Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 39
Filtrar
Mais filtros










Intervalo de ano de publicação
2.
Sci Total Environ ; 718: 137237, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32109810

RESUMO

Sanitary inspection is used in low-, medium- and high-income settings to assess the risk of microbial contamination at water sources. However, the relationship between sanitary inspection and water quality is not well understood. We conducted a critical literature review and synthesized the findings of 25 studies comparing the results of sanitary inspection and microbial water quality analysis. Most studies used sub-standard sanitary inspection and water quality analysis methods, and applied simplistic comparisons that do not characterize the complexity of the relationship. Sanitary risk score was used to represent sanitary inspection results in 21 (84%) studies; of which 12 (57%) found a significant association between score and microbial water quality and nine (43%) did not. Participatory sanitary inspection (12%) and reporting results back to communities (24%) were uncommon. Most studies relied on laboratory-based water quality analysis as an independently sufficient measure of safety, but reported inadequate quality control (52%) and/or sub-standard sample processing methods (66%). We found that sanitary inspections could contribute to improving water safety through four mechanisms: guiding remedial action at individual water sources, allowing operators and external support programs to prioritize repairs, identifying programmatic issues, and contributing to research. The purpose of the sanitary inspection should be considered when planning sanitary inspection execution, data analysis, and reporting to ensure appropriate methods are employed and results are fit for purpose. Further exploration should recognize that sanitary risk factors represent sources of contamination, pathways for contaminants to enter water supplies, and breakdowns in barriers to contamination. These different sanitary risk factor types have different and inter-dependent effects on water quality.

3.
BMC Med ; 17(1): 173, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462230

RESUMO

BACKGROUND: Three large new trials of unprecedented scale and cost, which included novel factorial designs, have found no effect of basic water, sanitation and hygiene (WASH) interventions on childhood stunting, and only mixed effects on childhood diarrhea. Arriving at the inception of the United Nations' Sustainable Development Goals, and the bold new target of safely managed water, sanitation and hygiene for all by 2030, these results warrant the attention of researchers, policy-makers and practitioners. MAIN BODY: Here we report the conclusions of an expert meeting convened by the World Health Organization and the Bill and Melinda Gates Foundation to discuss these findings, and present five key consensus messages as a basis for wider discussion and debate in the WASH and nutrition sectors. We judge these trials to have high internal validity, constituting good evidence that these specific interventions had no effect on childhood linear growth, and mixed effects on childhood diarrhea. These results suggest that, in settings such as these, more comprehensive or ambitious WASH interventions may be needed to achieve a major impact on child health. CONCLUSION: These results are important because such basic interventions are often deployed in low-income rural settings with the expectation of improving child health, although this is rarely the sole justification. Our view is that these three new trials do not show that WASH in general cannot influence child linear growth, but they do demonstrate that these specific interventions had no influence in settings where stunting remains an important public health challenge. We support a call for transformative WASH, in so much as it encapsulates the guiding principle that - in any context - a comprehensive package of WASH interventions is needed that is tailored to address the local exposure landscape and enteric disease burden.


Assuntos
Diarreia/etiologia , Transtornos do Crescimento/etiologia , Higiene , Saneamento , Água/efeitos adversos , Criança , Saúde da Criança , Humanos , Pobreza , Saúde Pública/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , População Rural
4.
Sci Total Environ ; 683: 331-340, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31132712

RESUMO

The Solomon Islands, like other small island developing states in the Pacific, face significant challenges from a changing climate, and from increasing extreme weather events, while also lagging behind the rest of the world in terms of drinking water, sanitation and hygiene (WaSH) services. In order to support planning for the implementation of national WaSH strategies and policies, this study contextualizes representative urban and rural baselines for Sustainable Development Goal (SDG) 6 ("by 2030, achieve access to adequate and equitable sanitation and hygiene for all and end open defecation"). We highlight specific threats to the current sanitation services under extreme weather events such as flooding and drought, both of which are commonly observed in the country, and provide suggestions for structural improvements to sanitation facilities to increase resiliency. As the first detailed nationally representative cross-sectional sanitation study in urban and rural areas in the Solomon Islands, the results of this paper inform national WaSH policy, strategic planning and programming by the Solomon Islands Government and stakeholders.

5.
Environ Sci Technol ; 51(13): 7542-7551, 2017 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-28582618

RESUMO

Intermittent water supply (IWS) is prevalent throughout low and middle-income countries. IWS is associated with increased microbial contamination and potentially elevated risk of waterborne illness. We used existing data sets to estimate the population exposed to IWS, assess the probability of infection using quantitative microbial risk assessment, and calculate the subsequent burden of diarrheal disease attributable to consuming fecally contaminated tap water from an IWS. We used reference pathogens Campylobacter, Cryptosporidium, and rotavirus as conservative risk proxies for infections via bacteria, protozoa, and viruses, respectively. Results indicate that the median daily risk of infection is an estimated 1 in 23 500 for Campylobacter, 1 in 5 050 000 for Cryptosporidium, and 1 in 118 000 for rotavirus. Based on these risks, IWS may account for 17.2 million infections causing 4.52 million cases of diarrhea, 109 000 diarrheal DALYs, and 1560 deaths each year. The burden of diarrheal disease associated with IWS likely exceeds the WHO health-based normative guideline for drinking water of 10-6 DALYs per person per year. Our results underscore the importance water safety management in water supplies and the potential benefits of point-of-use treatment to mitigate risks.


Assuntos
Cryptosporidium , Medição de Risco , Microbiologia da Água , Doenças Transmissíveis , Humanos , Poluição da Água , Abastecimento de Água
6.
Bull World Health Organ ; 94(6): 424-32, 2016 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-27274594

RESUMO

OBJECTIVE: To assess, within communities experiencing Ebola virus outbreaks, the risks associated with the disposal of human waste and to generate recommendations for mitigating such risks. METHODS: A team with expertise in the Hazard Analysis of Critical Control Points framework identified waste products from the care of individuals with Ebola virus disease and constructed, tested and confirmed flow diagrams showing the creation of such products. After listing potential hazards associated with each step in each flow diagram, the team conducted a hazard analysis, determined critical control points and made recommendations to mitigate the transmission risks at each control point. FINDINGS: The collection, transportation, cleaning and shared use of blood-soiled fomites and the shared use of latrines contaminated with blood or bloodied faeces appeared to be associated with particularly high levels of risk of Ebola virus transmission. More moderate levels of risk were associated with the collection and transportation of material contaminated with bodily fluids other than blood, shared use of latrines soiled with such fluids, the cleaning and shared use of fomites soiled with such fluids, and the contamination of the environment during the collection and transportation of blood-contaminated waste. CONCLUSION: The risk of the waste-related transmission of Ebola virus could be reduced by the use of full personal protective equipment, appropriate hand hygiene and an appropriate disinfectant after careful cleaning. Use of the Hazard Analysis of Critical Control Points framework could facilitate rapid responses to outbreaks of emerging infectious disease.


Assuntos
Ebolavirus , Eliminação de Resíduos de Serviços de Saúde/métodos , Doença pelo Vírus Ebola/prevenção & controle , Humanos
7.
Stem Cells Dev ; 25(11): 848-60, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27059084

RESUMO

Human bone marrow multipotent mesenchymal stromal cell (hMSC) number decreases with aging. Subpopulations of hMSCs can differentiate into cells found in bone, vasculature, cartilage, gut, and other tissues and participate in their repair. Maintaining throughout adult life such cell subpopulations should help prevent or delay the onset of age-related degenerative conditions. Low oxygen tension, the physiological environment in progenitor cell-rich regions of the bone marrow microarchitecture, stimulates the self-renewal of marrow-isolated adult multilineage inducible (MIAMI) cells and expression of Sox2, Nanog, Oct4a nuclear accumulation, Notch intracellular domain, notch target genes, neuronal transcriptional repressor element 1 (RE1)-silencing transcription factor (REST), and hypoxia-inducible factor-1 alpha (HIF-1α), and additionally, by decreasing the expression of (i) the proapoptotic proteins, apoptosis-inducing factor (AIF) and Bak, and (ii) senescence-associated p53 expression and ß-galactosidase activity. Furthermore, low oxygen increases canonical Wnt pathway signaling coreceptor Lrp5 expression, and PI3K/Akt pathway activation. Lrp5 inhibition decreases self-renewal marker Sox2 mRNA, Oct4a nuclear accumulation, and cell numbers. Wortmannin-mediated PI3K/Akt pathway inhibition leads to increased osteoblastic differentiation at both low and high oxygen tension. We demonstrate that low oxygen stimulates a complex signaling network involving PI3K/Akt, Notch, and canonical Wnt pathways, which mediate the observed increase in nuclear Oct4a and REST, with simultaneous decrease in p53, AIF, and Bak. Collectively, these pathway activations contribute to increased self-renewal with concomitant decreased differentiation, cell cycle arrest, apoptosis, and/or senescence in MIAMI cells. Importantly, the PI3K/Akt pathway plays a central mechanistic role in the oxygen tension-regulated self-renewal versus osteoblastic differentiation of progenitor cells.


Assuntos
Apoptose/efeitos dos fármacos , Células da Medula Óssea/citologia , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Autorrenovação Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Oxigênio/farmacologia , Transdução de Sinais/efeitos dos fármacos , Adulto , Apoptose/genética , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Diferenciação Celular/genética , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Autorrenovação Celular/genética , Separação Celular , Senescência Celular/genética , Criança , Pré-Escolar , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Modelos Biológicos , Fator 3 de Transcrição de Octâmero/metabolismo , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/genética , Células Estromais/citologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo
8.
Expert Opin Ther Targets ; 20(9): 1087-98, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26941128

RESUMO

INTRODUCTION: Bone marrow-derived mesenchymal stem cells (MSCs) can differentiate into multiple cell types, including osteoblasts, chondrocytes, and adipocytes. These pluripotent cells secrete hepatocyte growth factor (HGF), which regulates cell growth, survival, motility, migration, mitogenesis and is important for tissue development/regeneration. HGF has four splice variants, NK1, NK2, NK3, and NK4 which have varying functions and affinities for the HGF receptor, cMET. HGF promotes osteoblastic differentiation of MSCs into bone forming cells, playing a role in bone development, health and repair. AREAS COVERED: This review will focus on the effects of HGF in osteogenesis, bone repair and bone health, including structural and functional insights into the role of HGF in the body. EXPERT OPINION: Approximately 6.2 million Americans experience a fracture annually, with 5-10% being mal- or non-union fractures. HGF is important in priming MSCs for osteogenic differentiation in vitro and is currently being studied to assess its role during bone repair in vivo. Due to the high turnover rate of systemic HGF, non-classic modes of HGF-treatment, including naked-plasmid HGF delivery and the use of HGF splice variants (NK1 & NK2) are being studied to find safe and efficacious treatments for bone disorders, such as mal- or non-union fractures.


Assuntos
Osso e Ossos/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Osteogênese/genética , Adipócitos/citologia , Processamento Alternativo/genética , Animais , Diferenciação Celular , Condrócitos/citologia , Regulação da Expressão Gênica , Fator de Crescimento de Hepatócito/administração & dosagem , Fator de Crescimento de Hepatócito/genética , Humanos , Células-Tronco Mesenquimais/citologia , Osteoblastos/citologia
9.
Cancer Res ; 76(2): 491-504, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26744520

RESUMO

Consequences of the obesity epidemic on cancer morbidity and mortality are not fully appreciated. Obesity is a risk factor for many cancers, but the mechanisms by which it contributes to cancer development and patient outcome have yet to be fully elucidated. Here, we examined the effects of coculturing human-derived adipocytes with established and primary breast cancer cells on tumorigenic potential. We found that the interaction between adipocytes and cancer cells increased the secretion of proinflammatory cytokines. Prolonged culture of cancer cells with adipocytes or cytokines increased the proportion of mammosphere-forming cells and of cells expressing stem-like markers in vitro. Furthermore, contact with immature adipocytes increased the abundance of cancer cells with tumor-forming and metastatic potential in vivo. Mechanistic investigations demonstrated that cancer cells cultured with immature adipocytes or cytokines activated Src, thus promoting Sox2, c-Myc, and Nanog upregulation. Moreover, Sox2-dependent induction of miR-302b further stimulated cMYC and SOX2 expression and potentiated the cytokine-induced cancer stem cell-like properties. Finally, we found that Src inhibitors decreased cytokine production after coculture, indicating that Src is not only activated by adipocyte or cytokine exposures, but is also required to sustain cytokine induction. These data support a model in which cancer cell invasion into local fat would establish feed-forward loops to activate Src, maintain proinflammatory cytokine production, and increase tumor-initiating cell abundance and metastatic progression. Collectively, our findings reveal new insights underlying increased breast cancer mortality in obese individuals and provide a novel preclinical rationale to test the efficacy of Src inhibitors for breast cancer treatment.


Assuntos
Adipócitos/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Citocinas/metabolismo , Obesidade/complicações , RNA Mensageiro/metabolismo , Quinases da Família src/metabolismo , Adipócitos/citologia , Animais , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Humanos , Camundongos , RNA Mensageiro/genética , Fatores de Transcrição SOXB1 , Transdução de Sinais , Transfecção , Quinases da Família src/genética
10.
PLoS One ; 10(4): e0123642, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25849854

RESUMO

The transcription factor p63 is required for skeletal formation, and is important for the regulation of 1α,25(OH)2D3 receptor (VDR) in human mesenchymal stem cells (hMSC). Herein we report that TAp63γ and ΔNp63ß appear to be an integral part of the osteoblastic differentiation of hMSC and are differentially regulated by the vitamin D3 metabolites 1α,25(OH)2D3 and 24R,25(OH)2D3. We compared the endogenous expression of p63 isoforms (TA- and ΔNp63) and splice variants (p63α, -ß, -γ), in naive hMSC and during osteoblastic differentiation of hMSC. TAp63α and -ß were the predominant p63 variants in naive, proliferating hMSC. In contrast, under osteoblastic differentiation conditions, expression of p63 changed from the TAp63α and -ß to the TAp63γ and ΔNp63ß variants. Transient overexpression of the p63 variants demonstrated that TAp63ß, ΔNp63ß, and ΔNp63γ increased alkaline phosphatase activity and ΔNp63α and -γ increased the expression of mRNA for osteocalcin and osterix. Our results support the hypothesis that TAp63α and -ß promote a naive state in hMSC. Moreover, TAp63γ is increased during and promotes early osteoblastic differentiation through the expression of pro-osteogenic genes; VDR, Osterix, Runx2 and Osteopontin. ΔNp63ß also appears to support osteogenic maturation through increased alkaline phosphatase activity. Treatment with 1α,25(OH)2D3 increased the expression of mRNA for ΔNp63, while addition of 24R,25(OH)2D3 increased the expression of TA- and ΔNp63γ variants. These novel findings demonstrate for the first time that p63 variants are differentially expressed in naive hMSC (TAp63α,ß), are important during the osteoblastic differentiation of hMSC (TAp63γ and ΔNp63ß), and are differentially regulated by the vitamin D3 metabolites, 1α,25(OH)2D3 and 24R,25(OH)2D3. The molecular nuances and mechanisms of osteoblastic differentiation presented here will hopefully improve our understanding of bone development, complications in bone repair (mal- and non-union fractures), osteoporosis and possibly lead to new modalities of treatment.


Assuntos
24,25-Di-Hidroxivitamina D 3/farmacologia , Células-Tronco Mesenquimais/fisiologia , Osteoblastos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Vitaminas/farmacologia , Adolescente , Adulto , Processamento Alternativo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Criança , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Adulto Jovem
11.
Mol Endocrinol ; 28(5): 644-58, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24597546

RESUMO

Although 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] is considered the most biologically active vitamin D3 metabolite, the vitamin D3 prohormone, 25-hydroxyvitamin D3 [25(OH)D3], is metabolized into other forms, including 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3]. Herein we show that 24R,25(OH)2D3 is fundamental for osteoblastic differentiation of human mesenchymal stem cells (hMSCs). Our approach involved analyses of cell proliferation, alkaline phosphatase activity, and pro-osteogenic genes (collagen 1A1, osteocalcin, vitamin D receptor [VDR], vitamin D3-hydroxylating enzymes [cytochrome P450 hydroxylases: CYP2R1, CYP27A1, CYP27B1 and CYP24A1]) and assessment of Ca(2+) mineralization of extracellular matrix. 24R,25(OH)2D3 inhibited hMSC proliferation, decreased 1α-hydroxylase (CYP27B) expression, thereby reducing the ability of hMSCs to convert 25(OH)D3 to 1α,25(OH)2D3, and promoted osteoblastic differentiation through increased alkaline phosphatase activity and Ca(2+) mineralization. 24R,25(OH)2D3 decreased expression of the 1α,25(OH)2D3 receptor, VDR. 24R,25(OH)2D3 but not 1α,25(OH)2D3 induced Ca(2+) mineralization dependent on the absence of the glucocorticoid analog, dexamethasone. To elucidate the mechanism(s) for dexamethasone-independent 1α,25(OH)2D3 inhibition/24R,25(OH)2D3 induction of Ca(2+) mineralization, we demonstrated that 1α,25(OH)2D3 increased whereas 24R,25(OH)2D3 decreased reactive oxygen species (ROS) production. 25(OH)D3 also decreased ROS production, potentially by conversion to 24R,25(OH)2D3. Upon inhibition of the vitamin D3-metabolizing enzymes (cytochrome P450s), 25(OH)D3 increased ROS production, potentially due to its known (low) affinity for VDR. We hypothesize that vitamin D3 actions on osteoblastic differentiation involve a regulatory relationship between 24R,25(OH)2D3 and 1α,25(OH)2D3. These results implicate 24R,25(OH)2D3 as a key player during hMSC maturation and bone development and support the concept that 24R,25(OH)2D3 has a bioactive role in the vitamin D3 endocrine system.


Assuntos
24,25-Di-Hidroxivitamina D 3/fisiologia , Diferenciação Celular , Células-Tronco Mesenquimais/fisiologia , Osteoblastos/metabolismo , 24,25-Di-Hidroxivitamina D 3/farmacologia , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Calcificação Fisiológica , Calcitriol/farmacologia , Calcitriol/fisiologia , Proliferação de Células , Células Cultivadas , Criança , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Adulto Jovem
12.
Mol Endocrinol ; 28(5): 722-30, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24673557

RESUMO

Hepatocyte growth factor (HGF) is a paracrine factor involved in organogenesis, tissue repair, and wound healing. We report here that HGF promotes osteogenic differentiation through the transcription of key osteogenic markers, including osteocalcin, osterix, and osteoprotegerin in human mesenchymal stem cells and is a necessary component for the establishment of osteoblast mineralization. Blocking endogenous HGF using PHA665752, a c-Met inhibitor (the HGF receptor), or an HGF-neutralizing antibody attenuates mineralization, and PHA665752 markedly reduced alkaline phosphatase activity. Moreover, we report that HGF promotion of osteogenic differentiation involves the rapid phosphorylation of p38 and differential regulation of its isoforms, p38α and p38ß. Western blot analysis revealed a significantly increased level of p38α and p38ß protein, and reverse transcription quantitative PCR revealed that HGF increased the transcriptional level of both p38α and p38ß. Using small interfering RNA to reduce the transcription of p38α and p38ß, we saw differential roles for p38α and p38ß on the HGF-induced expression of key osteogenic markers. In summary, our data demonstrate the importance of p38 signaling in HGF regulation of osteogenic differentiation.


Assuntos
Diferenciação Celular , Fator de Crescimento de Hepatócito/fisiologia , Células-Tronco Mesenquimais/fisiologia , Proteína Quinase 11 Ativada por Mitógeno/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Antígenos de Diferenciação/metabolismo , Células Cultivadas , Criança , Pré-Escolar , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Osteogênese , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-met/metabolismo
13.
Aging (Albany NY) ; 6(12): 1049-63, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25567453

RESUMO

Vascular disease is one of the leading causes of death worldwide. Vascular repair, essential for tissue maintenance, is critically reduced during vascular disease and aging. Efficient vascular repair requires functional adult stem cells unimpaired by aging or mutation. One protein candidate for reducing stem cell?mediated vascular repair is progerin, an alternative splice variant of lamin A. Progerin results from erroneous activation of cryptic splice sites within the LMNA gene, and significantly increases during aging. Mutations triggering progerin overexpression cause the premature aging disorder Hutchinson-Gilford Progeria Syndrome (HGPS), in which patients die at approximately 13-years of age due to atherosclerosis-induced disease. Progerin expression affects tissues rich in cells that can be derived from marrow stromal cells (MSCs. Studies using various MSC subpopulations and models have led to discrepant results. Using a well-defined, immature subpopulation of MSCs, Marrow Isolated Adult Multilineage Inducible (MIAMI) cells, we find progerin significantly disrupts expression and localization of self-renewal markers, proliferation, migration, and membrane elasticity. One potential treatment, farnesyltransferase inhibitor, ameliorates some of these effects. Our results confirm proposed progerin-induced mechanisms and suggest novel ways in which progerin disturbs critical stem cell functions collectively required for proper tissue repair, offering promising treatment targets for future therapies.


Assuntos
Células-Tronco Adultas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Proteínas Nucleares/metabolismo , Precursores de Proteínas/metabolismo , Regeneração , Adolescente , Adulto , Células-Tronco Adultas/efeitos dos fármacos , Células-Tronco Adultas/enzimologia , Células-Tronco Adultas/patologia , Idoso , Membrana Celular/metabolismo , Membrana Celular/patologia , Movimento Celular , Proliferação de Células , Criança , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Farnesiltranstransferase/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Humanos , Lamina Tipo A , Masculino , Fluidez de Membrana , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/enzimologia , Células-Tronco Mesenquimais/patologia , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Precursores de Proteínas/genética , RNA Mensageiro/metabolismo , Regeneração/efeitos dos fármacos , Transdução de Sinais , Fatores de Tempo , Transfecção , Adulto Jovem
14.
Bone ; 51(1): 69-77, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22521434

RESUMO

Bone formation and remodeling require generation of osteoprogenitors from bone marrow stem cells (MSC), which are regulated by growth factors and hormones, with putative roles in mesenchymal cell differentiation. Hepatocyte growth factor (HGF) is a pleiotropic growth factor, and together with its high affinity receptor cMet are widely expressed in normal tissues. 1,25-dihydroxyvitamin D (1,25OHD) is the most active metabolite of vitamin D; produced mainly in the kidney, but also by osteoblasts. We previously reported that HGF and 1,25OHD act together to increase osteogenic differentiation of human MSC (hMSC) potentially through increasing p53. Although p53 does not induce the vitamin D receptor (VDR), p63, a member of the p53 family of transcription factors has been reported to up-regulate VDR expression in some tumor cell lines, and thus might play a part in HGF-regulated VDR expression. Our hypothesis is that the combination of HGF and 1,25OHD can induce hMSC differentiation by up-regulation of 1,25OHD and/or VDR expression to increase cell response(s) to 1,25OHD. Using real-time RT-qPCR, Western blots, luciferase reporter assays, and siRNAs, as well as antibodies to specific signaling molecules we showed that HGF induced VDR gene expression, as well as up-regulated p63 gene expression. p63 gene knockdown by siRNA eliminated the effects of HGF on VDR gene expression as measured by RT-qPCR, Western blots and luciferase reporter assay, and downstream on osteogenic differentiation markers, including alkaline phosphatase staining. Differentiation is a coordinated process of cell cycle exit and tissue-specific gene expression. These results suggest HGF might be a good candidate to coordinate the regulation of these two processes during hMSC osteogenic differentiation. p63 could be a key connecting molecule on the pathway of HGF-induced VDR expression. Understanding the role of these factors and their actions could have important clinical implications for the use of hMSC in the development of novel stem cell therapies.


Assuntos
Células da Medula Óssea/citologia , Fator de Crescimento de Hepatócito/farmacologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Vitamina D/análogos & derivados , Fosfatase Alcalina/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Imunoprecipitação da Cromatina , Humanos , Regiões Promotoras Genéticas/genética , Receptores de Calcitriol/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Vitamina D/farmacologia
15.
Bone ; 49(6): 1194-204, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21907315

RESUMO

Human bone marrow-derived stem cells (hMSCs) are a major source of osteoprogenitors. Hepatocyte growth factor (HGF), a glycoprotein constitutively produced by hMSCs, is reported to act on differentiated osteoblasts and also osteoclasts. Moreover, HGF has been shown by us and others to enhance osteoblastic differentiation from hMSCs. Typically, the pro-differentiation effects of HGF have required cooperative action with regulatory factors such as vitamin D or bone matrix material. Here, we have pursued the molecular mechanisms underlying the osteogenic effect of HGF on hMSCs, the principal precursors to bone forming cells. HGF treatment of hMSCs reduced the cell number over time and increased G1/S cell-cycle arrest compared to control (non-treated) cells. RT-qPCR showed treatment with HGF increased gene expression of the cell-cycle inhibitors p53, p21, and p27, possibly explaining the cell growth inhibition and G1 arrest, a step critical to phenotypic differentiation. Transfection of siRNA specific for cMet, the HGF receptor, eliminated the HGF anti-proliferation effect on hMSCs and the HGF-mediated increase in p53, p21, and p27, strongly supporting a role for these cell-cycle inhibitors in HGF's regulation of hMSCs. HGF in combination with a known inducer of osteogenic differentiation, 1,25-dihydroxyvitamin D, significantly increased cell maturation/differentiation as indicated by an increase in several osteoblast markers. Taken together these results demonstrate that HGF significantly enhances hMSC osteoblast differentiation by 1,25-dihydroxyvitamin D.


Assuntos
Células da Medula Óssea/citologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Fator de Crescimento de Hepatócito/farmacologia , Células-Tronco/citologia , Células-Tronco/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Adolescente , Adulto , Idoso , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteogênese/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteína do Retinoblastoma/metabolismo , Células-Tronco/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Vitamina D/análogos & derivados , Vitamina D/farmacologia , Adulto Jovem
16.
J Neurochem ; 119(5): 972-88, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21496021

RESUMO

Cell-based therapies for global cerebral ischemia represent promising approaches for neuronal damage prevention and tissue repair promotion. We examined the potential of marrow-isolated adult multilineage-inducible (MIAMI) cells, a homogeneous subpopulation of immature human mesenchymal stromal cell, injected into the hippocampus to prevent neuronal damage induced by global ischemia using rat organotypic hippocampal slices exposed to oxygen-glucose deprivation and rats subjected to asphyxial cardiac arrest. We next examined the value of combining fibronectin-coated biomimetic microcarriers (FN-BMMs) with epidermal growth factor (EGF)/basic fibroblast growth factor (bFGF) pre-treated MIAMI compared to EGF/bFGF pre-treated MIAMI cells alone, for their in vitro and in vivo neuroprotective capacity. Naïve and EGF/bFGF pre-treated MIAMI cells significantly protected the Cornu Ammonis layer 1 (CA1) against ischemic death in hippocampal slices and increased CA1 survival in rats. MIAMI cells therapeutic value was significantly increased when delivering the cells complexed with FN-BMMs, probably by increasing stem cell survival and paracrine secretion of pro-survival and/or anti-inflammatory molecules as concluded from survival, differentiation and gene expression analysis. Four days after oxygen and glucose deprivation and asphyxial cardiac arrest, few transplanted cells administered alone survived in the brain whereas stem cell survival improved when injected complexed with FN-BMMs. Interestingly, a large fraction of the transplanted cells administered alone or in complexes expressed ßIII-tubulin suggesting that partial neuronal transdifferentiation may be a contributing factor to the neuroprotective mechanism of MIAMI cells.


Assuntos
Materiais Biomiméticos/farmacologia , Isquemia Encefálica/patologia , Isquemia Encefálica/terapia , Diferenciação Celular/fisiologia , Hipocampo/citologia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Multipotentes/citologia , Animais , Células da Medula Óssea/citologia , Células Cultivadas , Humanos , Ácido Láctico/farmacologia , Masculino , Células-Tronco Mesenquimais/citologia , Neurônios/patologia , Técnicas de Cultura de Órgãos , Ácido Poliglicólico/farmacologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos , Transplante Heterólogo/métodos , Adulto Jovem
17.
J Alzheimers Dis ; 19(1): 97-109, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20061629

RESUMO

The clinical hallmark of Alzheimer's disease (AD) is impairment of cognition associated with loss of synapses, accumulation of amyloid-beta (Abeta) both within neurons and as extracellular deposits, and neurofibrillary degeneration composed of phospho-tau. Neurons in the hippocampus are among those that are most vulnerable. The purpose of this study was to investigate the expression of genes associated with cognition, synapse, and mitochondrial function in hippocampal neurons of AD compared to normal individuals. Neurons from the hippocampus with intraneuronal Abeta immunoreactivity were captured with laser microdissection; RNA was extracted; and levels of brain-derived neurotrophic factor (BDNF), TrkB (BDNF receptor), dynamin-1 (DYN), and cytochrome C oxidase subunit II (COX2) were assessed with quantitative real-time polymerase chain reaction. We found no significant differences in the expression of these genes in AD between neurons associated with Abeta compared to those lacking Abeta immunoreactivity. Double immunofluorescence microscopy showed the number of hippocampal neurons coexpressing Abeta or phospho-tau and either BDNF, TrkB, or DYN was similar in AD and controls. Our results suggest that neither intraneuronal Abeta nor phospho-tau has obligatory effects on reducing the expression of genes important for memory and cognition in hippocampus of AD.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/genética , Regulação da Expressão Gênica , Líquido Intracelular/metabolismo , Neurônios/metabolismo , Proteínas tau/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/biossíntese , Cognição/fisiologia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Estudos Longitudinais , Proteínas Mitocondriais/genética , Neurônios/patologia , Estudos Prospectivos , Sinapses/genética , Proteínas tau/biossíntese
19.
J Water Health ; 5(4): 585-97, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17878569

RESUMO

Water safety plans (WSPs) are promoted by the WHO as the most effective means of securing drinking water safety. To date most experience with WSPs has been within utility supplies, primarily in developed countries. There has been little documented experience of applying WSPs to small community-managed systems, particularly in developing countries. This paper presents a case study from Bangladesh describing how WSPs can be developed and implemented for small systems. Model WSPs were developed through consultation with key water sector practitioners in the country. Simplified tools were developed to translate the formal WSPs into a format that was meaningful and accessible for communities to use. A series of pilot projects were implemented by Non-Governmental Organisations (NGOs) across the country covering all major water supplies. The results show that WSPs can be developed and implemented for small community managed water supplies and improve the sanitary condition and water quality of water sources. Hygiene behaviour improved and household water quality showed a significant reduction in contamination. Chlorination was found to be important for some technologies, thus increasing the costs of water supply and raising important problems with respect to transfer to the communities. Simple tools for community monitoring were found to be effective in supporting better water safety management.


Assuntos
Educação em Saúde/organização & administração , Higiene , Engenharia Sanitária/métodos , Abastecimento de Água , Bangladesh , Países em Desenvolvimento , Humanos , Avaliação de Programas e Projetos de Saúde , Medição de Risco
20.
Int J Environ Health Res ; 17(3): 207-18, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17479384

RESUMO

Arsenic contamination of shallow groundwater in Bangladesh is a major public health problem; the main response to date has been installing alternative water supplies. A survey of the functional status of a statistically representative sample of water supplies was undertaken in 2005 to assess whether these provide a sustainable water supply to arsenic-affected communities. A questionnaire was administered in communities containing a total 1060 water supplies. Eight percent of water supplies could not be located and only 64% of those located were working at the time of the survey. When weighted for the numbers of different technologies across the country, the results indicate 76% of alternative water supplies would be working. Water supplies working at the time of the survey often broke down. Community contributions were found to be important in determining whether a water supply would be functional. Recommendations are made for revisions of the current mitigation strategy.


Assuntos
Arsênico/química , Poluentes Químicos da Água/química , Purificação da Água , Abastecimento de Água , Bangladesh/epidemiologia , Participação da Comunidade , Monitoramento Ambiental , Monitoramento Epidemiológico , Humanos , Avaliação de Programas e Projetos de Saúde , Inquéritos e Questionários
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA