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Vasoactive intestinal peptide (VIP): Historic perspective and future potential
Neil Foster
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00001]
Vasoactive intestinal peptide (VIP) as a novel therapeutic against gram negative sepsis
Hiba Ibrahim, Paul Barrow, Neil Foster
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00002]
VIP in Inflammatory Bowel disease: state of the art
Catalina Abad, Rosa Gomariz, James Waschek, Javier Leceta, Carmen Martinez, Yasmina Juarranz, Alicia Arranz
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00003]
VIP in neurological disease: More than a neuropeptide
Maria Morell, Luciana Souza-Moreira, Elena Gonzalez-Rey
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00004]
Potential applications of vasoactive intestinal peptide-based therapies on transplantation
Luciana Souza-Moreira, Virginia Delgado-Maroto, Mario Delgado
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00005]
Clinical Potential of VIP by Modified Pharmako-kinetics and Delivery Mechanisms
Bernhard Burian, Anna Ortner, Ruth Prass, Andreas Zimmer, Wilhelm Mosgoeller
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00006]
The sphingolipid rheostat: a potential target for improving pancreatic islet survival and function
Claire F. Jessup, Claudine S. Bonder, Stuart M. Pitson, P.Toby H. Coates
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00007]
The Impact of Bacterial Lipolysaccharides on the Endothelial System: Pathological Consequences and Therapeutic Countermeasures
Magrone T and Jirillo E
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00009]
The sphingolipid rheostat: a potential target for improving pancreatic islet survival and function
Claire F. Jessup, Claudine S. Bonder, Stuart M. Pitson, P.Toby H. Coates
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00010]
The regulation of FoxP3-expressing regulatory T cells
Rizwanul Haque, Fengyang Lei, Xiaofang Xiong and Jianxun Song
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00011]
The role of PPARβ/δ in the management of metabolic syndrome and its associated cardiovascular complications
Elisa Benetti, Nimesh S. A. Patel, Massimo Collino
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00012]
FGF10 and FGF21 as Regulators in Adipocyte Development and Metabolism
Hiroya Ohta, Morichika Konishi and Nobuyuki Itoh
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00013]
Sex-Gender Differences In Diabetes Vascular Complications And Treatment
Franconi F, Campesi I, Occhioni S and Tonolo G
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00014]
Bone marrow microenvironment: a newly recognized target for diabetes-induced cellular damage
Giuseppe Mangialardi, Atsuhiko Oikawa, Carlotta Reni and Paolo Madeddu
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00015]
Cerebrovascular Complications of Diabetes: Focus on Stroke
Adviye Ergul, Aisha Kelly-Cobbs, Maha Abdalla and Susan C. Fagan
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00016]
Cardiac effects of HDL and its components on diabetic cardiomyopathy
Frank Spillmann, Sophie Van Linthout and Carsten Tschöpe
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00017]
Molecular mechanisms of diabetes and atherosclerosis: Role of adiponectin
Ken Kishida, Tohru Funahashi and Iichiro Shimomura
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00018]
Diabetes-induced epigenetic signature in vascular cells
Tijana Mitić and Costanza Emanueli
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00019]
Emerging therapy for diabetic neuropathy: Cell therapy targeting vessels and nerves
Hyongbum Kim, Julie J. Kim and Young-sup Yoon
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00020]
Glucocorticoid Analogues: Potential Therapeutic Alternatives for Treating Inflammatory Muscle Diseases
Erica K.M. Reeves, Sree Rayavarapu, Jesse M. Damsker and Kanneboyina Nagaraju
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00021]
Regulation of leptin receptor expression in human polarized Caco-2/15 cells
Philippe G Cammisotto, Moise Bendayan and Emile Levy
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00022]
State Of The Art In The Therapeutic Maintenance And Management Of Dental Implants Today: Focus On Mucositis And Perimplantitis
Lucrezia Bottalico, Roberto G. CarlaioLuigi Santacroce
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00023]
Immune Modulation by Regulatory T cells in Helicobacter pylori-Associated Diseases
Sukanya Raghavan and Marianne Quiding-Järbrink
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00024]
Cystic Echinococcosis: Aspects of Immune Response, Immunopathogenesis and Immune Evasion from the Human Host
Alessandra Siracusano, Federica Delunardo, Antonella Teggi and Elena Ortona
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00025]
Wolbachia and its implications for the immunopathology of filariasis
Claudio Genchi, Laura H. Kramer, Davide Sassera and Claudio Bandi
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00026]
Toxocara infection and its association with allergic manifestations
Elena Pinelli and Carmen Aranzamendi
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00027]
Immunomodulation in trichinellosis: does Trichinella really escape the host immune system?
Fabrizio Bruschi and Lorena Chiumiento
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00028]
Schistosoma mansoni antigens as modulators of the allergic inflammatory response in asthma
L. S. Cardoso, S.C. Oliveira, M.I. Araujo
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00029]
Immunomodulatory properties of ES-62, a phosphorylcholine - containing glycoprotein secreted by Acanthocheilonema viteae
Lamyaa Al-Riyami and William Harnett
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00030]
Incidence And Prevalence Of Hypothyroidism In Patients Affected By Chronic Heart Failure: Role Of Amiodarone
Vincenzo Triggiani, Massimo Iacoviello, Fabio Monzani, Agata Puzzovivo, Pietro Guida, Cinzia Forleo, Marco Matteo Ciccone, Raffaella Catanzaro, Emilio Tafaro, Brunella Licchelli, Vito Angelo Giagulli, Edoardo Guastamacchia and Stefano Favale
[Abstract] [FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00031]
Abstracts
Vasoactive intestinal peptide (VIP): Historic perspective and future potential
Neil Foster
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00001]
Vasoactive intestinal peptide (VIP) has shown potential as a novel therapeutic in many diverse inflammatory diseases. These include autoimmune diseases, bacterial sepsis, inflammatory bowel disease, encephalomyelitis and disease of the lungs and airways and others. Although VIP inhibits cellular pathways at different levels, the inhibitory effect of VIP on inflammatory pathways ultimately occurs due to its effect on essential transcription factors produced by inflammatory cells of the innate immune system. Furthermore, VIP promotes development of anti-inflammatory type II CD4+ T lymphocytes and supressor T lymphocytes and immunological memory responses in each case.
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Vasoactive intestinal peptide (VIP) as a novel therapeutic against gram negative sepsis
Hiba Ibrahim, Paul Barrow, Neil Foster
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00002]
Gram negative sepsis remains a high cause of mortality and places a great burden on public health finance in both the developed and developing world. Treatment of sepsis, using antibiotics, is often ineffective since pathology associated with the disease occurs due to dysregulation of the immune system (failure to return to steady state conditions) which continues after the bacteria, which induced the immune response, have been cleared. Immune modulation is therefore a rational approach to the treatment of sepsis but to date no drug has been developed which is highly effective, cheap and completely safe to use. One potential therapeutic agent is VIP, which is a natural peptide and is highly homologous in all vertebrates. In this review we will discuss the effect of VIP on components of the immune system, relevant to gram negative sepsis, and present data from animal models. Furthermore we will hypothesise on how these studies could be improved in future and speculate on the possible different ways in which VIP could be used in clinical medicine.
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VIP in Inflammatory Bowel disease: state of the art
Catalina Abad, Rosa Gomariz, James Waschek, Javier Leceta, Carmen Martinez, Yasmina Juarranz, Alicia Arranz
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00003]
The pathogenesis of inflammatory bowel syndrome (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC) is poorly understood. However, an inflammatory component is a common hallmark. It has been suggested that CD principally involves Th1 and/or Th17 cells, while UC is considered to be more Th2 driven. Because vasoactive intestinal peptide (VIP) has emerged in the last decade as a putative candidate for the treatment of inflammatory diseases with a Th1 component, it may as well serve as a therapeutic target in CD. In addition, experiments using mice deficient in VIP or its receptors have revealed that the endogenously-produced VIP may participate in the regulation of immunity. The aim of the present review is to summarize the quite considerable array of data which suggests that the VIP-receptor system plays a key role in modulating multiple molecular and cellular players involved in IBD.
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VIP in neurological disease: More than a neuropeptide
Maria Morell, Luciana Souza-Moreira, Elena Gonzalez-Rey
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00004]
A hallmark in most neurological disorders is a massive neuronal cell death, in which uncontrolled immune response is usually involved, leading to neurodegeneration. The vasoactive intestinal peptide (VIP) is a pleiotropic peptide that combines neuroprotective and immunomodulatory actions. Alterations on VIP/VIP receptors in patients with neurodenegerative diseases, together with its involvement in the development of embryonic nervous tissue, and findings found in VIP-deficient mutant mice, have showed the relevance of this endogenous peptide in normal physiology and in pathologic states of the central nervous system (CNS). In this review, we will summarize the role of VIP in normal CNS and in neurological disorders. The studies carried out with this peptide have demonstrated its therapeutic effect and render it as an attractive candidate to be considered in several neurological disorders linked to neuroinflammation.
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Potential applications of vasoactive intestinal peptide-based therapies on transplantation
Luciana Souza-Moreira, Virginia Delgado-Maroto, Mario Delgado
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00005]
Vasoactive intestinal peptide (VIP) is a well-known immunoregulatory neuropeptide produced by the immune system in response to inflammation, autoimmunity or alloantigens as a natural endogenous mechanism of induction of tolerance. VIP has been proven therapeutically effective in various experimental models of autoimmune disorders and recently in human sarcoidosis. Numerous studies clearly show that VIP exerts its immunomodulatory effects by downregulating both inflammatory and Th1 responses. Recent evidences suggest that new actors enter in scene to play a role in this scenario of tolerance. By inducing antigen-specific regulatory T cells and tolerogenic dendritic cells, VIP seems to reinforce/reinstall immune tolerance, especially under autoimmune conditions. Transplantation is also a condition where VIP-related therapies emerge as promising tools for clinical application. Induction of alloantigen-specific tolerance is critical to achieve organ transplant tolerance and to avoid graft-versus-host responses following allogeneic hematopoietic transplantation. This review will focus on describing the capacity of VIP to induce suppressive/regulatory immune cells and how we can manage this cell-based therapeutic strategy to induce transplant tolerance in subjects free of immunosuppressive drugs.
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Clinical Potential of VIP by Modified Pharmako-kinetics and Delivery Mechanisms
Bernhard Burian, Anna Ortner, Ruth Prass, Andreas Zimmer, Wilhelm Mosgoeller
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00006]
Vasoactive intestinal peptide (VIP) conveys various physiological effects in the digestive tract, nervous and cardiovascular system, airways, reproductive system, endocrine system, and more. A family of specific membrane bound receptors, termed VPAC1, VPAC2, and PAC1, binds VIP and triggers the effects. Many of them are of clinical interest.
To date more than two thousand publications suggest the use of VIP in diseases like asthma, erectile dysfunction, blood pressure regulation, inflammation, endocrinology, tumours, etc. Despite this considerable potential, the peptide is not regularly used in clinical settings. A key problem is the short half life of inhaled or systemically administered VIP due to rapid enzymatic degradation.
This shortcoming could be overcome with stable derivates or improved pharmacokinetics. A promising strategy is to use biocompatible and degradable depots, to protect the peptide from early degradation and allow for controlled release.
This review focuses on theaspects of clinical applications of VIP and the idea to use formulations based on biodegradable particles, to constitute a dispersible VIP-depot. Smart particle systems protect the peptide from early degradation, and assist the sustainable cell targeting with VIP for therapeutic or imaging purposes.
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The sphingolipid rheostat: a potential target for improving pancreatic islet survival and function
Claire F. Jessup, Claudine S. Bonder, Stuart M. Pitson, P.Toby H. Coates
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00007]
Beta cell apoptosis and suboptimal islet function are implicated in the development of Type I (T1D) and Type II (T2D) diabetes, as well as the failure of the only current clinical beta cell replacement therapy for T1D, islet transplantation. Sphingosine kinase (SK) is a ubiquitous lipid kinase that controls the balance between prosurvival and proapoptotic precursors (e.g. sphingosine-1-phosphate (S1P) and ceramide, respectively), the so-called ‘sphingolipid rheostat’, in many cell types. S1P, a potent lipid mediator, acts intracellularly through second messengers and extracellularly through five G-protein coupled receptors (S1P1-5), to promote calcium mobilization, intracellular signaling events, cytoskeleton rearrangements and mitogenesis. SK is important for revascularization responses, regulating the maturation of vascular endothelial progenitors and controlling cellular recruitment. The aim of this review is to highlight the sphingolipid rheostat in pancreatic biology as a therapeutic target for pharmacological and therapeutic intervention for diabetes and islet transplantation. SK and the sphingolipid rheostat are likely to be important for both islet function and beta cell survival and represent a common therapeutic target to protect the beta cell from diabetogenic insults and ultimately improve pancreatic islet function. A number of SK inhibitors and S1P receptor agonists/antagonists (including FTY720 (fingolimod) and its newer derivatives) have been recently described, with some now being used in the clinic. Recent developments in SK biochemistry and islet biology indicate the potential importance of the sphingolipid rheostat in determining islet survival and function. Pharmacological manipulation of this pathway represents a novel therapeutic strategy to prevent diabetes and improve islet transplantation outcomes.
[Back to top]
The Impact of Bacterial Lipolysaccharides on the Endothelial System: Pathological Consequences and Therapeutic Countermeasures
Magrone T and Jirillo E
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00009]
Endothelial cells (ECs) express on their membrane Toll like receptor (TLR)-4 and, therefore, are able to interact with lipopolysaccharides (LPS) or endotoxins, major constituents of the Gram-negative bacteria outer membrane. The impact of LPS on ECs can be either direct or mediated via release of cytokines and/or chemokines originated from monocytes/macrophages.
In this review, the effect of the interaction between LPS and ECs on the outcome of various human diseases such as preeclampsia, hereditary haemorrhagic teleangiectasia, atherosclerosis and sepsis will be illustrated.
Finally, the major therapeutic attempts aimed at neutralizing LPS and, therefore, their influence on ECs will be discussed.
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The sphingolipid rheostat: a potential target for improving pancreatic islet survival and function
Claire F. Jessup, Claudine S. Bonder, Stuart M. Pitson, P.Toby H. Coates
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00010]
Beta cell apoptosis and suboptimal islet function are implicated in the development of Type I (T1D) and Type II (T2D) diabetes, as well as the failure of the only current clinical beta cell replacement therapy for T1D, islet transplantation. Sphingosine kinase (SK) is a ubiquitous lipid kinase that controls the balance between prosurvival and proapoptotic precursors (e.g. sphingosine-1-phosphate (S1P) and ceramide, respectively), the so-called ‘sphingolipid rheostat’, in many cell types. S1P, a potent lipid mediator, acts intracellularly through second messengers and extracellularly through five G-protein coupled receptors (S1P1-5), to promote calcium mobilization, intracellular signaling events, cytoskeleton rearrangements and mitogenesis. SK is important for revascularization responses, regulating the maturation of vascular endothelial progenitors and controlling cellular recruitment. The aim of this review is to highlight the sphingolipid rheostat in pancreatic biology as a therapeutic target for pharmacological and therapeutic intervention for diabetes and islet transplantation. SK and the sphingolipid rheostat are likely to be important for both islet function and beta cell survival and represent a common therapeutic target to protect the beta cell from diabetogenic insults and ultimately improve pancreatic islet function. A number of SK inhibitors and S1P receptor agonists/antagonists (including FTY720 (fingolimod) and its newer derivatives) have been recently described, with some now being used in the clinic. Recent developments in SK biochemistry and islet biology indicate the potential importance of the sphingolipid rheostat in determining islet survival and function. Pharmacological manipulation of this pathway represents a novel therapeutic strategy to prevent diabetes and improve islet transplantation outcomes.
[Back to top]
The regulation of FoxP3-expressing regulatory T cells
Rizwanul Haque, Fengyang Lei, Xiaofang Xiong and Jianxun Song
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00011]
Regulatory T (Treg) cells play an important role in the maintenance of self-tolerance and are involved in the prevention of autoimmune diseases and reduce/inhibit the progression of chronic inflammatory diseases. Forkhead box P3 (FoxP3) expression in Treg cells is believed to be a critical factor in the maintenance of Treg cells suppressive function. Multiple mechanisms of action of Treg cells have been proposed, including cell contact–dependent and cytokine-dependent mechanisms. However, no clear picture is available to fully elucidate the regulation of FoxP3 gene expression in Treg cells and how FoxP3-expressing Treg cells mediate the immune response in vivo. This review will discuss the research advancements in Treg cell biology including the transcription factors and signaling pathways involved in the expression of FoxP3 gene as well as the advancements in the understanding of the factors involved in the Treg cell-mediated suppressive mechanisms.
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The role of PPARβ/δ in the management of metabolic syndrome and its associated cardiovascular complications
Elisa Benetti, Nimesh S. A. Patel, Massimo Collino
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00012]
The association between metabolic syndrome and cardiovascular diseases raises important questions about the underlying pathological processes, especially for designing targeted therapeutic interventions. The Peroxisome Proliferators Activated Receptors (PPARs) are ligand-activated transcription factors that control lipid and glucose metabolism. Accumulating data suggest that PPARs may serve as potential targets for treating metabolic diseases and their cardiovascular complications. PPARs regulate gene expression by binding with RXR as a heterodimeric partner to specific DNA sequences, termed PPAR response elements. In addition, PPARs may modulate gene transcription also by directly interfering with other transcription factor pathways in a DNA-binding independent manner. To date, three different PPAR isoforms, designated α, β/δ and γ, have been identified. PPARα and PPARγ are the most extensively examined and characterized, mainly because they are activated by compounds, such as fibrates and thiazolidinediones, that are in clinical use for the treatment of hypertriglyceridemia and insulin resistance, respectively. In contrast the role of PPARβ/δ in metabolism has been less investigated. The recent availability of specific PPARβ/δ agonists revealed that PPARβ/δ plays a crucial role in fatty acid metabolism in several tissues. Besides, PPARβ/δ activation exerts beneficial effects against organ-related ischemic events, such as myocardial and cerebral infarction, which are among the most critical cardiovascular complications evoked by metabolic dysregulation. This paper reviews the evidence and recent developments relating to the potential therapeutic effects of PPARβ/δ agonists in the treatment of metabolic syndrome and its associated cardiovascular risk factors.
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FGF10 and FGF21 as Regulators in Adipocyte Development and Metabolism
Hiroya Ohta, Morichika Konishi and Nobuyuki Itoh
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00013]
The FGF family comprises twenty-two evolutionarily related members with diverse functions in development, metabolism, and neuronal activities. FGF10 and FGF21 play unique roles in adipocyte development and metabolism, respectively. FGF10 mediates biological responses by activating FGF receptor 2b (FGFR2b) with heparin/heparan sulfate in a paracrine manner. In contrast, FGF21 mediates biological responses by activating FGFRs with bKlotho in cultured cells. However, FGF21 acts in an autocrine manner via a β Klotho-independent signaling pathway in mice. Fgf10 knockout mice die shortly after birth. Preadipocyte proliferation and adipogenesis are greatly impaired in Fgf10 knockout mouse embryos. FGF10 stimulates preadipocyte proliferation through the Ras/MAPK pathway followed by the cyclin D2-dependent phosphorylation of p130. FGF10 also stimulates adipogenesis by inducing the expression of pRb through the Ras/MAPK pathway. pRb binds C/EBPαThe pRb-C/EBPa complex induces adipogenesis. Fgf21 is abundantly expressed in the liver. Hepatic Fgf21 expression is markedly induced in mice by fasting. FGF21 exerts pharmacological effects on glucose and lipid metabolism in hepatocytes and adipocytes. However, the phenotypes of Fgf21 knockout mice, which are apparently normal and fertile, indicate FGF21 not to be a physiological regulator for hepatic functions. Hepatic FGF21 inhibits lipolysis in adipoctyes, and so is a negative regulator of lipolysis during fasting. FGF21 may be a “thrifty factor”. Serum FGF21 levels are increased in patients with metabolic diseases related with obesity, indicating potential roles of FGF21 in adipocyte metabolism.
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Sex-Gender Differences In Diabetes Vascular Complications And Treatment
Franconi F, Campesi I, Occhioni S and Tonolo G
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00014]
Diabetes mellitus and cardiovascular diseases act as two sides of the same coin: diabetes is an important risk factor for cardiovascular disease while patients with ischemic cardiovascular diseases often have diabetes or pre-diabetes. As firstly shown by Framingham study, diabetic women have an increased cardiovascular risk some 3.5 fold higher than non diabetic women, against an increase of “only” 2.1 fold found in male subjects. In view of the impact of sexual hormones on glucose homeostasis, the molecular pathways involved in insulin resistance suggests a gender specificity mechanism in the development of diabetic complications leading to the unmet need of gender therapeutic approaches. This has also been seen in other diabetic complications such as renal diseases, which seems to progress at a faster rate in females compared with males and women benefit less from treatment than do men. Of note, none of the trials done so far are primarily designed to assess sex and gender differences in the benefit from a specific intervention strategy, de facto excluding fertile women from experimentation. In order to provide a more base evidenced medicine for women and to reach equity between men and women, gender epidemiological reports, preclinical and clinical research are mandatory to evaluate the impact of gender on the outcomes and to improve gender awareness and competency in the health care system. Future studies should consider gender differences in the setting of randomized controlled trials with drugs.
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Bone marrow microenvironment: a newly recognized target for diabetes-induced cellular damage
Giuseppe Mangialardi, Atsuhiko Oikawa, Carlotta Reni and Paolo Madeddu
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00015]
Diabetes mellitus is considered a cardiovascular disease owing to its prevalent association with cardiovascular morbidity and mortality. Cardiovascular events are not only more frequent but also complicated with more severe outcomes in diabetic patients as compared with non-diabetic patients. One mechanism accounting for this difference consists of the impairment of the regenerative cellular machinery, which contributes to tissue healing. Recent evidence indicates the contribution of resident progenitor cells in post-ischemic tissue remodeling. In addition, a wide spectrum of cells from distant sources, including the bone marrow, is attracted and home to the healing tissue. Diabetes affects the process of mobilization and recruitment as well as intrinsic functional properties of bone marrow-derived progenitor cells. This review highlights current evidence for diabetes-induced damage of bone marrow hematopoietic progenitor cells in the endosteal and vascular niches.
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Cerebrovascular Complications of Diabetes: Focus on Stroke
Adviye Ergul, Aisha Kelly-Cobbs, Maha Abdalla and Susan C. Fagan
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00016]
Cerebrovascular complications make diabetic patients 2-6 times more susceptible to a stroke event and this risk is magnified in younger individuals and in patients with hypertension and complications in other vascular beds. In addition, when patients with diabetes and hyperglycemia experience an acute ischemic stroke they are more likely to die or be severely disabled and less likely to benefit from the one FDA-approved therapy, intravenous tissue plasminogen activator. Experimental stroke models have revealed that chronic hyperglycemia leads to deficits in cerebrovascular structure and function that may explain some of the clinical observations. Increased edema, neovascularization and protease expression as well as altered vascular reactivity and tone may be involved and point to potential therapeutic targets. Further study is needed to fully understand this complex disease state and the breadth of its manifestation in the cerebrovasculature.
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Cardiac effects of HDL and its components on diabetic cardiomyopathy
Frank Spillmann, Sophie Van Linthout and Carsten Tschöpe
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00017]
Diabetic cardiopathy includes a specific cardiomyopathy, which occurs in the absence of coronary heart disease and hypertension under diabetes mellitus. Hyperglycemia, hyperinsulinemia, and hyperlipidemia, characteristic metabolic disturbances evident in diabetes mellitus, all three lead to a specific altered cardiac structure and function. Recently, it has been demonstrated that altered HDL, be it low HDL or dysfunctional HDL is not only a consequence of diabetes mellitus, but can also contribute to the development of diabetes mellitus, and therefore also of diabetic cardiomyopathy. This review summarizes how HDL can indirectly affect diabetic cardiomyopathy via their influence on the metabolic triggers hyperglycemia, hyperinsulinemia, and hyperlipidemia, and how they can directly influence the cardiac cellular consequences, typical for diabetic cardiomyopathy, including inflammation, oxidative stress, apoptosis, fibrosis, Ca2+ handling, glucose homeostasis, and endothelial dysfunction.
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Molecular mechanisms of diabetes and atherosclerosis: Role of adiponectin
Ken Kishida, Tohru Funahashi and Iichiro Shimomura
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00018]
Type 2 diabetes mellitus (T2DM) is a disease characterized by inadequate beta-cell response due to progressive insulin resistance that typically accompanies physical inactivity and weight gain. T2DM is associated with substantial morbidity and mortality related to the associated atherosclerotic cardiovascular risks and diabetic vasculopathies, including microangiopathies (e.g., blindness and renal failure) and macroangiopathies (atherosclerosis). The increasing global prevalence of T2DM is linked to the rising rates of obesity, especially abdominal obesity. Visceral fat accumulation is upstream of obesity-related disorders including atherosclerotic cardiovascular disease (ACVD), and is associated with impaired insulin sensitivity and atherosclerosis through dysregulated production of adipocytokines, especially hypoadiponectinemia. This review article discusses the pathophysiological mechanisms responsible for T2DM and atherosclerosis, focusing on adiponectin. Clinical and experimental studies have shown that hypoadiponectinemia contributes to a variety of life style-related diseases including T2DM and atherosclerosis. It is likely that life-style modification, visceral fat reduction and use of medications that increase serum adiponectin levels (e.g., rimonabant, thiazolidinediones, fibrates, angiotensin receptor blocker and mineralocorticoid receptor blockade) when provided in combination can improve hypoadiponectinemia and thus prevent the development of life style-related diseases including T2DM and ACVD.
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Diabetes-induced epigenetic signature in vascular cells
Tijana Mitić and Costanza Emanueli
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00019]
Vascular dysfunction is a common consequence of diabetes mellitus. Stable propagation of gene expression from cell to cell during development of diseases (like diabetes) is regulated by epigenetic mechanisms. These are heritable patterns of gene expression that cannot solely be explained by changes in the DNA sequence. Recent evidence shows that diabetes-induced epigenetic changes can affect gene expression in vascular endothelial cells and vascular smooth muscles cells. Such effects further influence inflammatory pathways (e.g. IL-8 production via the NF-κB pathway, crosstalk between cyclo-oxygenase and nitric oxide pathway etc.) leading on to an impaired insulin production in these cells. As a consequence, a long-term memory is ensued, whereby epigenetic changes are maintained even long after restoring normo-glycaemic conditions by appropriate therapeutic approaches. This review focuses on the epigenetic marks, which endure on the vascular chromatin under diabetic conditions.
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Emerging therapy for diabetic neuropathy: Cell therapy targeting vessels and nerves
Hyongbum Kim, Julie J. Kim and Young-sup Yoon
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00020]
Diabetic neuropathy (DN), the most common complication of diabetes, frequently leads to foot ulcers and may progress to limb amputations. Despite continuous increase in incidences, there is no clinical therapy to effectively treat DN. Pathogenetically, DN is characterized by reduced vascularity in peripheral nerves and deficiency in angiogenic and neurotrophic factors. We will briefly review the pathogenic mechanisms of DN and the effects of cell therapies for DN. To reverse the changes of DN, studies have attempted neurotrophic or angiogenic factors for treatment in the form of protein or gene therapy; however, the effects were modest if not ineffective. Recent studies have demonstrated that bone marrow (BM)-derived cells such as mononuclear cells or endothelial progenitor cells (EPCs) can effectively treat various cardiovascular diseases through their paracrine effects. Becuase BM-derived cells can produce multiple angiogenic and neurotrophic cytokines, they were used for treating experimental DN and found to reverse manifestations of DN. Particularly, EPCs were shown to exert favorable therapeutic effects through enhanced neural neovascularization and neuro-protective effects. These findings clearly indicate that DN is a complex disorder with pathogenic involvement of both vascular and neural components. Therefore, cell therapies which target both vascular and neural elements are shown to be advantageous in treating DN.
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Glucocorticoid Analogues: Potential Therapeutic Alternatives for Treating Inflammatory Muscle Diseases
Erica K.M. Reeves, Sree Rayavarapu, Jesse M. Damsker and Kanneboyina Nagaraju
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00021]
Glucocorticoids (GCs) have been prescribed to treat a variety of diseases, including inflammatory myopathies and Duchenne muscular dystrophy for over 50 years. However, their prescription remains controversial due to the significant side effects associated with the chronic treatment. It is a common belief that the clinical efficacy of GCs is due to their transrepression of pro-inflammatory genes through inhibition of inflammatory transcription factors (i.e. NF-κB, AP-1) whereas the adverse side effects are attributed to the glucocorticoid receptor (GR) -mediated transcription of target genes (transactivation). The past decade has seen an increased interest in the development of GR modulators that maintain the effective anti-inflammatory properties but lack the GR-dependent transcriptional response as a safe alternative to traditional GCs. Many of these analogues or “dissociative” compounds show potential promise in in vitro studies but fail to reach human clinical trials. In this review, we discuss molecular effects of currently prescribed GCs on skeletal muscle and also discuss the current state of development of GC analogues as alternative therapeutics for inflammatory muscle diseases.
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Regulation of leptin receptor expression in human polarized Caco-2/15 cells
Philippe G Cammisotto, Moise Bendayan and Emile Levy
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00022]
BACKGROUND: Leptin receptors (LEPR) are expressed in intestinal epithelial cells from the duodenum to the colon. Since their role is fundamental for the proper control of nutrient absorption, mucus secretion and mucosa renewal, the regulation of LEPR expression is for the first time investigated as a function of various potential effectors.
METHODOLOGY/PRINCIPAL FINDINGS: Fully differentiated Caco-2/15 cells were incubated for 24 hours with nutrients [carbohydrates, fatty acids (FA), amino acids and sterols], hormones (leptin, insulin, hydrocortisone and epithelial growth factor), inflammatory agents (Interferon-γ, LPS, TNF-α), and PPAR agonists (rosiglitazone and WY14643). Levels of LEPR mRNA and protein expressions were measured by RT-PCR and Western blots, respectively.
Results: Long (219.1) and short (219.3) isoforms of the LEPR were detected in Caco-2/15 cells, while absence of the isoform 219.2 was noted. Their gene expression was modulated by carbohydrates, FA, PPAR agonists, biliary salts, insulin and leptin itself. On the other hand, LEPR protein expression was modulated by FA, cholesterol, biliary salts, PPAR agonists and insulin. Interestingly, the same effectors may have opposite effects on the short and the long LEPR isoforms, as well as on mRNA and protein levels. Finally, Caco-2/15 cells were found to be sensitive to the effector location, i.e. apical or basolateral compartment.
CONCLUSIONS/SIGNIFICANCE: Our results suggest that (i) the expression of LEPR in Caco-2/15 cell line is not constitutive; (ii) the agents present in the apical or basolateral medium have different effects on LEPR mRNA and/or protein levels; and (iii) short and long isoforms of LEPR follow different patterns of regulation.
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State Of The Art In The Therapeutic Maintenance And Management Of Dental Implants Today: Focus On Mucositis And Perimplantitis
Lucrezia Bottalico, Roberto G. CarlaioLuigi Santacroce
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00023]
Current oral rehabilitation protocols using implants is aimed at substituting the wasted and lost dental pillar, thus realizing a stable prosthesis.
Obviously, the increasing utilization of oral implants has determined an evolution of rehabilitative implant protocols requiring a proper adaption of the dental professionals. Postsurgical case management to preserve the reached rehabilitative results through implant prosthesis is supported, at now, by a number of consolidated protocols of dental hygiene. This practice plays a decisive role into prevention of peri-implantar pathologies by application of a preventive and/or therapeutic protocols. Dental industries, furthermore, in order to satisfy the new operative needs of professional oral hygiene, have contrived and produced new instrumentations, in accordance with achieved scientific results.
The purpose of this review is a brief survey of the “state of the art” in post-surgical dental implant management, with the aim to report the current protocols available to reduce the risk of oral disease and to arrest the progression of the peri-implant complications. Either surgical or non surgical therapy for mucositis and peri-implantitis are considered.
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Immune Modulation by Regulatory T cells in Helicobacter pylori-Associated Diseases
Sukanya Raghavan and Marianne Quiding-Järbrink
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00024]
Regulatory T cells (Treg) have the ability to suppress the activity of most other lymphoid cells as well as dendritic cells through cell-cell contact dependent mechanisms, which have not yet been fully defined. Treg are a key component of a functional immune system, and Treg deficiency is associated with severe autoimmunity and allergies. Antigen-specific Treg accumulate in gastric tissue during both Helicobacter pylori-induced gastritis and peptic ulcer disease (PUD). Several studies suggest that the local Treg response protects the gastric mucosa from exaggerated inflammation and tissue damage, and the risk of PUD is inversely related to Treg frequencies. At the same time the reduction of the inflammatory response achieved by Treg leads to increased bacterial density. Furthermore, the inability to mount a protective inflammatory response will lead to chronic infection and in some patients to the development of atrophic gastritis and gastric cancer progression. Treg actively infiltrate gastric adenocarcinomas and are predicted to promote tumor escape from cytotoxic immune responses. In addition, the presence of a potent Treg response will probably be an obstacle when constructing a future therapeutic vaccine against H. pylori. In this article, we will review the proposed mechanisms of action for Treg, their accumulation in the gastric mucosa in the different H. pylori-associated diseases, and how they may affect the immune response induced by H. pylori infection and the course of PUD and gastric adenocarcinomas.
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Cystic Echinococcosis: Aspects of Immune Response, Immunopathogenesis and Immune Evasion from the Human Host
Alessandra Siracusano, Federica Delunardo, Antonella Teggi and Elena Ortona
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00025]
Cystic echinococcosis (CE) is a neglected infectious disease caused by the larva stage of Echinococcus granulosus. It constitutes a major public health problem in developing countries. During CE, the distinguishing feature of the host-parasite relationship is that chronic infection coexists with detectable humoral and cellular responses against the parasite. In order to establish successfully an infection, E. granulosus releases molecules that directly modulate the host immune responses favoring a strong anti-inflammatory response and perpetuating parasite survival in the host. In vitro and in vivo immunological approaches, together with molecular biology and immunoproteomic technologies provided us exciting insights into the mechanisms involved in the initiation of E. granulosus infection and the consequent induction and regulation of the immune response. Here, we review some of the recent developments and discuss how these observations helped to understand the immunology of E. granulosus infection in man. Although the last decade has clarified many aspects of host-relationship in human CE, establishing the full mechanisms that cause the disease require more studies. We need to define more clearly the events that manipulate the host immune response to protect the E. granulosus from elimination and minimizing severe pathology in the host.
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Wolbachia and its implications for the immunopathology of filariasis
Claudio Genchi, Laura H. Kramer, Davide Sassera and Claudio Bandi
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00026]
Filarial infections are characterized by immunopathological phenomena, that are responsible for the onset of often dramatic pathological outcomes, such as blindness (Onchocerca volvulus) and elephantiasis (W. bancrofti). In addition, the long-term survival (as long as 10 years) of these parasites in otherwise immunocompetent hosts indicates that these nematodes are capable of manipulating the host immune response. The ground-breaking discovery of the bacterial endosymbiont Wolbachia, which resides in most filarial nematodes causing disease, has led to increasing interest in the role it may play in immuno-modulation, pro-inflammatory pathology and other aspects of filarial infection. Indeed, Wolbachia has been shown to be responsible for exacerbating inflammation (as in river blindness), while at the same time blocking efficient elimination of parasites through the host immune response (Onchocerca ochengi). While studies aimed at identifying Wolbachia as a potential target for anti-filarial therapy are at the forefront of current research, understanding its role in the immunology of filarial infection is a fascinating field that has yet to uncover many secrets.
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Toxocara infection and its association with allergic manifestations
Elena Pinelli and Carmen Aranzamendi
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00027]
Toxocara canis and Toxocara cati are roundworms of dogs and cats that can also infect humans worldwide. Although these parasites do not reach the adult stage in the human host the larvae migrate to different organs and can persist for many years. Migration of larvae through the lungs may result in respiratory distress such as wheezing, coughs, mucous production and hyper-reactivity of the airways. Epidemiological and experimental studies suggest that infection with this helminth contributes to the development of allergic manifestations, including asthma. These findings are however conflicting since in others studies no association between these two immunopathologies has been found. This article reviews information on Toxocara spp. and findings from epidemiological and experimental studies on the association between Toxocara infection and allergic manifestations. In addition, the immunological mechanisms and the factors involved in the helminth allergy-association are discussed.
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Immunomodulation in trichinellosis: does Trichinella really escape the host immune system?
Fabrizio Bruschi and Lorena Chiumiento
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00028]
This review describes different aspects of the host immune response to Trichinella. The role of antibodies, T cells, mast cells, eosinophils and neutrophils, respectively, in immune reaction to this nematode is considered, in the light of the recent data derived from experimental models, both in vivo and in vitro. The knowledge of immune response mechanisms against Trichinella is fundamental to understand how the parasite can escape such mechanisms. The principal evasion mechanisms of host immune response occurring in trichinellosis are described, some of which are shared by other parasites, some others are peculiar of this parasite, but particular attention is focused on immunomodulation and the possibilities to exploit this parasite ability to verify the effects on immuno-mediated diseases.
In conclusion, some considerations on the actual ability to escape the host immune response by the parasite are discussed, taking into account recent data showing that the parasite might rather drive immune system of the host towards a less dangerous response.
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Schistosoma mansoni antigens as modulators of the allergic inflammatory response in asthma
L. S. Cardoso, S.C. Oliveira, M.I. Araujo
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00029]
Epidemiologic evidence has accumulated suggesting that helminth infection or their products protect against the development of autoimmune and allergic diseases. The mechanisms underlying this protection may include regulatory cells and cytokines. Both helminth infection and allergic diseases drive the immune system toward the Th2 type response with high production of IgE. However, while this antibody response is associated with the pathogenesis of allergic diseases, IgE production in regions endemic for parasite diseases, such as schistosomiasis, might be associated with a protection against infection. In individuals chronically exposed to Schistosoma sp infection, regulatory cells and cytokines which may develop to protect the host against harmful parasite antigens may also protect the host against allergic diseases. We have demonstrated that helminthic infections are associated with a poor response to allergy skin-prick tests and with low asthma pathology. This review summarizes the immune response that is associated with the pathology of allergic diseases such as asthma and with the resistance to helminth infections. Moreover, it is discussed how helminth infection, particularly Schistosoma mansoni or their products may influence the development of atopic asthma.
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Immunomodulatory properties of ES-62, a phosphorylcholine - containing glycoprotein secreted by Acanthocheilonema viteae
Lamyaa Al-Riyami and William Harnett
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00030]
Filarial nematodes are parasites that have the ability to persist in their hosts for extended periods of time due to the employment of various mechanisms to divert or down-regulate the host’s immune responses. One of these mechanisms is the production of immunomodulatory excretory-secretory (ES) products. This review will discuss the properties of one such product, ES-62, which over the years, has been shown to interact with and modulate the activities of a variety of cells of the immune system including B and T lymphocytes, dendritic cells, macrophages and mast cells. Overall, ES-62 diverts the immune system towards an anti-inflammatory phenotype and consistent with this it has been shown to have therapeutic potential in models of inflammatory disease associated with autoimmunity and allergy.
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Incidence And Prevalence Of Hypothyroidism In Patients Affected By Chronic Heart Failure: Role Of Amiodarone
Vincenzo Triggiani, Massimo Iacoviello, Fabio Monzani, Agata Puzzovivo, Pietro Guida, Cinzia Forleo, Marco Matteo Ciccone, Raffaella Catanzaro, Emilio Tafaro, Brunella Licchelli, Vito Angelo Giagulli, Edoardo Guastamacchia and Stefano Favale
[FULL-TEXT INQUIRY] [BSP/EMIDDT/E-Pub/00031]
Background. It has been demonstrated that hypothyroidism can lead to significant hemodynamic alterations favoring the onset of chronic heart failure (CHF) as well as its progression. Furthermore, amiodarone, an iodine-containing antiarhythmic drug frequently used in CHF patients, is often the cause of primary hypothyroidism.
Aim of the study. To define the prevalence and incidence of hypothyroidism in a group of CHF outpatients in stable clinical conditions, with particular reference to the role of amiodarone therapy.
Results. Among the 422 enrolled patients (326 males, aged 65±12 years), 51 (12%) had a previous diagnosis of hypothyroidism while 21 (5%) were newly diagnosed at the enrolment. Then, the overall prevalence of hypothyroidism at the first evaluation was 17% and, as expected, it was significantly higher in females than males (33% vs 13%; p<0.001). During follow-up (median 28 months) hypothyroidism occurred in further 19 patients (incidence rate: 26/1000/year) and it was mainly attributable to amiodarone therapy. Considering all together the hypothyroid patients, either those affected by thyroid failure at the enrolment than those developing hypothyroidism during the follow-up, levothyroxine therapy was continued or started in 69% of them; however, normal serum TSH values were obtained only in 76% of treated cases (mean levothyroxine dose: 69±44 mcg/day). In any case, in the group of patients affected by hypothyroidism a significantly greater occurrence of heart failure progression was observed.
Conclusions. Hypothyroidism, especially the subclinical form, frequently occurs in patients affected by CHF receiving amiodarone therapy. Given the unfavorable impact of hypothyroidism on the progression and prognosis of CHF, and the opportunity to adequately manage thyroid failure by means of levothyroxine replacement therapy without the need to withdraw amiodarone, we recommend regular testing of thyroid function in CHF patients, in particular in those submitted to amiodarone therapy, in order to early diagnose a condition of hypothyroidism and titrate substitutive treatment.
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