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BACKGROUND AND OBJECTIVE: Venlafaxine hydrochloride extended-release (ER) capsules are commonly used to treat depression and anxiety disorders. Evaluation of the bioequivalence of generic formulations with reference products is essential to ensure therapeutic equivalence. The objective of this study was to evaluate the bioequivalence, safety, and tolerability of Chinese-manufactured venlafaxine hydrochloride extended-release capsules compared with USA-manufactured EFFEXOR® XR in healthy Chinese volunteers under fed conditions. METHODS: A randomized, open-label, single-dose, crossover study was conducted. Subjects were randomly assigned to receive the test formulation (one 150-mg ER capsule manufactured in China) or the reference formulation (one 150-mg ER capsule manufactured in the USA). The bioequivalence of the two drugs was assessed using the area under the plasma concentration-time curve from time zero to the last sampling time (AUC0-t) and the maximum observed concentration (Cmax). RESULTS: A total of 28 subjects were enrolled and randomly assigned to receive a single dose of either the test or reference capsule. All the subjects completed the study and were included in the pharmacokinetic (PK) and safety analyses. The mean AUC0-t and Cmax of venlafaxine and its active metabolite O-desmethylvenlafaxine were comparable between the test and reference products with both parameters close to 100% and the corresponding 90% confidence intervals within the specified 80-125% bioequivalence boundary. Safety was also assessed between the two products and all adverse events (AEs) in this study were mild in severity. CONCLUSIONS: Both the test and reference venlafaxine hydrochloride ER capsules were bioequivalent and showed a similar safety and tolerability profile in the population studied. CLINICAL TRIALS REGISTRATION: This study was registered at the Drug Clinical Trial Registration and Information Publicity Platform ( http://www.chinadrugtrials.org.cn/index.html ) with registration number CTR20211243, date: June 1, 2021.
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Cápsulas , Estudios Cruzados , Preparaciones de Acción Retardada , Voluntarios Sanos , Equivalencia Terapéutica , Clorhidrato de Venlafaxina , Humanos , Clorhidrato de Venlafaxina/farmacocinética , Clorhidrato de Venlafaxina/administración & dosificación , Clorhidrato de Venlafaxina/efectos adversos , Masculino , Adulto , Preparaciones de Acción Retardada/farmacocinética , Femenino , Adulto Joven , Área Bajo la Curva , Medicamentos Genéricos/farmacocinética , Medicamentos Genéricos/administración & dosificación , Medicamentos Genéricos/efectos adversos , Pueblo Asiatico , China , Persona de Mediana Edad , Pueblos del Este de AsiaRESUMEN
Candesartan is an antihypertensive agent that acts on an angiotensin II receptor. Candesartan cilexetil is a prodrug that is converted into the active form of candesartan during intestinal absorption. This study aimed to assess the pharmacokinetics and bioequivalence of a reference and a test formulation of candesartan cilexetil tablets in healthy Chinese volunteers. A randomized, open-label, single-dose, crossover study was conducted with two treatment periods. Forty-eight healthy Chinese volunteers participated under fasted conditions. Qualified subjects were randomly divided into two groups (1:1 ratio) to receive either the test or reference formulation first. A washout period of 14 days separated the administration of the two formulations. Blood samples were collected at specific time points and analyzed for candesartan concentration using Ultra High-Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). The maximum concentration (Cmax), the AUC from time zero to the last measured time point (AUC0-t) and the AUC from time zero to infinity (AUC0-∞) fell within the bioequivalence range of 80% to 125%. These results suggest that the test and reference formulations of candesartan cilexetil tablets are bioequivalent, meaning they have similar rates and extents of absorption in healthy Chinese volunteers. No serious adverse events or side effects were reported throughout the study.
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Myocarditis is an inflammatory disease of the cardiac muscle and one of the primary causes of dilated cardiomyopathy. Group B coxsackievirus (CVB) is one of the leading causative pathogens of viral myocarditis, which primarily affects children and young adults. Due to the lack of vaccines, the development of antiviral medicines is crucial to controlling CVB infection and the progression of myocarditis. In this study, we investigated the antiviral effect of baicalein, a flavonoid extracted from Scutellaria baicaleinsis. Our results demonstrated that baicalein treatment significantly reduced cytopathic effect and increased cell viability in CVB3-infected cells. In addition, significant reductions in viral protein 3D, viral RNA, and viral particles were observed in CVB3-infected cells treated with baicalein. We found that baicalein exerted its inhibitory effect in the early stages of CVB3 infection. Baicalein also suppressed viral replication in the myocardium and effectively alleviated myocarditis induced by CVB3 infection. Our study revealed that baicalein exerts its antiviral effect by inhibiting the activity of caspase-1 and viral protease 2A. Taken together, our findings demonstrate that baicalein has antiviral activity against CVB3 infection and may serve as a potential therapeutic option for the myocarditis caused by enterovirus infection.
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Antivirales , Caspasa 1 , Enterovirus Humano B , Flavanonas , Miocarditis , Replicación Viral , Flavanonas/farmacología , Replicación Viral/efectos de los fármacos , Enterovirus Humano B/efectos de los fármacos , Enterovirus Humano B/fisiología , Antivirales/farmacología , Animales , Miocarditis/tratamiento farmacológico , Miocarditis/virología , Humanos , Caspasa 1/metabolismo , Proteínas Virales/metabolismo , Proteínas Virales/antagonistas & inhibidores , Proteínas Virales/genética , Infecciones por Coxsackievirus/tratamiento farmacológico , Infecciones por Coxsackievirus/virología , Ratones , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cisteína Endopeptidasas/metabolismo , Ratones Endogámicos BALB C , Masculino , Scutellaria baicalensis/química , Efecto Citopatogénico Viral/efectos de los fármacosRESUMEN
Dihydroxyaluminum aminoacetate, heavy magnesium carbonate, and aspirin tablets is a new combined aspirin preparation, each containing aspirin (81 mg), dihydroxyaluminum aminoacetate (11 mg), and heavy magnesium carbonate (22 mg). This study was conducted to evaluate the pharmacokinetic (PK) and bioequivalence in healthy Chinese subjects. This randomized, open-label, single-dose, 2-sequence, and 2-period crossover study included 78 healthy volunteers (fasting, n = 36; postprandial, n = 42). Blood samples were collected for PK analysis. Aspirin and salicylic acid concentrations in human plasma were determined by liquid chromatography-tandem mass spectrometry. Safety and tolerability were monitored. There were no significant differences between the test and reference formulations in maximum plasma concentration, area under the plasma concentration-time curve (AUC) from time 0 to time t, or AUC from time 0 to infinity. The 90% confidence intervals of the test and reference formulations of maximum plasma concentration, AUC from time 0 to time t, and AUC from time 0 to infinity were within the acceptable range (80%-125%) under fasting and postprandial conditions. All adverse events were mild and no serious adverse events were observed in the study. Both compounds were well tolerated in healthy Chinese volunteers.
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Objective: To evaluate the resolution of chromosomal virulence D (chvD) as a novel marker for mycobacterial species identification. Methods: A segment of chvD (652 bp) was amplified by PCR from 63 mycobacterial reference strains, 163 nontuberculous mycobacterial clinical isolates, and 16 M. tuberculosis complex (MTBC) clinical isolates. A phylogenetic tree based on the reference strains was constructed by the neighbor-joining and IQ-tree methods. Comparative sequence analysis of the homologous chvD gene efficiently differentiated the species within the genus Mycobacterium. Slowly growing Mycobacterium (SGM) and rapidly growing Mycobacterium (RGM) were separated in the phylogenetic tree based on the chvD gene. Results: The sequence discrepancies were obvious between M. kansasii and M. gastri, M. chelonae and M. abscessus, and M. avium and M. intracellulare, none of which could be achieved by 16S ribosomal RNA (rRNA) homologous gene alignment. Furthermore, chvD manifested larger intraspecies diversity among members of M. intracellulare subspecies. A total of 174 of the 179 (97.21%) clinical isolates, consisting of 12 mycobacterial species, were identified correctly by chvD blast. Four M. abscessus subsp. abscessus were identified as M. abscessus subsp. bolletii by chvD. MTBC isolates were indistinguishable, because they showed 99.84%-100% homology. Conclusion: Homologous chvD is a promising gene marker for identifying mycobacterial species, and could be used for highly accurate species identification among mycobacteria.
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Heart failure (HF) is often complicated by renal dysfunction. Tolvaptan and valsartan are two well-known agents for the treatment of HF. However, the role of tolvaptan/valsartan combination on HF with renal dysfunction remains unclear. To establish a mice model with HF with renal dysfunction, mice were intraperitoneally injected with doxorubicin (Dox). Echocardiogram was applied to assess the left ventricular function. Additionally, serum aldosterone (ALD) and angiotensin II (Ang II) level in mice were determined by ELISA. Meanwhile, western blot assay was used to evaluate the expressions of B cell lymphoma-2 (Bcl-2), Bcl-2 associated X (Bax) and cleaved caspase 3 in the heart and kidney tissues of mice. In this study, we found that compared to tolvaptan or valsartan alone treatment group, tolvaptan/valsartan combination obviously improved the left ventricular ejection fraction (LVEF) and the left ventricular fractional shortening (LVFS), and reduced serum ALD and Ang II level in Dox-treated mice. Additionally, tolvaptan/valsartan combination significantly prevented the inflammation and fibrosis of heart and kidney tissues in Dox-treated mice. Meanwhile, tolvaptan/valsartan combination notably inhibited the myocardial and renal cell apoptosis in Dox-treated mice via upregulation of Bcl-2 and downregulation of Bax and cleaved caspase 3, compared to the single drug treatment. Collectively, tolvaptan/valsartan combination could improve cardiac and renal functions, as well as prevent the fibrosis, inflammation and apoptosis of heart and kidney tissues in Dox-treated mice. Taken together, combining tolvaptan with valsartan might be a promising approach to achieve enhanced therapeutic effect for treatment of HF with renal dysfunction.
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Insuficiencia Cardíaca , Enfermedades Renales , Ratones , Animales , Valsartán/farmacología , Valsartán/uso terapéutico , Tolvaptán/uso terapéutico , Tolvaptán/farmacología , Volumen Sistólico , Caspasa 3 , Función Ventricular Izquierda/fisiología , Proteína X Asociada a bcl-2 , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/tratamiento farmacológico , Doxorrubicina/efectos adversos , Riñón/metabolismo , Fibrosis , InflamaciónRESUMEN
Yersinia pestis, the cause of plague, is a newly evolved Gram-negative bacterium. Through the acquisition of the plasminogen activator (Pla), Y. pestis gained the means to rapidly disseminate throughout its mammalian hosts. It was suggested that Y. pestis utilizes Pla to interact with the DEC-205 (CD205) receptor on antigen-presenting cells (APCs) to initiate host dissemination and infection. However, the evolutionary origin of Pla has not been fully elucidated. The PgtE enzyme of Salmonella enterica, involved in host dissemination, shows sequence similarity with the Y. pestis Pla. In this study, we demonstrated that both Escherichia coli K-12 and Y. pestis bacteria expressing the PgtE-protein were able to interact with primary alveolar macrophages and DEC-205-transfected CHO cells. The interaction between PgtE-expressing bacteria and DEC-205-expressing transfectants could be inhibited by the application of an anti-DEC-205 antibody. Moreover, PgtE-expressing Y. pestis partially re-gained the ability to promote host dissemination and infection. In conclusion, the DEC-205-PgtE interaction plays a role in promoting the dissemination and infection of Y. pestis, suggesting that Pla and the PgtE of S. enterica might share a common evolutionary origin.
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Escherichia coli K12 , Salmonella enterica , Yersinia pestis , Animales , Proteínas Bacterianas/genética , Cricetinae , Cricetulus , Activadores PlasminogénicosRESUMEN
OBJECTIVE: To observe the changes of F waves on electrocardiograms (ECGs) in patients with persistent atrial fibrillation during the insertion of a peripherally inserted central catheter (PICC), and to analyze the application effect of the ECG method (through F wave changes) for guiding PICC tip positioning. METHODS: Seventy-two patients who met the inclusion criteria and needed a PICC catheter were selected as the research subjects. We observed waveforms in the ECGs when the tip of the catheter reached a predetermined position. The chest X-ray results were used as the gold standard to calculate the sensitivity and specificity, and judge the safety and accuracy of ECG-guided PICC tip positioning in patients with atrial fibrillation. RESULTS: Of the 72 patients, there was no significant difference between the ECG method and chest X-ray results (χ2 = 0.2, p > 0.05). Sixty-one patients had F wave changes on ECG and 10 had no obvious changes (X-ray results confirmed that five patients had a tip position that was too shallow, two had ectopic tip positions, and three were located in the correct place). The sensitivity of the method was 95.7% and the specificity was 80%. CONCLUSION: As the ECG baselines of patients with persistent atrial fibrillation were difficult to judge and the F wave was irregular, we found that the F wave was significantly higher than before catheter insertion and fell back while withdrawing the catheter, so the catheter should be fed until the F wave significantly increased as the correct position of the catheter tip.
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Fibrilación Atrial , Cateterismo Venoso Central , Cateterismo Periférico , Catéteres Venosos Centrales , Fibrilación Atrial/terapia , Cateterismo Venoso Central/métodos , Cateterismo Periférico/métodos , Electrocardiografía/métodos , HumanosRESUMEN
Pungency is one of the most important mouthfeel characteristics that is primarily related to the sensory quality of distilled spirits. However, the chemical basis of pungency is still unclear. A set of Baijiu samples with different levels of pungency was characterized by sensory analysis and volatile compound analyses. Several esters, aldehydes, and acids significantly correlated with pungency. Ethyl hexanoate, ethyl acetate, 3-methylbutyl hexanoate, acetaldehyde, acetal, and 3-methylbutanal were confirmed to be the strongest contributors to the pungency of Baijiu by the two-alternative forced-choice test. Sensory recombination testing further revealed that the contribution of esters to pungency was much higher than that of the aldehydes, and acid compounds at low concentrations suppress the pungency perception. In this study, the importance of esters in the pungency of distilled spirits is first reported. The results provide an instructive basis for further research into optimizing the quality of products.
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Bebidas Alcohólicas , Odorantes , Bebidas Alcohólicas/análisis , Odorantes/análisisRESUMEN
Pungency is increasingly being recognized as an important factor of overall sensory quality, palatability, and consumer preference of distilled spirits. The characterization of pungency is necessary to evaluate the potential sensory quality of distilled spirits. In this study, the temporal profiles of pungency of Baijiu with different aging times were evaluated using time-intensity (TI) and temporal dominance of sensations (TDS) methods, considering both pungency intensity and pungency sub-qualities. TI results indicated significant differences in release rate of pungency during Baijiu consumption. Compared to young Baijiu, old Baijiu tend to show higher release rate of pungency, the areas under the curve and duration of pungency were significantly decreased in old Baijiu. The TDS results showed significant differences in the combination of dominant sub-qualities, as well as in the maximum dominance rates and the dominant duration of sub-qualities among Baijiu. The young Baijiu were mainly characterized by the dominant sub-qualities of "burning" and "numbing", whereas for old Baijiu, "burning", "prickle", and "drying" were dominant. The application of TI and TDS provided dynamic and temporal profiles of pungency to fully characterize pungency differences of distilled beverages.
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Sensación , Gusto , Bebidas , Comportamiento del ConsumidorRESUMEN
Pungency is a crucial sensory feature that influences consumers' appreciation and preferences toward alcoholic beverages. However, the quantitation of pungency is challenging to achieve using sensory analysis because of persistence, accumulation, and desensitization to the pungency perception. This study aimed to design a novel pungency evaluation method based on the measurement of tongue surface temperature. An infrared thermal (IRT) imager technique for measuring tongue surface temperature was established. To validate its feasibility, the IRT technique was used to measure tongue surface temperatures after the tongue was stimulated by (1) water and Baijiu, (2) different concentrations of ethanol aqueous solution (10, 20, 30, 40, and 50%, v/v), (3) ethanol aqueous solution and Baijiu samples with the same ethanol content, and (4) 26 Baijiu samples with different pungency level. For all cases, tongue surface temperatures showed large differences as a result of the different stimulation. The results showed that the tongue surface temperature correlated with the pungency intensity obtained by the sensory analysis. The relationship between tongue surface temperature and pungency intensity was established by multiple linear regression analysis. The IRT technique was able to be a useful support tool to quantitatively predict the pungency of alcoholic beverages, based on the measurement of tongue surface temperature.
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Neisseria gonorrhoeae (N. gonorrhoeae, gonococci, or GC), the etiologic agent of gonorrhea, is a human-obligate bacterial pathogen. The GC surface contains pili that mediate the adherence to host cells. Studies have shown that GC pili, coded by pilin genes, undergo remarkable changes during human experimental gonorrhea, possibly generated by DNA phase variation during infection. The question that arises is whether the changes in pilins can alter the adherence capacity of N. gonorrhoeae to host cells. In this study, six variants initially isolated from male volunteers infected with one single clone of GC were examined for their adherence patterns with human Chang conjunctiva cells. In this study, we showed that the variants showed distinct adherence patterns to this cell line under light microscopy and scanning electron microscopy. Moreover, two reisolates showed higher adherence capacities than that of the input strain. The results provide an additional example as to how the pilus variation may play a role in the pathogenesis of N. gonorrhoeae.
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Introduction. Shigella sonnei, the cause of bacillary dysentery, belongs to Gram-negative enteropathogenic bacteria. S. sonnei contains a 210 kb virulence plasmid that encodes an O-antigen gene cluster of LPSs. However, this virulence plasmid is frequently lost during replication. It is well-documented that after losing the O-antigen and becoming rough strains, the Gram-negative bacteria may express an LPS core on its surface. Previous studies have suggested that by using the LPS core, Gram-negative bacteria can interact with several C-type lectin receptors that are expressed on antigen-presenting cells (APCs).Hypothesis/Gap Statement. S. sonnei by losing the virulence plasmid may hijack APCs via the interactions of LPS-CD209/CD207.Aim. This study aimed to investigate if the S. sonnei rough strain, by losing the virulence plasmid, interacted with APCs that express C-type lectins of human CD207, human CD209a and mouse CD209b.Methodology. SDS-PAGE silver staining was used to examine the O-antigen expression of S. sonnei WT and its rough strain. Invasion assays and inhibition assays were used to examine the ability of S. sonnei WT and its rough strain to invade APCs and investigate whether CD209 and CD207 are receptors for phagocytosis of rough S. sonnei. Animal assays were used to observe the dissemination of S. sonnei.Results. S. sonnei did not express O-antigens after losing the virulence plasmid. The S. sonnei rough strain invades with APCs, including human dendritic cells (DCs) and mouse macrophages. CD209 and CD207 are receptors for phagocytosis of rough S. sonnei. Expression of the O-antigen reduces the ability of the S. sonnei rough strain to be disseminated to mesenteric lymph nodes and spleens.Conclusion. This work demonstrated that S. sonnei rough strains - by losing the virulence plasmid - invaded APCs through interactions with CD209 and CD207 receptors.
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Antígenos CD/inmunología , Moléculas de Adhesión Celular/inmunología , Disentería Bacilar/microbiología , Lectinas Tipo C/inmunología , Lectinas de Unión a Manosa/inmunología , Antígenos O , Plásmidos , Receptores de Superficie Celular/inmunología , Shigella sonnei/patogenicidad , Virulencia/genética , Animales , Células CHO , Cricetulus , Células Dendríticas/microbiología , Interacciones Huésped-Patógeno , Humanos , Macrófagos/microbiología , Ratones , Antígenos O/genética , Antígenos O/metabolismo , Shigella sonnei/genéticaRESUMEN
Endothelial progenitor cell (EPC) transplantation is a safe and effective method to treat acute myocardial infarction (AMI). However, oxidative stress leads to the death of a large number of EPCs in the early stage of transplantation, severely weakening the therapeutic effect. Previous studies demonstrated that microRNAs regulate the biological function of EPCs. The aim of the current study was to investigate the effect of microRNA on the biological function of EPCs under oxidative stress. Quantitative reverse transcription PCR was performed to detect the expression of miR-126, miR-508-5p, miR-150, and miR-16 in EPCs from rats, among which miR-126 showed a relatively higher expression. Treatment with H2O2 decreased miR-126 expression in EPCs in a dose-dependent manner. EPCs were further transfected with miR-126 mimics or inhibitors, followed by H2O2 treatment. Overexpression of miR-126 enhanced the proliferation, migration, and tube formation of H2O2-treated EPCs. MiR-126 overexpression also inhibited reactive oxygen species and malondialdehyde levels and enhanced superoxide dismutase levels, as well as increased angiopoietin (Ang)1 expression and decreased Ang2 expression in H2O2-treated EPCs. Moreover, miR-126 participated in the regulation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3ß (GSK3ß) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in EPCs, where both pathways were activated after miR-126 overexpression in H2O2-treated EPCs. Overall, we showed that miR-126 promoted the biological function of EPCs under H2O2-induced oxidative stress by activating the PI3K/Akt/GSK3ß and ERK1/2 signaling pathway, which may serve as a new therapeutic approach to treat AMI.
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Células Progenitoras Endoteliales/metabolismo , MicroARNs/metabolismo , Transducción de Señal , Animales , Proteínas de Ciclo Celular/metabolismo , Células Progenitoras Endoteliales/trasplante , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Infarto del Miocardio/terapia , Estrés Oxidativo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Proteínas de Schizosaccharomyces pombe/metabolismoRESUMEN
Comprehensive 2D gas chromatography-time-of-flight mass spectrometry was combined with descriptive sensory analysis to elucidate the specificity of strong-aroma type Baijiu (Chinese liquor) from different regions, based on regionally distinct flavor characterized by chemical and sensory profiles. Numerous potential aroma compounds (262) were identified, among which 58 aroma compounds were significantly different between the samples from Sichuan and Jianghuai regions. Relationships between these potential aroma compounds and sensory attributes were investigated by partial least squares regression and network analysis. The compounds that dominantly contributed to the important sensory attributes were identified. The high pyrazines, furanoids, and carbonyls amounts contributed to the high intensities of the cellar, toasted, and grain aroma profiles of the Sichuan region samples, while the high ester and alcohol levels contributed to the fruity and floral aroma profiles of the Jianghuai region samples. This approach may have practical application in flavor characterization of other alcoholic beverages.
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Bebidas Alcohólicas/análisis , Análisis de los Alimentos/métodos , Cromatografía de Gases y Espectrometría de Masas/métodos , Odorantes/análisis , Compuestos Orgánicos Volátiles/análisis , China , Ésteres/análisis , Análisis de los Alimentos/estadística & datos numéricos , Cromatografía de Gases y Espectrometría de Masas/estadística & datos numéricos , Humanos , Análisis de los Mínimos Cuadrados , Análisis Multivariante , Pirazinas/análisis , GustoRESUMEN
Chlamydia pneumonia (C.pn) is a common respiratory pathogen that is involved in human cardiovascular diseases and promotes the development of atherosclerosis in hyperlipidemic animal models. C.pn reportedly up-regulated lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells. Recently, the anti-atherosclerotic activity of peroxisome proliferator-activated receptor γ (PPARγ) has been documented. In the present study, we investigated the effect of C.pn on LOX-1 expression in human umbilical vein endothelial cells (HUVECs) and identified the involvement of the PPARγ signaling pathway therein. The results showed that C.pn increased the expression of LOX-1 in HUVECs in a dose- and time-dependent manner. C.pn-induced up-regulation of LOX-1 was mediated by ERK1/2, whereas p38 MAPK and JNK had no effect on this process. C.pn induced apoptosis, inhibited cell proliferation, and decreased the expression PPARγ in HUVECs. Additionally, LOX-1 activity and cell injury caused by C.pn through activation of ERK1/2 was completely inhibited by rosiglitazone, a PPARγ agonist. In conclusion, we inferred that activation of PPARγ in HUVECs suppressed C.pn-induced LOX-1 expression and cell damage by inhibiting ERK1/2 signaling.
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Aterosclerosis/genética , Enfermedades Cardiovasculares/genética , PPAR gamma/genética , Receptores Depuradores de Clase E/genética , Apoptosis/genética , Aterosclerosis/microbiología , Aterosclerosis/patología , Enfermedades Cardiovasculares/microbiología , Enfermedades Cardiovasculares/patología , Proliferación Celular/genética , Chlamydophila pneumoniae/genética , Chlamydophila pneumoniae/patogenicidad , Regulación de la Expresión Génica/genética , Células Endoteliales de la Vena Umbilical Humana/microbiología , Humanos , Sistema de Señalización de MAP Quinasas/genética , PPAR gamma/agonistas , Rosiglitazona/farmacología , Transducción de Señal/efectos de los fármacos , Venas Umbilicales/metabolismo , Venas Umbilicales/patología , Proteínas Quinasas p38 Activadas por Mitógenos/genéticaRESUMEN
Yersinia pestis, a Gram-negative bacterium, is the etiologic agent of plague. A hallmark of Y. pestis infection is the organism's ability to rapidly disseminate through an animal host. Y. pestis expresses the outer membrane protein, Ail (Attachment invasion locus), which is associated with host invasion and serum resistance. However, whether Ail plays a role in host dissemination remains unclear. In this study, C57BL/6J mice were challenged with a defined Y. pestis strain, KimD27, or an isogenic ail-deleted mutant derived from KimD27 via metacarpal paw pad inoculation, nasal drops, orogastric infection, or tail vein injection to mimic bubonic, pneumonic, oral, or septicemic plague, respectively. Our results showed that ail-deleted Y. pestis KimD27 lost the ability to invade host cells, leading to failed host dissemination in the pneumonic and oral plague models but not in the bubonic or septicemic plague models, which do not require invasiveness. Therefore, this study demonstrated that whether Ail plays a role in Y. pestis pathogenesis depends on the infection route.
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Proteínas de la Membrana Bacteriana Externa/metabolismo , Peste/microbiología , Factores de Virulencia/metabolismo , Virulencia , Yersinia pestis , Animales , Proteínas Bacterianas/metabolismo , Modelos Animales de Enfermedad , Pulmón/microbiología , Ratones , Ratones Endogámicos C57BL , Boca/microbiología , Yersinia pestis/metabolismo , Yersinia pestis/patogenicidadRESUMEN
INTRODUCTION: Asthma is one of the most common diseases in children. A self-management program can effectively improve the outcomes for children with asthma and reduce the burden on healthcare services. OBJECTIVES: The aim of this project was to integrate the best evidence on asthma self-management with practice in a children's respiratory clinic and to improve compliance with best practice. METHODS: Seven audit criteria were developed for the pre- and post-audit based on the best available evidence. The Joanna Briggs Institute (JBI) Practical Application of Clinical Evidence System and Getting Research into Practice audit and feedback tools were used in this project. RESULTS: The baseline audit showed a gap between clinical practice and the best evidence. The only criterion that achieved high compliance was provision of inhaler guidance (100%). After implementation, there were substantial improvements in compliance for many criteria. Training of clinicians increased from 13% at baseline to 67% at follow-up. Education of parents improved, with specific education about asthma triggers increasing from 55% to 100%, education about warning signs from 30% to 85% and education about effective asthma treatment options from 40% to 85%. Use of written asthma action plans increased from 0% to 25%. CONCLUSION: Strategies developed in this project were effective at providing necessary information for parents and improved the compliance with evidence. Further implementation strategies and audits are still needed to improve the use of asthma action plans and ensure they are reviewed periodically.
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Asma/terapia , Práctica Clínica Basada en la Evidencia , Personal de Salud/educación , Padres/educación , Automanejo , Niño , Conocimientos, Actitudes y Práctica en Salud , Hospitalización , Humanos , Monitoreo Fisiológico , Nebulizadores y VaporizadoresRESUMEN
Salmonella enterica serovar Typhimurium, a Gram-negative bacterium, can cause infectious diseases ranging from gastroenteritis to systemic dissemination and infection. However, the molecular mechanisms underlying this bacterial dissemination have yet to be elucidated. A study indicated that using the lipopolysaccharide (LPS) core as a ligand, S Typhimurium was able to bind human dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (hCD209a), an HIV receptor that promotes viral dissemination by hijacking antigen-presenting cells (APCs). In this study, we showed that S Typhimurium interacted with CD209s, leading to the invasion of APCs and potentially the dissemination to regional lymph nodes, spleen, and liver in mice. Shielding of the exposed LPS core through the expression of O-antigen reduces dissemination and infection. Thus, we propose that similar to HIV, S Typhimurium may also utilize APCs via interactions with CD209s as a way to disseminate to the lymph nodes, spleen, and liver to initiate host infection.
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Moléculas de Adhesión Celular/fisiología , Lectinas Tipo C/fisiología , Receptores de Superficie Celular/fisiología , Salmonella typhimurium/patogenicidad , Animales , Células Presentadoras de Antígenos/microbiología , Femenino , Interacciones Huésped-Patógeno , Humanos , Lipopolisacáridos/fisiología , Mananos/farmacología , Ratones , Ratones Endogámicos C57BL , Antígenos O/fisiología , Ganglios Linfáticos Agregados/fisiología , Fagocitosis , Células RAW 264.7RESUMEN
Yersinia pestis, a Gram-negative bacterium and the etiologic agent of plague, has evolved from Yersinia pseudotuberculosis, a cause of a mild enteric disease. However, the molecular and biological mechanisms of how Y. pseudotuberculosis evolved to such a remarkably virulent pathogen, Y. pestis, are not clear. The ability to initiate a rapid bacterial dissemination is a characteristic hallmark of Y. pestis infection. A distinguishing characteristic between the two Yersinia species is that Y. pseudotuberculosis strains possess an O-antigen of lipopolysaccharide (LPS) while Y. pestis has lost the O-antigen during evolution and therefore exposes its core LPS. In this study, we showed that Y. pestis utilizes its core LPS to interact with SIGNR1 (CD209b), a C-type lectin receptor on antigen presenting cells (APCs), leading to bacterial dissemination to lymph nodes, spleen and liver, and the initiation of a systemic infection. We therefore propose that the loss of O-antigen represents a critical step in the evolution of Y. pseudotuberculosis into Y. pestis in terms of hijacking APCs, promoting bacterial dissemination and causing the plague.