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1.
Eur Heart J Case Rep ; 7(11): ytad525, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37942350

RESUMO

Background: Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory condition characterized by a classical triad of symptoms that include prolonged fever, polyarthritis, and a characteristic salmon-pink skin rash. It can affect a variety of organ systems resulting in many different clinical presentations and is usually a diagnosis of exclusion. Myocarditis complicated by cardiogenic shock is a rare and life-threatening manifestation of AOSD, typically affecting younger patients. There is a limited experience and evidence in how best to manage this challenging patient cohort. Case summary: A previously fit and well 22-year-old male presented with fever, arthralgia, and general malaise. On clinical examination, he was pyrexial and hypotensive, requiring vasopressor support for presumed septic shock. Subsequent transthoracic echocardiography and cardiac MRI findings were in keeping with fulminant myocarditis. Further septic and auto-immune screens were negative although he responded well to high-dose intravenous corticosteroids. Attempts to wean immunosuppression were unsuccessful, and his ferritin was markedly elevated (20 233 µg/L). A diagnosis of AOSD was suspected after exclusion of other possible causes. The successful addition of tocilizumab (an interleukin-6 receptor antagonist) therapy allowed for gradual de-escalation of steroid therapy and disease remission, with on-going remission at 18 months on maintenance therapy. Discussion: This case highlights the importance of considering AOSD as a rare cause for myocarditis, especially when fever is present, or disease is severe. Failure to improve with first-line therapy involving high-dose corticosteroids, or inability to wean that therapy, should prompt consideration for escalation of therapy, with tocilizumab seemingly an effective treatment option.

2.
Clin Exp Allergy ; 53(8): 833-845, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36916778

RESUMO

INTRODUCTION: Prenatal and early-life dog exposure has been linked to reduced childhood allergy and asthma. A potential mechanism includes altered early immune development in response to changes in the gut microbiome among dog-exposed infants. We thus sought to determine whether infants born into homes with indoor dog(s) exhibit altered gut microbiome development. METHODS: Pregnant women living in homes with dogs or in pet-free homes were recruited in southeast Michigan. Infant stool samples were collected at intervals between 1 week and 18 months after birth and microbiome was assessed using 16S ribosomal sequencing. Perinatal maternal vaginal/rectal swabs and stool samples were sequenced from a limited number of mothers. Mixed effect adjusted models were used to assess stool microbial community trajectories comparing infants from dog-keeping versus pet-free homes with adjustment for relevant covariates. RESULTS: Infant gut microbial composition among vaginally born babies became less similar to the maternal vaginal/rectal microbiota and more similar to the maternal gut microbiota with age-related accumulation of bacterial species with advancing age. Stool samples from dog-exposed infants were microbially more diverse (p = .041) through age 18 months with enhanced diversity most apparent between 3 and 6 months of age. Statistically significant effects of dog exposure on ß-diversity metrics were restricted to formula-fed children. Across the sample collection period, dog exposure was associated with Fusobacterium genera enrichment, as well as enrichment of Collinsella, Ruminococcus, Clostridaceae and Lachnospiraceae OTUs. CONCLUSION: Prenatal/early-life dog exposure is associated with an altered gut microbiome during infancy and supports a potential mechanism explaining lessened atopy and asthma risk. Further research directly linking specific dog-attributable changes in the infant gut microbiome to the risk of allergic disorders is needed.


Assuntos
Asma , Microbioma Gastrointestinal , Hipersensibilidade , Microbiota , Humanos , Cães , Feminino , Gravidez , Animais , Fezes/microbiologia , RNA Ribossômico 16S
3.
J Dev Orig Health Dis ; 14(2): 175-181, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36408681

RESUMO

High-quality evidence from prospective longitudinal studies in humans is essential to testing hypotheses related to the developmental origins of health and disease. In this paper, the authors draw upon their own experiences leading birth cohorts with longitudinal follow-up into adulthood to describe specific challenges and lessons learned. Challenges are substantial and grow over time. Long-term funding is essential for study operations and critical to retaining study staff, who develop relationships with participants and hold important institutional knowledge and technical skill sets. To maintain contact, we recommend that cohorts apply multiple strategies for tracking and obtain as much high-quality contact information as possible before the child's 18th birthday. To maximize engagement, we suggest that cohorts offer flexibility in visit timing, length, location, frequency, and type. Data collection may entail multiple modalities, even at a single collection timepoint, including measures that are self-reported, research-measured, and administrative with a mix of remote and in-person collection. Many topics highly relevant for adolescent and young adult health and well-being are considered to be private in nature, and their assessment requires sensitivity. To motivate ongoing participation, cohorts must work to understand participant barriers and motivators, share scientific findings, and provide appropriate compensation for participation. It is essential for cohorts to strive for broad representation including individuals from higher risk populations, not only among the participants but also the staff. Successful longitudinal follow-up of a study population ultimately requires flexibility, adaptability, appropriate incentives, and opportunities for feedback from participants.


Assuntos
Coorte de Nascimento , Adolescente , Criança , Adulto Jovem , Humanos , Estudos Prospectivos , Autorrelato
4.
Cell Rep Med ; 3(8): 100713, 2022 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-35932762

RESUMO

Maternal asthma status, prenatal exposures, and infant gut microbiota perturbation are associated with heightened risk of atopy and asthma risk in childhood, observations hypothetically linked by intergenerational microbial transmission. Using maternal vaginal (n = 184) and paired infant stool (n = 172) samples, we identify four compositionally and functionally distinct Lactobacillus-dominated vaginal microbiota clusters (VCs) that relate to prenatal maternal health and exposures and infant serum immunoglobulin E (IgE) status at 1 year. Variance in bacteria shared between mother and infant pairs relate to VCs, maternal allergy/asthma status, and infant IgE levels. Heritable bacterial gene pathways associated with infant IgE include fatty acid synthesis and histamine and tryptophan degradation. In vitro, vertically transmitted Lactobacillus jensenii strains induce immunosuppressive phenotypes on human antigen-presenting cells. Murine supplementation with L. jensenii reduces lung eosinophils, neutrophilic expansion, and the proportion of interleukin-4 (IL-4)+ CD4+ T cells. Thus, bacterial and atopy heritability are intimately linked, suggesting a microbial component of intergenerational disease transmission.


Assuntos
Asma , Microbioma Gastrointestinal , Hipersensibilidade Imediata , Animais , Asma/genética , Bactérias/genética , Feminino , Microbioma Gastrointestinal/genética , Humanos , Tolerância Imunológica/genética , Imunoglobulina E , Lactente , Camundongos , Gravidez
5.
Int J Obes (Lond) ; 44(10): 2023-2034, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32873910

RESUMO

BACKGROUND/OBJECTIVES: The association between mode of delivery and childhood obesity remains inconclusive. Because few studies have separated C-section types (planned or unplanned C-section), our objective was to assess how these subtypes relate to preadolescent obesity. SUBJECTS/METHODS: The study consisted of 570 maternal-child pairs drawn from the WHEALS birth cohort based in Detroit, Michigan. Children were followed-up at 10 years of age where a variety of anthropometric measurements were collected. Obesity was defined based on BMI percentile (≥95th percentile), as well as through Gaussian finite mixture modeling on the anthropometric measurements. Risk ratios (RRs) and 95% confidence intervals (CIs) for obesity comparing planned and unplanned C-sections to vaginal deliveries were computed, which utilized inverse probability weights to account for loss to follow-up and multiple imputation for covariate missingness. Mediation models were fit to examine the mediation role of breastfeeding. RESULTS: After adjusting for marital status, maternal race, prenatal tobacco smoke exposure, maternal age, maternal BMI, any hypertensive disorders during pregnancy, gestational diabetes, prenatal antibiotic use, child sex, parity, and birthweight z-score, children born via planned C-section had 1.77 times higher risk of obesity (≥95th percentile), relative to those delivered vaginally ((95% CI) = (1.16, 2.72); p = 0.009). No association was found comparing unplanned C-section to vaginal delivery (RR (95% CI) = 0.75 (0.45, 1.23); p = 0.25). The results were similar but slightly stronger when obesity was defined by anthropometric class (RR (95% CI) = 2.78 (1.47, 5.26); p = 0.002). Breastfeeding did not mediate the association between mode of delivery and obesity. CONCLUSIONS: These findings indicate that children delivered via planned C-section-but not unplanned C-section-have a higher risk of preadolescent obesity, suggesting that partial labor or membrane rupture (typically experienced during unplanned C-section delivery) may offer protection. Additional research is needed to understand the biological mechanisms behind this effect, including whether microbiological differences fully or partially account for the association.


Assuntos
Cesárea/efeitos adversos , Obesidade Infantil/etiologia , Índice de Massa Corporal , Aleitamento Materno , Cesárea/classificação , Criança , Parto Obstétrico/métodos , Feminino , Humanos , Masculino , Michigan
7.
BMC Pediatr ; 19(1): 390, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31660906

RESUMO

BACKGROUND: While the keeping of pets has been shown to protect against childhood allergic disease and obesity, less is known regarding potential associations of prenatal pet keeping and attention deficit hyperactivity disorder (ADHD). We sought to examine the associations between prenatal dog or cat keeping with caregiver-reported ADHD in preadolescents in the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) birth cohort (N = 1258). METHODS: At an interview with the caregiver at child age 10-12 years, caregivers reported if the WHEALS child had ever been diagnosed with ADHD. Similarly, during an interview with the mother prenatally, pet keeping (defined as dog or cat kept inside ≥1 h/day) was ascertained. Logistic regression models were fit to examine the association of prenatal pet keeping (dog keeping and cat keeping, separately) with ADHD. RESULTS: A subset of 627 children were included in the analyses: 93 who had ADHD and 534 with neurotypical development. After accounting for confounders and loss to follow-up, maternal prenatal dog exposure was associated with 2.23 times (95% CI: 1.15, 4.31; p = 0.017) greater odds of ADHD among boys. Prenatal dog keeping was not statistically significantly associated with ADHD in girls (odds ratio = 0.27, 95% CI: 0.06, 1.12; p = 0.070). Prenatal cat keeping was not associated with ADHD. CONCLUSIONS: In boys, but not girls, maternal prenatal dog keeping was positively associated with ADHD. Further study to confirm these findings and to identify potential mechanisms of this association (e.g., modification of the gut microbiome, exposure to environmental toxicants or pet-related medications) is needed.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Cuidadores , Gatos , Cães , Animais de Estimação , Efeitos Tardios da Exposição Pré-Natal/etiologia , Adulto , Animais , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Cuidadores/estatística & dados numéricos , Criança , Desenvolvimento Infantil , Pré-Escolar , Estudos de Coortes , Exposição Ambiental , Feminino , Inquéritos Epidemiológicos/estatística & dados numéricos , Humanos , Lactente , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Fatores Sexuais , Estados Unidos , Adulto Jovem
8.
J Pediatr Gastroenterol Nutr ; 66 Suppl 3: S11-S13, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29762369

RESUMO

OBJECTIVES: Maltase-glucoamylase and sucrase-isomaltase are enzymes in the brush-border membrane of the small intestinal lumen responsible for the breakdown of postamylase starch polysaccharides to release monomeric glucose. As such, they are critical players in healthy nutrition and their malfunction can lead to severe disorders. METHODS: This review covers investigations of the structures and functions of these enzymes. RESULTS: Each consists of 2 enzyme domains of the glycoside hydrolase family GH31 classification, yet with somewhat differing enzymatic properties. CONCLUSIONS: Crystallographic structures of 3 of the domains have been published. Insights into substrate binding and specificity will be discussed, along with future lines of inquiry related to the enzymes' roles in disease and potential avenues for therapeutics.


Assuntos
Intestino Delgado/fisiologia , Complexo Sacarase-Isomaltase/química , alfa-Glucosidases/química , Cristalografia , Humanos , Amido/metabolismo , Complexo Sacarase-Isomaltase/fisiologia , alfa-Glucosidases/fisiologia
9.
J Reprod Med ; 60(9-10): 392-6, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26592064

RESUMO

OBJECTIVE: To assess whether body mass index (BMI) was associated with self-reported pain, well-being, or procedure satisfaction in the 3 months after hysterectomy. STUDY DESIGN: Prospective cohort study that recruited women undergoing hysterectomy. Data was collected over 1 year for 245 women. RESULTS: BMI was not associated with pain either at baseline or in the 3 months after surgery versus no pain; odds ratio [OR] = 1.0, 95% confidence interval [CI] 0.97-1.03, p = 0.88 for a 1 unit increase in BMI) or being fully satisfied with the procedure (versus not fully satisfied; OR = 1.01, 95% CI 0.97-1.04, p = 0.77 for a 1unit increase in BMI). Similarly, patient's perception of well-being was also not influenced by BMI as reflected in their well-being score (0.98 increase in score, 95% CI 0.95-1.02, p = 0.40, for a 1-unit increase in BMI). CONCLUSION: The data from this prospectively studied cohort of women who had undergone hysterectomy suggest that BMI is not associated with self-report of pain, well-being, -or procedure satisfaction in the 3 month after surgery.


Assuntos
Histerectomia , Obesidade/epidemiologia , Dor/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Doenças Uterinas/cirurgia , Adulto , Índice de Massa Corporal , Estudos de Coortes , Comorbidade , Feminino , Humanos , Modelos Lineares , Pessoa de Meia-Idade , Razão de Chances , Avaliação de Resultados da Assistência ao Paciente , Estudos Prospectivos , Autorrelato , Doenças Uterinas/epidemiologia
10.
Ethn Dis ; 24(1): 104-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24620456

RESUMO

OBJECTIVE: There is consistent evidence demonstrating that pet-keeping, particularly of dogs, is beneficial to human health. We explored relationships between maternal race and prenatal dog-keeping, accounting for measures of socioeconomic status that could affect the choice of owning a pet, in a demographically diverse, unselected birth cohort. DESIGN: Self-reported data on mothers' race, socioeconomic characteristics and dog-keeping practices were obtained during prenatal interviews and analyzed cross-sectionally. Robust methods of covariate balancing via propensity score analysis were utilized to examine if race (Black vs White), independent of other participant traits, influenced prenatal dog-keeping. SETTING: A birth cohort study conducted in a health care system in metropolitan Detroit, Michigan between September 2003 and November 2007. PARTICIPANTS: 1065 pregnant women (n=775 or 72.8% Black), between ages 21 and 45, receiving prenatal care. MAIN OUTCOME MEASURES: Participant's self-report of race/ethnicity and prenatal dog-keeping, which was defined as her owning or caring for > or =1 dog for more than 1 week at her home since learning of her pregnancy, regardless of whether the dog was kept inside or outside of her home. RESULTS: In total, 294 women (27.6%) reported prenatal dog-keeping. Prenatal dog-keeping was significantly lower among Black women as compared to White women (20.9% vs 45.5%, P<.001), and remained significantly different even after propensity score analysis was applied. CONCLUSION: Findings suggest that there are persistent racial differences in dog-keeping not fully explained by measures of socioeconomic status. Racial differences in prenatal dog-keeping may contribute to childhood health disparities.


Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Disparidades nos Níveis de Saúde , Animais de Estimação , População Branca/estatística & dados numéricos , Adulto , Animais , Asma/etnologia , Cães , Feminino , Nível de Saúde , Humanos , Hipersensibilidade/etnologia , Modelos Logísticos , Michigan , Pessoa de Meia-Idade , Mães , Gravidez , Pontuação de Propensão , Classe Social , Adulto Jovem
11.
Mol Nutr Food Res ; 58(5): 1111-21, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24442968

RESUMO

SCOPE: The four mucosal α-glucosidases, which differ in their digestive roles, generate glucose from glycemic carbohydrates and accordingly can be viewed as a control point for rate of glucose delivery to the body. In this study, individual recombinant enzymes were used to understand how α-glucan oligomers are digested by each enzyme, and how intermediate α-amylolyzed starches are hydrolyzed, to elucidate a strategy for moderating the glycemic spike of rapidly digestible starchy foods. METHODS AND RESULTS: The C-terminal maltase-glucoamylase (ctMGAM, commonly termed "glucoamylase") was able to rapidly hydrolyze longer maltooligosaccharides, such as maltotetraose and maltopentaose, to glucose. Moreover, it was found to convert larger size maltodextrins, as would be produced early in α-amylase digestion of starch, efficiently to glucose. It is postulated that ctMGAM has the additional capacity to hydrolyze large α-amylase products that are produced immediately on starch digestion in the duodenum and contribute to the rapid generation of glucose from starch-based meals. CONCLUSION: The findings suggest that partial inhibition of ctMGAM, such as by natural inhibitors found in foods, might be used to moderate the early stage of high glycemic response, as well as to extend digestion distally; thereby having relevance in regulating glucose delivery to the body.


Assuntos
Glucose/metabolismo , Amido/química , alfa-Glucosidases/metabolismo , Glicemia/metabolismo , Digestão , Duodeno/metabolismo , Humanos , Hidrólise , Maltose/análogos & derivados , Maltose/metabolismo , Mucosa/metabolismo , Oligossacarídeos/metabolismo , Polissacarídeos/metabolismo , Período Pós-Prandial , Proteínas Recombinantes/metabolismo , alfa-Amilases/metabolismo
12.
PLoS One ; 8(4): e59745, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23565164

RESUMO

For digestion of starch in humans, α-amylase first hydrolyzes starch molecules to produce α-limit dextrins, followed by complete hydrolysis to glucose by the mucosal α-glucosidases in the small intestine. It is known that α-1,6 linkages in starch are hydrolyzed at a lower rate than are α-1,4 linkages. Here, to create designed slowly digestible carbohydrates, the structure of waxy corn starch (WCS) was modified using a known branching enzyme alone (BE) and an in combination with ß-amylase (BA) to increase further the α-1,6 branching ratio. The digestibility of the enzymatically synthesized products was investigated using α-amylase and four recombinant mammalian mucosal α-glucosidases. Enzyme-modified products (BE-WCS and BEBA-WCS) had increased percentage of α-1,6 linkages (WCS: 5.3%, BE-WCS: 7.1%, and BEBA-WCS: 12.9%), decreased weight-average molecular weight (WCS: 1.73×10(8) Da, BE-WCS: 2.76×10(5) Da, and BEBA-WCS 1.62×10(5) Da), and changes in linear chain distributions (WCS: 21.6, BE-WCS: 16.9, BEBA-WCS: 12.2 DPw). Hydrolysis by human pancreatic α-amylase resulted in an increase in the amount of branched α-limit dextrin from 26.8% (WCS) to 56.8% (BEBA-WCS). The α-amylolyzed samples were hydrolyzed by the individual α-glucosidases (100 U) and glucogenesis decreased with all as the branching ratio increased. This is the first report showing that hydrolysis rate of the mammalian mucosal α-glucosidases is limited by the amount of branched α-limit dextrin. When enzyme-treated materials were gavaged to rats, the level of postprandial blood glucose at 60 min from BEBA-WCS was significantly higher than for WCS or BE-WCS. Thus, highly branched glucan structures modified by BE and BA had a comparably slow digesting property both in vitro and in vivo. Such highly branched α-glucans show promise as a food ingredient to control postprandial glucose levels and to attain extended glucose release.


Assuntos
Glucose/biossíntese , Glucose/química , Polissacarídeos/química , Polissacarídeos/metabolismo , alfa-Glucosidases/metabolismo , Animais , Glicemia , Humanos , Hidrólise , Masculino , Peso Molecular , Mucosa/enzimologia , Ressonância Magnética Nuclear Biomolecular , Ratos , Proteínas Recombinantes/metabolismo , Amido/química , Amido/metabolismo
15.
J Biol Chem ; 287(38): 31929-38, 2012 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-22851177

RESUMO

Starch digestion involves the breakdown by α-amylase to small linear and branched malto-oligosaccharides, which are in turn hydrolyzed to glucose by the mucosal α-glucosidases, maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI). MGAM and SI are anchored to the small intestinal brush-border epithelial cells, and each contains a catalytic N- and C-terminal subunit. All four subunits have α-1,4-exohydrolytic glucosidase activity, and the SI N-terminal subunit has an additional exo-debranching activity on the α-1,6-linkage. Inhibition of α-amylase and/or α-glucosidases is a strategy for treatment of type 2 diabetes. We illustrate here the concept of "toggling": differential inhibition of subunits to examine more refined control of glucogenesis of the α-amylolyzed starch malto-oligosaccharides with the aim of slow glucose delivery. Recombinant MGAM and SI subunits were individually assayed with α-amylolyzed waxy corn starch, consisting mainly of maltose, maltotriose, and branched α-limit dextrins, as substrate in the presence of four different inhibitors: acarbose and three sulfonium ion compounds. The IC(50) values show that the four α-glucosidase subunits could be differentially inhibited. The results support the prospect of controlling starch digestion rates to induce slow glucose release through the toggling of activities of the mucosal α-glucosidases by selective enzyme inhibition. This approach could also be used to probe associated metabolic diseases.


Assuntos
Glucose/metabolismo , Mucosa/enzimologia , alfa-Glucosidases/metabolismo , Animais , Diabetes Mellitus/metabolismo , Drosophila melanogaster , Glicosídeo Hidrolases/química , Glicosilação , Humanos , Hidrólise , Concentração Inibidora 50 , Mucosa Intestinal/metabolismo , Cinética , Camundongos , Modelos Químicos , Obesidade/metabolismo , Estrutura Terciária de Proteína , Proteínas Recombinantes/química
16.
Chemistry ; 17(52): 14817-25, 2011 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-22127878

RESUMO

The synthesis and glucosidase inhibitory activities of two C-3'- and C-5'-ß-maltose-extended analogues of the naturally occurring sulfonium-ion inhibitor, de-O-sulfonated ponkoranol, are described. The compounds are designed to test the specificity towards four intestinal glycoside hydrolase family 31 (GH31) enzyme activities, responsible for the hydrolysis of terminal starch products and sugars into glucose, in humans. The target sulfonium-ion compounds were synthesized by means of nucleophilic attack of benzyl protected 1,4-anhydro-4-thio-D-arabinitol at the C-6 position of 6-O-trifluoromethanesulfonyl trisaccharides as alkylating agents. The alkylating agents were synthesized from D-glucose by glycosylation at C-4 or C-2 with maltosyl trichloroacetimidate. Deprotection of the coupled products by using a two-step sequence, followed by reduction afforded the final compounds. Evaluation of the target compounds for inhibition of the four glucosidase activities indicated that selective inhibition of one enzyme over the others is possible.


Assuntos
Mucosa Intestinal/metabolismo , Intestinos/enzimologia , Maltose/antagonistas & inibidores , Maltose/química , Maltose/síntese química , Amido/química , Complexo Sacarase-Isomaltase/antagonistas & inibidores , Complexo Sacarase-Isomaltase/metabolismo , Compostos de Sulfônio/antagonistas & inibidores , Compostos de Sulfônio/química , Tiofenos/antagonistas & inibidores , Tiofenos/síntese química , alfa-Glucosidases/química , alfa-Glucosidases/síntese química , Catálise , Inibidores Enzimáticos/farmacologia , Humanos , Estrutura Molecular , Estereoisomerismo , Tiofenos/química
17.
Bioorg Med Chem Lett ; 21(21): 6491-4, 2011 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-21924903

RESUMO

Human maltase glucoamylase (MGAM) and sucrase isomaltase (SI) are two human intestinal glucosidases responsible for the final step of starch hydrolysis. MGAM and SI are anchored to the small intestinal brush border epithelial cells and contain two catalytic N-terminal and C-terminal subunits. In this study, we report the inhibition profile of 3'-O-methylponkoranol for the individual recombinant N and C terminal enzymes and compare the inhibitory activities of this compound with de-O-sulfonated ponkoranol. We show that 3'-O-methylponkoranol inhibits the different subunits to different extents, with extraordinary selectivity for C-terminal SI (K(i)=7±2nM). The enzymes themselves could serve as therapeutic targets for the treatment of digestive disorders or their sequelae.


Assuntos
Inibidores Enzimáticos/farmacologia , Gastroenteropatias/tratamento farmacológico , Inibidores de Glicosídeo Hidrolases , Complexo Sacarase-Isomaltase/antagonistas & inibidores , Tiofenos/farmacologia , Amilopectina/química , Amilose/química , Sequência de Carboidratos , Inibidores Enzimáticos/uso terapêutico , Humanos , Dados de Sequência Molecular , Tiofenos/uso terapêutico
18.
Chem Commun (Camb) ; 47(32): 9134-6, 2011 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-21750824

RESUMO

The synthesis of selenium analogues of de-O-sulfonated ponkoranol, a naturally occurring sulfonium-ion glucosidase inhibitor isolated from Salacia reticulata, and their evaluation as glucosidase inhibitors against two recombinant intestinal enzymes maltase glucoamylase (MGAM) and sucrase isomaltase (SI) are described.


Assuntos
Inibidores Enzimáticos/química , Inibidores de Glicosídeo Hidrolases , Intestinos/enzimologia , Salacia/química , Selênio/química , Tiofenos/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Humanos , Modelos Moleculares , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Selênio/farmacologia , Enxofre/química , Tiofenos/farmacologia , alfa-Glucosidases/metabolismo
19.
Bioorg Med Chem ; 19(13): 3929-34, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21669536

RESUMO

Inhibition of intestinal α-glucosidases and pancreatic α-amylases is an approach to controlling blood glucose and serum insulin levels in individuals with Type II diabetes. The two human intestinal glucosidases are maltase-glucoamylase and sucrase-isomaltase. Each incorporates two family 31 glycoside hydrolases responsible for the final step of starch hydrolysis. Here we compare the inhibition profiles of the individual N- and C-terminal catalytic subunits of both glucosidases by clinical glucosidase inhibitors, acarbose and miglitol, and newly discovered glucosidase inhibitors from an Ayurvedic remedy used for the treatment of Type II diabetes. We show that features of the compounds introduce selectivity towards the subunits. Together with structural data, the results enhance the understanding of the role of each catalytic subunit in starch digestion, helping to guide the development of new compounds with subunit specific antidiabetic activity. The results may also have relevance to other metabolic diseases such as obesity and cardiovascular disease.


Assuntos
Amido/metabolismo , Complexo Sacarase-Isomaltase/metabolismo , alfa-Glucosidases/metabolismo , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/química , 1-Desoxinojirimicina/farmacologia , Acarbose/química , Acarbose/farmacologia , Domínio Catalítico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Glicosídeo Hidrolases , Cinética , Monossacarídeos/química , Compostos de Selênio/química , Compostos de Selênio/farmacologia , Complexo Sacarase-Isomaltase/antagonistas & inibidores , Álcoois Açúcares/química , Álcoois Açúcares/farmacologia , Sulfatos/química , Sulfatos/farmacologia
20.
Bioorg Med Chem Lett ; 20(19): 5686-9, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20801033

RESUMO

Ponkoranol is a naturally occurring glucosidase inhibitor isolated from the plant Salacia reticulata. The compound comprises a sulfonium ion with an internal sulfate counter ion. We report here an efficient synthetic route to 3'-O-methyl ponkoranol to test the hypothesis that occupation of a hydrophobic pocket by a methyl group instead of the polar sulfate ion within the active site of human N-terminal maltase glucoamylase would be beneficial. The synthetic strategy relies on the nucleophilic attack of 2,3,5-tri-O-benzyl-1,4-anhydro-4-thio-D-arabinitol at the C-6 position of benzyl 6-O-p-toluenesulfonyl ß-D-glucopyranoside, followed by deprotection using boron trichloride and reduction with sodium borohydride. The target compound inhibited the N-terminal catalytic domain of intestinal human maltase glucoamylase (ntMGAM) with a K(i) value of 0.50 ± 0.04 µM, higher than those of de-O-sulfonated ponkoranol (K(i)=43 ± 3 nM), or its 5'-stereoisomer (K(i)=15 ± 1 nM). We conclude that the interaction of the methyl group with hydrophobic residues in the active site is not as beneficial to inhibition of ntMGAM as the other interactions of the polyhydroxylated chain with active-site residues.


Assuntos
Inibidores de Glicosídeo Hidrolases , Intestinos/enzimologia , Éteres Metílicos/química , Sulfatos/química , Tiofenos/química , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Humanos , Estrutura Terciária de Proteína , Tiofenos/farmacologia , alfa-Glucosidases/metabolismo
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