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Indole is an important element of many natural and synthetic molecules with significant biological activity. Nonetheless, the co-presence of transitional metals in organic scaffold may represent an important factor in the development of effective medicinal agents. This review covers some of the latest and most relevant achievements in the biological and pharmacological activity of important indole-containing metal complexes in the area of drug discovery.
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Complexos de Coordenação , Complexos de Coordenação/farmacologia , Descoberta de Drogas , Indóis/farmacologiaRESUMO
Multiple sclerosis is the most common progressive neurological disability in young adults. Sexual quality of life is mainly attributed to feelings of sexual attraction, showing interest and participating in sexual activity. The PLISSIT model shows 4 levels of intervention: Permission, limited Information, Specific Suggestions, and Intensive Therapy. The purpose of this study was to investigate the effect of counseling based on the PLISSIT model on the sexual quality of life of married women with multiple sclerosis referring to MS center in 2019. This randomized controlled trial study was conducted on 62 married women with multiple sclerosis. In the experimental group, based on the PLISSIT model, face-to-face counseling was conducted weekly in 4 sessions and each session lasted between 45 and 75 min. The control group received no intervention. Due to ethical issues, after completing the research, an educational guide on the quality of sexual life was given to the control group. The data collection tool was a questionnaire of sexual quality of life containing 18 questions. Data were analyzed using descriptive statistics and SPSS software. The results showed that there was no significant difference between the two groups before the intervention (P > 0.05). However, 2 weeks and 2 months after the intervention, the overall level of sexual quality of life in the experimental group was significantly better than the control group (P < 0.05). This study showed that counseling based on the PLISSIT model could have better results on the quality of life in sex.
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Esclerose Múltipla , Qualidade de Vida , Aconselhamento , Feminino , Humanos , Comportamento Sexual , Inquéritos e Questionários , Adulto JovemRESUMO
Activation of Gs-coupled receptors enhances engraftment of hematopoietic stem and progenitor cells (HSPCs). We tested the hypothesis that treprostinil, a prostacyclin analog approved for the treatment of pulmonary hypertension, can be repurposed to improve hematopoietic stem cell transplantation. Murine and human HSPCs were isolated from bone marrow and umbilical cord blood, respectively. Prostanoid receptor agonists and the combination thereof with forskolin were tested for their capacity to stimulate [(3)H]cAMP accumulation in HSPCs. Three independent approaches were employed to verify the ability of agonist-activated HSPCs to reconstitute the bone marrow in lethally irradiated recipient mice. The underlying mechanism was explored in cellular migration assays and by blocking C-X-C motif chemokine receptor 4 (CXCR4). Among several prostanoid agonists tested in combination with forskolin, treprostinil was most efficacious in raising intracellular cAMP levels in murine and human HPSCs. Injection of murine and human HSPCs, which had been pretreated with treprostinil and forskolin, enhanced survival of lethally irradiated recipient mice. Survival was further improved if recipient mice were subcutaneously administered treprostinil (0.15 mg kg(-1) 8 h(-1)) for 10 days. This regimen also reduced the number of HSPCs required to rescue lethally irradiated mice. Enhanced survival of recipient mice was causally related to treprostinil-enhanced CXCR4-dependent migration of HSPCs. Treprostinil stimulates the engraftment of human and murine hematopoietic stem cells without impairing their capacity for self-renewal. The investigated dose range corresponds to the dose approved for human use. Hence, these findings may be readily translated into a clinical application.
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Reposicionamento de Medicamentos , Epoprostenol/análogos & derivados , Transplante de Células-Tronco Hematopoéticas , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Transplante de Medula Óssea , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CXCL12/farmacologia , Toxina da Cólera/farmacologia , Colforsina/farmacologia , AMP Cíclico/metabolismo , Epoprostenol/administração & dosagem , Epoprostenol/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Receptores CXCR4/metabolismo , Receptores de Epoprostenol/metabolismo , Análise de Sobrevida , Irradiação Corporal TotalRESUMO
Introduction and importance: This research was conducted to investigate the effectiveness of neurofeedback on the symptoms of hyperactivity and attention deficit in primary school students with attention deficit/hyperactivity disorder (ADHD) disorder. Case presentation: The present study utilized a randomized clinical trial with pre-test and post-test measurements and included a control group. The research population included all primary school students with ADHD in 2023; 50 of these children were selected as the experimental group based on the accessible sampling method, and 50 were also included in the control group. Neurofeedback treatment sessions for the experimental group were 30 sessions. Research data were collected in three stages: pre-test and post-test, using a questionnaire based on the Conners rating scale from parents. SPSS-25 analyzed the data. Clinical discussion: The results showed that neurofeedback is associated with significant effectiveness in the symptoms of attention deficit disorder and hyperactivity of students (P<0.05). Conclusion: Based on the findings of this research, it can be said that neurofeedback treatment is effective in reducing attention deficit and hyperactivity symptoms of students with ADHD disorder. It is suggested to widely use neurofeedback to reduce the symptoms of attention deficit and hyperactivity disorder.
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All over the world, the level of special air pollutants that have the potential to cause diseases is increasing. Although the relationship between exposure to air pollutants and mortality has been proven, the health risk assessment and prediction of these pollutants have a therapeutic role in protecting public health, and need more research. The purpose of this research is to evaluate the ill-health caused by PM2.5 pollution using AirQ + software and to evaluate the different effects on PM2.5 with time series linear modeling by R software version 4.1.3 in the cities of Arak, Esfahan, Ahvaz, Tabriz, Shiraz, Karaj and Mashhad during 2019-2020. The pollutant hours, meteorology, population and mortality information were calculated by the Environmental Protection Organization, Meteorological Organization, Statistics Organization and Statistics and Information Technology Center of the Ministry of Health, Treatment and Medical Education for 24 h of PM2.5 pollution with Excel software. In addition, having 24 h of PM2.5 pollutants and meteorology is used to the effect of variables on PM2.5 concentration. The results showed that the highest and lowest number of deaths due to natural deaths, ischemic heart disease (IHD), lung cancer (LC), chronic obstructive pulmonary disease (COPD), acute lower respiratory infection (ALRI) and stroke in The effect of disease with PM2.5 pollutant in Ahvaz and Arak cities was 7.39-12.32%, 14.6-17.29%, 16.48-8.39%, 10.43-18.91%, 12.21-22.79% and 14.6-18.54 % respectively. Another result of this research was the high mortality of the disease compared to the mortality of the nose. The analysis of the results showed that by reducing the pollutants in the cities of Karaj and Shiraz, there is a significant reduction in mortality and linear modeling provides a suitable method for air management planning.
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In big and industrial cities of developing countries, illness and mortality from long-term exposure to air pollutants have become a serious issue. This research was carried out in 2019-2020 to estimate the health impacts of PM10, NO2 and O3 pollutants by using AirQ+ and R statistical programming software in Arak, Isfahan, Tabriz, Shiraz, Karaj, and Mashhad. Mortality statistics, number of people in required age groups, and amount of pollutants were gathered respectively from different agencies like Statistics and Information Technology of the Ministry of Health, Statistical Center, and Department of Environment and by using Excel, the average 24-hour and 1-hour concentration and maximum 8-hour concentration for PM10, NO2 and O3 pollutants were gathered. We used linear mixed impacts model to account for the longitudinal observations and heterogeneity of the cities. The results of the study showed high number of deaths due to chronic bronchitis in adults, premature death of infants, and respiratory diseases in Mashhad. This research highlights the importance of estimation of health impacts from exposure to air pollutants on residents of the studied cities.
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INTRODUCTION: /Objective: The aim of this study was to investigate the effectiveness of group cognitive behavioral therapy in depression and anxiety symptoms in patients with Parkinson's Tehran city. METHODS: This quasi-experimental study was conducted with experimental and control groups at pretest, posttest, and follow-up. Patients 60-75 years old with Parkinson's disease centers and psychiatric services made up the study population. Based on a random sample of 90 people in Tehran city who scored highly on both the Beck Anxiety Inventory and the Beck Depression Scale, in two 45-person groups-the experimental group and the control group-were randomly assigned. The experimental group underwent group cognitive behavioral therapy for 8 weeks, while the control group just received training once per week. Methods of analysis of variance with repeated measures were employed to test the hypotheses. RESULTS: The outcomes showed the independent variable is successful in lowering symptoms of anxiety and depression. Patients with Parkinson's disease who participated in group cognitive behavioral therapy for stress reduction showed a reduction in their anxiety and depressive symptoms. CONCLUSION: Effective psychological interventions, like group cognitive behavioral therapy, can improve mood, lessen anxiety and depression, and help patients adhere more closely to treatment guidelines. As a result, these patients can help prevent the complications of Parkinson's disease and take effective action to raise their level of physical and mental health.
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Terapia Cognitivo-Comportamental , Doença de Parkinson , Humanos , Pessoa de Meia-Idade , Idoso , Depressão/etiologia , Depressão/terapia , Depressão/psicologia , Doença de Parkinson/complicações , Doença de Parkinson/terapia , Doença de Parkinson/psicologia , Irã (Geográfico) , Ansiedade/etiologia , Ansiedade/terapia , Ansiedade/psicologiaRESUMO
Among the metals contaminants, cadmium (Cd) is one of the most toxic elements in cultivated soils, causing loss of yield and productivity in plants. Recently, nanomaterials have been shown to mitigate the negative consequences of environmental stresses in different plants. However, little is known about foliar application of titanium dioxide nanoparticles (TiO2 NPs) to alleviate Cd stress in medicinal plants, and their dual interactions on essential oil production. The objective of this study was to investigate the effects of foliar-applied TiO2 NPs on growth, Cd uptake, chlorophyll fluorescence, photosynthetic pigments, malondialdehyde (MDA) and hydrogen peroxide (H2O2) contents, total phenols, anthocyanins, flavonoids, antioxidant enzymes (SOD, CAT and POD) activity and essential oil content of Mentha piperita L. (peppermint) under Cd stress. For this purpose, plants were grown in Cd-contaminated (0, 20, 40, and 60 mg L-1) soil, and different concentrations of TiO2 NPs (0, 75, and 150 mg L-1) were foliar sprayed at three times after full establishment until the beginning of flowering. Exposure to TiO2 NPs significantly (P < 0.01) increased shoot dry weight (37.8%) and the number of lateral branches (59.4%) and decreased Cd uptake in plant tissues as compared to the control. Application of TiO2 NPs increased the content of plastid pigments, and the ratio Fv/Fm (13.4%) as compared to the control. Additionally, TiO2 NPs reduced the stress markers, MDA and H2O2 contents and enhanced the activity of the phenylalanine ammonia-lyase (PAL) enzyme (60.5%), total phenols (56.1%), anthocyanins (42.6%), flavonoids (25.5%), and essential oil content (52.3%) in Cd-stressed peppermint compared to the control. The results also demonstrated that foliar spray of TiO2 NPs effectively improved the growth and chlorophyll fluorescence parameters and reduced Cd accumulation in peppermint, which was mainly attributed to the reduction of oxidative burst and enhancement of the enzymatic (SOD, CAT, and POD) antioxidant defense system due to the uptake of NPs. The findings provide insights into the regulatory mechanism of TiO2 NPs on peppermint plants growth, physiology and secondary metabolites production in Cd-contaminated soil.
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Nanopartículas , Óleos Voláteis , Poluentes do Solo , Cádmio/metabolismo , Mentha piperita , Antocianinas , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Peróxido de Hidrogênio , Nanopartículas/química , Solo/química , Clorofila/metabolismo , Superóxido Dismutase/metabolismo , Compostos Fitoquímicos , Óleos Voláteis/farmacologia , Fenóis , Poluentes do Solo/metabolismoRESUMO
BACKGROUND: Physical and sexual harassment has extensive psychological consequences on people's lives. Therefore, the using of a valid measure to identify this unpleasant experience in people can be useful both in determining the starting point of interventions related to victims and in general screenings in the society. In this regard, due to the lack of native and multidimensional measures to investigate this phenomenon, the aim of this study was to design and validation of the psychosexual harassment questionnaire. METHODS: The research method was applied in terms of purpose and descriptive in terms of nature. The study population included all university students aged 18 to 30 in Hamadan province from 2021-2022. From this population, a sample of 600 participants was selected based on a multi-stage cluster sampling method according to the population of the studied cities. The measures were a 27-item researcher-made psychosexual harassment questionnaire and the Ryff Psychological Well-being Scale. RESULTS: The results showed that the factor load was 27 items appropriate and 2 items inappropriate which were removed from the questionnaire. Finally, four factors including sexual harassment, physical harassment, sexual-virtual harassment, and verbal harassment were identified, in total, four factors could explain 58% of the variance of psychosexual harassment. Based on this, the four identified factors explained 33, 12, 8, and 5 percent of the variance of the structure of the psychosexual harassment construct, respectively. The adequacy of Kaiser-Meyer-Olkin sampling and Bartlett sphericity test (7332.2132) was calculated to be significant at the level of 0.001. The overall reliability of this questionnaire was calculated based on Cronbach's alpha coefficient equal to 0.91 and the reliability of physical, sexual, sexual-virtual and verbal harassment dimensions equal to 0.90, 0.88, 0.81, and 0.82, respectively. CONCLUSIONS: As a result, given the validity and reliability of this measure, researchers can use this measure to determine the level of four cases of abuse expressed. Also, due to having a nominal table and its interaction with each of the four dimensions of the measure, followed by obtaining very accurate and detailed information from the subject, clinicians can use this measure for clients and patients, especially in the category of disorders.
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Cosmetic products, especially perfumes and colognes, are widely used in various communities. However, the use of these products can have side effects on consumers. This article aims to review the relevant literature published up to August 2020 to determine whether perfumes and colognes can affect people's health. Relevant articles were identified through electronic search. A total of 562 articles were selected and finally 37 related articles were included in the study after the screening process. The results of this systematic study showed that phthalates, aldehydes, parabens and aluminum-based salts are the most important contaminants in aromatic products that cause side effects such as allergies, breast cancer, reproductive disorders, especially in males, skin allergies, nervous system damage and migraine headaches for consumers. The incidence of complications in people using these products depends on parameters such as age, gender, race, amount of substance consumed, duration of use and economic status, and regarding the relationship between diseases such as cancer, respiratory disorders and endocrine with common contaminants in aromatic products, incidence of these diseases is probable in consumers which require further research to prove.
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We report Ni-Mn-Se supported on Ni foam as a highly active and stable bifunctional electrocatalyst that exhibits overpotentials of 28 and 122 mV to reach a current density of 10 mA cm-2 for the hydrogen evolution reaction (HER) and urea oxidation reaction (UOR), respectively, and maintains its stability for over 50 h in both reactions. In addition, an overall urea splitting cell voltage of 1.352 V is needed at the current density of 10 mA cm-2 for the optimized electrode.
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To investigate the mechanisms by which O-linked ß-N-acetylglucosamine modification of nucleocytoplasmic proteins (O-GlcNAc) confers stress tolerance to multiple forms of cellular injury, we explored the role(s) of O-GlcNAc in the regulation of heat shock protein (HSP) expression. Using a cell line in which deletion of the O-GlcNAc transferase (OGT; the enzyme that adds O-GlcNAc) can be induced by 4-hydroxytamoxifen, we screened the expression of 84 HSPs using quantitative reverse transcriptase PCR. In OGT null cells the stress-induced expression of 18 molecular chaperones, including HSP72, were reduced. GSK-3ß promotes apoptosis through numerous pathways, including phosphorylation of heat shock factor 1 (HSF1) at Ser(303) (Ser(P)(303) HSF1), which inactivates HSF1 and inhibits HSP expression. In OGT null cells we observed increased Ser(P)(303) HSF1; conversely, in cells in which O-GlcNAc levels had been elevated, reduced Ser(P)(303) HSF1 was detected. These data, combined with those showing that inhibition of GSK-3ß in OGT null cells recovers HSP72 expression, suggests that O-GlcNAc regulates the activity of GSK-3ß. In OGT null cells, stress-induced inactivation of GSK-3ß by phosphorylation at Ser(9) was ablated providing a molecular basis for these findings. Together, these data suggest that stress-induced GlcNAcylation increases HSP expression through inhibition of GSK-3ß.
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Acetilglucosamina/metabolismo , Regulação Enzimológica da Expressão Gênica , Quinase 3 da Glicogênio Sintase/metabolismo , Proteínas de Choque Térmico/metabolismo , Animais , Células COS , Núcleo Celular/metabolismo , Chaperoninas/química , Chlorocebus aethiops , Glicogênio Sintase Quinase 3 beta , Glicosilação , Proteínas de Choque Térmico HSP72/metabolismo , Camundongos , Chaperonas Moleculares/metabolismo , Serina/química , Transdução de SinaisRESUMO
BACKGROUND: The present study aims to investigate the knowledge, attitude, and performance of Iranian Healthcare Professionals (HP) about Complementary and Alternative Medicine (CAM) modalities. METHODS: This cross-sectional study was carried out on 210 HP in 2019. Samples were selected from healthcare centers, clinics, and hospitals using census sampling. Data collection tools included demographic information, attitude, knowledge, and the amount of use of CAM modalities. Data analysis was performed using SPSS ver. 24. RESULTS: In this study, the response rate was 85.3% (n=209). A majority of respondents had a positive attitude toward CAM (n=166, 79%), but their level of knowledge was limited (n=154, 73.6%). The most commonly used CAM modalities were herbal medicine (93.2%), exercise therapy (75.4%), and hydrotherapy (75.2%), respectively, and the least commonly used ones were magnetic therapy (2.9%) and hypnosis (4.8%). The most important reasons for the use of CAM modalities by HP included fewer side effects than medical treatments (57.4%), its lowest cost than medical treatments (34.9%), non-serious disease with no need for referral to a clinic (32.1%), and its more convenient access than medical treatments (30.6%). The results showed that there was a significant relationship between the education level and the use of CAM modalities (p<0.05). There was also a significant relationship between the suggestion of CAM modalities and the amount of use of these modalities, and those who used these modalities would also have recommended them to their clients more frequently (p<0.05). CONCLUSION: The results showed that most of HP used at least one of the CAM modalities and had a positive attitude towards CAM. As the level of knowledge was limited, training courses should be implemented to increase health practitioner's level of knowledge on CAM.
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Terapias Complementares/psicologia , Conhecimentos, Atitudes e Prática em Saúde , Pessoal de Saúde/psicologia , Adulto , Terapias Complementares/métodos , Estudos Transversais , Feminino , Pessoal de Saúde/estatística & dados numéricos , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto JovemRESUMO
Aim: Bacterial micro leakage at implant-abutment interface under functional loading is an important factor, may lead to crestal bone loss and affect the long term success of dental implants. Due to the limited studies about the implant systems with a connection of Slip joint design, this study aimed to evaluate the effect of dynamic loading on bacterial leakage at the implant-abutment interface with slip joint connection. Settings and Design: In vitro- comparative study. Materials and Methods: A total of 20 implants and abutments with slip joint connections (Tapered Screw-Vent, 3.7 mm ×10 mm, Zimmer Dental, USA) was examined and depends on using functional loading were divided into two groups; loaded and unloaded. Initially, 10 µl of Brain Heart Infusion (BHI) culture broth was pipetted to the internal lumen of each implant, then the abutments were tightened to the fixtures and crowns were cemented. In the unloaded group, samples were immersed in E-Coli suspension for 5 days. In the loaded group, samples were immersed in microbial suspension under 500000 cycles using a cyclic load device. Following disconnection of fixtures and abutments, microbial samples were taken from the internal lumen of implants and colonies were counted. Data were analyzed using. Statistical Analysis Used: Mann-Whitney statistical test, SPSS version 24. Results: The mean rate of micro leakage in unloaded and loaded groups was 4000 CFU/ml and 27000 ± 31640 CFU/ml respectively. Bacterial colonies grew in 10% of unloaded samples and 50% of loaded samples. This difference was statistically significant. (P < 0.05). Conclusions: Microbial micro leakage at the implant-abutment interface with slip joint design increased significantly after functional loading.
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Implantes Dentários , Coroas , Escherichia coli , Teste de Materiais , Propriedades de SuperfícieRESUMO
The coastal pollution has been evaluated using indexes like Clean Coast Index (CCI) in many countries. In this study, several coasts and urban areas in northern of Iran along the Caspian Sea, were assessed in terms of number and composition of litters. Furthermore, Clean Environment Index (CEI) was used for the first time to interpret the results. The results indicated that 60% of the coasts and 50% of the urban areas were in a dirty status and only 22% of the total surveyed areas were found to be in a clean status. The highest number of litters observed in the study areas was cigarette butt. Due to the impact of risk factor of different types of littered waste, it was obviously clear that CEI offers a more realistic and rigorous interpretation than CCI. Therefore, this new index can be considered to evaluate litters pollution in various areas.
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Monitoramento Ambiental , Plásticos , Mar Cáspio , Poluição Ambiental , Irã (Geográfico)RESUMO
The COVID-19 pandemic has affected everyone's lifestyle and this has resulted in a change in the quantity and composition of municipal solid wastes. Moreover, the post-pandemic waste management is very important as a bad management may lead to the more spread of the disease. The objective of this study was to evaluate the application of guidelines presented for the era of the COVID-19 pandemic in proper solid waste management. To this end, the data were collected by using interviews and field researches and then the obtained data were compared with the international guidelines presented by international organizations. By investigating the municipal waste management during this pandemic and its changes compared to pre-COVID-19, coordination of the plans with the guidelines was investigated. The activities of storage, collection, transportation, recycling, final landfill, as well as the observation of the health instructions by staff and informal sections were assessed in the current research. Although the results showed that the situation was satisfactory in the sections like health and safety of waste management operators due to the existence of protocols and general educations, the waste management plans have not been changed much from before the epidemic of the Coronavirus. The absence of a national policy and plan for waste management in the era of a pandemic and ignoring the guidelines developed by other countries and organizations were observable. Therefore, the codification of new policies for municipal waste management during an epidemic is necessary.
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Landfilling is known to be the most widely used method in municipal solid waste management in many countries. Landfill leachate containing different recalcitrant compounds are recognized to contaminate the soil and water and accordingly threat both the human health and environment. A variety of chemical and biological methods have recently been employed for landfill leachate treatment, one of which is the ultrasonic process. In this review, the efficiency of the ultrasound-assisted method for leachate treatment, factors influencing the treatment process are studied by defining a search protocol. The results showed that ultrasound can reduce pollutants by creating cavitation, microstreaming, and microturbulence. Increasing turbidity in initial of irradiation time and increasing the cost of treatment are the disadvantages of using ultrasonic in leachate treatment. Moreover, ultrasound-assisted method leads to improve the leachate quality, especially the COD/BOD. Therefore, ultrasound can be considered a good pretreatment for biological processes. Although, the application of this process in combination with other treatment processes such as biological processes and advanced oxidation increases the efficiency of leachate treatment, its efficiency depends on several factors such as exploitation features and leachate quality.
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Poluentes Ambientais , Eliminação de Resíduos , Gerenciamento de Resíduos , Poluentes Químicos da Água , Humanos , Oxirredução , Resíduos Sólidos/análise , Poluentes Químicos da Água/análiseRESUMO
The cell dose in umbilical cord blood units is a major determinant for the outcome of hematopoietic cell transplantation. Prostaglandin analogs and dipeptidylpeptidase-4 (DPP4/CD26)-inhibitors enhance the ability of hematopoietic stem cells (HSCs) to reconstitute hematopoiesis. Here we explored the synergism between treprostinil, a stable prostaglandin agonist, and the DPP4/CD26-inhibitor vildagliptin. The combination of treprostinil and forskolin caused a modest but statistically significant increase in the surface levels of DPP4/CD26 on hematopoietic stem and progenitor cells (HSPCs) derived from murine bone and human cord blood. Their migration towards stromal cell-derived factor-1 (SDF-1/CXCL12) was enhanced, if they were pretreated with treprostinil and forskolin, and further augmented by vildagliptin. Administration of vildagliptin rescued 25% of lethally irradiated recipient mice injected with a limiting number of untreated HSPCs, but 90 to 100% of recipients injected with HSPCs preincubated with treprostinil and forskolin. The efficacy of vildagliptin surpassed that of treprostinil (60% rescue). Surprisingly, concomitant administration of vildagliptin and treprostinil resulted in poor survival of recipients indicating mutual antagonism, which was recapitulated when homing of and colony formation by HSPCs were assessed. These observations of regimen-dependent synergism and antagonism of treprostinil and vildagliptin are of translational relevance for the design of clinical trials. KEY MESSAGES: Pretreatment with treprostinil increases surface levels of DPP4/CD26 in HSPCs. Vildagliptin enhances in vitro migration of pretreated HSPCs. Vildagliptin enhances in vivo homing and engraftment of pretreated HSPCs. Unexpected mutual antagonism in vivo by concomitant administration of vildagliptin and treprostinil.
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Anti-Hipertensivos/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Epoprostenol/análogos & derivados , Transplante de Células-Tronco Hematopoéticas , Vildagliptina/administração & dosagem , Animais , Células Cultivadas , Dipeptidil Peptidase 4/metabolismo , Antagonismo de Drogas , Sinergismo Farmacológico , Epoprostenol/administração & dosagem , Sangue Fetal/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , CamundongosRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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STAT5B is often mutated in hematopoietic malignancies. The most frequent STAT5B mutation, Asp642His (N642H), has been found in over 90 leukemia and lymphoma patients. Here, we used the Vav1 promoter to generate transgenic mouse models that expressed either human STAT5B or STAT5BN642H in the hematopoietic compartment. While STAT5B-expressing mice lacked a hematopoietic phenotype, the STAT5BN642H-expressing mice rapidly developed T cell neoplasms. Neoplasia manifested as transplantable CD8+ lymphoma or leukemia, indicating that the STAT5BN642H mutation drives cancer development. Persistent and enhanced levels of STAT5BN642H tyrosine phosphorylation in transformed CD8+ T cells led to profound changes in gene expression that were accompanied by alterations in DNA methylation at potential histone methyltransferase EZH2-binding sites. Aurora kinase genes were enriched in STAT5BN642H-expressing CD8+ T cells, which were exquisitely sensitive to JAK and Aurora kinase inhibitors. Together, our data suggest that JAK and Aurora kinase inhibitors should be further explored as potential therapeutics for lymphoma and leukemia patients with the STAT5BN642H mutation who respond poorly to conventional chemotherapy.