RESUMO
Triptolide (TP) is the principal bioactive compound of Tripterygium wilfordii with significant anti-tumor, anti-inflammatory and immunosuppressive activities. However, its severe hepatotoxicity greatly limits its clinical use. The underlying mechanism of TP-induced liver damage is still poorly understood. Here, we estimate the role of the gut microbiota in TP hepatotoxicity and investigate the bile acid metabolism mechanisms involved. The results of the antibiotic cocktail (ABX) and fecal microbiota transplantation (FMT) experiment demonstrate the involvement of intestinal flora in TP hepatotoxicity. Moreover, TP treatment significantly perturbed gut microbial composition and reduced the relative abundances of Lactobacillus rhamnosus GG (LGG). Supplementation with LGG reversed TP-induced hepatotoxicity by increasing bile salt hydrolase (BSH) activity and reducing the increased conjugated bile acids (BA). LGG supplementation upregulates hepatic FXR expression and inhibits NLRP3 inflammasome activation in TP-treated mice. In summary, this study found that gut microbiota is involved in TP hepatotoxicity. LGG supplementation protects mice against TP-induced liver damage. The underlying mechanism was associated with the gut microbiota-BA-FXR axis. Therefore, LGG holds the potential to prevent and treat TP hepatotoxicity in the clinic.
Assuntos
Ácidos e Sais Biliares , Doença Hepática Induzida por Substâncias e Drogas , Diterpenos , Compostos de Epóxi , Microbioma Gastrointestinal , Lacticaseibacillus rhamnosus , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fenantrenos , Receptores Citoplasmáticos e Nucleares , Animais , Diterpenos/farmacologia , Fenantrenos/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Compostos de Epóxi/farmacologia , Ácidos e Sais Biliares/metabolismo , Masculino , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Probióticos/uso terapêutico , Probióticos/farmacologia , Transplante de Microbiota Fecal , Inflamassomos/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Peutz-Jeghers Syndromeis a rare autosomal dominant genetic disease characterized by gastrointestinal hamartomatous polyps and skin and mucous membrane pigmentation. The pathogenesis of PJS remains unclear; however, it may be associated with mutations in the STK11 gene, and there is currently no effective treatment available. The gut microbiota plays an important role in maintaining intestinal homeostasis in the human body, and an increasing number of studies have reported a relationship between gut microbiota and human health and disease. However, relatively few studies have been conducted on the gut microbiota characteristics of patients with PJS. In this study, we analyzed the characteristics of the gut microbiota of 79 patients with PJS using 16 S sequencing and measured the levels of short-chain fatty acids in the intestines. The results showed dysbiosis in the gut microbiota of patients with PJS, and decreased synthesis of short-chain fatty acids. Bacteroides was positively correlated with maximum polyp length, while Agathobacter was negatively correlated with age of onset. In addition, acetic acid, propionic acid, and butyric acid were positively correlated with the age of onset but negatively correlated with the number of polyps. Furthermore, the butyric acid level was negatively correlated with the frequency of endoscopic surgeries. In contrast, we compared the gut microbiota of STK11-positive and STK11-negative patients with PJS for the first time, but 16 S sequencing analysis revealed no significant differences. Finally, we established a random forest prediction model based on the gut microbiota characteristics of patients to provide a basis for the targeted diagnosis and treatment of PJS in the future.
Assuntos
Microbioma Gastrointestinal , Síndrome de Peutz-Jeghers , Humanos , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/patologia , Mutação em Linhagem Germinativa , Ácidos Graxos Voláteis , ButiratosRESUMO
BACKGROUND: Gastric cancer (GC) is one of the most pernicious tumors that seriously harm human healthcare. GC metastasis is one of the prime cause of failed cancer treatment, but correlation between N6-methyladenosine (m6A) and GC metastasis was less reported. METHODS: Methylated RNA immunoprecipitation sequencing (MeRIP-seq) of GC tissues was conducted. Quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry (IHC) were taken to determine the expression of ALKBH5 in GC tissues and cell lines. RNA-seq together with MeRIP-qRT-PCR was used to screen the target gene of ALKBH5. RNA pulldown, mass spectrometry and RNA immunoprecipitation (RIP) were used to search the "reader" protein of target gene. The mechanism was also validated via a tail vein injection method for lung metastasis model. RESULTS: Decreased expression of ALKBH5 was detected in GC samples, and it was correlated with clinical tumor distal metastasis and lymph node metastasis. ALKBH5 interference promoted metastasis of GC cells and this effect was closely related to the demethylase activity of ALKBH5. PKMYT1, as a downstream target of ALKBH5, promoted invasion and migration in GC. Caused by ALKBH5 knockdown or its demethylase activity mutation, upregulated expression of PKMYT1 indicated that ALKBH5 modulates expression of PKMYT1 in an m6A-dependent manner. IGF2BP3 helped stabilize the mRNA stability of PKMYT1 via its m6A modification site. CONCLUSIONS: This study established an ALKBH5-PKMYT1-IGF2BP3 regulation system in metastasis, representing a new therapeutic target for GC metastasis.
Assuntos
Neoplasias Gástricas , Adenosina/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Humanos , Proteínas de Membrana , Proteínas Serina-Treonina Quinases , Proteínas Tirosina Quinases/metabolismo , Estabilidade de RNA , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: Tea polyphenols are the prominent component in tea. After the fermentation process, tea polyphenols are oxidized by polyphenol oxidase to form oxidized tea polyphenols (OTPs). OTPs contain a significant amount of hydrophobic phenyl groups that can bind with non-aqueous materials. Here, we determined whether OTPs can bind with lipids and reduce fat uptake and assessed the effect of OTPs on decreasing obesity and alleviating hyperlipidaemia and other metabolic syndromes. METHODS: Rats were divided into three groups: control, high-fat diet (HFD) and OTP groups. The control and HFD groups were fed a chow diet and a high-fat diet, respectively, for 12 weeks; the OTP group was fed a high-fat diet for 6 weeks and then a high-fat diet containing 2 % OTP for 6 weeks. The serum and excrement triglyceride (TAG) and total cholesterol (CHOL) concentrations were determined, and liver tissue and white adipose tissue were collected to detect the expression levels of genes involved in lipid metabolism. RESULTS: Our results revealed that OTPs failed to decrease the serum concentrations of TAG and CHOL. OTPs alleviated the accumulation of lipids in the liver tissue and changed the expression levels of the regulators of lipid metabolism, i.e., peroxisome proliferation-activated receptors (ppars), compared with the rats fed a high-fat diet alone. We also observed a significantly decreased reduction of weight in the visceral white adipose, enhanced regulation of fatty acid ß-oxidation by PPARα and enhanced biosynthesis of mitochondria in the visceral white adipose of the OTP rats compared with the HFD rats. Additionally, OTPs promoted the excretion of lipids. CONCLUSION: Our results suggest that OTPs alleviate the accumulation of lipids in liver and visceral white adipose tissue and promote lipid excretion in rats in vivo.
Assuntos
Gordura Intra-Abdominal/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Polifenóis/farmacologia , Chá/química , Animais , Biomarcadores/sangue , Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fezes/química , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , Gordura Intra-Abdominal/metabolismo , Fígado/metabolismo , Masculino , Obesidade/sangue , Obesidade/tratamento farmacológico , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Triglicerídeos/sangueRESUMO
Self-assembled functionalized multiwalled carbon nanotube (MWNT) films were successfully constructed, linked by a kind of strong binding strength from the self-complementary hydrogen-bonding array of ureidopyrimidinone-based modules (UPM) attached. Employing the feasible reaction of isocyanate containing ureidopyrimidinone with amine modified MWNTs, the UPMs composed of ureidopyrimidinone and ureido were attached to MWNTs with the content as low as 0.6 mmol/g MWNTs. Upon multiple hydrogen-bonding interactions from incorporation of the AADD (A, hydrogen-bonding acceptor; D, hydrogen-bonding donor) quadruple hydrogen bonds of ureidopyrimidinone and the double hydrogen bonds of ureido group, UPM functionalized MWNTs (MWNT-UPM) can be well dispersed in the polar solvent of N,N-dimethylformamide (DMF), while they tend to self-assemble to give a self-supported film in the apolar solvent of CHCl3. In addition, by using the multiple hydrogen-bonding interactions as the driving force, the layer-by-layer (LBL) MWNT-UPM films with high coverage on solid slides can be processed. Because of the self-association of MWNT-UPM in apolar solvent, it was found that the LBL assembly of MWNT-UPM was more favorable in the polar solvent of DMF than in the apolar solvent of CHCl3. Moreover, the hydrogen-bonding linked MWNT-UPM films showed good stability upon soaking in different solvents. Furthermore, the as-prepared LBL films showed electrochemical active behaviors, exhibiting a remarkable catalytic effect on the reduction of nifedipine.
RESUMO
2-Ureido-4(1H)-pyrimidinone-bridged ferrocene-fullerene assembly I is designed and synthesized for elaborating the photoinduced electron-transfer processes in self-complementary quadruply hydrogen-bonded modules. Unexpectedly, steady-state and time-resolved spectroscopy reveal an inefficient electron-transfer process from the ferrocene to the singlet or triplet excited state of the fullerene, although the electron-transfer reactions are thermodynamically feasible. Instead, an effective intra-assembly triplet-triplet energy-transfer process is found to be operative in assembly I with a rate constant of 9.2×10(5) s(-1) and an efficiency of 73% in CH(2)Cl(2) at room temperature.
RESUMO
OBJECTIVE: Human leukocyte antigens (HLA) play an important role in presenting virus antigens to immune cells that are responsible for the clearance of virus-infected cells and tumor cells. Herein, we evaluated whether genetic variants of HLA-DP and HLA-DQ are associated with cervical cancer risk. METHODS: We genotyped four single nucleotide polymorphisms (SNPs) in HLA-DP (rs3077 and rs9277535) and HLA-DQ (rs2856718 and rs7453920) in a two-stage case-control study with a total of 2317 cervical cancer cases and 2109 cancer-free controls using TaqMan allelic discrimination assay. RESULTS: We found consistently significant associations of HLA-DP rs3077 and rs9277535 with increased risks of cervical cancer (dominant genetic model: adjusted OR=1.51, 95% CI=1.32-1.71 for rs3077; adjusted OR=1.29, 95% CI=1.12-1.49 for rs9277535). When combining the effects of HLA-DP rs3077 and rs9277535, subjects carrying "≥1" variant alleles had a 1.55-fold increased risk of cervical cancer (95% CI=1.32-1.81), compared with those carrying "0" variant allele. And cervical cancer risk significantly increased with the increasing number of variant alleles of the two SNPs in a dose-dependent manner (P for trend=4.33×10(-10)). However, there were no significant associations for HLA-DQ rs2856718 and rs7453920 in our population. CONCLUSIONS: These findings indicate that HLA-DP rs3077 and rs9277535 were candidate susceptibility markers for cervical cancer in Chinese females. Further validation studies with different ethnic background, biological function analyses and especially HPV typing together were needed.
Assuntos
Carcinoma/genética , Predisposição Genética para Doença , Antígenos HLA-DP/genética , Antígenos HLA-DQ/genética , Polimorfismo de Nucleotídeo Único , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Povo Asiático , Carcinoma/etnologia , Estudos de Casos e Controles , China , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Técnicas de Genotipagem , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada , Risco , Neoplasias do Colo do Útero/etnologiaRESUMO
Resistance to anoikis, the subtype of apoptosis induced by lack of matrix adhesion, contributes to malignant transformation and development of metastasis. MicroRNAs play key regulatory roles in tumorigenesis and metastasis. In this study, we described that miR-26a, which is usually downregulated in tumor cells, is involved in the acquisition of anoikis-resistance of human esophageal adenocarcinoma (EA) cells. Results of qRT-PCR in clinical samples showed that downregulated miR-26a expression is related to tumorigenesis and metastasis of EA. In vitro experiments determined that miR-26a directly participates in the regulation of cell cycle and anoikis of human EA OE33 cells. Further, we identified that Rb1 is the direct functional target of miR-26a, and revealed that the reduction of miR-26a expression leads to increased Rb1 protein level and thus inhibits the function of E2F1, by which it influences the phenotypes of cell cycle and anoikis. The findings we reported here presented the evidence that miR-26a may be involved in regulation of anoikis-resistance of EA cells. Targeting miR-26a may provide a novel strategy to inhibit metastasis.
Assuntos
Adenocarcinoma/metabolismo , Anoikis , Fator de Transcrição E2F1/metabolismo , Neoplasias Esofágicas/metabolismo , MicroRNAs/fisiologia , Proteína do Retinoblastoma/genética , Regiões 3' não Traduzidas , Adenocarcinoma/secundário , Animais , Sequência de Bases , Sítios de Ligação , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação para Baixo , Neoplasias Esofágicas/patologia , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Camundongos , Camundongos Nus , Transplante de Neoplasias , Interferência de RNA , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais , Transcrição GênicaRESUMO
Regarded as one of the popular cathode materials in aqueous zinc ion batteries (ZIBs), VS2 has unsatisfied cycling stability and relatively low capacity owing to its poor conductivity and low mechanical properties. To this regard, compositing VS2 with high-conductive 2D transition metal carbide (MXene) has been an effective method recently. However, the Zn dendrite on the anode electrode derived from the uncontrollable sluggish migration of solvated Zn2+ /H2 O ions seriously threatens the application safety of ZIB batteries. To effectively regulate the diffusion of zinc ions, in this work a conductive polymeric electrolyte of sulfonated polyaniline (SPANI) is added in the electrolyte solution. Under the Zn2+ /SPANI interactions confirmed by X-ray diffraction, Raman, and zeta potential experiments, the Zn2+ /H2 O combination is weakened, and the deposition rate of Zn2+ is increased evaluated by the galvanostatic intermittent titration technique. Theoretical simulation shows that the electrostatic shielding by SPANI combining Zn2- at the zinc/electrolyte interface has important contribution to the significant suppression of Zn dendrite. Accordingly, the fabricated VS2 @MXene||ZnSO4 +SPANI||Zn battery shows high capacity (368.0 mAh g-1 at 0.1 A g-1 ), which remains 96% after 5000 cyclic charge-discharge operations. This work develops an available strategic idea for suppressing growth of metallic dendrites to improve the ZIB performances.
RESUMO
Intrahepatic cholestasis of pregnancy (ICP) is a female pregnancy-specific disorder that is characterized by increased serum bile acid and adverse fetal outcomes. The aetiology and mechanism of ICP are poorly understood; thus, existing therapies have been largely empiric. Here we show that the gut microbiome differed significantly between individuals with ICP and healthy pregnant women, and that colonization with gut microbiome from ICP patients was sufficient to induce cholestasis in mice. The gut microbiomes of ICP patients were primarily characterized by Bacteroides fragilis (B. fragilis), and B. fragilis was able to promote ICP by inhibiting FXR signaling via its BSH activity to modulate bile acid metabolism. B. fragilis-mediated FXR signaling inhibition was responsible for excessive bile acid synthesis and interrupted hepatic bile excretion to ultimately promote the initiation of ICP. We propose that modulation of the gut microbiota-bile acid-FXR axis may be of value for ICP treatment.
Assuntos
Colestase Intra-Hepática , Microbioma Gastrointestinal , Complicações na Gravidez , Feminino , Gravidez , Humanos , Animais , Camundongos , Complicações na Gravidez/metabolismo , Ácidos e Sais BiliaresRESUMO
Single-nucleotide polymorphisms (SNPs) of TERT rs2736098, rs2736100, and CLPTM1L rs402710 at 5p15.33 are significantly associated with risk of a spectrum of cancers. However, cervical cancer has been rarely evaluated. In this study, we genotyped the three SNPs in a case-control study with 1,033 cervical cancer cases and 1,053 cancer-free controls in a Chinese population. Logistic regression analyses showed that the two TERT SNPs both significantly associated with cervical cancer risk in the recessive model (rs2736098, AA vs. AG/GG: adjusted OR = 1.35, 95% CI = 1.06-1.72; rs2736100, CC vs. AC/AA: adjusted OR = 1.38, 95% CI = 1.11-1.73). However, no association was found between CLPTM1L rs402710 and cervical cancer. These results suggest that genetic variants in 5p15.33, especially in TERT, may be markers for susceptibility to cervical cancer.
Assuntos
Polimorfismo de Nucleotídeo Único , Telomerase/genética , Neoplasias do Colo do Útero/genética , Adulto , Idoso , Povo Asiático/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 5 , Feminino , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Menarca , Pessoa de Meia-Idade , Distribuição AleatóriaRESUMO
Heparanase (HPA) is the predominant enzyme that cleaves heparan sulfate and plays a critical role in a variety of pathophysiological processes. HPA activity has been traditionally correlated with tumor metastasis due to participation in the cleavage and remodeling of the extracellular matrix (ECM). Apart from its well-characterized catalytic properties, HPA was noticed to exert biological functions not rely on its enzymatic activity. This feature is supported by studies showing induction of signaling events, such as Src and AKT, by nonenzymatic HPA mutant. We provide evidence here that active HPA and inactive HPA mutant proteins enhance gastric cancer cell growth, possibly attributed to TFEB-mediated autophagy. Similarly, HPA gene silencing resulted in decreased gastric cancer cell proliferation and autophagy. Besides, TFEB inhibition reduced cell growth and autophagy induced by nonenzymatic HPA. Notably, HPA and TFEB were significantly elevated in gastric carcinomas compared with the adjacent gastric tissue. Moreover, the elevation of HPA gene expression and upregulation of TFEB levels have been associated with advanced clinical stage and poor prognosis of gastric cancer, providing strong clinical support for a connection between TFEB and HPA. Thus, neutralizing the nonenzymatic function of HPA and the related TFEB-driven autophagy may profoundly impact gastric cancer progression.
RESUMO
Supramolecular self-assembly of nanoparticles in two orthogonal directions would potentially allow one to fabricate nanomaterials with fascinating properties. In this study of a hydrothermal polycondensation of melamine/cyanuric acid, graphitic carbon nitride-based quantum dots (CNQD, â¼2 nm) are in situ arranged along two orthogonal directions through lateral hydrogen bonding, and free-floating two-dimensional hydrogen-bonded films of CNQD (2D CNQD) are built. On the basis of the universality of this hydrothermal in situ supramolecular self-assembly technique, 2D films linked by other quantum dots such as sulfur-doped graphitic carbon nitride and CdTe are also constructed. With the benefits of stimuli responsiveness and the reversibility of hydrogen bonds, controllable assembly/disassembly of the 2D CNQD film is feasibly achieved by external stimuli such as inletting CO2/N2, which endows the assembled 2D CNQD films optimal electrochemical superiorities of both 2D film and zero-dimensional (0D) quantum dots. Accordingly, the 2D CNQD film delivers a high bifunctional activity in both a nitrogen reduction reaction (NRR) and an oxygen evolution reaction (OER). Especially in NRR, it exhibits the high yield rate of NH3 reaching 75.07 µg h-1 mg-1 at -0.85 V versus reversible hydrogen electrode at ambient condition. Strikingly, the power density of the rechargeable Zn-N2 battery using 2D CNQD film as cathode reaches 31.94 mW cm-2, outperforming the majority of Zn-N2 batteries. Density functional theory calculations proved the promoted adsorption of N2 and stabilized NRR intermediates on 2D CNQD cooperated by multiply hydrogen-bonding interactions are the main reasons for the excellent NRR electrocatalytic performances. This work hints that hydrothermal in situ supramolecular self-assembly is a feasible and direct way to integrate 0D quantum dots into 2D directional arrays, and the hydrogen bond that interlinks enables this free-floating 2D structure to maintain the electrochemical superiority of both 0D and 2D structures.
RESUMO
Given the great importance of Yundang lagoon (China), a detailed evaluation and source identification of multiple potentially toxic elements (PTEs) is required. Low concentrations of the PTEs were found in the Diversion canal, while high in the Main canal, Inner lagoon, and Outer lagoon. Evaluation results indicated that the pollution of PTEs was widespread, and that the extremely high eco-risks and evident toxicity were owing to the great contributions of Hg and Cd. Positive matrix factorization model demonstrated that the PTEs were from both natural and different types of anthropogenic sources. TOC played a critical role in the PTEs. It was also found that the limited environmental carrying capacity and the poor hydrological condition of the lagoon may still accumulate the pollution in a progressive fashion. These findings provide a detailed information on making effective strategies of new directions for long-term prevention of PTEs pollution in the landscape urban lagoon.
Assuntos
Metais Pesados , Poluentes do Solo , China , Monitoramento Ambiental , Poluição Ambiental , Metais Pesados/análise , Medição de Risco , Poluentes do Solo/análiseRESUMO
This study was carried out in Luoyuan Bay in March 2021. The species composition of microalgae community colonizing on microplastics called epimicroplastic microalgae (EMP-MA) was analyzed and compared with planktonic microalgae (PM) community. The species number of EMP-MA community (73) was higher than that of PM community (56). However Simpson Index and Pielou Evenness Index of EMP-MA community were significantly lower than that of PM community (P < 0.05). Although diatom was the most diverse and abundant taxa in both EMP-MA and PM community, their species compositions were significantly different (P < 0.05). Dominant species were also different between the two communities. Moreover, 12 harmful algal species were found in EMP-MA community, which may drift with microplastics and increase the risks of harmful algal blooms (HABs). This study is helpful to reveal the dispersal mechanism of HABs and potential impacts of EMP-MA on marine ecosystem.
Assuntos
Microalgas , Microplásticos , Baías , China , Ecossistema , Proliferação Nociva de Algas , Plâncton , PlásticosRESUMO
Nonalcoholic steatohepatitis (NASH) has been linked with the gut-liver axis. Here, we investigate the potential for repurposing disulfiram (DSF), a drug commonly used to treat chronic alcoholism, for NASH. Using a mouse model, we show that DSF ameliorates NASH in a gut microbiota-dependent manner. DSF modulates the gut microbiota and directly inhibits the growth of Clostridium. Administration of Clostridium abolishes the ameliorating effects of DSF on NASH. Mechanistically, DSF reduces Clostridium-mediated 7α-dehydroxylation activity to suppress secondary bile acid biosynthesis, which in turn activates hepatic farnesoid X receptor signaling to ameliorate NASH. To assess the effect of DSF on human gut microbiota, we performed a self-controlled clinical trial (ChiCTR2100048035), including 23 healthy volunteers who received 250 mg-qd DSF for 7 days. The primary objective outcomes were to assess the effects of the intervention on the diversity, composition and functional profile of gut microbiota. The pilot study shows that DSF also reduces Clostridium-mediated 7α-dehydroxylation activity. All volunteers tolerated DSF well and there were no serious adverse events in the 7-day follow-up period. Transferring fecal microbiota obtained from DSF-treated humans into germ-free mice ameliorates NASH. Collectively, the observations of similar ameliorating effects of DSF on mice and humans suggest that DSF ameliorates NASH by modulating the gut microbiota and bile acid metabolism.
Assuntos
Microbioma Gastrointestinal , Hepatopatia Gordurosa não Alcoólica , Humanos , Ácidos e Sais Biliares/metabolismo , Clostridium , Dissulfiram/farmacologia , Dissulfiram/uso terapêutico , Dissulfiram/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Projetos PilotoRESUMO
Increasing evidence indicates that gut microbiota may play a key role in vaccination immunity. Here, we investigate whether the human gut microbiota and metabolic function correlate with the BBIBP-CorV vaccine response. A total of 207 participants who received the BBIBP-CorV vaccine are enrolled. The gut microbiome and metabolic functions are investigated using metagenomic sequencing and metabolomic assays. We find that BBIBP-CorV vaccination is accompanied by altered microbiome composition and functional pathways, and the gut microbiome and its functional profiles correlate with the vaccine response. The levels of short-chain fatty acids (SCFAs) are much higher in the high antibody response group compared to the low response group, and several SCFAs display a positive correlation with the antibody response. Our study highlights that the gut microbiome and its function is associated with the BBIBP-CorV vaccine response, providing evidence for further exploration of microbiome modulation to improve COVID-19 vaccine efficacy.
Assuntos
COVID-19 , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/fisiologia , Vacinas contra COVID-19 , Formação de Anticorpos , Ácidos Graxos Voláteis/metabolismoRESUMO
Intrauterine adhesion (IUA) is a common clinical endometrial disease, which can severely damage the fertility and quality of life in women. This study aims to find the differentially expressed endogenous peptides and their possible roles in IUA. Liquid chromatography-mass spectrometry was used to identify the peptidomic profiling of IUA tissues, and the differentially expressed peptides were screened out. Using real-time quantitative PCR, Western blotting, and immunocytochemistry staining, the function of six endogenous peptides was verified in vitro. It was found that peptide 6 (T6) (peptide sequence: TFGGAPGFPLGSPLSSVFPR) could inhibit the expression of TGF-ß1-induced cell fibrosis in human endometrial stromal cell line and primary human endometrial stromal cell at a concentration of 50 µmol/L. This study provides new targets for further clarifying the formation and prevention of IUA.
RESUMO
BACKGROUND: Gastric carcinoma (GC) is one of the most deadly diseases due to tumour metastasis and resistance to therapy. Understanding the molecular mechanism of tumour progression and drug resistance will improve therapeutic efficacy and develop novel intervention strategies. METHODS: Differentially expressed long non-coding RNAs (lncRNAs) in clinical specimens were identified by LncRNA microarrays and validated in different clinical cohorts by quantitative real-time polymerase chain reaction (qRT-PCR), in situ hybridisation and bioinformatics analysis. Biological functions of lncRNA were investigated by using cell proliferation assays, migration assays, xenograft tumour models and bioinformatics analysis. Effects of lncSLCO1C1 on GC cell survival were assessed by comet assays and immunofluorescence assays. Underlying molecular mechanisms were further explored by using a number of technologies including RNA pull-down, mass spectrometry analysis, RNA immunoprecipitation, co-immunoprecipitation, miRNA sequencing, luciferase reporter assays and molecular modelling. RESULTS: LncSLCO1C1 was highly upregulated in GC tissue samples and associated with GC patients' poor overall survival. Overexpression of lncSLCO1C1 promoted proliferation and migration, whereas decreased lncSLCO1C1 expression produced the opposite effects. lncSLCO1C1 also mediated tumour resistance to chemotherapy with oxaliplatin by reducing DNA damage and increasing cell proliferation. Despite sequence overlapping between lncSLCO1C1 and PDE3A, alternations of PDE3A expression had no effect on the GC cell progression, indicating that lncSLCO1C1, not PDE3A, related with the progression of GC cells. Mechanistically, lncSLCO1C1 serves as a scaffold for the structure-specific recognition protein 1 (SSRP1)/H2A/H2B complex and regulates the function of SSRP1 in reducing DNA damage. Meanwhile, lncSLCO1C1 functions as a sponge to adsorb miR-204-5p and miR-211-5p that target SSRP1 mRNA, and thus increases SSRP1 expression. Patients with high expressions of both lncSLCO1C1 and SSRP1 have poor overall survival, highlighting the role of lncSLCO1C1 in GC progression. CONCLUSIONS: LncSLCO1C1 promotes GC progression by enhancing cell growth and preventing DNA damage via interacting and scaffolding the SSRP1/H2A/H2b complex and absorbing both miR-211-5p and miR-204-5p to increase SSRP1 expression.
Assuntos
MicroRNAs , RNA Longo não Codificante , Neoplasias Gástricas , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Grupo de Alta Mobilidade/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Transportadores de Ânions Orgânicos , Oxaliplatina/farmacologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Fatores de Elongação da Transcrição/genética , Fatores de Elongação da Transcrição/metabolismoRESUMO
BACKGROUND: Well-balanced interactions between gut microbiota and the immune system are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). Toll-like receptor 4 (TLR4) functions as a sensor mediating the crosstalk between the intestinal commensal microbiome and host immunity, but the influence of TLR4 on the shaping of intestinal microbiota and immune responses during colon inflammation remains poorly characterized. We investigated whether the different susceptibilities to colitis between wild-type (WT) and TLR4-/- mice were gut microbiota-dependent and aimed to identify the potential immunity modulation mechanism. METHODS: We performed antibiotic depletion of the microbiota, cohousing experiments, and faecal microbiota transplantation (FMT) in WT and TLR4-/- mice to assess the influence of TLR4 on intestinal microbial ecology. 16S rRNA sequencing was performed to dissect microbial discrepancies, and dysbiosis-associated immune perturbation was investigated by flow cytometry. Akkermansia muciniphila (A. muciniphila)-mediated immune modulation was confirmed through the T-cell transfer colitis model and bone marrow chimaera construction. RESULTS: TLR4-/- mice experienced enhanced susceptibility to DSS-induced colitis. 16S rRNA sequencing showed notable discrepancy in the gut microbiota between WT and TLR4-/- mice. In particular, A. muciniphila contributed most to distinguishing the two groups. The T-cell transfer colitis model and bone marrow transplantation (BMT) consistently demonstrated that A. muciniphila ameliorated colitis by upregulating RORγt+ Treg cell-mediated immune responses. Mucosal biopsies from human manifested parallel outcomes with colon tissue from WT mice, as evidenced by the positive correlation between TLR4 expression and intestinal A. muciniphila colonization during homeostasis. CONCLUSIONS: Our results demonstrate a novel protective role of TLR4 against intestinal inflammation, wherein it can modulate A. muciniphila-associated immune responses. These findings provide a new perspective on host-commensal symbiosis, which may be beneficial for developing potential therapeutic strategies. Video abstract.