The association between PGC-1a and Alzheimer’s disease

Gary Sweeney,Juhyun Song 대한해부학회 2016 Anatomy & Cell Biology Vol.49 No.1

Alzheimer’s disease (AD) is a neurodegenerative disorder and its reported pathophysiological features in the brain include the deposition of amyloid beta peptide, chronic inflammation, and cognitive impairment. The incidence of AD is increasing worldwide and researchers have studied various aspects of AD pathophysiology in order to improve our understanding of the disease. Thus far, the onset mechanisms and means of preventing AD are completely unknown. Peroxisome proliferator-activated receptor-g coactivator (PGC-1a) is a protein related to various cellular mechanisms that lead to the alteration of downstream gene regulation. It has been reported that PGC-1a could protect cells against oxidative stress and reduce mitochondrial dysfunction. Moreover, it has been demonstrated to have a regulatory role in inflammatory signaling and insulin sensitivity related to cognitive function. Here, we present further evidence of the involvement of PGC-1a in AD pathogenesis. Clarifying the relationship between PGC-1a and AD pathology might highlight PGC-1a as a possible target for therapeutic intervention in AD.

Functional and Mechanistic Integration of Infection and the Metabolic Syndrome

Sommer, Peter,Sweeney, Gary Korean Diabetes Association 2010 Korean diabetes journal Vol.34 No.2

<P>The metabolic syndrome refers to a well defined group of risk factors, including central obesity and inflammation, for the development of diabetes and cardiovascular disease. Interestingly, many studies have recently led to the emergence of somewhat unexpected relationships between several infectious diseases and various aspects of the metabolic syndrome. Our understanding of the mechanisms underlying these interactions is also rapidly developing and some of these are summarized in this article. We will focus first on bacterial infection, and most notably the role of gut microbiota in regulaton of both obesity and inflammation. In particular, we focus on the role of inflammasomes and propose that understanding the role of Toll-like receptors and Nod-like receptors in the pathogenesis of inflammatory disorders with or without infection may provide novel targets for prevention and/or treatment of associated diseases. Secondly, chronic bacterial or viral infection and emerging links with metabolism will be reviewed. Finally, consideratons of biomarkers for metabolic syndrome, in particular lipocalin-2, and their link with infection will be discussed.</P>

Reviews : Functional and Mechanistic Integration of Infection and the Metabolic Syndrome

( Peter Sommer ),( Gary Sweeney ) 대한당뇨병학회 2010 Diabetes and Metabolism Journal Vol.34 No.2

The metabolic syndrome refers to a well defined group of risk factors, including central obesity and inflammation, for the development of diabetes and cardiovascular disease. Interestingly, many studies have recently led to the emergence of somewhat unexpected relationships between several infectious diseases and various aspects of the metabolic syndrome. Our understanding of the mechanisms underlying these interactions is also rapidly developing and some of these are summarized in this article. We will focus first on bacterial infection, and most notably the role of gut microbiota in regulaton of both obesity and inflammation. In particular, we focus on the role of inflammasomes and propose that understanding the role of Toll-like receptors and Nod-like receptors in the pathogenesis of inflammatory disorders with or without infection may provide novel targets for prevention and/or treatment of associated diseases. Secondly, chronic bacterial or viral infection and emerging links with metabolism will be reviewed. Finally, consideratons of biomarkers for metabolic syndrome, in particular lipocalin-2, and their link with infection will be discussed.

Crosstalk between the heart and peripheral organs in heart failure

James Won Suk Jahng,Gary Sweeney,Erfei Song 생화학분자생물학회 2016 Experimental and molecular medicine Vol.48 No.-

Mediators from peripheral tissues can influence the development and progression of heart failure (HF). For example, in obesity, an altered profile of adipokines secreted from adipose tissue increases the incidence of myocardial infarction (MI). Less appreciated is that heart remodeling releases cardiokines, which can strongly impact various peripheral tissues. Inflammation, and, in particular, activation of the nucleotide-binding oligomerization domain-like receptors with pyrin domain (NLRP3) inflammasome are likely to have a central role in cardiac remodeling and mediating crosstalk with other organs. Activation of the NLRP3 inflammasome in response to cardiac injury induces the production and secretion of the inflammatory cytokines interleukin (IL)-1β and IL-18. In addition to having local effects in the myocardium, these pro-inflammatory cytokines are released into circulation and cause remodeling in the spleen, kidney, skeletal muscle and adipose tissue. The collective effects of various cardiokines on peripheral organs depend on the degree and duration of myocardial injury, with systematic inflammation and peripheral tissue damage observed as HF progresses. In this article, we review mechanisms regulating myocardial inflammation in HF and the role of factors secreted by the heart in communication with peripheral tissues.

Regulation of Iron and Its Significance in Obesity and Complications

Yee Kwan Chan,Hye Kyoung Sung,Gary Sweeney 대한비만학회 2014 The Korean journal of obesity Vol.23 No.4

Iron is an essential micronutrient with important roles in many critical physiological processes, especially as a structural component of hemoglobinresponsible for oxygen transport. Iron homeostasis is tightly regulated, yet perturbations resulting in iron deficiency as well as iron overloadare linked with obesity and associated metabolic abnormalities, such as insulin resistance and type 2 diabetes. The endocrine system playsan active role in regulating iron homeostasis and here we have highlighted the importance of lipocalin-2 (Lcn2) and hepcidin. Circulating andadipose tissue expression of the proinflammatory Lcn2 are elevated in obesity and this may be an important, and underestimated, regulator ofiron homeostasis. Hepcidin is also markedly elevated during obesity and by inducing the internalization of ferroportin, it leads to an accumulationof tissue iron stores but deficiency in circulating iron, a key feature of functional iron deficiency. Due to the critical importance of ironhomeostasis in health and disease, there are currently several well established methods for clinical diagnosis of iron levels and various therapeuticshave proven effective in restoring normal iron level in iron deficient or overload conditions. Further explorations in the endocrine regulationof iron homeostasis are warranted to develop a better understanding of the pathophysiological roles of iron in obesity and related metabolicdiseases.

Altered Transendothelial Transport of Hormones as a Contributor to Diabetes

Nanyoung Yoon,Thanh Q. Dang,Helen Chasiotis,Scott P. Kelly,Gary Sweeney 대한당뇨병학회 2014 Diabetes and Metabolism Journal Vol.38 No.2

The vascular endothelium is a dynamic structure responsible for the separation and regulated movement of biological material between circulation and interstitial fluid. Hormones and nutrients can move across the endothelium either via a transcellular or paracellular route. Transcellular endothelial transport is well understood and broadly acknowledged to play an important role in the normal and abnormal physiology of endothelial function. However, less is known about the role of the paracellular route. Although the concept of endothelial dysfunction in diabetes is now widely accepted, we suggest that alterations in paracellular transport should be studied in greater detail and incorporated into this model. In this review we provide an overview of endothelial paracellular permeability and discuss its potential importance in contributing to the development of diabetes and associated complications. Accordingly, we also contend that if better understood, altered endothelial paracellular permeability could be considered as a potential therapeutic target for diabetes.

Iron Reshapes the Gut Microbiome and Host Metabolism

Botta Amy,Barra Nicole G.,Lam Nhat Hung,Chow Samantha,Pantopoulos Kostas,Schertzer Jonathan D.,Sweeney Gary 한국지질동맥경화학회 2021 지질·동맥경화학회지 Vol.10 No.2

Compelling studies have established that the gut microbiome is a modifier of metabolic health. Changes in the composition of the gut microbiome are influenced by genetics and the environment, including diet. Iron is a potential node of crosstalk between the host-microbe relationship and metabolic disease. Although iron is well characterized as a frequent traveling companion of metabolic disease, the role of iron is underappreciated because the mechanisms of iron's influence on host metabolism are poorly characterized. Both iron deficiency and excessive amounts leading to iron overload can have detrimental effects on cardiometabolic health. Optimal iron homeostasis is critical for regulation of host immunity and metabolism in addition to regulation of commensal and pathogenic enteric bacteria. In this article we review evidence to support the notion that altering composition of the gut microbiome may be an important route via which iron impacts cardiometabolic health. We discuss reshaping of the microbiome by iron, the physiological significance and the potential for therapeutic interventions.

Association of Lp-PLA₂ activity and LDL size with interleukin-6, an inflammatory cytokine and oxidized LDL, a marker of oxidative stress, in women with metabolic syndrome

Chae, Jey Sook,Kim, Oh Yoen,Paik, Jean Kyung,Kang, Ryungwoo,Seo, Woo Ju,Jeong, Tae-Sook,Sweeney, Gary,Lee, Sang-Hyun,Lee, Jong Ho Elsevier 2011 Atherosclerosis Vol.218 No.2

<P><B>Abstract</B></P><P><B>Objective</B></P><P>We investigated an association between lipoprotein-associated phospholipase A<SUB>2</SUB> (Lp-PLA<SUB>2</SUB>) activity, inflammation, and oxidative stress in women with metabolic syndrome (MS).</P><P><B>Methods</B></P><P>We performed a case–control study in MS women (<I>n</I>=368) and non-MS women (<I>n</I>=854). Lp-PLA<SUB>2</SUB> activity LDL particle size; leukocyte number; ox-LDL, LDL-cholesterol, TNF-α, IL-6, and CRP levels were measured.</P><P><B>Results</B></P><P>MS women had smaller LDL particle size; higher plasma ox-LDL levels and Lp-PLA<SUB>2</SUB> activity; and higher serum TNF-α, IL-6, and CRP, than non-MS women. In controls, Lp-PLA<SUB>2</SUB> activity weakly but significantly correlated with LDL-cholesterol; in MS women, Lp-PLA<SUB>2</SUB> activity positively correlated with LDL-cholesterol, ox-LDL, TNF-α, and IL-6 after adjusting for age and BMI. The relationship between Lp-PLA<SUB>2</SUB> activity and ox-LDL still maintained after further adjustment for LDL-cholesterol. Additionally, Lp-PLA<SUB>2</SUB> activity together with LDL particle size were significant independent predictors of MS (multivariate analysis), and ox-LDL was a major contributor to the increase in Lp-PLA<SUB>2</SUB> activity in MS women (multiple stepwise regression). In a subgroup analysis, Lp-PLA<SUB>2</SUB> activity was negatively associated with IL-6 levels in non-MS postmenopausal women, but positively with IL-6 in both postmenopausal and premenopausal women with MS. Postmenopausal women with MS had significantly higher Lp-PLA<SUB>2</SUB> activity, ox-LDL and IL-6 than those without MS, and premenopausal women with or without MS, after the adjustment.</P><P><B>Conclusions</B></P><P>Elevated plasma Lp-PLA<SUB>2</SUB> activity was associated with an increase in inflammatory cytokines, particularly IL-6 and ox-LDL in MS women. This association was also affected by menopause status, suggesting that Lp-PLA<SUB>2</SUB> may represent a novel marker for oxidation and inflammation in MS.</P>