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Anal Chem ; 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31593446


Imaging mass spectrometry (IMS) enables the spatially targeted molecular assessment of biological tissues at cellular resolutions. New developments and technologies are essential for uncovering the molecular drivers of native physiological function and disease. Instrumentation must maximize spatial resolution, throughput, sensitivity, and specificity, because tissue imaging experiments consist of thousands to millions of pixels. Here, we report the development and application of a matrix-assisted laser desorption/ionization (MALDI) trapped ion-mobility spectrometry (TIMS) imaging platform. This prototype MALDI timsTOF instrument is capable of 10 µm spatial resolutions and 20 pixels/s throughput molecular imaging. The MALDI source utilizes a Bruker SmartBeam 3-D laser system that can generate a square burn pattern of <10 × 10 µm at the sample surface. General image performance was assessed using murine kidney and brain tissues and demonstrate that high-spatial-resolution imaging data can be generated rapidly with mass measurement errors <5 ppm and ∼40 000 resolving power. Initial TIMS-based imaging experiments were performed on whole-body mouse pup tissue demonstrating the separation of closely isobaric [PC(32:0) + Na]+ and [PC(34:3) + H]+ (3 mDa mass difference) in the gas phase. We have shown that the MALDI timsTOF platform can maintain reasonable data acquisition rates (>2 pixels/s) while providing the specificity necessary to differentiate components in complex mixtures of lipid adducts. The combination of high-spatial-resolution and throughput imaging capabilities with high-performance TIMS separations provides a uniquely tunable platform to address many challenges associated with advanced molecular imaging applications.

MBio ; 10(5)2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31662455


The reverse transsulfuration pathway is the major route for the metabolism of sulfur-containing amino acids. The role of this metabolic pathway in macrophage response and function is unknown. We show that the enzyme cystathionine γ-lyase (CTH) is induced in macrophages infected with pathogenic bacteria through signaling involving phosphatidylinositol 3-kinase (PI3K)/MTOR and the transcription factor SP1. This results in the synthesis of cystathionine, which facilitates the survival of pathogens within myeloid cells. Our data demonstrate that the expression of CTH leads to defective macrophage activation by (i) dysregulation of polyamine metabolism by depletion of S-adenosylmethionine, resulting in immunosuppressive putrescine accumulation and inhibition of spermidine and spermine synthesis, and (ii) increased histone H3K9, H3K27, and H3K36 di/trimethylation, which is associated with gene expression silencing. Thus, CTH is a pivotal enzyme of the innate immune response that disrupts host defense. The induction of the reverse transsulfuration pathway by bacterial pathogens can be considered an unrecognized mechanism for immune escape.IMPORTANCE Macrophages are professional immune cells that ingest and kill microbes. In this study, we show that different pathogenic bacteria induce the expression of cystathionine γ-lyase (CTH) in macrophages. This enzyme is involved in a metabolic pathway called the reverse transsulfuration pathway, which leads to the production of numerous metabolites, including cystathionine. Phagocytized bacteria use cystathionine to better survive in macrophages. In addition, the induction of CTH results in dysregulation of the metabolism of polyamines, which in turn dampens the proinflammatory response of macrophages. In conclusion, pathogenic bacteria can evade the host immune response by inducing CTH in macrophages.

J Am Heart Assoc ; 8(1): e010606, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30606084


Background Trimethylamine-N-oxide ( TMAO ), a diet-derived, gut microbial-host cometabolite, has been associated with adverse cardiovascular outcomes in patient populations; however, evidence is lacking from prospective studies conducted in general populations and non-Western populations. Methods and Results We evaluated urinary levels of TMAO and its precursor metabolites (ie, choline, betaine, and carnitine) in relation to risk of coronary heart disease ( CHD ) among Chinese adults in a nested case-control study, including 275 participants with incident CHD and 275 individually matched controls. We found that urinary TMAO , but not its precursors, was associated with risk of CHD . The odds ratio for the highest versus lowest quartiles of TMAO was 1.91 (95% CI, 1.08-3.35; Ptrend=0.008) after adjusting for CHD risk factors including obesity, diet, lifestyle, and metabolic diseases and 1.75 (95% CI, 0.96-3.18; Ptrend=0.03) after further adjusting for potential confounders or mediators including central obesity, dyslipidemia, inflammation, and intake of seafood and deep-fried meat or fish, which were associated with TMAO level in this study. The odds ratio per standard deviation increase in log- TMAO was 1.30 (95% CI, 1.03-1.63) in the fully adjusted model. A history of diabetes mellitus modified the TMAO - CHD association. A high TMAO level (greater than or equal to versus lower than the median) was associated with odds ratios of 6.21 (95% CI, 1.64-23.6) and 1.56 (95% CI, 1.00-2.43), respectively, among diabetic and nondiabetic participants ( Pinteraction=0.02). Diabetes mellitus status also modified the associations of choline, betaine, and carnitine with risk of CHD ; significant positive associations were found among diabetic participants, but null associations were noted among total and nondiabetic participants. Conclusions Our study suggests that TMAO may accelerate the development of CHD , highlighting the importance of diet-gut microbiota-host interplay in cardiometabolic health.