The effect of chromosome 9p21 variants on cardiovascular disease may be modified by dietary intake: evidence from a case/control and a prospective study

Background

One of the most robust genetic associations for cardiovascular disease (CVD) is the Chromosome 9p21 region. However, the interaction of this locus with environmental factors has not been extensively explored. We investigated the association of 9p21 with myocardial infarction (MI) in individuals of different ethnicities, and tested for an interaction with environmental factors.

Methods and Findings

We genotyped four 9p21 SNPs in 8,114 individuals from the global INTERHEART study. All four variants were associated with MI, with odds ratios (ORs) of 1.18 to 1.20 (1.85×10⁻⁸≤p≤5.21×10⁻⁷). A significant interaction (p = 4.0×10⁻⁴) was observed between rs2383206 and a factor-analysis-derived “prudent” diet pattern score, for which a major component was raw vegetables. An effect of 9p21 on MI was observed in the group with a low prudent diet score (OR = 1.32, p = 6.82×10⁻⁷), but the effect was diminished in a step-wise fashion in the medium (OR = 1.17, p = 4.9×10⁻³) and high prudent diet scoring groups (OR = 1.02, p = 0.68) (p = 0.014 for difference). We also analyzed data from 19,129 individuals (including 1,014 incident cases of CVD) from the prospective FINRISK study, which used a closely related dietary variable. In this analysis, the 9p21 risk allele demonstrated a larger effect on CVD risk in the groups with diets low or average for fresh vegetables, fruits, and berries (hazard ratio [HR] = 1.22, p = 3.0×10⁻⁴, and HR = 1.35, p = 4.1×10⁻³, respectively) compared to the group with high consumption of these foods (HR = 0.96, p = 0.73) (p = 0.0011 for difference). The combination of the least prudent diet and two copies of the risk allele was associated with a 2-fold increase in risk for MI (OR = 1.98, p = 2.11×10⁻⁹) in the INTERHEART study and a 1.66-fold increase in risk for CVD in the FINRISK study (HR = 1.66, p = 0.0026).

Conclusions

The risk of MI and CVD conferred by Chromosome 9p21 SNPs appears to be modified by a prudent diet high in raw vegetables and fruits. Please see later in the article for the Editors'' Summary     

A functional analysis of mitochondrial respiratory chain cytochrome bc1 complex in Gaeumannomyces tritici by RNA silencing as a possible target of carabrone

Gaeumannomyces tritici, an ascomycete soilborne fungus, causes a devastating root disease in wheat. Carabrone, a botanical bicyclic sesquiterpenic lactone, is a promising fungicidal agent that can effectively control G. tritici. However, the mechanism of action of carabrone against G. tritici remains largely unclear. Here, we used immunogold for subcellular localization of carabrone and the results showed that carabrone is subcellularly localized in the mitochondria of G. tritici. We then explored the functional analysis of genes GtCytc₁, GtCytb, and GtIsp of the mitochondrial respiratory chain cytochrome bc₁ complex in G. tritici by RNA silencing as a possible target of carabrone. The results showed that the silenced mutant ∆GtIsp is less sensitive to carabrone compared to ∆GtCytc₁ and ∆GtCytb. Compared with the control, the activities of complex III in all the strains, except ∆GtIsp and carabrone-resistant isolate 24-HN-1, were significantly decreased following treatment with carabrone at EC₂₀ and EC₈₀ in vitro (40%–50% and 70%–80%, respectively). The activities of mitochondrial respiratory chain complex III and the mitochondrial respiration oxygen consumption rates in all the strains, except ∆GtIsp and 24-HN-1, were higher with respect to the control when treated with carabrone at EC₂₀ in vivo. The rates of mitochondrial respiration of all strains, except ∆GtIsp, were significantly inhibited following treatment with carabrone at EC₈₀ (ranging from 57% to 81%). This study reveals that the targeting of the iron–sulphur protein encoded by GtIsp is highly sensitive to carabrone and provides a direction for the research of carabrone's target.     

Protective effects of dihydromyricetin on primary hippocampal astrocytes from cytotoxicity induced by comorbid diabetic neuropathic pain and depression

Activated astrocytes play a key role in diabetic neuropathic pain and depression. We aimed to assess the protective effects of dihydromyricetin (DHM) on primary hippocampal astrocytes cultured with high glucose (HG), substance P (SP), and corticosterone (CORT). Culturing with HG + SP + CORT resulted in damage to primary hippocampal astrocytes, which simulates the clinical damage caused by comorbidity of diabetic neuropathic pain and depression. Western blot, qPCR, and immunofluorescence analyses revealed that HG + SP + CORT increased P2X₇ receptor expression in primary hippocampal astrocytes, which was reversed by DHM treatment. Further, HG + SP + CORT elevated TNF-α, IL-1β, free Ca²⁺, and ERK1/2 phosphorylation levels, which was inhibited by DHM or P2X₇ shRNA treatment. Moreover, DHM significantly reduced the P2X₇ agonist-activated currents in HEK293 cells transfected with the P2X₇ receptor. These findings suggest that DHM can protect primary hippocampal astrocytes cultured with HG + SP + CORT from P2X₇ receptor-mediated damage. Culturing cells with HG + SP + CORT might be a viable cell model for cellular injury exploration of diabetic comorbid pain and depression.

     

Colorimetric detection of mercury, lead and copper ions simultaneously using protein-functionalized gold nanoparticles

A simple, cost-effective and rapid colorimetric method for any or all of Hg(2+), Pb(2+) and Cu(2+) detection using papain-functionalized gold nanoparticles (P-AuNPs) has been developed. Papain is a protein with seven cystein residues, which can selectively bind with Hg(2+), Pb(2+) and Cu(2+). We functionalized gold nanoparticles with papain. The P-AuNPs could be used to simultaneously detect Hg(2+), Pb(2+) and Cu(2+), and showed different responses to the three ions in an aqueous solution based on the aggregation-induced color change of gold nanoparticles. The P-AuNPs displayed the most obvious response to mercury ions in water in contrast to lead and copper ions, and the real water sample analysis verified the conclusion. The sensitivity of the detection system was influenced by the pH of the P-AuNPs solution, the concentration of P-AuNPs and the size of gold nanoparticles, and we found that larger gold nanoparticles contributed to more sensitive results. The detection system can detect as low as 200 nM Hg(2+), Pb(2+) or Cu(2+) using 42 nm gold nanoparticles. We expect our approach to have wide-ranging applications in the developing region for monitoring water quality in some areas.     

Conservation of the salt overly sensitive pathway in rice

The salt tolerance of rice (Oryza sativa) correlates with the ability to exclude Na+ from the shoot and to maintain a low cellular Na+/K+ ratio. We have identified a rice plasma membrane Na+/H+ exchanger that, on the basis of genetic and biochemical criteria, is the functional homolog of the Arabidopsis (Arabidopsis thaliana) salt overly sensitive 1 (SOS1) protein. The rice transporter, denoted by OsSOS1, demonstrated a capacity for Na+/H+ exchange in plasma membrane vesicles of yeast (Saccharomyces cerevisiae) cells and reduced their net cellular Na+ content. The Arabidopsis protein kinase complex SOS2/SOS3, which positively controls the activity of AtSOS1, phosphorylated OsSOS1 and stimulated its activity in vivo and in vitro. Moreover, OsSOS1 suppressed the salt sensitivity of a sos1-1 mutant of Arabidopsis. These results represent the first molecular and biochemical characterization of a Na+ efflux protein from monocots. Putative rice homologs of the Arabidopsis protein kinase SOS2 and its Ca2+-dependent activator SOS3 were identified also. OsCIPK24 and OsCBL4 acted coordinately to activate OsSOS1 in yeast cells and they could be exchanged with their Arabidopsis counterpart to form heterologous protein kinase modules that activated both OsSOS1 and AtSOS1 and suppressed the salt sensitivity of sos2 and sos3 mutants of Arabidopsis. These results demonstrate that the SOS salt tolerance pathway operates in cereals and evidences a high degree of structural conservation among the SOS proteins from dicots and monocots.     

Hindered tomato reproductive development by altered brassinosteroid sensitivity1 mutant

Plant Growth Regulation - The extracellular domain of bri1 perceives brassinosteroids (BRs), and its signal transduction mediates the kinase signal transduction pathway. Disruption in this...     

Identification of novel interactors and potential phosphorylation substrates of GsSnRK1 from wild soybean (Glycine soja)

The plant sucrose nonfermenting kinase 1 (SnRK1) kinases play the central roles in the processes of energy balance, hormone perception, stress resistance, metabolism, growth, and development. However, the functions of these kinases are still elusive. In this study, we used GsSnRK1 of wild soybean as bait to perform library‐scale screens by the means of yeast two‐hybrid to identify its interacting proteins. The putative interactions were verified by yeast retransformation and β‐galactosidase assays, and the selected interactions were further confirmed in planta by bimolecular fluorescence complementation and biochemical Co‐IP assays. Protein phosphorylation analyses were carried out by phos‐tag assay and anti‐phospho‐(Ser/Thr) substrate antibodies. Finally, we obtained 24 GsSnRK1 interactors and several putative substrates that can be categorized into SnRK1 regulatory β subunit, protein modification, biotic and abiotic stress‐related, hormone perception and signalling, gene expression regulation, water and nitrogen transport, metabolism, and unknown proteins. Intriguingly, we first discovered that GsSnRK1 interacted with and phosphorylated the components of soybean nodulation and symbiotic nitrogen fixation. The interactions and potential functions of GsSnRK1 and its associated proteins were extensively discussed and analysed. This work provides plausible clues to elucidate the novel functions of SnRK1 in response to variable environmental, metabolic, and physiological requirements.