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This study aimed to develop an intranasal nanovaccine by combining chiral nanoparticles with the RSV pre-fusion protein (RSV protein) to create L-nanovaccine (L-Vac). The results showed that L-NPs increased antigen attachment in the nasal cavity by 3.83 times and prolonged its retention time to 72 h. In vivo experimental data demonstrated that the intranasal immunization with L-Vac induced a 4.86-fold increase in secretory immunoglobulin A (sIgA) secretion in the upper respiratory tract, a 1.85-fold increase in the lower respiratory tract, and a 20.61-fold increase in RSV-specific immunoglobin G (IgG) titer levels in serum, compared with the commercial Alum Vac, while the neutralizing activity against the RSV authentic virus is 1.66-fold higher. The mechanistic investigation revealed that L-Vac activated the tumor necrosis factor (TNF) signaling pathway in nasal epithelial cells (NECs), in turn increasing the expression levels of interleukin-6 (IL-6) and C-C motif chemokine ligand 20 (CCL20) by 1.67-fold and 3.46-fold, respectively, through the downstream nuclear factor kappa-B (NF-κB) signaling pathway. Meanwhile, CCL20 recruited dendritic cells (DCs) and L-Vac activated the Toll-like receptor signaling pathway in DCs, promoting IL-6 expression and DCs maturation, and boosted sIgA production and T-cell responses. The findings suggested that L- Vac may serve as a candidate for the development of intranasal medicine against various types of respiratory infections.
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Respiratory Syncytial Virus (RSV) is a leading cause of acute lower respiratory infections, imposing a substantial burden on healthcare systems globally. While lipid disorders have been observed in the lungs of infants and young children with RSV pneumonia, the specific characterization of these lipids and their roles in the development and progression of RSV pneumonia remain largely unexplored. To address this tissue, we established a non-targeted high-resolution lipidomics platform using UHPLC-Q-Exactive-MS to analyze lipid profiles in bronchoalveolar lavage fluid (BALF) obtained from mice infected with RSV. Through the lipidomics analysis, a total of 72 lipids species were identified, with 40 lipids were significantly changed. Notably, the primary changes were observed in ether phospholipids and lysophospholipids. Furthermore, a targeted lipidomics analysis utilizing UHPLC-QQQ-MS/MS was developed to specifically assess the levels of lysophospholipids, including lysophosphocholine 16:0 (LPC 16:0), lysophosphoethanolamine 16:0 (LPE 16:0) and lysophosphoglycerol 16:0 (LPG 16:0), in RSV-infected mice compared to control mice. Animal experiments revealed that LPE 16:0, rather than LPC 16:0 or LPG 16:0, provided protection against RSV-induced weight loss, reduced lung viral load, regulated immune cells and mitigated lung injury in mice afflicted with RSV pneumonia. In summary, our findings suggested that the host responses to RSV infection pathology are closely with various lipid metabolic. Additionally, our results elucidated novel biological functions of LPE 16:0 and offering new avenues for drug development against RSV pneumonia.
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Líquido da Lavagem Broncoalveolar , Lipidômica , Lisofosfolipídeos , Infecções por Vírus Respiratório Sincicial , Espectrometria de Massas em Tandem , Animais , Lipidômica/métodos , Camundongos , Espectrometria de Massas em Tandem/métodos , Lisofosfolipídeos/metabolismo , Líquido da Lavagem Broncoalveolar/química , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Camundongos Endogâmicos BALB C , Pulmão/virologia , Pulmão/metabolismo , Modelos Animais de Doenças , Vírus Sinciciais Respiratórios/efeitos dos fármacos , HumanosRESUMO
OBJECTIVE: Bushen Zhuyun Decoction (BSZY), a traditional Chinese herbal prescription has shown promising effects on gynecological infertility, but the mechanism for endometrial receptivity is still unclear. This study aimed to investigate the regulatory effects of BSZY on endometrial receptivity, which plays a key role in colonization of embryo, and its regulatory mechanisms associated with NF- κB/NLRP3 pathway. METHODS: SD rats at reproductive age with affected endometrial receptivity was established using mifepristone (RU486), and the regulatory effects of BSZY on endometrial receptivity were evaluated by H&E staining, and changes in sex hormones by ELISA and Western blot. Moreover, human endometrial RL95-2 cells were treated with H2O2, and inflammatory cytokines in rats and RL95-2 cells were analyzed by ELISA. The activation of NF-κB/NLRP3 signaling pathway in RL95-2 cells were characterized using immunofluorescence and Western blot. Mitochondrial morphology and function in RL95-2 cells were observed by transmission electron microscope and cell mitochondrial stress test. RESULTS: BSZY increased uterine endometrial thickness and attenuate histopathological changes induced by RU486. BSZY can regulate endometrial estrogen receptor and progesterone receptor, and the levels of sex hormones and inflammatory cytokines in pregnant rats. BSZY-containing serum also showed strong anti-inflammatory and cytoprotective effects in vitro. In addition, BSZY-containing serum inhibited the activation of NF-κB/NLRP3 signaling pathway, and improve mitochondrial morphology and function in RL95-2 cells. CONCLUSION: BSZY can improve endometrial receptivity, potentially by improving mitochondrial morphology and function to inhibit the activation of NF-κB/NLRP3 signaling pathway in endometrial cells, thus regulate inflammation to improve endometrial receptivity.
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Allergic rhinitis (AR) is a prevalent upper airway chronic inflammatory disease in children worldwide. The role of bioactive lipids in the regulation of AR has been recognized, but the underlying serum lipidomic basis of its pathology remains unclear. We utilized ultra-performance liquid chromatography (UPLC)-Q-Exactive Orbitrap/mass spectrometry (MS) to investigate the serum lipidomic profiles of children with AR. The lipidomic analysis identified 42 lipids that were differentially expressed (p < 0.05, fold change > 2) between the AR (n = 75) and normal control groups (n = 44). Specifically, the serum levels of diacylglycerol (DG), triacylglycerol (TG), fatty acid (FA), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine, phosphatidyl-ethanolamine, and cardiolipins were significantly higher in the AR group. The diagnostic potential of the identified lipids was further evaluated using receiver operating characteristic curve analysis. The analysis revealed that five lipids, including FA 30:7, LPC O-18:1, LPC 18:0, LPC 16:0, and DG 34:0, had area under the curve values greater than 0.9 (p < 0.05). Furthermore, serum levels of IgE and IL-33, markers of AR severity, were found to have a significant positive correlation (p < 0.05) with DGs, LPCs, TGs, and FAs in AR patients. This study revealed the lipid disorders associated with AR and its severity, providing new insights into the pathological process of AR.
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Lipidômica , Lipídeos , Rinite Alérgica , Humanos , Criança , Lipidômica/métodos , Masculino , Feminino , Rinite Alérgica/sangue , Lipídeos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Biomarcadores/sangue , Pré-Escolar , Interleucina-33/sangue , Índice de Gravidade de Doença , Imunoglobulina E/sangue , Adolescente , Espectrometria de Massas/métodosRESUMO
Dexamethasone, a glucocorticoid commonly used in pediatric patients, has potent anti-inflammatory and immunosuppressive properties. However, it is associated with side effects such as reduced lung function and decreased immunity. Pulmonary surfactant lipids are closely linked to lung disease and play a role in reducing surface tension, immune response and antiviral activity. The dysregulation of lipid metabolism is closely associated with lung disease. Hence, untargeted lipidomics may be instrumental in elucidating the effects of dexamethasone on pulmonary surfactant lipids. We obtained surfactant lipid samples from the bronchoalveolar lavage fluid of young mice injected subcutaneously with dexamethasone and conducted a comprehensive lipidomic analysis, comparing them with a control group. We observed a decrease in lipids, such as phosphatidylcholine, phosphatidylglycerol and phosphatidylethanolamine, and an increase in ceramide, fatty acid, diacylglycerol and monoglyceride, which may impact lung health. This study revealed the influence of dexamethasone on pulmonary surfactant lipids, offering new insights into adverse reactions in clinical settings.
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Líquido da Lavagem Broncoalveolar , Dexametasona , Lipidômica , Lipídeos , Surfactantes Pulmonares , Animais , Lipidômica/métodos , Dexametasona/farmacologia , Surfactantes Pulmonares/análise , Surfactantes Pulmonares/metabolismo , Camundongos , Líquido da Lavagem Broncoalveolar/química , Lipídeos/química , Lipídeos/análise , Camundongos Endogâmicos C57BL , Metabolismo dos Lipídeos/efeitos dos fármacos , MasculinoRESUMO
Introduction: Respiratory syncytial virus (RSV) fusion (F) protein is essential for facilitating virus entry into host cells, providing a hopeful path for combating viral diseases. However, F protein inhibitors can rapidly select for viral resistance. Thus, discovering new inhibitors of F-protein is necessary to enrich the RSV drug development pipeline. Methods: In this study, we screen 25 bioactive compounds from Chinese herbal medicines that exhibit a strong binding to the RSV-F protein using surface plasmon resonance. Results: After screening, we found emodin could strongly bind to RSV-F protein, and could effectively curb RSV infection. Further investigations certificated that emodin specifically disrupts the attachment and internalization phases of RSV infection by targeting the RSV-F protein. In vivo studies with mice infected with RSV demonstrated that emodin effectively reduces lung pathology. This therapeutic effect is attributed to emodin's capacity to diminish pro-inflammatory cytokine production and reduce viral load in the lungs. Discussion: In conclusion, our findings provide initial insights into the mechanism by which emodin counters RSV infection via engagement with the RSV-F protein, establishing it as a viable contender for the development of novel therapeutic agents aimed at RSV.
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BACKGROUND: Quercetin has received extensive attention for its therapeutic potential treating respiratory syncytial virus (RSV) infection diseases. Recent studies have highlighted quercetin's ability of suppressing alveolar macrophages (AMs)-derived lung inflammation. However, the anti-inflammatory mechanism of quercetin against RSV infection still remains elusive. PURPOSE: This study aims to elucidate the mechanism about quercetin anti-inflammatory effect on RSV infection. METHODS: BALB/c mice were intranasally infected with RSV and received quercetin (30, 60, 120 mg/kg/d) orally for 3 days. Additionally, an in vitro infection model utilizing mouse alveolar macrophages (MH-S cells) was employed to validate the proposed mechanism. RESULTS: Quercetin exhibited a downregulatory effect on glycolysis and tricarboxylic acid (TCA) cycle metabolism in RSV-infected AMs. However, it increased itaconic acid production, a metabolite derived from citrate through activating immune responsive gene 1 (IRG1), and further inhibiting succinate dehydrogenase (SDH) activity. While the suppression of SDH activity orchestrated a cascading downregulation of Hif-1α/NLRP3 signaling, ultimately causing AMs polarization from M1 to M2 phenotypes. CONCLUSION: Our study demonstrated quercetin stimulated IRG1-mediated itaconic acid anabolism and further inhibited SDH/Hif-1α/NLRP3 signaling pathway, which led to M1 to M2 polarization of AMs so as to ameliorate RSV-induced lung inflammation.
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Subunidade alfa do Fator 1 Induzível por Hipóxia , Macrófagos Alveolares , Camundongos Endogâmicos BALB C , Proteína 3 que Contém Domínio de Pirina da Família NLR , Quercetina , Infecções por Vírus Respiratório Sincicial , Succinatos , Animais , Succinatos/farmacologia , Macrófagos Alveolares/efeitos dos fármacos , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Quercetina/farmacologia , Camundongos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Succinato Desidrogenase/metabolismo , Glicólise/efeitos dos fármacos , Feminino , Transdução de Sinais/efeitos dos fármacos , Ciclo do Ácido Cítrico/efeitos dos fármacos , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , HidroliasesRESUMO
Resveratrol, renowned as an antioxidant, also exhibits significant potential in combatting severe respiratory infections, particularly the respiratory syncytial virus (RSV). Nevertheless, the specific mechanism underlying its inhibition of RSV replication remains unexplored. Heparan sulfate proteoglycans (HSPGs) play a pivotal role as attachment factors for numerous viruses, offering a promising avenue for countering viral infections. Our research has unveiled that resveratrol effectively curbs RSV infection in a dose-dependent manner. Remarkably, resveratrol disrupts the early stages of RSV infection by engaging with HSPGs, rather than interacting with RSV surface proteins like fusion (F) protein and glycoprotein (G). Resveratrol's affinity appears to be predominantly directed towards the negatively charged sites on HSPGs, thus impeding the binding of viral receptors. In an in vivo study involving RSV-infected mice, resveratrol demonstrates its potential by ameliorating pulmonary pathology. This improvement is attributed to the inhibition of pro-inflammatory cytokine expression and a reduction in viral load within the lungs. Notably, resveratrol specifically alleviates inflammation characterized by an abundance of neutrophils in RSV-infected mice. In summation, our data first shows how resveratrol combats RSV infection through interactions with HSPGs, positioning it as a promising candidate for innovative drug development targeting RSV infections. Our study provides insight into the mechanism of resveratrol antiviral infection.
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Infecções por Vírus Respiratório Sincicial , Vírus Sinciciais Respiratórios , Animais , Camundongos , Vírus Sinciciais Respiratórios/fisiologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/patologia , Proteoglicanas de Heparan Sulfato/farmacologia , Resveratrol/farmacologia , Pulmão/patologiaRESUMO
Diseases in pregnancy endanger millions of fetuses worldwide every year. The onset of these diseases can be early warned by the dynamic abnormalities of biochemicals in amniotic fluid, thus requiring real-time monitoring. However, when continuously penetrated by detection devices, the amnion is prone to loss of robustness and rupture, which is difficult to regenerate. Here, an interface-stabilized fiber sensor is presented for real-time monitoring of biochemical dynamics in amniotic fluid during pregnancy. The sensor is seamlessly integrated into the amnion through tissue adhesion, amniotic regeneration, and uniform stress distribution, posing no risk to the amniotic fluid environment. The sensor demonstrates a response performance of less than 0.3% fluctuation under complex dynamic conditions and an accuracy of more than 98% from the second to the third trimester. By applying it to early warning of diseases such as intrauterine hypoxia, intrauterine infection, and fetal growth restriction, fetal survival increases to 95% with timely intervention.
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Âmnio , Líquido Amniótico , Gravidez , Feminino , HumanosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Allergic asthma is a recurring respiratory condition that typically manifests during childhood or adolescence. It is characterized by a dominant type II immune response triggered by the identification and capturing of inhaled allergens by dendritic cells (DCs). Jiangqi Pingxiao Formula (JQPXF), a prescription medicine used for the treatment of pediatric asthma, has been clinically proven to be both safe and effective. However, its mechanism of action in the treatment of asthma has not been fully been fully elucidated. Recent research suggests that several natural compounds have the potential to target dendritic cells (DCs) and alleviate ovalbumin (OVA)-induced asthma, which may also be found within JQPXF. AIM OF THE STUDY: This study aimed to elucidate the effect of JQPXF on OVA-induced asthma model and its molecular mechanism targeting DCs. MATERIALS AND METHODS: The main constituents of JQPXF were analyzed by ultra performance liquid chromatography (UPLC). An asthma model was established by OVA. Hematoxylin-eosin staining and measurement of respiratory function was used to evaluate the treatment effect of JQPXF on asthmatic mice. Cytokine (IL-5, IL-13 and IgE) concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Flow cytometry was employed to evaluate inflammatory cell infiltration (T helper 2 cells and DCs) in vivo and DC survival in vivo and vitro. Western blot and immunofluorescence were used to verify the molecular mechanisms. RESULTS: The results suggest that JQPXF can ameliorate pathological conditions and improve lung function in asthmatic mice, as well as the Th2 cells. Treatment with JQPXF significantly reduced the number of DCs and increased the number of Propidium iodide+ (PI) DCs. Furthermore, JQPXF upregulated protein levels of the pro-apoptotic factors Cleaved-caspase-3 and Bax, while downregulating the anti-apoptotic factor Bcl-2. Simultaneously, JQPXF increased autophagy levels by facilitating p62 degradation and promoting translation from LC3B I to LC3B II of DCs in vitro, as well as reducing the integrated optical density (IOD) of p62 within the CD11c-positive area in the lung. 3-Methyladenine (3-MA) was used to block autophagic flux and the apoptotic effect of JQPXF on DCs was abolished in vitro, with the number of DCs decreased by JQPXF being reversed in vivo. We further investigated the upstream key regulator of autophagy, the AMPK/mTOR pathway, and found that JQPXF increased AMPK phosphorylation while decreasing mTOR phosphorylation levels. Additionally, we employed Compound C (CC) as an AMPK inhibitor to inhibit this signaling pathway, and our findings revealed that both autophagic flux and apoptotic levels in DCs were abolished in vitro. CONCLUSIONS: In summary, we have demonstrated that JQPXF could alleviate type II inflammation in an asthmatic model by promoting the apoptosis of DCs through an autophagy-dependent mechanism, achieved by regulating the AMPK/mTOR signaling pathway.
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Proteínas Quinases Ativadas por AMP , Asma , Humanos , Criança , Camundongos , Animais , Ovalbumina , Proteínas Quinases Ativadas por AMP/metabolismo , Modelos Animais de Doenças , Asma/induzido quimicamente , Asma/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo , Autofagia , Células Dendríticas , Apoptose , Camundongos Endogâmicos BALB CRESUMO
Interferon-gamma (IFN-γ) signaling is necessary for the proinflammatory activation of macrophages but IFN-γ-independent pathways, for which the initiating stimuli and downstream mechanisms are lesser known, also contribute. Here we identify, by high-content screening, SEPTIN2 (SEPT2) as a negative regulation of IFN-γ-independent macrophage autoactivation. Mechanistically, endoplasmic reticulum (ER) stress induces the expression of SEPT2, which balances the competition between acetylation and ubiquitination of heat shock protein 5 at position Lysine 327, thereby alleviating ER stress and constraining M1-like polarization and proinflammatory cytokine release. Disruption of this negative feedback regulation leads to the accumulation of unfolded proteins, resulting in accelerated M1-like polarization, excessive inflammation and tissue damage. Our study thus uncovers an IFN-γ-independent macrophage proinflammatory autoactivation pathway and suggests that SEPT2 may play a role in the prevention or resolution of inflammation during infection.
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Interferon gama , Ativação de Macrófagos , Humanos , Interferon gama/metabolismo , Macrófagos/metabolismo , Citocinas/metabolismo , Inflamação/metabolismoRESUMO
Research on novel bioactive lipids has garnered increasing interest. Although lipids can be identified by searching mass spectral libraries, the discovery of novel lipids remains challenging as the query spectra of such lipids are not included in libraries. In this study, we propose a strategy to discover novel carboxylic acid-containing acyl lipids by integrating molecular networking with an extended in silico spectral library. Derivatization was performed to improve the response of this method. The tandem mass spectrometry spectra enriched by derivatization facilitated the formation of molecular networking and 244 nodes were annotated. We constructed consensus spectra for these annotations based on molecular networking and developed an extended in silico spectral library based on these consensus spectra. The spectral library included 6879 in silico molecules covering 12,179 spectra. Using this integration strategy, 653 acyl lipids were discovered. Among these, O-acyl lactic acids and N-lactoyl amino acid-conjugated lipids were annotated as novel acyl lipids. Compared with conventional methods, our proposed method allows for the discovery of novel acyl lipids, and extended in silico libraries significantly increase the size of the spectral library.
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Aminoácidos , Software , Espectrometria de Massas em Tandem/métodos , Biblioteca Gênica , Lipídeos/análiseRESUMO
Electrical stimulation is a promising strategy for treating neural diseases. However, current energy suppliers cannot provide effective power for in situ electrical stimulation. Here, an implantable tubular zinc-oxygen battery is reported as the power source for in situ electrical stimulation during the neural repair. The battery exhibited a high volumetric energy density of 231.4 mWh cm-3 based on the entire anode and cathode in vivo. Due to its superior electrochemical properties and biosafety, the battery can be directly wrapped around the nerve to provide in situ electrical stimulation with a minimal size of 0.86 mm3 . The cell and animal experiments demonstrated that the zinc-oxygen battery-based nerve tissue engineering conduit effectively promoted regeneration of the injured long-segment sciatic nerve, proving its promising applications for powering implantable neural electronics in the future.
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Oxigênio , Zinco , Animais , Zinco/química , Fontes de Energia Elétrica , Próteses e Implantes , Estimulação ElétricaRESUMO
INTRODUCTION: Human respiratory syncytial virus (HRSV) infection causes significant morbidity, and no effective treatments are currently available. Viral infections induce substantial metabolic changes in the infected cells to optimize viral production. Metabolites that reflect the interactions between host cells and viruses provided an opportunity to identify the pathways underlying severe infections. OBJECTIVE: To better understand the metabolic changes caused by HRSV infection, we analyzed temporal metabolic profiling to provide novel targets for therapeutic strategies for inhaled HRSV infection. METHODS: The epithelial cells and BALB/c mice were infected with HRSV. Protein and mRNA levels of inflammation factors were measured by using quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Untargeted metabolomics, lipidomics and proteomics were performed using liquid chromatography coupled with mass spectrometry to profile the metabolic phenotypic alterations in HRSV infection. RESULTS: In this study, we evaluated the inflammatory responses in vivo and in vitro and investigated the temporal metabolic rewiring of HRSV infection in epithelial cells. We combined metabolomics and proteomic analyses to demonstrate that the redox imbalance was further provoked by increasing glycolysis and anaplerotic reactions. These responses created an oxidant-rich microenvironment that elevated reactive oxygen species levels and exacerbated glutathione consumption. CONCLUSION: These observations indicate that adjusting for metabolic events during a viral infection could represent a valuable approach for reshaping the outcome of infections.
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Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Animais , Camundongos , Humanos , Infecções por Vírus Respiratório Sincicial/metabolismo , Vírus Sincicial Respiratório Humano/genética , Proteômica , Metabolômica , Células Epiteliais/metabolismoRESUMO
Opioids are excellent analgesics for the clinical treatment of various types of acute and chronic pain, particularly cancer-related pain. Nevertheless, it is well known that opioids have some nasty side effects, including immunosuppression, which is commonly overlooked. As a result, the incidence of opportunistic bacterial and viral infections increases in patients with long-term opioid use. Nowadays, there are no effective medications to alleviate opioid-induced immunosuppression. Understanding the underlying molecular mechanism of opioids in immunosuppression can enable researchers to devise effective therapeutic interventions. This review comprehensively summarized the exogenous opioids-induced immunosuppressive effects and their underlying mechanisms, the regulatory roles of endogenous opioids on the immune system, the potential link between opioid immunosuppressive effect and the function of the central nervous system (CNS), and the future perspectives in this field.
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Imunidade Adaptativa , Analgésicos Opioides , Sistema Nervoso Central , Tolerância Imunológica , Imunidade Inata , Peptídeos Opioides , Infecções Oportunistas , Analgésicos Opioides/efeitos adversos , Imunidade Inata/efeitos dos fármacos , Imunidade Adaptativa/efeitos dos fármacos , Humanos , Infecções Oportunistas/induzido quimicamente , Infecções Oportunistas/epidemiologia , Infecções Oportunistas/imunologia , Incidência , Sistema Imunitário , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/imunologia , Peptídeos Opioides/metabolismoRESUMO
BACKGROUND: Increasing hepatic insulin signaling is found to be an important mechanism of Platycodon grandiflorus root to alleviate metabolic syndrome (MetS) symptoms such as insulin resistance, obesity, hyperlipidemia and hepatic steatosis, but the details are not yet clear. Since the main constituents of Platycodon grandiflorus root were hard to be absorbed by gastrointestinal tract, getting opportunity to interact with gut microbiota, we speculate the gut microorganisms may mediate its effect. PURPOSE: Our work aimed to confirm the critical role of gut microbes in the intervention of Platycodon grandiflorus root extract (PRE) on MetS, and investigate the mechanism. METHODS: Biochemical analyses, glucose tolerance test and hepatic lipidomics analysis were used to evaluate the anti-MetS effect of PRE on high fat diet (HFD) fed mice. Perform 16S rDNA analysis, qPCR analysis and in vitro co-incubation experiment to study its effect on gut microbes, followed by fecal microbiota transplantation (FMT) experiment and antibiotics intervention experiment. Also, the effect of Akkermansia muciniphila treatment on HFD mice was investigated. RESULTS: PRE alleviated lipid accumulation and insulin resistance in HFD mice and remodeled the fecal microbiome. It also increased the gene expression of colonic tight junction proteins, alleviated metabolic endotoxemia and inflammation, so that reduced TNF-α induced hepatic JNK-dependent IRS-1 serine phosphorylation and the impairment of PI3K/PIP3/Akt insulin signaling pathway. A. muciniphila was one of the most significantly enriched microbes by PRE treatment, and its administration to HFD mice showed similar effects to PRE, repairing the gut barrier and activating hepatic PI3K/PIP3/Akt pathway. Finally, anti-MetS effect of PRE could be delivered to FMT recipients, and PRE could not further attenuate MetS in gut microbiota depleted mice. CONCLUSION: We demonstrated for the first time that PRE alleviated MetS in a gut microbiota dependent manner, and found activation of hepatic insulin signaling mediated by gut A. muciniphila was a potential mechanism of it.
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Resistência à Insulina , Síndrome Metabólica , Platycodon , Animais , Camundongos , Insulina/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Extratos Vegetais/farmacologia , Transdução de Sinais , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Opioids are widely used in clinical practice. However, their long-term administration causes respiratory depression, addiction, tolerance, and severe immunosuppression. Traditional Chinese medicine (TCM) can alleviate opioid-induced adverse effects. Compound 511 is particularly developed for treating opioid addiction, based on Jiumi Liangfang, an ancient Chinese drug treatment and rehabilitation monograph completed in 1833 A.D. It is an herbal formula containing eight plants, each of them contributing to the overall pharmacological effect of the product: Panax ginseng C. A. Meyer (8.8%), Astragalus membranaceus (Fisch.) (18.2%), Datura metel Linn. (10.95%), Corydalis yanhusuo W. T. Wang (14.6%), Acanthopanar gracilistµlus W. W. Smith (10.95%), Ophiopogon japonicus (Linn. f.) Ker-Gawl. (10.95%), Gynostemma pentaphyllum (Thunb.) Makino (10.95%), Polygala arvensis Willd. (14.6%). This formula effectively ameliorates opioid-induced immunosuppression. However, the underlying mechanism remains unclear. PURPOSE: To reveal the effects of Compound 511 on the immune response of morphine-induced immunosuppressive mice and their potential underlying molecular mechanism. This study provides information for a better clinical approach and scientific use of opioids. METHODS: Immunosuppression was induced in mice by repeated morphine administration. Th1/Th2/Th17/Treg cell levels were measured using flow cytometry. Splenic transcription factors of Th1/Th2/Th17/Treg and outputs of the regulatory PI3K/AKT/mTOR signaling pathway were determined. Subsequently, methicillin-resistant Staphylococcus aureus (MRSA) was administered intranasally to morphine-induced immunosuppressive mice pretreated with Compound 511. Their lung inflammatory status was assessed using micro-computer tomography (CT), hematoxylin and eosin (H&E) staining, and enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared to morphine, Compound 511 significantly decreased the immune organ indexes of mice, corrected the Th1/Th2 and Treg/Th17 imbalance in the immune organs and peripheral blood, reduced the mRNA levels of FOXP3 and GATA3, and increased those of STAT3 and T-bet in the spleen. It improved immune function and reduced MRSA-induced lung inflammation. CONCLUSION: Compound 511 ameliorates opioid-induced immunosuppression by regulating the balance of Th1/Th2 and Th17/Treg via PI3K/AKT/mTOR signaling pathway. Thus, it effectively reduces susceptibility of morphine-induced immunosuppressive mice to MRSA infection.
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Medicamentos de Ervas Chinesas , Pneumopatias , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Animais , Camundongos , Analgésicos Opioides/farmacologia , Terapia de Imunossupressão , Morfina/farmacologia , Morfina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfócitos T Reguladores , Células Th17 , Serina-Treonina Quinases TOR/metabolismo , Pneumopatias/tratamento farmacológico , Pneumopatias/microbiologia , Infecções Estafilocócicas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêuticoRESUMO
Cyclophosphamide (CP) has been proven to be an embryo-fetal toxic. However, the mechanism responsible for the toxicity of the teratogenic agent has not been fully explored. This study aimed to examine the teratogenicity of CP when administered in the sensitive period of pregnant rats. The effect of CP on the lipid and metabolic profiles of amniotic fluid was evaluated using a UHPLC-Q-Exactive Orbitrap MS-based method. Metabolome analysis was performed using the MS-DIAL software with LipidBlast and NIST. Initially, we identified 636 and 154 lipid compounds in the positive and negative ion modes and 118 metabolites for differential analysis. Mainly 4 types of oxidized lipids in the amniotic fluid were found to accumulate most significantly after CP treatment, including very-long-chain unsaturated fatty acids (VLCUFAs), polyunsaturated fatty acid (PUFA)-containing triglycerides (TGs), oxidized phosphatidylcholine (PC), and sphingomyelin (SM). Tryptophan and some long-chain saturated fatty acids were lowered pronouncedly after CP treatment. These findings suggest that CP may exert teratogenic toxicity on pregnant rats through maternal and fetal oxidative stress. The UHPLC-Q-Exactive Orbitrap MS-based lipidomics approach is worthy of wider application for evaluating the potential toxicity of other agents (toxicants) during embryonic development.
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Respiratory syncytial virus (RSV) is a single-stranded negative-sense RNA virus that is the primary etiologic pathogen of bronchitis and pneumonia in infants and the elderly. Currently, no preventative vaccine has been approved for RSV infection. However, advances in the characterization, and structural resolution, of the RSV surface fusion glycoprotein have revolutionized RSV vaccine development by providing a new target for preventive interventions. In general, six different approaches have been adopted in the development of preventative RSV therapeutics, namely, particle-based vaccines, vector-based vaccines, live-attenuated or chimeric vaccines, subunit vaccines, mRNA vaccines, and monoclonal antibodies. Among these preventive interventions, MVA-BN-RSV, RSVpreF3, RSVpreF, Ad26. RSV.preF, nirsevimab, clesrovimab and mRNA-1345 is being tested in phase 3 clinical trials, and displays the most promising in infant or elderly populations. Accompanied by the huge success of mRNA vaccines in COVID-19, mRNA vaccines have been rapidly developed, with many having entered clinical studies, in which they have demonstrated encouraging results and acceptable safety profiles. In fact, Moderna has received FDA approval, granting fast-track designation for an investigational single-dose mRNA-1345 vaccine against RSV in adults over 60 years of age. Hence, mRNA vaccines may represent a new, more successful, chapter in the continued battle to develop effective preventative measures against RSV. This review discusses the structure, life cycle, and brief history of RSV, while also presenting the current advancements in RSV preventatives, with a focus on the latest progress in RSV mRNA vaccine development. Finally, future prospects for this field are presented.
Assuntos
COVID-19 , Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Vírus Sincicial Respiratório Humano , Adulto , Humanos , Pessoa de Meia-Idade , Idoso , Vacinas de mRNA , Anticorpos Antivirais , Vírus Sincicial Respiratório Humano/genética , Vacinas contra Vírus Sincicial Respiratório/genética , Vacinas contra Vírus Sincicial Respiratório/uso terapêutico , Infecções por Vírus Respiratório Sincicial/prevenção & controle , RNA Mensageiro/genéticaRESUMO
Pulmonary surfactant constitutes an important barrier that pathogens must cross to gain access to the rest of the organism via the respiratory surface. The presence of pulmonary surfactant prevents the dissemination of pathogens, modulates immune responses, and optimizes lung biophysical activity. Thus, the application of pulmonary surfactant for the treatment of respiratory diseases provides an effective strategy. Currently, several clinical trials are investigating the use of surfactant preparations to treat patients with coronavirus disease 2019 (COVID-19). Some factors have been considered in the application of pulmonary surfactant for the treatment COVID-19, such as mechanical ventilation strategy, timing of treatment, dose delivered, method of delivery, and preparation utilized. This review supplements this list with two additional factors: accurate measurement of surfactants in patients and proper selection of pulmonary surfactant components. This review provides a reference for ongoing exogenous surfactant trials involving patients with COVID-19 and provides insight for the development of surfactant preparations for the treatment of viral respiratory infections.