RESUMEN
Conventional wound dressings are monolithically designed to cover the injured areas as well as absorb the exudates at injured site. Furthermore, antibacterial drugs and growth prompting factors are additionally appended to realize sensible and omnibearing wound management, exhibiting long and tedious treatment process in practice. Consequently, the creation of multifunctional wound dressings that combines wound repair enhancement with antibacterial properties turns out to be significant for simplifying wound managements. In our investigation, electronegative human epidermal growth factor (hEGF) was combined with the positively charged Zn-Al layered double hydroxides (Zn-Al LDHs) via electrostatic interaction while the obtained hEGF/LDH was integrated with sodium hyaluronate hydrogel (SH) hydrogel, forming a composite hydrogel with synergistic benefits for wound management. The innovative hEGF/LDH@SH hydrogel equipped with fine biocompatibility was designed to optimize wound healing in which hEGF stimulates epithelial cell growth while LDH released antibacterial factor Zn2+ against Methicillin-resistant staphylococcus aureus (MRSA) and Escherichia coli (E.coli) under acidic wound environment. Additionally, the SH hydrogel constructed a three-dimensional structure that not only safeguarded the wound area but also maintained a moist environment conducive to recovery. The synthesized hEGF/LDH was confirmed via fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and thermo-gravimetry (TG) measurements. The release of Zn2+ from Zn-Al LDH under acid circumstance was detected via inductively coupled plasma (ICP) and the in vitro bactericidal experiments endowed the antibacterial property of hEGF/LDH@SH hydrogel. In vitro drug release experiments illustrated the controlled-release of hEGF from hEGF/LDH which promoted the long-term affect of hEGF at wound site. In vitro cell experiments verified that the hEGF/LDH@SH hydrogel motivated the promotion on cell proliferation and migration without cytotoxicity. An in vivo study of the repairing of MRSA-infected wound in mice indicated that hEGF/LDH@SH hydrogel serves as a simple and novel, innoxious and efficient wound healing approach. This brand new hydrogel possesses properties of promoting the regeneration of skin tissue, achieving antimicrobial therapy without any accessional antibacterial drugs as well as realizing controlled release of hEGF.
Asunto(s)
Antibacterianos , Ácido Hialurónico , Hidrogeles , Staphylococcus aureus Resistente a Meticilina , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/química , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Hidrogeles/química , Hidrogeles/farmacología , Animales , Ratones , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Humanos , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Factor de Crecimiento Epidérmico/farmacología , Factor de Crecimiento Epidérmico/química , Pruebas de Sensibilidad Microbiana , Zinc/química , Zinc/farmacología , Concentración de Iones de HidrógenoRESUMEN
BACKGROUND: Autoimmune hepatitis (AIH) is an immune-mediated liver disease of unknown etiology accompanied by intestinal dysbiosis and a damaged intestinal barrier. Berberine (BBR) is a traditional antibacterial medicine that has a variety of pharmacological properties. It has been reported that BBR alleviates AIH, but relevant mechanisms remain to be fully explored. METHODS: BBR was orally administered at doses of 100 mgâ kg-1â d-1 for 7 days to mice before concanavalin A-induced AIH model establishment. Histopathological, immunohistochemical, immunofluorescence, western blotting, ELISA, 16S rRNA analysis, flow cytometry, real-time quantitative PCR, and fecal microbiota transplantation studies were performed to ascertain BBR effects and mechanisms in AIH mice. RESULTS: We found that liver necrosis and apoptosis were decreased upon BBR administration; the levels of serum transaminase, serum lipopolysaccharide, liver proinflammatory factors TNF-α, interferon-γ, IL-1ß, and IL-17A, and the proportion of Th17 cells in spleen cells were all reduced, while the anti-inflammatory factor IL-10 and regulatory T cell proportions were increased. Moreover, BBR treatment increased beneficial and reduced harmful bacteria in the gut. BBR also strengthened ileal barrier function by increasing the expression of the tight junction proteins zonula occludens-1 and occludin, thereby blocking lipopolysaccharide translocation, preventing lipopolysaccharide/toll-like receptor 4 (TLR4)/ NF-κB pathway activation, and inhibiting inflammatory factor production in the liver. Fecal microbiota transplantation from BBR to model mice also showed that BBR potentially alleviated AIH by altering the gut microbiota. CONCLUSIONS: BBR alleviated concanavalin A-induced AIH by modulating the gut microbiota and related immune regulation. These results shed more light on potential BBR therapeutic strategies for AIH.
Asunto(s)
Berberina , Microbioma Gastrointestinal , Hepatitis A , Hepatitis Autoinmune , Ratones , Animales , Hepatitis Autoinmune/tratamiento farmacológico , Hepatitis Autoinmune/etiología , Berberina/farmacología , Berberina/uso terapéutico , Concanavalina A/farmacología , Lipopolisacáridos/farmacología , ARN Ribosómico 16SRESUMEN
Alcoholic liver disease (ALD) is a globally prevalent liver-related disorder characterized by severe oxidative stress and inflammatory liver damage, for which no effective treatment is currently available. Hydrogen gas (H2) has been demonstrated to be an efficient antioxidant in various diseases in animals as well as humans. However, the protective effects of H2 on ALD and its underlying mechanisms remain to be elucidated. The present study demonstrated that H2 inhalation ameliorated liver injury, and attenuated liver oxidative stress, inflammation, and steatosis in an ALD mouse model. Moreover, H2 inhalation improved gut microbiota, including increasing the abundance of Lachnospiraceae and Clostridia, and decreasing the abundance of Prevotellaceae and Muribaculaceae, and also improved intestinal barrier integrity. Mechanistically, H2 inhalation blocked activation of the LPS/TLR4/NF-κB pathway in liver. Notably, it was further demonstrated that the reshaped gut microbiota may accelerate alcohol metabolism, regulate lipid homeostasis and maintain immune balance by bacterial functional potential prediction (PICRUSt). Fecal microbiota transplantation from mice that had undergone H2 inhalation significantly alleviated acute alcoholic liver injury. In summary, the present study showed that H2 inhalation alleviated liver injury by reducing oxidative stress and inflammation, while also improving intestinal flora and enhancing the intestinal barrier. H2 inhalation may serve as an effective intervention for preventing and treating ALD in a clinical context.
Asunto(s)
Microbioma Gastrointestinal , Hepatopatías Alcohólicas , Humanos , Ratones , Animales , Antioxidantes/uso terapéutico , Antioxidantes/metabolismo , Microbioma Gastrointestinal/fisiología , Hígado/metabolismo , Inflamación/metabolismo , Antiinflamatorios/uso terapéutico , Antiinflamatorios/metabolismo , Ratones Endogámicos C57BLRESUMEN
Autoimmune hepatitis (AIH) is a liver disease characterized by chronic liver inflammation. The intestinal barrier and microbiome play critical roles in AIH progression. AIH treatment remains challenging because first-line drugs have limited efficacy and many side effects. Thus, there is growing interest in developing synbiotic therapies. This study investigated the effects of a novel synbiotic in an AIH mouse model. We found that this synbiotic (Syn) ameliorated liver injury and improved liver function by reducing hepatic inflammation and pyroptosis. The Syn reversed gut dysbiosis, as indicated by an increase in beneficial bacteria (e.g., Rikenella and Alistipes) and a decrease in potentially harmful bacteria (e.g., Escherichia-Shigella) and lipopolysaccharide (LPS)-bearing Gram-negative bacterial levels. The Syn maintained intestinal barrier integrity, reduced LPS, and inhibited the TLR4/NF-κB and NLRP3/Caspase-1 signaling pathway. In addition, microbiome phenotype prediction by BugBase and bacterial functional potential prediction using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) showed that Syn improved gut microbiota function involving inflammatory injury, metabolism, immune response, and pathopoiesia. Furthermore, the new Syn was as effective as prednisone against AIH. Therefore, this novel Syn could be a candidate drug for alleviating AIH through its anti-inflammatory and antipyroptosis properties that relieve endothelial dysfunction and gut dysbiosis. IMPORTANCE Synbiotics can ameliorate liver injury and improve liver function by reducing hepatic inflammation and pyroptosis. Our data indicate that our new Syn not only reverses gut dysbiosis by increasing beneficial bacteria and decreasing lipopolysaccharide (LPS)-bearing Gram-negative bacteria but also maintains intestinal barrier integrity. Thus, its mechanism might be associated with modulating gut microbiota composition and intestinal barrier function by inhibiting the TLR4/NF-κB/NLRP3/pyroptosis signaling pathway in the liver. This Syn is as effective as prednisone in treating AIH without side effects. Based on these findings, this novel Syn represents a potential therapeutic agent for AIH in clinical practice.
Asunto(s)
Microbioma Gastrointestinal , Hepatitis Autoinmune , Simbióticos , Animales , Ratones , FN-kappa B/genética , Lipopolisacáridos/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Receptor Toll-Like 4/genética , Disbiosis/tratamiento farmacológico , Prednisona/farmacología , Filogenia , Transducción de Señal , InflamaciónRESUMEN
Alcoholic liver disease (ALD) is a worldwide health threaten lack of effective treatment. Gut dysbiosis and concomitant augmented intestinal permeability are strongly implicated in the pathogenesis and progression of ALD. Research on the protective effect of probiotics on ALD is limited, and more effective intestinal microecological regulators and the related mechanisms still need to be further explored. In the present study, the protective effects and mechanisms of a compound probiotic against acute alcohol-induced liver injury in vivo were explod. It was showed that the compound probiotic ameliorated liver injury in acute ALD mice and stabilized the levels of ALT, AST, and TG in serum. The compound probiotic reversed acute alcohol-induced gut dysbiosis and maintained the intestinal barrier integrity by upregulating the production of mucus and the expression of tight junction (TJ) proteins and thus reduced LPS level in liver. Meanwhile, the compound probiotic reduced inflammation level by inhibiting TLR4/NF-κB signaling pathway and suppressed oxidative stress level in liver. Furthermore, the compound probiotic alleviated liver lipid accumulation by regulating fatty acid metabolism-associated genes and AMPK-PPARα signaling pathway. Noteworthy, fecal microbiota transplantation (FMT) realized comparable protective effect with that of compound probiotic. In conclusion, present study demonstrates the beneficial effects and underlying mechanism of the compound probiotic against acute alcohol-induced liver injury. It provides clues for development of novel strategy for treatment of ALD.
Asunto(s)
Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Microbioma Gastrointestinal , Hepatopatías Alcohólicas , Probióticos , Ratones , Animales , Disbiosis/terapia , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/complicaciones , Hepatopatías Alcohólicas/tratamiento farmacológico , EtanolRESUMEN
Nonresponse, or acquired resistance to immune checkpoint inhibitors in colorectal cancer (CRC) highlight the importance of finding potential tolerance mechanisms. Low expression of major histocompatibility complex, class I (MHC-I) on the cell surface of the tumor is one of the main mechanisms of tumor escape from T-cell recognition and destruction. In this study, we demonstrated that a high level of calnexin (CANX) in the tumors is positively correlated with the overall survival in colorectal cancer patients. CANX is a chaperone protein involved in the folding and assembly of MHC-I molecules. Using miRNA target prediction databases and luciferase assays, we identified miR-148a-3p as a potential regulator of CANX. Inhibition of miR-148a-3p restores surface levels of MHC-I and significantly enhanced the effects of CD8+ T-cell-mediated immune attack in vitro and in vivo by promoting CANX expression. These results reveal that miR-148a-3p can function as a tumor promotor in CRC by targeting the CANX/MHC-I axis, which provides a rationale for immunotherapy through targeting the miR-148a-3p/CANX/MHC-I pathway in patients with CRC.