RESUMO
BACKGROUND: Empiric therapy for Helicobacter pylori infection results in significantly increased antibiotic resistance and decreased eradication efficacy. The genotypic testing of clarithromycin resistance from stool specimens is a promising method for individualized diagnosis and treatment. This study aimed to determine the status of research and application on this method through a systematic review and meta-analysis. METHODS: PubMed, Embase, MEDLINE, and WAN FANG database were searched for relevant literature. The quality of included diagnostic articles was evaluated using the quality Assessment of Diagnostic Accuracy Studies-2 tool. A bivariate random-effect model was conducted to calculate the diagnostic accuracy of genotypic testing of clarithromycin resistance. RESULTS: A total of 16 diagnostic-related were included and analyzed after exclusions. The pooled sensitivity and specificity of diagnostic meta-analysis were 0.93 (95% confidence interval [CI]: 0.90-0.96) and 0.98 (95% CI: 0.93-1.00), respectively. The area under the curve (AUC) of the summary receiver operating characteristic was 0.97 (95% CI: 0.95-0.98). The genotypic testing in stool samples had heterogeneous sensitivity (Q = 37.82, p < .01, I2 = 37.82) and specificity (Q = 60.34, p < .01, I2 = 93.72) in detecting clarithromycin resistance. Purification method, stool sample weight, real-time PCR, and antimicrobial susceptibility testing as reference accounted for the heterogeneity of pooled sensitivity, while patient age, purification method, stool sample weight, and real-time PCR for the heterogeneity of pooled specificity. CONCLUSION: The genotypic testing of clarithromycin resistance from stool specimens is an accurate, convenient, noninvasive, and rapid detection technology, providing a definitive diagnosis of clarithromycin resistance and guiding the rational antibiotic selection.
Assuntos
Infecções por Helicobacter , Helicobacter pylori , Humanos , Claritromicina/farmacologia , Claritromicina/uso terapêutico , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/tratamento farmacológico , Farmacorresistência Bacteriana/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Testes de Sensibilidade MicrobianaRESUMO
BACKGROUND: Helicobacter pylori eradication in penicillin-allergic patients is challenging. The effective regimen is lacking in areas with high antibiotic resistance and tetracycline unavailable. Minocycline, cefuroxime, and full-dose metronidazole are promising drugs. AIMS: To compare the eradication rate, safety, and compliance among three new bismuth quadruple therapies for first-line H. pylori eradication in penicillin-allergic patients. METHODS: This randomized trial was conducted on 450 naive patients with H. pylori infection and penicillin allergy. The 14-day minocycline-metronidazole-containing (minocycline 100 mg twice daily and metronidazole 400 mg four times/day), minocycline-cefuroxime-containing (minocycline 100 mg twice daily and cefuroxime 500 mg twice daily), and cefuroxime-metronidazole-containing (cefuroxime 500 mg twice daily and metronidazole 400 mg four times/day) bismuth quadruple therapies were randomly assigned to the participants. Safety and compliance were assessed within 3 days after eradication. Urea breath test was performed 4-8 weeks after eradication to evaluate outcome. RESULTS: The differences of eradication rates in either intention-to-treat (84.0%, 82.7%, and 23 82.0%, p = .896) or per-protocol (91.7%, 90.9%, and 88.2%, p = .599) analysis among minocycline-metronidazole, minocycline-cefuroxime, and cefuroxime-metronidazole-containing bismuth quadruple therapies were statistically insignificant. The incidence of adverse events (35.1%, 22.6%, and 28.9%) and compliance (90.5%, 91.8%, and 91.9%) were similar. Taste distortion, nausea, and anorexia were more common in metronidazole-containing regimens, and dizziness was more common in minocycline-containing regimens. The allergy was rare (~3%). CONCLUSIONS: The efficacies of three bismuth quadruple therapies containing minocycline, cefuroxime, and full-dose metronidazole (pairwise) for first-line H. pylori eradication in penicillin-allergic patients were similarly satisfactory with relatively good safety and compliance. The study was registered in the Chinese Clinical Trials Registration (ChiCTR1900023702).
Assuntos
Infecções por Helicobacter , Helicobacter pylori , Hipersensibilidade , Humanos , Infecções por Helicobacter/tratamento farmacológico , Penicilinas/efeitos adversos , Bismuto/uso terapêutico , Metronidazol/uso terapêutico , Cefuroxima/farmacologia , Cefuroxima/uso terapêutico , Minociclina/farmacologia , Minociclina/uso terapêutico , Antibacterianos/uso terapêutico , Tetraciclina/uso terapêutico , Adesão à Medicação , Quimioterapia Combinada , Resultado do Tratamento , Amoxicilina/uso terapêuticoRESUMO
BACKGROUND: Due to general unavailability and common side effects of tetracycline, the clinical application of bismuth quadruple therapy (BQT) is greatly limited. Whether amoxicillin can replace tetracycline in BQT remains unknown. This study aimed to compare the eradication rate, safety and compliance between amoxicillin-containing and tetracycline-containing BQT as a first-line regimen for Helicobacter pylori eradication. METHODS: This randomized trial was conducted on 404 naïve patients for H. pylori eradication. The participants were randomly assigned to 14-day amoxicillin-containing (bismuth potassium citrate 110 mg four times/day, esomeprazole 20 mg twice daily, metronidazole 400 mg four times/day and amoxicillin 500 mg four times/day) and tetracycline-containing (tetracycline 500 mg four times/day and the other three drugs used as above) BQT. Safety and compliance were assessed within 3 days after eradication. Urea breath test was performed 4-8 weeks after eradication to evaluate outcome. RESULTS: As for the eradication rates of amoxicillin-containing and tetracycline-containing BQT, the results of both intention-to-treat and per-protocol analyses showed that the difference rate of the lower limit of 95% confidence interval was above -10.0% (intention-to-treat analysis: 81.7% vs. 83.2%, with a rate difference of -1.5% [-6.3% to 9.3%]; per-protocol analysis: 89.0% vs. 91.6%, -2.6% [-4.1% to 9.3%]). The incidence of adverse events in amoxicillin-containing BQT was significantly lower than tetracycline-containing BQT (29.5% vs. 39.7%). Both groups achieved relatively good compliance (92.0% vs. 89.9%). CONCLUSION: The eradication efficacy of amoxicillin-containing BQT was non-inferior to tetracycline-containing BQT as a first-line regimen for H. pylori eradication with better safety and similar compliance.
Assuntos
Infecções por Helicobacter , Helicobacter pylori , Humanos , Amoxicilina/efeitos adversos , Metronidazol/efeitos adversos , Bismuto/efeitos adversos , Esomeprazol/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Antibacterianos/efeitos adversos , Tetraciclina/efeitos adversos , Quimioterapia CombinadaRESUMO
Bacterial outer membrane proteins (Omps) are essential for environmental sensing, stress responses, and substance transport. Our previous study discovered that OmpA contributes to planktonic growth, biocide resistance, biofilm formation, and swimming motility in Citrobacter werkmanii, whereas the molecular functions of OmpF in this strain are largely unknown. Thus, in this study, the ompF gene was firstly knocked out from the genome of C. werkmanii using a homologous recombination method, and its phenotypical alternations of ∆ompF were then thoroughly characterized using biochemical and molecular approaches with the parental wild type (WT) and complementary (∆ompF-com) strains. The results demonstrated that the swimming ability of ∆ompF on semi-solid plates was reduced compared to WT due to the down-regulation of flgC, flgH, fliK, and fliF. Meanwhile, ompF deletion reduces biofilm formation on both glass and polystyrene surfaces due to decreased cell aggregation. Furthermore, ompF inactivation induced different osmotic stress (carbon sources and metal ions) responses in its biofilms when compared to WT and ∆ompF-com. Finally, a total of 6 maltose metabolic genes of lamB, malE, malK, malG, malM, and malF were all up-regulated in ∆ompF. The gene knockout and HPLC results revealed that the MalEFGK2 cluster was primarily responsible for maltose transport in C. werkmanii. Furthermore, we discovered for the first time that the upstream promoter of OmpF and its transcription can be combined with and negatively regulated by MalT. Overall, OmpF plays a role in a variety of biochemical processes and molecular functions in C. werkmanii, and it may even act as a targeted site to inhibit biofilm formation.
Assuntos
Maltose , Natação , Osmorregulação , Proteínas da Membrana Bacteriana Externa/genética , BiofilmesRESUMO
BACKGROUND: Systematic reviews suggested that the eradication efficacy of PPI-amoxicillin dual therapy is similar to that of other commonly used regimens. However, it might be affected by the medication frequency. Basic and clinical studies have shown that dual therapy administered four-times daily has a reliable pathophysiological basis and could achieve satisfactory efficacy. Therefore, a systematic review of RCTs of dual therapy and other regimens was conducted to clarify whether dual therapy is superior to guidelines recommended regimens. MATERIALS AND METHODS: The RCTs comparing dual therapy with other regimens were subjected to meta-analysis to evaluate the eradication rate, adverse reactions, and compliance using a random-effects model. RESULTS: Dual therapy administered four-times daily had a higher eradication rate than other regimens (intention-to-treat analysis: 89.7% vs 84.6%, OR: 1.52, 95%CI 1.08-2.14, p = 0.02; per-protocol analysis: 92.6% vs 88.2%, OR: 1.54, 95%CI 1.01-2.34, p = 0.04). In first-line therapy, according to intention-to-treat analysis, the eradication rate of dual therapy was higher than other regimens (89.8% vs 84.2%, OR: 1.63, 95%CI 1.02-2.61, p = 0.04). In per-protocol analysis, dual therapy showed better efficacy than others (92.9% vs 88.3%, OR: 1.68, 95% CI 0.98-2.89, p = 0.06), but not significantly. In salvage treatment, no significant difference was detected. The safety of dual therapy was significantly better than other regimens (19.6% vs 36.7%, p < 0.01), but no difference was observed in compliance (p = 0.58). CONCLUSION: PPI-amoxicillin dual therapy administered four-times daily has better efficacy and safety in H. pylori eradication than current guidelines recommended regimens, especially in first-line therapy, and mainly in Asia.
Assuntos
Infecções por Helicobacter , Helicobacter pylori , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Ásia , Claritromicina/uso terapêutico , Quimioterapia Combinada , Infecções por Helicobacter/tratamento farmacológico , Humanos , Inibidores da Bomba de Prótons/uso terapêutico , Resultado do TratamentoRESUMO
Through our previous study, we found an up-regulation in the expression of nitrite reductase (nirS) in the isothiazolone-resistant strain of Pseudomonas aeruginosa. However, the definitive molecular role of nirS in ascribing the resistance remained elusive. In the present study, the nirS gene was deleted from the chromosome of P. aeruginosa ATCC 9027 and the resulting phenotypic changes of ΔnirS were studied alongside the wild-type (WT) strain under aerobic conditions. The results demonstrated a decline in the formations of biofilms but not planktonic growth by ΔnirS as compared to WT, especially in the presence of benzisothiazolinone (BIT). Meanwhile, the deletion of nirS impaired swimming motility of P. aeruginosa under the stress of BIT. To assess the influence of nirS on the transcriptome of P. aeruginosa, RNA-seq experiments comparing the ΔnirS with WT were also performed. A total of 694 genes were found to be differentially expressed in ΔnirS, of which 192 were up-regulated, while 502 were down-regulated. In addition, these differently expressed genes were noted to significantly enrich the carbon metabolism along with glyoxylate and dicarboxylate metabolisms. Meanwhile, results from RT-PCR suggested the contribution of mexEF-oprN to the development of BIT resistance by ΔnirS. Further, c-di-GMP was less in ΔnirS than in WT, as revealed by HPLC. Taken together, our results confirm that nirS of P. aeruginosa ATCC 9027 plays a role in BIT resistance along with biofilm formation and further affects several metabolic patterns under aerobic conditions.
Assuntos
Nitrito Redutases/metabolismo , Pseudomonas aeruginosa/enzimologia , Aerobiose , Biofilmes , Regulação Bacteriana da Expressão Gênica , Nitrito Redutases/genética , Pseudomonas aeruginosa/genética , TranscriptomaRESUMO
MicroRNAs (miRNAs) have been shown to play a key role in spermatogenesis. However, whether the miRNAs influence androgen/androgen receptor (AR) signaling during spermatogenesis remains unclear. Using a bioinformatic approach, a potential miRNA, miR-130a, which could bind to Ar-3'untranslated region directly was identified. The expression pattern of miR-130a was further characterized by quantitative real-time polymerase chain reaction. It was found that miR-130a was abundant in testis and its expression level was negatively correlated with age. Overexpression of miR-130a could inhibit AR expression both in vitro and in vivo. Moreover, the mice with an intratesticular injection of miR-130a showed defects in spermatogenesis and increased germ cell apoptosis. Taken together, these results suggest that miR-130a could negatively regulate AR expression in mouse Sertoli cell, which further cause defects in spermatogenesis.
Assuntos
Apoptose , Regulação da Expressão Gênica , MicroRNAs/biossíntese , Receptores Androgênicos/biossíntese , Células de Sertoli/metabolismo , Espermatogênese , Animais , Linhagem Celular , Masculino , Camundongos , MicroRNAs/genética , Receptores Androgênicos/genética , Células de Sertoli/citologiaRESUMO
Phenotype-driven mutagenesis is an unbiased method to identify novel genes involved in spermatogenesis and other reproductive processes. Male repro29/repro29 mice generated by the Reproductive Genomics Program at the Jackson Laboratory were infertile with deformed sperm and poor motility. Using selected exonic capture and massively parallel sequencing technologies, we identified a nonsense mutation in the exon 6 of coiled-coil domain-containing 62 gene (Ccdc62), which results in a formation of a premature stop codon and a truncated protein. Among the tissues examined, CCDC62 was found to be expressed at the highest level in mouse testis by reverse transcriptase-PCR (RT-PCR) and Western blot analysis. With immunofluorescent staining, we demonstrated that CCDC62 was expressed in the cytoplasm and the developing acrosome in the spematids of mouse testis, and was specifically localized at the acrosome in mature sperm. The complementation analysis by mating repro29/+ mice with Ccdc62 -/- mice (generated by CRISPR-Cas9 strategy) further provided genetic proof that the infertility of repro29/repro29 mice was caused by Ccdc62 mutation. Finally, it was found that intracellular colocalization and interaction of CCDC62 and Golgi-associated PDZ and coiled-coil motif-containing protein may be important for acrosome formation. Taken together, this study identified a nonsense mutation in Ccdc62, which directly results in male infertility in repro29/repro29 mice.
Assuntos
Infertilidade Masculina/genética , Espermatogênese/genética , Fatores de Transcrição/genética , Acrossomo/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Sequência de Bases , Proteínas de Transporte/metabolismo , Códon sem Sentido , Etilnitrosoureia , Feminino , Proteínas da Matriz do Complexo de Golgi , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Camundongos , Camundongos Knockout , Análise de Sequência de DNA , Testículo/crescimento & desenvolvimento , Testículo/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Primary renal cell carcinomas (pRCCs) have a high degree of intratumoral heterogeneity and are composed of multiple distinct subclones. However, it remains largely unknown that whether metastatic renal cell carcinomas (mRCCs) also have startling intratumoral heterogeneity or whether development of mRCCs is due to early dissemination or late diagnosis. To decipher the evolution of mRCC, we analyzed the multilayered molecular profiles of pRCC, local invasion of the vena cava (IVC), and distant metastasis to the brain (MB) from the same patient using whole-genome sequencing, whole-exome sequencing, DNA methylome profiling, and transcriptome sequencing. We found that mRCC had a lower degree of heterogeneity than pRCC and was likely to result from recent clonal expansion of a rare, advantageous subclone. Consequently, some key pathways that are targeted by clinically available drugs showed distinct expression patterns between pRCC and mRCC. From the genetic distances between different tumor subclones, we estimated that the progeny subclone giving rise to distant metastasis took over half a decade to acquire the full potential of metastasis since the birth of the subclone that evolved into IVC. Our evidence supported that mRCC was monoclonal and distant metastasis occurred late during renal cancer progression. Thus, there was a broad window for early detection of circulating tumor cells and future targeted treatments for patients with mRCCs should rely on the molecular profiles of metastases.
Assuntos
Neoplasias Encefálicas/genética , Carcinogênese/genética , Carcinoma de Células Renais/genética , Metástase Neoplásica/genética , Neoplasias Encefálicas/secundário , Carcinoma de Células Renais/metabolismo , Exoma/genética , Perfilação da Expressão Gênica , Heterogeneidade Genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células Neoplásicas CirculantesRESUMO
Numerous attempts for detection of circulating tumor cells (CTC) have been made to develop reliable assays for early diagnosis of cancers. In this study, we validated the application of folate receptor α (FRα) as the tumor marker to detect CTC through tumor-specific ligand PCR (LT-PCR) and assessed its utility for diagnosis of bladder transitional cell carcinoma (TCC). Immunohistochemistry for FRα was performed on ten bladder TCC tissues. Enzyme-linked immunosorbent assay (ELISA) for FRα was performed on both urine and serum specimens from bladder TCC patients (n = 64 and n = 20, respectively) and healthy volunteers (n = 20 and n = 23, respectively). Western blot analysis and qRT-PCR were performed to confirm the expression of FRα in bladder TCC cells. CTC values in 3-mL peripheral blood were measured in 57 bladder TCC patients, 48 healthy volunteers, and 15 subjects with benign urologic pathologies by the folate receptor α ligand-targeted PCR. We found that FRα protein was overexpressed in both bladder TCC cells and tissues. The levels of FRα mRNA were also much higher in bladder cancer cell lines 5637 and SW780 than those of leukocyte. Values of FRα were higher in both serum and urine specimens of bladder TCC patients than those of control. CTC values were also higher in 3-mL peripheral blood of bladder TCC patients than those of control (median 26.5 Cu/3 mL vs 14.0 Cu/3 mL). Area under the receiver operating characteristic (ROC) curve for bladder TCC detection was 0.819, 95 % CI (0.738-0.883). At the cutoff value of 15.43 Cu/3 mL, the sensitivity and the specificity for detecting bladder cancer are 82.14 and 61.9 %, respectively. We concluded that quantitation of CTCs through FRα ligand-PCR could be a promising method for noninvasive diagnosis of bladder TCC.
Assuntos
Carcinoma de Células de Transição/sangue , Receptor 1 de Folato/sangue , Células Neoplásicas Circulantes , Neoplasias da Bexiga Urinária/sangue , Biomarcadores Tumorais/sangue , Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Receptor 1 de Folato/isolamento & purificação , Humanos , Ligantes , Masculino , RNA Mensageiro/biossíntese , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/patologiaRESUMO
Androgen signaling plays a crucial role in spermatogenesis, yet few downstream targets for this signaling pathway have been identified. In the current study, we found that the expression of heat-shock transcription factor 1 (Hsf1) was increased in the testes of Sertoli cell-selective androgen receptor knockout (S-AR(-/y) ) mice compared with wild-type mice by quantitative real-time PCR, and the expression of HSF1 in the S-AR(-/y) Sertoli cells was significantly increased, based on immunofluorescence analysis. In vitro cell-culture studies showed that testosterone repressed the expression of Hsf1 in TM4 cells, a mouse Sertoli cell line. Moreover, a luciferase assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay showed that testosterone repressed Hsf1 expression by facilitating the binding of androgen receptor to the Hsf1 promoter. Our experiments also demonstrated that testosterone-mediated inhibition of Hsf1 transcription down-regulated the expression of heat-shock proteins HSP105 and HSP60. Taken together, these results reveal that Hsf1 is a novel target of androgen receptor in mouse Sertoli cells, and testosterone and its receptor regulate the process of spermatogenesis partially by inhibiting Hsf1 expression.
Assuntos
Proteínas de Ligação a DNA/biossíntese , Receptores Androgênicos/metabolismo , Células de Sertoli/metabolismo , Espermatogênese/fisiologia , Fatores de Transcrição/biossíntese , Animais , Linhagem Celular , Chaperonina 60/biossíntese , Chaperonina 60/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica/fisiologia , Proteínas de Choque Térmico HSP110/biossíntese , Proteínas de Choque Térmico HSP110/genética , Fatores de Transcrição de Choque Térmico , Masculino , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/biossíntese , Proteínas Mitocondriais/genética , Receptores Androgênicos/genética , Células de Sertoli/citologia , Testosterona/genética , Testosterona/metabolismo , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Methionine adenosyltransferase 2A (MAT2A) is an enzyme that catalyzes the formation of S-adenosylmethionine (SAMe) by joining methionine and ATP. SAMe is a methyl donor for transmethylation and has an important role for DNA and/or protein methylation. MAT2A is expressed widely in many tissues especially in kidney. Several studies have demonstrated that there are abnormal expressions of MAT2A in several kinds of cancers such as liver and colon cancers. But the relationship of MAT2A between renal cell carcinomas (RCC) is less understood. METHODS: The mRNA expression level of the MAT2A gene was determined in 24 RCC patients and 4 RCC cell lines, using real-time quantitative-polymerase chain reaction (RT-PCR). The MAT2A protein content was measured by western blotting and immunohistochemical analysis in 55 RCC patients. The mRNA levels of heme oxygenase-1 (HO-1) and cyclooxygenase-2 (COX-2) were also analysized in patients using RT-PCR. The correlations between the MAT2A and HO-1 as well as COX-2 were analyzed with nonparametric Spearman method. RESULTS: MAT2A transcript was significantly downregulated in cancer tissues compared to normal tissues (P < 0.05). Immunohistochemical analysis and western blotting indicated that level of MAT2A protein was decreased in cancer tissues. The statistical analysis reveals a negative correlation between MAT2A and HO-1 expression in RCC patients and cell lines (P < 0.01). CONCLUSIONS: This study demonstrated that MAT2A was lower expression in cancer tissues, suggesting that it may be involved in the development of RCC. MAT2A is a transcriptional corepressor for HO-1 expression by supplying SAM for methyltransferases, which may be one of potential mechanism of MAT2A as tumor suppressor in kidney carcinogenesis.
Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Metionina Adenosiltransferase/genética , Metionina Adenosiltransferase/metabolismo , Adulto , Idoso , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Heme Oxigenase-1/genética , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , S-Adenosilmetionina/metabolismoRESUMO
Using Illumina sequencing technology, we generated complete mitochondrial genomes (mitogenomes) of three constituent species of the aphid genus Hyalopterus Koch, Hyalopterus amygdali (Blanchard), Hyalopterus arundiniformis Ghulamullah, and Hyalopterus pruni (Geoffroy). The sizes of the Hyalopterus mitogenomes range from 15,306 to 15,410 bp, primarily due to variations in the length of non-coding regions. The Hyalopterus mitogenomes consist of 37 coding genes arranged in the order of the ancestral insect mitogenome, a control region, and a repeat region between trnE and trnF. According to the COI-based analysis, one previously reported mitogenome of H. pruni should be assigned to H. arundiniformis. The gene order, nucleotide composition, and codon usage in the Hyalopterus mitogenomes are highly conserved and similar to those of other species of Aphidinae. The tandem repeat units differ in nucleotide composition, length, and copy number across three Hyalopterus species. Within the widespread Eurasian species H. arundiniformis, variation in repeat units among different geographic populations is observed, indicating that the repeat region may provide valuable insights for studying the intraspecific diversification of aphids. Phylogenetic analyses based on 28 complete mitogenomes of Aphidinae supported the monophyly of Aphidinae, Aphidini, Macrosiphini, and two subtribes of Aphidini. Hyalopterus was monophyletic. H. amygdali and H. pruni formed a sister group, while H. arundiniformis was placed basally. Characterization of the mitogenomes of Hyalopterus provides valuable resources for further comparative studies and for advancing our understanding of the aphid mitogenome architecture.
RESUMO
BACKGROUND: Difficulty in obtaining tetracycline, increased adverse reactions, and relatively complicated medication methods have limited the clinical application of the classic bismuth quadruple therapy. Therefore, the search for new alternative drugs has become one of the research hotspots. In recent years, minocycline, as a semisynthetic tetracycline, has demonstrated good potential for eradicating Helicobacter pylori (H. pylori) infection, but the systematic evaluation of its role remains lacking. AIM: To explore the efficacy, safety, and compliance of minocycline in eradicating H. pylori infection. METHODS: We comprehensively retrieved the electronic databases of PubMed, Embase, Web of Science, China National Knowledge Infrastructure, SinoMed, and Wanfang database as of October 30, 2023, and finally included 22 research reports on H. pylori eradication with minocycline-containing regimens as per the inclusion and exclusion criteria. The eradication rates of H. pylori were calculated using a fixed or a random effect model, and the heterogeneity and publication bias of the studies were measured. RESULTS: The single-arm meta-analysis revealed that the minocycline-containing regimens achieved good overall H. pylori eradication rates, reaching 82.3% [95% confidence interval (CI): 79.7%-85.1%] in the intention-to-treat analysis and 90.0% (95%CI: 87.7%-92.4%) in the per-protocol analysis. The overall safety and compliance of the minocycline-containing regimens were good, demonstrating an overall incidence of adverse reactions of 36.5% (95%CI: 31.5%-42.2%). Further by traditional meta-analysis, the results showed that the minocycline-containing regimens were not statistically different from other commonly used eradication regimens in eradication rate and incidence of adverse effects. Most of the adverse reactions were mild to moderate and well-tolerated, and dizziness was relatively prominent in the minocycline-containing regimens (16%). CONCLUSION: The minocycline-containing regimens demonstrated good efficacy, safety, and compliance in H. pylori eradication. Minocycline has good potential to replace tetracycline for eradicating H. pylori infection.
Assuntos
Antibacterianos , Quimioterapia Combinada , Infecções por Helicobacter , Helicobacter pylori , Minociclina , Humanos , Minociclina/efeitos adversos , Minociclina/administração & dosagem , Minociclina/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Helicobacter pylori/efeitos dos fármacos , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Quimioterapia Combinada/métodos , Resultado do Tratamento , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/uso terapêutico , Inibidores da Bomba de Prótons/administração & dosagem , Adesão à MedicaçãoRESUMO
Neoadjuvant chemoradiotherapy (NACRT) was the standard treatment for patients with locally advanced rectal cancer (LARC) with proficient mismatch repair (pMMR) proteins. In this randomized phase 2 trial (ClinicalTrial.gov: NCT04304209), 134 pMMR LARC patients were randomly (1:1) assigned to receive NACRT or NACRT and the programmed cell death protein 1 (PD-1) antibody sintilimab. As the primary endpoint, the total complete response (CR) rate is 26.9% (18/67, 95% confidence interval [CI] 16.0%-37.8%) and 44.8% (30/67, 95% CI 32.6%-57.0%) in the control and experimental arm, respectively, with significant difference (p = 0.031 for chi-squared test). Response ratio is 1.667 (95% CI 1.035-2.683). Immunohistochemistry shows PD-1 ligand 1 (PD-L1) combined positive score is associated with the synergistic effect. The safety profile is similar between the arms. Adding the PD-1 antibody sintilimab to NACRT significantly increases the CR rate in pMMR LARC, with a manageable safety profile. PD-L1 positivity may help identify patients who might benefit most from the combination therapy.
RESUMO
Many genes are regulated by androgen and its receptor (AR), but the direct target genes of AR, especially those involved in spermatogenesis and male infertility, remain unclear. Here, we identified ubiquitin-conjugating enzyme E2B (Ube2b) as a critical target gene of AR. The expression of UBE2B was decreased in the testes of Sertoli cell AR knockout (S-AR(-/y)) mice analyzed by quantitative RT-PCR (qRT-PCR) and immunofluorescence. The upregulation of Ube2b gene by testosterone was further demonstrated by Western blot and qRT-PCR in TM4 cells, a mouse Sertoli cell line. Moreover, luciferase assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay validated that the ligand-bound AR activated Ube2b transcription via direct binding to the androgen-responsive element of the Ube2b promoter. In vitro analyses showed that testosterone increased UBE2B expression and activated H2A ubiquitylation, while downregulation of UBE2B blocked the testosterone-induced H2A ubiquitylation. The ubiquitylation of H2A was markedly decreased in the testes of S-AR(-/y) mice by immunohistochemistry. Digital gene expression analysis showed that 113 genes were significantly downregulated and 71 were upregulated by UBE2B in TM4 cells. These results suggest that Ube2b, as a direct AR transcriptional target in Sertoli cells, mediates the function of AR in spermatogenesis by promoting H2A ubiquitylation.
Assuntos
Receptores Androgênicos/metabolismo , Células de Sertoli/metabolismo , Espermatogênese/fisiologia , Enzimas de Conjugação de Ubiquitina/metabolismo , Animais , Células Cultivadas , Regulação para Baixo/fisiologia , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Knockout , Receptores Androgênicos/genética , Transdução de Sinais/fisiologia , Enzimas de Conjugação de Ubiquitina/genética , Ubiquitinação/fisiologia , Regulação para Cima/fisiologiaRESUMO
BACKGROUND: Chronic glomerulonephritis (CGN) is a primary glomerular disease. As a circulating protein, growth and differentiation factor 15 (GDF15) participates in a variety of biological processes. OBJECTIVE: We aimed to investigate the role of GDF15 in CGN. METHODS: HBZY-1 cells were induced by lipopolysaccharide (LPS). Cell viability was detected using a cell counting kit-8 (CCK-8) assay, and a western blot was applied for the detection of GDF15 protein expression. After GDF15 silencing, cell proliferation was evaluated by CCK-8 assay and 5-ethynyl-2'-deoxyuridine (EDU) staining. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect the levels of inflammatory cytokines. Autophagy was assessed by GFP-LC3B assay. Besides, the expression of NF-κB signaling-, autophagy- (LC3II/I, Beclin l and p62) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling-related proteins were measured by western blot. Afterwards, PI3K agonist 740Y-P was used to clarify whether GDF15 affected LPS-induced HBZY-1 cells via PI3K/AKT/mTOR signaling. RESULTS: LPS induction increased cell viability and elevated GDF15 expression in HBZY-1 cells. After GDF15 expression depletion, the increased proliferation of LPS-induced HBZY-1 cells was decreased. Additionally, GDF15 knockdown suppressed the release of inflammatory factors in LPS-induced HBZY-1 cells and activated autophagy. Moreover, the PI3K/AKT/ mTOR signal was evidenced to be activated by GDF15 deficiency. The further addition of 740Y-P reversed the impacts of GDF15 deficiency on the proliferation, inflammation, and autophagy of LPS-induced HBZY-1 Conclusion: Collectively, GDF15 downregulation could protect against CGN via blocking PI3K/AKT/mTOR signaling.
RESUMO
Anti-bacterial photodynamic therapy is the most promising treatment protocol for bacterial infection, but low accumulation of photosensitizers has seriously hindered their development in clinical application. Here, with inherent outstanding affinity to bacterial cell envelope, sophorolipid produced from Candida bombicola has been conjugated to toluidine blue (SL-TB) through amidation reaction. The structure of SL-TB conjugates was identified by 1H-NMR, FT-IR and ESI-HRMS. The interfacial assembly and photophysical properties of SL-TB conjugates have been disclosed through surface tension, micro-polarity, electronic and fluorescence spectra. After light irradiation, the log10 (reduced CFU) of free toluidine blue to P. aeruginosa and S. aureus were 4.5 and 7.9, respectively. In contrast, SL-TB conjugates showed a higher bactericidal activity, with a reduction of 6.3 and 9.7 log10 units of CFU against P. aeruginosa and S. aureus, respectively. The fluorescence quantitative results showed that SL-TB could accumulate 2850 nmol/1011 cells and 4360 nmol/1011 cells by P. aeruginosa and S. aureus, which was much higher than the accumulation of 462 nmol/1011 cells and 827 nmol/1011 cells of free toluidine blue. Through the cooperation of triple factors, including sophorose affinity to bacterial cells, hydrophobic association with plasma membrane, and electrostatic attraction, higher SL-TB accumulation was acquired, which has enhanced antibacterial photodynamic efficiencies.
RESUMO
Citrobacter werkmanii, an aerobe and mesophilic Proteobacterium, is universal in industrial putrefaction, coastal water, and human blood. Our previous studies have discovered that outer membrane protein X (OmpX) of C. werkmanii is involved in calcium response, but the underlying mechanisms and its molecular characteristics remain elusive. To that end, the ompX gene was deleted from the genome of C. werkmanii and its phenotypic variations were thoroughly investigated in conjunction with the wild type (WT) and complementary strains using biochemical and molecular techniques such as RNA-Seq, respectively. The results demonstrated that deleting ompX reduces biofilm formation on polystyrene and glass surfaces. Meanwhile, ΔompX's swimming ability but not for its twitching or swarming abilities, was also reduced on semi-solid plates compared with WT, which was caused by inhibition of flagellar assembly genes, such as flgC, flhB, and fliE, etc. Furthermore, ompX inactivation altered susceptibility to various bactericide classes, as well as responses to Ca2+ and Mg2+ stress. In addition, when compared to WT, ΔompX captures a total of 1,357 deferentially expressed genes (DEGs), of which 465 were up-regulated and 892 were down-regulated, which can be enriched into various GO ontology and KEGG pathway terms. Furthermore, ompX, as well as ompD and ompW, can be modulated at the transcriptional levels by rbsR and tdcA. Overall, the ompX gene contributed to a variety of biological functions in C. werkmanii and could be served as a targeted site for controlling biofilm formation and developing new bactericides.
Assuntos
Citrobacter , Natação , Humanos , Citrobacter/genética , BiofilmesRESUMO
BACKGROUND: Given the general unavailability, common adverse effects, and complicated administration of tetracycline, the clinical application of classic bismuth quadruple therapy (BQT) is greatly limited. Whether minocycline can replace tetracycline for Helicobacter pylori ( H . pylori ) eradication is unknown. We aimed to compare the eradication rate, safety, and compliance between minocycline- and tetracycline-containing BQT as first-line regimens. METHODS: This randomized controlled trial was conducted on 434 naïve patients with H . pylori infection. The participants were randomly assigned to 14-day minocycline-containing BQT group (bismuth potassium citrate 110 mg q.i.d., esomeprazole 20 mg b.i.d., metronidazole 400 mg q.i.d., and minocycline 100 mg b.i.d.) and tetracycline-containing BQT group (bismuth potassium citrate/esomeprazole/metronidazole with doses same as above and tetracycline 500 mg q.i.d.). Safety and compliance were assessed within 3 days after eradication. Urea breath test was performed at 4-8 weeks after eradication to evaluate outcome. We used a noninferiority test to compare the eradication rates of the two groups. The intergroup differences were evaluated using Pearson chi-squared or Fisher's exact test for categorical variables and Student's t -test for continuous variables. RESULTS: As for the eradication rates of minocycline- and tetracycline-containing BQT, the results of both intention-to-treat (ITT) and per-protocol (PP) analyses showed that the difference rate of lower limit of 95% confidence interval (CI) was >-10.0% (ITT analysis: 181/217 [83.4%] vs . 180/217 [82.9%], with a rate difference of 0.5% [-6.9% to 7.9%]; PP analysis: 177/193 [91.7%] vs . 176/191 [92.1%], with a rate difference of -0.4% [-5.6% to 6.4%]). Except for dizziness more common (35/215 [16.3%] vs . 13/214 [6.1%], P = 0.001) in minocycline-containing therapy groups, the incidences of adverse events (75/215 [34.9%] vs . 88/214 [41.1%]) and compliance (195/215 [90.7%] vs . 192/214 [89.7%]) were similar between the two groups. CONCLUSION: The eradication efficacy of minocycline-containing BQT was noninferior to tetracycline-containing BQT as first-line regimen for H . pylori eradication with similar safety and compliance. TRIAL REGISTRATION: ClinicalTrials.gov, ChiCTR 1900023646.