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1.
Microbiol Spectr ; 10(1): e0247721, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-35170994

RESUMO

Bedaquiline (BDQ) was historically listed by the World Health Organization (WHO) in 2018 as the preferred option for rifampin-resistant tuberculosis (RR-TB) and multidrug-resistant tuberculosis (MDR-TB). However, when there is no other effective regimen, the side effects and weaknesses of BDQ limit its use of MDR-TB. There is a black box warning in the package insert of BDQ to warn patients and health care professionals that this drug may increase the risk of unexplained mortality and QT prolongation, which may lead to abnormal and potentially fatal cardiac rhythm. In addition, the phenomenon of elevated liver enzymes in clinical trials of BDQ is a potential sign of hepatotoxicity. Therefore, it is still a medical need to develop new compounds with better safety profiles, patient compliance, affordability, and the ability to retain the efficacy of BDQ. After extensive lead generation and optimization, a new analog, sudapyridine (WX-081), was selected as a potential new antituberculosis candidate to move into clinical trials. Here, we evaluated WX-081's overall preclinical profile, including efficacy, pharmacokinetics, and toxicology. The in vitro activity of WX-081 against drug-sensitive and drug-resistant tuberculosis was comparable to that of BDQ, and there was comparable efficacy between WX-081 and BDQ in both acute and chronic mouse tuberculosis models using low-dose aerosol infection. Moreover, WX-081 improved pharmacokinetic parameters and, more importantly, had no adverse effects on blood pressure, heart rate, or qualitative ECG parameters from nonclinical toxicology studies. WX-081 is under investigation in a phase 2 study in patients. IMPORTANCE This study is aimed at chemotherapy for multidrug-resistant tuberculosis (MDR-TB), mainly to develop new anti-TB drugs to kill Mycobacterium tuberculosis, a microorganism with strong drug resistance. In this study, the structure of a potent antituberculosis compound, bedaquiline (BDQ), was optimized to generate a new compound, sudapyridine (WX-081). This experiment showed that its efficacy was similar to that of BDQ, its cardiotoxicity was lower, and it had good kinetic characteristics. This compound will certainly achieve significant results in the control and treatment of tuberculosis in the future.


Assuntos
Antituberculosos/administração & dosagem , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Animais , Antituberculosos/efeitos adversos , Antituberculosos/química , Antituberculosos/farmacocinética , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/fisiologia , Tuberculose/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos
2.
Clin Microbiol Infect ; 27(7): 1000-1006, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33421578

RESUMO

OBJECTIVES: Delay in diagnosis of tuberculosis (TB) is an important but under-appreciated problem. Our study aimed to analyse the patient pathway and possible risk factors of long diagnostic delay (LDD). METHODS: We enrolled 400 new bacteriologically diagnosed patients with pulmonary TB from 20 hospitals across China. LDD was defined as an interval between the initial care visit and the confirmation of diagnosis exceeding 14 days. Its potential risk factors were investigated by multivariate logistic regression and multilevel logistic regression. Hospitals in China were classified by increasing size, from level 0 to level 3. TB laboratory equipment in hospitals was also evaluated. RESULTS: The median diagnostic delay was 20 days (IQR: 7-72 days), and 229 of 400 patients (57.3%, 95%CI 52.4-62.1) had LDD; 15% of participants were diagnosed at the initial care visit. Compared to level 0 facilities, choosing level 2 (OR 0.27, 95%CI 0.12-0.62, p 0.002) and level 3 facilities (OR 0.34, 95%CI 0.14-0.84, p 0.019) for the initial care visit was independently associated with shorter LDD. Equipping with smear, culture, and Xpert at initial care visit simultaneously also helped to avoid LDD (OR 0.28, 95%CI 0.09-0.82, p 0.020). The multilevel logistic regression yielded similar results. Availability of smear, culture, and Xpert was lower in level 0-1 facilities than in level 2-3 facilities (p < 0.001, respectively). CONCLUSIONS: Most patients failed to be diagnosed at the initial care visit. Patients who went to low-level facilities initially had a higher risk of LDD. Improvement of TB laboratory equipment, especially at low-level facilities, is urgently needed.


Assuntos
Mycobacterium tuberculosis/isolamento & purificação , Tuberculose/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Técnicas Bacteriológicas/instrumentação , Técnicas Bacteriológicas/estatística & dados numéricos , China/epidemiologia , Diagnóstico Tardio , Feminino , Hospitais , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Tuberculose/epidemiologia , Adulto Jovem
3.
Acta Pharmacol Sin ; 42(9): 1535-1546, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33244163

RESUMO

Vicagrel, a novel irreversible P2Y12 receptor inhibitor, is undergoing phase III trials for the treatment of acute coronary syndromes in China. In this study, we evaluated the pharmacokinetics, mass balance, and metabolism of vicagrel in six healthy male Chinese subjects after a single oral dose of 20 mg [14C]vicagrel (120 µCi). Vicagrel absorption was fast (Tmax = 0.625 h), and the mean t1/2 of vicagrel-related components was ~38.0 h in both plasma and blood. The blood-to-plasma radioactivity AUCinf ratio was 0.55, suggesting preferential distribution of drug-related material in plasma. At 168 h after oral administration, the mean cumulative excreted radioactivity was 96.71% of the dose, including 68.03% in urine and 28.67% in feces. A total of 22 metabolites were identified, and the parent vicagrel was not detected in plasma, urine, or feces. The most important metabolic spot of vicagrel was on the thiophene ring. In plasma pretreated with the derivatization reagent, M9-2, which is a methylated metabolite after thiophene ring opening, was the predominant drug-related component, accounting for 39.43% of the radioactivity in pooled AUC0-8 h plasma. M4, a mono-oxidation metabolite upon ring-opening, was the most abundant metabolite in urine, accounting for 16.25% of the dose, followed by M3-1, accounting for 12.59% of the dose. By comparison, M21 was the major metabolite in feces, accounting for 6.81% of the dose. Overall, renal elimination plays a crucial role in vicagrel disposition, and the thiophene ring is the predominant metabolic site.


Assuntos
Fenilacetatos/metabolismo , Fenilacetatos/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/metabolismo , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Tiofenos/metabolismo , Tiofenos/farmacocinética , Administração Oral , Adulto , Clopidogrel , Humanos , Masculino , Fenilacetatos/sangue , Fenilacetatos/química , Antagonistas do Receptor Purinérgico P2Y/sangue , Antagonistas do Receptor Purinérgico P2Y/química , Tiofenos/sangue , Tiofenos/química
4.
BMC Med Genomics ; 13(1): 59, 2020 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-32252754

RESUMO

BACKGROUND: Escherichia coli are mostly commensals but also contain pathogenic lineages. It is largely unclear whether the commensal E. coli as the potential origins of pathogenic lineages may consist of monophyletic or polyphyletic populations, elucidation of which is expected to lead to novel insights into the associations of E. coli diversity with human health and diseases. METHODS: Using genomic sequencing and pulsed field gel electrophoresis (PFGE) techniques, we analyzed E. coli from the intestinal microbiota of three groups of healthy individuals, including preschool children, university students, and seniors of a longevity village, as well as colorectal cancer (CRC) patients, to probe the commensal E. coli populations for their diversity. RESULTS: We delineated the 2280 fresh E. coli isolates from 185 subjects into distinct genome types (genotypes) by PFGE. The genomic diversity of the sampled E. coli populations was so high that a given subject may have multiple genotypes of E. coli, with the general diversity within a host going up from preschool children through university students to seniors. Compared to the healthy subjects, the CRC patients had the lowest diversity level among their E. coli isolates. Notably, E. coli isolates from CRC patients could suppress the growth of E. coli bacteria isolated from healthy controls under nutrient-limited culture conditions. CONCLUSIONS: The coexistence of multiple E. coli lineages in a host may help create and maintain a microbial environment that is beneficial to the host. As such, the low diversity of E. coli bacteria may be associated with unhealthy microenvironment in the intestine and hence facilitate the pathogenesis of diseases such as CRC.


Assuntos
Neoplasias Colorretais/patologia , DNA Bacteriano/análise , Infecções por Escherichia coli/complicações , Escherichia coli/classificação , Escherichia coli/genética , Variação Genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , China/epidemiologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/microbiologia , DNA Bacteriano/genética , Infecções por Escherichia coli/microbiologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , Microambiente Tumoral , Adulto Jovem
5.
Mol Cell Probes ; 52: 101568, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32251686

RESUMO

Gene fusion is caused by the linkage of previously separate genes or sequences. Recently, an increasing number of novel fusion genes have been identified and associated with tumor progression, and several of them have been suggested as promising targets for tumor therapy. However, there are hardly any studies reporting the association of fusion genes with the progression of oral squamous cell carcinoma (OSCC). In this study, we identified a total of 11 fused genes in OSCC cells. We further analyzed the structure of one fused gene, TRIM52-RACK1, and detected its function in tumor progression in vitro. We found that TRIM52-RACK1 was caused by a deletion of 181,257,187-181,247,386 at 5q35.3 and it promoted OSCC cell proliferation, migration, and invasion. Therefore, TRIM52-RACK1 can be a promising target for tumor therapy in OSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Bucais/genética , Proteínas de Fusão Oncogênica/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Humanos , Invasividade Neoplásica , Proteínas de Fusão Oncogênica/metabolismo
6.
BMC Genomics ; 20(1): 930, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801462

RESUMO

BACKGROUND: Salmonella bongori infect mainly cold-blooded hosts, but infections by S. bongori in warm-blooded hosts have been reported. We hypothesized that S. bongori might have diverged into distinct phylogenetic lineages, with some being able to infect warm-blooded hosts. RESULTS: To inspect the divergence status of S. bongori, we first completely sequenced the parakeet isolate RKS3044 and compared it with other sequenced S. bongori strains. We found that RKS3044 contained a novel T6SS encoded in a pathogenicity island-like structure, in addition to a T6SS encoded in SPI-22, which is common to all S. bongori strains so far reported. This novel T6SS resembled the SPI-19 T6SS of the warm-blooded host infecting Salmonella Subgroup I lineages. Genomic sequence comparisons revealed different genomic sequence amelioration events among the S. bongori strains, including a unique CTAG tetranucleotide degeneration pattern in RKS3044, suggesting non-overlapping gene pools between RKS3044 and other S. bongori lineages/strains leading to their independent accumulation of genomic variations. We further proved the existence of a clear-cut genetic boundary between RKS3044 and the other S. bongori lineages/strains analyzed in this study. CONCLUSIONS: The warm-blooded host-infecting S. bongori strain RKS3044 has diverged with distinct genomic features from other S. bongori strains, including a novel T6SS encoded in a previously not reported pathogenicity island-like structure and a unique genomic sequence degeneration pattern. These findings alert cautions about the emergence of new pathogens originating from non-pathogenic ancestors by acquiring specific pathogenic traits.


Assuntos
Ilhas Genômicas , Periquitos/microbiologia , Salmonella/classificação , Sequenciamento Completo do Genoma/métodos , Animais , Evolução Molecular , Especiação Genética , Tamanho do Genoma , Genoma Bacteriano , Humanos , Filogenia , Salmonella/genética , Salmonella/patogenicidade , Fatores de Virulência/genética
7.
Artigo em Inglês | MEDLINE | ID: mdl-31065547

RESUMO

Lung cancer (LC) is one of the most serious malignant tumors, which has the fastest growing morbidity and mortality worldwide. A role of the lung microbiota in LC pathogenesis has been analyzed, but a comparable role of the gut microbiota has not yet been investigated. In this study, the gut microbiota of 30 LC patients and 30 healthy controls were examined via next-generation sequencing of 16S rRNA and analyzed for diversity and biomarkers. We found that there was no decrease in significant microbial diversity (alpha diversity) in LC patients compared to controls (P observed = 0.1422), while the composition (beta diversity) differed significantly between patients and controls (phylum [stress = 0.153], class [stress = 0.16], order [stress = 0.146], family [stress = 0.153]). Controls had a higher abundance of the bacterial phylum Actinobacteria and genus Bifidobacterium, while patients with LC showed elevated levels of Enterococcus. These bacteria were found as possible biomarkers for LC. A decline of normal function of the gut microbiome in LC patients was also observed. These results provide the basic guidance for a systematic, multilayered assessment of the role of the gut microbiome in LC, which has a promising potential for early prevention and targeted intervention.


Assuntos
Bactérias/classificação , Bactérias/genética , Disbiose , Microbioma Gastrointestinal , Neoplasias Pulmonares/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Fezes/microbiologia , Feminino , Humanos , Masculino , Metagenômica , Pessoa de Meia-Idade , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Adulto Jovem
8.
Mol Genet Genomics ; 294(3): 597-605, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30710177

RESUMO

Antimicrobial resistance makes pathogenic bacteria hard to control, but little is known about the general processes of resistance gain or loss. Here, we compared distinct S. typhimurium DT104 strains resistant to zero, two, five, or more of the tested antimicrobials. We found that common resistance phenotypes could be encoded by distinct genes, on SGI-1 or plasmid. We also demonstrated close clonality among all the tested non-resistant and differently resistant DT104 strains, demonstrating dynamic acquisition or loss (by total deletion or gradual decaying of multi-drug resistance gene clusters) of the genetic traits. These findings reflect convergent processes to make the bacteria resistant to multiple antimicrobials by acquiring the needed traits from stochastically available origins. When the antimicrobial stress is absent, the resistance genes may be dropped off quickly, so the bacteria can save the cost for maintaining unneeded genes. Therefore, this work reiterates the importance of strictly controlled use of antimicrobials.


Assuntos
Adaptação Fisiológica/genética , Farmacorresistência Bacteriana Múltipla/genética , Evolução Molecular , Salmonella typhimurium/genética , Estresse Fisiológico , Adaptação Fisiológica/efeitos dos fármacos , Antibacterianos/farmacologia , Sequência de Bases , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Genes Bacterianos/genética , Genoma Bacteriano/genética , Filogenia , Plasmídeos/classificação , Plasmídeos/genética , Salmonella typhimurium/classificação , Salmonella typhimurium/efeitos dos fármacos , Homologia de Sequência do Ácido Nucleico
9.
Diabetes Obes Metab ; 20(9): 2113-2120, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29707866

RESUMO

AIMS: To investigate the pharmacokinetics and pharmacodynamics of a dual-acting glucokinase activator, dorzagliatin, and its safety, tolerability and effect on pancreatic ß-cell function in Chinese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: A total of 24 T2D patients were selected, utilizing a set of predefined clinical biomarkers, and were randomized to receive dorzagliatin 75 mg twice or once daily (BID, QD respectively) for 28 days. Changes in HbA1c and glycaemic parameters from baseline to Day 28 were assessed. In addition, changes in ß-cell function from baseline to Day 32 were evaluated. RESULTS: Significant reductions in HbA1c were observed in both regimens on Day 28 (-0.79%, 75 mg BID; -1.22%, 75 mg QD). Similar trends were found in the following parameters, including reductions from baseline in fasting plasma glucose by 1.20 mmol/L and 1.51 mmol/L, in 2-hour postprandial glucose by 2.48 mmol/L and 5.03 mmol/L, and in glucose AUC0-24 by 18.59% and 20.98%, for the BID and QD groups, respectively. Both regimens resulted in improvement in ß-cell function as measured by steady state HOMA 2 parameter, %B, which increased by 36.31% and 40.59%, and by dynamic state parameter, ΔC30 /ΔG30 , which increased by 24.66% and 167.67%, for the BID and QD groups, respectively. Dorzagliatin was well tolerated in both regimens, with good pharmacokinetic profiles. CONCLUSIONS: Dorzagliatin treatment for 28 days in Chinese T2D patients, selected according to predefined biomarkers, resulted in significant improvement in ß-cell function and glycaemic control. The safety and pharmacokinetic profile of dorzagliatin supports a subsequent Phase II trial design and continued clinical development.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativadores de Enzimas/uso terapêutico , Glucoquinase/metabolismo , Hipoglicemiantes/uso terapêutico , Seleção de Pacientes , Pirazóis/farmacologia , Biomarcadores/sangue , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Feminino , Hemoglobina A Glicada/análise , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Pirazóis/uso terapêutico , Resultado do Tratamento
10.
Mitochondrial DNA B Resour ; 3(2): 1263-1264, 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33474486

RESUMO

In the present study, the complete mitochondrial genome of Glossaulax reiniana was determined using the next-generation sequencing. The circular genome was found to be 15,254 bp in length and had an overall nucleotide composition of 30.6% A, 14.1% C, 15.8% G, and 39.5% T. Similar to the typical caenogastropod mitochondrial genomes, it contained 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes, and a potential control origin. All protein-coding genes started with standard initiation codons (ATA and ATG) and ended by TAA or TAG. The lengths of 12S ribosomal RNA and 16S ribosomal RNA were 948 and 1353 bp, respectively. The largest noncoding region considered to contain the origin of replication was 59 bp in length. The complete mitochondrial genome reported here would provide useful information for molecular phylogeny, genetic conservation, and sustainable management of G. reiniana.

11.
Sci Rep ; 7(1): 10985, 2017 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-28887484

RESUMO

When bacteria diverge, they need to adapt to the new environments, such as new hosts or different tissues of the same host, by accumulating beneficial genomic variations, but a general scenario is unknown due to the lack of appropriate methods. Here we profiled the ACTAGT sequence and its degenerated forms (i.e., hexa-nucleotide sequences with one of the six nucleotides different from ACTAGT) in Salmonella to estimate the nucleotide amelioration processes of bacterial genomes. ACTAGT was mostly located in coding sequences but was also found in several intergenic regions, with its degenerated forms widely scattered throughout the bacterial genomes. We speculated that the distribution of ACTAGT and its degenerated forms might be lineage-specific as a consequence of different selection pressures imposed on ACTAGT at different genomic locations (in genes or intergenic regions) among different Salmonella lineages. To validate this speculation, we modelled the secondary structures of the ACTAGT-containing sequences conserved across Salmonella and many other enteric bacteria. Compared to ACTAGT at conserved regions, the degenerated forms were distributed throughout the bacterial genomes, with the degeneration patterns being highly similar among bacteria of the same phylogenetic lineage but radically different across different lineages. This finding demonstrates biased amelioration under distinct selection pressures among the bacteria and provides insights into genomic evolution during bacterial divergence.


Assuntos
Genes Bacterianos , Salmonella/genética , Substituição de Aminoácidos , Escherichia coli/genética , Evolução Molecular , Variação Genética , Genômica , Conformação de Ácido Nucleico , Salmonella/classificação , Seleção Genética
12.
Oncotarget ; 8(30): 49574-49591, 2017 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-28484095

RESUMO

Cancer as a large group of complex diseases is believed to result from the interactions of numerous genetic and environmental factors but may develop in people without any known genetic or environmental risks, suggesting the existence of other powerful factors to influence the carcinogenesis process. Much attention has been focused recently on particular members of the intestinal microbiota for their potential roles in promoting carcinogenesis. Here we report the identification and characterization of intestinal bacteria that exhibited potent anti-malignancy activities on a broad range of solid cancers and leukemia. We collected fecal specimens from healthy individuals of different age groups (preschool children and university students), inspected their effects on cancer cells, and obtained bacteria with potent anti-malignancy activities. The bacteria mostly belonged to Actinobacteria but also included lineages of other phyla such as Proteobacteria and Firmicutes. In animal cancer models, sterile culture supernatant from the bacteria highly effectively inhibited tumor growth. Remarkably, intra-tumor administration of the bacterial products prevented metastasis and even cleared cancer cells at remote locations from the tumor site. This work demonstrates the prevalent existence of potent malignancy-killers in the human intestinal microbiota, which may routinely clear malignant cells from the body before they form cancers.


Assuntos
Microbioma Gastrointestinal , Neoplasias/etiologia , Adolescente , Adulto , Animais , Bactérias/classificação , Bactérias/genética , Fenômenos Fisiológicos Bacterianos , Sobrevivência Celular , Criança , Pré-Escolar , Modelos Animais de Doenças , Fezes/microbiologia , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Células HeLa , Humanos , Masculino , Metagenoma , Metagenômica/métodos , Camundongos , Neoplasias/patologia , Filogenia , RNA Ribossômico 16S/genética , Adulto Jovem
13.
J Diabetes Res ; 2017: 6305370, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28459073

RESUMO

Objective. To investigate the effects of static magnetic field (SMF) on cutaneous wound healing of Streptozotocin- (STZ-) induced diabetic rats. Methods. 20 STZ-induced diabetic rats were randomly divided into two groups (10 in each group): diabetic rats with SMF exposure group which were exposed to SMF by gluing one magnetic disk of 230 mT intensity and diabetic rats with sham SMF exposure group (sham group). 10 normal Wistar rats were used as the control group. One open circular wound with 2 cm diameter in the dorsum was generated on both normal and diabetic rats and then covered with sterile gauzes. Wound healing was evaluated by wound area reduction rate, mean time to wound closure, and wound tensile strength. Results. The wound area reduction rate in diabetic rats in comparison with the control group was significantly decreased (P < 0.01). Compared with sham magnet group, diabetic rats under 230 mT SMF exposure demonstrated significantly accelerated wound area reduction rate on postoperative days 7, 14, and 21 and decreased gross time to wound closure (P < 0.05), as well as dramatically higher wound tissue strength (P < 0.05) on 21st day. Conclusion. 230 mT SMF promoted the healing of skin wound in diabetic rats and may provide a non-invasive therapeutic tool for impaired wound healing of diabetic patients.


Assuntos
Diabetes Mellitus Experimental , Terapia de Campo Magnético , Pele/lesões , Cicatrização , Animais , Estudos de Casos e Controles , Campos Magnéticos , Masculino , Ratos , Ratos Wistar
14.
Sci Rep ; 7: 43565, 2017 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-28262684

RESUMO

Highly conserved short sequences help identify functional genomic regions and facilitate genomic annotation. We used Salmonella as the model to search the genome for evolutionarily conserved regions and focused on the tetranucleotide sequence CTAG for its potentially important functions. In Salmonella, CTAG is highly conserved across the lineages and large numbers of CTAG-containing short sequences fall in intergenic regions, strongly indicating their biological importance. Computer modeling demonstrated stable stem-loop structures in some of the CTAG-containing intergenic regions, and substitution of a nucleotide of the CTAG sequence would radically rearrange the free energy and disrupt the structure. The postulated degeneration of CTAG takes distinct patterns among Salmonella lineages and provides novel information about genomic divergence and evolution of these bacterial pathogens. Comparison of the vertically and horizontally transmitted genomic segments showed different CTAG distribution landscapes, with the genome amelioration process to remove CTAG taking place inward from both terminals of the horizontally acquired segment.


Assuntos
Sequência Conservada , DNA Intergênico , Motivos de Nucleotídeos , Sequências Repetitivas de Ácido Nucleico , Salmonella/genética , Evolução Molecular , Genoma Bacteriano , Genômica/métodos , Conformação de Ácido Nucleico , Filogenia
15.
Int J Legal Med ; 131(2): 473-478, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27726028

RESUMO

In forensic medicine, the diagnosis of death due to neurogenic shock is considered to be an aporia, as lacking objective indicators and presenting atypical symptoms in autopsy. Medico-legal disputes and complaints occasionally result from this ambiguity. To explore potential objective indicators of neurogenic shock, we set up a model of neurogenic shock by applying an external mechanical force on the carotid sinus baroreceptor in rabbits. The serum atrial natriuretic peptide (ANP) level was measured by radioimmunoassay in the control group (n = 8), survival group (n = 15) and death group (n = 5) both before and after the insult. The serum ANP level showed a significant increase after the insult in the death group compared with the serum obtained before the insult (P = 0.006), while the serum ANP level after the insult in the survival group and control group was not statistically significant compared with the serum obtained before the insult (P = 0.332 and P = 0.492, respectively). To verify the repeatability of the model and the postmortem behavior of serum ANP, five healthy adult rabbits underwent the same procedure as the experimental group. The mortality rate was consistent with the former experiment (20 %). There were no significant changes in serum ANP level in vitro and in vivo (within 48 and 24 h, respectively). But there was a significant decrease in serum ANP level at 48 h postmortem in vivo (P = 0.001). A female patient who expired due to neurogenic shock during a hysteroscopy was reported. Neither fatal primary disease nor evidence for mechanical injuries or intoxication was found according to the autopsy. The serum ANP level was assayed as a supplementary indicator and was found to be three-fold higher than the normal maximum limit. Combined with the animal experiment, this case highlights that serum ANP has the potential to be an objective indicator for the diagnosis of death due to neurogenic shock.


Assuntos
Fator Natriurético Atrial/sangue , Choque/diagnóstico , Adulto , Animais , Biomarcadores/sangue , Seio Carotídeo/patologia , Feminino , Humanos , Imunoglobulina E/sangue , Isquemia Miocárdica/patologia , Miocárdio/patologia , Coelhos , Radioimunoensaio
16.
Mol Med Rep ; 13(4): 3581-7, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26936285

RESUMO

Increasing evidence indicates that the hepatitis B virus (HBV) replicates in peripheral blood mononuclear cells (PBMCs), but at a low level. The present study aimed to establish a reliable and sensitive method that effectively detects HBV viral products for monitoring antiviral therapy, organ transplantation screening, and diagnosing occult HBV infection. In the present study, PBMCs (obtained from six healthy volunteers) were inoculated with HBV, and cultured with phytohemagglutinin (PHA) and interleukin­2 (IL­2) to stimulate cell proliferation. PBMCs were harvested, and quantitative detection of HBV DNA in cell suspension and intracellular hepatitis B surface antigen (HBsAg) was conducted on days 0, 1, 6 and 12, respectively. In situ hybridization, immunohistochemistry and reverse transcription­polymerase chain reaction (RT­PCR) were performed to analyze the HBV infection. The results demonstrated that HBV DNA increased concurrently with proliferation of PBMCs isolated from three of six healthy volunteers, and the mean number of PBMCs on day 12 was 13.61 times higher than the initially seeded cell number (P<0.01). The mean copies of HBV DNA at day 12 were 2.98 times higher compared with initial levels (P<0.05). Furthermore, intracellular HBsAg levels increased concurrently with proliferation of PBMCs in one group of cultured PBMCs, which was accompanied by increased HBV DNA levels. In addition, HBV nucleic acids were detected in PBMCs using in situ hybridization. Intracellular HBsAg was observed in PBMCs and HBV RNA was also detected by RT­PCR. The present study demonstrated that HBV replicates in proliferating PBMCs, which were induced by PHA and IL­2. This method offers a novel investigative tool to detect HBV infection in PBMCs and to monitor the course of HBV infection.


Assuntos
DNA Viral/análise , Vírus da Hepatite B/metabolismo , Adulto , Feminino , Antígenos de Superfície da Hepatite B/metabolismo , Humanos , Hibridização in Situ Fluorescente , Interleucina-2/farmacologia , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/virologia , Masculino , Microscopia de Fluorescência , Fito-Hemaglutininas/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Replicação Viral/efeitos dos fármacos , Adulto Jovem
17.
Stand Genomic Sci ; 10: 30, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26203341

RESUMO

Salmonella arizonae (also called Salmonella subgroup IIIa) is a Gram-negative, non-spore-forming, motile, rod-shaped, facultatively anaerobic bacterium. S. arizonae strain RKS2983 was isolated from a human in California, USA. S. arizonae lies somewhere between Salmonella subgroups I (human pathogens) and V (also called S. bongori; usually non-pathogenic to humans) and so is an ideal model organism for studies of bacterial evolution from non-human pathogen to human pathogens. We hence sequenced the genome of RKS2983 for clues of genomic events that might have led to the divergence and speciation of Salmonella into distinct lineages with diverse host ranges and pathogenic features. The 4,574,836 bp complete genome contains 4,203 protein-coding genes, 82 tRNA genes and 7 rRNA operons. This genome contains several characteristics not reported to date in Salmonella subgroup I or V and may provide information about the genetic divergence of Salmonella pathogens.

18.
Asian Pac J Cancer Prev ; 16(1): 245-51, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25640360

RESUMO

OBJECTIVES: Intrahepatic recurrence is the major cause of death among patients with hepatitis B virus (HBV)- related hepatocellular carcinoma (HCC) after curative surgical resection. Several approaches have been reported to decrease the recurrence rate. The objective of our study was to compare the clinical effects of transcatheter arterial chemoembolization (TACE) combined with interferon-alpha (IFN-α) therapy on recurrence after hepatic resection in patients with HBV-related HCC with that of TACE chemotherapy alone. METHODS: We retrospectively analyzed the data from 228 patients who were diagnosed with HBV-related HCC and underwent curative resection between January 2001 to December 2008. The patients were divided into TACE (n = 126) and TACE-IFN-α (n = 102) groups for postoperative chemotherapy. The TACE regimen consisted of 5-fluorouracil (5-FU), cisplatin (DDP) , and the emulsion mixed with mitomycin C (MMC) and lipiodol. The recurrence rates, disease-free survival (DFS), overall survival (OS), and risk of recurrence were evaluated. RESULTS: The clinicopathological parameters and adverse effects were similar between the 2 groups (P > 0.05). The median OS for the TACE- IFN-α group (36.3 months) was significantly longer than that of the TACE group (24.5 months, P < 0.05). The 3-and 5-year OS for the TACE-IFN-α group were significantly longer than those of the TACE group (P < 0.05) and the recurrence rate was significantly lower (P < 0.05). The TACE and IFN-α combination therapy, active hepatitis HBV infection, the number of tumor nodules, microvascular invasion, liver cirrhosis, and the BCLC stage were independent predictors of OS and DFS. CONCLUSIONS: The use of the TACE and IFN-α combination chemotherapy after curative hepatic resection safely and effectively improves OS and decreases recurrence in patients with HBV-related HCC who are at high risk. Our findings can serve as a guide for the selection of postoperative adjuvant chemotherapy for patients with HBV-related HCC who are at high risk of recurrence.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Hepatocelular/virologia , Quimioembolização Terapêutica/efeitos adversos , Quimioembolização Terapêutica/métodos , Cisplatino/administração & dosagem , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Intervalo Livre de Doença , Óleo Etiodado/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Hepatite B/virologia , Vírus da Hepatite B , Humanos , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Recidiva Local de Neoplasia/terapia , Recidiva Local de Neoplasia/virologia , Estudos Retrospectivos , Adulto Jovem
19.
PLoS One ; 9(8): e103388, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25137186

RESUMO

BACKGROUND: The bacterial genus Salmonella contains thousands of serotypes that infect humans or other hosts, causing mild gastroenteritis to potentially fatal systemic infections in humans. Pathogenically distinct Salmonella serotypes have been classified as individual species or as serological variants of merely one or two species, causing considerable confusion in both research and clinical settings. This situation reflects a long unanswered question regarding whether the Salmonella serotypes exist as discrete genetic clusters (natural species) of organisms or as phenotypic (e.g. pathogenic) variants of a single (or two) natural species with a continuous spectrum of genetic divergence among them. Our recent work, based on genomic sequence divergence analysis, has demonstrated that genetic boundaries exist among Salmonella serotypes, circumscribing them into clear-cut genetic clusters of bacteria. METHODOLOGIES/PRINCIPAL FINDINGS: To further test the genetic boundary concept for delineating Salmonella into clearly defined natural lineages (e.g., species), we sampled a small subset of conserved genomic DNA sequences, i.e., the endonuclease cleavage sites that contain the highly conserved CTAG sequence such as TCTAGA for XbaI. We found that the CTAG-containing cleavage sequence profiles could be used to resolve the genetic boundaries as reliably and efficiently as whole genome sequence comparisons but with enormously reduced requirements for time and resources. CONCLUSIONS: Profiling of CTAG sequence subsets reflects genetic boundaries among Salmonella lineages and can delineate these bacteria into discrete natural clusters.


Assuntos
DNA Bacteriano/genética , Genoma Bacteriano , Tipagem Molecular/métodos , Filogenia , Salmonella/classificação , Salmonella/genética , Sequência de Bases , Mapeamento Cromossômico , Sequência Conservada , Clivagem do DNA , Desoxirribonucleases de Sítio Específico do Tipo II/metabolismo , Humanos , Dados de Sequência Molecular , Família Multigênica , Salmonella/isolamento & purificação , Salmonella/patogenicidade , Sorotipagem , Terminologia como Assunto
20.
Virology ; 462-463: 149-57, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24992041

RESUMO

Hepatitis B virus (HBV) infection is the leading cause of liver diseases. However, the molecular mechanisms of HBV infection and carcinogenesis have not been fully elucidated. In this study, we found that cyclin D2 was upregualted in HBV-expressing cells and liver tissues of HBV-transgenic mice. Gene silencing of cyclin D2 inhibited HBV DNA replicative intermediates, 3.5 kb mRNA, core protein level, as well as the secretions of HBsAg and HBeAg. On the contrary, overexpression of cyclin D2 promoted HBV replication. Furthermore, cyclin D2 regulated HBV replication by enhancing the activity of HBV core and Sp1 promoters by targeting transcription factor CREB2. Silencing of CREB2 abolished enhancement of HBV replication induced by cyclin D2. Together, our study has uncovered a positive role of cyclin D2 in HBV replication. It is conceivable that therapeutic application of cyclin D2 inhibitor in HBV infection therapy.


Assuntos
Ciclina D2/metabolismo , Vírus da Hepatite B/fisiologia , Interações Hospedeiro-Patógeno , Replicação Viral , Animais , Células Hep G2 , Hepatócitos , Humanos , Camundongos , Camundongos Transgênicos
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