Publications by authors named "Alexander V Sorokin"

31 Publications

Subclinical Liver Disease is Associated with Subclinical Atherosclerosis in Psoriasis: Results from Two Observational Studies.

J Invest Dermatol 2021 Jul 19. Epub 2021 Jul 19.

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Psoriasis is associated with a higher risk of liver diseases. We investigated the impact of hepatic steatosis (European cohort) and hepatic inflammation (United States cohort) on subclinical atherosclerosis. In the European cohort (n=76 psoriasis participants and 76 controls), non-alcoholic fatty liver disease (NAFLD), assessed by the sonographic hepatorenal index (SHRI), was more prevalent in psoriasis than controls (61% vs 45%; p=.04). Psoriasis participants with NAFLD had a higher prevalence of subclinical atherosclerosis (ultrasonographic presence of plaque in femoral or carotid arteries) than psoriasis without NAFLD (61% vs 23%; p=.006) and controls with NAFLD (61% vs 32%; p<.05). SHRI was a determinant of subclinical atherosclerosis in psoriasis (OR, 3.5; p=.01). In the United States cohort, (n=162 psoriasis participants who underwent positron emission tomography and coronary CT angiography), those with high hepatic F-FDG uptake had higher noncalcified (1.3 (0.49 mm) vs 1.0 (0.40 mm)), fibrofatty (0.23 (0.15 mm) vs 0.11 (0.087 mm)), and lipid rich necrotic core (4.3 (2.3 mm) vs 3.0 (1.7 mm)) coronary burden (all p<.001,). Hepatic F-FDG uptake associated with noncalcified (β=0.28; p<.001), fibrofatty (β=0.49; p<.001) and lipid rich necrotic core (β=0.28; p=.003) burden. These results demonstrate the downstream cardiovascular effects of subclinical liver disease in psoriasis.
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http://dx.doi.org/10.1016/j.jid.2021.05.034DOI Listing
July 2021

Chronic inflammatory diseases and coronary heart disease: Insights from cardiovascular CT.

J Cardiovasc Comput Tomogr 2021 Jun 24. Epub 2021 Jun 24.

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Epidemiological and clinical studies have demonstrated a consistent relationship between increased systemic inflammation and increased risk of cardiovascular events. In chronic inflammatory states, traditional risk factors only partially account for the development of coronary artery disease (CAD) but underestimate total cardiovascular risk likely due to the residual risk of inflammation. Computed coronary tomography angiography (CCTA) may aid in risk stratification by noninvasively capturing early CAD, identifying high risk plaque morphology and quantifying plaque at baseline and in response to treatment. In this review, we focus on reviewing studies on subclinical atherosclerosis by CCTA in individuals with chronic inflammatory conditions including rheumatoid arthritis (RA), systemic lupus erythematous (SLE), human immunodeficiency virus (HIV) infection and psoriasis. We start with a brief review on the role of inflammation in atherosclerosis, highlight the utility of using CCTA to delineate vessel wall and plaque characteristics and discuss combining CCTA with laboratory studies and emerging technologies to complement traditional risk stratification in chronic inflammatory states.
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http://dx.doi.org/10.1016/j.jcct.2021.06.003DOI Listing
June 2021

The relationship between TNF-alpha driven inflammation, lipids and endothelial function in rheumatoid arthritis: a complex puzzle continues.

Cardiovasc Res 2021 Jun 4. Epub 2021 Jun 4.

Section of Inflammation and Cardiovascular Diseases, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.

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http://dx.doi.org/10.1093/cvr/cvab190DOI Listing
June 2021

Metabolic syndrome and its factors are associated with noncalcified coronary burden in psoriasis: An observational cohort study.

J Am Acad Dermatol 2021 May 3;84(5):1329-1338. Epub 2021 Feb 3.

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

Background: Psoriasis is associated with a heightened risk of cardiovascular disease and higher prevalence of metabolic syndrome.

Objective: Investigate the effect of metabolic syndrome and its factors on early coronary artery disease assessed as noncalcified coronary burden by coronary computed tomography angiography in psoriasis.

Methods: This cross-sectional study consisted of 260 participants with psoriasis and coronary computed tomography angiography characterization. Metabolic syndrome was defined according to the harmonized International Diabetes Federation criteria.

Results: Of the 260 participants, 80 had metabolic syndrome (31%). The metabolic syndrome group had a higher burden of cardiometabolic disease, systemic inflammation, noncalcified coronary burden, and high-risk coronary plaque. After adjusting for Framingham risk score, lipid-lowering therapy, and biologic use, metabolic syndrome (β = .31; P < .001) and its individual factors of waist circumference (β = .33; P < .001), triglyceride levels (β = .17; P = .005), blood pressure (β = .18; P = .005), and fasting glucose (β = .17; P = .009) were significantly associated with noncalcified coronary burden. After adjusting for all other metabolic syndrome factors, blood pressure and waist circumference remained significantly associated with noncalcified coronary burden.

Limitations: Observational nature with limited ability to control for confounders.

Conclusions: In psoriasis, individuals with metabolic syndrome had more cardiovascular disease risk factors, systemic inflammation, and noncalcified coronary burden. Efforts to increase metabolic syndrome awareness in psoriasis should be undertaken to reduce the heightened cardiovascular disease risk.
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http://dx.doi.org/10.1016/j.jaad.2020.12.044DOI Listing
May 2021

Oxidized Lipids and Lipoprotein Dysfunction in Psoriasis.

J Psoriasis Psoriatic Arthritis 2020 Oct 26;5(4):139-146. Epub 2020 Aug 26.

Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

Background: Psoriasis is a chronic immune-mediated inflammatory skin disease associated with increased development of metabolic abnormalities including obesity and dyslipidemia, as well as increased cardiovascular disease (CVD) risk. Shared pathophysiological mechanisms linking psoriasis to CVD include altered immune activation, elevated chronic systemic inflammation, and lipoprotein dysfunction characterized by oxidative damage to lipids and apolipoproteins.

Objective: This review aims to provide evidence-based proof for existing relationships between psoriatic inflammation, lipid oxidation, and increased CVD risk.

Methods: We included review articles and original research papers, published between 1980 and 2020, using the following key words: psoriasis, oxidized lipids, oxidation, dyslipidemia, and inflammation.

Results: Systemic inflammation underlying psoriasis leads to increased skin accumulation of pro-inflammatory oxidized lipids, derived from the omega-6 fatty acids, along with counteracting anti-inflammatory lipid mediators, products of the omega-3 polyunsaturated fatty acids. Imbalance in these metabolites culminates in impaired inflammation resolution and results in multisystemic biological alterations. Sustained systemic inflammation results in excessive lipid oxidation, generating proatherogenic oxidized low- and high-density lipoproteins. Together, these pathophysiological mechanisms contribute to increased CVD risk associated with psoriasis disease.

Conclusion: Available anti-inflammatory treatment showed promising clinical results in treating psoriasis, although further research is warranted on managing associated dyslipidemia and establishing novel cardiometabolic markers specific for both skin and vascular pathology.
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http://dx.doi.org/10.1177/2475530320950268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646705PMC
October 2020

Chronic inflammation in psoriasis promotes visceral adiposity associated with noncalcified coronary burden over time.

JCI Insight 2020 11 19;5(22). Epub 2020 Nov 19.

National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.

BACKGROUNDPsoriasis is a chronic inflammatory skin disease associated with increased obesity, noncalcified coronary artery burden (NCB), and incident myocardial infarction. Here, we sought to assess the relationship among inflammation, visceral adipose tissue (VAT), and NCB. Furthermore, we evaluated whether improvement in VAT would be associated with reduction in NCB over time in psoriasis.METHODSConsecutive psoriasis patients underwent coronary CT angiography to quantify NCB and abdominal CT to calculate VAT at baseline (n = 237), 1 year (n = 176), and 4 years (n = 50).RESULTSPatients with high levels of high-sensitivity C-reactive protein (hs-CRP) had significantly greater visceral adiposity (17,952.9 ± 849.2 cc3 vs. 13370.7 ± 806.8 cc3, P < 0.001) and noncalcified coronary burden (1.26 ± 0.03 vs. 1.07 ± 0.02 mm2) than those with low levels of hs-CRP. Those with higher levels of VAT had more systemic inflammation (hs-CRP, median [IQR], 2.5 mg/L [1.0-5.3 mg/L] vs. 1.2 mg/L [0.6-2.9 mg/L]), with approximately 50% higher NCB (1.42 ± 0.6 mm2 vs. 0.91 ± 0.2 mm2, P < 0.001). VAT associated with NCB in fully adjusted models (β = 0.47, P < 0.001). At 1-year follow-up, patients who had worsening hs-CRP had an increase in VAT (14,748.7 ± 878.1 cc3 to 15,158.7 ± 881.5 cc3; P = 0.03), whereas those who had improved hs-CRP improved their VAT (16,876.1 ± 915.2 cc3 to 16310.4 ± 889.6 cc3; P = 0.04). At 1 year, there was 10.3% reduction in NCB in those who had decreased VAT (β = 0.26, P < 0.0001), which persisted in a subset of patients at 4 years (β = 0.39, P = 0.003).CONCLUSIONSInflammation drives development of VAT, increased cardiometabolic risk, and NCB in psoriasis. Reduction of inflammation associated with reduction in VAT and associated with longitudinal improvement in NCB. These findings demonstrate the important role of inflammation in the development of VAT in humans and its effect on early atherogenesis.TRIAL REGISTRATIONClinicalTrials.gov NCT01778569.FUNDINGThis study was supported by the National Heart, Lung, and Blood Institute Intramural Research Program (HL006193-05), the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation (no. 2014194), the American Association for Dental Research, the Colgate-Palmolive Company, Genentech, and Elsevier as well as private donors.
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http://dx.doi.org/10.1172/jci.insight.142534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710282PMC
November 2020

COVID-19-Associated dyslipidemia: Implications for mechanism of impaired resolution and novel therapeutic approaches.

FASEB J 2020 08 26;34(8):9843-9853. Epub 2020 Jun 26.

Lipoprotein Metabolism Laboratory, Translational Vascular Medicine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

The current coronavirus disease 2019 (COVID-19) pandemic presents a global challenge for managing acutely ill patients and complications from viral infection. Systemic inflammation accompanied by a "cytokine storm," hemostasis alterations and severe vasculitis have all been reported to occur with COVID-19, and emerging evidence suggests that dysregulation of lipid transport may contribute to some of these complications. Here, we aim to summarize the current understanding of the potential mechanisms related to COVID-19 dyslipidemia and propose possible adjunctive type therapeutic approaches that modulate lipids and lipoproteins. Specifically, we hypothesize that changes in the quantity and composition of high-density lipoprotein (HDL) that occurs with COVID-19 can significantly decrease the anti-inflammatory and anti-oxidative functions of HDL and could contribute to pulmonary inflammation. Furthermore, we propose that lipoproteins with oxidized phospholipids and fatty acids could lead to virus-associated organ damage via overactivation of innate immune scavenger receptors. Restoring lipoprotein function with ApoA-I raising agents or blocking relevant scavenger receptors with neutralizing antibodies could, therefore, be of value in the treatment of COVID-19. Finally, we discuss the role of omega-3 fatty acids transported by lipoproteins in generating specialized proresolving mediators and how together with anti-inflammatory drugs, they could decrease inflammation and thrombotic complications associated with COVID-19.
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http://dx.doi.org/10.1096/fj.202001451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361619PMC
August 2020

Comparison of Omega-3 Eicosapentaenoic Acid Versus Docosahexaenoic Acid-Rich Fish Oil Supplementation on Plasma Lipids and Lipoproteins in Normolipidemic Adults.

Nutrients 2020 Mar 12;12(3). Epub 2020 Mar 12.

Lipoprotein Metabolism Section, Translational Vascular Medicine Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892-1666, USA.

Background: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have both shared and different cardiovascular effects, and commonly used fish oil supplements have considerably varied EPA/DHA ratios.

Aims: We compared the effects of fish oil supplements with different EPA/DHA ratios on lipoprotein metabolism.

Methods: In a double-blind, randomized cross-over study, normolipidemic adults (n = 30) consumed 12 g/day of EPA-rich (EPA/DHA: 2.3) or DHA-rich (EPA/DHA: 0.3) fish oil for 8-weeks, separated by an 8-week washout period.

Results: Both fish oil supplements similarly lowered plasma TG levels and TG-related NMR parameters versus baseline ( < 0.05). There were no changes in plasma cholesterol-related parameters due to either fish oil, although on-treatment levels for LDL particle number were slightly higher for DHA-rich oil compared with EPA-rich oil ( < 0.05). Both fish oil supplements similarly altered HDL subclass profile and proteome, and down regulated HDL proteins related to inflammation, with EPA-rich oil to a greater extent. Furthermore, EPA-rich oil increased apoM abundance versus DHA-rich oil ( < 0.05).

Conclusions: Overall, fish oil supplements with varied EPA/DHA ratios had similar effects on total lipids/lipoproteins, but differences were observed in lipoprotein subfraction composition and distribution, which could impact on the use of EPA versus DHA for improving cardiovascular health.
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http://dx.doi.org/10.3390/nu12030749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146314PMC
March 2020

Supplementation with saury oil, a fish oil high in omega-11 monounsaturated fatty acids, improves plasma lipids in healthy subjects.

J Clin Lipidol 2020 Jan - Feb;14(1):53-65.e2. Epub 2019 Oct 31.

Lipoprotein Metabolism Section, Translational Vascular Medicine Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA.

Background: Fish oil enriched in omega-11 long-chain monounsaturated fatty acids (LCMUFAs; C20:1 and C22:1 isomers combined) have shown lipid-lowering and atheroprotective effects in animal models.

Objective: To perform a first-in-human trial of LCMUFA-rich saury fish oil supplementation to test its safety and possible effect on plasma lipids.

Methods: A double-blind, randomized, crossover clinical trial was carried out in 30 healthy normolipidemic adults (BMI <25 kg/m; mean TG, 84 mg/dL). Treatment periods of 8 weeks were separated by an 8-week washout period. Subjects were randomized to receive either 12 g of saury oil (3.5 g of LCMUFA and 3.4 g of omega-3 FAs) or identical capsules with control oil (a mixture of sardine and olive oil; 4.9 g of shorter-chain MUFA oleate and 3 g of omega-3 FAs).

Results: Saury oil supplementation was safe and resulted in LDL particle counts 12% lower than control oil (P < .001). Saury oil also had a minor effect on increasing HDL particle size (9.8 nm vs 9.7 nm; P < .05) based on a linear mixed effect model. In contrast, control oil, but not saury oil, increased LDL-C by 7.5% compared with baseline (P < .05). Saury oil had similar effects compared with control oil on lowering plasma TG levels, VLDL, and TG-rich lipoprotein particle counts (by ∼16%, 25%, and 35%, respectively; P < .05), and increasing HDL-C and cholesterol efflux capacity (by ∼6% and 8%, respectively; P < .05) compared with baseline.

Conclusion: Saury oil supplementation is well tolerated and has beneficial effects on several cardiovascular parameters, such as LDL particle counts, HDL particle size, and plasma TG levels.
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http://dx.doi.org/10.1016/j.jacl.2019.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336206PMC
June 2021

PCSK9 inhibition as a novel therapeutic target for alcoholic liver disease.

Sci Rep 2019 11 20;9(1):17167. Epub 2019 Nov 20.

Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.

Alcoholic liver disease (ALD) causes significant morbidity and mortality, and pharmacological treatment options are limited. In this study, we evaluated the PCSK9 inhibitor alirocumab, a monoclonal antibody that robustly reduces low-density lipoprotein cholesterol (LDL-C), for the treatment of ALD using a rat model of chronic alcohol exposure. Alirocumab (50 mg/kg) or vehicle was administered weekly for 6 weeks to rats receiving a 12% alcohol liquid diet or an isocaloric control diet. At the end of the alcohol exposure protocol, serum and liver samples were obtained for molecular characterization and histopathological analysis. PCSK9 inhibition with alirocumab attenuated alcohol-induced hepatic triglyceride accumulation through regulation of lipid metabolism (mRNA expression of modulators of fatty acid synthesis (FAS) and catabolism (PPARα and CPT1)), hepatocellular injury (ALT), hepatic inflammation (mRNA expression of pro-inflammatory cytokines/chemokines (TNFa, IL-1β, IL-22, IL-33, IL-17α, IL-2, MIP-2, and MCP-1), and neutrophil infiltration (myeloperoxidase staining)). Alirocumab treatment also attenuated alcohol-induced PCSK9 mRNA elevation and upregulated LDL-receptor (LDL-R) via modulation of the transcription factors (SREBP-1, SREBP-2, and E2F1) in liver. We demonstrated that chronic anti-PCSK9 treatment using the monoclonal antibody alirocumab attenuated alcohol-induced steatohepatitis in the rat model. Given the large unmet clinical need for effective and novel treatments for ALD, anti-PCSK9 treatment with the monoclonal antibody that spares liver metabolism is a viable new therapeutic possibility. Future studies are needed to elucidate the exact role of PCSK9 in ALD and alcohol use disorder (AUD) and to evaluate efficacy and safety of anti-PCSK9 treatment in clinical populations with ALD/AUD.
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http://dx.doi.org/10.1038/s41598-019-53603-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868240PMC
November 2019

Association Between Soluble Lectinlike Oxidized Low-Density Lipoprotein Receptor-1 and Coronary Artery Disease in Psoriasis.

JAMA Dermatol 2020 02;156(2):151-157

National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland.

Importance: Psoriasis, a chronic inflammatory skin disease associated with accelerated noncalcified coronary burden (NCB) by coronary computed tomography angiography (CCTA), accelerates lipoprotein oxidation in the form of oxidized modified lipoproteins. A transmembrane scavenger receptor for these oxidized modified lipoproteins is lectinlike oxidized low-density lipoprotein receptor-1 (LOX-1), which has been reported to be associated with coronary artery disease. It is unknown whether this receptor is associated with coronary artery disease in psoriasis.

Objective: To assess the association between soluble LOX-1 (sLOX-1) and NCB in psoriasis over time.

Design, Setting, And Participants: In a cohort study at the National Institutes of Health, 175 consecutive patients with psoriasis were referred from outpatient dermatology practices between January 1, 2013, and October 1, 2017. A total of 138 consecutively recruited patients with psoriasis were followed up at 1 year.

Exposures: Circulating soluble lectinlike oxidized low-density lipoprotein receptor-1 levels were measured blindly by field scientists running undiluted serum using an enzyme-linked immunosorbent assay.

Main Outcomes And Measures: Coronary computed tomography angiography scans were performed to quantify NCB in all 3 major epicardial coronary arteries by a reader blinded to patient demographics, visit, and treatment status.

Results: Among the 175 patients with psoriasis, the mean (SD) age was 49.7 (12.6) years and 91 were men (55%). The cohort had relatively low median cardiovascular risk by Framingham risk score (median, 2.0 [interquartile range (IQR), 1.0-6.0]) and had a mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) suggestive of overweight profiles (29.6 [6.0]). Elevated sLOX-1 levels were found in patients with psoriasis compared with age- and sex-matched controls (median, 210.3 [IQR, 110.9-336.2] vs 83.7 [IQR, 40.1-151.0]; P < .001), and were associated with Psoriasis Area Severity Index (PASI) score (β = 0.23; 95% CI, 0.082-0.374; P = .003). Moreover, sLOX-1 was associated with NCB independent of hyperlipidemia status (β = 0.11; 95% CI, 0.016-0.200; P = .023), an association which persisted after adjusting for traditional cardiovascular risk factors, statin use, and biologic psoriasis treatment (β = 0.10; 95% CI, 0.014-0.193; P = .03). At 1 year, in those who had clinical improvement in PASI (eg, >50% improvement), a reduction in sLOX-1 (median, 311.1 [IQR, 160.0-648.8] vs median, 224.2 [IQR, 149.1 - 427.4]; P = .01) was associated with a reduction in NCB (β = 0.14; 95% CI, 0.028-0.246; P = .02).

Conclusions And Relevance: Soluble lectinlike oxidized low-density lipoprotein receptor-1 levels were elevated in patients with psoriasis and were associated with severity of skin disease. Moreover, sLOX-1 associated with NCB independent of hyperlipidemia status, suggesting that inflammatory sLOX-1 induction may modulate lipid-rich NCB in psoriasis. Improvement of skin disease was associated with a reduction of sLOX-1 at 1 year, demonstrating the potential role of sLOX-1 in inflammatory atherogenesis in psoriasis.
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http://dx.doi.org/10.1001/jamadermatol.2019.3595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902165PMC
February 2020

Colchicine's effects on lipoprotein particle concentrations in adults with metabolic syndrome: A secondary analysis of a randomized controlled trial.

J Clin Lipidol 2019 Nov - Dec;13(6):1016-1022.e2. Epub 2019 Oct 22.

Section on Growth and Obesity, Division of Intramural Research (DIR), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA.

Background: Colchicine has received renewed interest for its potential beneficial effects in secondary prevention of cardiovascular disease. This was presumed to be primarily because of its anti-inflammatory effects; however, limited data exist regarding colchicine's impact on other cardiovascular risk factors.

Objective: The aim of this study was to examine if colchicine's anti-inflammatory actions would lead to reduced circulating concentrations of oxidized low-density lipoprotein (oxLDL) in metabolically unhealthy individuals. We also examined if colchicine would improve concentrations of other atherogenic lipoprotein subfractions.

Methods: This is a secondary analysis of a double-blind, randomized, placebo-controlled pilot study in which 40 adults with metabolic syndrome were randomized to colchicine 0.6 mg or placebo twice daily for 3 months. Blood samples were collected in the fasted state. OxLDL was measured using enzyme-linked immunosorbent assay. Nuclear magnetic resonance spectroscopy was used to measure other lipoprotein particle subfraction concentrations.

Results: Compared with placebo, colchicine reduced markers of inflammation, including C-reactive protein, erythrocyte sedimentation rate, and GlycA (P < .01). Concentrations of oxLDL (P = .019) and small LDL (P = .022) appeared significantly increased in the colchicine arm. Colchicine had no significant effect on other lipoprotein subfractions or lipoprotein particle sizes (all P > .05).

Conclusion: Although colchicine may have benefit in secondary prevention of cardiovascular disease in at-risk individuals, we found no evidence that these effects are because of improvements in circulating atherogenic lipoprotein particle concentrations. Further studies are needed to confirm whether colchicine increases circulating oxLDL and small LDL levels in adults with metabolic syndrome. If true, additional research is warranted to elucidate the mechanisms underlying these associations.
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http://dx.doi.org/10.1016/j.jacl.2019.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911837PMC
July 2020

Association Between Oxidation-Modified Lipoproteins and Coronary Plaque in Psoriasis.

Circ Res 2018 11;123(11):1244-1254

From the Section of Inflammation and Cardiometabolic Diseases, Cardiovascular Branch, (A.V.S., Y.A.E., A.K.D., A.P.S., C.L.H., Y.B., J.A.R., M.Y.C., A.A.J., M.P.P., N.N.M.), National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.

Rationale: Psoriasis is a systemic inflammatory skin disease associated with cardiovascular disease and lipid dysfunction. However, traditional lipid parameters have limited prognostic value, whereas assessing oxidation-modified lipids in this inflammatory driven condition may capture additional risk. Recently, a study showed that psoriasis was associated with increased lipid-rich coronary plaques; therefore, investigating potential relationships with oxidation-modified lipids may speed understanding of increased cardiovascular disease in psoriasis.

Objective: To understand whether oxidation-modified lipids associate with traditional lipid phenotypes, cardiometabolic disease biomarkers, and total coronary plaque, with focus on noncalcified burden (NCB) by coronary computed tomographic angiography in psoriasis.

Methods And Results: Psoriasis subjects and controls (n=252) had profiling for oxidation-modified LDL (low-density lipoprotein), HDL (high-density lipoprotein), Lp(a) (lipoprotein[a]), cholesterol efflux capacity, lipoprotein particle size and number by NMR spectroscopy, and PON-1 (paraoxonase-1) activity. Blinded coronary computed tomographic angiography coronary artery disease characterization included total burden, NCB, and dense-calcified burden. Compared with healthy volunteers, psoriasis subjects were older (mean age, 50.1), had increased body mass index, and homeostatic model assessment of insulin resistance. Psoriasis subjects had increase in oxidized Lp(a), Lp(a), and oxidized HDL (oxHDL; P <0.05 for all) with significant association of oxidized LDL (β=0.10; P=0.020) and oxHDL (β=-0.11; P=0.007) with NCB. Moreover, psoriasis subjects expressed significantly higher PON-1 (kU/µL) activity compared with healthy volunteers (8.55±3.21 versus 6.24±3.82; P=0.01). Finally, psoriasis treatment was associated with a reduction in oxHDL (U/mL; 203.79±88.40 versus 116.36±85.03; P<0.001) and with a concomitant decrease in NCB at 1 year (1.04±0.44 versus 0.95±0.32; P=0.03).

Conclusions: Traditional lipids did not capture risk of lipid-rich plaque as assessed by NCB, whereas assaying oxidation-modification of lipids revealed significant association with oxidized LDL and oxHDL. The PON-1 activity was increased in psoriasis suggesting possible compensatory antioxidative effect. Psoriasis treatment was associated with a reduction in oxHDL. These findings support performance of larger studies to understand oxidation-modified lipids in inflammatory states.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.313608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6345554PMC
November 2018

Chronic Stress-Related Neural Activity Associates With Subclinical Cardiovascular Disease in Psoriasis: A Prospective Cohort Study.

JACC Cardiovasc Imaging 2020 02 15;13(2 Pt 1):465-477. Epub 2018 Nov 15.

Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

Objectives: This study hypothesized that there is an association between chronic stress (as indexed by resting amygdalar activity [AmygA]), hematopoietic system activity (HMPA), and subclinical cardiovascular indexes (aortic vascular inflammation [VI] and noncalcified coronary plaque burden [NCB]) in psoriasis (PSO). The study also hypothesized that treatment of PSO would improve these parameters.

Background: PSO is a stress-related chronic inflammatory condition that is associated with increased prevalence of subclinical cardiovascular disease (CVD). In individuals without PSO, stress has been linked to CVD through a serial biological pathway that involves the amygdala, hematopoietic tissues, and atherosclerotic plaques.

Methods: A total of 164 consecutive patients with PSO and 47 healthy volunteers underwent 18-fluorodeoxyglucose positron emission tomography/computed tomography scans for assessment of AmygA, HMPA, and VI, as well as coronary computed tomography angiography scans for quantifying NCB. Furthermore, a consecutive subset of 30 patients with severe PSO (Psoriasis Area Severity Index Score >10) were followed at 1 year to assess the relationship between skin disease improvement and AmygA, HMPA, VI, and NCB.

Results: The PSO cohort was middle-aged (mean age: 50 years), had low cardiovascular risk (Framingham risk score: median: 3) and had mild to moderate PSO activity (median Psoriasis Area Severity Index Score: 5.6). AmygA was higher in patients with PSO compared to volunteer participants. AmygA was associated with HMPA (bone marrow activity: β = 0.20, p = 0.01) and subclinical CVD (VI: β = 0.31, p < 0.001; NCB: β = 0.27, p < 0.001) The AmygA-CVD association was in part mediated by HMPA (VI: 20.9%, NCB: 36.7%). Following 1 year of PSO treatment in those with severe disease, improvement in skin disease was accompanied by a reduction in AmygA, bone marrow activity, and VI, with no progression of NCB.

Conclusions: In PSO, a chronic inflammatory disease state, AmygA, which is a manifestation of chronic stress, substantially contributes to the risk of subclinical CVD. Additional studies that use psychometric measures of stress are required to explore therapeutic impact.
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http://dx.doi.org/10.1016/j.jcmg.2018.08.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506409PMC
February 2020

Identification of proresolving and inflammatory lipid mediators in human psoriasis.

J Clin Lipidol 2018 Jul - Aug;12(4):1047-1060. Epub 2018 Apr 6.

Section of Inflammation and Cardiometabolic Diseases, Cardio-Pulmonary Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Background: Psoriasis (PSO) is an immune-mediated inflammatory disease associated with metabolic and cardiovascular comorbidities. It is now known that resolution of inflammation is an active process locally controlled by specialized proresolving mediators (SPMs), named resolvins (Rvs), protectins, and maresins.

Objective: It is unknown whether these potent lipid mediators (LMs) are involved in PSO pathophysiology and if the skin and blood have disease-specific SPMs phenotype profiles.

Methods: We used liquid chromatography-tandem mass spectrometry-based LM metabololipidomics to obtain skin and peripheral blood LM profiles from PSO compared to healthy subjects. Some LMs were tested in cell culture experiments with corresponding gene expression and protein concentration analyses.

Results: The levels of several LM were significantly elevated in lesional PSO skin compared to nonlesional and skin from healthy subjects. Particularly, RvD5, protectins Dx, and aspirin-triggered forms of lipoxin were present only in lesional PSO skin, whereas protectin D1 was present in nonlesional PSO skin. To determine specific roles of SPMs on skin-related inflammatory cytokines, RvD1 and RvD5 were incubated with human keratinocytes. RvD1 and RvD5 reduced the expression levels of interleukin 24 and S100A12, whereas only RvD1 significantly abrogated interleukin-24 production by keratinocytes.

Conclusions: These findings suggest that an imbalance between locally produced proresolution and proinflammatory LMs identified in PSO skin and blood compartments might play a role in PSO pathophysiology. Moreover, some of the PSO-related cytokines can be modified by specific SPMs and involved mechanisms support investigation of targeting novel proresolving lipid mediators as a therapy for PSO.
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http://dx.doi.org/10.1016/j.jacl.2018.03.091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112609PMC
October 2019

Bioactive Lipid Mediator Profiles in Human Psoriasis Skin and Blood.

J Invest Dermatol 2018 07 15;138(7):1518-1528. Epub 2018 Feb 15.

Section of Inflammation and Cardiometabolic Diseases, Cardio-Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. Electronic address:

Psoriasis is a chronic immune-mediated disease that represents a unique model for investigating inflammation at local and systemic levels. Bioactive lipid mediators (LMs) are potent compounds reported to play a role in the development and resolution of inflammation. Currently, it is not known to what extent these LMs are involved in psoriasis pathophysiology and related metabolic dysfunction. Here, we use targeted and untargeted liquid chromatography-tandem mass spectrometry approaches to quantify LMs in skin and peripheral blood from psoriasis patients and compared them with those of healthy individuals. Lesional psoriasis skin was abundant in arachidonic acid metabolites, as 8-, 12- and 15-hydroxyeicosatetraenoic acid, compared with adjacent nonlesional and skin from healthy individuals. Additionally, a linoleic acid-derived LM, 13-hydroxyoctadecadienoic acid, was significantly increased compared with healthy skin (607.9 ng/g vs. 5.4 ng/g, P = 0.001). These psoriasis skin differences were accompanied by plasma decreases in antioxidant markers, including glutathione, and impaired lipolysis characterized by lower concentrations of primary and secondary bile acids. In conclusion, our study shows that psoriasis skin and blood have disease-specific phenotype profiles of bioactive LMs represented by omega-6 fatty acid-oxidized derivatives. These findings provide insights into psoriasis pathophysiology that could potentially contribute to new biomarkers and therapeutics.
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http://dx.doi.org/10.1016/j.jid.2018.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121727PMC
July 2018

Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis.

JCI Insight 2018 01 11;3(1). Epub 2018 Jan 11.

Section of Inflammation and Cardiometabolic Diseases and.

Inflammation is critical to atherogenesis. Psoriasis is a chronic inflammatory skin disease that accelerates atherosclerosis in humans and provides a compelling model to understand potential pathways linking these diseases. A murine model capturing the vascular and metabolic diseases in psoriasis would accelerate our understanding and provide a platform to test emerging therapies. We aimed to characterize a new murine model of skin inflammation (Rac1V12) from a cardiovascular standpoint to identify novel atherosclerotic signaling pathways modulated in chronic skin inflammation. The RacV12 psoriasis mouse resembled the human disease state, including presence of systemic inflammation, dyslipidemia, and cardiometabolic dysfunction. Psoriasis macrophages had a proatherosclerotic phenotype with increased lipid uptake and foam cell formation, and also showed a 6-fold increase in cholesterol crystal formation. We generated a triple-genetic K14-RacV12-/+/Srb1-/-/ApoER61H/H mouse and confirmed psoriasis accelerates atherogenesis (~7-fold increase). Finally, we noted a 60% reduction in superoxide dismutase 2 (SOD2) expression in human psoriasis macrophages. When SOD2 activity was restored in macrophages, their proatherogenic phenotype reversed. We demonstrate that the K14-RacV12 murine model captures the cardiometabolic dysfunction and accelerates vascular disease observed in chronic inflammation and that skin inflammation induces a proatherosclerotic macrophage phenotype with impaired SOD2 function, which associated with accelerated atherogenesis.
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http://dx.doi.org/10.1172/jci.insight.97179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821196PMC
January 2018

A systems approach for discovering linoleic acid derivatives that potentially mediate pain and itch.

Sci Signal 2017 Aug 22;10(493). Epub 2017 Aug 22.

Department of Perioperative Medicine, Clinical Center, NIH, Bethesda, MD 20814, USA.

Chronic pain and itch are common hypersensitivity syndromes that are affected by endogenous mediators. We applied a systems-based, translational approach to predict, discover, and characterize mediators of pain and itch that are regulated by diet and inflammation. Profiling of tissue-specific precursor abundance and biosynthetic gene expression predicted that inflamed skin would be abundant in four previously unknown 11-hydroxy-epoxy- or 11-keto-epoxy-octadecenoate linoleic acid derivatives and four previously identified 9- or 13-hydroxy-epoxy- or 9- or 13-keto-epoxy-octadecenoate linoleic acid derivatives. All of these mediators were confirmed to be abundant in rat and human skin by mass spectrometry. However, only the two 11-hydroxy-epoxy-octadecenoates sensitized rat dorsal root ganglion neurons to release more calcitonin gene-related peptide (CGRP), which is involved in pain transmission, in response to low pH (which mimics an inflammatory state) or capsaicin (which activates ion channels involved in nociception). The two 11-hydroxy-epoxy-octadecenoates share a 3-hydroxy--pentenyl--epoxide moiety, thus suggesting that this substructure could mediate nociceptor sensitization. In rats, intradermal hind paw injection of 11-hydroxy-12,13--epoxy-(9)-octadecenoate elicited C-fiber-mediated sensitivity to thermal pain. In a randomized trial testing adjunctive strategies to manage refractory chronic headaches, reducing the dietary intake of linoleic acid was associated with decreases in plasma 11-hydroxy-12,13--epoxy-(9)-octadecenoate, which correlated with clinical pain reduction. Human psoriatic skin had 30-fold higher 9-keto-12,13--epoxy-(10)-octadecenoate compared to control skin, and intradermal injection of this compound induced itch-related scratching behavior in mice. Collectively, these findings define a family of endogenous mediators with potential roles in pain and itch.
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http://dx.doi.org/10.1126/scisignal.aal5241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805383PMC
August 2017

Association Between Skin and Aortic Vascular Inflammation in Patients With Psoriasis: A Case-Cohort Study Using Positron Emission Tomography/Computed Tomography.

JAMA Cardiol 2017 09;2(9):1013-1018

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.

Importance: Inflammation is critical in the development of atherosclerosis. Psoriasis is a chronic inflammatory skin disease that is associated with increased vascular inflammation by 18fluorodeoxyglucose positron emission tomography/computed tomography in vivo and future cardiovascular events. It provides a human model to understand the effect of treating inflammation in a target organ (eg, the skin) on vascular diseases.

Objective: To investigate the association between change in skin disease severity and change in vascular inflammation at 1 year and to characterize the impact of 1 year of anti-tumor necrosis factor therapy on vascular inflammation.

Design, Setting, And Participants: In this prospective cohort study, 220 participants from outpatient practices were recruited at the US National Institutes of Health. A total of 115 consecutively recruited patients with psoriasis were followed up at 1 year. The study was conducted from January 1, 2013, through October 31, 2016, with data analyzed in November 2016.

Exposure: Skin inflammation measured as Psoriasis Area and Severity Index (PASI) score.

Main Outcomes And Measures: Vascular inflammation assessed as target-to-background ratio by 18fluorodeoxyglucose positron emission tomography/computed tomography.

Results: Among the 115 patients, the mean (SD) age at 1-year follow-up was 50.8 (12.8) years and 68 were men (59%). The cohort had a low cardiovascular risk by Framingham risk score and mild-to-moderate psoriasis, with a median PASI score of 5.2 (interquartile range, 3.0-8.9). At follow-up, the total cohort had a median improvement in PASI score of 33%, with use of topical therapy (60%), biological therapy (66%, mostly anti-tumor necrosis factor) and phototherapy (15%) (P < .001). Moreover, improvement in PASI score was associated with improvement in target-to-background ratio of 6%, mainly driven by those with higher responses in PASI score (P < .001). This association persisted beyond traditional risk factors (β = 0.19; 95% CI, 0.012-0.375; P = .03) and was the strongest in those initiated with anti-tumor necrosis factor therapy (β = 0.79; 95% CI, 0.269-1.311; P = .03).

Conclusions And Relevance: Improvement in psoriasis skin disease severity was associated with improvement in aortic vascular inflammation by 18fluorodeoxyglucose positron emission tomography/computed tomography, with greater improvement in aortic vascular inflammation observed in those who had higher than 75% reduction in skin disease severity. These findings suggest that controlling remote target organ inflammation (eg, in the skin) may improve vascular diseases; however, randomized clinical trials are needed to confirm these findings.
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http://dx.doi.org/10.1001/jamacardio.2017.1213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815046PMC
September 2017

Addition of aspirin to a fish oil-rich diet decreases inflammation and atherosclerosis in ApoE-null mice.

J Nutr Biochem 2016 09 19;35:58-65. Epub 2016 Jun 19.

Lipoprotein Metabolism Section, Cardio-Pulmonary Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Aspirin (ASA) is known to alter the production of potent inflammatory lipid mediators, but whether it interacts with omega-3 fatty acids (FAs) from fish oil to affect atherosclerosis has not been determined. The goal was to investigate the impact of a fish oil-enriched diet alone and in combination with ASA on the production of lipid mediators and atherosclerosis. ApoE(-/-) female mice were fed for 13weeks one of the four following diets: omega-3 FA deficient (OD), omega-3 FA rich (OR) (1.8g omega-3 FAs/kg·diet per day), omega-3 FA rich plus ASA (ORA) (0.1g ASA/kg·diet per day) or an omega-3 FA deficient plus ASA (ODA) with supplement levels equivalent to human doses. Plasma lipids, atherosclerosis, markers of inflammation, hepatic gene expression and aortic lipid mediators were determined. Hepatic omega-3 FAs were markedly higher in OR (9.9-fold) and ORA (7-fold) groups. Mice in both OR and ORA groups had 40% less plasma cholesterol in very low-density lipoprotein-cholesterol and low-density lipoprotein fractions, but aortic plaque area formation was only significantly lower in the ORA group (5.5%) compared to the OD group (2.5%). Plasma PCSK9 protein levels were approximately 70% lower in the OR and ORA groups. Proinflammatory aortic lipid mediators were 50%-70% lower in the ODA group than in the OD group and more than 50% lower in the ORA group. In summary, less aortic plaque lesions and aortic proinflammatory lipid mediators were observed in mice on the fish oil diet plus ASA vs. just the fish oil diet.
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http://dx.doi.org/10.1016/j.jnutbio.2016.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5201429PMC
September 2016

Self-reported depression in psoriasis is associated with subclinical vascular diseases.

Atherosclerosis 2016 08 27;251:219-225. Epub 2016 May 27.

National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Background And Aims: Psoriasis is a chronic inflammatory disorder associated with vascular inflammation, measured by 18-fluorodeoxyglucose positron emission tomography/computed tomography (18-FDG PET/CT), and an increased risk of myocardial infarction. Patients with psoriasis are also more likely to suffer from comorbid depression. Whether depression accelerates the development of subclinical atherosclerosis in psoriasis is unknown.

Methods: Patients were selected from within a larger psoriasis cohort. Those who reported a history of depression (N = 36) on survey were matched by age and gender to patients who reported no history of psychiatric illness (N = 36). Target-to-background ratio from FDG PET/CT was used to assess aortic vascular inflammation and coronary CT angiography scans were analyzed to determine coronary plaque burden. Multivariable linear regression was performed to understand the effect of self-reported depression on vascular inflammation and coronary plaque burden after adjustment for Framingham risk (standardized β reported).

Results: In unadjusted analyses, vascular inflammation and coronary plaque burden were significantly increased in patients with self-reported depression as compared to patients with psoriasis alone. After adjustment for Framingham Risk Score, vascular inflammation (β = 0.26, p = 0.02), total plaque burden (β = 0.17, p = 0.03), and non-calcified burden (β = 0.17, p = 0.03) were associated with self-reported depression.

Conclusions: Self-reported depression in psoriasis is associated with increased vascular inflammation and coronary plaque burden. Depression may play an important role in promoting subclinical atherosclerosis beyond traditional cardiovascular risk factors.
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http://dx.doi.org/10.1016/j.atherosclerosis.2016.05.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5305805PMC
August 2016

Association of matrix metalloproteinase 3 and γ-glutamyltransferase 1 gene polymorphisms with the cardio-ankle vascular index in young Russians.

Cardiol Young 2016 Aug 10;26(6):1238-40. Epub 2016 May 10.

3Department of Biology, Medical Genetics and Ecology,Kursk State Medical University,Kursk,Russia.

Specific gene polymorphisms are known to be associated with a different arterial physiology in the younger generation. The present study found that young Russians with the matrix metalloproteinase 3 6A/6A and γ-glutamyltransferase 1AA genotypes have lower levels of the cardio-ankle vascular index - a recent measure of arterial stiffness. This observation may serve as an additional tool for cardiovascular disease prevention in the young population.
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http://dx.doi.org/10.1017/S104795111600069XDOI Listing
August 2016

Antioxidant-related gene polymorphisms associated with the cardio-ankle vascular index in young Russians.

Cardiol Young 2016 Apr 17;26(4):677-82. Epub 2015 Jun 17.

3Department of Biology, Medical Genetics and Ecology,Kursk State Medical University,Kursk,Russia.

The cardio-ankle vascular index is a measure of arterial stiffness, whereas oxidative stress underlies arterial pathology. This study aimed to investigate the association between the cardio-ankle vascular index and antioxidant-related gene polymorphisms in young Russians. A total of 89 patients (mean age, 21.6 years) were examined by the cardio-ankle vascular index and for 15 gene polymorphisms related to antioxidant enzymes including FMO3 (flavin-containing monooxygenase 3), GPX1 (glutathione peroxidase 1), and GPX4 (glutathione peroxidase 4). A higher cardio-ankle vascular index level was detected in carriers with the KK-genotype of FMO3 polymorphism rs2266782 than in those without (mean levels: 6.2 versus 5.6, respectively, p<0.05). Similarly, a higher cardio-ankle vascular index level was seen in carriers with the CC-genotype of GPX4 polymorphism rs713041 than in those without (6.0 versus 5.5, respectively, p<0.05). We did not observe significant associations between the cardio-ankle vascular index levels and the other gene polymorphisms. Although carriers with the LL-genotype of GPX1 polymorphism rs1050450 showed a higher diastolic blood pressure level than those without, the polymorphism did not affect the cardio-ankle vascular index level. This study showed a significant association between rs2266782 and rs713041 polymorphisms and arterial stiffness, as measured by the cardio-ankle vascular index, in young Russians. The pathways utilised by antioxidant enzymes may be responsible for early arterial stiffening in the Russian population.
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http://dx.doi.org/10.1017/S104795111500102XDOI Listing
April 2016

Clusters of orthologous genes for 41 archaeal genomes and implications for evolutionary genomics of archaea.

Biol Direct 2007 Nov 27;2:33. Epub 2007 Nov 27.

National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.

Background: An evolutionary classification of genes from sequenced genomes that distinguishes between orthologs and paralogs is indispensable for genome annotation and evolutionary reconstruction. Shortly after multiple genome sequences of bacteria, archaea, and unicellular eukaryotes became available, an attempt on such a classification was implemented in Clusters of Orthologous Groups of proteins (COGs). Rapid accumulation of genome sequences creates opportunities for refining COGs but also represents a challenge because of error amplification. One of the practical strategies involves construction of refined COGs for phylogenetically compact subsets of genomes.

Results: New Archaeal Clusters of Orthologous Genes (arCOGs) were constructed for 41 archaeal genomes (13 Crenarchaeota, 27 Euryarchaeota and one Nanoarchaeon) using an improved procedure that employs a similarity tree between smaller, group-specific clusters, semi-automatically partitions orthology domains in multidomain proteins, and uses profile searches for identification of remote orthologs. The annotation of arCOGs is a consensus between three assignments based on the COGs, the CDD database, and the annotations of homologs in the NR database. The 7538 arCOGs, on average, cover approximately 88% of the genes in a genome compared to a approximately 76% coverage in COGs. The finer granularity of ortholog identification in the arCOGs is apparent from the fact that 4538 arCOGs correspond to 2362 COGs; approximately 40% of the arCOGs are new. The archaeal gene core (protein-coding genes found in all 41 genome) consists of 166 arCOGs. The arCOGs were used to reconstruct gene loss and gene gain events during archaeal evolution and gene sets of ancestral forms. The Last Archaeal Common Ancestor (LACA) is conservatively estimated to possess 996 genes compared to 1245 and 1335 genes for the last common ancestors of Crenarchaeota and Euryarchaeota, respectively. It is inferred that LACA was a chemoautotrophic hyperthermophile that, in addition to the core archaeal functions, encoded more idiosyncratic systems, e.g., the CASS systems of antivirus defense and some toxin-antitoxin systems.

Conclusion: The arCOGs provide a convenient, flexible framework for functional annotation of archaeal genomes, comparative genomics and evolutionary reconstructions. Genomic reconstructions suggest that the last common ancestor of archaea might have been (nearly) as advanced as the modern archaeal hyperthermophiles. ArCOGs and related information are available at: ftp://ftp.ncbi.nih.gov/pub/koonin/arCOGs/.
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http://dx.doi.org/10.1186/1745-6150-2-33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2222616PMC
November 2007

Pseudoisocyanine J-aggregate to optical waveguiding crystallite transition: microscopic and microspectroscopic exploration.

J Phys Chem B 2006 Sep;110(36):17772-5

Institute for Scintillation Materials, STC Institute for Single Crystals, 60 Lenin Avenue, 61001 Kharkov, Ukraine.

Using fluorescent microscopy and microspectroscopy, optical properties and morphology transformations in individual pseudoisocyanine (PIC) J-aggregates in aqueous electrolyte solutions have been explored. A stringlike structure of J-aggregates with a string diameter much less than 1 microm has been observed. Photodestruction of the strings under short-wavelength excitation has been revealed. Rodlike PIC crystallites, about 1 microm in diameter, have been observed with time. The fluorescence spectrum of rodlike crystallites has been found to differ from that of stringlike J-aggregate and from PIC crystal powder spectra. The crystallites are very stable, and their photodestruction has not been observed under any excitation conditions. It has been found that rodlike crystallites in contrast to stringlike J-aggregates possess optical waveguide properties. The luminescence of crystallites can be observed only at the excitation spot and at butt ends located up to hundreds of micrometers from the excitation spot.
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http://dx.doi.org/10.1021/jp061965tDOI Listing
September 2006

Assaying the probabilities of obtaining maternally inherited heteroplasmy as the basis for modeling OXPHOS diseases in animals.

Biochim Biophys Acta 2006 May-Jun;1757(5-6):679-85. Epub 2006 May 19.

Department of Molecular Genetics, Institute of Experimental Medicine, 12 Pavlov Street, Saint-Petersburg 197376, Russia.

Gross alterations in cell energy metabolism underlie manifestations of hereditary OXPHOS (oxidative phosphorylation) diseases, many of which depend on proportion of mutant mitochondrial DNA (mtDNA) in tissues. An animal model of OXPHOS disease with maternal inheritance of mitochondrial heteroplasmy might help understanding the peculiarities of abnormal mtDNA distribution and its effect on pre- and postnatal development. Previously we obtained mice that carry human mtDNA in some tissues. It co-existed with murine mtDNA (heteroplasmy) and was transmitted maternally to the progeny of animals developed from zygotes injected with human mitochondria. To analyze the probability of obtaining heteroplasmic mice we increased the number of experiments with early embryos and obtained more specimens from F1. About 33% of zygotes injected with human mtDNA developed into post-implantation embryos (7th-13th days). Lower amount of such developed into neonate mice (ca. 21%). Among post-implantation embryos and in generations F0 and F1 percentages of human mtDNA-carriers were ca. 14-16%. Such percentages are sufficient for modeling maternally inherited heteroplasmy in small animal groups. More data are needed to understand the regularities of anomalous mtDNA distribution among cells and tissues and whether heart and muscles frequently carrying human mtDNA in our experiments are particularly susceptible to heteroplasmy.
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http://dx.doi.org/10.1016/j.bbabio.2006.05.021DOI Listing
September 2006

Obtaining mice that carry human mitochondrial DNA transmitted to the progeny.

Mol Reprod Dev 2004 Jul;68(3):299-307

Department of Molecular Genetics, Institute for Experimental Medicine, 12 Pavlov str., Saint-Petersburg, Russia.

To study human diseases associated with mutations in mitochondrial DNA one needs an animal model in which the distribution of abnormal mtDNA and its impact on the phenotype might be followed. We isolated human mitochondria from HepG2 cell culture and microinjected them into murine zygotes, upon which those were transplanted to the pseudopregnant mice. PCR with species-specific primers allowed detecting human mtDNA in the tissues of 7-13-day embryos. No serious alterations in the development of transmitochondrial embryos were noticed. Among various organs/tissues of the 13-day embryos, human mtDNA was detected only in the heart, skeletal muscles, and stomach, which is in line with its uneven distribution among the blastomeres of an early mouse embryo that we described previously. In four recipient females, the microinjected zygotes were allowed to develop to term, the four neonate males of their joint litter were sacrificed, and in three of them human mtDNA was detected in the heart, skeletal muscles, stomach, brain, testes, and bladder. Six females of that joint litter were grown and mated to intact males. In the progeny (F1) of one of the females two mice were carrying human mtDNA in the heart, skeletal muscles, stomach, brain, lungs, uterus, ovaries, and kidneys. The study confirms the possibility to obtain transmitochondrial mice carrying human mtDNA that is transmitted to the animals of the next generation. Our results also indicate that among the organs to which human mtDNA is distributed some are more likely to receive it than others.
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http://dx.doi.org/10.1002/mrd.20075DOI Listing
July 2004

A comprehensive evolutionary classification of proteins encoded in complete eukaryotic genomes.

Genome Biol 2004 15;5(2):R7. Epub 2004 Jan 15.

National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.

Background: Sequencing the genomes of multiple, taxonomically diverse eukaryotes enables in-depth comparative-genomic analysis which is expected to help in reconstructing ancestral eukaryotic genomes and major events in eukaryotic evolution and in making functional predictions for currently uncharacterized conserved genes.

Results: We examined functional and evolutionary patterns in the recently constructed set of 5,873 clusters of predicted orthologs (eukaryotic orthologous groups or KOGs) from seven eukaryotic genomes: Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Arabidopsis thaliana, Saccharomyces cerevisiae, Schizosaccharomyces pombe and Encephalitozoon cuniculi. Conservation of KOGs through the phyletic range of eukaryotes strongly correlates with their functions and with the effect of gene knockout on the organism's viability. The approximately 40% of KOGs that are represented in six or seven species are enriched in proteins responsible for housekeeping functions, particularly translation and RNA processing. These conserved KOGs are often essential for survival and might approximate the minimal set of essential eukaryotic genes. The 131 single-member, pan-eukaryotic KOGs we identified were examined in detail. For around 20 that remained uncharacterized, functions were predicted by in-depth sequence analysis and examination of genomic context. Nearly all these proteins are subunits of known or predicted multiprotein complexes, in agreement with the balance hypothesis of evolution of gene copy number. Other KOGs show a variety of phyletic patterns, which points to major contributions of lineage-specific gene loss and the 'invention' of genes new to eukaryotic evolution. Examination of the sets of KOGs lost in individual lineages reveals co-elimination of functionally connected genes. Parsimonious scenarios of eukaryotic genome evolution and gene sets for ancestral eukaryotic forms were reconstructed. The gene set of the last common ancestor of the crown group consists of 3,413 KOGs and largely includes proteins involved in genome replication and expression, and central metabolism. Only 44% of the KOGs, mostly from the reconstructed gene set of the last common ancestor of the crown group, have detectable homologs in prokaryotes; the remainder apparently evolved via duplication with divergence and invention of new genes.

Conclusions: The KOG analysis reveals a conserved core of largely essential eukaryotic genes as well as major diversification and innovation associated with evolution of eukaryotic genomes. The results provide quantitative support for major trends of eukaryotic evolution noticed previously at the qualitative level and a basis for detailed reconstruction of evolution of eukaryotic genomes and biology of ancestral forms.
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http://dx.doi.org/10.1186/gb-2004-5-2-r7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC395751PMC
March 2005

Remarkable interkingdom conservation of intron positions and massive, lineage-specific intron loss and gain in eukaryotic evolution.

Curr Biol 2003 Sep;13(17):1512-7

National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.

Sequencing of eukaryotic genomes allows one to address major evolutionary problems, such as the evolution of gene structure. We compared the intron positions in 684 orthologous gene sets from 8 complete genomes of animals, plants, fungi, and protists and constructed parsimonious scenarios of evolution of the exon-intron structure for the respective genes. Approximately one-third of the introns in the malaria parasite Plasmodium falciparum are shared with at least one crown group eukaryote; this number indicates that these introns have been conserved through >1.5 billion years of evolution that separate Plasmodium from the crown group. Paradoxically, humans share many more introns with the plant Arabidopsis thaliana than with the fly or nematode. The inferred evolutionary scenario holds that the common ancestor of Plasmodium and the crown group and, especially, the common ancestor of animals, plants, and fungi had numerous introns. Most of these ancestral introns, which are retained in the genomes of vertebrates and plants, have been lost in fungi, nematodes, arthropods, and probably Plasmodium. In addition, numerous introns have been inserted into vertebrate and plant genes, whereas, in other lineages, intron gain was much less prominent.
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http://dx.doi.org/10.1016/s0960-9822(03)00558-xDOI Listing
September 2003
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