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Purpose To explore the role of cardiac MRI feature tracking (FT) and T1 mapping in predicting sustained ventricular arrhythmias (VA) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and to investigate their possible incremental value beyond ARVC risk score. Materials and Methods The retrospective study analyzed 91 patients with ARVC (median age, 36 years [IQR, 27-50 years]; 60 male, 31 female) who underwent cardiac MRI examinations between November 2010 and March 2022. The primary end point was the first occurrence of sustained VA after cardiac MRI to first VA, with censoring of patients who were alive without VA at last follow-up. Cox regression analysis was performed to assess the association between variables and time to sustained VA. Time-dependent receiver operating characteristic (ROC) analysis was performed to determine the incremental value of cardiac MRI FT and T1 mapping. Results During a median follow-up of 55.0 months (IQR, 37.0-76.0 months), 36 of 91 (40%) patients experienced sustained VA. A 1% worsening in left ventricular global longitudinal peak strain (GLS), 1% worsening in right ventricular GLS, and a 1% increase in extracellular volume fraction (ECV) were associated with increased risk of sustained VA, with hazard ratios of 1.14 (95% CI: 1.06, 1.23; P = .001), 1.09 (95% CI: 1.02, 1.16; P = .02), and 1.13 (95% CI: 1.08, 1.18; P < .001), respectively, after adjustment for ARVC risk score. Adding both biventricular GLS and ECV to ARVC risk score showed significant incremental value for predicting sustained VA (area under the ROC curve: 0.73 vs 0.65; P < .001). Conclusion Cardiac MRI-derived biventricular GLS and ECV provided independent and incremental value for predicting sustained VA beyond ARVC risk score alone in patients with ARVC. Keywords: Cardiovascular MRI, Feature Tracking, T1 Mapping, Arrhythmogenic Right Ventricular Cardiomyopathy, Sustained Ventricular Arrhythmias Supplemental material is available for this article Published under a CC BY 4.0 license.
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Displasia Arritmogênica Ventricular Direita , Imagem Cinética por Ressonância Magnética , Humanos , Masculino , Feminino , Displasia Arritmogênica Ventricular Direita/diagnóstico por imagem , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Adulto , Pessoa de Meia-Idade , Estudos Retrospectivos , Prognóstico , Imagem Cinética por Ressonância Magnética/métodos , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/patologia , Imageamento por Ressonância Magnética/métodosRESUMO
The failure or delay in healing of critical bone defects is primarily due to early local anoxic conditions and reduced osteogenic activity. In this research, we integrated calcium peroxide (CPO) embedded polycaprolactone (PCL) microspheres and osteoinductive nanoparticles (Hydroxyapatite/Laponite) into a thermosensitive hydrogel (Pluronic F127), thereby formulating an injectable oxygen-releasing osteogenic thermosensitive hydrogel. Notably, the oxygen-releasing microspheres (ORMs) within the composite hydrogel provide stable oxygen release for up to 21 days, ensuring the survival, migration, and bioactivity of both mesenchymal stem cells and endothelial cells under anoxic conditions. Additionally, the composite hydrogel significantly augments the osteogenic potential of bone marrow mesenchymal stem cells by providing a biomimetic microenvironment with the incorporation of nano-hydroxyapatite/laponite. Ultimately, the injectable composite hydrogel successfully stimulated bone regeneration within a cranial defect in a rat model after 8 weeks, with enhanced vascularization and bone quality. The engineered hydrogel provides a minimally invasive approach to stimulate bone regeneration with a sustained oxygen supply and osteogenic microenvironment provision, underlining its potential for treating critical bone defects.
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Reconstruction of bone defects has long been a major clinical challenge. Limited by the various shortcomings of conventional treatment like autologous bone grafting and inorganic substitutes, the development of novel bone repairing strategies is on top priority. Injectable biomimetic hydrogels that deliver stem cells and growth factors in a minimally invasive manner can effectively promote bone regeneration and thus represent a promising alternative. Therefore, in this study, we designed and constructed an injectable nanocomposite hydrogel co-loaded with Laponite (Lap) and vascular endothelial growth factor (VEGF) through a simplified and convenient scheme of physical co-mixing (G@Lap/VEGF). The introduced Lap not only optimized the injectability of GelMA by the electrostatic force between the nanoparticles, but also significantly delayed the release of VEGF-A. In addition, Lap promoted high expression of osteogenic biomarkers in mesenchymal stem cells (MSCs) and enhanced the matrix mineralization. Besides, VEGF-A exerted chemotactic effects recruiting endothelial progenitor cells (EPCs) and inducing neovascularization. Histological and micro-CT results demonstrated that the critical-sized calvarial bone defect lesions in the SD rats after treated with G@Lap/VEGF exhibited significant in vivo bone repairing. In conclusion, the injectable G@Lap/VEGF nanocomposite hydrogel constructed in our study is highly promising for clinical transformation and applications, providing a convenient and simplified scheme for clinical bone repairing, and contributing to the further development of the injectable biomimetic hydrogels.
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Regeneração Óssea , Preparações de Ação Retardada , Gelatina , Hidrogéis , Células-Tronco Mesenquimais , Ratos Sprague-Dawley , Silicatos , Fator A de Crescimento do Endotélio Vascular , Animais , Regeneração Óssea/efeitos dos fármacos , Hidrogéis/química , Fator A de Crescimento do Endotélio Vascular/metabolismo , Gelatina/química , Silicatos/química , Silicatos/farmacologia , Preparações de Ação Retardada/química , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Ratos , Osteogênese/efeitos dos fármacos , Metacrilatos/química , MasculinoRESUMO
BACKGROUND: Diabetic wounds present significant challenges, specifically in terms of bacterial infection and delayed healing. Therefore, it is crucial to address local bacterial issues and promote accelerated wound healing. In this investigation, we utilized electrospinning to fabricate microgel/nanofiber membranes encapsulating MXene-encapsulated microgels and chitosan/gelatin polymers. RESULTS: The film dressing facilitates programmed photothermal therapy (PPT) and mild photothermal therapy (MPTT) under near-infrared (NIR), showcasing swift and extensive antibacterial and biofilm-disrupting capabilities. The PPT effect achieves prompt sterilization within 5 min at 52 °C and disperses mature biofilm within 10 min. Concurrently, by adjusting the NIR power to induce local mild heating (42 °C), the dressing stimulates fibroblast proliferation and migration, significantly enhancing vascularization. Moreover, in vivo experimentation successfully validates the film dressing, underscoring its immense potential in addressing the intricacies of diabetic wounds. CONCLUSIONS: The MXene microgel-loaded nanofiber dressing employs temperature-coordinated photothermal therapy, effectively amalgamating the advantageous features of high-temperature sterilization and low-temperature promotion of wound healing. It exhibits rapid, broad-spectrum antibacterial and biofilm-disrupting capabilities, exceptional biocompatibility, and noteworthy effects on promoting cell proliferation and vascularization. These results affirm the efficacy of our nanofiber dressing, highlighting its significant potential in addressing the challenge of diabetic wounds struggling to heal due to infection.
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Antibacterianos , Bandagens , Nanofibras , Terapia Fototérmica , Cicatrização , Cicatrização/efeitos dos fármacos , Nanofibras/química , Terapia Fototérmica/métodos , Animais , Antibacterianos/farmacologia , Antibacterianos/química , Camundongos , Biofilmes/efeitos dos fármacos , Quitosana/química , Masculino , Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Experimental/complicações , Temperatura , Ratos , Raios Infravermelhos , Proliferação de Células/efeitos dos fármacos , Ratos Sprague-Dawley , Humanos , Infecção dos Ferimentos/terapiaRESUMO
The proficient handling of diabetic wounds, a rising issue coinciding with the global escalation of diabetes cases, poses significant clinical difficulties. A range of biofunctional dressings have been engineered and produced to expedite the healing process of diabetic wounds. This study proposes a multifunctional hydrogel dressing for diabetic wound healing, which is composed of Polyvinyl Alcohol (PVA) and N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N1, N1, N3, N3-teramethylpropane-1, 3-diaminium (TSPBA), and a dual-drug loaded Gelatin methacryloyl (GM) microgel. The GM microgel is loaded with sodium fusidate (SF) and nanoliposomes (LP) that contain metformin hydrochloride (MH). Notably, adhesive and self-healing properties the hydrogel enhance their therapeutic potential and ease of application. In vitro assessments indicate that SF-infused hydrogel can eliminate more than 98% of bacteria within 24 h and maintain a sustained release over 15 days. Additionally, MH incorporated within the hydrogel has demonstrated effective glucose level regulation for a duration exceeding 15 days. The hydrogel demonstrates a sustained ability to neutralize ROS throughout the entire healing process, predominantly by electron donation and sequestration. This multifunctional hydrogel dressing, which integrated biological functions of efficient bactericidal activity against both MSSA and MRSA strains, blood glucose modulation, and control of active oxygen levels, has successfully promoted the healing of diabetic wounds in rats in 14 days. The hydrogel dressing exhibited significant effectiveness in facilitating the healing process of diabetic wounds, highlighting its considerable promise for clinical translation.
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Antibacterianos , Bandagens , Hidrogéis , Álcool de Polivinil , Espécies Reativas de Oxigênio , Cicatrização , Animais , Cicatrização/efeitos dos fármacos , Hidrogéis/química , Hidrogéis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ratos , Antibacterianos/farmacologia , Antibacterianos/química , Álcool de Polivinil/química , Masculino , Hiperglicemia/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Ratos Sprague-Dawley , Gelatina/química , Metformina/farmacologia , Metformina/química , Lipossomos/química , Staphylococcus aureus/efeitos dos fármacos , Metacrilatos/química , Metacrilatos/farmacologia , Adesivos/química , Adesivos/farmacologia , InjeçõesRESUMO
Prosthetic eye is indispensable as filler after enucleation in patients with anophthalmia, whereas there are still many complications including postoperative infection and eye socket depression or extrusion during the conventional artificial eye material applications. Some Ca-silicate biomaterials showed superior bioactivity but their biological stability in vivo limit the biomedical application as long-term or permanent implants. Herein we aimed to understand the physicochemical and potential biological responses of zinc doping in wollastonite bioceramic used for orbital implants. The wollastonite powders with different zinc dopant contents (CSi-Znx) could be fabricated as porous implants with strut or curve surface pore geometries (cubic, IWP) via ceramic stereolithography. The experimental results indicated that, by increasing zinc-substituting-Ca ratio (up to 9%), the sintering and mechanical properties could be significantly enhanced, and meanwhile the bio-dissolution in vitro and biodegradability in vivo were thoroughly inhibited. In particular, an appreciable angiogenic activity and expected antibacterial efficacy (over 90 %) were synergistically achieved at 9 mol% Zn dopant. In the back-embedding and enucleation and implantation model experiments in rabbits, the superior continuous angiogenesis was corroborated from the 2D/3D fibrovascular reconstruction in the IWP-pore CSi-Zn9 and CSi-Zn13.5 groups within very short time stages. Totally, the present silicate-based bioceramic via selective Zn doping could produce outstanding structural stability and bifunctional biological responses which is especially valuable for developing the next-generation implants with vascular insertion and fixation in orbital reconstruction prothesis.
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Diabetic wounds pose a challenge to healing due to increased bacterial susceptibility and poor vascularization. Effective healing requires simultaneous bacterial and biofilm elimination and angiogenesis stimulation. In this study, we incorporated polyaniline (PANI) and S-Nitrosoglutathione (GSNO) into a polyvinyl alcohol, chitosan, and hydroxypropyltrimethyl ammonium chloride chitosan (PVA/CS/HTCC) matrix, creating a versatile wound dressing membrane through electrospinning. The dressing combines the advantages of photothermal antibacterial therapy and nitric oxide gas therapy, exhibiting enduring and effective bactericidal activity and biofilm disruption against methicillin-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and Escherichia coli. Furthermore, the membrane's PTT effect and NO release exhibit significant synergistic activation, enabling a nanodetonator-like burst release of NO through NIR irradiation to disintegrate biofilms. Importantly, the nanofiber sustained a uniform release of nitric oxide, thereby catalyzing angiogenesis and advancing cellular migration. Ultimately, the employment of this membrane dressing culminated in the efficacious amelioration of diabetic-infected wounds in Sprague-Dawley rats, achieving wound closure within a concise duration of 14 days. Upon applying NIR irradiation to the PVA-CS-HTCC-PANI-GSNO nanofiber membrane, it swiftly eradicates bacteria and biofilm within 5 min, enhancing its inherent antibacterial and anti-biofilm properties through the powerful synergistic action of PTT and NO therapy. It also promotes angiogenesis, exhibits excellent biocompatibility, and is easy to use, highlighting its potential in treating diabetic wounds.
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Antibacterianos , Bandagens , Biofilmes , Óxido Nítrico , Terapia Fototérmica , Ratos Sprague-Dawley , Cicatrização , Animais , Cicatrização/efeitos dos fármacos , Óxido Nítrico/farmacologia , Óxido Nítrico/metabolismo , Ratos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/uso terapêutico , Biofilmes/efeitos dos fármacos , Terapia Fototérmica/métodos , Masculino , Quitosana/química , Quitosana/farmacologia , Nanofibras/química , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Staphylococcus aureus/efeitos dos fármacos , Álcool de Polivinil/química , Álcool de Polivinil/farmacologia , S-Nitrosoglutationa/farmacologia , S-Nitrosoglutationa/químicaRESUMO
Injectable hydrogels, offering adaptable drug delivery of growth factors (GFs), hold promise for treating bone defects. To optimize osteogenic efficacy, the release of GFs should mirror the natural bone healing. We developed an injectable thermo-responsive hydrogel/microgels platform for dual GF delivery for bone regeneration. Stromal cell-derived factor-1 alpha (SDF-1a) and the Methacrylate Gelatin (GelMA) microgels which encapsulated insulin-like growth factor-1 (IGF-1) loaded liposomes (Ls) were introduced into Poloxamer 407 (P407) hydrogel matrix. This system achieved the biomimetic release profile of SDF-1a and IGF-1, which covered the early stage from day 1 to 7 and the continuous stage from day 5 to 21, respectively. In vitro study confirmed the enhanced migration, osteogenic biomarker expression, and matrix mineralization of the bone marrow mesenchymal stem cells (BMSCs) co-cultivated with the dual GFs delivering hydrogel/microgels. Transcriptome sequencing revealed that the potential mechanism was associated with mitogen-activated protein kinase (MAPK) signaling activation and its downstream ribosomal protein S6 kinase 2 (RSK2) upregulation. In a critical-sized calvarial defect model in Sprague-Dawley (SD) rats, the injectable hydrogel/microgels system promoted significant bone regeneration. Collectively, our study suggested the current hydrogel/microgels system with the biomimetic release of SDF-1a and IGF-1 efficiently promoted bone regeneration, informing the future development of GF delivery systems intended for bone regeneration therapies.
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Regeneração Óssea , Quimiocina CXCL12 , Gelatina , Hidrogéis , Fator de Crescimento Insulin-Like I , Poloxâmero , Animais , Regeneração Óssea/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Quimiocina CXCL12/farmacologia , Quimiocina CXCL12/administração & dosagem , Gelatina/química , Hidrogéis/química , Poloxâmero/química , Ratos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Ratos Sprague-Dawley , Metacrilatos/química , Osteogênese/efeitos dos fármacos , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Liberação Controlada de Fármacos , Injeções , MasculinoRESUMO
Antibody-drug conjugates (ADCs) combine the high specificity of antibodies with the cytotoxicity of payloads and have great potential in pan-cancer immunotherapy. However, the current payloads for clinical uses have limited the therapeutic window due to their uncontrollable off-site toxicity. There is unmet needs to develop more potent ADC payloads with better safety and efficacy profiles. Nitric oxide (NO) is a special molecule that has low toxicity itself, which can kill tumor cells effectively when highly concentrated, has broad application prospects. Previously, we prepared for the first time an antibody-nitric oxide conjugate (ANC)-HN01, which showed inhibitory activity against hepatocellular carcinoma. However, the random conjugation method made HN01 highly heterogeneous and unstable. Here, we used site-specific conjugation-based engineered cysteine sites (CL-V211C) of anti-CD24 antibody to prepare a second-generation ANC with a drug-to-antibody ratio of 2. The homogeneous ANC, HN02 was stable in human plasma, shown in vitro bystander effect to neighboring cells and antiproliferative activity to CD24-targeted tumor cells. Compared with HN01, HN02 significantly prolonged the survival of tumor-bearing mice. In summary, we developed a stable and homogeneous site-specific conjugated ANC, which showed good antitumor activity and improved safety profile both in vitro and in vivo. This study provides new insight into the development of next generation of ADC candidates.
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Imunoconjugados , Óxido Nítrico , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Animais , Imunoconjugados/farmacologia , Imunoconjugados/química , Imunoconjugados/uso terapêutico , Camundongos , Óxido Nítrico/metabolismo , Linhagem Celular Tumoral , Antígeno CD24/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/química , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias/tratamento farmacológicoRESUMO
BACKGROUND: Poly ADP-ribose polymerase (PARP) inhibitors are approved for the treatment of some men with advanced prostate cancer. Rare but serious side effects include myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The impact of PARP inhibitors on clonal hematopoiesis (CH), a potential precursor lesion associated with MDS and AML, is incompletely understood in prostate cancer. We hypothesized that PARP inhibitors would increase CH prevalence and abundance. METHODS: We prospectively enrolled participants with advanced prostate cancer treated with PARP inhibitors. The presence of CH was assessed from leukocytes using an ultra-deep error-corrected dual unique molecular identifiers sequencing method targeting 49 genes most commonly mutated in CH and myeloid malignancies. Variant allele frequencies (VAF) of ≥0.5% were considered clinically significant. Blood samples were collected before and after PARP inhibitor treatment. RESULTS: Ten men were enrolled; mean age of 67 years. Six patients had Gleason 7 disease, and four had Gleason ≥8 disease at diagnosis. Nine had localized disease at diagnosis, and eight had prior treatment with radiation. The mean time between pre- and post-treatment blood samples was 11 months (range 2.6-31 months). Six patients (60%) had CH identified prior to PARP inhibitor treatment, three with multiple clones. Of 11 CH clones identified in follow-up, 5 (45%) appeared or increased after treatment. DNMT3A, TET2, and PPM1D were the most common CH alterations observed. The largest post-treatment increase involved the PPM1D gene. CONCLUSION: CH alterations are frequently found after treatment with PARP inhibitors in patients with prostate cancer and this may be one mechanism by which PARP inhibitors lead to increased risk of MDS/AML.
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Hematopoiese Clonal , Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias da Próstata , Humanos , Masculino , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Idoso , Pessoa de Meia-Idade , Hematopoiese Clonal/genética , Estudos Prospectivos , Progressão da Doença , Prevalência , Idoso de 80 Anos ou mais , Proteínas de Ligação a DNA , DioxigenasesRESUMO
SUMMARY: Immunocytokines are a promising immunotherapeutic approach in cancer therapy. Anti-VEGFR2-interferon α (IFNα) suppressed colorectal cancer (CRC) growth and enhanced CD8 + T-cell infiltration in the tumor microenvironment, exhibiting great clinical translational potential. However, the mechanism of how the anti-VEGFR2-IFNα recruits T cells has not been elucidated. Here, we demonstrated that anti-VEGFR2-IFNα suppressed CRC metastasis and enhanced CD8 + T-cell infiltration. RNA sequencing revealed a transcriptional activation of CCL5 in metastatic CRC cells, which was correlated with T-cell infiltration. IFNα but not anti-VEGFR2 could further upregulate CCL5 in tumors. In immunocompetent mice, both IFNα and anti-VEGFR2-IFNα increased the subset of tumor-infiltrating CD8 + T cells through upregulation of CCL5. Knocking down CCL5 in tumor cells attenuated the infiltration of CD8 + T cells and dampened the antitumor efficacy of anti-VEGFR2-IFNα treatment. We, therefore, propose upregulation of CCL5 is a key to enhance infiltration of CD8 + T cells in metastatic CRC with IFNα and IFNα-based immunocytokine treatments. These findings may help the development of IFNα related immune cytokines for the treatment of less infiltrated tumors.
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Linfócitos T CD8-Positivos , Quimiocina CCL5 , Neoplasias Colorretais , Interferon-alfa , Linfócitos do Interstício Tumoral , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Animais , Feminino , Humanos , Camundongos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Quimiocina CCL5/metabolismo , Quimiocina CCL5/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Interferon-alfa/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Microambiente Tumoral/imunologia , Regulação para Cima , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
Exogenous supplementation of guanidinoacetic acid can mechanistically regulate the energy distribution in muscle cells. This study aimed to investigate the effects of guanidinoacetic acid supplementation on liver and breast muscle fat deposition, lipid levels, and lipid metabolism-related gene expression in ducks. We randomly divided 480 42 days-old female Jiaji ducks into four groups with six replicates and 20 ducks for each replicate. The control group was fed the basal diet, and the experimental groups were fed the basal diet with 400, 600, and 800 mg/kg (GA400, GA600, and GA800) guanidinoacetic acid, respectively. Compared with the control group, (1) the total cholesterol (p = 0.0262), triglycerides (p = 0.0357), malondialdehyde (p = 0.0452) contents were lower in GA400, GA600 and GA800 in the liver; (2) the total cholesterol (p = 0.0365), triglycerides (p = 0.0459), and malondialdehyde (p = 0.0326) contents in breast muscle were decreased in GA400, GA600 and GA800; (3) the high density lipoprotein (p = 0.0356) and apolipoprotein-A1 (p = 0.0125) contents were increased in GA600 in the liver; (4) the apolipoprotein-A1 contents (p = 0.0489) in breast muscle were higher in GA600 and GA800; (5) the lipoprotein lipase contents (p = 0.0325) in the liver were higher in GA600 and GA800; (6) the malate dehydrogenase contents (p = 0.0269) in breast muscle were lower in GA400, GA600, and GA800; (7) the insulin induced gene 1 (p = 0.0326), fatty acid transport protein 1 (p = 0.0412), and lipoprotein lipase (p = 0.0235) relative expression were higher in GA400, GA600, and GA800 in the liver; (8) the insulin induced gene 1 (p = 0.0269), fatty acid transport protein 1 (p = 0.0234), and lipoprotein lipase (p = 0.0425) relative expression were increased in GA400, GA600, and GA800 in breast muscle. In this study, the optimum dosage of 600 mg/kg guanidinoacetic acid improved the liver and breast muscle fat deposition, lipid levels, and lipid metabolism-related gene expression in ducks.
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The meniscus is vital for maintaining knee homeostasis and function. Meniscal calcification is one of the earliest radiological indicators of knee osteoarthritis (KOA), and meniscal calcification is associated with alterations in biomechanical properties. Meniscal calcification originates from a biochemical process similar to vascular calcification. Advanced glycation end products (AGEs) and their receptors (RAGEs) reportedly play critical roles in vascular calcification. Herein, we investigated whether targeting AGE-RAGE is a potential treatment for meniscal calcification. In our study, we demonstrated that AGE-RAGE promotes the osteogenesis of meniscal cells and exacerbates meniscal calcification. Mechanistically, AGE-RAGE activates mTOR and simultaneously promotes ATF4 accumulation, thereby facilitating the ATF4-mTOR positive feedback loop that enhances the osteogenic capacity of meniscal cells. In this regard, mTOR inhibits ATF4 degradation by reducing its ubiquitination, while ATF4 activates mTOR by increasing arginine uptake. Our findings substantiate the unique role of AGE-RAGE in the meniscus and reveal the role of the ATF4-mTOR positive feedback loop during the osteogenesis of meniscal cells; these results provide potential therapeutic targets for KOA.
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Menisco , Osteoartrite do Joelho , Calcificação Vascular , Humanos , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Retroalimentação , Produtos Finais de Glicação Avançada/metabolismo , Menisco/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Serina-Treonina Quinases TOR , Calcificação Vascular/metabolismoRESUMO
The experiment aimed to investigate the effects of dietary lycopene on the growth performance, antioxidant capacity, meat quality, intestine histomorphology, and cecal microbiota in broiler chickens. We randomly divided five hundred and seventy-six one-day-old male broilers into four groups each with six replicates and 24 chickens in each replicate. The control group (CG) was fed the basal diet, and the other groups were given powder lycopene of 10, 20, and 30 mg/kg lycopene (LP10, LP20, and LP30, respectively). Compared with the control group, (1) the dietary lycopene increased (p = 0.001) the average daily gain and decreased (p = 0.033) the feed conversion ratio in the experimental groups; (2) the glutathione peroxidase enzyme contents in LP20 were higher (p =< 0.001) in myocardium; (3) the crude protein contents were higher (p = 0.007) in the group treated with 30 mg/kg dietary lycopene; (4) the jejunum villous height was higher (p = 0.040) in LP20; (5) the Unclassified-f-Ruminococcaceae relative abundance was significantly higher (p = 0.043) in LP20. In this study, adding 20 mg/kg dietary lycopene to the broiler chickens' diets improved the growth performance, antioxidant capacity, meat quality, intestine histomorphology, and cecal microbiota in broiler chickens.
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This experiment was conducted to investigate the effects of fermented feed on growth performance, antioxidant activity, immune function, intestinal digestive enzyme activity, morphology, and microflora of yellow-feather chickens. A total of 240 one-day-old female yellow-feathered (Hexi dwarf) chickens were randomly divided into two treatment groups, with six replicates per group and 20 chickens per replicate. The control group (CK) received a basal diet, whereas the experimental group was fed a basal diet of +2.00% fermented feed (FJ). The trial lasted for 22 days. Compared with the CK, (1) the growth performance was not affected (p > 0.05); (2) immunoglobin a, immunoglobin g, immunoglobin m, interleukin-1ß, and interleukin-6 were affected (p < 0.05); (3) liver superoxide dismutase, glutathione peroxidase, and catalase were higher (p < 0.05); (4) trypsin activity in the duodenum and cecal Shannon index were increased (p < 0.05); (5) the relative abundance of Actinobacteriota in cecum was increased (p < 0.05); (6) the abundance of dominant microflora of Bacteroides as well as Clostridia UCG-014_norank were increased (p < 0.05). In summary, the fermented feed improved the growth performance, antioxidant activity, immune function, intestinal digestive enzyme activity, morphology, and microflora of yellow-feather chickens.
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This study aimed to investigate the effects of dietary semen vaccariae extracts (SVE) on the production performance, colostrum components, and relative gene expression related to mammogenesis of lactating sows. 48 pregnant sows were selected and randomly allocated into four groups, with six replicates and two sows per replicate. The first group was the control (CON), while the other groups received the same diet further supplemented with 1.5, 3.0 and 4.5 g SVE per kg (SV1, SV2 and SV3, respectively). Compared with the control group, (1) the average daily gain was increased (p < 0.05) in SV1, SV2, and SV3 during the 11-21 days and 1-21 days of lactation; (2) the serum insulin-like growth factor-1, insulin, prolactin, and estrogen contents in SV1, SV2, and SV3 were increased (p < 0.05) on the 1st and 21st day of lactation; (3) The plasma Lysine, Threonine, and Tryptophan concentrations were also higher (p < 0.05) in SV1, SV2, and SV3 on the 1st and 21st day of lactation; (4) The milk Lysine, Methionine, Threonine, and Tryptophan concentrations were higher (p < 0.05) in SV1, SV2, and SV3 on the 1st and 21st day of lactation; (5) The milk lactose ratio and milk protein content were increased (p < 0.05) in the groups treated with semen vaccariae on the 1st day of lactation, while the milkfat ratio and milk protein content were increased (p < 0.05) in SV2 and SV3 on the 21st day of lactation; (6) the immunoglobulin M, A, and G contents were increased (p < 0.05) in the groups treated with the semen vaccariae on the first day of lactation; and (7) the relative PRLR, STAT5a, FcRn, CSN2, and LALBA expressions were higher (p < 0.05) in the groups treated with the semen vaccariae on the 1st and 21st day of lactation. In this study, the optimum dosage was 3.0 g/kg semen vaccariae, which increased the average daily gain of piglets, total lactation yield, and serum hormone levels, improved the amino acid levels in plasma, and facilitated the milk quality, up-regulated the relative gene expressions in the mammogenesis.
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BACKGROUND: The 2019 arrhythmogenic right ventricular cardiomyopathy (ARVC) risk model has proved insufficient in the capability of predicting ventricular arrhythmia (VA) risk in non-classical arrhythmogenic cardiomyopathy (ACM). Furthermore, the prognostic value of ringlike late gadolinium enhancement (LGE) of the left ventricle in non-classical ACM remains unknown. We aimed to assess the incremental value of ringlike LGE over the 2019 ARVC risk model in predicting sustained VA in patients with non-classical ACM. METHODS: In this retrospective study, consecutive patients with non-classical ACM who underwent CMR from January 2011 to January 2022 were included. The pattern of LGE was categorized as no, non-ringlike, and ringlike LGE. The primary outcome was defined as the occurrence of sustained VA. Univariable and multivariable Cox regression analysis was used to evaluate the impact of LGE patterns on sustained VA and area under curve (AUC) was calculated for the incremental value of ringlike LGE. RESULTS: A total of 73 patients were collected in the final cohort (mean age, 39.3 ± 14.4 years, 51 male), of whom 10 (13.7%) had no LGE, 33 (45.2%) had non-ringlike LGE, and 30 (41.1%) had ringlike LGE. There was no statistically significant difference in the 5-year risk score among the three groups (P = 0.190). During a median follow-up of 34 (13-56) months, 34 (46.6%) patients experienced sustained VA, including 1 (10.0%), 13 (39.4%) and 20 (66.7%) of patients with no, non-ringlike and ringlike LGE, respectively. After multivariable adjustment, ringlike LGE remained independently associated with the presence of sustained VA (adjusted hazard ratio: 6.91, 95% confidence intervals: 1.89-54.60; P = 0.036). Adding ringlike LGE to the 2019 ARVC risk model showed significantly incremental prognostic value for sustained VA (AUC: 0.80 vs. 0.67; P = 0.024). CONCLUSION: Ringlike LGE provides independent and incremental prognostic value over the 2019 ARVC risk model in patients with non-classical ACM.
Assuntos
Displasia Arritmogênica Ventricular Direita , Meios de Contraste , Humanos , Masculino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Prognóstico , Gadolínio , Estudos Retrospectivos , Valor Preditivo dos Testes , Arritmias Cardíacas , Displasia Arritmogênica Ventricular Direita/diagnóstico por imagem , Imagem Cinética por Ressonância MagnéticaRESUMO
Liposomal doxorubicin exhibits stronger drug accumulation at the tumor site due to the Enhanced Permeability and Retention (EPR) effect. However, the prognosis for the patient is poor due to this drug's lack of targeting and tumor metastasis during treatment. Vascular epidermal growth factor receptor (VEGFR2) plays an important role in angiogenesis and cancer metastasis. To enhance antitumor efficacy of PEGylated liposomal doxorubicin, we constructed a VEGFR2-targeted and doxorubicin-loaded immunoliposome (Lipo-DOX-C00) by conjugating a VEGFR2-specific, single chain antibody fragment to DSPE-PEG2000-MAL, and then we inserted the antibody-conjugated polymer into liposomal doxorubicin (Lipo-DOX). The immunoliposome was formed uniformly with high affinity for VEGFR2. In vitro, Lipo-DOX-C00 enhanced doxorubicin internalization into LLC and 4T1 cells compared with non-conjugated, liposomal doxorubicin. In vivo, Lipo-DOX-C00 delivered DOX to tumor tissues effectively, which exhibited an improved antitumor and anti-metastasis efficacy in both LLC subcutaneous tumor models and 4T1 tumor models. In addition, the combined therapy of a VEGFR2-MICA bispecific antibody (JZC01) and Lipo-DOX-C00 achieved enhanced inhibition of cancer growth and metastasis due to activation of the immune system. Our study provides a promising approach to clinical application of liposomal doxorubicin.
RESUMO
In recent years, electroconductive hydrogels (ECHs) have shown great potential in promoting nerve regeneration and motor function recovery following diabetic peripheral nerve injury (PNI), attributed to their similar electrical and mechanical characteristics to innate nervous tissue. It is well-established that PNI causes motor deficits and pain, especially in diabetics. Current evidence suggests that ropivacaine (ROP) encapsulated in poly lactic-co-glycolic acid (PLGA) microspheres (MSs) yield a sustained analgesic effect. In this study, an ECH electroconductive network loaded with MS/ROP (ECH-MS/ROP) was designed as a promising therapeutic approach for diabetic PNI to exert lasting analgesia and functional recovery. This dual delivery system allowed ROP's slow and sequential release, achieving sustained analgesia as demonstrated by our in vivo experiments. Meanwhile, this system was designed like a lamellar dressing, with desirable adhesive and self-curling properties, convenient for treating injured nerve tissues via automatically wrapping tube-like structures, facilitating the process of implantation. Our in vitro assays verified that ECH-MS/ROP was able to enhance the adhesion and motility of Schwann cells. Besides, both in vitro and in vivo studies substantiated that ECH-MS/ROP stimulated myelinated axon regeneration through the MEK/ERK signaling pathway, thereby improving muscular denervation atrophy and facilitating functional recovery. Therefore, this study suggests that the ECH-MS/ROP dressing provides a promising strategy for treating diabetic PNI to facilitate nerve regeneration, functional recovery and pain relief.