bioactive molecules, has a significant potential for enhancing the regeneration and rejuvenation of the skin.

3D printed Si-CaP scaffold released SiO32- and Ca2+ to synergistically promote angiogenesis.

Structuring scaffold with both osteogenic and angiogenesis capabilities is a challenge for bone tissue engineering. Powder structured Si-CaP materials have shown excellent osteogenic properties and induction of stem cell differentiation. Our research group have successful produced 3D printed Si-CaP scaffolds by DLP technology. This study aims to explore the angiogenic effects of SiO32- and Ca2+ released by 3D printed Si-CaP scaffold, and whether there is a synergistic effect between the two ions. The 3D printed Si-CaP scaffolds were immersed in endothelial cell medium solution for 24h. The Si, Ca ion released was detected by Inductively coupled plasma-optical emission spectrometry. We used detected data as a standard to prepare the simulated solution to investigate the effect of SiO32-, Ca2+ separately. Experiment was divided into control group, Si ion group, Ca ion group and Si + Ca ion group. We evaluated different ionic effect on HUVECs viability, proliferation, migration, gene expression, and tube formation on different groups. The concentration of SiO32- was detected as 15.71 ± 0.04μg/mL, Ca2+ as 67.14 ± 0.95μg/mL. Na2SiO3 and CaCl2 were used to prepare the simulated solution. There were no statistically difference between simulated solution from ion released by scaffold. Si + Ca group promoted the gene expression significantly compared with the control group, p < .01. Expression of vascular-associated protein in Si + Ca ion group was higher than that in Si ion group, Ca ion group and control group. Si + Ca ion group significantly enhanced endothelial cell on migration and tube formation assay. The 3D printed Si-CaP scaffold can release effective physiological concentrations of Si, Ca ions. Si and Ca ions have a synergistic effect on promoting angiogenesis of HUVECs. 3D printed Si-CaP scaffold is promising in vascularized bone tissue engineering application.

Mild hyperthermia-assisted chitosan hydrogel with photothermal antibacterial property and CAT-like activity for infected wound healing

Infected wounds pose a serious threat to public health and pose a significant challenge and financial burden worldwide. The treatment of infected wounds is now an urgent problem to be solved. Herein, mild hyperthermia-assisted hydrogels composed of carboxymethyl chitosan (CMCs), oxidized dextran (Odex), epigallocatechin gallate (EGCG) and PtNPs@PVP (CAT-like nanoenzymes) were proposed for the repair of infected wounds. The incorporation of PtNPs@PVP nanoenzymes give the hydrogels excellent photothermal property and CAT-like activity. When the temperature is maintained at 42–45 °C under 808 nm near infrared (NIR) exposure, the CMCs/Odex/EGCG/Nanoenzymes (COEN2) hydrogel demonstrated highly enhanced antibacterial ability (95.9 % in vivo), hydrogen peroxide (H2O2) scavenging ratio (85.1 % in vitro) and oxygen supply (20.7 mg/L in vitro). Furthermore, this mild-heat stimulation also promoted angiogenesis in the damaged skin area. Overall, this multifunctional hydrogel with antibacterial, antioxidant, oxygen supply, hemostasis, and angiogenesis capabilities has shown great promise in the repair of infected wounds. This study establishes the paradigm of enhanced infected wound healing by mild hyperthermia-assisted H2O2 scavenging, oxygen supplemental, and photothermal antibacterial hydrogels.

Estrogen receptor-related receptor γ uppresses hypoxia-induced angiogenesis by regulating VEGFA in endometrial cancer

Objective Estrogen receptor-related receptor γ (ERRγ), is implicated in cancer cell proliferation and metastasis. The function of ERRγ in tumor angiogenesis, however, is to be revealed. This study was designed to elaborate the regulatory effect of ERRγ on angiogenesis in endometrial cancer (EC). Methods Immunohistochemistry (IHC) was adopted to determine the protein expression of ERRγ, VEGFA, CD31 and hypoxia-inducible factor-1 (HIF-1) in tumor tissues. HEC-1A cells stably expressing ERRγ were established bytransfection, and then an endothelial cell tube formation assay was performed. CCK-8 assay was employed for cell viability, and wound healing assay for cell migration ability. Besides, western blot, ELISA and qRT-PCR were used to examine the VEGFA expression. After hypoxia treatment of ERRγ overexpressing HEC-1A cells, the ERRγ expression and VEGFA expression were determined by western blot. Finally, EC xenografts in nude mice were constructed by subcutaneous injection of ERRγ stably expressing HEC-1A cells and control HEC-1A cells. Results IHC results revealed a negative correlation between the expression of ERRγ and VEGFA in EC tissues. ERRγ overexpression significantly decreased the level of HIF-1 in tumor tissue of nude mice. ERRγ overexpression down-regulated inhibited angiogenesis capability and inhibited the proliferation and migration of HEC-1A cells. Furthermore, ERRγ expression was suppressed under the condition of hypoxia while restoration of ERRγ partially inhibited hypoxia-induced VEGFA expression in HEC-1A cells. Conclusions ERRγ is an angiogenesis suppressor and involved in hypoxia-induced VEGFA expression in EC. Hence, ERRγ might be a promising antiangiogenic target for human EC.

Hypoxia-induced TMTC3 expression in esophageal squamous cell carcinoma potentiates tumor angiogenesis through Rho GTPase/STAT3/VEGFA pathway

BackgroundHypoxia is one of most typical features in the tumor microenvironment of solid tumor and an inducer of endoplasmic reticulum (ER) stress, and HIF-1α functions as a key transcription factor regulator to promote tumor angiogenesis in the adaptive response to hypoxia. Increasing evidence has suggested that hypoxia plays an important regulatory role of ER homeostasis. We previously identified TMTC3 as an ER stress mediator under nutrient-deficiency condition in esophageal squamous cell carcinoma (ESCC), but the molecular mechanism in hypoxia is still unclear.MethodsRNA sequencing data of TMTC3 knockdown cells and TCGA database were analyzed to determine the association of TMTC3 and hypoxia. Moreover, ChIP assay and dual-luciferase reporter assay were performed to detect the interaction of HIF-1α and TMTC3 promoter. In vitro and in vivo assays were used to investigate the function of TMTC3 in tumor angiogenesis. The molecular mechanism was determined using co-immunoprecipitation assays, immunofluorescence assays and western blot. The TMTC3 inhibitor was identified by high-throughput screening of FDA-approved drugs. The combination of TMTC3 inhibitor and cisplatin was conducted to confirm the efficiency in vitro and in vivo.ResultsThe expression of TMTC3 was remarkably increased under hypoxia and regulated by HIF-1α. Knockdown of TMTC3 inhibited the capability of tumor angiogenesis and ROS production in ESCC. Mechanistically, TMTC3 promoted the production of GTP through interacting with IMPDH2 Bateman domain. The activity of Rho GTPase/STAT3, regulated by cellular GTP levels, decreased in TMTC3 knockdown cells, whereas reversed by IMPDH2 overexpression. Additionally, TMTC3 regulated the expression of VEGFA through Rho GTPase/STAT3 pathway. Allopurinol inhibited the expression of TMTC3 and further reduced the phosphorylation and activation of STAT3 signaling pathway in a dose-dependent manner in ESCC. Additionally, the combination of allopurinol and cisplatin significantly inhibited the cell viability in vitro and tumor growth in vivo, comparing with single drug treatment, respectively.ConclusionsCollectively, our study clarified the molecular mechanism of TMTC3 in regulating tumor angiogenesis and highlighted the potential therapeutic combination of TMTC3 inhibitor and cisplatin, which proposed a promising strategy for the treatment of ESCC.

Copper deprivation enhances the chemosensitivity of pancreatic cancer to rapamycin by mTORC1/2 inhibition

Cuproplasia, or copper-dependent cell proliferation, has been observed in varieties of solid tumors along with aberrant copper homeostasis. Several studies reported good response of patients to copper chelator assisted neoadjuvant chemotherapy, however, the internal target molecules are still undetermined. Unravel copper-associated tumor signaling would be valuable to forge new links to translate biology of copper into clinical cancer therapies. We evaluated the significance of high-affinity copper transporter-1 (CTR1) by bioinformatic analysis, and in 19 pairs of clinical specimens. Then, with the help of gene interference and chelating agent, enriched signaling pathways were identified by KEGG analysis and immunoblotting. Accompanying biological capability of pancreatic carcinoma-associated proliferation, cell cycle, apoptosis, and angiogenesis were investigated. Furthermore, a combination of mTOR inhibitor and CTR1 suppressor has been assessed in xenografted tumor mouse models. Hyperactive CTR1 was investigated in pancreatic cancer tissues and proven to as the key point of cancer copper homeostasis. Intracellular copper deprivation induced by CTR1 gene knock-down or systematic copper chelation by tetrathiomolybdate suppressed proliferation and angiogenesis of pancreatic cancer cell. PI3K/AKT/mTOR signaling pathway was suppressed by inhibiting the activation of p70(S6)K and p-AKT, and finally inhibited mTORC1 and mTORC2 after copper deprivation. Additionally, CTR1 gene silencing successfully improved the anti-cancer effect of mTOR inhibitor rapamycin. Our study reveals that CTR1 contributes to pancreatic tumorigenesis and progression, by up-regulating the phosphorylation of AKT/mTOR signaling molecules. Recovering copper balance by copper deprivation addresses as promising strategy for improved cancer chemotherapy.

Resveratrol-induced SIRT1 activation inhibits glycolysis-fueled angiogenesis under rheumatoid arthritis conditions independent of HIF-1α.

This study investigated the impacts of SIRT1 activation on rheumatoid arthritis (RA)-related angiogenesis. HUVECs were cultured by different human serum. Intracellular metabolites were quantified by UPLC-MS. Next, HUVECs and rat vascular epithelial cells under different inflammatory conditions were treated by a SIRT1 agonist resveratrol (RSV). Cytokines and biochemical indicators were detected by corresponding kits. Protein and mRNA expression levels were assessed by immunoblotting and PCR methods, respectively. Angiogenesis capabilities were evaluated by migration, wound-healing and tube-formation experiments. To down-regulate certain signals, gene-specific siRNA were applied. Metabolomics study revealed the accelerated glycolysis in RA serum-treated HUVECs. It led to ATP accumulation, but did not affect GTP levels. RSV inhibited pro-angiogenesis cytokines production and glycolysis in both the cells, and impaired the angiogenesis potentials. These effects were mimicked by an energy metabolism interrupter bikini in lipopolysaccharide (LPS)-primed HUVECs, largely independent of HIF-1α. Both RSV and bikinin can inhibit the activation of the GTP-dependent pathway Rho/ROCK and reduce VEGF production. Abrogation of RhoA signaling reinforced HIF-1α silencing-brought changes in LPS-stimulated HUVECs, and overshadowed the anti-angiogenesis potentials of RSV. Glycolysis provides additional energy to sustain Rho/ROCK activation in RA subjects, which promotes VEGF-driven angiogenesis and can be inhibited by SIRT1 activation.

In-vivo oogenesis of oogonial and mesenchymal stem cells seeded in transplanted ovarian extracellular matrix

Objective (s)One way to overcome the recurrence of cancer cells following ovarian tissue transplantation is to use decellularized tissues as a scaffold that does not have any cellular components. These cell-free scaffolds can be seeded with different type of stem cells for ovarian restoration.Materials and methodsOSCs, PMSCs and BMSCs (oogonial, peritoneal and bone marrow mesenchymal stem cells, respectively) were seeded into human decellularized ovarian tissue as 4 groups: Scaffold + OSCs (SO), Scaffold + OSC + PMSCs (SOP), Scaffold + OSC + BMSCs (SOB) and Scaffold + OSC + PMSCs + BMSCs (SOPB). The produced grafts were transplanted into the sub-peritoneal space of ovariectomized NMRI mice as artificial ovary (AO). The expression of Vegf, CD34, Gdf9, Zp3, Ddx4, Amh and Lhr genes in AOs were measured by qRT-PCR. Also, histotechniques were considered to detect the anti GFP, PCNA, VEGF, GDF9, ZP3 and AMH proteins.ResultsH & E staining showed follicle-like structures in all groups; the number of these structures, in the SOP and SOB groups, were the highest. In SO group, differentiation ability to oocyte and granulosa cells was observed. Endothelial, oocyte, germ, and granulosa cell-like cells were specially seen in SOP and angiogenesis capability was more in SOB group. However, angiogenesis ability and differentiation to theca cell-like cells were more often in SOPB group. While none of the groups showed a significant difference in AMH level, estradiol levels were significantly higher in SOPB group.ConclusionIntegration of OSCs + PMSCs and those OSCs + BMSCs were more conducive to oogenesis.

Aquaculture derived hybrid skin patches for wound healing

• The proposed patches are based on the derivatives of fish and crabs. • The acellular fish skin present porous surface for drug loading. • The patch owns brilliant biocompatibility, antibacterial and angiogenesis capability. • The proposed patches show effect on accelerating wound healing Natural biomaterials have been widely applied in wound treatment. Hotspots in this area are focused on reducing their immunogenicity and improving their therapeutic effect. In this work, we present a novel aquaculture derived hybrid skin patch based on acellular fish skin (AFS) and chitosan (CS) for wound healing. Such functional patch was simply constructed by infiltrating the vascular endothelial growth factor (VEGF)-loaded CS pregel into the porous scaffold of the AFS. As the natural molecules and structure of fish skin are well-retained during the synthesis processes, the final patch presented brilliant tensile property, water-absorption property, good biocompatibility and low immunogenicity. In addition, the integrated CS and VEGF endow the patch with antibacterial and angiogenesis capability respectively for promoting tissue growth and wound healing. Thus, in a full-thickness wound rat model, the hybrid patch has been demonstrated with dramatic therapeutic efficacy in inhibiting inflammatory, accelerating angiogenesis, collagen deposition, and tissue generation during the wound repair procedure. These features imply the practical value of this multifunctional aquaculture derived hybrid skin patch in clinical wound management. A novel aquaculture derived hybrid skin patch based on acellular fish skin (AFS) and chitosan (CS) for wound healing was presented. Such functional patch was simply constructed by infiltrating the vascular endothelial growth factor (VEGF)-loaded CS pregel into the porous scaffold of the AFS. The resultant patch owns brilliant tensile property, water-absorption property, good biocompatibility, antibacterial and angiogenesis capability. It is demonstrated that patches show effect on accelerating wound healing.

Soluble epoxide hydrolase inhibitor promotes the healing of oral ulcers

ObjectiveOral ulcers are a lesion in the oral mucosa that impacts chewing or drinking. Epoxyeicosatrienoic Acids (EETs) have enhanced angiogenic, regenerative, anti-inflammatory, and analgesic effects. The present study aims to evaluate the effects of 1-Trifluoromethoxyphenyl-3-(1-Propionylpiperidin-4-yl) Urea (TPPU), a soluble epoxide hydrolase inhibitor for increasing EETs level, on the healing of oral ulcers. MethodsThe chemically-induced oral ulcers were established in Sprague Dawley rats. The ulcer area was treated with TPPU to evaluate the healing time and pain threshold of ulcers. The expression of angiogenesis and cell proliferation-related protein in the ulcer area was detected using immunohistochemical staining. The effects of TPPU on migration and angiogenesis capability were measured with scratch assay and tube formation. ResultsCompared with the control group, TPPU promoted wound healing of oral ulcers with a shorter healing time, and raised pain thresholds. Immunohistochemical staining showed that TPPU increased the expression of angiogenesis and cell proliferation-related protein with reduced inflammatory cell infiltration in the ulcer area. TPPU enhanced cell migration and tube-forming potential in vitro. ConclusionsThe present results support the potential of TPPU with multiple biological effects for the treatment of oral ulcers by targeting soluble epoxide hydrolase.

Silver doped-silica nanoparticles reinforced poly (ethylene glycol) diacrylate/hyaluronic acid hydrogel dressings for synergistically accelerating bacterial-infected wound healing

Various cutaneous wounds are easily infected with external bacteria, which might result in a chronic wound and ongoing consequences. However, the appropriate development of biomaterials for the controllable delivery of antibacterial silver (Ag) and the simultaneous enhancement of mechanical adhesiveness remains an urgent challenge. Herein, we proposed a double network (DN) hydrogel dressings based on a covalent network of polyethylene glycol diacrylate (PEGDA) and a coordination network between catechol-modified hyaluronic acid (C-HA) and Ag-doped mesoporous silica nanoparticle (AMSN) for promoting the bacterial-infected full-thickness skin wound regeneration. This distinctive dual cross-linked structure of PEGDA/C-HA-AMSN significantly improved physicochemical properties, including gelation time, mechanical performance, and tissue adhesion strength. Importantly, PEGDA/C-HA-AMSN served as a hydrogel dressing that can respond to the acidic environment of bacterial-infected wounds leading to the controllable and optimized delivery of Ag, enabling the durable antibacterial activity accompanied by favorable cytocompatibility and angiogenesis capability. Further in vivo studies validated the higher efficacy of hydrogel dressings in treating wound healing by the synergistic antibacterial, anti-inflammatory, and pro-vascular strategies, meaning the prominent potential of the prepared dressings for overcoming the concerns of wound theranostics.

Atractylenolide I inhibited the development of malignant colorectal cancer cells and enhanced oxaliplatin sensitivity through the PDK1-FoxO1 axis.

Colorectal cancer (CRC) is a type of ordinary malignancy of the gastrointestinal tract. Atractylenolide I (AT-I) has been shown to inhibit the process of CRC. However, the specific mechanism by which AT-I inhibits CRC is not yet well understood. Cell Counting Kit-8 and colony formation assays were conducted to examine cell proliferation. The cell apoptosis was detected by terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL). Cell invasion and migration were evaluated by wound-healing and Transwell assay. The angiogenesis capabilities of the cells were examined by tube formation experiments. Western blot was conducted to examine the apoptosis and angiogenesis-associated proteins, pyruvate dehydrogenase kinase 1 (PDK1), and Forkhead box protein O1 (FoxO1) expression. We found that AT-I inhibited the proliferative, migratory and invasive abilities of Human colorectal cancer cell line HCT116 cells but stimulated cell death by promoting cell apoptosis via the PDK1/FoxO1 axis. In addition, the upregulation of PDK1 decreased the inhibitory effect of AT-I on HCT116 angiogenesis, and AT-I increased oxaliplatin sensitivity via the PDK1/FoxO1 axis. Collectively, AT-I inhibited the malignant development of CRC cells and increased oxaliplatin sensitivity by decreasing PDK1 and inhibiting FoxO1 phosphorylation. Thus, AT-I has protective potential and could be a promising agent for CRC treatment.

Scalable Formation of Highly Viable and Functional Hepatocellular Carcinoma Spheroids in an Oxygen-Permeable Microwell Device for Anti-Tumor Drug Evaluation.

For high-throughput anti-cancer drug screening, microwell arrays may serve as an effective tool to generate uniform and scalable tumor spheroids. However, microwell arrays are commonly anchored in non-oxygen-permeable culture plates, leading to limited oxygen supply for avascular spheroids. Herein, a polydimethylsiloxane (PDMS)-based oxygen-permeable microwell device is introduced for generating highly viable and functional hepatocellular carcinoma (HCC) spheroids. The PDMS sheets at the bottom of the microwell device provide a high flux of oxygen like in vivo neighboring hepatic sinusoids. Owing to the better oxygen supply, the generated HepG2 spheroids are larger in size and exhibit higher viability and proliferation with less cell apoptosis and necrosis. These spheroids also exhibit lower levels of anaerobic cellular respiration and express higher levels of liver-related functions. In anti-cancer drug testing, spheroids cultured in PDMS plates show a significantly stronger resistance against doxorubicin because of the stronger stem-cell and multidrug resistance phenotype. Moreover, higher expression of vascular endothelial growth factor-A produces a stronger angiogenesis capability of the spheroids. Overall, compared to the spheroids cultured in conventional non-oxygen-permeable plates, these spheroids can be used as a more favorable model for early-stage HCCs and be applied in high-throughput anti-cancer drug screening.

Multifunctional fish gelatin hydrogel inverse opal films for wound healing

BackgroundWound healing has become a worldwide healthcare issue. Attempts in the area focus on developing patches with the capabilities of avoiding wound infection, promoting tissue remolding, and reporting treatment status that are of great value for wound treatment.ResultsIn this paper, we present a novel inverse opal film (IOF) patch based on a photo-crosslinking fish gelatin hydrogel with the desired features for wound healing and dynamic monitoring. The film with vibrant structure colors was constructed by using the mixture of fish gelatin methacryloyl, chitosan, and polyacrylic acid (PAA) to replicate colloidal crystal templates. As the structures of these natural biomolecules are well-retained during the fabrication, the resultant IOF was with brilliant biocompatibility, low immunogenicity, antibacterial property, as well as with the functions of promoting tissue growth and wound healing. In addition, the IOF presented interconnected nanopores and high specific surface areas for vascular endothelial growth factor loading, which could further improve its angiogenesis capability. More attractively, as the pH-responsive PAA was incorporated, the IOF patch could report the wound healing status through its real-time structural colors or reflectance spectra.ConclusionsThese features implied the practical value of the multifunctional fish gelatin hydrogel IOFs in clinical wound management.Graphical

Novel Therapeutic Strategy for Bacteria‐Contaminated Bone Defects: Reconstruction with Multi‐Biofunctional GO/Cu‐Incorporated 3D Scaffolds

AbstractLarge‐scale bone defects caused by traumatic injury or tumor resection, are accompanied by relatively high bacterial infection rates. Relevant clinical therapy encounters challenges of infection recurrence, poor vascularization, and bone destruction. Engineered substitutes endowed with multiple functions of bacterial eradication, osteoconductivity, and angiogenesis are urgently needed to address these challenges. Herein, graphene oxide/copper (GO/Cu) nanocomposite‐decorated polylactide‐co‐glycolide (PLGA)/β‐tricalcium phosphate (TCP) (P/T/GO/Cu) scaffolds are fabricated using 3D printing technology. A comprehensive evaluation of material characteristics and biological activities of these scaffolds is conducted and compared. This novel bone substitute has unique surface characteristics, and the incorporation of GO/Cu nanocomposites into the scaffolds exhibits improved antimicrobial and osteogenic potential and displays acceptable cytocompatibility. A subcutaneous implantation model in rats confirms the effective inhibition of abscess formation and inflammatory reactions, satisfactory neovascularization and tissue integration, and good biosafety of the implanted P/T/GO/Cu scaffolds. Eventually, a bacteria‐contaminated bone defect model is established in rabbits and significantly better new cancellous bone formation featuring collagen or osteoid deposition is clearly found in the defect regions implanted with P/T/GO/Cu scaffolds. Thus, this novel bone substitute with excellent bacterial inhibition, osteogenesis, and angiogenesis capabilities represents a promising strategy to satisfy the multiple demands for the repair of bacteria‐contaminated bone defects.