RESUMO
This study evaluated the chlorine dioxide (ClO2) gas mediated inactivation of the biofilm cells of foodborne pathogens on food contact surfaces. Biofilm cells of Escherichia coli O157:H7, Salmonella Typhimurium, and Listeria monocytogenes were developed on stainless steel (SS) and high density polyethylene (HDPE) coupon surfaces, and 5-day-old biofilms were treated with ClO2 gas at 60 and 90% relative humidity (RH) for up to 20 min. With an increase in gas concentration and treatment time, significant differences (p < 0.05) were observed between reduction levels under different RH conditions. Treatment with 50 ppmv of ClO2 gas (60% RH) for 20 min resulted in log reductions from 2.08 to 4.62 and 2.08 to 4.41 of the biofilm cells of three pathogens on SS and HDPE surfaces, respectively. The levels of biofilm cells of E. coli O157:H7, S. Typhimurium, and L. monocytogenes on SS and HDPE surfaces were reduced to below the detection limit (0.48 log CFU/cm2) within 15, 20, and 20 min, respectively, when exposure to 50 ppmv of ClO2 gas at 90% RH.
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Brain mosaic mutations are a major cause of refractory focal epilepsies with cortical malformations such as focal cortical dysplasia, hemimegalencephaly, malformation of cortical development with oligodendroglial hyperplasia in epilepsy, and ganglioglioma. Here, we collected cerebrospinal fluid (CSF) during epilepsy surgery to search for somatic variants in cell-free DNA (cfDNA) using targeted droplet digital polymerase chain reaction. In 3 of 12 epileptic patients with known somatic mutations previously identified in brain tissue, we here provide evidence that brain mosaicism can be detected in the CSF-derived cfDNA. These findings suggest future opportunities for detecting the mutant allele driving epilepsy in CSF. ANN NEUROL 2021;89:1248-1252.
Assuntos
Encéfalo , Ácidos Nucleicos Livres/líquido cefalorraquidiano , Epilepsia Resistente a Medicamentos/genética , Adolescente , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/líquido cefalorraquidiano , Feminino , Humanos , Lactente , Masculino , MutaçãoRESUMO
We aimed to investigate the effects of sleep duration on impaired fasting glucose and diabetes in Korean adults with periodontal disease. This cross-sectional study was performed using data for 10,465 subjects aged >19 years who completed the periodontal examination and questionnaires in the Sixth Korea National Health and Nutrition Examination Survey (2013-2015). The effect of sleep was confirmed by a complex-sample multinomial logistic regression analysis. Confounding variables were age, sex, household income, education level, smoking status, and sleep duration. Of all participants, 25.7% had periodontitis, of which 28.6% had fasting serum glucose disorder and 14.2% had diabetes. Among participants with periodontitis, the prevalence of diabetes was 1.49 times higher in participants with an average sleep duration of ≥8 h than those with an average sleep duration of 6-7 h. The prevalence of diabetes among participants without periodontitis was 1.49 times and 1.57 times higher in participants with an average sleep duration of ≤5 and ≥8 h, respectively, than those with an average sleep duration of 6-7 h. We found that altered sleep duration may be a risk factor for diabetes and that proper sleep duration is important to control diabetes incidence.
Assuntos
Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Periodontite , Transtornos do Sono-Vigília , Sono , Adulto , Idoso , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Periodontite/epidemiologia , Prevalência , República da Coreia/epidemiologia , Fatores de Risco , Transtornos do Sono-Vigília/complicações , Adulto JovemRESUMO
BACKGROUND: Cytoplasmic inclusions of transactive response DNA binding protein of 43 kDa (TDP-43) in neurons and astrocytes are a feature of some neurodegenerative diseases, such as frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). However, the role of TDP-43 in astrocyte pathology remains largely unknown. METHODS: To investigate whether TDP-43 overexpression in primary astrocytes could induce inflammation, we transfected primary astrocytes with plasmids encoding Gfp or TDP-43-Gfp. The inflammatory response and upregulation of PTP1B in transfected cells were examined using quantitative RT-PCR and immunoblot analysis. Neurotoxicity was analysed in a transwell coculture system of primary cortical neurons with astrocytes and cultured neurons treated with astrocyte-conditioned medium (ACM). We also examined the lifespan, performed climbing assays and analysed immunohistochemical data in pan-glial TDP-43-expressing flies in the presence or absence of a Ptp61f RNAi transgene. RESULTS: PTP1B inhibition suppressed TDP-43-induced secretion of inflammatory cytokines (interleukin 1 beta (IL-1ß), interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-α)) in primary astrocytes. Using a neuron-astrocyte coculture system and astrocyte-conditioned media treatment, we demonstrated that PTP1B inhibition attenuated neuronal death and mitochondrial dysfunction caused by overexpression of TDP-43 in astrocytes. In addition, neuromuscular junction (NMJ) defects, a shortened lifespan, inflammation and climbing defects caused by pan-glial overexpression of TDP-43 were significantly rescued by downregulation of ptp61f (the Drosophila homologue of PTP1B) in flies. CONCLUSIONS: These results indicate that PTP1B inhibition mitigates the neuronal toxicity caused by TDP-43-induced inflammation in mammalian astrocytes and Drosophila glial cells.
Assuntos
Astrócitos/metabolismo , Proteínas de Ligação a DNA/biossíntese , Mediadores da Inflamação/metabolismo , Degeneração Neural/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/biossíntese , Animais , Animais Geneticamente Modificados , Astrócitos/patologia , Células Cultivadas , Proteínas de Ligação a DNA/genética , Drosophila , Expressão Gênica , Mediadores da Inflamação/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Degeneração Neural/genética , Degeneração Neural/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/genéticaRESUMO
This study aimed to determine the association between the number of existing teeth (NET) and socioeconomic status (SES), oral health-related behaviours, and metabolic syndrome in Korean adults aged 55-79 years. The study included 3255 adults who underwent oral health examinations and answered questionnaires regarding SES, oral health-related behaviours, and metabolic diseases in the Sixth Korea National Health and Nutrition Examination Survey (2013-2015). The dependent variable was the binary status based on the median NET in each age group. The independent variables were based on SES, oral health-related behaviours, and the presence of metabolic syndrome. The study findings showed that the factors associated with the NET were sex, household income, education level, region of residence, daily toothbrushing frequency, dental visit within 1 year, smoking, and metabolic syndrome. NET was lower in males (adjusted OR: 0.74), in low household income group (adjusted OR: 0.77), in primary school graduates (adjusted OR: 0.53), in rural residents (adjusted OR: 0.78), and in medicaid beneficiaries (adjusted OR: 0.78). The interventions aimed at preserving existing teeth in elderly population should consider their SES, oral health-related behaviours, and metabolic syndrome and overhauling current oral healthcare system and redefining the roles of oral health professionals.
Assuntos
Comportamentos Relacionados com a Saúde , Síndrome Metabólica/epidemiologia , Saúde Bucal/estatística & dados numéricos , Perda de Dente/epidemiologia , Escovação Dentária/estatística & dados numéricos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Classe Social , Inquéritos e QuestionáriosRESUMO
This study aimed to evaluate the association between periodontitis and metabolic syndrome (MetS) and to investigate risk factors associated with MetS in Korean adults aged 35 to 79 years. Among individuals aged 35-79 years who participated in the Korea National Health and Nutrition Examination Survey 2013-2015, 8314 participants who completed the required examinations and questionnaires were included. Confounding variables related to demographic and socioeconomic status and systemic and oral health-related behaviors were age, gender, household income, education level, smoking, alcohol intake, physical activity, and frequency of daily toothbrushing. Of the 8314 participants, 32.2% were diagnosed with MetS. The prevalence of MetS was 26.6% and 41.6% in those without and with periodontitis, respectively. Among individuals with periodontitis, the prevalence of MetS was 44.3% in males and 36.9% in females. Compared to non-periodontitis, periodontitis was associated with MetS (adjusted OR = 1.422, 95% CI: 1.26-1.61). Age, frequency of daily toothbrushing, and periodontitis were associated with MetS in both males and females. While current smoking and alcohol intake more than twice a week were significantly associated with MetS in males, household income and education level were significantly associated with MetS in females. The findings suggest that periodontitis can be associated with MetS.
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Síndrome Metabólica/epidemiologia , Periodontite/epidemiologia , Medição de Risco/métodos , Adulto , Fatores Etários , Idoso , República Democrática Popular da Coreia/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , República da Coreia/epidemiologia , Fatores de Risco , Fatores Sexuais , Classe SocialRESUMO
BACKGROUND: Inflammation is an essential response against bacterial infection as a host defense mechanism, which can lead to tissue damage. Aggregatibacter actinomycetemcomitans (Aa) is major pathogen for aggressive periodontitis characterized by rapid destruction of periodontal tissue surrounding teeth. Trans-cinnamic aldehyde is a key bioactive compound of the cinnamon extracts, which has anti-inflammatory, antioxidant, antipyretic, antimicrobial, and anti-cancer properties. The objective of the present study was to investigate the anti-inflammatory effect of trans-cinnamic aldehyde against Aa infection in human THP-1 derived macrophages and on Aa-induced periodontitis in mice. METHODS: THP-1 cells were differentiated with phorbol 12-mystristate 13-acetate and were infected with live Aa. Trans-cinnamic aldehyde was pretreated 30 minutes before the bacterial infection. Cytokine production was determined by enzyme-linked immunosorbent assay (ELISA) and protein expressions were detected by Western blot analysis. Autophagosome formation was detected by Cyto-ID. Viable cell count was carried out to determine bacterial adhesion, internalization, and intracellular survival. Experimental periodontitis was induced by inoculating Aa orally to mice, and microcomputed tomography was used to evaluate bone loss. RESULTS: Pretreatment of trans-cinnamic aldehyde significantly inhibited Aa-stimulated release of tumor necrosis factor-α and interleukin (IL)-1ß. Pretreatment of trans-cinnamic aldehyde inhibited Aa-induced expression of TLR signaling pathway as well as the phosphorylation of JNK, p38, and nuclear factor (NF)-κB. Also, trans-cinnamic aldehyde treatment downregulated the expression of pro-IL-1ß, caspase-1, and inflammasome components. Trans-cinnamic aldehyde treatment significantly decreased intracellular survival of Aa. Moreover, the autophagosome formation and the expressions of autophagy markers including Beclin-1, ATG5, and LC3 were increased. Finally, trans-cinnamic aldehyde significantly inhibited bone loss in Aa-induced mouse periodontitis. CONCLUSIONS: Trans-cinnamic aldehyde inhibited Aa-stimulated expression of inflammatory responses and inhibited intracellular bacterial survival via autophagy activation. These results suggest that trans-cinnamic aldehyde may serve as an anti-inflammatory agent for aggressive periodontitis.
Assuntos
Aggregatibacter actinomycetemcomitans , Autofagia , Acroleína/análogos & derivados , Animais , Humanos , Inflamação , Lipopolissacarídeos , Macrófagos , Camundongos , Microtomografia por Raio-XRESUMO
BACKGROUND: Oral health greatly affects well-being throughout the different stages of life from childhood to late adulthood. Loss of teeth due to poor oral health hinders mastication, leading to poor nutrition absorption, and affects pronunciation and aesthetics, leading to interpersonal difficulties. As social activities become limited, a sense of isolation and loneliness, stress, and depression grows while happiness decreases. This study aimed to examine the association of stress, depression, and suicidal ideation with oral health status and oral functions in a large nationwide sample of Korean adults aged 35 years or more. METHODS: The sample comprised 15,716 adults, selected using a rolling survey sampling method and data were extracted from the Fifth Korea National Health and Nutrition Examination Survey (KNHANES) (2010-2012). Participants were interviewed about their self-evaluation of health including oral health status and mental health, such as stress, depression, and suicidal ideation. Data from 11,347 adults were finally selected after excluding participants with missing answers. The dependent variables were stress, depression, and suicidal ideation. The independent variables were gender, age, household income, education, smoking, drinking, oral health perception, chewing, and speaking. Complex samples logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Participants met the criteria for stress (25.4%), depression (13.0%), and suicidal ideation (13.9%). Subjective oral health status was not significantly associated with stress, depression, and suicidal ideation. However, the presence of very uncomfortable chewing problems was significantly associated with stress (OR = 2.294, 95% CI = 1.41, 3.72), depression (OR = 3.232, 95% CI = 1.97, 5.31), and suicidal ideation (OR = 2.727, 95% CI = 1.58, 4.72). The presence of very uncomfortable speaking problems was significantly associated with stress (OR = 1.592, 95% CI = 1.13, 2.24) but not significantly associated with depression and suicidal ideation. CONCLUSIONS: Oral functional problems including chewing and speaking difficulties can be associated with mental health. It is necessary to develop oral health promotion programs for adults and help them maintain a good quality of life and mental health.
Assuntos
Depressão/epidemiologia , Saúde Bucal , Estresse Psicológico/epidemiologia , Ideação Suicida , Adulto , Idoso , Depressão/complicações , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Saúde Bucal/estatística & dados numéricos , República da Coreia/epidemiologia , Estresse Psicológico/complicaçõesRESUMO
Several lines of evidence suggest that endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Protein tyrosine phosphatase 1B (PTP1B) is known to regulate the ER stress signaling pathway, but its role in neuronal systems in terms of ER stress remains largely unknown. Here, we showed that rotenone-induced toxicity in human neuroblastoma cell lines and mouse primary cortical neurons was ameliorated by PTP1B inhibition. Moreover, the increase in the level of ER stress markers (eIF2α phosphorylation and PERK phosphorylation) induced by rotenone treatment was obviously suppressed by concomitant PTP1B inhibition. However, the rotenone-induced production of reactive oxygen species (ROS) was not affected by PTP1B inhibition, suggesting that the neuroprotective effect of the PTP1B inhibitor is not associated with ROS production. Moreover, we found that MG132-induced toxicity involving proteasome inhibition was also ameliorated by PTP1B inhibition in a human neuroblastoma cell line and mouse primary cortical neurons. Consistently, downregulation of the PTP1B homologue gene in Drosophila mitigated rotenone- and MG132-induced toxicity. Taken together, these findings indicate that PTP1B inhibition may represent a novel therapeutic approach for ER stress-mediated neurodegenerative diseases.
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Estresse do Retículo Endoplasmático/efeitos dos fármacos , Doenças Neurodegenerativas/enzimologia , Neurônios/efeitos dos fármacos , Neuroproteção , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Animais , Morte Celular , Córtex Cerebral/enzimologia , Regulação para Baixo , Drosophila/enzimologia , Fator de Iniciação 2 em Eucariotos/efeitos dos fármacos , Humanos , Leupeptinas/farmacologia , Camundongos , Neurônios/enzimologia , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Rotenona/farmacologia , Células Tumorais Cultivadas , Desacopladores/farmacologia , eIF-2 Quinase/efeitos dos fármacosRESUMO
BACKGROUND: Periodontitis is a chronic inflammatory disease resulting from an inflammatory response to subgingival plaque bacteria, including Porphyromonas gingivalis. MicroRNA (miRNA) is a current focus in regulating the inflammatory processes. In this study, the inflammatory miRNA expression in gingival tissues of patients with periodontitis and of healthy individuals is compared, and its role in regulating the inflammatory response is examined. METHODS: Gingival tissues from patients with periodontitis and healthy individuals were collected for miRNA microarray. THP-1 and CA9-22 cells were challenged with P. gingivalis, and miRNA expression was determined by real-time polymerase chain reaction. Target genes for miRNA were predicted using TargetScanHuman database, and miRNA gene expressions were reviewed using public databases. For the functional study, THP-1 cells were transfected with a miRNA-128 mimic, and target gene expression was compared with THP-1 cells challenged with P. gingivalis. For the tolerance test, THP-1 cells transfected with miRNA-128 mimic were treated with phorbol 12-myristate 13-acetate (PMA) or paraformaldehyde (PFA)-fixed Escherichia coli. Tumor necrosis factor (TNF)-α production was determined by enzyme-linked immunosorbent assay, and mitogen-activated protein kinase (MAPK) protein phosphorylation was determined by Western blot. RESULTS: Gingival tissues from patients with periodontitis showed increased expression of miRNA-128, miRNA-34a, and miRNA-381 and decreased expression of miRNA-15b, miRNA-211, miRNA-372, and miRNA-656. THP-1 cells and CA9-22 cells challenged with P. gingivalis showed increased miRNA-128 expression. Among the predicted miRNA-128 target genes, several genes that are involved in MAPK signaling pathway showed similar gene expression pattern between P. gingivalis challenge and miRNA-128 mimic transfection. In THP-1 cells transfected with miRNA-128 mimic, TNF-α production was lower, and phosphorylation of p38 was inhibited when challenged with PMA or PFA-fixed E. coli. CONCLUSION: miRNA-128 may be involved in mitigating the inflammatory response induced by P. gingivalis in periodontitis.
Assuntos
MicroRNAs , Periodontite/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Escherichia coli , Humanos , Macrófagos , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: Interleukin (IL)-1ß, which is elevated in oral diseases including gingivitis, stimulates epithelial cells to produce IL-8 and perpetuate inflammatory responses. This study investigates stimulatory effects of salivary IL-1ß in IL-8 production and determines if aloin inhibits IL-1ß-stimulated IL-8 production in epithelial cells. METHODS: Saliva was collected from volunteers to determine IL-1ß and IL-8 levels. Samples from volunteers were divided into two groups: those with low and those with high IL-1ß levels. KB cells were stimulated with IL-1ß or saliva with or without IL-1 receptor agonist or specific mitogen-activated protein kinase (MAPK) inhibitors. IL-8 production was measured by enzyme-linked immunosorbent assay (ELISA). MAPK protein expression involved in IL-1ß-induced IL-8 secretion was detected by Western blot. KB cells were pretreated with aloin, and its effect on IL-1ß-induced IL-8 production was examined by ELISA and Western blot analysis. RESULTS: Saliva with high IL-1ß strongly stimulated IL-8 production in KB cells, and IL-1 receptor agonist significantly inhibited IL-8 production. Low IL-1ß-containing saliva did not increase IL-8 production. IL-1ß treatment of KB cells induced activation of MAPK signaling molecules as well as nuclear factor-kappa B. IL-1ß-induced IL-8 production was decreased by p38 and extracellular signal-regulated kinase (ERK) inhibitor treatment. Aloin pretreatment inhibited IL-1ß-induced IL-8 production in a dose-dependent manner and inhibited activation of the p38 and ERK signaling pathway. Finally, aloin pretreatment also inhibited saliva-induced IL-8 production. CONCLUSIONS: Results indicated that IL-1ß in saliva stimulates epithelial cells to produce IL-8 and that aloin effectively inhibits salivary IL-1ß-induced IL-8 production by mitigating the p38 and ERK pathway. Therefore, aloin may be a good candidate for modulating oral inflammatory diseases.
Assuntos
Emodina/análogos & derivados , Interleucina-1beta/fisiologia , Interleucina-8/metabolismo , Doenças da Boca/metabolismo , Células Cultivadas , Emodina/farmacologia , Humanos , Interleucina-6/fisiologia , Células KB/metabolismo , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
BACKGROUND: Aggressive periodontitis is characterized by rapid destruction of periodontal tissue caused by Aggregatibacter actinomycetemcomitans. Interleukin (IL)-1ß is a proinflammatory cytokine, and its production is tightly regulated by inflammasome activation. Xylitol, an anticaries agent, is anti-inflammatory, but its effect on inflammasome activation has not been researched. This study investigates the effect of xylitol on inflammasome activation induced by A. actinomycetemcomitans. METHODS: The differentiated THP-1 macrophages were stimulated by A. actinomycetemcomitans with or without xylitol and the expressions of IL-1ß and inflammasome components were detected by real time PCR, ELISA, confocal microscopy and Immunoblot analysis. The effects of xylitol on the adhesion and invasion of A. actinomycetemcomitans to cells were measured by viable cell count. RESULTS: A. actinomycetemcomitans increased pro IL-1ß synthesis and IL-1ß secretion in a multiplicity of infection- and time-dependent manner. A. actinomycetemcomitans also stimulated caspase-1 activation. Among inflammasome components, apoptosis-associated speck-like protein containing a CARD (ASC) and absent in melanoma 2 (AIM2) proteins were upregulated by A. actinomycetemcomitans infection. When cells were pretreated with xylitol, proIL-1ß and IL-1ß production by A. actinomycetemcomitans infection was significantly decreased. Xylitol also inhibited ASC and AIM2 proteins and formation of ASC puncta. Furthermore, xylitol suppressed internalization of A. actinomycetemcomitans into differentiated THP-1 macrophages without affecting viability of A. actinomycetemcomitans within cells. CONCLUSIONS: A. actinomycetemcomitans induced IL-1ß production and AIM2 inflammasome activation. Xylitol inhibited these effects, possibly by suppressing internalization of A. actinomycetemcomitans into cells. Thus, this study proposes a mechanism for IL-1ß production via inflammasome activation and discusses a possible use for xylitol in periodontal inflammation caused by A. actinomycetemcomitans.
Assuntos
Aggregatibacter actinomycetemcomitans/patogenicidade , Proteínas de Ligação a DNA/fisiologia , Inflamassomos , Interleucina-1beta/fisiologia , Edulcorantes/farmacologia , Xilitol/farmacologia , Caspase 1 , Humanos , Macrófagos , Proteína 3 que Contém Domínio de Pirina da Família NLRRESUMO
The first synthetic route to 5'-deoxy-6',6'-difluoro-carbocyclic C-nucleoside [9-deazaadenosine, (pyrrolo[3,2-d]pyrimidine)] phosphonic acids from commercially available epichlorohydrin 5 was described. The key C-C bond formation from cyclopentanone to base precursor was performed using the Knoevenagel-type condensation. Synthesized C-nucleoside phosphonic acids were tested for anti-HIV and anti-leukemic activities. They showed moderate cytotoxicity-derived anti-HIV and anti-leukemic activities.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/síntese química , Antineoplásicos/síntese química , Leucemia/tratamento farmacológico , Ácidos Fosforosos/síntese química , Nucleosídeos de Purina/síntese química , Animais , Fármacos Anti-HIV/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Desenho de Fármacos , HIV-1/efeitos dos fármacos , Humanos , Camundongos , Ácidos Fosforosos/farmacologia , Nucleosídeos de Purina/farmacologiaRESUMO
The syntheses of novel C-nucleoside phosphonic acids as potential antiviral agents are described. The sugar moiety that served as the nucleoside skeleton was produced starting from commercially available 1,3-dihydroxy cyclopentane. The key C-C bond formation from sugar to base precursor was performed using the Knoevenagel-type condensation. The synthesized compounds exhibited anti-HIV activity and cytotoxicity. Also, the synthesized compounds were screened in vitro for tumor growth inhibitory activity against mouse leukemia cell lines (L-1210, P-815).
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Fármacos Anti-HIV/síntese química , Leucemia/tratamento farmacológico , Nucleosídeos/síntese química , Ácidos Fosforosos/síntese química , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/química , Linhagem Celular Tumoral , Ciclopentanos/síntese química , Ciclopentanos/química , HIV-1/efeitos dos fármacos , Humanos , Leucemia/patologia , Camundongos , Estrutura Molecular , Nucleosídeos/administração & dosagem , Nucleosídeos/química , Ácidos Fosforosos/administração & dosagem , Ácidos Fosforosos/químicaRESUMO
The first synthetic route to 4'-trifluoromethylated 5'-deoxycarbocyclic-9-deazaadenosine analog and its phosphonic acid derivatives was described from α-trifluoromethyl-α,ß-unsaturated ester. The C-C bond connection between cyclopentane and base moiety was accomplished using Knoevenagel type condensation from ketone derivative 11. Synthesized nucleoside and phosphonic acid analogs were tested for anti-HIV activity as well as cytotoxicity.
Assuntos
Antivirais/síntese química , Ácidos Fosforosos/síntese química , Tubercidina/análogos & derivados , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Antivirais/química , Antivirais/farmacologia , Células Cultivadas , HIV-1/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Ácidos Fosforosos/química , Ácidos Fosforosos/farmacologia , Tubercidina/síntese química , Tubercidina/química , Tubercidina/farmacologiaRESUMO
Novel 4 'α-trifluoromethyl-2 'ß-methyl carbocyclic nucleoside analogs have been prepared and evaluated for inhibition of hepatitis C virus (HCV) RNA replication in cell cultures. Construction of cyclopentene intermediate 10a was achieved via sequential Johnson-Claisen orthoester rearrangement and ring-closing metathesis starting from the α-trifluoromethyl-α,ß-unsaturated ester 5. Stereoselective dihydroxylation and desilylation yielded the target carbodine analogs. The synthesized nucleoside analogs mentioned above (18 and 19) were assayed for their ability to inhibit HCV RNA replication in a subgenomic replicon Huh7 cell line (LucNeo#2). However, the synthesized nucleosides showed neither significant antiviral activity nor toxicity up to 50 µM.
Assuntos
Antivirais/síntese química , Citidina/análogos & derivados , Hepatite C/tratamento farmacológico , Linhagem Celular Tumoral , Ciclopentanos/química , Citidina/síntese química , Ésteres , Humanos , Estrutura Molecular , Nucleosídeos/química , RNA Viral/química , Proteínas não Estruturais Virais/química , Replicação ViralRESUMO
A phase I trial of first-line vorinostat, an orally bio-available histone deacetylase inhibitor, in combination with capecitabine plus cisplatin (XP) was performed to assess recommend phase II trial dose in patients with advanced gastric cancer. Five dose levels of three-weekly vorinostat-XP were tested; vorinostat was dosed at 300-400 mg once daily on Days 1-14, capecitabine at 800-1,000 mg/m(2) twice daily on Days 1-14, and cisplatin at 60-80 mg/m(2) on Day 1. To assess the pharmacodynamics of vorinostat, histone H3 acetylation was assessed in peripheral blood mononuclear cells before the study treatment and at Day 8 of cycle 1. In total, 30 patients with unresectable or metastatic gastric adenocarcinoma were included. Dose-limiting toxicities were thrombocytopenia, fatigue, stomatitis, and anorexia. The following doses were recommended for phase II trial: 400 mg of vorinostat once daily, 1,000 mg/m(2) of capecitabine twice daily, and 60 mg/m(2) of cisplatin. The most common grade 3-4 toxicities were neutropenia (47 %), anorexia (20 %), thrombocytopenia (17 %), and fatigue (13 %). In overall, response rate was 56 % (95 % confidence interval [CI]: 32-81). With a median follow-up of 14.1 months, the median progression-free survival and overall survival were 7.1 months (95 % CI: 3.8-10.3) and 18.0 months (95 % CI: 4.8-31.1), respectively. The change in H3 acetylation after treatment with vorinostat correlated significantly with the vorinostat dose (300 vs. 400 mg/day) and the baseline level of H3 acetylation before treatment. Three-weekly vorinostat-XP regimen is feasible and recommended for further development in advanced gastric cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Acetilação , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neoplasias Gástricas/metabolismo , VorinostatRESUMO
PURPOSE: Obesity is a risk factor for asthma and type II diabetes. Peroxisome proliferator- activated receptor (PPAR)-γ has been suggested to regulate inflammatory responses in diabetes and asthma. We investigated whether PPAR-α, PPAR-γ, adiponectin receptors (AdipoR1, AdipoR2), leptin, and tumor necrosis factor (TNF)-α are expressed in rat lung tissues and whether the expression differs between obese Otsuka Long-Evans Tokushima Fatty (OLETF) and lean Long Evans Tokushima Otsuka (LETO) rats. MATERIALS AND METHODS: Obese and lean rats were given with a high fat diet or a 30% restricted diet for 32 weeks, and their blood glucose levels and weights were monitored. After 32 weeks, mRNA levels of PPAR-α, PPAR-γ, AdipoR1, AdipoR2, leptin, and TNF-α in lung tissues were measured using real time PCR. RESULTS: PPAR-α, PPAR-γ, AdipoR1, AdipoR2, leptin, and TNF-α were expressed in both obese and lean rat lung tissues. Increased serum glucose levels on intraperitoneal glucose tolerance testing and a higher weight gain at 32 weeks were observed in OLETF control rats compared to OLETF diet restricted rats. PPAR-γ expression was markedly elevated in obese control and diet restricted rats compared to lean rats, although PPAR-γ expression in obese rats was not affected by diet restriction. Leptin was highly expressed in OLETF rats compared to LETO rats. TNF-α expression was enhanced in OLETF control rats compared LETO diet restricted rats, and decreased by diet restriction. PPAR-α, AdipoR1, and AdipoR2 expression were not significantly different between obese and lean rats. CONCLUSION: PPAR-γ was highly expressed in the lung tissues of obese rats and may be a novel treatment target for regulating lung inflammation associated with obesity.
Assuntos
Pulmão/metabolismo , Obesidade/metabolismo , PPAR gama/metabolismo , Animais , Peso Corporal , Teste de Tolerância a Glucose , Leptina/genética , Leptina/metabolismo , Masculino , Obesidade/genética , PPAR gama/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Long-Evans , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: The use of amplitude-integrated electroencephalography (aEEG) is increasing during the neonatal intensive care of preterm infants. OBJECTIVE: This prospective study was designed to assess factors that affect the maturation of aEEG activity in preterm infants with a gestational age (GA) of <32 weeks. METHODS: aEEGs with cerebral function monitoring were performed weekly in preterm infants, and the recordings were evaluated and scored to assess the degree of continuity, the degree of sleep-wake cycling, and the amplitude of the lower border. Subjects with any of the following conditions were excluded: intraventricular hemorrhage or periventricular leukomalacia on cranial ultrasonography, sedation, hypotension, or respiratory instability (FiO(2) >50%). RESULTS: The authors analyzed 207 recordings in 35 infants (GA 24-31 weeks, birth weight 440-1,980 g, postmenstrual age 25-38 weeks). At postmenstrual age 34-36 weeks, the aEEG total score was higher in preterm infants with a GA from 24 to 28 weeks than in less premature infants with a GA from 29 to 31 weeks (aEEG total score 12 vs. 10, p < 0.05). Logistic regression analysis revealed that the sleep-wake cycling was more prominent in infants with higher postnatal age (OR 3.32, 95% CI 2.40-4.59) or those receiving aminophylline (OR 3.28, 95% CI 1.06-10.08). CONCLUSIONS: The maturation of aEEG activity was found to be significantly correlated with postnatal age and with aminophylline use in clinically stable preterm infants. Most notably, aminophylline was found to be significantly associated with the degree of sleep-wake cycling as indicated by aEEG activity.