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BACKGROUND AND AIMS: Vascular calcification (VC) is a strong predictor of cardiovascular events and all-cause mortality in cardiovascular diseases (CVD). Renal dysfunction is closely related to VC. Serum creatinine, as an important indicator of renal function in chronic kidney disease (CKD), is closely associated with increased VC. Here, to explore the potential role of serum creatinine in CVD, we examined the association between serum creatinine level and aortic arch calcification (AAC) presence in a larger general population. METHODS: A total of 9067 participants aged > 45 years were included in this study. All participants underwent postero-anterior chest X-ray examination to diagnose AAC. According to the distribution characteristics, serum creatinine levels in male and female were divided into tertiles respectively. Univariate and multivariate logistic regression analysis were used to analyze the association between aortic calcification and serum creatinine. RESULTS: Participants included 3776 men and 5291 women, and 611 and 990 AAC were detected, respectively. Serum creatinine level in the female AAC group was significantly higher than that in the non-AAC group (p < 0.001), while there was no significant difference in male serum creatinine between the two groups (p = 0.241). After logistic regression analysis excluded confounding factors, with the first tertile of serum creatinine as the reference, multivariable-adjusted ORs and 95% CIs of the second and the highest tertile of female and male were 1.045 (0.856-1.276), 1.263 (1.036-1.539); 0.953 (0.761-1.193), 0.948 (0.741-1.198), respectively. CONCLUSION: Elevated serum creatinine levels are independently associated with higher AAC incidence in female aged > 45 years old. Measuring serum creatinine levels may assist the early screening individuals at high risk of developing CVD. And higher attention should be given to female's serum creatinine levels in daily clinical practice.
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Enfermedades de la Aorta , Enfermedades Cardiovasculares , Calcificación Vascular , Adulto , Anciano , Aorta Abdominal , Aorta Torácica/diagnóstico por imagen , Enfermedades de la Aorta/complicaciones , Enfermedades de la Aorta/diagnóstico por imagen , Enfermedades de la Aorta/epidemiología , Enfermedades Cardiovasculares/complicaciones , China/epidemiología , Creatinina , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/epidemiologíaRESUMEN
The detection of autoantibodies is critical for diagnosis of autoimmune diseases. However, the sensitivity is often limited by the properties of the antigens and the detection systems such as enzyme-linked immunosorbent assay (ELISA). Here, employing the multidisplay ability of ferritin, a highly sensitive nanocage-based capture-detection system is designed, of which the sensitivity is 100-1000-fold higher than that of conventional ELISA methods. The capture nanocages are constructed by displaying the primary Sjögren's syndrome (pSS)-related antigenic peptides on ferritin nanocage, which present epitopes effectively and high affinity, leading to tenfold higher capture capability for autoantibodies. Human IgG Fc-binding peptides are also engineered on ferritin nanocage, which enable high binding affinity and efficient horseradish peroxidase (HRP)-labeling. Compared with commercial HRP-conjugated anti-human IgG antibody, the nanocage-based detecting probe exhibited more than tenfold increased sensitivity. Autoantibodies are then examined in 91 sera from patients with pSS, 51 from rheumatoid arthritis, 54 from systemic lupus erythematosus, and 55 from healthy individuals by using the nanocage-based ELISA. The results indicate that the nanocage-based capture-detection system is an effective detection platform and provide a novel and more sensitive method for the diagnosis of autoimmune diseases.
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Artritis Reumatoide , Enfermedades Autoinmunes , Lupus Eritematoso Sistémico , Síndrome de Sjögren , Autoanticuerpos , Enfermedades Autoinmunes/diagnóstico , Ensayo de Inmunoadsorción Enzimática , Humanos , Lupus Eritematoso Sistémico/diagnósticoRESUMEN
BACKGROUND AND AIMS: The increased serum uric acid (SUA) level is associated with the prevalence of cardiovascular disease (CVD) risks. Aortic arch calcification (AAC) reflects subclinical coronary atherosclerosis and is linked to subsequent cardiovascular morbidity and mortality risks closely. To better understand the role of SUA on arteriosclerosis and CVD, we aim to determine the association between SUA and the presence of AAC. METHODS AND RESULTS: A total of 5920 individuals aged >45 years old without prior CVD disease were included. The prevalence rate of AAC was 14.4% in all participants and a significantly increasing trend for AAC prevalence rate was found across the SUA tertiles (p < 0.001 for trend). Subsequent subgroup analyses revealed that this positive association trend was only significant in female subjects. After adjusting for confounders, SUA is an independent predictor for the presence of AAC in overall participants and in women. CONCLUSION: SUA is independently associated with AAC in middle-aged and elderly population, especially in the women. More research needs to determine whether lower thresholds for CVD risk screening for those middle-aged and elderly women with higher SUA tertile even without hyperuricemia are warranted.
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Aorta Torácica , Enfermedades de la Aorta/epidemiología , Hiperuricemia/epidemiología , Ácido Úrico/sangre , Calcificación Vascular/epidemiología , Factores de Edad , Anciano , Aorta Torácica/diagnóstico por imagen , Enfermedades de la Aorta/diagnóstico por imagen , Biomarcadores/sangre , China/epidemiología , Estudios Transversales , Femenino , Humanos , Hiperuricemia/sangre , Hiperuricemia/diagnóstico , Persona de Mediana Edad , Prevalencia , Medición de Riesgo , Factores de Riesgo , Factores Sexuales , Regulación hacia Arriba , Calcificación Vascular/diagnóstico por imagenRESUMEN
Adipogenesis is essential for soft tissue reconstruction following trauma or tumor resection. We demonstrate that CD31(-)/34(+)/146(-) cells, a subpopulation of the stromal vascular fraction (SVF) of human adipose tissue, were robustly adipogenic. Insulin growth factor-1 (IGF1) promoted a lineage bias towards CD31(-)/34(+)/146(-) cells at the expense of CD31(-)/34(+)/146(+) cells. IGF1 was microencapsulated in poly(lactic-co-glycolic acid) scaffolds and implanted in the inguinal fat pad of C57Bl6 mice. Control-released IGF1 induced remarkable adipogenesis in vivo by recruiting endogenous cells. In comparison with the CD31(-)/34(+)/146(+) cells, CD31(-)/34(+)/146(-) cells had a weaker Wnt/ß-catenin signal. IGF1 attenuated Wnt/ß-catenin signaling by activating Axin2/PPARγ pathways in SVF cells, suggesting IGF1 promotes CD31(-)/34(+)/146(-) bias through tuning Wnt signal. PPARγ response element (PPRE) in Axin2 promoter was crucial for Axin2 upregulation, suggesting that PPARγ transcriptionally activates Axin2. Together, these findings illustrate an Axin2/PPARγ axis in adipogenesis that is particularly attributable to a lineage bias towards CD31(-)/34(+)/146(-) cells, with implications in adipose regeneration.
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Adipocitos/metabolismo , Adipogénesis , Antígenos de Diferenciación/metabolismo , Diferenciación Celular , Factor I del Crecimiento Similar a la Insulina/metabolismo , Células Madre/metabolismo , Adulto , Animales , Femenino , Humanos , Ratones , Persona de Mediana EdadRESUMEN
Neovascularization is a critical determinant of wound-healing outcomes for deep burn injuries. We hypothesize that dextran-based hydrogels can serve as instructive scaffolds to promote neovascularization and skin regeneration in third-degree burn wounds. Dextran hydrogels are soft and pliable, offering opportunities to improve the management of burn wound treatment. We first developed a procedure to treat burn wounds on mice with dextran hydrogels. In this procedure, we followed clinical practice of wound excision to remove full-thickness burned skin, and then covered the wound with the dextran hydrogel and a dressing layer. Our procedure allows the hydrogel to remain intact and securely in place during the entire healing period, thus offering opportunities to simplify the management of burn wound treatment. A 3-week comparative study indicated that dextran hydrogel promoted dermal regeneration with complete skin appendages. The hydrogel scaffold facilitated early inflammatory cell infiltration that led to its rapid degradation, promoting the infiltration of angiogenic cells into the healing wounds. Endothelial cells homed into the hydrogel scaffolds to enable neovascularization by day 7, resulting in an increased blood flow significantly greater than treated and untreated controls. By day 21, burn wounds treated with hydrogel developed a mature epithelial structure with hair follicles and sebaceous glands. After 5 weeks of treatment, the hydrogel scaffolds promoted new hair growth and epidermal morphology and thickness similar to normal mouse skin. Collectively, our evidence shows that customized dextran-based hydrogel alone, with no additional growth factors, cytokines, or cells, promoted remarkable neovascularization and skin regeneration and may lead to novel treatments for dermal wounds.
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Quemaduras/terapia , Dextranos/uso terapéutico , Hidrogel de Polietilenoglicol-Dimetacrilato/uso terapéutico , Neovascularización Fisiológica/fisiología , Fenómenos Fisiológicos de la Piel , Andamios del Tejido , Cicatrización de Heridas/fisiología , Análisis de Varianza , Animales , Ratones , Microscopía Electrónica de RastreoRESUMEN
In recent years, there has been a significant increase in the prevalence of chronic wounds, such as pressure ulcers, diabetic foot ulcers, and venous ulcers of the lower extremities. The main contributors to chronic wound formation are bacterial infection, prolonged inflammation, and peripheral vascular disease. However, effectively treating these chronic wounds remains a global challenge. Hydrogels have extensively explored as wound healing dressing because of their excellent biocompatibility and structural similarity to extracellular matrix (ECM). Nonetheless, much is still unknown how the hydrogels promote wound repair and regeneration. Signaling pathways play critical roles in wound healing process by controlling and coordinating cells and biomolecules. Hydrogels, along with their therapeutic ingredients that impact signaling pathways, have the potential to significantly enhance the wound healing process and its ultimate outcomes. Understanding this interaction will undoubtedly provide new insights into developing advanced hydrogels for wound repair and regeneration. This paper reviews the latest studies on classical signaling pathways and potential targets influenced by hydrogel scaffolds in chronic wound healing. This work hopes that it will offer a different perspective in developing more efficient hydrogels for treating chronic wounds.
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Pie Diabético , Hidrogeles , Humanos , Hidrogeles/farmacología , Hidrogeles/uso terapéutico , Hidrogeles/química , Cicatrización de Heridas , Vendajes , Pie Diabético/tratamiento farmacológico , Transducción de SeñalRESUMEN
Diabetic complications can be ameliorated by inhibiting excessive oxidative stress with antioxidants. To enhance therapeutic intervention, it is crucial to develop intelligent scaffolds for efficient delivery of antioxidants to diabetic wounds. This study introduces reversible boronic bonds to create an intelligent antioxidant hydrogel scaffold. This study modifies gelatin methacryloyl (GelMA) with 4-carboxyphenyboronic acid (CPBA) to synthesize a derivative of GelMA (GelMA-CPBA), and then photo cross-links GelMA-CPBA with (-)-epigallocatechin-3-gallate (EGCG) to form GelMA-CPBA/EGCG (GMPE) hydrogel. The GMPE hydrogel responds to changes in glucose levels, and more EGCG is released as glucose level increases due to the dissociation of boronic ester bonds. The GMPE hydrogel shows good biocompatibility and biodegradability, and its mechanical property is similar to that of the skin tissue. Both in vitro and in vivo results demonstrate that the GMPE hydrogel scaffolds effectively eliminate reactive oxygen species (ROS), reduce the inflammation, and promote angiogenesis, thereby improve collagen deposition and tissue remodeling during diabetic wound healing. This strategy offers new insight into glucose-responsive scaffolds, and this responsive antioxidan hydrogel scaffold holds great potential for the treatment of chronic diabetic wounds.
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Diabetes Mellitus , Hidrogeles , Humanos , Hidrogeles/farmacología , Hidrogeles/química , Antioxidantes/farmacología , Glucosa , Cicatrización de Heridas , Gelatina/farmacología , Gelatina/química , Diabetes Mellitus/tratamiento farmacológicoRESUMEN
Wound healing is an evolved dynamic biological process. Though many research and clinical approaches have been explored to restore damaged or diseased skin, the current treatment for deep cutaneous injuries is far from being perfect, and the ideal regenerative therapy remains a significant challenge. Of all treatments, bioengineered scaffolds play a key role and represent great progress in wound repair and skin regeneration. In this review, we focus on the latest advancement in biomaterial scaffolds for wound healing. We discuss the emerging philosophy of designing biomaterial scaffolds, followed by precursor development. We pay particular attention to the therapeutic interventions of bioengineered scaffolds for cutaneous wound healing, and their dual effects while conjugating with bioactive molecules, stem cells, and even immunomodulation. As we review the advancement and the challenges of the current strategies, we also discuss the prospects of scaffold development for wound healing.
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Hyaluronic acid (HA)-based antioxidant hydrogels have achieved remarkable results in diabetic wound repair. However, the realization of their glucose-responsive antioxidant functions remains a significant challenge. In this study, we modified hyaluronic acid methacrylate (HAMA) with phenylboronic acid (PBA) and developed a glucose-responsive HA derivative (HAMA-PBA). A glucose-responsive HAMA-PBA/catechin (HMPC) hydrogel platform was then fabricated by forming a borate ester bond between HAMA-PBA and catechin. The results showed that the HMPC hybrid hydrogel not only had a three-dimensional network structure and Young's modulus similar to those of skin tissue, but also possessed biocompatibility. The HMPC hydrogel also showed unique glucose-responsive catechin release behavior and remarkable antioxidant capability, which could effectively eliminate intracellular reactive oxygen species and protect cells from oxidative stress damage (increased superoxide dismutase activity, stabilized reduced glutathione/oxidized glutathione ratio, and reduced malondialdehyde content). Additionally, in vitro and in vivo experimental results showed that the HMPC hydrogel effectively promoted angiogenesis (enhanced VEGF and CD31 expression) and reduced inflammatory responses (decreased IL-6 level and increased IL-10 level), thus rapidly repairing diabetic wounds (within three weeks). This was a significant improvement as compared to that observed for the untreated control group and the HMP hydrogel group. These results indicated the potential for the application of the HMPC hydrogel for treating diabetic wounds. STATEMENT OF SIGNIFICANCE: At present, the delayed closure rate of diabetic chronic wounds caused by excessive reactive oxygen species (ROS) remains a worldwide challenge. Hyaluronic acid (HA)-based antioxidant hydrogels have made remarkable achievements in diabetic wound repair; however, the realization of their glucose-responsive antioxidant functions is a tough challenge. In this work, we developed a novel HA-based hydrogel platform with glucose-responsive antioxidant activity for rapid repair of diabetic wounds. In vitro and in vivo experimental results showed that the HMPC hydrogel could effectively promote angiogenesis (enhanced VEGF and CD31 expression) and reduce inflammatory response (decreased IL-6 level and increased IL-10 level), thus rapidly repairing diabetic wounds (within 3 weeks). These results indicated the potential of the HMPC hydrogel for application in diabetic wound treatment.
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Catequina , Diabetes Mellitus , Antioxidantes/farmacología , Glucosa , Humanos , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Hidrogeles/química , Hidrogeles/farmacología , Interleucina-10 , Interleucina-6 , Especies Reactivas de Oxígeno , Factor A de Crecimiento Endotelial Vascular , Cicatrización de HeridasRESUMEN
Rationale: With the advantages of tumor-targeting, pH-responsive drug releasing, and biocompatibility, ferritin nanocage emerges as a promising drug carrier. However, its wide applications were significantly hindered by the low loading efficiency of hydrophobic drugs. Herein, we redesigned the inner surface of ferritin drug carrier (ins-FDC) by fusing the C- terminus of human H ferritin (HFn) subunit with optimized hydrophobic peptides. Methods: Hydrophobic and hydrophilic drugs were encapsulated into the ins-FDC through the urea-dependent disassembly/reassembly strategy and the natural drug entry channel of the protein nanocage. The morphology and drug loading/releasing abilities of the drug-loaded nanocarrier were then examined. Its tumor targeting character, system toxicity, application in synergistic therapy, and anti-tumor action were further investigated. Results: After optimization, 39 hydrophobic Camptothecin and 150 hydrophilic Epirubicin were encapsulated onto one ins-FDC nanocage. The ins-FDC nanocage exhibited programed drug release pattern and increased the stability and biocompatibility of the loaded drugs. Furthermore, the ins-FDC possesses tumor targeting property due to the intrinsic CD71-binding ability of HFn. The loaded drugs may penetrate the brain blood barrier and accumulate in tumors in vivo more efficiently. As a result, the drugs loaded on ins-FDC showed reduced side effects and significantly enhanced efficacy against glioma, metastatic liver cancer, and chemo-resistant breast tumors. Conclusions: The ins-FDC nanocarrier offers a promising novel means for the delivery of hydrophobic compounds in cancer treatments, especially for the combination therapies that use both hydrophobic and hydrophilic chemotherapeutics.
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Ferritinas , Glioma , Apoferritinas/uso terapéutico , Línea Celular Tumoral , Doxorrubicina/uso terapéutico , Portadores de Fármacos/uso terapéutico , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Epirrubicina , Ferritinas/química , Glioma/tratamiento farmacológico , HumanosRESUMEN
The success of repair or regeneration depends greatly on the architecture of 3D scaffolds that finely mimic natural extracellular matrix to support cell growth and assembly. Polysaccharides have excellent biocompatibility with intrinsic biological cues and they have been extensively investigated as scaffolds for tissue engineering and regenerative medicine (TERM). The physical and biochemical structures of natural polysaccharides, however, can barely meet all the requirements of tissue-engineered scaffolds. To take advantage of their inherent properties, many innovative approaches including chemical, physical, or joint modifications have been employed to improve their properties. Recent advancement in molecular and material building technology facilitates the fabrication of advanced 3D structures with desirable properties. This review focuses on the latest progress of polysaccharide-based scaffolds for TERM, especially those that construct advanced architectures for tissue regeneration.
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Ingeniería de Tejidos , Andamios del Tejido , Matriz Extracelular , Polisacáridos , Andamios del Tejido/químicaRESUMEN
The progress of biomaterials and tissue engineering has led to significant advances in wound healing, but the clinical therapy to regenerate perfect skin remains a great challenge. The implantation of biomaterial scaffolds to heal wounds inevitably leads to a host immune response. Many recent studies revealed that the immune system plays a significant role in both the healing process and the outcome. Immunomodulation or immuno-engineering has thus become a promising approach to develop pro-regenerative scaffolds for perfect skin regeneration. In this paper, we will review recent advancements in immunomodulating biomaterials in the field of skin repair and regeneration, and discuss strategies to modulate the immune response by tailoring the chemical, physical and biological properties of the biomaterials. Understanding the important role of immune responses and manipulating the inherent properties of biomaterials to regulate the immune reaction are approaches to overcome the current bottleneck of skin repair and regeneration.
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Amine groups are the building units of proteins. The incorporation of amine groups into polyethylene glycol diacrylate (PEGDA) hydrogel through dextran-allyl isocyanate-ethylamine (Dex-AE) enhances sustained protein release by introducing effective interactions. To investigate such an interaction effect and to improve protein release, we impregnated self-assembled tubular structures from dextran-bromoethylamine (Dex-BH) and dextran-chloroacetic acid (Dex-CA) into Dex-AE/PEGDA hydrogel. The morphology data obtained from scanning electron microscopy (SEM) reveal that pure PEGDA hydrogel had no effect on the distribution of the self-assembled tubules; the introduction of Dex-AE brought about the dispersion of these tubules, and an increase in Dex-AE content led to more evenly distributed structures. Moreover, the implantation of the self-assembled tubules had no distinct effect on the swelling capacity of the hybrid self-assembly embedded hydrogels. The in vitro albumin release study was carried out in a pH 7.4 buffer solution; the results show that the implantation of the self-assembly into the hydrogels reduced the burst release and prolonged the protein release time. These findings demonstrate that the impregnation of tubular self-assembly into hydrogel makes the hybrid hydrogel an excellent protein delivery system.
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Dextranos/química , Hidrogeles/química , Albúminas/química , Tamaño de la Partícula , Polietilenglicoles/química , Propiedades de SuperficieRESUMEN
Agents inducing O(6)-methylguanine (O(6)MeG) in DNA such as N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) are cytotoxic and a deficiency in mismatch repair (MMR) results in lack of sensitivity to this genotoxin (termed alkylation tolerance). Here, we show that ING2, a member of the inhibitor of growth family, is required for cell death induced by MNNG. We further observe that MNNG treatment increases cellular protein levels of ING2 that is dependent on intact MMR function and that MNNG-induced ING2 localizes and associates with p73alpha in the nucleus. Suppression of ING2 by short hairpin RNA (shRNA) in MMR-proficient colorectal cancer cells decreased its sensitivity to MNNG and, in addition, abrogated MNNG-induced stabilization and acetylation of p73alpha. Interestingly, suppression of p73alpha had a greater impact on MNNG-induced cell death than ING2 leading us to conclude that ING2 regulates the cell death response, in part, through p73alpha. Inhibition of c-Abl by STI571 or suppression of c-Abl expression by shRNA blocked ING2 induction and p73alpha acetylation induced by this alkylator. Similarly, suppression of MMR (MLH1) by shRNA abrogated ING2 induction/p73alpha acetylation. Taken together, these results demonstrate that MLH1/c-Abl-dependent activation of ING2>p73alpha signaling regulates cell death triggered by MNNG and further suggests that dysregulation of this event may, in part, be responsible for alkylation tolerance observed in MMR compromised cells.
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Alquilantes/toxicidad , Apoptosis , Carcinógenos/toxicidad , Reparación de la Incompatibilidad de ADN , Proteínas de Unión al ADN/metabolismo , Proteínas de Homeodominio/metabolismo , Metilnitronitrosoguanidina/toxicidad , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-abl/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Proteínas Adaptadoras Transductoras de Señales/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antineoplásicos/farmacología , Benzamidas , Proteínas de Unión al ADN/antagonistas & inhibidores , Células HeLa , Proteínas de Homeodominio/agonistas , Humanos , Mesilato de Imatinib , Homólogo 1 de la Proteína MutL , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/efectos de los fármacos , Oligonucleótidos/metabolismo , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-abl/efectos de los fármacos , Pirimidinas/farmacología , ARN Interferente Pequeño/metabolismo , Receptores Citoplasmáticos y Nucleares/agonistas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Transfección , Proteína Tumoral p73 , Proteína p53 Supresora de Tumor/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/agonistas , Proteínas Supresoras de Tumor/antagonistas & inhibidoresRESUMEN
Lubrication is the key to efficient function of human tissues and has significant impact on the comfort level. However, the construction of a lubricating nanofibrous membrane has not been reported as yet, especially using a one-step surface modification method. Here, bioinspired by the superlubrication mechanism of articular cartilage, we successfully construct hydration-enhanced lubricating nanofibers via one-step in situ grafting of a copolymer synthesized by dopamine methacrylamide (DMA) and 2-methacryloyloxyethyl phosphorylcholine (MPC) onto electrospun polycaprolactone (PCL) nanofibers. The zwitterionic MPC structure provides the nanofiber surface with hydration lubrication behavior. The coefficient of friction (COF) of the lubricating nanofibrous membrane decreases significantly and is approximately 65% less than that of pure PCL nanofibers, which are easily worn out under friction regardless of hydration. The lubricating nanofibers, however, show favorable wear-resistance performance. Besides, they possess a strong antiadhesion ability of fibroblasts compared with pure PCL nanofibers. The cell density decreases approximately 9-fold, and the cell area decreases approximately 12 times on day 7. Furthermore, the in vivo antitendon adhesion data reveals that the lubricating nanofiber group has a significantly lower adhesion score and a better antitissue adhesion. Altogether, our developed hydration-enhanced lubricating nanofibers show promising applications in the biomedical field such as antiadhesive membranes.
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Skin and skin appendages protect the body from harmful environment and prevent internal organs from dehydration. Superficial epidermal wounds usually heal without scarring, however, deep dermal wound healing commonly ends up with nonfunctioning scar formation with substantial loss of skin appendage. Wound healing is one of the most complex dynamic biological processes, during which a cascade of biomolecules combine with stem cell influx and matrix synthesis and synergistically contribute to wound healing at all levels. Although many approaches have been investigated to restore complete skin, the clinically effective therapy is still unavailable and the regeneration of perfect skin still remains a significant challenge. The complete mechanism behind scarless skin regeneration still requires further investigation. Fortunately, recent advancement in regenerative medicine empowers us more than ever to restore tissue in a regenerative manner. Many studies have elucidated and reviewed the contribution of stem cells and growth factors to scarless wound healing. This article focuses on recent advances in scarless wound healing, especially strategies to engineer pro-regenerative scaffolds to restore damaged skin in a regenerative manner.
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Medicina Regenerativa/métodos , Animales , Humanos , Hidrogeles/química , Macrófagos/metabolismo , Neovascularización Fisiológica/fisiología , Cicatrización de Heridas/fisiologíaRESUMEN
The transformation of fibrotic healing process to regenerative one has great potential to fully restore wounded skin. The M2 macrophage phenotype promotes constructive tissue remodeling and instructs tissue repair in a regenerative manner. It is hypothesized that hydrogels that can establish robustness of endogenous cells to regulate M2 phenotype will promote constructive dermal remodeling. Toward this end, a series of dextran-based bioabsorbable hydrogels are developed and self-crosslinkable dextran-isocyanatoethyl methacrylate-ethylamine (DexIEME) is identified as the potential scaffold. The initial screening study revealed that DexIEME has superior biocompatibility in varying concentrations. Although DexIEME brings about low proinflammatory responses, it promotes M2 macrophage phenotype. Then the optimized hydrogel formulation is tested for acute skin injuries using both murine and porcine models. Preliminary data demonstrated that the innovative DexIEME hydrogel promotes complete skin regeneration with hair regrowth on pre-existing scars, while untreated scars remain intact. Preclinical studies further demonstrated that the DexIEME hydrogel regenerated perfect skin during deep porcine wound healing. Overall, the approach to investigate immune-modulated hydrogels yields pro-regenerative DexIEME hydrogel, which may lead to greater clinical success in treating deep dermal injury and attenuating scar formation.
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Cicatriz/metabolismo , Dextranos , Hidrogeles , Ensayo de Materiales , Piel/lesiones , Piel/metabolismo , Animales , Células COS , Chlorocebus aethiops , Cicatriz/patología , Dextranos/química , Dextranos/farmacología , Humanos , Hidrogeles/química , Hidrogeles/farmacología , Ratones , Piel/patología , Porcinos , Células THP-1RESUMEN
Homeobox D10 (HoxD10) plays important roles in the differentiation of embryonic cells and progression of breast cancer. Our previous report revealed that insulin-like growth factor binding protein-3 (IGFBP3) was regulated by HoxD10 in gastric cancer cells; however, the functional roles and underlying mechanisms of IGFBP3 in gastric cancer remain unclear. Here, we found that the expression of IGFBP3 were upregulated after ectopic expression of HoxD10 in gastric cancer cells. Chromatin immunoprecipitation assay showed that HoxD10 bound to three potential regions of IGFBP3 promoter. Exogenous HoxD10 significantly enhanced the activity of luciferase reporter containing these binding regions in gastric cancer cells. Further data showed that all of these binding sites had Hox binding element "TTAT". Immunohistochemical staining results revealed that IGFBP3 expression was significantly downregulated in 86 gastric adenocarcinomas tissues relative to their adjacent non-cancerous tissues (p<0.001). Moreover, IGFBP3 expression was significantly lower in gastric tumor with lymph node metastasis compared with that without lymph node metastasis (p=0.045). Patients with high expression level of IGFBP3 showed favorable 5 year overall survival (p=0.011). Knockdown of IGFBP3 accelerated gastric cancer cell migration and invasion and induced the expression of invasive factors including MMP14, uPA and uPAR. Thus, our data suggest that HoxD10-targeted gene IGFBP3 may suppress gastric cancer cell invasion and favors the survival of gastric cancer patients.