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BACKGROUND: Eradicating Helicobacter pylori infection by bismuth quadruple therapy (BQT) is effective. However, the effect of BQT and subsequent fecal microbiota transplant (FMT) on the gut microbiota is less known. MATERIALS AND METHODS: This prospective randomized controlled trial was conducted at a tertiary hospital in China from January 2019 to October 2020, with the primary endpoints the effect of BQT on the gut microbiota and the effect of FMT on the gut microbiota after bismuth quadruple therapy eradication therapy. A 14-day BQT with amoxicillin and clarithromycin was administered to H. pylori-positive subjects, and after eradication therapy, patients received a one-time FMT or placebo treatment. We then collected stool samples to assess the effects of 14-day BQT and FMT on the gut microbiota. 16 s rDNA and metagenomic sequencing were used to analyze the structure and function of intestinal flora. We also used Gastrointestinal Symptom Rating Scale (GSRS) to evaluate gastrointestinal symptom during treatment. RESULTS: A total of 30 patients were recruited and 15 were assigned to either FMT or placebo groups. After eradication therapy, alpha-diversity was decreased in both groups. At the phylum level, the abundance of Bacteroidetes and Firmicutes decreased, while Proteobacteria increased. At the genus level, the abundance of beneficial bacteria decreased, while pathogenic bacteria increased. Eradication therapy reduced some resistance genes abundance while increased the resistance genes abundance linked to Escherichia coli. While they all returned to baseline by Week 10. Besides, the difference was observed in Week 10 by the diarrhea score between two groups. Compared to Week 2, the GSRS total score and diarrhea score decreased in Week 3 only in FMT group. CONCLUSIONS: The balance of intestinal flora in patients can be considerably impacted by BQT in the short term, but it has reverted back to baseline by Week 10. FMT can alleviate gastrointestinal symptoms even if there was no evidence it promoted restoration of intestinal flora.
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Antibacterianos , Bismuto , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Infecções por Helicobacter , Helicobacter pylori , Humanos , Infecções por Helicobacter/terapia , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Transplante de Microbiota Fecal/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Helicobacter pylori/efeitos dos fármacos , Adulto , Antibacterianos/uso terapêutico , Estudos Prospectivos , Bismuto/uso terapêutico , Quimioterapia Combinada , China , Amoxicilina/uso terapêutico , Claritromicina/uso terapêutico , Resultado do Tratamento , Idoso , Fezes/microbiologiaRESUMO
Background and Objectives: Irritable Bowel Syndrome (IBS) is a common gastrointestinal disorder often exacerbated by stress, influencing the brain-gut axis (BGA). BGA dysregulation, disrupted intestinal barrier function, altered visceral sensitivity and immune imbalance defects underlying IBS pathogenesis have been emphasized in recent investigations. Phosphoproteomics reveals unique phosphorylation details resulting from environmental stress. Here, we employ phosphoproteomics to explore the molecular mechanisms underlying IBS-like symptoms, mainly focusing on the role of ZO-1 and IL-1RAP phosphorylation. Materials and Methods: Morris water maze (MWM) was used to evaluate memory function for single prolonged stress (SPS). To assess visceral hypersensitivity of IBS-like symptoms, use the Abdominal withdrawal reflex (AWR). Colonic bead expulsion and defecation were used to determine fecal characteristics of the IBS-like symptoms. Then, we applied a phosphoproteomic approach to BGA research to discover the molecular mechanisms underlying the process of visceral hypersensitivity in IBS-like mice following SPS. ZO-1, p-S179-ZO1, IL-1RAP, p-S566-IL-1RAP and GFAP levels in BGA were measured by western blotting, immunofluorescence staining, and enzyme-linked immunosorbent assay to validate phosphorylation quantification. Fluorescein isothiocyanate-dextran 4000 and electron-microscopy were performed to observe the structure and function of the intestinal epithelial barrier. Results: The SPS group showed changes in learning and memory ability. SPS exposure affects visceral hypersensitivity, increased fecal water content, and significant diarrheal symptoms. Phosphoproteomic analysis displayed that p-S179-ZO1 and p-S566-IL-1RAP were significantly differentially expressed following SPS. In addition, p-S179-ZO1 was reduced in mice's DRG, colon, small intestine, spinal and hippocampus and intestinal epithelial permeability was increased. GFAP, IL-1ß and p-S566-IL-1RAP were also increased at the same levels in the BGA. And IL-1ß showed no significant difference was observed in serum. Our findings reveal substantial alterations in ZO-1 and IL-1RAP phosphorylation, correlating with increased epithelial permeability and immune imbalance. Conclusions: Overall, decreased p-S179-ZO1 and increased p-S566-IL-1RAP on the BGA result in changes to tight junction structure, compromising the structure and function of the intestinal epithelial barrier and exacerbating immune imbalance in IBS-like stressed mice.
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Eixo Encéfalo-Intestino , Proteína Acessória do Receptor de Interleucina-1 , Síndrome do Intestino Irritável , Proteína da Zônula de Oclusão-1 , Animais , Humanos , Masculino , Camundongos , Modelos Animais de Doenças , Proteína Acessória do Receptor de Interleucina-1/metabolismo , Síndrome do Intestino Irritável/metabolismo , Síndrome do Intestino Irritável/patologia , Camundongos Endogâmicos C57BL , Fosforilação , Estresse Psicológico/metabolismo , Estresse Psicológico/imunologia , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
Osteoporosis disproportionately affects older women, yet gender differences in human osteoblasts remain unexplored. Identifying mechanisms and biomarkers of osteoporosis will enable the development of preventative and therapeutic approaches. Transcriptome data of 187 osteoblast samples from men and women were compared. Differentially expressed genes (DEGs) were identified, and weighted gene co-expression network analysis (WGCNA) was used to discover co-expressed modules. Enrichment analysis was performed to annotate DEGs. Preservation analysis determined whether modules and pathways were similar between genders. Blood methylation, transcriptome data, mouse phenotype data, and drug treatment data were utilized to identify key osteoporosis genes. We identified 1460 DEGs enriched in immune response, neurogenesis, and GWAS osteoporosis-related genes. WGCNA uncovered 8 modules associated with immune response, development, collagen metabolism, mitochondrion, and amino acid synthesis. Preservation analysis indicated modules and pathways were generally similar between genders. Incorporating GWAS and mouse phenotype data revealed 9 key genes, including GMDS, SMOC2, SASH1, MMP2, AHCYL1, ARRDC2, IGHMBP2, ATP6V1A, and CTSK. These genes were differentially methylated in patient blood and differentiated high and low bone mineral density patients in pre- and postmenopausal women. Denosumab treatment in postmenopausal women down-regulated 6 key genes, up-regulated T cell proportions, and down-regulated fibroblast proportion. qRT-PCR was used to confirm the genes in postmenopausal women. We identified 9 key osteoporosis genes by comparing the transcriptome of osteoblasts in women and men. Our findings' clinical implications were confirmed by multi-omics data and qRT-PCR, and our study provides novel biomarkers and therapeutic targets for osteoporosis diagnosis and treatment.
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Osteoporose , Transcriptoma , Humanos , Feminino , Masculino , Animais , Camundongos , Idoso , Osteoporose/genética , Osteoporose/metabolismo , Perfilação da Expressão Gênica , Biomarcadores , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genéticaRESUMO
OBJECTIVES: The development of new human leukocyte antigens (HLAs) and donor-specific antibodies (DSAs) in patients are associated with worse outcomes following lung transplantation. The authors aimed to examine the relationship between blood product transfusion in the first 72 hours after lung transplantation and the development of HLA antibodies, including DSAs. DESIGN: A retrospective observational study. SETTING: At a single academic tertiary center. PARTICIPANTS: Adult lung transplant recipients who underwent transplantation between September 2014 and June 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 380 patients were included in this study, and 87 (23%) developed de novo donor-specific antibodies in the first year after transplantation. Eighty-five patients (22%) developed new HLA antibodies that were not donor-specific, and 208 patients (55%) did not develop new HLA antibodies in the first year after transplantation. Factors associated with increased HLA and DSA development included donor pulmonary infection, non-infectious indication for transplant, increased recipient body mass index, and a preoperative calculated panel reactive antibody value above 0. Multivariate analysis identified platelet transfusion associated with an increased risk of de novo HLA antibody development compared to the negative group (odds ratio [OR; 95% CI] 1.18 [1.02-1.36]; p = 0.025). Cryoprecipitate transfusion was associated with de novo DSA development compared to the negative group (OR [95% CI] 2.21 [1.32-3.69] for 1 v 0 units; p = 0.002). CONCLUSIONS: Increased perioperative transfusion of platelets and cryoprecipitate are associated with de novo HLA and DSA development, respectively, in lung transplant recipients during the first year after transplantation.
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Isoanticorpos , Transplante de Pulmão , Humanos , Adulto , Rejeição de Enxerto , Doadores de Tecidos , Transplante de Pulmão/efeitos adversos , Estudos Retrospectivos , Antígenos HLARESUMO
Environmental and occupational exposure to cadmium (Cd) poses a serious threat to human health. Recent studies indicate that Cd perturbs the immune system and increases the risk of pathogenicity and mortality of bacterial or virus infection. However, the underlying mechanism of Cd-modulated immune responses remains unclear. In this study, we aim to investigate the role of Cd in the immune function of mouse spleen tissues and its primary T cells with Concanavalin A (ConA, a well-known T cell mitogen) activation condition, and elucidate the molecular mechanism. The results showed that Cd exposure inhibited ConA-induced the expressions of tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) in mouse spleen tissues. Furthermore, the transcriptomic profile by RNA-sequence reveals that: (1) Cd exposure can alter immune system process; (2) Cd may affect the NFκB signaling pathway. Both in vitro and in vivo results showed that Cd exposure reduced ConA-activated toll-like receptor 9 (TLR9)-IκBα-NFκB signaling, and the expressions of TLR9, TNF-α and IFN-γ, which were effectively reversed by autophagy-lysosomal inhibitors. All these results confirmedly demonstrated that, by promoting the autophagy-lysosomal degradation of TLR9, Cd suppressed immune response under ConA activation condition. This study provides insight on the mechanism of Cd immunnotoxicity, which might contribute to the prevention of Cd toxicity in the future.
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Cádmio , Receptor Toll-Like 9 , Camundongos , Animais , Humanos , Cádmio/toxicidade , Receptor Toll-Like 9/metabolismo , Fator de Necrose Tumoral alfa/genética , Inibidor de NF-kappaB alfa/metabolismo , Transdução de Sinais , NF-kappa B/metabolismo , Terapia de Imunossupressão , AutofagiaRESUMO
Atractylenolide-III (AT-III) is well known as its role in antioxidant and anti-inflammatory. Present study was aimed to figure out its effects on osteoarthritis and potential mechanisms. Rat model, human osteoarthritis cartilage explants as well as rat/human chondrocyte cultures were prepared to test AT-III's effects on osteoarthritis progression and chondrocyte senescence. Potential targeted molecules of AT-III were predicted using network pharmacology and molecular docking, assessed by Western blotting and then verified with rescue experiments. AT-III treatment alleviated osteoarthritis severity (shown by OARSI grading score and micro-CT) and chondrocyte senescence (indexed by levels of SA-ß-gal, P16, P53, MMP13, ROS and ratio of healthy/collapsed mitochondrial membrane potentials). Network pharmacology and molecular docking suggested that AT-III might play role through NF-κB pathway. Further experiments revealed that AT-III reduced phosphorylation of IKKα/ß, IκBα and P65 in NF-κB pathway. As well as nuclear translocation of p65. Both in vivo and in vitro experiments indicated that AT-III's effects on osteoarthritis and anti-senescence were reversed by an NF-κB agonist. AT-III could alleviate osteoarthritis by inhibiting chondrocyte senescence through NF-κB pathway, which indicated that AT-III is a prospective drug for osteoarthritis treatment.
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During biliary tree homeostasis, BECs are largely in a quiescent state and their turnover is slow for maintaining normal tissue homeostasis. BTSCs continually replenish new BECs in the luminal surface of EHBDs. In response to various types of biliary injuries, distinct cellular sources, including HPCs, BTSCs, hepatocytes, and BECs, repair or regenerate the injured bile duct. BEC, biliary epithelial cell; BTSC, biliary tree stem/progenitor cell; EHBD, extrahepatic bile ducts; HPC, hepatic progenitor cell.The biliary tree comprises intrahepatic bile ducts and extrahepatic bile ducts lined with epithelial cells known as biliary epithelial cells (BECs). BECs are a common target of various cholangiopathies for which there is an unmet therapeutic need in clinical hepatology. The repair and regeneration of biliary tissue may potentially restore the normal architecture and function of the biliary tree. Hence, the repair and regeneration process in detail, including the replication of existing BECs, expansion and differentiation of the hepatic progenitor cells and biliary tree stem/progenitor cells, and transdifferentiation of the hepatocytes, should be understood. In this paper, we review biliary tree homeostasis, repair, and regeneration and discuss the feasibility of regenerative therapy strategies for cholangiopathy treatment.
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Sistema Biliar , Sistema Biliar/fisiologia , Células Epiteliais , Hepatócitos , Homeostase , Humanos , RegeneraçãoRESUMO
Phytophenol dimerization, which is a radical-mediated coupling reaction, plays a critical role in many fields, including lignin biosynthesis. To understand the reaction, 2,2-diphenyl-1-picrylhydrazyl radical was used to initiate a series of phytophenol dimerization reactions in methanol. The products were identified using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-Q-TOF-MS/MS) analysis in situ. The identified products mainly included biphenols, magnolol, honokiol, gingerol 6,6'-dimers, 3,6-dimethoxylcatechol ß,ß' dimer, euphorbetin, bis-eugenol, dehydrodiisoeugenol, trans-ε-viniferin, (+) pinoresinol, and (-) pinoresinol. Structure-function relationship analysis allowed four basic rules to be defined: meta-excluded, C-C bonding domination, ortho-diOH co-activation, and exocyclic C=C involvement. The exocyclic C=C involvement, however, required conjugation with the phenolic core and the para-site of the -OH group, to yield a furan-fused dimer with two chiral centers. Computational chemistry indicated that the entire process was completed via a radical coupling reaction and an intramolecular conjugate addition reaction. Similar results were also found for the horseradish peroxidase (HRP)-catalyzed coniferyl alcohol dimerization, which produced (+) and (-) pinoresinols (but no (-) epipinoresinol), suggesting that the HRP-catalyzed process was essentially an exocyclic C=C-involved phytophenol dimerization reaction. The reaction was highly diastereoselective. This was attributed to the intramolecular reaction, which prohibited Re-attack. The four basic rules and diastereoselectivity can explain and even predict the main products in various chemical and biological events, especially oxidase-catalyzed lignin cyclization.
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Lignina , Espectrometria de Massas em Tandem , Antioxidantes/química , Cromatografia Líquida de Alta Pressão/métodos , Dimerização , Espectrometria de Massas por Ionização por Electrospray/métodosRESUMO
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide. Recent studies revealed that the ferroptosis pathway is involved in the death process of dopaminergic neurons in PD. The aberrant endosomal sorting pathway, which results in aberrant iron level in eukaryotic cells, may serve a role in the ferroptosis pathway in PD condition. However, its specific molecular mechanisms remained unclear. In the present study, we performed chromatin immunoprecipitation (ChIP) assay, the rank ordering of super-enhancers (ROSE) algorithm, and RNA interference (RNAi) to explore the regulatory mechanism of PD-specific super-enhancer (SE) in the endosomal sorting pathway and ferroptosis pathway of 6-OHDA-lesioned rats and cells. The ChIP assay and ROSE algorithm results showed that there are specific SEs expression in 6-OHDA-lesioned SNc of PD rats, and the most significant expression gene is Sorting Nexin 5 (SNX5). SNX5 silencing by RNAi experiments significantly decreased the level of ferroptosis in 6-OHDA-lesioned PC12 cells, suggesting the correlation between the SNX5, ferroptosis, and PD. In conclusion, this study investigated the mechanism by which PD-specific SE driven SNX5 promoted the ferroptosis level in PD models. This study further improved the understanding of the mechanism of ferroptosis during PD injury and provided potential therapeutic targets and clinical diagnostic markers in PD condition.
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Neurônios Dopaminérgicos/patologia , Ferroptose , Doença de Parkinson/patologia , Nexinas de Classificação/genética , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Expressão Gênica , Masculino , Células PC12 , Doença de Parkinson/genética , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Osteosarcoma (OS) is a common type of bone malignancy that often occurs in children and adolescents. Chemoresistance is a huge barrier to cancer therapy. This study aimed to investigate the role and potential mechanism of circ_0001721 in doxorubicin (DXR) resistance and OS development. METHODS: The levels of circ_0001721, miR-758 and transcription factor 4 (TCF4) were detected by quantitative real-time polymerase chain reaction or western blot assay. Cell Counting Kit-8 (CCK-8) assay was used to calculate the half inhibition concentration (IC50) of DXR and assess cell viability. Cell migration and invasion were evaluated by transwell assay. Cell apoptosis was monitored by flow cytometry. The levels of multidrug resistance-related and Wnt/ß-catenin pathway-related proteins were measured by western blot assay. The interaction among circ_0001721, miR-758 and TCF4 were confirmed by dual-luciferase reporter assay, RNA immunoprecipitation assay or RNA pull-down assay. The xenograft model was established to analyze tumor growth in vivo. RESULTS: Circ_0001721 and TCF4 were upregulated, whereas miR-758 was down-regulated in DXR-resistant OS tissues and cells. Circ_0001721 silence reduced DXR resistance of KHOS/DXR and MG63/DXR cells. Circ_0001721 regulated DXR resistance via sponging miR-758. Moreover, miR-758 modulated DXR resistance by targeting TCF4. Besides, circ_0001721 knockdown inhibited tumor growth in vivo. CONCLUSION: Circ_0001721 potentiated DXR resistance and facilitated the progression of OS by regulating miR-758/TCF4 axis, which provides promising therapeutic targets for OS treatment.
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Sr_{2}CuTeO_{6} is a square-lattice Néel antiferromagnet with superexchange between first-neighbor S=1/2 Cu spins mediated by plaquette centered Te ions. Substituting Te by W, the affected impurity plaquettes have predominantly second-neighbor interactions, thus causing local magnetic frustration. Here we report a study of Sr_{2}CuTe_{1-x}W_{x}O_{6} using neutron diffraction and µSR techniques, showing that the Néel order vanishes already at x=0.025±0.005. We explain this extreme order suppression using a two-dimensional Heisenberg spin model, demonstrating that a W-type impurity induces a deformation of the order parameter that decays with distance as 1/r^{2} at temperature T=0. The associated logarithmic singularity leads to loss of order for any x>0. Order for small x>0 and T>0 is induced by weak interplane couplings. In the nonmagnetic phase of Sr_{2}CuTe_{1-x}W_{x}O_{6}, the µSR relaxation rate exhibits quantum critical scaling with a large dynamic exponent, z≈3, consistent with a random-singlet state.
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BACKGROUND: Small intestinal bacterial overgrowth (SIBO) is characterized by the condition that bacteria overgrowth in the small intestine. Fecal microbiota transplantation (FMT) has been applied as an effective tool for reestablishing the structure of gut microbiota. However, whether FMT could be applied as a routine SIBO treatment has not been investigated. METHODS: In this trial, 55 SIBO patients were enrolled. All participants were randomized in two groups, and were given FMT capsule or placebo capsules once a week for 4 consecutive weeks. Measurements including the lactulose hydrogen breath test gastrointestinal symptoms, as well as fecal microbiota diversity were assessed before and after FMT therapy. RESULTS: Gastrointestinal symptoms significantly improved in SIBO patients after treatment with FMT compared to participants in placebo group. The gut microbiota diversity of FMT group had a significant increase, while placebo group showed none. CONCLUSIONS: This study suggests that applying FMT for patients with SIBO can alleviate gastrointestinal symptoms, indicating that FMT may be a promising and novel therapeutic regimen for SIBO. Trial registry This study was retrospectively registered with the Chinese Clinical Trial registry on 2019.7.10 (ID: ChiCTR1900024409, http://www.chictr.org.cn ).
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Infecções Bacterianas , Microbioma Gastrointestinal , Transplante de Microbiota Fecal , Humanos , Lactulose , Resultado do TratamentoRESUMO
BACKGROUND: Aberrant activation of Wnt/ß-catenin signaling by dysregulated post-translational protein modifications, especially ubiquitination is causally linked to cancer development and progression. Although Lys48-linked ubiquitination is known to regulate Wnt/ß-catenin signaling, it remains largely obscure how other types of ubiquitination, such as linear ubiquitination governs its signaling activity. METHODS: The expression and regulatory mechanism of linear ubiquitin chain assembly complex (LUBAC) on Wnt/ß-catenin signaling was examined by immunoprecipitation, western blot and immunohistochemical staining. The ubiquitination status of ß-catenin was detected by ubiquitination assay. The impacts of SHARPIN, a core component of LUBAC on malignant behaviors of gastric cancer cells were determined by various functional assays in vitro and in vivo. RESULTS: Unlike a canonical role in promoting linear ubiquitination, SHARPIN specifically interacts with ß-catenin to maintain its protein stability. Mechanistically, SHARPIN competes with the E3 ubiquitin ligase ß-Trcp1 for ß-catenin binding, thereby decreasing ß-catenin ubiquitination levels to abolish its proteasomal degradation. Importantly, SHARPIN is required for invasiveness and malignant growth of gastric cancer cells in vitro and in vivo, a function that is largely dependent on its binding partner ß-catenin. In line with these findings, elevated expression of SHARPIN in gastric cancer tissues is associated with disease malignancy and correlates with ß-catenin expression levels. CONCLUSIONS: Our findings reveal a novel molecular link connecting linear ubiquitination machinery and Wnt/ß-catenin signaling via SHARPIN-mediated stabilization of ß-catenin. Targeting the linear ubiquitination-independent function of SHARPIN could be exploited to inhibit the hyperactive ß-catenin signaling in a subset of human gastric cancers.
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Carcinogênese/genética , Neoplasias Gástricas/genética , Ubiquitinação/genética , Ubiquitinas/genética , beta Catenina/genética , Humanos , Via de Sinalização Wnt/genéticaRESUMO
BACKGROUND: Multiple organ failure (MOF) may lead to an increased mortality rate of moderately severe (MSAP) or severe acute pancreatitis (SAP). This study is aimed to use machine learning to predict the risk of MOF in the course of disease. METHODS: Clinical and laboratory features with significant differences between patients with and without MOF were screened out by univariate analysis. Prediction models were developed for selected features through six machine learning methods. The models were internally validated with a five-fold cross-validation, and a series of optimal feature subsets were generated in corresponding models. A test set was used to evaluate the predictive performance of the six models. RESULTS: 305 (68%) of 455 patients with MSAP or SAP developed MOF. Eighteen features with significant differences between the group with MOF and without it in the training and validation set were used for modeling. Interleukin-6 levels, creatinine levels, and the kinetic time were the three most important features in the optimal feature subsets selected by K-fold cross-validation. The adaptive boosting algorithm (AdaBoost) showed the best predictive performance with the highest AUC value (0.826; 95% confidence interval: 0.740 to 0.888). The sensitivity of AdaBoost (80.49%) and specificity of logistic regression analysis (93.33%) were the best scores among the six models in the test set. CONCLUSIONS: A predictive model of MOF complicated by MSAP or SAP was successfully developed based on machine learning. The predictive performance was evaluated by a test set, for which AdaBoost showed a satisfactory predictive performance. The study is registered with the China Clinical Trial Registry (Identifier: ChiCTR1800016079).
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Insuficiência de Múltiplos Órgãos , Pancreatite , Doença Aguda , Estudos de Coortes , Humanos , Aprendizado de Máquina , Insuficiência de Múltiplos Órgãos/etiologiaRESUMO
Non-alcoholic fatty liver disease (NAFLD) has been the most common chronic liver disease in the world, including the developing countries. NAFLD is metabolic disease with significant lipid deposition in the hepatocytes of the liver, which is usually associated with oxidative stress, inflammation and fibrogenesis, and insulin resistance. Progressive NAFLD can develop into non-alcoholic steatohepatitis (NASH) or hepatocellular carcinoma. The current evidence proposes that environmental pollutants promote development and progression of NAFLD, and autophagy plays a vital role but is multifactorial affected in NAFLD. In this review, we analyzed on the regulations of common environmental pollutants on autophagy in NAFLD. To clarify the involved roles of autophagy, we discussed the dysregulation of autophagy by environmental pollutants in adipose tissue and gut, and their interactions with liver, as well as epigenetic regulation on autophagy by environmental pollutants. Furthermore, protective roles of potential therapeutic treatments on the multiple-hits of autophagy in NAFLD were descripted.
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Autofagia/fisiologia , Poluentes Ambientais/toxicidade , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Tecido Adiposo/metabolismo , Carcinoma Hepatocelular/metabolismo , Poluentes Ambientais/metabolismo , Epigênese Genética , Hepatócitos/metabolismo , Humanos , Inflamação/metabolismo , Resistência à Insulina/fisiologia , Fígado/metabolismo , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Estresse OxidativoRESUMO
Synthetic arylamines and dietary phytophenolics could inhibit ferroptosis, a recently discovered regulated cell death process. However, no study indicates whether their inhibitory mechanisms are inherently different. Herein, the ferroptosis-inhibitory mechanisms of selected ferrostatin-1 (Fer-1) and two dietary stilbenes (piceatannol and astringin) were compared. Cellular assays suggested that the ferroptosis-inhibitory and electron-transfer potential levels decreased as follows: Fer-1 >> piceatannol > astringin; however, the hydrogen-donating potential had an order different from that observed by the antioxidant experiments and quantum chemistry calculations. Quantum calculations suggested that Fer-1 has a much lower ionization potential than the two stilbenes, and the aromatic N-atoms were surrounded by the largest electron clouds. By comparison, the C4'O-H groups in the two stilbenes exhibited the lowest bond disassociation enthalpies. Finally, the three were found to produce corresponding dimer peaks through ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry analysis. In conclusion, Fer-1 mainly depends on the electron transfer of aromatic N-atoms to construct a redox recycle. However, piceatannol and astringin preferentially donate hydrogen atoms at the 4'-OH position to mediate the conventional antioxidant mechanism that inhibits ferroptosis, and to ultimately form dimers. These results suggest that dietary phytophenols may be safer ferroptosis inhibitors for balancing normal and ferroptotic cells than arylamines with high electron-transfer potential.
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Cicloexilaminas/farmacologia , Dieta , Ferroptose/efeitos dos fármacos , Glucosídeos/farmacologia , Fenilenodiaminas/farmacologia , Estilbenos/farmacologia , Animais , Antioxidantes/análise , Óxidos N-Cíclicos/química , Cicloexilaminas/química , Glucosídeos/química , Imidazóis/química , Concentração Inibidora 50 , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Modelos Moleculares , Fenilenodiaminas/química , Piperazinas/farmacologia , Ratos Sprague-Dawley , Eletricidade Estática , Estilbenos/químicaRESUMO
The search for a safe and effective inhibitor of ferroptosis, a recently described cell death pathway, has attracted increasing interest from scientists. Two hydrolyzable tannins, chebulagic acid and chebulinic acid, were selected for the study. Their optimized conformations were calculated using computational chemistry at the B3LYP-D3(BJ)/6-31G and B3LYP-D3(BJ)/6-311 + G(d,p) levels. The results suggested that (1) chebulagic acid presented a chair conformation, while chebulinic acid presented a skew-boat conformation; (2) the formation of chebulagic acid requires 762.1729 kcal/mol more molecular energy than chebulinic acid; and (3) the 3,6-HHDP (hexahydroxydiphenoyl) moiety was shown to be in an (R)- absolute stereoconfiguration. Subsequently, the ferroptosis inhibition of both tannins was determined using a erastin-treated bone marrow-derived mesenchymal stem cells (bmMSCs) model and compared to that of ferrostatin-1 (Fer-1). The relative inhibitory levels decreased in the following order: Fer-1 > chebulagic acid > chebulinic acid, as also revealed by the in vitro antioxidant assays. The UHPLC-ESI-Q-TOF-MS analysis suggested that, when treated with 16-(2-(14-carboxytetradecyl)-2-ethyl-4,4-dimethyl-3-oxazolidinyloxy free radicals, Fer-1 generated dimeric products, whereas the two acids did not. In conclusion, two hydrolyzable tannins, chebulagic acid and chebulinic acid, can act as natural ferroptosis inhibitors. Their ferroptosis inhibition is mediated by regular antioxidant pathways (ROS scavenging and iron chelation), rather than the redox-based catalytic recycling pathway exhibited by Fer-1. Through antioxidant pathways, the HHDP moiety in chebulagic acid enables ferroptosis-inhibitory action of hydrolyzable tannins.
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Benzopiranos/farmacologia , Ferroptose/efeitos dos fármacos , Glucosídeos/farmacologia , Taninos Hidrolisáveis/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Benzopiranos/química , Células Cultivadas , Glucosídeos/química , Taninos Hidrolisáveis/química , Células-Tronco Mesenquimais/citologia , Modelos Moleculares , Ratos Sprague-DawleyRESUMO
Recent evidence suggests that belatacept reduces the durability of preexisting antibodies to class I and class II human leukocyte antigens (HLAs). In this case series of 163 highly sensitized kidney transplant candidates whose calculated panel-reactive antibody (cPRA) activity was ≥98% to 100%, the impact of belatacept on preexisting HLA antibodies was assessed. Of the 163 candidates, 72 underwent transplantation between December 4, 2014 and April 15, 2017; 60 of these transplanted patients remained on belatacept consecutively for at least 6 months. We observed a decrease in the breadth and/or strength of HLA class I antibodies as assessed by FlowPRA in belatacept-treated patients compared to controls who did not receive belatacept. Specifically, significant HLA antibody reduction was evident for class I (P < .0009). Posttransplant belatacept-treated patients also had a clinically significant reduction in their cPRA compared to controls (P < .01). Collectively, these findings suggest belatacept can reduce HLA class I antibodies in a significant proportion of highly sensitized recipients and could be an option to improve pretransplant compatibility with organ donors.
Assuntos
Abatacepte/uso terapêutico , Antígenos HLA/efeitos dos fármacos , Imunossupressores/uso terapêutico , Transplante de Rim , Adulto , Feminino , Humanos , Terapia de Imunossupressão/métodos , Masculino , Pessoa de Meia-Idade , TransplantadosRESUMO
Hepatocellular carcinoma is the second leading cause of cancer-related death worldwide. Neural regulation plays an important role in the development of hepatocellular carcinoma, and activation of sympathetic nervous system can promote the migration and invasion of cancer cells. However, little research has been conducted on how the vagus nerve influences hepatocellular carcinoma. In this study, we found that the expression of vesicular acetylcholine transporter, a biomarker of vagus nerve, was associated with hepatocellular carcinoma patients' clinicopathological characteristics by immunohistochemistry. Further, activation of muscarinic acetylcholine receptor 1 (M1R) promoted HepG2 and SMMC-7721 cells migration and invasion and epithelial-mesenchymal transition via PI3K/Akt pathway. Moreover, inhibition of M1R by antagonist or shRNA suppressed hepatocellular carcinoma cells migration and invasion in vitro and in vivo, inhibited epithelial-mesenchymal transition and PI3K/Akt pathway. Therefore, these results indicate that activation of M1R promotes invasion of hepatocellular carcinoma through epithelial-mesenchymal transition and PI3K/Akt pathway.
Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Receptor Muscarínico M1/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Transição Epitelial-Mesenquimal , Feminino , Células Hep G2 , Xenoenxertos , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Nervo Vago/patologiaRESUMO
A large linear negative thermal expansion (NTE) and expanded NTE temperature range (ΔTNTE) were obtained in magnetoelastic CrTe1-xSex (0 ≤ x ≤ 0.15) compounds. For CrTe compound, its thermal expansion coefficient of volume (αV) was calculated to be -28.8 ppm K-1 with the temperature ranging from 280 to 340 K. Substituting Te with Se atoms, the NTE behavior and magnetic properties can be well manipulated. With increasing Se in CrTe1-xSex (0 ≤ x ≤ 0.15) compounds, the ΔTNTE increases from 60 K (280-340 K for x = 0), to 80 K (240-320 K for x = 0.05), to 95 K (200-295 K for x = 0.1), and finally to 100 K (170-270 K for x = 0.15). Furthermore, a linear NTE remains independent of temperature for samples with x ≤ 0.1. The relationship between tunable NTE and magnetic properties was analyzed in detail, indicating that the NTE in CrTe1-xSex compounds originates from the magnetovolume effect (MVE).