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1.
World J Clin Cases ; 12(12): 2056-2064, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38680254

RESUMO

BACKGROUND: Various non-steroidal anti-inflammatory drugs (NSAIDs) have been used for juvenile idiopathic arthritis (JIA). However, the optimal method for JIA has not yet been developed. AIM: To perform a systematic review and network meta-analysis to determine the optimal instructions. METHODS: We searched for randomized controlled trials (RCTs) from PubMed, EMBASE, Google Scholar, CNKI, and Wanfang without restriction for publication date or language at August, 2023. Any RCTs that comparing the effectiveness of NSAIDs with each other or placebo for JIA were included in this network meta-analysis. The surface under the cumulative ranking curve (SUCRA) analysis was used to rank the treatments. P value less than 0.05 was identified as statistically significant. RESULTS: We included 8 RCTs (1127 patients) comparing 8 different instructions including meloxicam (0.125 qd and 0.250 qd), Celecoxib (3 mg/kg bid and 6 mg/kg bid), piroxicam, Naproxen (5.0 mg/kg/d, 7.5 mg/kg/d and 12.5 mg/kg/d), inuprofen (30-40 mg/kg/d), Aspirin (60-80 mg/kg/d, 75 mg/kg/d, and 55 mg/kg/d), Tolmetin (15 mg/kg/d), Rofecoxib, and placebo. There were no significant differences between any two NSAIDs regarding ACR Pedi 30 response. The SUCRA shows that celecoxib (6 mg/kg bid) ranked first (SUCRA, 88.9%), rofecoxib ranked second (SUCRA, 68.1%), Celecoxib (3 mg/kg bid) ranked third (SUCRA, 51.0%). There were no significant differences between any two NSAIDs regarding adverse events. The SUCRA shows that placebo ranked first (SUCRA, 88.2%), piroxicam ranked second (SUCRA, 60.5%), rofecoxib (0.6 mg/kg qd) ranked third (SUCRA, 56.1%), meloxicam (0.125 mg/kg qd) ranked fourth (SUCRA, 56.1%), and rofecoxib (0.3 mg/kg qd) ranked fifth (SUCRA, 56.1%). CONCLUSION: In summary, celecoxib (6 mg/kg bid) was found to be the most effective NSAID for treating JIA. Rofecoxib, piroxicam, and meloxicam may be safer options, but further research is needed to confirm these findings in larger trials with higher quality studies.

2.
Inflamm Res ; 73(4): 541-562, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38345635

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) is an increasingly prevalent global health concern that has garnered substantial attention. However, the underlying mechanisms are still unclear and the current treatments have significant limitations. Intestinal organoids provide an in vitro model to explore the pathogenesis, test the therapeutic effects, and develop regenerative treatments as well as offer the potential to transform drug discovery of IBD. METHODS: To advance our understanding of the whole story of IBD spanning from the pathogenesis to the current therapeutic strategies and latest advancements, a comprehensive search of major databases including PubMed, Scopus, and Web of Science was conducted to retrieve original articles and reviews related to IBD, organoids, pathogenesis and therapy. RESULTS: This review deciphers the etiopathogenesis and the current therapeutic approaches in the treatment of IBD. Notably, critical aspects of intestinal organoids in IBD, such as their potential applications, viability, cell renewal ability, and barrier functionality are highlighted. We also discuss the advances, limitations, and prospects of intestinal organoids for precision medicine. CONCLUSION: The latest strides made in research about intestinal organoids help elucidate intricate aspects of IBD pathogenesis, and pave the prospective avenues for novel therapeutic interventions.


Assuntos
Doenças Inflamatórias Intestinais , Humanos , Estudos Prospectivos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Intestinos/patologia , Organoides/patologia
3.
Infect Immun ; 92(3): e0001224, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38358274

RESUMO

How the LuxS/AI-2 quorum sensing (QS) system influences the pathogenicity of K. pneumoniae is complicated by the heterogeneity of the bacterial mucoid phenotypes. This study aims to explore the LuxS-mediated regulation of the pathogenicity of K. pneumoniae with diverse mucoid phenotypes, including hypermucoid, regular-mucoid, and nonmucoid. The wild-type, luxS knockout, and complemented strains of three K. pneumoniae clinical isolates with distinct mucoid phenotypes were constructed. The results revealed the downregulation of virulence genes of regular-mucoid, and nonmucoid but not hypermucoid strains. The deletion of luxS reduced the pathogenicity of the regular-mucoid, and nonmucoid strains in mice; while in hypermucoid strain, luxS knockout reduced virulence in late growth but enhanced virulence in the early growth phase. Furthermore, the absence of luxS led the regular-mucoid and nonmucoid strains to be more sensitive to the host cell defense, and less biofilm-productive than the wild-type at both the low and high-density growth state. Nevertheless, luxS knockout enhanced the resistances to adhesion and phagocytosis by macrophage as well as serum-killing, of hypermucoid K. pneumoniae at its early low-density growth state, while it was opposite to those in its late high-density growth phase. Collectively, our results suggested that LuxS plays a crucial role in the pathogenicity of K. pneumoniae, and it is highly relevant to the mucoid phenotypes and growth phases of the strains. LuxS probably depresses the capsule in the early low-density phase and promotes the capsule, biofilm, and pathogenicity during the late high-density phase, but inhibits lipopolysaccharide throughout the growth phase, in K. pneumoniae.IMPORTANCECharacterizing the regulation of physiological functions by the LuxS/AI-2 quorum sensing (QS) system in Klebsiella pneumoniae strains will improve our understanding of this important pathogen. The genetic heterogeneity of K. pneumoniae isolates complicates our understanding of its pathogenicity, and the association of LuxS with bacterial pathogenicity has remained poorly addressed in K. pneumoniae. Our results demonstrated strain and growth phase-dependent variation in the contributions of LuxS to the virulence and pathogenicity of K. pneumoniae. Our findings provide new insights into the important contribution of the LuxS/AI-2 QS system to the networks that regulate the pathogenicity of K. pneumoniae. Our study will facilitate our understanding of the regulatory mechanisms of LuxS/AI-2 QS on the pathogenicity of K. pneumoniae under the background of their genetic heterogeneity and help develop new strategies for diminished bacterial virulence within the clinical K. pneumoniae population.


Assuntos
Klebsiella pneumoniae , Percepção de Quorum , Camundongos , Animais , Virulência/genética , Biofilmes , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Fenótipo , Liases de Carbono-Enxofre/genética , Liases de Carbono-Enxofre/metabolismo
4.
Medicine (Baltimore) ; 102(45): e35938, 2023 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-37960718

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignancies globally with poor prognosis. Cancer-associated fibroblasts (CAFs) play multiple functions in the regulation of tumorigenesis, metastasis and therapeutic resistance of cancer. The current study aimed to explore the role of CAFs-related genes in the prognosis and immunotherapy response in HCC. CAFs-related genes were identified by using single-cell RNA-sequencing analysis. Least absolute shrinkage and selection operator (LASSO) analysis was conducted to develop a CAFs-related prognostic signature (FRPS) in TCGA dataset and verified in ICGC, GSE14520 and GSE76427 cohorts. Several tools, including Tumor Immune Dysfunction and Exclusion (TIDE) score, immunophenoscore, and Tumor Mutation Burden (TMB) score were used to evaluate the value of FRPS in predicting immunotherapy benefits. The FRPS constructed based on 10 genes (RGS5, CNN3, PALLD, FLNA, KLHL23, MYC, NDRG2, SERPINE1, CD151 CALU) served as an independent risk factor and showed stable and powerful performance in predicting the overall survival rate of HCC patients with an AUCs of 0. 734, 0.727, and 0.717 in 2-, 3-, and 4-year ROC curve in TCGA cohort. Low risk score indicated a higher abundance of CD8+ T cells and NK, and lower abundance of Treg. Moreover, HCC patients with low risk score had a higher PD1&CTLA4 immunophenoscore, higher TMB score, and lower TIDE score. Moreover, high risk score indicated a lower IC50 value of 5-fluorouracil, camptothecin, cisplatin, docetaxel, gemcitabine, paclitaxel, afatinib, crizotinib, dasatinib, erlotinib, erlotinib, gefitinib, lapatinib, and osimertinib in HCC. Our study develops a novel FRPS HCC. The FRPS acts as a risk factor for the prognosis of HCC patients and it can predict the immunotherapy benefits of HCC patients.


Assuntos
Fibroblastos Associados a Câncer , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Cloridrato de Erlotinib , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Prognóstico , Imunoterapia , Proteínas Supressoras de Tumor
5.
Medicine (Baltimore) ; 102(42): e35195, 2023 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-37861525

RESUMO

Pyroptosis is a new type of programmed cell death involved in all stages of tumorigenesis. Herein, a comprehensive study was conducted to evaluate the prognostic significance of pyroptosis-related lncRNAs in bladder cancer. Consensus clustering analysis was performed to identify the subclusters of bladder cancer. The prognostic pyroptosis-related lncRNA signature was constructed using LASSO Cox regression analysis. Consensus clustering identified 2 clusters of bladder cancer. Interestingly, significant differences in the ESTIMAE score, immune cell infiltration and immune checkpoint expression were obtained between the 2 clusters. A signature consisting of 11 pyroptosis-related lncRNAs was established and it had a good performance in predicting the overall survival rate of bladder cancer, with an AUC of 0.713. Moreover, pyroptosis-related lncRNA signature acted as a risk factor in bladder cancer. Bladder cancer patients with high-risk score had a higher tumor grade and higher clinical stage. A significant correlation was obtained between the risk score and immune cell infiltration. The expression of most checkpoints was higher in bladder cancer patients with high-risk score. A novel pyroptosis-related lncRNA signature was identified with prognostic value for bladder cancer patients. Pyroptosis-related lncRNAs have a potential role in cancer immunology and may serve as prognostic or therapeutic targets in bladder cancer.


Assuntos
RNA Longo não Codificante , Neoplasias da Bexiga Urinária , Humanos , Piroptose , RNA Longo não Codificante/genética , Neoplasias da Bexiga Urinária/genética , Prognóstico , Apoptose
6.
ACS Infect Dis ; 9(10): 1858-1866, 2023 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-37669401

RESUMO

The goal of this study was to clarify the synergistic antibacterial activity of the combination of tigecycline (TGC) and rifampicin (RIF). Additionally, the study sought to investigate the impact of this combination on the development of mutational resistance and to assess its efficacy in an in vivo model using Galleria mellonella. Through a checkerboard test, we found that the combination of TGC and RIF showed synergistic antibacterial activity against carbapenem-resistant Klebsiella pneumoniae (CRKP). The fractional inhibition concentration index (FICI) was found to be ≤0.5, confirming the potency of the combination. Additionally, this synergistic effect was further validated in vivo using the G. mellonella infection model. TGC-RIF treatment had a lower mutant prevention concentration (MPC) than that of monotherapy, indicating its potential to reduce the development of mutational resistance. We observed a substantial variation in the MPCs of TGC and RIF when they were measured at different proportions in the combinations. Furthermore, during the resistant mutant selection window (MSW) test, we noticed a correlation between strains with low FICI and low MSW. The expression of efflux-pump-related genes, namely rarA and acrB, is significantly decreased in the combination therapy group. This indicates that altered expression levels of certain efflux pump regulator genes are associated with a combined decrease in bacterial mutation resistance. In conclusion, the combination of TGC and RIF effectively suppresses antibiotic resistance selection in CRKP. This study establishes a paradigm for evaluating drug-resistant mutant suppression in antimicrobial combination therapy.

7.
BMC Microbiol ; 23(1): 256, 2023 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-37704976

RESUMO

BACKGROUND: Chlorhexidine (CHG) is a disinfectant commonly used in hospitals. However, it has been reported that the excessive use of CHG can cause resistance in bacteria to this agent and even to other clinical antibiotics. Therefore, new methods are needed to alleviate the development of CHG tolerance and reduce its dosage. This study aimed to explore the synergistic effects of CHG in combination with bacteriophage against CHG-tolerant Pseudomonas aeruginosa (P. aeruginosa) and provide ideas for optimizing disinfection strategies in clinical environments as well as for the efficient use of disinfectants. METHODS: The CHG-tolerant P. aeruginosa strains were isolated from the First Affiliated Hospital of Wenzhou Medical University in China. The bacteriophage vB3530 was isolated from the sewage inlet of the hospital, and its genome was sequenced. Time-killing curve was used to determine the antibacterial effects of vB3530 and chlorohexidine gluconate (CHG). The phage sensitivity to 16 CHG-tolerant P. aeruginosa strains and PAO1 strain was detected using plaque assay. The emergence rate of resistant bacterial strains was detected to determine the development of phage-resistant and CHG-tolerant strains. Finally, the disinfection effects of the disinfectant and phage combination on the surface of the medical devices were preliminarily evaluated. RESULTS: The results showed that (1) CHG combined with bacteriophage vB3530 significantly inhibited the growth of CHG-resistant P. aeruginosa and reduced the bacterial colony forming units (CFUs) after 24 h. (2) The combination of CHG and bacteriophage inhibited the emergence of phage-resistant and CHG-tolerant strains. (3) The combination of CHG and bacteriophage significantly reduced the bacterial load on the surface of medical devices. CONCLUSIONS: In this study, the combination of bacteriophage vB3530 and CHG presented a combined inactivation effect to CHG-tolerant P. aeruginosa and reduced the emergence of strains resistant to CHG and phage. This study demonstrated the potential of bacteriophage as adjuvants to traditional disinfectants. The use of bacteriophage in combination with commercial disinfectants might be a promising method for controlling the spread of bacteria in hospitals.


Assuntos
Bacteriófagos , Desinfetantes , Humanos , Clorexidina/farmacologia , Pseudomonas aeruginosa , Desinfetantes/farmacologia , Antibacterianos
8.
Microbiol Spectr ; : e0366622, 2023 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-37707450

RESUMO

Colistin is a potent antibiotic for the treatment of carbapenem-resistant Gram-negative bacteria and is considered a last-resort drug. Unfortunately, the incidence of colistin-resistant bacteria isolated from patients is continuously growing due to clinical reuse of colistin. In this study, we found that the combination of colistin and eugenol has a significant synergistic antibacterial effect and reverses the sensitivity of colistin-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae against colistin, as confirmed by checkerboard and time-kill assays. Crystal violet staining and scanning electron microscopy revealed colistin and eugenol's synergistic antibiofilm action. Concerning the synergy mechanism, the results revealed that the combination of eugenol and colistin increases membrane permeability and causes considerable membrane damage, further inhibiting bacteria synergistically. Meanwhile, up to 500 µg/mL of eugenol is non-toxic to RAW 264.7 cells, and the colistin/eugenol combination is also efficacious in vivo, as demonstrated by the Galleria mellonella infection model. Our findings indicate that the colistin/eugenol combination is a viable treatment option for colistin-resistant P. aeruginosa and K. pneumoniae clinical infections. IMPORTANCE Colistin is used as a last resort for severe infections caused by multidrug-resistant Gram-negative bacteria, however, colistin resistance is increasing. As a result, we investigated the synergistic effect of eugenol/colistin combination, and the results revealed significant antibacterial and antibiofilm action. Eugenol may help clinical colistin-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae recover their susceptibility. These findings suggest that combining eugenol and colistin may be a viable treatment option for colistin-resistant pathogen clinical infections.

9.
Infect Drug Resist ; 16: 5697-5705, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37667809

RESUMO

Objective: Acinetobacter baumannii is a hazardous bacterium that causes hospital-acquired nosocomial infections, and the advent of multidrug-resistant A. baumannii (MDR-AB) strains is concerning. Novel antibacterial therapeutic strategies must be developed. The biological effects of glabridin on MDR-AB were investigated in this study. Methods: The minimum inhibitory concentrations (MICs) of glabridin against eight clinical MDR-AB strains were determined using the broth microdilution technique. Crystal violet staining was used to assess biofilm development, which has significant contribution to bacterial resistance. Swarming motility was measured according to surface growth zone of MDR-AB on LB agar medium. qRT-PCR was used to evaluate the expression of quorum sensing genes abaI and abaR. Glabridin and routinely used therapeutic antimicrobial agents were tested for synergistic action using the checkerboard method. Results: According to our findings, glabridin suppressed MDR-AB growth at high doses (512-1024 µg/mL). The 1/4 MIC of glabridin significantly decreased MDR-AB biofilm formation by 19.98% (P < 0.05), inhibited MDR-AB motility by 44.27% (P < 0.05), whereas the 1/2 MIC of glabridin dramatically reduced MDR-AB biofilm development by 27.43% (P < 0.01), suppressed MDR-AB motility by 50.64% (P < 0.05). Mechanistically, glabridin substantially downregulated the expression of quorum sensing-related genes abaI and abaR by up to 39.12% (P < 0.001) and 25.19% (P < 0.01), respectively. However, no synergistic effect between glabridin and antibacterial drugs was found. Conclusion: Glabridin might be a quorum sensing inhibitor that inhibits MDR-AB biofilm development and swarming motility.

10.
BMC Genomics ; 24(1): 506, 2023 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-37649002

RESUMO

BACKGROUND: The emergence and wide spread of carbapenemase-producing Enterobacteriaceae (CPE) poses a growing threat to global public health. However, clinically derived carbapenemase-producing Citrobacter causing multiple infections has rarely been investigated. Here we first report the isolation and comparative genomics of two blaNDM-5 carrying Citrobacter freundii (C. freundii) isolates from a patient with bloodstream and urinary tract infections. RESULTS: Antimicrobial susceptibility testing showed that both blaNDM-5 carrying C. freundii isolates were multidrug-resistant. Positive modified carbapenem inactivation method (mCIM) and EDTA-carbapenem inactivation method (eCIM) results suggested metallo-carbapenemase production. PCR and sequencing confirmed that both metallo-carbapenemase producers were blaNDM-5 positive. Genotyping and comparative genomics analyses revealed that both isolates exhibited a high level of genetic similarity. Plasmid analysis confirmed that the blaNDM-5 resistance gene is located on IncX3 plasmid with a length of 46,161 bp, and could successfully be transferred to the recipient Escherichia coli EC600 strain. A conserved structure sequence (ISAba125-IS5-blaNDM-5-trpF-IS26-umuD-ISKox3) was found in the upstream and downstream of the blaNDM-5 gene. CONCLUSIONS: The data presented in this study showed that the conjugative blaNDM-5 plasmid possesses a certain ability to horizontal transfer. The dissemination of NDM-5-producing C. freundii isolates should be of close concern in future clinical surveillance. To our knowledge, this is the first study to characterize C. freundii strains carrying the blaNDM-5 gene from one single patient with multiple infections.


Assuntos
Carbapenêmicos , Citrobacter freundii , Humanos , Citrobacter freundii/genética , Mapeamento Cromossômico , Sequência Conservada , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Escherichia coli , Genômica
11.
Inflamm Res ; 72(7): 1391-1408, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37326693

RESUMO

OBJECTIVE: Triggering receptors expressed on myeloid cells-1 (TREM-1) has been shown to participate in inflammatory autoimmune diseases. Nevertheless, the detailed underlying mechanisms and therapeutic benefits by targeting TREM-1 remain elusive, especially in myeloid dendritic cells (mDCs) and systemic lupus erythematosus (SLE). Disorders of epigenetic processes including non-coding RNAs give rise to SLE, resulting in complicated syndromes. Here, we aim to address this issue and explore the miRNA to inhibit the activation of mDCs and alleviate the progress of SLE by targeting TREM-1 signal axis. METHODS: Bioinformatics methods were used to analyze the differentially expressed genes (DEGs) between patients with SLE and healthy individuals by four mRNA microarray datasets from Gene Expression Omnibus (GEO). Then we identified the expression of TREM-1 and its soluble form (sTREM-1) in clinical samples by ELISA, quantitative real-time PCR and Western blot. Phenotypic and functional changes of mDCs elicited by TREM-1 agonist were determined. Three databases of miRNAs target prediction and a dual-luciferase reporter assay were used to screen and verify miRNAs that can directly inhibit TREM-1 expression in vitro. Moreover, pristane-induced lupus mice were injected with miR-150-5p agomir to evaluate the effects of miR-150-5p on mDCs in lymphatic organs and disease activity in vivo. RESULTS: We screened TREM-1 as one of the hub genes closely correlated with the progression of SLE and identified sTREM-1 in serum as a valuable diagnostic biomarker for SLE. Moreover, activation of TREM-1 by its agonist promoted activation and chemotaxis of mDCs and increased the production of inflammatory cytokines and chemokines, showing higher expression of IL-6, TNF-α, and MCP-1. We showed that lupus mice displayed a unique miRNA signature in spleen, among which miR-150 was the most significantly expressed miRNA that targeting TREM-1 compared with wild type group. Transfection of miRNA-150-5p mimics directly suppressed the expression of TREM-1 by binding to its 3' UTR. Our in vivo experiments first indicated that administration of miR-150-5p agomir effectively ameliorated lupus symptoms. Intriguingly, miR-150 inhibited the over activation of mDCs through TREM-1 signal pathway in lymphatic organs and renal tissues. CONCLUSIONS: TREM-1 represents a potentially novel therapeutic target and we identify miR-150-5p as one of the mechanisms to alleviate lupus disease, which is attributable for inhibiting mDCs activation through TREM-1 signaling pathway.


Assuntos
Lúpus Eritematoso Sistêmico , MicroRNAs , Animais , Camundongos , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , MicroRNAs/metabolismo , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/genética , Inflamação/metabolismo , Células Dendríticas
12.
World J Diabetes ; 14(6): 862-882, 2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-37383585

RESUMO

BACKGROUND: Current approaches for the therapy of diabetic retinopathy (DR), which was one of leading causes of visual impairment, have their limitations. Animal experiments revealed that restructuring of intestinal microbiota can prevent retinopathy. AIM: To explore the relationship between intestinal microbiota and DR among patients in the southeast coast of China, and provide clues for novel ways to prevention and treatment methods of DR. METHODS: The fecal samples of non-diabetics (Group C, n = 15) and diabetics (Group DM, n = 30), including 15 samples with DR (Group DR) and 15 samples without DR (Group D), were analyzed by 16S rRNA sequencing. Intestinal microbiota compositions were compared between Group C and Group DM, Group DR and Group D, as well as patients with proliferative diabetic retinopathy (PDR) (Group PDR, n = 8) and patients without PDR (Group NPDR, n = 7). Spearman correlation analyses were performed to explore the associations between intestinal microbiota and clinical indicators. RESULTS: The alpha and beta diversity did not differ significantly between Group DR and Group D as well as Group PDR and Group NPDR. At the family level, Fusobacteriaceae, Desulfovibrionaceae and Pseudomonadaceae were significantly increased in Group DR than in Group D (P < 0.05, respectively). At the genera level, Fusobacterium, Pseudomonas, and Adlercreutzia were increased in Group DR than Group D while Senegalimassilia was decreased (P < 0.05, respectively). Pseudomonas was negatively correlated with NK cell count (r = -0.39, P = 0.03). Further, the abundance of genera Eubacterium (P < 0.01), Peptococcus, Desulfovibrio, Acetanaerobacterium and Negativibacillus (P < 0.05, respectively) were higher in Group PDR compared to Group NPDR, while Pseudomonas, Alloprevotella and Tyzzerella (P < 0.05, respectively) were lower. Acetanaerobacterium and Desulfovibrio were positively correlated with fasting insulin (r = 0.53 and 0.61, respectively, P < 0.05), when Negativibacillus was negatively correlated with B cell count (r = -0.67, P < 0.01). CONCLUSION: Our findings indicated that the alteration of gut microbiota was associated with DR and its severity among patients in the southeast coast of China, probably by multiple mechanisms such as producing short-chain fatty acids, influencing permeability of blood vessels, affecting levels of vascular cell adhesion molecule-1, hypoxia-inducible factor-1, B cell and insulin. Modulating gut microbiota composition might be a novel strategy for prevention of DR, particularly PDR in population above.

13.
Antimicrob Agents Chemother ; 67(7): e0026223, 2023 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-37358468

RESUMO

Nanoparticle-based antibiotic delivery systems are essential in combating antibiotic-resistant bacterial infections arising from acquired resistance and/or biofilm formation. Here, we report that the ceftazidime-decorated gold nanoparticles (CAZ_Au NPs) can effectively kill clinical ceftazidime-avibactam-resistant Enterobacteriaceae with various resistance mechanisms. Further study of underlying antibacterial mechanisms suggests that CAZ_Au NPs can damage the bacterial cell membrane and increase the level of intracellular reactive oxygen species. Moreover, CAZ_Au NPs show great potential in inhibiting biofilm formation and eradicating mature biofilms via crystal violet and scanning electron microscope assays. In addition, CAZ_Au NPs demonstrate excellent performance in improving the survival rate in the mouse model of abdominal infection. In addition, CAZ_Au NPs show no significant toxicity at bactericidal concentrations in the cell viability assay. Thus, this strategy provides a simple way to drastically improve the potency of ceftazidime as an antibiotic and its use in further biomedical applications.


Assuntos
Ceftazidima , Nanopartículas Metálicas , Animais , Camundongos , Ceftazidima/farmacologia , Enterobacteriaceae , Ouro , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/farmacologia , Combinação de Medicamentos
14.
mSphere ; 8(3): e0054922, 2023 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-37017551

RESUMO

Multidrug-resistant bacteria pose a tremendous challenge to public health worldwide. Many bacteria resistant to last-resort antibiotics due to antibiotic misuse have been recently reported, which may give rise to serious infections without effective treatment. Therefore, it is imperative to develop novel antimicrobial strategies. Natural phenols are known to increase bacterial membrane permeability and are potential candidates for the development of new antimicrobial agents. In this study, gold nanoparticles (Au NPs) carrying natural phenols were synthesized to combat bacteria resistant to last-resort antibiotics. Transmission electron microscopy, dynamic light scattering, zeta potential, and UV-visible spectra were used to characterize the synthesized Au NPs, which showed good monodispersity and uniform particle size. Evaluation of antibacterial activity using the broth microdilution method revealed that thymol-decorated gold nanoparticles (Thymol_Au NPs) had a broad antibacterial spectrum and higher bactericidal effects than last-resort antibiotics against last-resort-antibiotic-resistant bacteria. Considering the underlying antibacterial mechanism, the results showed that Thymol_Au NPs destroyed bacterial cell membranes. Further, Thymol_Au NPs were effective in treating mouse abdominal infections and exhibited acceptable biocompatibility without any significant toxicity in cell viability and histopathological assays, respectively, at most bactericidal concentrations. However, attention should be paid to changes in white blood cells, reticulocyte percentages, and superoxide dismutase activity during Thymol_Au NP treatment. In conclusion, Thymol_Au NPs have the potential for treating clinical infections caused by bacteria resistant to last-resort antibiotics. IMPORTANCE Excessive use of antibiotics can lead to bacterial resistance and the development of multidrug-resistant bacteria. Antibiotic misuse can also promote resistance against last-resort antibiotics. It is thus crucial to develop alternatives to antibiotics to retard the development of multidrug resistance. In recent years, the use of several nanodosage forms of antibacterial drugs has been investigated. These agents kill bacteria through a variety of mechanisms and avoid the problem of resistance. Among them, Au NPs, which are safer to use for medical applications than other metal nanoparticles, have attracted interest as potential antibacterial agents. To combat bacterial resistance to last-resort antibiotics and mitigate the problem of antimicrobial resistance, it is important and meaningful to develop antimicrobial agents based on Au NPs.


Assuntos
Anti-Infecciosos , Infecções Bacterianas , Doenças Transmissíveis , Nanopartículas Metálicas , Animais , Camundongos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Timol/farmacologia , Timol/uso terapêutico , Ouro/farmacologia , Ouro/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Bactérias
15.
Medicine (Baltimore) ; 102(17): e33662, 2023 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-37115061

RESUMO

Renal clear cell carcinoma (KIRC) is a malignancy of the renal epithelial cells with poor prognosis. Notably, the JAK-STAT pathway mediates cell proliferation and immune response. Accumulating evidence suggests that STATs act as immune checkpoint inhibitors in various cancers. Nonetheless, the role of STAT2 in KIRC remains elusive. Herein, analyses were performed using a series of interactive web databases including Oncomine, GEPIA and TIMER. In sub-group analyses, STAT2 was upregulated at both the mRNA and protein levels in KIRC patients. Besides, KIRC patients with high STAT2 expression exhibited a poor overall survival. Moreover, Cox regression analysis revealed that STAT2 expression, nodal metastasis and clinical stage were independent factors affecting the prognosis of KIRC patients. There was a significant positive correlation between STAT2 expression, and the abundance of immune cells as well as the expression of immune biomarker sets. In addition, STAT2 was found to be implicated in immune response, cytokine-cytokine receptor interaction, and Toll-like receptor signaling pathways. Also, several cancer-related kinases, miRNAs, and transcription factors associated with STAT2 were identified. Conclusively, we revealed that STAT2 is a potential prognosis biomarker and associated with immune infiltration in kidney renal clear cell carcinoma. This study offers additional data that will help in further research on the roles of STAT2 protein in carcinogenesis.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Janus Quinases , Prognóstico , Fator de Transcrição STAT2 , Fatores de Transcrição STAT , Transdução de Sinais , Carcinoma de Células Renais/genética , Rim
16.
Drug Resist Updat ; 68: 100952, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36812748

RESUMO

AIMS: To investigate the effect of Klebsiella pneumoniae carbapenemase (KPC)-loaded outer membrane vesicles (OMVs) in protecting Pseudomonas aeruginosa against imipenem treatment and its mechanism. METHODS: The OMVs of carbapenem-resistant Klebsiella pneumonia (CRKP) were isolated and purified from the supernatant of bacterial culture by using ultracentrifugation and Optiprep density gradient ultracentrifugation. The transmission electron microscope, bicinchoninic acid, PCR and carbapenemase colloidal gold assays were applied to characterize the OMVs. Bacterial growth and larvae infection experiments were performed to explore the protective function of KPC-loaded OMVs for P. aeruginosa under imipenem treatment. Ultra-performance liquid chromatography, antimicrobial susceptibility testing, whole-genome sequencing and bioinformatics analysis were used to investigate the mechanism of P. aeruginosa resistance phenotype mediated by OMVs. RESULTS: CRKP secreted OMVs loaded with KPC, which protect P. aeruginosa from imipenem through hydrolysis of antibiotics in a dose- and time-dependent manner. Furthermore, carbapenem-resistant subpopulations were developed in P. aeruginosa by low concentrations of OMVs that were confirmed to inadequately hydrolyze imipenem. Interestingly, none of the carbapenem-resistant subpopulations obtained the exogenous antibiotic resistance genes, but all of them possessed OprD mutations, which was consistent with the mechanism of P. aeruginosa induced by sub-minimal inhibitory concentrations of imipenem. CONCLUSIONS: OMVs containing KPC provide a novel route for P. aeruginosa to acquire an antibiotic-resistant phenotype in vivo.


Assuntos
Antibacterianos , Imipenem , Imipenem/farmacologia , Antibacterianos/farmacologia , Pseudomonas aeruginosa/genética , Farmacorresistência Bacteriana/genética , Proteínas de Bactérias/genética , beta-Lactamases/genética , Carbapenêmicos/farmacologia , Mutação , Testes de Sensibilidade Microbiana
17.
Front Microbiol ; 14: 1221428, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38282729

RESUMO

Objective: The co-occurrence of colistin and tigecycline resistance genes in Klebsiella pneumoniae poses a serious public health problem. This study aimed to characterize a K. pneumoniae strain, K82, co-harboring a colistin resistance gene (CoRG) and tigecycline resistance gene (TRG), and, importantly, investigate the genetic characteristics of the plasmid with CoRG or TRG in GenBank. Methods: K. pneumoniae strain K82 was subjected to antimicrobial susceptibility testing, conjugation assay, and whole-genome sequencing (WGS). In addition, comparative genomic analysis of CoRG or TRG-harboring plasmids from K82 and GenBank was conducted. K. pneumoniae strain K82 was resistant to all the tested antimicrobials including colistin and tigecycline, except for carbapenems. Results: WGS and bioinformatic analysis showed that K82 belonged to the ST656 sequence type and carried multiple drug resistance genes, including mcr-1 and tmexCD1-toprJ1, which located on IncFIA/IncHI2/IncHI2A/IncN/IncR-type plasmid pK82-mcr-1 and IncFIB/IncFII-type plasmid pK82-tmexCD-toprJ, respectively. The pK82-mcr-1 plasmid was capable of conjugation. Analysis of the CoRG/TRG-harboring plasmid showed that mcr-8 and tmexCD1-toprJ1 were the most common CoRG and TRG of Klebsiella spp., respectively. These TRG/CoRG-harboring plasmids could be divided into two categories based on mash distance. Moreover, we found an IncFIB/IncHI1B-type plasmid, pSYCC1_tmex_287k, co-harboring mcr-1 and tmexCD1-toprJ1. To the best of our knowledge, this is the first report on the co-occurrence of mcr-1 and tmexCD1-toprJ1 on a single plasmid. Conclusion: Our research expands the known diversity of CoRG and TRG-harboring plasmids in K. pneumoniae. Effective surveillance should be implemented to assess the prevalence of co-harboring CoRG and TRG in a single K. pneumoniae isolate or even a single plasmid.

18.
Front Public Health ; 10: 991306, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36324461

RESUMO

Klebsiella pneumoniae (K. pneumoniae) is one of the most common causes of bacterial meningitis worldwide. The purpose of this study was to investigate the clinical and microbiological characteristics of K. pneumoniae meningitis, as well as the association of antimicrobial resistance, virulence, and patient prognosis. The clinical data of patients with K. pneumoniae meningitis from 2014 to 2020 in a tertiary teaching hospital were retrospectively evaluated. Antimicrobial susceptibility profiles were performed by the agar dilution method and broth microdilution method. The isolates were detected for virulence-related genes, resistance genes, capsular serotypes, and molecular subtypes. A total of 36 individuals with K. pneumoniae meningitis were included in the study, accounting for 11.3% (36/318) of all cases of bacterial meningitis. Of the 36 available isolates, K1, K47, and K64 were tied for the most frequent serotype (7/36, 19.4%). MLST analysis classified the isolates into 14 distinct STs, with ST11 being the most common (14/36, 38.9%). Carbapenem resistance was found in 44.4% (16/36) of the isolates, while hypervirulent K. pneumoniae (HvKP) was found in 66.7% (24/36) of the isolates. The isolates of hypervirulent carbapenem-resistant K. pneumoniae (Hv-CRKP) were then confirmed to be 36.1% (13/36). Importantly, individuals with meningitis caused by Hv-CRKP had a statistically significant higher mortality than the other patients (92.3%, 12/13 vs. 56.5%, 13/23; P < 0.05). The high percentage and fatality of K. pneumoniae-caused meningitis, particularly in Hv-CRKP strains, should be of significant concern. More effective surveillance and treatment solutions will be required in future to avoid the spread of these life-threatening infections over the world.


Assuntos
Enterobacteriáceas Resistentes a Carbapenêmicos , Infecções por Klebsiella , Meningite , Humanos , Klebsiella pneumoniae/genética , Infecções por Klebsiella/epidemiologia , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/microbiologia , Tipagem de Sequências Multilocus , Estudos Retrospectivos , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Carbapenêmicos/uso terapêutico , China/epidemiologia , Meningite/tratamento farmacológico
19.
Microb Pathog ; 171: 105722, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35985450

RESUMO

BACKGROUND: The continued rise of Klebsiella pneumoniae resistance to antibiotics is precipitating a medical crisis. Bacteriophages have been hailed as one possible therapeutic option to enhance the efficacy of antibiotics. This study describes the genomic characterization and biological property of a new bacteriophage vB_1086 and its potential for phage therapy application against Klebsiella pneumoniae. METHODS: In our study, the double-layer agar plate method isolated a lytic bacteriophage named vB_1086. Besides, we analyzed its biological characteristics and genetic background. Then the antibacterial ability of the bacteriophage vB_1086 combined with antibiotics were analyzed by the combined checkerboard method. The impact on the formation of biofilms was analyzed by crystal violet staining method. RESULTS: vB_1086 is a lytic bacteriophage with stable biological characteristics and clear genetic background, showing good antibacterial activity in combination with ceftriaxone, and the combination of phage and meropenem can effectively inhibit the formation of biofilm. Besides, the combination of bacteriophage and antimicrobials can effectively alleviate the generation of bacterial resistance and reduce the dosage of antimicrobials. CONCLUSION: vB_1086 is a novel phage. To some extent, these results provide valuable information that phage vB_1086 can be combined with antibiotics to reduce the dosage of antimicrobials and alleviate the generation of bacterial resistance.


Assuntos
Infecções Bacterianas , Bacteriófagos , Ágar/farmacologia , Antibacterianos/farmacologia , Bacteriófagos/genética , Ceftriaxona/farmacologia , Violeta Genciana , Humanos , Klebsiella pneumoniae , Meropeném/farmacologia
20.
Medicine (Baltimore) ; 101(22): e29254, 2022 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-35665729

RESUMO

BACKGROUND: Kidney renal clear cell carcinoma (KIRC) was the most prevalent malignancy of urinary system. Phosphatidylinositol 3-kinase pathway exerted a vital function in tumor proliferation, invasion, and survival by integrating extracellular growth signals. METHODS: The expression and clinical significance of PIK3CB in KIRC was explored using bioinformatics analysis. And qRT-PCR was performed to verify our results. RESULTS: PIK3CB was downregulated at mRNA and protein level in KIRC. KIRC patients with low PIK3CB expression indicated a worse overall survival, progression free survival, and disease-free survival. A predictive nomogram was constructed and demonstrated that the predicted calibration plots for 1-year, 3-year, and 5-year OS probabilities showed good agreement compared with the actual OS of KIRC patients. Validation research demonstrated a downregulation of PIK3CB in KIRC tissues and a poor overall survival in KIRC patients with low PIK3CB expression. Furthermore, Cox regression analysis revealed that PIK3CB expression was an independent prognostic factor for KIRC. PIK3CB expression showed positive correlation with the abundance of immune cells. Moreover, enrichment analysis revealed that PIK3CB and associated genes were mainly associated with RNA splicing and JAK-STAT signaling pathway. CONCLUSION: Our study suggested that PIK3CB was a potential biomarker for prognosis and correlated with immune infiltrates in KIRC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Biologia Computacional , Humanos , Neoplasias Renais/patologia , Prognóstico
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