The pathophysiology of acute graft versus host disease (GVHD) can be considered as a three-step process where the innate and adaptive immune systems interact (Fig. 1). The three steps are: 1) tissue damage to the recipient by the radiation/chemotherapy pre-transplant conditioning regimen, 2) donor T cell activation and clonal expansion, and 3) cellular and inflammatory factors. This schema underscores the importance of mononuclear phagocytes and other accessory cells to the development of GVHD after complex interactions with cytokines secreted by activated donor T cells. In step 1, the conditioning regimen (irradiation and/or chemotherapy) leads to damage and activation of host tissues throughout the body and the secretion of inflammatory cytokines Tumor Necrosis Factor (TNFα) and Interleukin (IL-1). These cytokines may enhance donor T cell recognition of host alloantigens by increasing expression of major histocompatibility complex (MHC) antigens and other molecules on host antigen presenting cells (APCs). Inflammatory cytokines may also stimulate chemokine release, recruiting donor T cells into host target organs. In step 2, host APCs present alloantigen (an HLApeptide complex) to the donor T cells. Co-stimulatory signals are required for T cell activation and these signals further activate APCs which in turn enhance T cell stimulation, characterized by cellular proliferation and the secretion of cytokines. IL-2 expands the T cell clones and induces cytotoxic T cell (CTL) responses; whereas, IFNγ has multiple effects, including the priming of mononuclear phagocytes to produce TNFα and IL-1. In step 3, effector functions of mononuclear phagocytes and neutrophils are triggered through a secondary signal provided by mediators such as lipopolysaccharides (LPS) that leak through the intestinal mucosa damaged during step 1. This inflammation, along with direct lysis of target cells by CTL, causes pathologic changes in target organs. Risk factors, as well as strategies to prevent GVHD, can be conceptualized according to this three-step model and will be reviewed in this article. Keywords: hematopoietic cell transplantation (HCT), major histocompatibility complex (MHC), antigen presenting cells, cytotoxic T lymphocytes, mycophenolate mofetil
The overall objective of this paper is to review the mechanisms by which various metabolic and cellular signals, as well as nuclear transcription factors, regulate the expression and function of the insulin responsive glucose transporter-4 (GLUT4) gene. Reviewing this information will help the reader to understand the molecular processes involved in both glucose homeostasis and the pathogenesis of abnormal metabolic states involving impaired insulin action, such as insulin resistance and diabetes mellitus type 2 (DM2). The same molecular mechanisms are also involved in tumorigenesis. Studies on GLUT4 regulation, its translocation machinery, and intrinsic activity have contributed valuable knowledge that may be useful for developing therapeutic strategies aimed at increasing GLUT4 protein levels, which could potentially improve glucose homeostasis in insulin resistance and diabetes. Keywords: glut4 intrinsic activity, glut4 promoter, ppargamma, human adipocytes, p53, foxo1, lipotoxicity, type 2 diabetes mellitus, insulin resistance
Graft-versus-host disease (GVHD) has been the primary limitation to the wide application of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is initiated by activation of donor T cells recognizing host tissue antigens, with subsequent dysregulated inflammatory cytokine production by monocytes and macrophages. These inflammatory cytokines are crucial for the pathogenesis of acute GVHD and these inflammatory manifestations are recognized as clinical acute GVHD. This paper presents a brief review of the mechanisms underlying inflammatory cytokine responses during acute GVHD and various strategies aimed at the prevention of acute GVHD. As cytokines and growth factors that are protective against GVHD are also produced during inflammatory cytokine responses, the factors contributing to the protection against GVHD are also reviewed. Attention has focused on the mechanisms responsible for the protection against GVHD conferred by hepatocyte growth factor and sphingosin-1-phosphate, which are abundantly stored in platelets. These factors are produced during inflammation and tissue injury and regulate immune, hematopoietic and regenerative responses. Novel therapies aimed at protection against GVHD using protective growth factors are discussed, although in most cases, their clinical relevance has not been established. Carefully designed clinical trials are awaited to evaluate their usefulness in the prevention and management of GVHD. Keywords: Cytokines, FTY720, graft-versus-host disease, growth factors, hematopoietic stem cell transplantation, hepatocyte growth factor, sphingosin-1-phosphate
The two members of the relaxin family of insulin-like peptide hormones, relaxin and INSL3, and their cognate G protein coupled receptors LGR7 and LGR8, respectively, are present in human tumor tissues. Although the physiological role and signal transduction pathways engaged by relaxin-like members in tumor tissues are still largely unknown, novel data mainly obtained from in-vitro cellular models suggest that relaxin-like peptides influence cellular functions associated with motility and migration, cytoskeletal rearrangement and enzyme production and secretion. The expression of relaxin-like peptides appears to be regulated in a tumor-specific context by the actions of various nuclear receptors. This review summarizes most recent findings on the potential functions of relaxin/ INSL3 ligand-receptor systems in tumor tissues and follows an organ-specific approach. Keywords: relaxin, insl, lgr, tumor biology, breast, prostate, thyroid, mtc
The prevalence of Type 2 diabetes (Non-Insulin-Dependent Diabetes Mellitus) increases at an alarming rate in the worlds population, reaching an epidemic proportion. Moreover, impaired glucose tolerance and insulin resistance are being diagnosed nowadays in a growing subpopulation of obese children and adolescents, mostly in Western societies. This adds to the concern that not only the number of NIDDM patients will increase dramatically to over 300 millions within 20 years, but also that overt diabetes and diabetes-related complications will develop earlier in life. The main goal of pharmacological therapy of diabetic patients is to reduce blood glucose levels to the normal range. Indeed, most diabetic patients require oral antihyperglycemic drug therapy; yet, the relatively high rate of failure of these drugs and the chronic nature of the disease, which is associated with progressive dysfunction and exhaustion of pancreatic insulinproducing β-cells, lead in many cases to insulin therapy. Most available antihyperglycemic drugs sensitize β-cells to secrete insulin or overcome peripheral insulin resistance by sensitizing insulin-responsive tissues towards insulin. Nevertheless, genuine insulin mimetic drugs or drugs aimed at directly augmenting the glucose transport system in insulinsensitive tissues are still being sought. This review describes briefly current molecular targets for antihyperglycemic drugs and discusses potential compounds that may act as insulin-mimetics or enhancers. In addition, a novel concept is introduced for the development of carbohydrate derivatives that may augment glucose transport in insulin-sensitive tissues in an insulin-independent manner. Keywords: Antihyperglycemic drugs, carbohydrates, D-glucose, diabetes, D-xylose, glucose transport, glucose transporters, hypoglycemic drugs, NIDDM, insulin
Active prevention of coronary heart disease (CHD) is usually started immediately after the first clinical manifestation of CHD. Secondary prevention focuses on risk reduction in patients with established CHD who are at high risk of recurrent cardiac events and death from cardiac causes. It is important to remember that the two main causes of death in these patients are sudden cardiac death (SCD) and heart failure (HF), often resulting from myocardial ischemia and subsequent necrosis. The main mechanism underlying recurrent cardiac events is myocardial ischemia resulting from atherosclerotic plaque rupture or ulceration. Plaque rupture is usually the consequence of intraplaque inflammation in relation with a high lipid content of the lesion, high concentration of leukocytes and lipid peroxidation products. Thus, in patients with established CHD, the three main aims of the preventive strategy are to prevent malignant ventricular arrhythmia and the development of severe ventricular dysfunction (and heart failure) and to minimize the risk of plaque inflammation and ulceration. Keywords: diet, coronary heart disease, sudden cardiac death, n-3 fatty acids, n-6 fatty acids, alcohol, antioxidants, mediterranean diet
A new bone marrow transplantation (BMT) method, "intra-bone marrow (IBM)-BMT" has recently been developed. This method was found to prevent not only graft-versus-host (GvH) reaction but also host-versus-graft (HvG) reaction, since IBM-BMT can efficiently recruit donor-derived stromal cells (including mesenchymal stem cells: MSCs), which produce immunosuppressive cytokines. This paper shows that IBM-BMT prevents GvHD even when donor lymphocyte infusion (DLI) is carried out, and that the combination of IBM-BMT + DLI not only prevents GvHD but also inhibits the growth of solid tumors in mice. In addition, it has been shown that IBM-BMT will be applicable to the treatment of various intractable diseases. Keywords: Bone marrow transplantation, graft-versus-host reaction, host-versus-graft reaction, donor lymphocyte infusion, graft-versus-tumor reaction
Relaxin has intrigued and confounded researchers since its discovery in 1926. While first characterized as a hormone of pregnancy, and believed to be of interest only in the female, we now know that relaxin is a multi functional hormone with non-reproductive actions in several systems. Relaxin is structurally similar to insulin and thus a part of the insulin superfamily. In total, seven relaxin-like peptides have been identified; relaxin-1, relaxin-2, relaxin-3 and the insulin- like (INSL) peptides INSL3, INSL4, INSL5 and INSL6. Four relaxin-like peptide family receptors have been identified to date, which are GPCRs and unlike the tyrosine kinase insulin receptor. Pharmacological and functional data show that LGR7 is the relaxin receptor and LGR8 the INSL3 receptor. However, complex systems of multiple interactions between the relaxin-like peptides and their receptors are being unraveled. Pharmacological data also show relaxin-3 to be a high affinity agonist for LGR7, as well as GPCR135 and GPCR142, while GPCR142 has a second ligand in INSL5. Surprisingly, LGR7 and LGR8 have invertebrate homologs, are only distantly related to GPCR135 and GPCR142, and have markedly different ectodomains. Structure- function studies are beginning to identify the peptide determinants of the interactions between the relaxin-like peptides and their receptors. Mechanisms for ligand binding and activation are unlikely to be similar between the different receptor types. The relaxin-like peptides have numerous clinical applications, and developing these to their full potential will require a complete understanding of the interplay between the relaxin-like peptides and their receptors. Keywords: insulin-like peptide, cancer, insulin superfamily, relaxin genes, porcine testis-specific transcript, epil peptides, somatostatin, gpcr superfamily
The glucose transporters (GLUTs) are currently a 13 member family of facilitative transmembrane proteins which transport glucose down its concentration gradient. The GLUTs have a tissue specific expression and regulation. Dysregulation of GLUTs have been implicated in the pathogenesis of a number of diseases including diabetes and cancer and are known to play an important role in the developing embryo. In addition, roles for GLUTs in cardiac function and embryonic development have been identified and will be discussed in this review. The ability to ablate or over-express GLUTs has advanced our understanding of the role these transporters play in the maintenance of normal glucose homeostasis and the pathogenesis of diabetes. The development of Cre-LoxP technology coupled with the existence of tissue specific promoters allows investigators to manipulate gene expression both globally and in a tissue specific manner. The major GLUTs which have been investigated using transgenic technology are GLUT1, GLUT4 and GLUT2. Overexpression of GLUT4 and GLUT1 results in increased glucose uptake and metabolism. However, only GLUT4 overexpression protects against the development of insulin resistance in transgenic mice. Genetic ablation of GLUT4 and GLUT2 results in impaired insulin tolerance and defects in both lipid and glucose metabolism. This review will present various transgenic models of GLUT modification and discuss what has been learned from these models about the role that GLUTs play in glucose homeostasis, insulin action and development. Keywords: glut, hypertrophy, transgenic, knockout, diabetes, cardiovascular, development, insulin
High-density lipoproteins (HDLs) have several metabolic actions in vitro that are potentially anti-atherogenic. In addition to their role in reverse cholesterol transport, native HDLs have been shown to protect low-density lipoproteins (LDLs) against oxidative modification, to have anti-inflammatory properties, and to inhibit platelet aggregation. These actions have been shown to occur also in vivo in both experimental animals and humans, when plasma HDL concentration is raised by intravenous infusion of native HDLs or reconstituted discoidal particles composed of the major HDL protein, apolipoprotein (apo) A-I, in association with phosphatidylcholine (PC) and, in the case of protection of LDLs against oxidative change, by lipid-free apo A-I and apo A-I mimetic polypeptides. Intravenous infusion of native HDLs, lipid-free apo A-I and apo A-I/PC discs, and oral administration of apo A-I peptides, have been found to prevent or reverse experimentally induced atherosclerosis in animals. A mutant form of apo A-I discovered in Italy (apo A-IMilano), the biological properties of which differ somewhat from those of normal apo A-I appears to be even more potent in this regard. The hope that this approach will provide a new effective therapy for atherosclerosis has been supported by a multi-center clinical trial, in which five weekly infusions of apo A-IMilano/PC discs induced significant regression of coronary lesions, as quantified by intravascular ultrasound, in men with clinical coronary heart disease. This article reviews the data from animal and human studies in this rapidly developing area. Keywords: apolipoprotein a, atherosclerosis, cholesterol, coronary heart disease, high-density lipoproteins
Reverse cholesterol transport (RCT) is one pathway for removing excessive cholesterol from extrahepatic cells and tissues and eventual transport to the liver for excretion thus reducing the accumulation of cholesterol in arteries. Activity of RCT is believed to be affected at least partially by the high density lipoprotein (HDL) concentration in the blood, since HDL is the major carrier of cellular cholesterol through RCT. This presumption lead to an assertion that raising HDL-C levels alone would improve RCT and provide enhanced protection against development of atherosclerosis. However, studies on RCT show that the concentration of HDL required for maximum recruitment of cellular cholesterol is far below the concentration of HDL in plasma. A more likely explanation is that the rate of RCT and the HDL concentration, which is partially determined by RCT, protect against atherosclerosis independently of each other. RCT may result in formation of dysfunctional HDL and a high level of HDL-C is not always synonymous with an efficient RCT. RCT consists of three major stages: cholesterol efflux, transport of cholesterol through the plasma compartment and uptake and excretion of cholesterol by liver. Each stage is a muti-step pathway or a combination of parallel pathways. The contribution and overall efficiency of these pathways often depends on specific metabolic circumstances. Finding the determinants of RCT would be valuable for choosing targets and evaluating the efficiency of possible therapy aimed at boosting RCT, raising HDL and enhancing protection against atherosclerosis. Keywords: reverse cholesterol transport, high density lipoprotein, atherosclerosis, lipoproteins, coronary heart disease
One of the most important metabolic actions of insulin is to promote glucose transport in skeletal muscle and adipose tissue. Insulin-stimulated glucose transport in these target tissues is mediated by translocation of the insulinresponsive glucose transporter GLUT4 from an intracellular location to the plasma membrane where GLUT4 facilitates entry of glucose into the cell. Over the past decade, tremendous progress has been made in elucidating insulin signaling pathways regulating translocation of GLUT4. One essential signaling pathway in this process is a PI 3-kinase-dependent pathway that controls activation of downstream ser/thr kinases such as PDK-1, Akt, and PKC-ζ leading to an increase in the exocytosis rate for GLUT4. Although activation of PI 3-kinase is necessary for insulin-stimulated translocation of GLUT4, it is not sufficient. Recently, a PI 3-kinase-independent pathway involving activation of TC10 (a GTPase belonging to the rho family) has been identified as another necessary element. Insulin-stimulated phosphorylation of Cbl results in assembly of signaling complexes that activate TC10. This leads to rearrangements of actin structures that facilitate translocation of GLUT4. In this review, we will discuss details of both the PI 3-kinase-dependent and - independent pathways mediating translocation of GLUT4 in response to insulin.
Adipose tissue secretes bioactive peptides, termed 'adipokines', which act locally and distally through autocrine, paracrine and endocrine effects. In obesity, increased production of most adipokines impacts on multiple functions such as appetite and energy balance, immunity, insulin sensitivity, angiogenesis, blood pressure, lipid metabolism and haemostasis, all of which are linked with cardiovascular disease. Enhanced activity of the tumour necrosis factor and interleukin 6 are involved in the development of obesity-related insulin resistance. Angiotensinogen has been implicated in hypertension and plasminogen activating inhibitor-1 (PAI-1) in impaired fibrinolysis. Other adipokines like adiponectin and leptin, at least in physiological concentrations, are insulin sparing as they stimulate beta oxidation of fatty acids in skeletal muscle. The role of resistin is less understood. It is implicated in insulin resistance in rats, but probably not in humans. Reducing adipose tissue mass, through weight loss in association with exercise, can lower TNF-alpha and IL-6 levels and increase adiponectin concentrations, whereas drugs such as thiazolinediones increase endogenous adiponectin production. In-depth understanding of the pathophysiology and molecular actions of adipokines may, in the coming years, lead to effective therapeutic strategies designed to protect against atherosclerosis in obese patients
