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K2P2.1 (TREK1), a two-pore domain potassium channel, has emerged as regulator of leukocyte transmigration into the central nervous system. In the context of skeletal muscle, immune cell infiltration constitutes the pathogenic hallmark of idiopathic inflammatory myopathies (IIMs). However, the underlying mechanisms remain to be elucidated. In this study, we investigated the role of K2P2.1 in the autoimmune response of IIMs. We detected K2P2.1 expression in primary skeletal muscle and endothelial cells of murine and human origin. We observed an increased pro-inflammatory cell response, adhesion and transmigration by pharmacological blockade or genetic deletion of K2P2.1 in vitro and in in vivo myositis mouse models. Of note, our findings were not restricted to endothelial cells as skeletal muscle cells with impaired K2P2.1 function also demonstrated a strong pro-inflammatory response. Conversely, these features were abrogated by activation of K2P2.1 and improved the disease course of a myositis mouse model. In humans, K2P2.1 expression was diminished in IIM patients compared to non-diseased controls arguing for the translatability of our findings. In summary, K2P2.1 may regulate the inflammatory response of skeletal muscle. Further research is required to understand whether K2P2.1 could serve as novel therapeutic target.
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Células Endoteliais , Miosite , Humanos , Animais , Camundongos , Células Endoteliais/patologia , Miosite/genética , Músculo Esquelético/patologia , Leucócitos/patologiaRESUMO
Chimeric antigen receptor (CAR) T cells are a cancer immunotherapy of extremes. Unprecedentedly effective, but complex and costly to manufacture, they are not yet a therapeutic option for all who would benefit. This disparity has motivated worldwide efforts to simplify treatment. Among the proposed solutions, the generation of CAR T cells directly in the patient, i.e., in vivo, is arguably simultaneously the most technically challenging and clinically useful approach to convert CAR therapy from a cell-based autologous medicinal product into a universally applicable off-the-shelf treatment. Here, we review the current state of the art of in vivo CAR therapy, focusing especially on the vector technologies used. These cover lentiviral vectors and adenovirus-associated vectors as well as synthetic polymer nanocarriers and lipid nanoparticles. Proof of concept, i.e., the generation of CAR cells directly in mouse models, has been demonstrated for all vector platforms. Receptor targeting of vector particles is crucial, as it can prevent CAR gene delivery into off-target cells, thus reducing toxicities. We discuss the properties of the vector platforms, such as their immunogenicity, potency, and modes of CAR delivery (permanent versus transient). Finally, we outline the work required to advance in vivo CAR therapy from proof of concept to a robust, scalable technology for clinical testing.
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Imunoterapia Adotiva , Medicina de Precisão , Receptores de Antígenos Quiméricos , Animais , Lipossomos , Camundongos , Nanopartículas , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Linfócitos TRESUMO
During the COVID-19 pandemic, many patients could not receive timely healthcare services due to limited availability and access to healthcare resources and services. Previous studies found that access to intensive care unit (ICU) beds saves lives, but they overlooked the temporal dynamics in the availability of healthcare resources and COVID-19 cases. To fill this gap, our study investigated daily changes in ICU bed accessibility with an enhanced two-step floating catchment area (E2SFCA) method in the state of Texas. Along with the increased temporal granularity of measurements, we uncovered two phenomena: 1) aggravated spatial inequality of access during the pandemic, and 2) the retrospective relationship between insufficient ICU bed accessibility and the high case-fatality ratio of COVID-19 in rural areas. Our findings suggest that those locations should be supplemented with additional healthcare resources to save lives in future pandemic scenarios.
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BACKGROUND: α-Lipoic acid (LA) is a dietary supplement for maintaining energy balance, but well-controlled clinical trials in otherwise healthy, overweight adults using LA supplementation are lacking. OBJECTIVES: The primary objective was to evaluate whether LA supplementation decreases elevated plasma triglycerides in overweight or obese adults. Secondary aims examined if LA promotes weight loss and improves oxidative stress and inflammation. METHODS: Overweight adults [n = 81; 57% women; 21-60 y old; BMI (in kg/m2) ≥ 25] with elevated plasma triglycerides ≥100 mg/dL were enrolled in a 24-wk, randomized, double-blind, controlled trial, assigned to either (R)-α-lipoic acid (R-LA; 600 mg/d) or matching placebo, and advised not to change their diet or physical activity. Linear models were used to evaluate treatment effects from baseline for primary and secondary endpoints. RESULTS: R-LA did not decrease triglyceride concentrations, but individuals on R-LA had a greater reduction in BMI at 24 wk than the placebo group (-0.8; P = 0.04). The effect of R-LA on BMI was correlated to changes in plasma triglycerides (r = +0.50, P = 0.004). Improvement in body weight was greater at 24 wk in R-LA subgroups than in placebo subgroups. Women and obese participants (BMI ≥ 35) showed greater weight loss (-5.0% and -4.8%, respectively; both P < 0.001) and loss of body fat (-9.4% and -8.6%, respectively; both P < 0.005). Antioxidant gene expression in mononuclear cells at 24 wk was greater in the R-LA group (Heme oxygenase 1 [HMOX1] : +22%; P = 0.02) than in placebo. Less urinary F2-isoprostanes (-25%; P = 0.005), blood leukocytes (-10.1%; P = 0.01), blood thrombocytes (-5.1%; P = 0.03), and ICAM-1 (-7.4%; P = 0.04) at 24 wk were also observed in the R-LA group than in placebo. CONCLUSIONS: Long-term LA supplementation results in BMI loss, greater antioxidant enzyme synthesis, and less potential for inflammation in overweight adults. Improved cellular bioenergetics is also evident in some individuals given R-LA.This trial was registered at clinicaltrials.gov as NCT00765310.
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Suplementos Nutricionais , Sobrepeso/tratamento farmacológico , Ácido Tióctico/administração & dosagem , Triglicerídeos/sangue , Adulto , Esquema de Medicação , Exercício Físico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Redução de Peso , Adulto JovemRESUMO
BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19) pandemic, has infected millions of people and caused hundreds of thousands of deaths. While COVID-19 has overwhelmed healthcare resources (e.g., healthcare personnel, testing resources, hospital beds, and ventilators) in a number of countries, limited research has been conducted to understand spatial accessibility of such resources. This study fills this gap by rapidly measuring the spatial accessibility of COVID-19 healthcare resources with a particular focus on Illinois, USA. METHOD: The rapid measurement is achieved by resolving computational intensity of an enhanced two-step floating catchment area (E2SFCA) method through a parallel computing strategy based on cyberGIS (cyber geographic information science and systems). The E2SFCA has two major steps. First, it calculates a bed-to-population ratio for each hospital location. Second, it sums these ratios for residential locations where hospital locations overlap. RESULTS: The comparison of the spatial accessibility measures for COVID-19 patients to those of population at risk identifies which geographic areas need additional healthcare resources to improve access. The results also help delineate the areas that may face a COVID-19-induced shortage of healthcare resources. The Chicagoland, particularly the southern Chicago, shows an additional need for resources. This study also identified vulnerable population residing in the areas with low spatial accessibility in Chicago. CONCLUSION: Rapidly measuring spatial accessibility of healthcare resources provides an improved understanding of how well the healthcare infrastructure is equipped to save people's lives during the COVID-19 pandemic. The findings are relevant for policymakers and public health practitioners to allocate existing healthcare resources or distribute new resources for maximum access to health services.
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Área Programática de Saúde/estatística & dados numéricos , Infecções por Coronavirus/epidemiologia , Recursos em Saúde/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Betacoronavirus , COVID-19 , Acessibilidade aos Serviços de Saúde/organização & administração , Número de Leitos em Hospital/estatística & dados numéricos , Humanos , Illinois , Unidades de Terapia Intensiva/estatística & dados numéricos , Pandemias , SARS-CoV-2 , Fatores Socioeconômicos , Análise Espacial , Ventiladores Mecânicos/provisão & distribuiçãoRESUMO
In 2018, two novel cancer therapies based on chimeric antigen receptors (CARs) were granted marketing authorization in the European Union. Authorized for use against advanced lymphoma and/or leukemia, the products were at the center of international attention, not only due to their novel mode of action and their encouraging efficacy but also because of their sometimes severe side effects and the economic and logistic challenges posed by their manufacture. Now, almost two years later, hundreds of active clinical trials emphasize the global drive to harness the full potential of CAR technology.In this article, we describe the mode of action of CAR T and CAR NK cells and review the clinical testing situation as well as early real-world data. In recent years, preclinical studies using advanced animal models have provided first insights into the mechanisms underlying the severe side effects of CAR T therapy. We summarize their results and describe the available models. Additionally, we discuss potential solutions to the hurdles currently limiting CAR technology. So far used as last-line treatment for patients with aggressive disease, CAR technology has the potential to become a new, broadly effective standard for tumor therapy.
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Receptores de Antígenos Quiméricos , Animais , Alemanha , Humanos , Imunoterapia Adotiva , Oncologia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos TRESUMO
Background: Inadequate vitamin E and magnesium intakes are of concern for older adults owing to the associated incidence of age-related diseases. Objective: This study was designed to determine the extent to which a 16-wk intervention with hazelnuts alters vitamin E and magnesium status in a group of older men and women, and used a pre-post intervention design without a control group to adjust for temporal changes. Methods: Participants (n = 32 including 22 women; mean ± SD age: 63 ± 6 y) consumed hazelnuts (â¼57 g/d) for 16 wk. Blood and urine samples and anthropomorphic measures were taken at the start and end of the intervention to determine plasma concentrations of α-tocopherol and serum concentrations of magnesium, lipids, glucose, insulin, and high-sensitivity C-reactive protein along with urinary vitamin E metabolites; several other micronutrients were measured by a lymphocyte proliferation assay. There were 3 primary endpoints, calculated as the mean changes in measurements between baseline and the end of the 16-wk intervention for 1) plasma α-tocopherol, 2) urinary α-carboxyethyl hydroxychromanol (α-CEHC; an α-tocopherol metabolite), and 3) serum magnesium. Results: Hazelnut consumption increased concentrations of the urinary α-tocopherol metabolite α-CEHC (mean ± SD: 0.84 ± 0.45 to 1.14 ± 0.50 µmol/g creatinine; P = 0.0006). In addition, hazelnut consumption increased serum concentrations of magnesium (+2.1%, P = 0.05), decreased concentrations of fasting glucose (-3.4%, P = 0.03) and LDL cholesterol (-6.0%, P = 0.02), and decreased total:HDL cholesterol ratios (-4.5%, P = 0.009). No significant changes were observed in blood pressure, lymphocyte proliferation assays, and serum concentrations of insulin, high-sensitivity C-reactive protein, triglyceride, α-tocopherol, or HDL cholesterol. Conclusions: Consuming hazelnuts improves a biomarker of vitamin E status in older adults. Vitamin E is a shortfall micronutrient, as identified by the Dietary Guidelines for Americans 2015-2020, which frequently is consumed at levels less than the Estimated Average Requirement of 12 mg/d; thus, hazelnuts should be considered as part of a healthy dietary pattern. This trial was registered at clinicaltrials.gov as NCT03485989.
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Corylus , alfa-Tocoferol/sangue , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/análise , Feminino , Humanos , Lipídeos/sangue , Ativação Linfocitária , Magnésio/sangue , Masculino , Pessoa de Meia-Idade , alfa-Tocoferol/urinaRESUMO
New evidence for the regulation of vitamin C homeostasis has emerged from several studies of human genetic variation. Polymorphisms in the genes encoding sodium-dependent vitamin C transport proteins are strongly associated with plasma ascorbate levels and likely impact tissue cellular vitamin C status. Furthermore, genetic variants of proteins that suppress oxidative stress or detoxify oxidatively damaged biomolecules, i.e., haptoglobin, glutathione-S-transferases, and possibly manganese superoxide dismutase, affect ascorbate levels in the human body. There also is limited evidence for a role of glucose transport proteins. In this review, we examine the extent of the variation in these genes, their impact on vitamin C status, and their potential role in altering chronic disease risk. We conclude that future epidemiological studies should take into account genetic variation in order to successfully determine the role of vitamin C nutriture or supplementation in human vitamin C status and chronic disease risk.
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Ácido Ascórbico/metabolismo , Variação Genética , Homeostase , Oxirredutases/metabolismo , Transportadores de Sódio Acoplados à Vitamina C/genética , Animais , Transporte Biológico , Humanos , Transportadores de Sódio Acoplados à Vitamina C/metabolismoRESUMO
The genesis of subacute cutaneous lupus erythematosus (SCLE) is multifactorial and includes idiopathic, drug-related and paraneoplastic etiologies. This article reports the case of a 70-year-old female patient with paraneoplastic SCLE in whom a lung adenocarcinoma was detected during the extended examination. A paraneoplastic SCLE should be considered when a patient with SCLE presents with lesions in regions of the skin not exposed to sunlight and beginning B symptoms.
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Neoplasias Pulmonares , Lúpus Eritematoso Cutâneo , Síndromes Paraneoplásicas , Humanos , Feminino , Lúpus Eritematoso Cutâneo/patologia , Lúpus Eritematoso Cutâneo/diagnóstico , Idoso , Síndromes Paraneoplásicas/patologia , Síndromes Paraneoplásicas/diagnóstico , Síndromes Paraneoplásicas/etiologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/diagnóstico , Adenocarcinoma/patologia , Adenocarcinoma/complicações , Adenocarcinoma/diagnóstico , Adenocarcinoma/radioterapia , Diagnóstico DiferencialRESUMO
Little is known about either the basal or stimulated homeostatic mechanisms regulating nuclear tenure of Nf-e2-related factor 2 (Nrf2), a transcription factor that mediates expression of over 200 detoxification genes. Our data show that stress-induced nuclear Nrf2 accumulation is largely from de novo protein synthesis, rather than translocation from a pre-existing cytoplasmic pool. HepG2 cells were used to monitor nuclear Nrf2 24h following treatment with the dithiol micronutrient (R)-α-lipoic acid (LA; 50µM), or vehicle. LA caused a ≥2.5-fold increase in nuclear Nrf2 within 1h. However, pretreating cells with cycloheximide (50µg/ml) inhibited LA-induced Nrf2 nuclear accumulation by 94%. Providing cells with the mTOR inhibitor, rapamycin, decreased basal Nrf2 levels by 84% after 4h, but LA overcame this inhibition. LA-mediated de novo protein translation was confirmed using HepG2 cells transfected with a bicistronic construct containing an internal ribosome entry sequence (IRES) for Nrf2, with significant (P<0.05) increase in IRES use under LA treatment. These results suggest that a dithiol stimulus mediates Nrf2 nuclear tenure via cap-independent protein translation. Thus, translational control of Nrf2 synthesis, rather than reliance solely on pre-existing protein, may mediate the rapid burst of Nrf2 nuclear accumulation following stress stimuli.
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Inativação Metabólica , Fator 2 Relacionado a NF-E2/biossíntese , Biossíntese de Proteínas/efeitos dos fármacos , Capuzes de RNA/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Ácido Tióctico/farmacologia , Sequência de Bases , Compartimento Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Células Hep G2 , Humanos , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma , Capuzes de RNA/efeitos dos fármacos , Sirolimo/farmacologiaRESUMO
Despite the reported prevalence of micronutrient deficiencies in older adults, it is not yet established whether multivitamin/multimineral (MV/MM) supplements improve blood micronutrient status in individuals over the age of 65. Therefore, a cohort of 35 healthy men (>67 years) was recruited for an MV/MM supplementation trial. The primary endpoint was, as an indicator of micronutrient status, changes in blood micronutrient biomarkers from baseline to at least six months of supplementation with MV/MM or placebo. The secondary endpoint was basal O2 consumption in monocytes as an indicator of cellular metabolism. MV/MM supplementation improved blood concentrations of pyridoxal phosphate, calcifediol, α-tocopherol, and ß-carotene concentrations throughout the cohort. By contrast, those in the placebo group generally showed declines in blood vitamin concentrations and an increased prevalence of suboptimal vitamin status during the study period. On the other hand, MV/MM supplementation did not significantly affect blood mineral concentrations, i.e., calcium, copper, iron, magnesium, and zinc. Interestingly, MV/MM supplementation prevented the decline in monocyte O2 consumption rate. Overall, MV/MM use improves or prevents declines in vitamin, but not mineral, status and limits declines in cellular O2 consumption, which may have important implications for metabolism and immune health in healthy older men.
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Oligoelementos , Vitaminas , Masculino , Humanos , Idoso , Suplementos Nutricionais , Minerais , Micronutrientes , Biomarcadores , Metabolismo Energético , Método Duplo-CegoRESUMO
Achieving optimal health is an aspirational goal for the population, yet the definition of health remains unclear. The role of nutrition in health has evolved beyond correcting malnutrition and specific deficiencies and has begun to focus more on achieving and maintaining 'optimal' health through nutrition. As such, the Council for Responsible Nutrition held its October 2022 Science in Session conference to advance this concept. Here, we summarize and discuss the findings of their Optimizing Health through Nutrition - Opportunities and Challenges workshop, including several gaps that need to be addressed to advance progress in the field. Defining and evaluating various indices of optimal health will require overcoming these key gaps. For example, there is a strong need to develop better biomarkers of nutrient status, including more accurate markers of food intake, as well as biomarkers of optimal health that account for maintaining resilience-the ability to recover from or respond to stressors without loss to physical and cognitive performance. In addition, there is a need to identify factors that drive individualized responses to nutrition, including genotype, metabotypes, and the gut microbiome, and to realize the opportunity of precision nutrition for optimal health. This review outlines hallmarks of resilience, provides current examples of nutritional factors to optimize cognitive and performance resilience, and gives an overview of various genetic, metabolic, and microbiome determinants of individualized responses.
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Microbioma Gastrointestinal , Ciências da Nutrição , Humanos , Estado Nutricional , BiomarcadoresRESUMO
Accomplishing the goals outlined in "Ending the HIV (Human Immunodeficiency Virus) Epidemic: A Plan for America Initiative" will require properly estimating and increasing access to HIV testing, treatment, and prevention services. In this research, a computational spatial method for estimating access was applied to measure distance to services from all points of a city or state while considering the size of the population in need for services as well as both driving and public transportation. Specifically, this study employed the enhanced two-step floating catchment area (E2SFCA) method to measure spatial accessibility to HIV testing, treatment (i.e., Ryan White HIV/AIDS program), and prevention (i.e., Pre-Exposure Prophylaxis [PrEP]) services. The method considered the spatial location of MSM (Men Who have Sex with Men), PLWH (People Living with HIV), and the general adult population 15-64 depending on what HIV services the U.S. Centers for Disease Control (CDC) recommends for each group. The study delineated service- and population-specific accessibility maps, demonstrating the method's utility by analyzing data corresponding to the city of Chicago and the state of Illinois. Findings indicated health disparities in the south and the northwest of Chicago and particular areas in Illinois, as well as unique health disparities for public transportation compared to driving. The methodology details and computer code are shared for use in research and public policy.
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Infecções por HIV , Profilaxia Pré-Exposição , Minorias Sexuais e de Gênero , Adulto , Chicago/epidemiologia , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Teste de HIV , Acessibilidade aos Serviços de Saúde , Homossexualidade Masculina , Humanos , Illinois , Masculino , Estados Unidos/epidemiologiaRESUMO
Inflammation results in heightened mitochondrial ceramide levels, which cause electron transport chain dysfunction, elevates reactive oxygen species, and increases apoptosis. As mitochondria in aged hearts also display many of these characteristics, we hypothesized that mitochondrial decay stems partly from an age-related ceramidosis that heretofore has not been recognized for the heart. Intact mitochondria or their purified inner membranes (IMM) were isolated from young (4-6 mo) and old (26-28 mo) rats and analyzed for ceramides by LC-MS/MS. Results showed that ceramide levels increased by 32% with age and three ceramide isoforms, found primarily in the IMM (e.g. C(16)-, C(18)-, and C(24:1)-ceramide), caused this increase. The ceramidosis may stem from enhanced hydrolysis of sphingomyelin, as neutral sphingomyelinase (nSMase) activity doubled with age but with no attendant change in ceramidase activity. Because (R)-α-lipoic acid (LA) improves many parameters of cardiac mitochondrial decay in aging and lowers ceramide levels in vascular endothelial cells, we hypothesized that LA may limit cardiac ceramidosis and thereby improve mitochondrial function. Feeding LA [0.2%, w/w] to old rats for two weeks prior to mitochondrial isolation reversed the age-associated decline in glutathione levels and concomitantly improved Complex IV activity. This improvement was associated with lower nSMase activity and a remediation in mitochondrial ceramide levels. In summary, LA treatment lowers ceramide levels to that seen in young rat heart mitochondria and restores Complex IV activity which otherwise declines with age.
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Envelhecimento/metabolismo , Ceramidas/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Ácido Tióctico/farmacologia , Administração Oral , Fatores Etários , Animais , Senescência Celular , Ceramidases/metabolismo , Cromatografia Líquida de Alta Pressão , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Glutationa/metabolismo , Hidrólise , Masculino , Mitocôndrias Cardíacas/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Ratos , Ratos Endogâmicos F344 , Esfingomielina Fosfodiesterase/metabolismo , Esfingomielinas/metabolismo , Espectrometria de Massas em Tandem , Ácido Tióctico/administração & dosagemRESUMO
Preclinical studies on gene delivery into mouse lymphocytes are often hampered by insufficient activity of lentiviral (LV) and adeno-associated vectors (AAVs) as well as missing tools for cell type selectivity when considering in vivo gene therapy. Here, we selected designed ankyrin repeat proteins (DARPins) binding to murine CD8. The top-performing DARPin was displayed as targeting ligand on both vector systems. When used on engineered measles virus (MV) glycoproteins, the resulting mCD8-LV transduced CD8+ mouse lymphocytes with near-absolute (>99%) selectivity. Despite its lower functional titer, mCD8-LV achieved 4-fold higher gene delivery to CD8+ cells than conventional VSV-LV when added to whole mouse blood. Addition of mCD8-LV encoding a chimeric antigen receptor (CAR) specific for mouse CD19 to splenocytes resulted in elimination of B lymphocytes and lymphoma cells. For display on AAV, the DARPin was inserted into the GH2-GH3 loop of the AAV2 capsid protein VP1, resulting in a DARPin-targeted AAV we termed DART-AAV. Stocks of mCD8-AAV contained similar genome copies as AAV2 but were >20-fold more active in gene delivery in mouse splenocytes, while exhibiting >99% specificity for CD8+ cells. These results suggest that receptor targeting can overcome blocks in transduction of mouse splenocytes.
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Cell entry of the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by its spike protein S. As a main antigenic determinant, S protein is in focus of various therapeutic strategies. Besides particle-cell fusion, S mediates fusion between infected and uninfected cells resulting in syncytia formation. Here, we present sensitive assay systems with a high dynamic range and high signal-to-noise ratios covering not only particle-cell and cell-cell fusion but also fusion from without (FFWO). In FFWO, S-containing viral particles induce syncytia independently of de novo synthesis of S. Neutralizing antibodies, as well as sera from convalescent patients, inhibited particle-cell fusion with high efficiency. Cell-cell fusion, in contrast, was only moderately inhibited despite requiring levels of S protein below the detection limit of flow cytometry and Western blot. The data indicate that syncytia formation as pathological consequence during coronavirus disease 2019 (COVID-19) can proceed at low levels of S protein and may not be effectively prevented by antibodies.
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Older adults are at increased risk for vitamin and mineral deficiencies that contribute to age-related immune system decline. Several lines of evidence suggest that taking a multi-vitamin and mineral supplement (MVM) could improve immune function in individuals 55 and older. To test this hypothesis, we provided healthy older adults with either an MVM supplement formulated to improve immune function (Redoxon® VI, Singapore) or an identical, inactive placebo control to take daily for 12 weeks. Prior to and after treatment, we measured (1) their blood mineral and vitamin status (i.e., vitamin C, zinc and vitamin D); (2) immune function (i.e., whole blood bacterial killing activity, neutrophil phagocytic activity, and reactive oxygen species production); (3) immune status (salivary IgA and plasma cytokine/chemokine levels); and (4) self-reported health status. MVM supplementation improved vitamin C and zinc status in blood and self-reported health-status without altering measures of immune function or status or vitamin D levels, suggesting that healthy older adults may benefit from MVM supplementation. Further development of functional assays and larger study populations should improve detection of specific changes in immune function after supplementation in healthy older adults. Clinical Trials Registration: ClinicalTrials.gov #NCT02876315.
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Envelhecimento/imunologia , Suplementos Nutricionais , Ingestão de Alimentos/imunologia , Fenômenos Fisiológicos da Nutrição do Idoso/imunologia , Minerais/administração & dosagem , Vitaminas/administração & dosagem , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Citocinas/sangue , Método Duplo-Cego , Ingestão de Alimentos/fisiologia , Fenômenos Fisiológicos da Nutrição do Idoso/fisiologia , Feminino , Humanos , Imunoglobulina A/metabolismo , Masculino , Minerais/sangue , Neutrófilos/imunologia , Fagocitose , Espécies Reativas de Oxigênio , Vitaminas/sangueRESUMO
Transport and distribution of vitamin C is primarily regulated by the function of sodium-dependent vitamin C transporters (SVCTs). SVCT1 is expressed in the small intestine, liver, and kidney, organs that play a vital role in whole body vitamin C homeostasis. Despite the importance of this protein, little is known about regulation of the gene encoding SVCT1, Slc23a1. In this study, we present the first investigation of the transcriptional regulation of human Slc23a1, identifying transcription factors that may influence its expression. A 1,239-bp genomic DNA fragment corresponding to the 5'-flanking region of Slc23a1 was isolated from a human hepatocarcinoma cell line (HepG2) and sequenced. When cloned into a reporter gene construct, robust transcriptional activity was seen in this sequence, nearly 25-fold above the control vector. Deletion analysis of the SVCT1 reporter gene vector defined the minimal active promoter as a small 135-bp region upstream of the transcriptional start site. While several transcription factor binding sites were identified within this sequence, reporter constructs showed that basal transcription required the binding of hepatic nuclear factor 1 (HNF-1) to its cognate sequence. Furthermore, mutation of this HNF-1 binding site resulted in complete loss of luciferase expression, even in the context of the whole promoter. Additionally, small interfering RNA knockdown of both members of the HNF-1 family, HNF-1alpha and HNF-1beta, resulted in a significant decline in SVCT1 transcription. Together, these data suggest that HNF-1alpha and/or HNF-1beta binding is required for SVCT1 expression and may be involved in the coordinate regulation of whole body vitamin C status.