scholarly journals Functional Difference of Mitochondrial Genome and Its Association with Traits of Common Complex Diseases in Humans

2017 ◽  
Author(s):  
Young Min Cho ◽  
Kyong Soo Park ◽  
Youngmi Kim Pak ◽  
Masashi Tanaka ◽  
Hong Kyu Lee
Keyword(s):  
Metabolic Syndrome ◽  
Mitochondrial Genome ◽  
Serum Triglyceride ◽  
Complex Diseases ◽  
Human Diseases ◽  
Dna Polymorphisms ◽  
Mitochondrial Genomes ◽  
Functional Difference

AbstractRecent evidence suggests that mitochondrial genomes harboring common mitochondrial DNA polymorphisms might have functional difference and could be associated with common complex human diseases such as metabolic syndrome and cancer that are related to mitochondrial dysfunction. However, there has been no report examining the functional difference of mitochondrial genome in the pathogenesis of such diseases at the cellular or molecular level. In order to examine the effect of mitochondrial genome on metabolic syndrome or cancer without interference from nuclear genes, we analyzed trans-mitochondrial cytoplasmic hybrid cells (cybrids) with common Asian mtDNA haplogroups A, B, D, and F from healthy volunteers. The mitochondrial oxygen consumption rates of cybrids were associated with multiple components of metabolic syndrome such as body mass index, waist circumference, serum triglyceride levels and high-density lipoprotein cholesterol levels. In addition, the cybrids showed varying degree of tumorigenicity both in vitro and in vivo. Especially, the cybrids harboring mtDNA haplogroup D had a significantly slower growth rate. These findings suggest that the phenotypes of common complex diseases in humans can be determined by their mitochondrial genomes. Therefore, not only nuclear genome but also mitochondrial genome should be considered in explaining the genetic pathogenesis of common complex human diseases.

scholarly journals GAGA Factor Isoforms Have Distinct but Overlapping Functions In Vivo

2001 ◽  
Vol 21 (24) ◽  
pp. 8565-8574 ◽  
Author(s):  
Anthony J. Greenberg ◽  
Paul Schedl
Keyword(s):  
Fusion Protein ◽  
Transcriptional Activation ◽  
Functional Difference ◽  
Wild Type ◽  
Gaga Factor ◽  
Phenotypic Analysis ◽  
Alternatively Spliced

ABSTRACT The Drosophila melanogaster GAGA factor (encoded by the Trithorax-like [Trl] gene) is required for correct chromatin architecture at diverse chromosomal sites. The Trl gene encodes two alternatively spliced isoforms of the GAGA factor (GAGA-519 and GAGA-581) that are identical except for the length and sequence of the C-terminal glutamine-rich (Q) domain. In vitro and tissue culture experiments failed to find any functional difference between the two isoforms. We made a set of transgenes that constitutively express cDNAs coding for either of the isoforms with the goal of elucidating their roles in vivo. Phenotypic analysis of the transgenes in Trl mutant background led us to the conclusion that GAGA-519 and GAGA-581 perform different, albeit largely overlapping, functions. We also expressed a fusion protein with LacZ disrupting the Q domain of GAGA-519. This LacZ fusion protein compensated for the loss of wild-type GAGA factor to a surprisingly large extent. This suggests that the Q domain either is not required for the essential functions performed by the GAGA protein or is exclusively used for tetramer formation. These results are inconsistent with a major role of the Q domain in chromatin remodeling or transcriptional activation. We also found that GAGA-LacZ was able to associate with sites not normally occupied by the GAGA factor, pointing to a role of the Q domain in binding site choice in vivo.

scholarly journals Enhanced phosphorylation of Na+–Cl− co-transporter in experimental metabolic syndrome: role of insulin

2012 ◽  
Vol 123 (11) ◽  
pp. 635-647 ◽  
Author(s):  
Radko Komers ◽  
Shaunessy Rogers ◽  
Terry T. Oyama ◽  
Bei Xu ◽  
Chao-Ling Yang ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Time Course ◽  
Kinase Inhibitor ◽  
Endogenous Expression ◽  
The Metabolic Syndrome ◽  
Mammalian Cell Lines ◽  
Phosphoinositide 3 Kinase

In the present study, we investigated the activity of the thiazide-sensitive NCC (Na+–Cl− co-transporter) in experimental metabolic syndrome and the role of insulin in NCC activation. Renal responses to the NCC inhibitor HCTZ (hydrochlorothiazide), as a measure of NCC activity in vivo, were studied in 12-week-old ZO (Zucker obese) rats, a model of the metabolic syndrome, and in ZL (Zucker lean) control animals, together with renal NCC expression and molecular markers of NCC activity, such as localization and phosphorylation. Effects of insulin were studied further in mammalian cell lines with inducible and endogenous expression of this molecule. ZO rats displayed marked hyperinsulinaemia, but no differences in plasma aldosterone, compared with ZL rats. In ZO rats, natriuretic and diuretic responses to NCC inhibition with HCTZ were enhanced compared with ZL rats, and were associated with a decrease in BP (blood pressure). ZO rats displayed enhanced Thr53 NCC phosphorylation and predominant membrane localization of both total and phosphorylated NCC, together with a different profile in expression of SPAK (Ste20-related proline/alanine-rich kinase) isoforms, and lower expression of WNK4. In vitro, insulin induced NCC phosphorylation, which was blocked by a PI3K (phosphoinositide 3-kinase) inhibitor. Insulin-induced reduction in WNK4 expression was also observed, but delayed compared with the time course of NCC phosphorylation. In summary, we report increased NCC activity in hyperinsulinaemic rodents in conjunction with the SPAK expression profile consistent with NCC activation and reduced WNK4, as well as an ability of insulin to induce NCC stimulatory phosphorylation in vitro. Together, these findings indicate that hyperinsulinaemia is an important driving force of NCC activity in the metabolic syndrome with possible consequences for BP regulation.

scholarly journals Revealing the high variability on nonconserved core and mobile elements of Austropuccinia psidii and other rust mitochondrial genomes

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0248054
Author(s):  
Jaqueline Raquel de Almeida ◽  
Diego Mauricio Riaño Pachón ◽  
Livia Maria Franceschini ◽  
Isaneli Batista dos Santos ◽  
Jessica Aparecida Ferrarezi ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Transmembrane Protein ◽  
Genome Structure ◽  
Rust Fungi ◽  
Mitochondrial Genomes ◽  
Phylogenomic Analysis ◽  
The Core ◽  
Mtdna Sequence ◽  
Austropuccinia Psidii

Mitochondrial genomes are highly conserved in many fungal groups, and they can help characterize the phylogenetic relationships and evolutionary biology of plant pathogenic fungi. Rust fungi are among the most devastating diseases for economically important crops around the world. Here, we report the complete sequence and annotation of the mitochondrial genome of Austropuccinia psidii (syn. Puccinia psidii), the causal agent of myrtle rust. We performed a phylogenomic analysis including the complete mitochondrial sequences from other rust fungi. The genome composed of 93.299 bp has 73 predicted genes, 33 of which encoded nonconserved proteins (ncORFs), representing almost 45% of all predicted genes. A. psidii mtDNA is one of the largest rust mtDNA sequenced to date, most likely due to the abundance of ncORFs. Among them, 33% were within intronic regions of diverse intron groups. Mobile genetic elements invading intron sequences may have played significant roles in size but not shaping of the rust mitochondrial genome structure. The mtDNAs from rust fungi are highly syntenic. Phylogenetic inferences with 14 concatenated mitochondrial proteins encoded by the core genes placed A. psidii according to phylogenetic analysis based on 18S rDNA. Interestingly, cox1, the gene with the greatest number of introns, provided phylogenies not congruent with the core set. For the first time, we identified the proteins encoded by three A. psidii ncORFs using proteomics analyses. Also, the orf208 encoded a transmembrane protein repressed during in vitro morphogenesis. To the best of our knowledge, we presented the first report of a complete mtDNA sequence of a member of the family Sphaerophragmiacea.

scholarly journals Production and Application of Multicistronic Constructs for Various Human Disease Therapies

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 580 ◽  
Author(s):  
Alisa A. Shaimardanova ◽  
Kristina V. Kitaeva ◽  
Ilmira I. Abdrakhmanova ◽  
Vladislav M. Chernov ◽  
Catrin S. Rutland ◽  
...  
Keyword(s):  
Human Diseases ◽  
Cellular Biology ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
New Methods ◽  
In Vivo Experiments ◽  
Mutant Genes ◽  
Methods Of Treatment

The development of multicistronic vectors has opened up new opportunities to address the fundamental issues of molecular and cellular biology related to the need for the simultaneous delivery and joint expression of several genes. To date, the examples of the successful use of multicistronic vectors have been described for the development of new methods of treatment of various human diseases, including cardiovascular, oncological, metabolic, autoimmune, and neurodegenerative disorders. The safety and effectiveness of the joint delivery of therapeutic genes in multicistronic vectors based on the internal ribosome entry site (IRES) and self-cleaving 2A peptides have been shown in both in vitro and in vivo experiments as well as in clinical trials. Co-expression of several genes in one vector has also been used to create animal models of various inherited diseases which are caused by mutations in several genes. Multicistronic vectors provide expression of all mutant genes, which allows the most complete mimicking disease pathogenesis. This review comprehensively discusses multicistronic vectors based on IRES nucleotide sequence and self-cleaving 2A peptides, including its features and possible application for the treatment and modeling of various human diseases.

scholarly journals Oxidative Stress, Antioxidant Capabilities, and Bioavailability: Ellagic Acid or Urolithins?

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 707 ◽  
Author(s):  
Silvana Alfei ◽  
Barbara Marengo ◽  
Guendalina Zuccari
Keyword(s):  
Oxidative Stress ◽  
Ellagic Acid ◽  
Functional Foods ◽  
Fruits And Vegetables ◽  
Human Diseases ◽  
Natural Polyphenols ◽  
Extreme Variability ◽  
Therapeutic Alternatives

Oxidative stress (OS), triggered by overproduction of reactive oxygen and nitrogen species, is the main mechanism responsible for several human diseases. The available one-target drugs often face such illnesses, by softening symptoms without eradicating the cause. Differently, natural polyphenols from fruits and vegetables possess multi-target abilities for counteracting OS, thus representing promising therapeutic alternatives and adjuvants. Although in several in vitro experiments, ellagitannins (ETs), ellagic acid (EA), and its metabolites urolithins (UROs) have shown similar great potential for the treatment of OS-mediated human diseases, only UROs have demonstrated in vivo the ability to reach tissues to a greater extent, thus appearing as the main molecules responsible for beneficial activities. Unfortunately, UROs production depends on individual metabotypes, and the consequent extreme variability limits their potentiality as novel therapeutics, as well as dietary assumption of EA, EA-enriched functional foods, and food supplements. This review focuses on the pathophysiology of OS; on EA and UROs chemical features and on the mechanisms of their antioxidant activity. A discussion on the clinical applicability of the debated UROs in place of EA and on the effectiveness of EA-enriched products is also included.

scholarly journals Beneficial Role of Bitter Melon Supplementation in Obesity and Related Complications in Metabolic Syndrome

2015 ◽  
Vol 2015 ◽  
pp. 1-18 ◽  
Author(s):  
Md Ashraful Alam ◽  
Riaz Uddin ◽  
Nusrat Subhan ◽  
Md Mahbubur Rahman ◽  
Preeti Jain ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Therapeutic Benefit ◽  
Bitter Melon ◽  
Metabolic Dysfunction ◽  
Beneficial Effects ◽  
Alternative Medicines ◽  
Daily Food ◽  
Treatment Of Diabetes

Diabetes, obesity, and metabolic syndrome are becoming epidemic both in developed and developing countries in recent years. Complementary and alternative medicines have been used since ancient era for the treatment of diabetes and cardiovascular diseases. Bitter melon is widely used as vegetables in daily food in Bangladesh and several other countries in Asia. The fruits extract of bitter melon showed strong antioxidant and hypoglycemic activities in experimental condition bothin vivoandin vitro. Recent scientific evaluation of this plant extracts also showed potential therapeutic benefit in diabetes and obesity related metabolic dysfunction in experimental animals and clinical studies. These beneficial effects are mediated probably by inducing lipid and fat metabolizing gene expression and increasing the function of AMPK and PPARs, and so forth. This review will thus focus on the recent findings on beneficial effect ofMomordica charantiaextracts on metabolic syndrome and discuss its potential mechanism of actions.

scholarly journals Distinct Gut Microbiota Induced by Different Fat-to-Sugar-Ratio High-Energy Diets Share Similar Pro-obesity Genetic and Metabolite Profiles in Prediabetic Mice

mSystems ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Kai Shan ◽  
Hongyan Qu ◽  
Keru Zhou ◽  
Liangfang Wang ◽  
Congmin Zhu ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Gut Microbiota ◽  
Early Stage ◽  
Amplicon Sequencing ◽  
High Energy ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients

ABSTRACT Gut microbiota play important roles in host metabolism, especially in diabetes. However, why different diets lead to similar diabetic states despite being associated with different microbiota is not clear. Mice were fed two high-energy diets (HED) with the same energy density but different fat-to-sugar ratios to determine the associations between the microbiota and early-stage metabolic syndrome. The two diets resulted in different microbiota but similar diabetic states. Interestingly, the microbial gene profiles were not significantly different, and many common metabolites were identified, including l-aspartic acid, cholestan-3-ol (5β, 3α), and campesterol, which have been associated with lipogenesis and inflammation. Our study suggests that different metabolic-syndrome-inducing diets may result in different microbiota but similar microbiomes and metabolomes. This suggests that the metagenome and metabolome are crucial for the prognosis and pathogenesis of obesity and metabolic syndrome. IMPORTANCE Various types of diet can lead to type 2 diabetes. The gut microbiota in type 2 diabetic patients are also different. So, two questions arise: whether there are any commonalities between gut microbiota induced by different pro-obese diets and whether these commonalities lead to disease. Here we found that high-energy diets with two different fat-to-sugar ratios can both cause obesity and prediabetes but enrich different gut microbiota. Still, these different gut microbiota have similar genetic and metabolite compositions. The microbial metabolites in common between the diets modulate lipid accumulation and macrophage inflammation in vivo and in vitro. This work suggests that studies that only use 16S rRNA amplicon sequencing to determine how the microbes respond to diet and associate with diabetic state are missing vital information.

scholarly journals Measles Virus Attenuation Associated with Transcriptional Impediment and a Few Amino Acid Changes in the Polymerase and Accessory Proteins

1998 ◽  
Vol 72 (11) ◽  
pp. 8690-8696 ◽  
Author(s):  
Makoto Takeda ◽  
Atsushi Kato ◽  
Fumio Kobune ◽  
Hiroko Sakata ◽  
Yan Li ◽  
...  
Keyword(s):  
Amino Acid ◽  
Vero Cell ◽  
Cell Line ◽  
Measles Virus ◽  
Vero Cells ◽  
Functional Difference ◽  
Pathogenic Potential ◽  
P Proteins

ABSTRACT Measles virus (MV) isolated in B95a cells, a marmoset B-cell line, retains full pathogenicity for cynomolgus monkeys, while its derivative obtained by adaptation to the growth in Vero cells, a monkey kidney cell line, loses the pathogenic potential (F. Kobune, H. Sakata, and A. Sugiura, J. Virol. 64:700–705, 1990). Here, we show with a pair of strains, a fresh isolate (9301B) in B95a cells and its Vero cell-adapted form (9301V), that the in vivo attenuation parallels the decrease of replication and syncytium-inducing capabilities in the original B95a cells and that these in vitro phenotypes are attributable to impediment of transcription, which is already obvious at the level of primary transcription catalyzed by the virion-associated RNA polymerase. On the other hand, cell fusion assays detected no functional difference between the glycoproteins of the two viruses. Essentially the same transcriptional impediment with reduced syncytium induction following Vero cell adaptation was found with two other pairs of strains that had been similarly prepared. Nucleotide sequence comparison between the 9301B and 9301V viruses revealed that a few (at most five) amino acid changes, which sporadically took place in the polymerase (L and P proteins) and/or accessory V and C proteins, were responsible for the in vitro and in vivo attenuation through adaptation to growth in Vero cells.

CD62E-Positive Endothelial Microparticle-Neutrophil Conjugates, a Novel Marker of Prothrombotic and Inflammatory Disorders.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3958-3958
Author(s):  
Julio A. Chirinos ◽  
Wenche Jy ◽  
Andres O. Soriano ◽  
Aurelio Castrellon ◽  
Freddy Del Carpio ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Metabolic Syndrome ◽  
Congestive Heart Failure ◽  
Neutrophil Activation ◽  
Disease States ◽  
Acute Venous Thromboembolism ◽  
Normal Controls

Abstract Background: In vitro studies have shown that endothelial-cell derived microparticles (EMP) can bind and activate leukocytes. It is unknown whether EMP binding to leukocytes regulates leukocyte activation in vivo. In this study, we examined the correlation between EMP binding to neutrophils (EMP-neutrophil conjugates) and neutrophil activation in various clinical conditions. Methods: We studied a total of 251 venous blood samples from 221 subjects with several prothrombotic and inflammatory conditions, including acute venous thromboembolism (n=25), atrial fibrillation (n=48), metabolic syndrome (n=37), congestive heart failure (n=44), early sepsis (n=35), late sepsis (n=30), as well as normal controls (n=32). Using flow cytometry, we measured leukocyte expression of activation marker CD11b and 2 different populations of EMP-neutrophil conjugates. Bitmapping by forward- and side-scatter gating was used to identify neutrophils; EMP62E+-neutrophil conjugates and EMP54+-neutrophil conjugates were measured based on the detection of E-selectin (CD62E) or CD54, respectively, co-expressed with CD45 in neutrophils. Neutrophil nitric oxide (NO) levels were measured by flow cytometry after loading neutrophils with the membrane permeable NO-selective fluorescent indicator DAF-DA. Results: Levels of EMP62E+-neutrophil conjugates consistently and significantly correlated with CD11b expression. This finding was present in patients with acute venous thromboembolism (r=0.46; p=0.02), atrial fibrillation (r=0.42; p=0.003), metabolic syndrome (r=0.56; p<0.0001), congestive heart failure (r=0.70; p<0.0001), early sepsis (r=0.50; p= 0.003), late sepsis (r=0.55;p=0.002), as well as normal controls (r=0.86; p<0.0001). In contrast, a correlation between EMP54+-neutrophil conjugates and neutrophil activation was not found in any of the studied populations (all p>0.05). EMP62E+-neutrophil conjugates correlated with NO levels in neutrophils in patients with congestive heart failure (r=0.48; p=0.001) and atrial fibrillation (r=0.33; p=0.02), but no correlation was seen in other disease states. Conclusions: EMP62E+-neutrophil conjugates strongly correlate with neutrophil activation in normal adults, as well as in multiple pro-inflammatory and pro-thrombotic disease states. EMP62E+-neutrophil conjugates may serve as a marker of prothrombotic and inflammatory states. Our results combined with prior in vitro studies suggest that EMP62E+ binding to neutrophils is an important and “universal” determining factor for neutrophil activation in vivo in humans. In contrast, binding of EMP54+ to neutrophils does not seem to regulate neutrophil activation. These findings also support the concept that different species of endothelial microparticles have different biologic functions. EMP binding to neutrophils seems to affect NO production in only some disease states.

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