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The development of peptide-based hydrogels characterized by both high biostability and potent antimicrobial activity, aimed at combating multidrug-resistant bacterial infections and providing scaffolds for cell cultures, continues to pose a significant challenge. The susceptibility of antimicrobial peptides (AMPs) to degradation by cations, serum, and proteases restricted their applications in clinical environments. In this study, we designed a peptide sequence (termed D-IK1) entirely consisting of D-amino acids, an enantiomer of a previously reported AMP IK1. Our results demonstrated remarkably improved antibacterial and anticancer activities of D-IK1 as compared to IK1. D-IK1 self-assembled into hydrogels that effectively inhibited bacterial and cancer cell growth by the controlled and sustained release of D-IK1. Importantly, D-IK1 was extremely stable in salt solutions and resisted serum and protease degradation. In addition, the D-IK1 hydrogel fostered cell adhesion and proliferation, proving its viability as a 3D scaffold for cell culture applications. Our research presents a versatile, highly stable antibacterial hydrogel scaffold with potential widespread applications in cell culture, wound healing, and the eradication of multidrug-resistant bacterial infections.
Assuntos
Antibacterianos , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/química , Humanos , Proliferação de Células/efeitos dos fármacos , Hidrogéis/química , Hidrogéis/farmacologia , Escherichia coli/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Peptídeos Antimicrobianos/química , Peptídeos Antimicrobianos/farmacologia , Staphylococcus aureus/efeitos dos fármacosRESUMO
Perfluorocarbon (PFC) nanodroplets (NDs) are expanding in a wide range of applications in biotechnology and nanotechnology. Their efficacy in biological systems is significantly influenced by their size uniformity and stability within bioelectrolyte contexts. Presently, methods for creating monodisperse, highly concentrated, and well-stabilized PFC NDs under harsh conditions using low energy consumption methods have not been thoroughly developed, and their stability has not been sufficiently explored. This gap restricts their applicability for advanced medical interventions in tissues with high pH levels and various electrolytic conditions. To tackle these challenges and to circumvent potential toxicity from surface stabilizers, we have conducted an in-depth investigation into the formation and stability of uncoated perfluorohexane (PFH) NDs, which were synthesized by using a low-energy consumption solvent exchange technique, across complex electrolyte compositions or a broad spectrum of pH levels. The results indicated that low concentrations of low-valent electrolyte ions facilitate the nucleation of NDs and consistently accelerate Ostwald ripening over an extended period. Conversely, high concentrations of highly valent electrolyte ions inhibit nucleation and decelerate the ripening process over time. Given the similarities between the properties of NDs and nanobubbles, we propose a potential stabilization mechanism. Electrolytes influence the Ostwald ripening of NDs by adjusting the adsorption and distribution of ions on the NDs' surface, modifying the thickness of the electric double layer, and fine-tuning the energy barrier between droplets. These insights enable precise control over the stability of PFC NDs through the meticulous adjustment of the surrounding electrolyte composition. This offers an effective preparation method and a theoretical foundation for employing bare PFC NDs in physiological settings.
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Although messenger RNA (mRNA) has proved effective as a vaccine, its potential as a general therapeutic modality is limited by its instability and low translation capacity. To increase the duration and level of protein expression from mRNA, we designed and synthesized topologically and chemically modified mRNAs with multiple synthetic poly(A) tails. Here we demonstrate that the optimized multitailed mRNA yielded ~4.7-19.5-fold higher luminescence signals than the control mRNA from 24 to 72 h post transfection in cellulo and 14 days detectable signal versus <7 days signal from the control in vivo. We further achieve efficient multiplexed genome editing of the clinically relevant genes Pcsk9 and Angptl3 in mouse liver at a minimal mRNA dosage. Taken together, these results provide a generalizable approach to synthesize capped branched mRNA with markedly enhanced translation capacity.
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Although surgery is the primary method to treat malignant melanoma, it has drawbacks such as residual tumor that could trigger cancer recurrence and wound infections that are especially difficult to heal in diabetics. In this research, we have constructed anti-cancer peptides/polyvinyl alcohol (PVA) double-network (DN) hydrogels for the treatment of melanoma. The maximum stress of the DN hydrogels is found to be larger than 2 MPa, which endows the DN hydrogels with ideal mechanical performance for therapeutic wound dressing. The peptides naphthalene-FIIIKKK (IK1) and phloretic acid-FIIIKKK (IK3) that were previously developed as effective antibacterial peptides, as well as the peptide/PVA DN hydrogels, are found to have good anti-cancer efficacy and target mouse melanoma cells B16-F10 while being nontoxic to normal cells. Further studies have revealed that IK1 and IK3 damage the tumor cell membrane and mitochondrial membrane and eventually trigger apoptosis. In the mouse melanoma model and the diabetic bacterial infection model, the DN hydrogels exhibit great anti-tumor, anti-bacterial, and wound healing promotion abilities in vivo. Because of their excellent mechanical properties, the DN hydrogels are promising soft materials for directly treating malignant melanomas as well as for preventing recurrence and bacterial infection after melanoma surgery that promote wound healing.
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Infecções Bacterianas , Melanoma , Camundongos , Animais , Hidrogéis/farmacologia , Hidrogéis/química , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antibacterianos/química , Cicatrização , Melanoma/tratamento farmacológico , Álcool de Polivinil/químicaRESUMO
BACKGROUND: Malnutrition-inflammation-atherosclerosis (MIA) syndrome may worsen the prognosis of peritoneal dialysis (PD) patients. Serum thymosin ß4 (sTß4) protects against inflammation, fibrosis and cardiac dysfunction. OBJECTIVES: The present study aimed to characterize the association between sTß4 and MIA syndrome as well as to investigate the potential of regulating sTß4 to improve the prognosis of PD patients. METHODS: We performed a cross-sectional, single-center pilot study involving 76 PD patients. Demographic characteristics, clinical characteristics, nutritional profiles, inflammatory mediators, atherosclerosis-related factors and sTß4 levels were collected and subjected to association analysis for sTß4 and MIA syndrome. RESULTS: sTß4 levels did not significantly vary with sex or primary disease in PD patients. Ages and PD features did not vary between patients with different levels of sTß4. PD patients with higher levels of sTß4 had significantly higher levels of nutritional indicators, including subjective global nutritional assessment (SGA) (p < 0.001) and serum albumin (ALB) (p < 0.001) but lower levels of inflammatory and atherosclerotic indicators, including serum C reaction protein (CRP) (p = 0.009), the right common carotid artery (RCCA) intimal thickness (p < 0.001) and the left common carotid artery (LCCA) intimal thickness (p = 0.02). Correlation analysis showed that sTß4 was positively associated with SGA (p < 0.001) and serum ALB (p < 0.001) but negatively associated with CRP (p = 0.020), RCCA intimal thickness (p < 0.001) and LCCA intimal thickness (p = 0.033). In multiple adjusted models, the prevalence of MIA syndrome was significantly decreased in PD patients with increased levels of sTß4 when patients without MIA syndrome were compared to those with all indicators of MIA syndrome (OR = 0.996, 95% CI 0.993-0.999, p = 0.003) or those with at least one indicator of MIA syndrome (OR = 0.997, 95% CI 0.995-0.998, p < 0.001). CONCLUSIONS: The sTß4 level decreases in PD patients with MIA syndrome. The prevalence of MIA syndrome decreases significantly as the level of sTß4 increases in PD patients.
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Aterosclerose , Falência Renal Crônica , Desnutrição , Diálise Peritoneal , Humanos , Estudos Transversais , Proteína C-Reativa/análise , Projetos Piloto , Biomarcadores , Inflamação/etiologia , Diálise Peritoneal/efeitos adversos , Desnutrição/etiologia , Albumina Sérica/análiseRESUMO
Rosai-Dorfman disease (RDD) is a non-malignant condition mainly manifesting as a proliferation of histiocytes in lymph nodes. Endotracheal RDD (ERDD) with an acute onset presentation is extremely rare. There are few case reports of ERDD mainly concerning its pathology, diagnostics and bronchoscopic treatment, without providing sufficient clinical information from a comprehensive perspective. As a novel and challenging technique, tracheal resection and reconstruction (TRR) with spontaneous-ventilation video-assisted thoracoscopic surgery (SV-VATS) has been reported as feasible and safe in highly selected patients, but few centres have shared their experience with this approach. This case-based discussion includes not only practical issues in the management of a life-threatening ERDD patient, but also specialists' views on the management of acute obstructive airway, and the surgeons' reflection on TRR with SV-VATS.
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Obstrução das Vias Respiratórias , Histiocitose Sinusal , Humanos , Histiocitose Sinusal/diagnóstico , Histiocitose Sinusal/cirurgia , Histiocitose Sinusal/patologia , Traqueia/cirurgia , Traqueia/patologia , Histiócitos/patologiaRESUMO
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). The authors have requested that this paper be retracted as they were unable to replicate the experimental data reported in Figure 1A. The authors posit that changes in reagents or experimental conditions might be the source of their inability to do so. Additional concerns were raised about the reliability of the Western blot results in Figure 1E, Figure 4B and F, Figure 5B, and Figure 6B, as regarding 'morphology space' similarities contained within a series of papers with distinctive eyebrow blots, tabulated here (https://docs.google.com/spreadsheets/d/149EjFXVxpwkBXYJOnOHb6RhAqT4a2llhj9LM60MBffM/edit#gid=0 [nam11.safelinks.protection.outlook.com] [nam11.safelinks.protection.outlook.com]). The journal requested the authors comment on these concerns and provide raw data. However, the authors were not able to fulfil this request and therefore the Editor-in-Chief decided to retract the article.
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Lesão Pulmonar Aguda/imunologia , Tecido Adiposo/patologia , Exossomos/metabolismo , Macrófagos/imunologia , Células-Tronco Mesenquimais/fisiologia , MicroRNAs/genética , Sepse/imunologia , Lesão Pulmonar Aguda/genética , Animais , Ceco/cirurgia , Diferenciação Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos , Células RAW 264.7 , Sepse/genética , Células Th2/imunologia , Receptor 4 Toll-Like/metabolismoRESUMO
Sepsis is characterized by a dysregulated immune response to infection leading to life-threatening organ dysfunction. Sepsis-induced liver injury is recognized as a powerful independent predictor of mortality in the intensive care unit. During systemic infections, the liver regulates immune defenses via bacterial clearance, production of acute-phase proteins (APPs) and cytokines, and metabolic adaptation to inflammation. Increased levels of inflammatory cytokines and impaired bacterial clearance and disrupted metabolic products can cause gut microbiota dysbiosis and disruption of the intestinal mucosal barrier. Changes in the gut microbiota play crucial roles in liver injury during sepsis. Bacterial translocation and resulting intestinal inflammation lead to a systemic inflammatory response and acute liver injury. The gut-liver crosstalk is a potential target for therapeutic interventions. This review analyzes the underlying mechanisms for the gut-liver crosstalk in sepsis-induced liver injury.
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Trato Gastrointestinal/fisiopatologia , Fígado/fisiopatologia , Sepse/complicações , Microbioma Gastrointestinal/fisiologia , Humanos , Fígado/anormalidades , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/fisiopatologia , Sepse/fisiopatologiaRESUMO
Myocardial infarction (MI) is a leading cause of mortality due to progression to ventricular arrhythmias (VAs) or heart failure (HF). Cardiac remodeling at the infarct border zone (IBZ) is the primary contributor for VAs or HF. Therefore, genes involved in IBZ remodeling may be potential targets for the treatment of MI, but the mechanism remains unclear. The present study aimed to explain the molecular mechanisms of IBZ remodeling based on the roles of long noncoding RNAs (lncRNAs). After downloading miRNA (GSE76592) and mRNA/lncRNA (GSE52313) datasets from the Gene Expression Omnibus database, 23 differentially expressed miRNAs (DEMs), 2,563 genes (DEGs) and 168 lncRNAs (DELs) were identified between IBZ samples of MI mice and sham controls. A total of 483 DEGs were predicted to be regulated by 23 DEMs, among which Itgam, Met and TNF belonged to hub genes after five topological parameters were calculated for genes in the proteinprotein interaction network. These hub genesassociated DEMs (mmumiR181a, mmumiR762) can also interact with six DELs (Gm15832, Gas5, Gm6634, Pvt1, Gm14636 and A330023F24Rik) to constitute the competing endogenous RNA (ceRNA) axes. Furthermore, a coexpression network was constructed based on the coexpression pairs between 44 DELs and 297 DEGs, in which Pvt1 and Bst1 were overlapped with the ceRNA network. Thus, Bst1associated ceRNA (Pvt1mmumiR181aBst1) and coexpression (PvtBst1) axes were also pivotal for MI. Accordingly, Pvt1 may be a crucial lncRNA for modification of cardiac remodeling in the IBZ after MI and may function by acting as a ceRNA for miR181a to regulate TNF/Met/Itgam/Bst1 or by coexpressing with Bst1.
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Infarto do Miocárdio/genética , RNA Longo não Codificante/genética , Regulação para Cima , Remodelação Ventricular/genética , Animais , Biologia Computacional , Bases de Dados Genéticas , Modelos Animais de Doenças , Redes Reguladoras de Genes , Humanos , Camundongos , MicroRNAs/genética , Infarto do Miocárdio/complicaçõesRESUMO
Acute pancreatitis (AP) is an inflammatory disease with high morbidity and mortality. Dysregulation of microRNAs (miRNAs) was involved in human diseases, including AP. However, the effects of miR-92b-3p on AP process and its mechanism remain not been fully clarified. The expression levels of miR-92b-3p and tumor necrosis factor receptor-associated factor-3 (TRAF3) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of TRAF3, tumor necrosis factor α (TNF-α) TNF-α, interleukin-6 (IL-6), phosphorylated mitogen-activated protein kinase kinase 3 (p-MKK3), MKK3, p38 and phosphorylated p38 (p-p38) were detected by western blot. The concentration of TNF-α and IL-6 in the medium was measured using ELISA kits. The possible binding sites of miR-92b-3p and TRAF3 were predicted by TargetScan and verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The expression level of miR-92b-3p was decreased and TRAF3 expression was increased in AR42J cells stimulated with caerulein. Moreover, the protein levels of pro-inflammatory cytokines (TNF-α and IL-6) were markedly elevated, and the expression levels of autophagy-related markers Beclin1 as well as the ratio of LC3-II/I were obviously increased in AR42J cells treated with caerulein. In addition, overexpression of miR-92b-3p or knockdown of TRAF3 significantly suppressed the release of pro-inflammatory cytokines and autophagy in caerulein-induced AR42J cells. Furthermore, TRAF3 was a direct target of miR-92b-3p and its upregulation reversed the effects of miR-92b-3p overexpression on inflammatory response and autophagy. Besides, overexpression of miR-92b-3p inhibited the activation of the MKK3-p38 pathway by affecting TRAF3 expression. In conclusion, miR-92b-3p attenuated inflammatory response and autophagy by downregulating TRAF3 and suppressing MKK3-p38 pathway in caerulein-induced AR42J cells, providing a novel avenue for treatment of AP.
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Autofagia , MicroRNAs/genética , MicroRNAs/metabolismo , Fator 3 Associado a Receptor de TNF/genética , Fator 3 Associado a Receptor de TNF/metabolismo , Células Acinares/metabolismo , Animais , Autofagia/genética , Linhagem Celular , Ceruletídeo/toxicidade , Citocinas/metabolismo , Inflamação/genética , MAP Quinase Quinase 3/metabolismo , MicroRNAs/imunologia , Pâncreas/metabolismo , Ratos , Transdução de Sinais/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
N6-methyladenosine (m6A) plays important roles in regulating messenger RNA processing. Despite rapid progress in this field, little is known about the genetic determinants of m6A modification and their role in common diseases. In this study, we mapped the quantitative trait loci (QTLs) of m6A peaks in 60 Yoruba (YRI) lymphoblastoid cell lines. We found that m6A QTLs are largely independent of expression and splicing QTLs and are enriched with binding sites of RNA-binding proteins, RNA structure-changing variants and transcriptional features. Joint analysis of the QTLs of m6A and related molecular traits suggests that the downstream effects of m6A are heterogeneous and context dependent. We identified proteins that mediate m6A effects on translation. Through integration with data from genome-wide association studies, we show that m6A QTLs contribute to the heritability of various immune and blood-related traits at levels comparable to splicing QTLs and roughly half of expression QTLs. By leveraging m6A QTLs in a transcriptome-wide association study framework, we identified putative risk genes of these traits.
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Adenosina/análogos & derivados , RNA Mensageiro/genética , Adenosina/genética , Mapeamento Cromossômico/métodos , Testes Genéticos/métodos , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Fenótipo , Locos de Características Quantitativas/genética , Característica Quantitativa Herdável , Splicing de RNA/genética , Transcriptoma/genéticaRESUMO
AKI is a common clinical condition associated with the risk of developing CKD and ESKD. Sepsis is the leading cause of AKI in the intensive care unit (ICU) and accounts for nearly half of all AKI events. Patients with AKI who require dialysis have an unacceptably high mortality rate of 60%-80%. During sepsis, endothelial activation, increased microvascular permeability, changes in regional blood flow distribution with resulting areas of hypoperfusion, and hypoxemia can lead to AKI. No effective drugs to prevent or treat human sepsis-induced AKI are currently available. Recent research has identified dysfunction in energy metabolism as a critical contributor to the pathogenesis of AKI. Mitochondria, the center of energy metabolism, are increasingly recognized to be involved in the pathophysiology of sepsis-induced AKI and mitochondria could serve as a potential therapeutic target. In this review, we summarize the potential role of mitochondria in sepsis-induced AKI and identify future therapeutic approaches that target mitochondrial function in an effort to treat sepsis-induced AKI.
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Injúria Renal Aguda/etiologia , Mitocôndrias/fisiologia , Sepse/complicações , Injúria Renal Aguda/tratamento farmacológico , Antioxidantes/uso terapêutico , Metabolismo Energético , Humanos , Mitocôndrias/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/metabolismoRESUMO
Sepsis is the leading cause of acute kidney injury (AKI) in the intensive care unit. As the most common treatment of septic AKI, it is believed that continuous renal replacement therapy (CRRT) can not only maintain the water balance and excrete the metabolic products but also regulate the inflammation and promote kidney recovery. CRRT can remove the inflammatory cytokines to regulate the metabolic adaption in kidney and restore the kidney recovery to protect the kidney in septic AKI. Second, CRRT can provide extra energy supply in septic AKI to improve the kidney energy balance in septic AKI. Third, the anticoagulant used in CRRT also regulates the inflammation in septic AKI. CRRT is not only a treatment to deal with the water balance and metabolic products, but also a method to regulate the inflammation in septic AKI.
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Metabolismo Energético , Rim , Recuperação de Função Fisiológica , Terapia de Substituição Renal , Sepse , Equilíbrio Hidroeletrolítico , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/fisiopatologia , Injúria Renal Aguda/terapia , Humanos , Rim/metabolismo , Rim/fisiopatologia , Sepse/metabolismo , Sepse/fisiopatologia , Sepse/terapiaRESUMO
OBJECTIVE: To study the risks on acute cerebral stroke (ACS) inducing systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). METHODS: Data from 1751 patients with acute cerebral stroke were studied by prospective analysis. RESULTS: In all of the ACS patients,the incidence rate (IR) of SIRS was 36.50% with 205 patients having ACS inducing MODS, to which the IR was 11.71%, and 93 deaths. The case fatality ratio (CFR) was 45.37%. The pathogeneses condition of patients and the MR after the occurrence of MODS had positive correlation with the numbers of dysfunction organs. Study on single factor analysis revealed that the incidence of MODS had some related risk factors in the ACS inducing MODS, including age, diseased region close to the mean line, GCS, level of blood sugar, blood white cell count and the chronic disease history etc. The IR of ACS inducing SIRS and MODS was much higher in the condition of the diseased region near the mean line and the ACS of the basilar artery system. CONCLUSION: SIRS seemed the base for MODS while the probability and the development degree were not only involved ACS but also SIRS. MODS induced by ACS could be reduced through the second grade program of disease precaution. The detection of those risk factors in the early period of the ACS course could provide some prediction of the prognosis and turnover, thus some early use of intervention methods might be helpful in the treatment of the disease.