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OBJECTIVES: There is a strong association among risk factors for oral cancer (ORCA), such as smoking, alcohol consumption, fiber intake, and red meat intake. The apparent synergistic effects reported in previous observational studies may also underestimate the independent effects. Our study aims to further explore the potential etiology and causality of oral cancer. MATERIALS AND METHODS: This study used the genome-wide associations study database (GWAS) in European populations for Mendelian randomization (MR) analysis to explore exposure factors associated with ORCA and detect the genetic causality between these exposures and ORCA risk. RESULTS: Our results demonstrated that in univariate MR analysis, the five exposure factors (celery intake, average weekly beer and cider intake, spirits intake, and pork intake) were risk factors, and oily fish intake was a safety factor, but in multivariate MR analysis, pork intake had the greatest impact on oral cancer when the five food/drink intakes were simultaneously consumed. CONCLUSIONS: The causal relationship between the five exposure factors (oily fish intake, celery intake, pork intake, average weekly beer and cider intake, and spirits intake) and oral cancer was analyzed. The causal effects of pork on oral cancer may be underestimated. CLINICAL RELEVANCE: Prevention of oral cancer requires better education about lifestyle-related risk factors, and improved awareness and tools for early diagnosis. Our study provides some risk factors that cannot be ignored for the cause prevention of oral cancer, such as pork intake, and its role in oral cancer prevention and control.
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Neoplasias Bucais , Animais , Consumo de Bebidas Alcoólicas , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Neoplasias Bucais/etiologia , Neoplasias Bucais/genética , Fatores de Risco , Humanos , Carne , SuínosRESUMO
Agaricus blazei is a rare medicinal and edible fungus with a crispy taste and delicious flavor. Both fruiting body and mycelium are rich in polysaccharides, sterols, terpenoids, peptides, lipids, polyphenols, and other active ingredients, which have strong pharmacological activities such as anti-tumor, lipid-lowering, glucose-lowering, immunomodulation, optimization of intestinal flora, and anti-oxidation. Therefore, it is a kind of fungal resource with a great prospect of edible and medicinal development. Among the reported chemical components of A. blazei, blazeispirol is a series of sterol compounds unique to A. blazei, which has a spiral structure and is different from classical steroids. It is an important active ingredient found in the mycelium of A. blazei and has significant hepatoprotective activity. It can be used as a phylogenetic and chemotaxonomic marker of A. blazei strains and is considered an excellent lead compound for drug development. According to the skeleton structure characteristics, the 17 discovered blazeispirol compounds can be divided into two types: blazeispirane and problazeispirane. In order to further explore the resource of blazeispirol compounds of A. blazei, the discovery, isolation, structure, biological activity, and biosynthetic pathways of blazeispirol compounds of A. blazei were systematically reviewed. Besides, the metabolic regulation strategies related to the fermentation synthesis of blazeispirol A by A. blazei were discussed. This review could provide a reference for the efficient synthesis and development of blazeispirol compounds, the research and development of related drugs and functional foods, and the quality improvement of A. blazei and other medicinal and edible fungi resources and derivatives.
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Agaricus , Neoplasias , Filogenia , Polissacarídeos , Esteroides , Agaricus/química , Agaricus/metabolismoRESUMO
PURPOSE: The aim of this study was to evaluate the accessibility and potential value of intraoperative optical coherence tomography (iOCT) during scleral suture intraocular lens (IOL) fixation. METHODS: This was a prospective cohort study in the Department of Ophthalmology, Eye and ENT Hospital, Fudan University, China. Seven eyes with insufficient capsular support and undergoing two-point scleral suture IOL fixation were included. The potential value of iOCT was evaluated, as well as the safety and efficacy of the surgery. RESULTS: Seven eyes were included. With a tailor-made iOCT, the structure of the anterior segment could be clearly visualized during the surgery. Intraoperatively, iOCT helped locate the proper place for fixation and access the position of the IOL. After an average 4.43-month follow-up, the spherical equivalent changed significantly ( P < 0.001), but the intraocular pressure, best-corrected visual acuity, and endothelial cell density remained unchanged ( P > 0.05). The IOL was well-centered with a horizontal and a vertical tilt of 0.74 ± 0.60° and 1.13 ± 0.65°, and decentration of 0.28 ± 0.12 mm and 0.30 ± 0.13 mm. The estimated IOL-induced astigmatism was -0.11 diopters (D) ± 0.46 D. CONCLUSION: Real-time high-resolution images of the anterior segment acquired by the iOCT helped the surgeon to achieve satisfactory results in scleral suture IOL fixation.
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Implante de Lente Intraocular , Lentes Intraoculares , Humanos , Implante de Lente Intraocular/métodos , Tomografia de Coerência Óptica , Estudos Prospectivos , Esclera/cirurgia , Suturas , Técnicas de Sutura , Estudos RetrospectivosRESUMO
BACKGROUND: Nowadays, acute leukemia (AL) among children has favorable outcome, yet some of them get refractory or relapse mainly due to drug resistance. High-mobility group box 1 (HMGB1) has been proven to have a important role in drug resistance via upregulation of autophagy after chemotherapy treatment in acute leukemia. However, the mechanism how extracellular HMGB1 acts on AL cells and leads to chemoresistance remains elusive. METHOD: CCK8 was used to examine the toxicity of chemotherapeutic drug. Elisa was performed to detect the release of HMGB1. Western blot and mRFP-GFP-LC3 adenoviral particles as well as transmission electron microscopy were used to detect the autophagy flux. Western blot and flow cytometry were applied to evaluate the apoptosis. qPCR and western blot were conducted to detect the expression of drug efflux protein. Lentivirus infection was applied to knock down RAGE. In addition, T-ALL NOD/SCID mice xenograft model was used to observe the effect of inhibiting HMGB1/RAGE axis. RESULTS: We found that extracellular HMGB1 do upregulate autophagy and in the meantime downregulate apoptosis, primarily through interaction with receptor for advanced glycation end products (RAGE). Suppression of RAGE by RNA interference alleviated the level of autophagy and enhanced apoptosis. What's more, HMGB1/RAGE induced autophagy was associated with the activation of ERK1/2 and decreased phosphorylation of mammalian target of rapamycin (mTOR), while HMGB1/RAGE limited apoptosis in a Bcl-2-regulated way mediated by P53. On the other hand, we found that HMGB1/RAGE activated the NF-κB pathway and promoted the expression of P-glycation protein (P-gp) as well as multidrug resistance-associated protein (MRP), both are ATP-binding cassette transporters. In vivo experiment, we found that blocking HMGB1/RAGE axis do have a mild pathological condition and a better survival in T-ALL mice. CONCLUSION: HMGB1/RAGE have a important role in drug resistance after chemotherapy treatment, mainly by regulating autophagy and apoptosis as well as promoting the expression of drug efflux protein such as P-gp and MRP. HMGB1/RAGE might be a promising target to cure AL, especially for those met with relapse and refractory.
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The BD FACSVia™ System features novel designs in hardware, software, and instrument QC. We compared the performance of the BD FACSVia System using the BD Leucocount™ kit with the BD FACSCalibur™ flow cytometer. Leucoreduced platelet (PLT, n = 252) and red blood cell (RBC, n = 278) specimens were enrolled at four sites. Each specimen was stained in four tubes using the BD Leucocount kit reagents and acquired on the two systems. BD Leucocount Control cells (high and low) were used to evaluate the inter-site reproducibility on the BD FACSVia System at three sites over 20 days. Deming regression and Bland-Altman analysis were performed to determine the WBC absolute counts on the BD FACSVia System vs. the BD FACSCalibur system. Assay accuracy for the range of 0-350 WBCs/µl was adequate. For samples with <25 WBCs/µl, the bias with 95% limits of agreement was 0.136 (-1.897 to 2.169) WBC/µl for PLTs (n = 184) and 0.170 (-2.025 to 2.365) WBC/µl for RBCs (n = 193). For inter-site reproducibility, the CV% was 6.46% (upper 95% CI 7.16%) for the PLT high control and 9.49% (10.52%) for the PLT low control. The CV% was 7.51% (8.32%) for the RBC high control and 10.76% (11.92%) for the RBC low control. The BD FACSVia System reported equivalent results of WBC absolute counts for leucoreduced PLT and RBC samples compared to the BD FACSCalibur system. The inter-laboratory reproducibility of the BD FACSVia System met study specifications. © 2018 The Authors. Cytometry Part A Published by Wiley Periodicals, Inc. on behalf of ISAC.
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Eritrócitos/citologia , Citometria de Fluxo/métodos , Leucócitos/citologia , Plaquetas/citologia , Humanos , Contagem de Leucócitos/métodos , Contagem de Plaquetas/métodos , Reprodutibilidade dos TestesRESUMO
Rationale: Adverse health impacts from outdoor air pollution occur across the United States, but the magnitude of these impacts varies widely by geographic region. Ambient pollutant concentrations, emission sources, baseline health conditions, and population sizes and distributions are all important factors that need to be taken into account to quantify local health burdens. Objectives: To determine health impacts from ambient air pollution concentrations in the United States that exceed the levels recommended by the American Thoracic Society. Methods: Using a methodology that has been well established in previous "Health of the Air" reports, this study provides policy-relevant estimates for every monitored county and city in the United States for the adverse health impacts of outdoor pollution concentrations using U.S. Environmental Protection Agency design values for years 2018-2020. Additionally, for the first time, the report includes adverse birth outcomes as well as estimates of health impacts specifically attributable to wildland fires using an exposure dataset generated through Community Multiscale Air Quality simulations. Results: The adverse health burdens attributable to air pollution occur across the entire age spectrum, including adverse birth outcomes (10,660 preterm and/or low-weight births; 95% confidence interval [CI], 3,180-18,330), in addition to mortality impacts (21,300 avoidable deaths; 95% CI, 16,180-26,200), lung cancer incidence (3,000 new cases; 95% CI, 1,550-4,390), multiple types of cardiovascular and respiratory morbidity (748,660 events; 95% CI, 326,050-1,057,080), and adversely impacted days (52.4 million days; 95% CI, 7.9-92.4 million days). Two different estimates of mortality impacts from wildland fires were created based on assumptions regarding the underlying toxicity of particles from wildland fires (low estimate of 4,080 deaths, 95% CI, 240-7,890; middle estimate of 28,000 deaths, 95% CI, 27,300-28,700). Conclusions: This year's report identified sizable health benefits that would be expected to occur across the United States with compliance with more health-protective air quality standards such as those recommended by the American Thoracic Society. This study also indicates that a large number of excess deaths are attributable to emissions from wildland fires; air quality management strategies outside what is required by the Clean Air Act will be needed to best address this important source of air pollution and its associated health risks.
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Poluentes Atmosféricos , Poluição do Ar , Complicações na Gravidez , Incêndios Florestais , Recém-Nascido , Humanos , Estados Unidos/epidemiologia , Feminino , Poluentes Atmosféricos/análise , Material Particulado/análise , Exposição Ambiental/efeitos adversos , Poluição do Ar/efeitos adversosRESUMO
Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is a highly heterogeneous disease. According to large-scale RNA sequencing (RNA-seq) data, B-ALL patients can be divided into more than 10 subgroups. However, many genomic defects associated with resistance mechanisms have not yet been identified. As an individual clinical tool for molecular diagnostic risk classification, RNA-seq and gene expression pattern-based therapy could be potential upcoming strategies. In this study, we retrospectively analyzed the RNA-seq gene expression profiles of 45 children whose molecular diagnostic classifications were inconsistent with the response to chemotherapy. The relationship between the transcriptome and chemotherapy response was analyzed. Fusion gene identification was conducted for the included patients who did not have known high-risk associated fusion genes or gene mutations. The most frequently detected fusion gene pair in the high-risk group was the DHRSX duplication, which is a novel finding. Fusions involving ABL1, LMNB2, NFATC1, PAX5, and TTYH3 at onset were more frequently detected in the high-risk group, while fusions involving LFNG, TTYH3, and NFATC1 were frequently detected in the relapse group. According to the pathways involved, the underlying drug resistance mechanism is related to DNA methylation, autophagy, and protein metabolism. Overall, the implementation of an RNA-seq diagnostic system will identify activated markers associated with chemotherapy response, and guide future treatment adjustments.
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Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Criança , Masculino , Feminino , Pré-Escolar , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Análise de Sequência de RNA , Adolescente , Resistencia a Medicamentos Antineoplásicos/genética , Lactente , Estudos Retrospectivos , Proteínas de Fusão Oncogênica/genéticaRESUMO
OBJECTIVE: To study the chemical constituents of Ajuga nipponensis. METHODS: The chemical constituents were isolated by repeated silica gel column chromatography and their structures were elucidated by phyisochemical properties and spectral analysis. RESULTS: Ten compounds were isolated and identified as:hexadecanoic acid(1), ajuforrestin A(2), beta-sitosterol(3), acacetin(4), apigenin(5), ajugamacrin B(6), ursolic acid(7), beta-ecdysone(8), 8-acetylharpagide(9) and daucosterol(10). CONCLUSION: Compounds 1-7 and 10 are isolated from this plant for the first time.
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Ajuga/química , Apigenina/química , Ácido Palmítico/química , Plantas Medicinais/química , Apigenina/isolamento & purificação , Flavonas/química , Flavonas/isolamento & purificação , Estrutura Molecular , Ácido Palmítico/isolamento & purificação , Sitosteroides/química , Sitosteroides/isolamento & purificação , Espectrofotometria UltravioletaRESUMO
This study presents an investigation focusing on the advancement of a robot designed for subretinal injections in the context of macular degeneration treatment. The technique of subretinal injection surgery stands as the most efficacious approach for the successful transplantation of stem cells into the retinal pigment epithelium layer. This particular procedure holds immense significance in advancing research and implementing therapeutic strategies involving retinal stem cell transplantation. The execution of artificial subretinal surgery poses considerable challenges which can be effectively addressed through the utilization of subretinal injection surgery robots. The development process involved a comprehensive modeling phase, integrating computer-aided design (CAD) and finite element analysis (FEA) techniques. These simulations facilitated iterative enhancements of the mechanical aspects pertaining to the robotic arm. Furthermore, MATLAB was employed to simulate and visualize the robot's workspace, and independent verification was conducted to ascertain the range of motion for each degree of freedom.
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Over the past two decades, the rapid evolution of transcatheter aortic valve replacement (TAVR) has revolutionized the management of severe aortic stenosis (AS) in the elderly. The prevalence of comorbidities in elderly AS patients presents a considerable challenge to the effectiveness and prognosis of patients after TAVR. In this article, we aim to summarize some of the clinical aspects of the current use of TAVR in elderly patients and attempt to highlight the challenges and issues that need further consideration.
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Wildfire outbreaks can lead to extreme biomass burning (BB) emissions of both oxidized (e.g., nitrogen oxides; NOx = NO+NO2) and reduced form (e.g., ammonia; NH3) nitrogen (N) compounds. High N emissions are major concerns for air quality, atmospheric deposition, and consequential human and ecosystem health impacts. In this study, we use both satellite-based observations and modeling results to quantify the contribution of BB to the total emissions, and approximate the impact on total N deposition in the western U.S. Our results show that during the 2020 wildfire season of August-October, BB contributes significantly to the total emissions, with a satellite-derived fraction of NH3 to the total reactive N emissions (median ~ 40%) in the range of aircraft observations. During the peak of the western August Complex Fires in September, BB contributed to ~55% (for the contiguous U.S.) and ~ 83% (for the western U.S.) of the monthly total NOx and NH3 emissions. Overall, there is good model performance of the George Mason University-Wildfire Forecasting System (GMU-WFS) used in this work. The extreme BB emissions lead to significant contributions to the total N deposition for different ecosystems in California, with an average August - October 2020 relative increase of ~78% (from 7.1 to 12.6 kg ha-1 year-1) in deposition rate to major vegetation types (mixed forests + grasslands/shrublands/savanna) compared to the GMU-WFS simulations without BB emissions. For mixed forest types only, the average N deposition rate increases (from 6.2 to 16.9 kg ha-1 year-1) are even larger at ~173%. Such large N deposition due to extreme BB emissions are much (~6-12 times) larger than low-end critical load thresholds for major vegetation types (e.g., forests at 1.5-3 kg ha-1 year-1), and thus may result in adverse N deposition effects across larger areas of lichen communities found in California's mixed conifer forests.
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Poluentes Atmosféricos , Poluição do Ar , Incêndios Florestais , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Ecossistema , Humanos , Nitrogênio/análise , Estados UnidosRESUMO
Acute lymphoblastic leukaemia (ALL) is one of the most common and curable types of cancer in paediatric patients. However, chemotherapeutic resistance is a difficult but common obstacle when treating leukaemia in the clinical setting. Studies have demonstrated that drug resistance is partly attributable to autophagy induced by multiple chemotherapeutic agents. As an evolutionarily conserved non-histone chromatin-binding protein, high mobility group box protein 1 (HMGB1) is considered to be an important factor in autophagy, and regulates autophagy at multiple levels via different subcellular localisations. In the present study, it was revealed that chemotherapeutic drugs induced autophagy in leukaemia cells and that translocation of HMGB1 from the nucleus to the cytoplasm is an important molecular event in this process. It was further demonstrated that poly (ADP-ribosylation) of HMGB1 facilitates its acetylation, thereby inducing HMGB1 translocation and ultimately promoting chemotherapy-induced autophagy in leukaemic cells. Targeted HMGB1 translocation may overcome chemotherapy-induced autophagy in leukaemia.
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High mobility group box protein 1 (HMGB1) is an evolutionarily conserved non-histone chromatin-binding protein. In a previous study, we showed that treating leukemic cells with chemotherapeutic drugs leads to the translocation of HMGB1, which is involved in autophagy and ultimately promotes chemoresistance in leukemia. However, the underlying translocation mechanism of HMGB1 in chemotherapy-induced autophagy remains unclear. In this study, we showed that knockdown of SIRT6 or PARP1 gene expression significantly inhibited HMGB1 cytoplasmic translocation and autophagy. Meanwhile, we found that SIRT6, an important upstream protein of PARP1, associated with PARP1, leading to the stimulation of polyADP-ribose polymerase activity. We further demonstrated that SIRT6 and PARP1 activation were required for chemotherapy-induced ADP-ribosylation of HMGB1 in leukemic cells and then influenced the acetylation of HMGB1, finally promoting the autophagy of leukemic cells mediated by HMGB1 translocation. These findings provide new insights into the mechanism of chemotherapeutic drug resistance. Targeting the HMGB1 translocation may overcome autophagy-related chemoresistance in leukemia.
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Autofagia , Daunorrubicina/farmacologia , Proteína HMGB1/metabolismo , Leucemia/patologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli ADP Ribosilação , Sirtuínas/metabolismo , Acetilação , Antibióticos Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Proteína HMGB1/genética , Humanos , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Poli(ADP-Ribose) Polimerase-1/genética , Sirtuínas/genética , Células Tumorais CultivadasRESUMO
Wearable sensors are gradually enabling decentralized healthcare systems. However, these sensors need to be closely attached to skin, which is unsuitable for long-term dynamic health monitoring of the patients, such as infants or persons with burn injuries. Here, a wearable capacitive sensor based on the capacitively coupled effect for healthcare monitoring in noncontact mode is reported. It consists of a ring-shaped top electrode, a disk-shaped bottom electrode, and a porous dielectric layer with low permittivity. This unique design enhanced the capacitively coupled effect of the sensor, which enables a high noncontact detectivity of capacitance change. When an object approaches the sensor, its capacitance change (ΔC/C i = -38.7%) is 3-5 times higher than that of previously reported sensors. Meanwhile, the sensor is insensitive to the stretching strain and pressure (ΔC/C i < 5%) due to the unique ring-shaped electrode and the incompressible closed cells of the porous dielectric material, respectively. Finally, various human physiological signals (pulse and respiratory) are recorded in noncontact mode, where a person wears loose and soft clothes implanted with the sensor. Thus, it is promising to build smart healthcare clothes based on it to develop wearable decentralized healthcare systems.
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The Covid-19 Open Research Dataset (CORD-19) is a growing resource of scientific papers on Covid-19 and related historical coronavirus research. CORD-19 is designed to facilitate the development of text mining and information retrieval systems over its rich collection of metadata and structured full text papers. Since its release, CORD-19 has been downloaded over 200K times and has served as the basis of many Covid-19 text mining and discovery systems. In this article, we describe the mechanics of dataset construction, highlighting challenges and key design decisions, provide an overview of how CORD-19 has been used, and describe several shared tasks built around the dataset. We hope this resource will continue to bring together the computing community, biomedical experts, and policy makers in the search for effective treatments and management policies for Covid-19.
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Deep convective transport of gaseous precursors to ozone (O3) and aerosols to the upper troposphere is affected by liquid phase and mixed-phase scavenging, entrainment of free tropospheric air and aqueous chemistry. The contributions of these processes are examined using aircraft measurements obtained in storm inflow and outflow during the 2012 Deep Convective Clouds and Chemistry (DC3) experiment combined with high-resolution (dx ≤ 3 km) WRF-Chem simulations of a severe storm, an air mass storm, and a mesoscale convective system (MCS). The simulation results for the MCS suggest that formaldehyde (CH2O) is not retained in ice when cloud water freezes, in agreement with previous studies of the severe storm. By analyzing WRF-Chem trajectories, the effects of scavenging, entrainment, and aqueous chemistry on outflow mixing ratios of CH2O, methyl hydroperoxide (CH3OOH), and hydrogen peroxide (H2O2) are quantified. Liquid phase microphysical scavenging was the dominant process reducing CH2O and H2O2 outflow mixing ratios in all three storms. Aqueous chemistry did not significantly affect outflow mixing ratios of all three species. In the severe storm and MCS, the higher than expected reductions in CH3OOH mixing ratios in the storm cores were primarily due to entrainment of low-background CH3OOH. In the air mass storm, lower CH3OOH and H2O2 scavenging efficiencies (SEs) than in the MCS were partly due to entrainment of higher background CH3OOH and H2O2. Overestimated rain and hail production in WRF-Chem reduces the confidence in ice retention fraction values determined for the peroxides and CH2O.
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BACKGROUND: Evaluation of microbicides for prevention of HIV-1 infection in macaque models for vaginal infection has indicated that the concentrations of active compounds needed for protection by far exceed levels sufficient for complete inhibition of infection in vitro. These experiments were done in the absence of seminal plasma (SP), a vehicle for sexual transmission of the virus. To gain insight into the possible effect of SP on the performance of selected microbicides, their anti-HIV-1 activity in the presence, and absence of SP, was determined. METHODS: The inhibitory activity of compounds against the X4 virus, HIV-1 IIIB, and the R5 virus, HIV-1 BaL was determined using TZM-bl indicator cells and quantitated by measuring beta-galactosidase induced by infection. The virucidal properties of cellulose acetate 1,2-benzene-dicarboxylate (CAP), the only microbicide provided in water insoluble, micronized form, in the presence of SP was measured. RESULTS: The HIV-1 inhibitory activity of the polymeric microbicides, poly(naphthalene sulfonate), cellulose sulfate, carrageenan, CAP (in soluble form) and polystyrene sulfonate, respectively, was considerably (range approximately 4 to approximately 73-fold) diminished in the presence of SP (33.3%). Formulations of micronized CAP, providing an acidic buffering system even in the presence of an SP volume excess, effectively inactivated HIV-1 infectivity. CONCLUSION: The data presented here suggest that the in vivo efficacy of polymeric microbicides, acting as HIV-1 entry inhibitors, might become at least partly compromised by the inevitable presence of SP. These possible disadvantages could be overcome by combining the respective polymers with acidic pH buffering systems (built-in for formulations of micronized CAP) or with other anti-HIV-1 compounds, the activity of which is not affected by SP, e.g. reverse transcriptase and zinc finger inhibitors.
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Fármacos Anti-HIV/antagonistas & inibidores , Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Sêmen , Administração Intravaginal , Anilidas/farmacologia , Fármacos Anti-HIV/administração & dosagem , Carragenina/farmacologia , Linhagem Celular , Celulose/análogos & derivados , Celulose/farmacologia , Relação Dose-Resposta a Droga , Furanos/farmacologia , HIV-1/fisiologia , Humanos , Naftalenossulfonatos/farmacologia , Poliestirenos/farmacologia , TioamidasRESUMO
For approximately 24 years the AIDS pandemic has claimed approximately 30 million lives, causing approximately 14,000 new HIV-1 infections daily worldwide in 2003. About 80% of infections occur by heterosexual transmission. In the absence of vaccines, topical microbicides, expected to block virus transmission, offer hope for controlling the pandemic. Antiretroviral chemotherapeutics have decreased AIDS mortality in industrialized countries, but only minimally in developing countries. To prevent an analogous dichotomy, microbicides should be acceptable, accessible, affordable, and accelerative in transition from development to marketing. Already marketed pharmaceutical excipients (inactive materials of drug dosage forms) or foods, with established safety records and adequate anti-HIV-1 activity, may provide this option. Therefore, fruit juices were screened for inhibitory activity against HIV-1 IIIB using CD4 and CXCR4 as cell receptors. The best juice was tested for inhibition of: (1) infection by HIV-1 BaL, utilizing CCR5 as the cellular coreceptor, and (2) binding of gp120 IIIB and gp120 BaL, respectively, to CXCR4 and CCR5. To remove most colored juice components, the adsorption of the effective ingredient(s) to dispersible excipients and other foods was investigated. A selected complex was assayed for inhibition of infection by primary HIV-1 isolates. The results indicate that HIV-1 entry inhibitors from pomegranate juice adsorb onto corn starch. The resulting complex blocks virus binding to CD4 and CXCR4/CCR5 and inhibits infection by primary virus clades A to G and group O. Therefore, these results suggest the possibility of producing an anti-HIV-1 microbicide from inexpensive, widely available sources, whose safety has been established throughout centuries, provided that its quality is adequately standardized and monitored.
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HIV-1/fisiologia , Lythraceae , Extratos Vegetais/farmacologia , Antígenos CD4/fisiologia , HIV-1/efeitos dos fármacos , Humanos , Fitoterapia , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/fisiologia , Receptores de HIV/antagonistas & inibidoresRESUMO
BACKGROUND: Cellulose acetate phthalate (CAP) has been used for several decades in the pharmaceutical industry for enteric film coating of oral tablets and capsules. Micronized CAP, available commercially as "Aquateric" and containing additional ingredients required for micronization, used for tablet coating from water dispersions, was shown to adsorb and inactivate the human immunodeficiency virus (HIV-1), herpesviruses (HSV) and other sexually transmitted disease (STD) pathogens. Earlier studies indicate that a gel formulation of micronized CAP has a potential as a topical microbicide for prevention of STDs including the acquired immunodeficiency syndrome (AIDS). The objective of endeavors described here was to develop a water dispersible CAP film amenable to inexpensive industrial mass production. METHODS: CAP and hydroxypropyl cellulose (HPC) were dissolved in different organic solvent mixtures, poured into dishes, and the solvents evaporated. Graded quantities of a resulting selected film were mixed for 5 min at 37 degrees C with HIV-1, HSV and other STD pathogens, respectively. Residual infectivity of the treated viruses and bacteria was determined. RESULTS: The prerequisites for producing CAP films which are soft, flexible and dispersible in water, resulting in smooth gels, are combining CAP with HPC (other cellulose derivatives are unsuitable), and casting from organic solvent mixtures containing approximately equal to 50 to approximately equal to 65% ethanol (EtOH). The films are approximately equal to 100 micron thick and have a textured surface with alternating protrusions and depressions revealed by scanning electron microscopy. The films, before complete conversion into a gel, rapidly inactivated HIV-1 and HSV and reduced the infectivity of non-viral STD pathogens >1,000-fold. CONCLUSIONS: Soft pliable CAP-HPC composite films can be generated by casting from organic solvent mixtures containing EtOH. The films rapidly reduce the infectivity of several STD pathogens, including HIV-1. They are converted into gels and thus do not have to be removed following application and use. In addition to their potential as topical microbicides, the films have promise for mucosal delivery of pharmaceuticals other than CAP.
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Anti-Infecciosos/farmacologia , Celulose/análogos & derivados , Celulose/química , Celulose/farmacologia , Fármacos Anti-HIV/farmacologia , Anti-Infecciosos/química , Etanol/química , HIV-1/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Filmes Cinematográficos , Água/químicaRESUMO
BACKGROUND: Cellulose acetate phthalate (CAP) in soluble form blocks coreceptor binding sites on the virus envelope glycoprotein gp120 and elicits gp41 six-helix bundle formation, processes involved in virus inactivation. CAP is not soluble at pH < 5.5, normal for microbicide target sites. Therefore, the interaction between insoluble micronized CAP and HIV-1 was studied. Carbomer 974P/BufferGel; carrageenan; cellulose sulfate; dextran/dextrin sulfate, poly(napthalene sulfonate) and poly(styrene-4-sulfonate) are also being considered as anti-HIV-1 microbicides, and their antiviral properties were compared with those of CAP. METHODS: Enzyme linked immunosorbent assays (ELISA) were used to (1) study HIV-1 IIIB and BaL binding to micronized CAP; (2) detect virus disintegration; and (3) measure gp41 six-helix bundle formation. Cells containing integrated HIV-1 LTR linked to the beta-gal gene and expressing CD4 and coreceptors CXCR4 or CCR5 were used to measure virus infectivity. RESULTS: 1) HIV-1 IIIB and BaL, respectively, effectively bound to micronized CAP. 2) The interaction between HIV-1 and micronized CAP led to: (a) gp41 six-helix bundle formation; (b) virus disintegration and shedding of envelope glycoproteins; and (c) rapid loss of infectivity. Polymers other than CAP, except Carbomer 974P, elicited gp41 six-helix bundle formation in HIV-1 IIIB but only poly(napthalene sulfonate), in addition to CAP, had this effect on HIV-1 BaL. These polymers differed with respect to their virucidal activities, the differences being more pronounced for HIV-1 BaL. CONCLUSIONS: Micronized CAP is the only candidate topical microbicide with the capacity to remove rapidly by adsorption from physiological fluids HIV-1 of both the X4 and R5 biotypes and is likely to prevent virus contact with target cells. The interaction between micronized CAP and HIV-1 leads to rapid virus inactivation. Among other anionic polymers, cellulose sulfate, BufferGel and aryl sulfonates appear most effective in this respect.