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2.
Physiol Genomics ; 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32628083

RESUMO

Lipocalin 2 (Lcn2) is a multifunctional innate immune protein that limits microbial overgrowth. Our previous study has demonstrated that the gut microbiota directly induces intestinal Lcn2 production, and Lcn2 deficient (Lcn2-/-) mice exhibit gut dysbiosis. Coincidentally, gut dysbiosis is associated with metabolic syndrome pathogenesis and elevated Lcn2 levels has been considered a potential clinical biomarker of metabolic syndrome. Yet, whether Lcn2 mitigates or exacerbates metabolic syndrome remains inconclusive. Our objective was to determine whether Lcn2 deficiency-induced compositional changes in gut microbiota contributes to gain in adiposity in aged mice. Utilizing Lcn2-/- mice and their WT littermates, we measured metabolic markers, including fasting blood glucose, serum lipids, fat pad weight, and insulin resistance at ages 3, 6 and 9 months old. Relative to WT mice, aged Lcn2-/- mice exhibited a gain in adiposity associated with numerous features of metabolic syndrome, including insulin resistance and dyslipidemia. Surprisingly, the supplementation with a high-fat diet did not further aggravate metabolic syndrome that spontaneously occurs in Lcn2-/- mice by 6 months of age. Interestingly, chow-fed Lcn2-/- mice displayed marked differences in the bacterial abundance and metabolomic profile of the gut microbiota compared to WT mice. Overall, our results demonstrate that Lcn2 is essential to maintain metabolic and gut microbiotal homeostasis, where deficiency induces spontaneous delayed onset of metabolic syndrome.

3.
Am J Hypertens ; 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32533696

RESUMO

Hypertension has been described as a condition of premature vascular aging, relative to actual chronological age. In fact, many factors that contribute to the deterioration of vascular function as we age are accelerated and exacerbated in hypertension. Nonetheless, the precise mechanisms that underlie the aged phenotype of arteries from hypertensive patients and animals remain elusive. Classically, the aged phenotype is the buildup of cellular debris and dysfunctional organelles. One means by which this can occur is insufficient degradation and cellular recycling. Mitophagy is the selective catabolism of damaged mitochondria. Mitochondria are organelles that contribute importantly to the determination of cellular age via their production of reactive oxygen species (ROS; Harman's free radical theory of aging). Therefore, the accumulation of dysfunctional and ROS-producing mitochondria could contribute to the acceleration of vascular age in hypertension. This review will address and critically evaluate the current literature on mitophagy in vascular physiology and hypertension.

4.
Hypertension ; 76(1): 59-72, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32450738

RESUMO

Alterations of diurnal rhythms of blood pressure (BP) and reshaping of gut microbiota are both independently associated with hypertension. However, the relationships between biorhythms of BP and gut microbial composition are unknown. We hypothesized that diurnal timing-associated alterations of microbial compositions are synchronous with diurnal rhythmicity, dip in BP, and renal function. To test this hypothesis, Dahl salt-sensitive (S) rats on low- and high-salt diets were examined for time of day effects on gut microbiota, BP, and indicators of renal damage. Major shifts in night and day patterns of specific groups of microbiota were observed between the dark (active) and light (rest) phases, which correlated with diurnal rhythmicity of BP. The diurnal abundance of Firmicutes, Bacteroidetes, and Actinobacteria were independently associated with BP. Discrete bacterial taxa were observed to correlate independently or interactively with one or more of the following 3 factors: (1) BP rhythm, (2) dietary salt, and (3) dip in BP. Phylogenetic Investigation of Communities revealed diurnal timing effects on microbial pathways, characterized by upregulated biosynthetic processes during the active phase of host, and upregulated degradation pathways of metabolites in the resting phase. Additional metagenomics functional pathways with rhythm variations were noted for aromatic amino acid metabolism and taurine metabolism. These diurnal timing dependent changes in microbiota, their functional pathways, and BP dip were associated with concerted effects of the levels of renal lipocalin 2 and kidney injury molecule-1 expression. These data provide evidence for a firm and concerted diurnal timing effects of BP, renal damage, and select microbial communities.

5.
Int J Mol Sci ; 21(10)2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32423033

RESUMO

Ischemic cardiomyopathy (ICM), characterized by pre-existing myocardial infarction or severe coronary artery disease, is the major cause of heart failure (HF). Identification of novel transcriptional regulators in ischemic HF can provide important biomarkers for developing new diagnostic and therapeutic strategies. In this study, we used four RNA-seq datasets from four different studies, including 41 ICM and 42 non-failing control (NF) samples of human left ventricle tissues, to perform the first RNA-seq meta-analysis in the field of clinical ICM, in order to identify important transcriptional regulators and their targeted genes involved in ICM. Our meta-analysis identified 911 differentially expressed genes (DEGs) with 582 downregulated and 329 upregulated. Interestingly, 54 new DEGs were detected only by meta-analysis but not in individual datasets. Upstream regulator analysis through Ingenuity Pathway Analysis (IPA) identified three key transcriptional regulators. TBX5 was identified as the only inhibited regulator (z-score = -2.89). F2R and SFRP4 were identified as the activated regulators (z-scores = 2.56 and 2.00, respectively). Multiple downstream genes regulated by TBX5, F2R, and SFRP4 were involved in ICM-related diseases such as HF and arrhythmia. Overall, our study is the first to perform an RNA-seq meta-analysis for clinical ICM and provides robust candidate genes, including three key transcriptional regulators, for future diagnostic and therapeutic applications in ischemic heart failure.

7.
Hypertension ; 75(6): 1386-1396, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32336227

RESUMO

For over 100 years, essential hypertension has been researched from different perspectives ranging from genetics, physiology, and immunology to more recent ones encompassing microbiology (microbiota) as a previously underappreciated field of study contributing to the cause of hypertension. Each field of study in isolation has uniquely contributed to a variety of underlying mechanisms of blood pressure regulation. Even so, clinical management of essential hypertension has remained somewhat static. We, therefore, asked if there are any converging lines of evidence from these individual fields that could be amenable for a better clinical prognosis. Accordingly, here we present converging evidence which support the view that metabolic dysfunction underlies essential hypertension.

8.
Gut Microbes ; 11(4): 1077-1091, 2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-32223398

RESUMO

Owing to their health benefits, dietary fermentable fibers, such as refined inulin, are increasingly fortified in processed foods to enhance their nutritional value. However, we previously demonstrated that when inulin was fed to Toll-like receptor 5 deficient (T5KO) mice susceptible to dysbiosis, a subset of them developed cholestasis and subsequently liver cancer in a gut microbiota-dependent manner. Therefore, we hypothesized that clearance of bacterial taxa, and thereby gut metabolites, involved in the onset and progression to liver cancer could abate the disease in these mice. Such a reshaping of microbiota by vancomycin treatment was sufficient to halt the development of liver cancer in inulin-fed T5KO mice; however, this intervention did not remedy disease penetrance for cholestatic liver injury and its sequelae, including hyperbilirubinemia, hypolipidemia, cholemia and liver fibrosis. Selective depletion of gut bacterial communities was observed in vancomycin-treated mice, including Gram-positive Lachnospiraceae and Ruminococcaceae belonging to the phylum Firmicutes, Bifidobacteria of the phylum Actinobacteria, which ferment fibers, and Clostridium cluster XIVa, which produce secondary bile acids. Lack of liver cancer in vancomycin-treated mice strongly correlated with the substantial loss of secondary bile acids in circulation. Although cholemia was unabated by vancomycin, the composition of serum bile acids shifted toward an abundance of hydrophilic primary bile acids, denoted by the increase in conjugated-to-unconjugated bile acid ratio. Taken together, the present study suggests that microbiotal regulation of bile acid metabolism is one of the critical mediators of fermentable fiber-induced liver cancer in dysbiotic mice.

9.
Physiol Genomics ; 52(5): 217-221, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32275178
10.
Dis Model Mech ; 13(5)2020 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-32238420

RESUMO

Red blood cell distribution width (RDW) is a measurement of the variation in size and volume of red blood cells (RBCs). Increased RDW, indicating a high heterogeneity of RBCs, is prominently associated with a variety of illnesses, especially cardiovascular diseases. However, the significance of this association to the onset and progression of cardiovascular and renal diseases is unknown. We hypothesized that a genetic predisposition for increased RDW is an early risk factor for cardiovascular and renal comorbidities. Since there is no known animal model of increased RDW, we examined a CRISPR/Cas9 gene-edited rat model (RfflTD) that presented with features of hematologic abnormalities as well as severe cardiac and renal comorbidities. A mass spectrometry-based quantitative proteomic analysis indicated anemia of these rats, which presented with significant downregulation of hemoglobin and haptoglobin. Decreased hemoglobin and increased RDW were further observed in RfflTD through complete blood count. Next, a systematic temporal assessment detected an early increased RDW in RfflTD, which was prior to the development of other comorbidities. The primary mutation of RfflTD is a 50 bp deletion in a non-coding region, and our study has serendipitously identified this locus as a novel quantitative trait locus (QTL) for RDW. To our knowledge, our study is the first to experimentally pinpoint a QTL for RDW and provides a novel genetic rat model mimicking the clinical association of increased RDW with poor cardio-renal outcome.

11.
J Nutr Biochem ; 80: 108360, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32163821

RESUMO

The metabolism of macro- and micronutrients is a complex and highly regulated biological process. An imbalance in the metabolites and their signaling networks can lead to nonresolving inflammation and consequently to the development of chronic inflammatory-associated diseases. Therefore, identifying the accumulated metabolites and altered pathways during inflammatory disorders would not only serve as "real-time" markers but also help in the development of nutritional therapeutics. In this review, we explore recent research that has delved into elucidating the effects of carbohydrate/calorie restriction, protein malnutrition, lipid emulsions and micronutrient deficiencies on metabolic health and inflammation. Moreover, we describe the integrated stress response in terms of amino acid starvation and lipemia and how this modulates new age diseases such as inflammatory bowel disease and atherosclerosis. Lastly, we explain the latest research on metaflammation and inflammaging. This review focuses on multiple signaling pathways, including, but not limited to, the FGF21-ß-hydroxybutryate-NLRP3 axis, the GCN2-eIF2α-ATF4 pathway, the von Hippel-Lindau/hypoxia-inducible transcription factor pathway and the TMAO-PERK-FoxO1 axis. Additionally, throughout the review, we explain how the gut microbiota responds to altered nutrient status and also how antimicrobial peptides generated from nutrient-based signaling pathways can modulate the gut microbiota. Collectively, it must be emphasized that metabolic starvation and inflammation are strongly regulated by both environmental (i.e., nutrition, gut microbiome) and nonenvironmental (i.e., genetics) factors, which can influence the susceptibility to inflammatory disorders.

13.
J Pediatr Surg ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-32037220

RESUMO

BACKGROUND: The inguinoscrotal stage of testicular descent is characterized by an increase in cell density and collagen fibers as the gubernaculum undergoes cell division and increases Extracellular Matrix (ECM) activity. Rats that lack the enzyme Adamts16, a known ECM proteinase, develop cryptorchidism postnatally and are infertile. Therefore, this study aims to investigate the link between the Adamts16 enzyme and congenital undescended testes (UDT) in Adamts16 knockout (KO) rats during postnatal development. METHODS: Formalin-fixed specimens of Wild-Type, Adamts16 heterozygous and Adamts16 homozygous KO rats post birth were sectioned and used for standard H&E histology and Masson's trichrome staining. A quantitative analysis on image J was performed to determine the intensity of collagen fibers within the inguinoscrotal fat pad (IFP) (n = 3 age/genotype). RESULTS: The migration of the gubernaculum within the Adamts16 heterozygous and Adamts16 KO rat was considerably disrupted. Furthermore, the Masson's trichrome staining demonstrated a significant increase in collagen fibers around the gubernaculum of rats that lacked Adamts16 enzyme at day 8. CONCLUSION: This study reports a failure of gubernacular migration leading to UDT in Adamts16 KO rats during development, suggesting that the expression of Adamts16 gene is critical for normal gubernacular migration through the breakdown of collagen fibers within the IFP.

14.
Endocrinology ; 161(2)2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31912132

RESUMO

Recent work shows that gut microbial dysbiosis contributes to the risk of obesity in children whose mothers consume a high-fat diet (HFD) during both gestation and lactation or during gestation alone. Obesity predisposes children to developing precocious puberty. However, to date, no study has examined how maternal HFD (MHFD) during lactation regulates the gut microbiota (GM), pubertal timing, and fertility of offspring. Here, we found that MHFD during lactation markedly altered the GM of offspring. The pups developed juvenile obesity, early puberty, irregular estrous cycles, and signs of disrupted glucose metabolism. Remarkably, permitting coprophagia between MHFD and maternal normal chow offspring successfully reversed the GM changes as well as early puberty and insulin insensitivity. Our data suggest that microbial reconstitution may prevent or treat early puberty associated with insulin resistance.

15.
Genes (Basel) ; 11(1)2020 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-31948008

RESUMO

Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure. Several studies have used RNA-sequencing (RNA-seq) to profile differentially expressed genes (DEGs) associated with DCM. In this study, we aimed to profile gene expression signatures and identify novel genes associated with DCM through a quantitative meta-analysis of three publicly available RNA-seq studies using human left ventricle tissues from 41 DCM cases and 21 control samples. Our meta-analysis identified 789 DEGs including 581 downregulated and 208 upregulated genes. Several DCM-related genes previously reported, including MYH6, CKM, NKX2-5 and ATP2A2, were among the top 50 DEGs. Our meta-analysis also identified 39 new DEGs that were not detected using those individual RNA-seq datasets. Some of those genes, including PTH1R, ADAM15 and S100A4, confirmed previous reports of associations with cardiovascular functions. Using DEGs from this meta-analysis, the Ingenuity Pathway Analysis (IPA) identified five activated toxicity pathways, including failure of heart as the most significant pathway. Among the upstream regulators, SMARCA4 was downregulated and prioritized by IPA as the top affected upstream regulator for several DCM-related genes. To our knowledge, this study is the first to perform a transcriptomic meta-analysis for clinical DCM using RNA-seq datasets. Overall, our meta-analysis successfully identified a core set of genes associated with DCM.

16.
J Am Heart Assoc ; 9(2): e014373, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31928175

RESUMO

Background Pediatric hypertension is recognized as an emerging global health concern. Although new guidelines are developed for facilitating clinical management, the reasons for the prevalence of hypertension in children remain unknown. Genetics and environmental factors do not fully account for the growing incidence of pediatric hypertension. Because stable bacterial flora in early life are linked with health outcomes later in life, we hypothesized that reshaping of gut microbiota in early life affects blood pressure (BP) of pediatric subjects. Methods and Results To test this hypothesis, we administered amoxicillin, the most commonly prescribed pediatric antibiotic, to alter gut microbiota of young, genetically hypertensive rats (study 1) and dams during gestation and lactation (study 2) and recorded their BP. Reshaping of microbiota with reductions in Firmicutes/Bacteriodetes ratio were observed. Amoxicillin treated rats had lower BP compared with untreated rats. In young rats treated with amoxicillin, the lowering effect on BP persisted even after antibiotics were discontinued. Similarly, offspring from dams treated with amoxicillin showed lower systolic BP compared with control rats. Remarkably, in all cases, a decrease in BP was associated with lowering of Veillonellaceae, which are succinate-producing bacteria. Elevated plasma succinate is reported in hypertension. Accordingly, serum succinate was measured and found lower in animals treated with amoxicillin. Conclusions Our results demonstrate a direct correlation between succinate-producing gut microbiota and early development of hypertension and indicate that reshaping gut microbiota, especially by depleting succinate-producing microbiota early in life, may have long-term benefits for hypertension-prone individuals.

17.
Physiol Genomics ; 52(1): 1-14, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31762410

RESUMO

Here we postulate that the heritability of complex disease traits previously ascribed solely to the inheritance of the nuclear and mitochondrial genomes is broadened to encompass a third component of the holobiome, the microbiome. To test this, we expanded on the selectively bred low capacity runner/high capacity runner (LCR/HCR) rat exercise model system into four distinct rat holobiont model frameworks including matched and mismatched host nuclear and mitochondrial genomes. Vertical selection of varying nuclear and mitochondrial genomes resulted in differential acquisition of the microbiome within each of these holobiont models. Polygenic disease risk of these novel models were assessed and subsequently correlated with patterns of acquisition and contributions of their microbiomes in controlled laboratory settings. Nuclear-mitochondrial-microbiotal interactions were not for exercise as a reporter of health, but significantly noted for increased adiposity, increased blood pressure, compromised cardiac function, and loss of long-term memory as reporters of disease susceptibility. These findings provide evidence for coselection of the microbiome with nuclear and mitochondrial genomes as an important feature impacting the heritability of complex diseases.

18.
Vascul Pharmacol ; 125-126: 106633, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31843471

RESUMO

Commensal microbiota within a holobiont contribute to the overall health of the host via mutualistic symbiosis. Disturbances in such symbiosis is prominently correlated with a variety of diseases affecting the modern society of humans including cardiovascular diseases, which are the number one contributors to human mortality. Given that a hallmark of all cardiovascular diseases is changes in vascular function, we hypothesized that depleting microbiota from a holobiont would induce vascular dysfunction. To test this hypothesis, young mice of both sexes raised in germ-free conditions were examined vascular contractility and structure. Here we observed that male and female germ-free mice presented a decrease in contraction of resistance arteries. These changes were more pronounced in germ-free males than in germ-free females mice. Furthermore, there was a distinct change in vascular remodeling between males and females germ-free mice. Resistance arteries from male germ-free mice demonstrated increased vascular stiffness, as shown by the leftward shift in the stress-strain curve and inward hypotrophic remodeling, a characteristic of chronic reduction in blood flow. On the other hand, resistance arteries from germ-free female mice were similar in the stress-strain curves to that of conventionally raised mice, but were distinctly different and showed outward hypertrophic remodeling, a characteristic seen in aging. Interestingly, we observed that reactive oxygen species (ROS) generation from bone marrow derived neutrophils is blunted in female germ-free mice, but it is exacerbated in male germ-free mice. In conclusion, these observations indicate that commensal microbiota of a holobiont are central to maintain proper vascular function and structure homeostasis, especially in males.

19.
Compr Physiol ; 9(4): 1305-1337, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31688958

RESUMO

Advances in molecular genetics have provided well-defined physical genetic maps and large numbers of genetic markers for both model organisms and humans. It is now possible to gain a fundamental understanding of the genetic architecture underlying quantitative traits, of which blood pressure (BP) is an important example. This review emphasizes analytical techniques and results obtained using the Dahl salt-sensitive (S) rat as a model of hypertension by presenting results in detail for three specific chromosomal regions harboring genetic elements of increasing complexity controlling BP. These results highlight the critical importance of genetic interactions (epistasis) on BP at all levels of structure, intragenic, intergenic, intrachromosomal, interchromosomal, and across whole genomes. In two of the three examples presented, specific DNA structural variations leading to biochemical, physiological, and pathological mechanisms are well defined. This proves the usefulness of the techniques involving interval mapping followed by substitution mapping using congenic strains. These classic techniques are compared to newer approaches using sophisticated statistical analysis on various segregating or outbred model-organism populations, which in some cases are uniquely useful in demonstrating the existence of higher-order interactions. It is speculated that hypertension as an outlier quantitative phenotype is dependent on higher-order genetic interactions. The obstacle to the identification of genetic elements and the biochemical/physiological mechanisms involved in higher-order interactions is not theoretical or technical but the lack of future resources to finish the job of identifying the individual genetic elements underlying the quantitative trait loci for BP and ascertaining their molecular functions. © 2019 American Physiological Society. Compr Physiol 9:1305-1337, 2019.

20.
PLoS One ; 14(8): e0221658, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31442284

RESUMO

Fine-mapping of regions linked to the inheritance of hypertension is accomplished by genetic dissection of blood pressure quantitative trait loci (BP QTLs) in rats. The goal of the current study was to further fine-map two genomic regions on rat chromosome 1 with opposing blood pressure effects (BP QTL1b1 and BP QTL1b1a), the homologous region of which on human chromosome 15 harbors BP QTLs. Two new substrains were constructed and studied from the previously reported BP QTL1b1, one having significantly lower systolic BP by 17 mmHg than that of the salt-sensitive (S) rat (P = 0.007). The new limits of BP QTL1b1 were between 134.09 Mb and 135.40 Mb with a 43% improvement from the previous 2.31 Mb to the current 1.31 Mb interval containing 4 protein-coding genes (Rgma, Chd2, Fam174b, and St8sia2), 2 predicted miRNAs, and 4 lncRNAs. One new substrain was constructed and studied from the previously reported BPQTL1b1a having a significantly higher systolic BP by 22 mmHg (P = 0.006) than that of the S rat. The new limits of BPQTL1b1a were between 133.53 Mb and 134.52 Mb with a 32% improvement from the previous1.45 Mb to the current 990.21 Kb interval containing 1 protein-coding gene, Mctp2, and a lncRNA. The congenic segments of these two BP QTLs overlapped between 134.09 Mb and 134.52 Mb. No exonic variants were detected in any of the genes. These findings reiterate complexity of genetic regulation of BP within QTL regions, where elements beyond protein-coding sequences could be factors in controlling BP.


Assuntos
Pressão Sanguínea/genética , Cromossomos Humanos Par 15/genética , Cromossomos de Mamíferos/genética , Predisposição Genética para Doença , Hipertensão/genética , Locos de Características Quantitativas/genética , Animais , Mapeamento Cromossômico , Humanos , Anotação de Sequência Molecular , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Endogâmicos Dahl
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