Diabetes in nonobese adults,m82 the cigar galaxy,jan philips 5814a ecg - Plans On 2016


Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic miceSiri Atma W. Fotos oben: Patientin Inken Helms - Und plA¶tzlich hatte sie nur noch riesigen DurstInken hat Diabetes.
Except where otherwise noted, this work is licensed under Creative Commons Attribution-NonCommercial 4.0 International License. Please cite this paper as:Kumar Kota S, Ugale S, Gupta N, Naik V, Krishna Kota S, Hari Kumar Kvs, Modi KD. The present study included 38 patients subjected to II + SG in the Department of Laparoscopic Surgery, Kirloskar Hospital, Hyderabad, India. United Kingdom Prospective Diabetes Study 24: A 6-Year, Randomized, Controlled Trial Comparing Sulfonylurea, Insulin, and Metformin Therapy in Patients with Newly Diagnosed Type 2 Diabetes That Could Not Be Controlled with Diet Therapy. Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields.
Although the etiology of SjS remains elusive, accumulating evidence indicates that both genetic factors and environmental triggers, such as viral infections, sex hormone changes and tissue injuries, contribute to the initiation of autoimmune process in SjS [3,7-10]. IFN-γ, the hallmark cytokine of Th1 and cytotoxic CD8 T cells, plays a pivotal role in cellular immunity and host defense against intracellular pathogens and tumor [20]. The salivary glands and saliva from patients with primary SjS exhibit elevated levels of IFN-γ compared to non-SjS subjects [29,30]. IL-12, produced mainly by macrophages and dendritic cells (DCs), is a critical promoter of the differentiation of IFN-γ-producing T cells, both Th1 and effector CD8 T cells [39,40]. IL-12 levels are elevated in the target organs of patients with SjS, with macrophages and DCs being the main cellular sources [45,46].
IL-18, a member of IL-1 family of pro-inflammatory cytokines, mediates a variety of inflammatory responses in the context of inflammation, infections and autoimmunity through affecting both immune and non-immune cells and both innate and adaptive immune systems [50-52]. Tumor necrosis factor-alpha (TNF-α) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reactions such as fever, cell death, sepsis, cachexia and inflammation.
IL-4, originally characterized as an anti-inflammatory cytokine, is the hallmark cytokine of Th2 immune response. IL-4 has been detected in the salivary glands of a portion of SjS patients, especially those with higher degree of B cell accumulation in the target organs [33,70]. IL-13 is originally characterized as a Th2 cytokine as it can be produced by these effector T cells and has overlapping effects with IL-4 on macrophages, B cells and inflammation [71-73]. IL-17, a potent pro-inflammatory cytokine that has been in the center of investigation in the field of autoimmunity and inflammation, is the hallmark cytokine produced by Th17 cells. Elevated IL-17 and IL-23 levels are reported in salivary gland and serum of patient with primary SjS [84-87]. IL-22 is an IL-10 family cytokine member that is expressed by Th17 and NK cells, among others [78,90]. Patients with SjS have significantly elevated serum IL-21 levels, which are positively correlated with levels of IgG1. IL-10, initially classified as a Th2 cytokine, is a potent antiinflammatory cytokine that suppresses both innate and adaptive immune response [105,106].
IL-10 levels are elevated in the saliva of SjS patients and correlated with severity of xerophthalmia and xerostomia [113]. As described in this review, findings from human SjS patients and various in vitro and in vivo studies using mouse SjS models have provided evidence implicating the functions of a number of T cellderived or T cell-affecting cytokines in the development and onset of this disease.
Many aspects proposed in this model need to be tested in future by in vivo functional studies in mouse models and by in vitro functional studies using T cells from SjS patients. Cytokines are crucial effectors and modulators of the autoimmune responses that lead to the onset of SjS.
Voulgarelis M, Tzioufas AG (2010) Pathogenetic mechanisms in the initiation and perpetuation of Sjögren's syndrome.
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Sakai A, Sugawara Y, Kuroishi T, Sasano T, Sugawara S (2008) Identification of IL-18 and Th17 cells in salivary glands of patients with Sjögren's syndrome, and amplification of IL-17-mediated secretion of inflammatory cytokines from salivary gland cells by IL-18. Mieliauskaite D, Dumalakiene I, Rugiene R, Mackiewicz Z (2012) Expression of IL-17, IL-23 and their receptors in minor salivary glands of patients with primary Sjögren's syndrome.
Katsifis GE, Rekka S, Moutsopoulos NM, Pillemer S, Wahl SM (2009) Systemic and local interleukin-17 and linked cytokines associated with Sjögren's syndrome immunopathogenesis.
Colonna M (2009) Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Sonnenberg GF, Fouser LA, Artis D (2011) Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22.
Spolski R, Leonard WJ (2008) Interleukin-21: basic biology and implications for cancer and autoimmunity. Spolski R, Leonard WJ (2008) The Yin and Yang of interleukin-21 in allergy, autoimmunity and cancer. Ma CS, Deenick EK, Batten M, Tangye SG (2012) The origins, function, and regulation of T follicular helper cells.
Yi JS, Cox MA, Zajac AJ (2010) Interleukin-21: a multifunctional regulator of immunity to infections.
Sarra M, Franzè E, Pallone F, Monteleone G (2011) Targeting interleukin-21 in inflammatory diseases. Spolski R, Leonard WJ (2010) IL-21 is an immune activator that also mediates suppression via IL-10.
Pot C, Apetoh L, Awasthi A, Kuchroo VK (2010) Molecular pathways in the induction of interleukin-27-driven regulatory type 1 cells. Liu H, Liu G, Gong L, Zhang Y, Jiang G (2012) Local suppression of IL-21 in submandibular glands retards the development of Sjögren's syndrome in non-obese diabetic mice. O'Garra A, Barrat FJ, Castro AG, Vicari A, Hawrylowicz C (2008) Strategies for use of IL-10 or its antagonists in human disease.
Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A (2001) Interleukin-10 and the interleukin-10 receptor.
Brooks DG, Walsh KB, Elsaesser H, Oldstone MB (2010) IL-10 directly suppresses CD4 but not CD8 T cell effector and memory responses following acute viral infection. Beebe AM, Cua DJ, de Waal Malefyt R (2002) The role of interleukin-10 in autoimmune disease: systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Levy Y, Brouet JC (1994) Interleukin-10 prevents spontaneous death of germinal center B cells by induction of the bcl-2 protein. 65 years, among nonsmokers, and among nonobese females, and patients without hypertension and without dyslipidemia (Table 3). B) activation and leads to oxidative stress, which exacerbates pathological processes leading to glucose intolerance and insulin resistance [35, 36]. November soll alljA¤hrlich auf die Bedeutung der chronischen Erkrankung Diabetes und ihrer SpA¤tfolgen aufmerksam machen.
Auf diesen Zusammenhang sind A„rzte durch Operationen von stark A?bergewichtigen Menschen gestoAYen. Dieses wird begA?nstigt durch falsche ErnA¤hrung und Bewegungsmangel.Wie macht sich Typ-2-Diabetes bemerkbar? Arzneimittel unter VerdachtBluthochdruck-Patienten droht eine Zuckerkrankheit nicht nur bei A?bergewicht und Fettleibigkeit, sondern auch als Nebenwirkung bestimmter Medikamente.
Ein Gesundheitsausschuss der amerikanischen Food and Drug Administration (FDA) sprach sich wegen des Verdachts gefA¤hrlicher Nebeneffekte gegen die Genehmigung des Mittels Rimonabant aus, das gegen Fett- leibigkeit und Diabetes wirken soll.
The hospital’s ethical committee approved the study, all patients were informed thoroughly about the benefits and risks involved, Subsequently the patients provided written, informed consent. Subjects and Preoperative EvaluationThe preoperative evaluation included a clinical history of T2DM, comorbidities, and complications, followed by a thorough physical examination. ProcedureThe operation was performed under general anesthesia via a standard 6-port laparoscopic technique. Postoperative Follow UpDiabetes and hypertension medications were adjusted postoperatively according to plasma glucose and blood pressure records. Statistical AnalysisAll outcome measures were evaluated at every visit prospectively from the third month onward.
DiscussionOur current report demonstrates, in 38 patients, the beneficial effects of the novel II + SG procedure for controlling T2DM, hypertension, obesity, and related metabolic abnormalities. At 6 years, patients allocated to insulin had lower fasting plasma glucose levels than did patients allocated to oral agents, but hemoglobin A1c concentrations were similar. Data from 458 patients allocated to insulin, sulfonylurea, or metformin therapy at 6 years are reported. The left panel shows data from nonobese patients; the right panel shows data from obese patients. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. SjS affects 2-4 million people in the US alone and greatly affects the life quality of the afflicted individuals. SjS affects 2-4 million people in the US alone, with 90% of the patients being women.
Both self-reactive T and B cells play crucial roles for the development and onset of SjS by driving exocrine gland inflammation and autoantibody production [3,5,11-13]. IFN-γ is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by Th1 cell and CD8+ cytotoxic T cells (CTL) during antigen-specific adaptive immune response. IL-12 potently induces and facilitates cellular immune responses by promoting proliferation, cytotoxic activity and IFN-γ production from effector T cells and NK cells [22,39,40].
One major effect of IL-18 on adaptive immunity is to enhance IL-12-induced Th1 responses [51,53].
It is produced by many cell types including Th1 cells and CD8 effector cells and implicated in the pathogenesis of various autoimmune and rheumatic diseases.
IL-4 amplifies Th2 differentiation, mediates asthma and allergy and provides critical stimulating signals for the growth and function of activated B cells [63,64].
Deficiency of IL-4 or STAT6 gene in NOD and NOD.B10-H2b mice abolishes the production of IgG1-type anti-M3R antibody, the crucial autoantibody causing the secretory dysfunction and xerostomia [14,17,48].
IL-13 enhances the activities of many cell types, such as B cells, fibroblasts and mast cells, and as a result plays pivotal roles in allergic asthma, anti-helminth immunity and tissue fibrosis [71]. It plays important roles in host defense against bacterial and fungal infections and has been shown to be the predominant pathogenic player in numerous autoimmune and inflammatory diseases [78-80]. Moreover, immunohistochemistry analysis has shown IL-17 and IL-23 proteins and their receptors within lymphocytic infiltrates and ductal areas in salivary glands of SjS patients [84,86,88].
Recent findings have shown important functions of IL-22 in autoimmunity, inflammation and epithelial cell and mucosal tissue homeostasis [78,90,91], with both tissue-protective effects and pro-inflammatory effects reported in different disease conditions [78,90,91]. IL-21 is produced by TFH, Th17 and NKT cells, with its receptor expressed on T cells and various types of immune cells and non-hematopoietic cells [94-96]. Immunohistochemistry analyses show that lymphocytic foci in the salivary glands from SjS patients express high levels of IL-21 compare to the controls [102].
IL-10 inhibits the maturation, function and cytokine production of antigen presenting cells and also can directly suppress T cell differentiation into pro-inflammatory Th1 and Th17 subsets [106-108]. Increased serum IL-10 levels are reported in patients with primary SjS, which are positively associated with the levels of IgG1 and immune cell-infiltration [114]. Among them, IL-4, IL-13, IFN-γ, IL-17, IL-21 and IL-10 have been convincingly shown to play distinct but essential roles in the pathogenic processes of this disease through in vivo loss-of-function studies using mouse SjS models.
Furthermore, the precise effects and the stage-dependent functions of many cytokines, the underlying mechanisms for the effects of these cytokines and the interactions, cross-regulation and redundancy among cytokines and Th subsets in the development and persistence of SjS are either completely uncharacterized or only partially delineated, and therefore await indepth investigations in future. Christophers, “Psoriasis—epidemiology and clinical spectrum,” Clinical and Experimental Dermatology, vol.
Dies hat die Internationale Diabetes-FA¶deration (IDF) fA?r ihren neuesten Diabetes-Atlas ermittelt. Das Medikament wird Patienten mit Diabetes Typ 2 verschieben, der mit A?bergewicht einhergeht. In Verdacht stehen A¤ltere Arzneimittel aus der Gruppe der Betablocker und der Diuretika, wie der Arzt Rainer DA?sing von der UniversitA¤t Bonn warnt.
DMSO, acetylsalicylic acid, emodin, physcion, rhein, resveratrol, and secondary Abs against mouse and rabbit sera were purchased from Sigma (MO, USA). Makino, “The murine autoimmune diabetes model: NOD and related strains,” Advances in Immunology, vol.
The potential benefits and the limited available data on this surgical procedure were explained specifically to nonobese diabetic patients. Exclusion criteria included type 1 diabetes, undetectable fasting C-peptide, positive urine ketones, pregnancy, coexisting severe hepatic, pulmonary, renal, cardiovascular, neurological, or psychiatric diseases, and obesity due to organic illness. The surgical procedure involved the creation of a 170-cm segment of ileum that started 30 cm proximal to the ileocecal junction. The patients maintained a liquid diet for 5–7 days, followed by a semisolid diet for 7 days, and finally a diet that included solids (to be consumed in small quantities). Taken in combination, the foregut and hindgut theories explain the resulting improved diabetes and weight loss after this surgery (31).
Forty-eight percent (95% CI, 37% to 58%) of patients in the primary diet failure group maintained hemoglobin A1c concentrations less than 0.08. The lighter dashed line indicates the estimated survivor function for all patients in the main randomization group (MR) who received intensive treatment.
Autoreactive effector T cells are central executors and orchestrators in the pathogenic processes of SjS by mediating target organ inflammation and destruction and by facilitating B cell responses and autoantibody production. Cytokines are powerful orchestrators and effectors of the innate and adaptive immune responses.
Among its plethora of biological effects, IFN-γ can activate macrophages and NK cells, enhance MHC expression and antigen presentation, induce expression of many chemokines and adhesion molecules in both immune and non-immune cells, promote differentiation of Th1 cells and induce apoptosis of various tissue and cell types [21,22].
IL-12 treatment decreases the frequency of regulatory T cells (Tregs) and downregulates Foxp3 levels in these cells [41]. IL-18 facilitates the development of autoimmune and inflammatory diseases, including pulmonary inflammatory disease, RA, type 1 diabetes and IBD [52-55]. SjS patients have higher salivary TNF-α level than non-SjS sicca patients [32]. Meanwhile, IL-4 inhibits the activation of Th1 response and cellular immunity, which largely accounts for its anti-inflammatory function [65,66].
IL-13 levels are increased in patients with rheumatic disease RA and SLE and correlated with disease severity [74,75]. IL-23, a member of IL-12 family of cytokines that comprises the p40 subunit of IL-12, has been shown to be a crucial cytokine for induction, stabilization and expansion of Th17 cells [39,79,81]. In addition, IL-17-producing- CD3+CD4-CD8- T cells are also expanded in the peripheral blood and salivary gland infiltrates in patients with SjS [89]. Serum levels of IL-22 were significantly elevated in patients with SjS and correlated with levels of autoantibodies and rheumatoid factor, suggesting a possible role of IL-22 in the development of this disease [92]. IL-21 can directly promote plasma cell differentiation and enhance germinal center B cell response, potentiate Th17 cell differentiation and enhance effector and memory CD8 T cell survival and function [79,81,96,97]. Consequently, IL-10 prevents the development of IBD, restrains the development of RA and experimental autoimmune encephalomyelitis, and limits tissue damage in response to certain microbial infections and chemical stimulants [107,109,110].
These lines of evidence suggest that IL-10, despite of its welldocumented immune-suppressive effects, may play a pathogenic role in SjS.
The roles of many other cytokines, including IL-12, IL-23, IL-18, TNF-α and IL-22, are strongly suggested but remain to be determined by in vivo loss-of-function studies.
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.AbstractBackground. Dirk MA?ller-Wieland, Chefarzt der Abteilung Innere Medizin mit den Schwerpunkten Endokrinologie, Diabetologie und Stoffwechsel an der Asklepios-Klinik, Hamburg, St. Mit zwA¶lf Prozent Diabetikern unter den 20- bis 79-JA¤hrigen liegt Deutschland in Europa an erster Stelle und auf Platz sechs von 165 LA¤ndern weltweit.
Naturally occurring anthraquinones are claimed as anti-inflammatory compounds; however, their actions are not clear. In 2005, the World Health Organization (WHO) stated that an estimated 1.6 billion adults in the world were overweight and at least 400 million were classified as obese. This segment was interposed into the jejunum, which was divided between 20 and 50 cm from the ligament of Treitz. The patients were discharged between the fourth and sixth postoperative days with vitamin supplements. Acknowledgments: The authors thank the patients and the National Health Serviceand non-National Health Service staff at the centers for their cooperation.


A variety of cytokines that are produced by effector T cells or capable of directly affecting effector T cells are elevated in the target organs and circulations of SjS patients. The primary clinical symptoms are xerostomia (dry mouth) and keratoconjunctivitis (dry eyes), which are presented as difficulty swallowing, chewing or talking, sandy or burning sensations in the eyes, dry or burning feelings at lips, nose and throat, and as a result, a higher incidence of dental caries. The differentiation of distinct effector T cells subsets, T helper (Th) 1, Th2, Th17 and T follicular helper (TFH) cells, are instructed or influenced by various cytokines.
IFN-γ has been shown to play a pathogenic role in mouse models of type 1 diabetes [23,24], systemic lupus erythematosus (SLE) [25,26], rheumatoid arthritis (RA) [27] and dextran sodium sulfate-induced inflammatory bowel diseases (IBD) [28]. Moreover, the Th1 response shows positive association with lymphocytic infiltration of the salivary glands [33]. IL-18 is detected in the serum, salivary glands and saliva of SjS patients and its levels correlate with the severity of the disease among the patients [56-58]. TNF-α enhances the surface expression of Ro (SS-A) and La (SS-B) on human keratinocytes, two important autoantigens involved in SjS and SLE [59]. Provision of exogenous IL-4 protects against development of type 1 diabetes and RA [67,68]. A rapidly growing knowledge in recent years about the pro-inflammatory functions of IL-17 and IL- 23-Th17 pathway has greatly advanced our understanding about the fundamental mechanisms causing autoimmunity and chronic inflammation, once attributed mainly to Th1 cells [39,78-81]. Moreover, in the salivary glands of patients with SjS, IL-22 mRNA and protein are both increased, with Th17 and NK cells as the main producers of this cytokine [93].
Rapidly growing evidence in recent years has identified IL-21 as a crucial new player in the pathogenesis of a number of autoimmune diseases, including IBD, SLE, type 1 diabetes and psoriasis [98,99].
Indeed, transgenic expression of IL-10 in salivary and lacrimal glands leads to SjS-like lymphocytic infiltration and enhanced apoptosis of glandular cells, which are underpinned by the effect of IL-10 to upregulate Fas ligand expression in CD4 T cells [115].
We propose a model delineating the specific functions and contributions of some of these cytokines in various pathogenic events leading to the onset of SjS (illustrated in Figure 1). Diabetes has been associated with psoriasis, but little is known about the association between psoriatic arthritis and diabetes. Betablocker senken den Blutdruck, indem sie den Herzschlag verlang- samen und abschwA¤chen. In klinischen Versuchen seien bei einer sehr kleinen Zahl von Patienten solche Symptome aufgetreten, betonten die amerikanischen Fachleute. This study aimed to investigate the effect and mechanism of catenarin on the inflammatory disease, T1D. All 3 anastomoses were performed side-by-side with an endo-GIA stapler (Ethicon Endo-surgery, Cincinnati, OH, USA) fitted with a 45-mm white cartridge. Patients allocated to insulin gained more weight and had more hypoglycemic attacks than did patients allocated to sulfonylurea. The recent advancement in the understanding about the functions of these cytokines, achieved by using both human samples and mouse disease models, has generated great insights into the cytokine control of autoimmune responses in the SjS disease setting.
Each effector T cell subset in turn produces a group of signature cytokines, which execute specialized effects on target tissues or pathogens and often simultaneously propel the further differentiation and expansion of the same effector subset. In non-obese diabetic (NOD) mice, a widely used model for type 1 diabetes and secondary SjS, IFN-γ-deficiency abolishes multiple pre-immunological abnormalities of the salivary glands, thus preventing the subsequent tissue-specific autoimmunity and clinical onset of SjS [15]. However, loss-of-function studies in mouse disease models are still needed to define the functional importance of endogenously produced IL-12 in the pathogenesis of SjS. Moreover, expression of IL-18 by salivary glandinfiltrating macrophages and DCs shows positive correlation with degree of leukocyte infiltration and lymphoma development in patients with primary SjS [45]. However, IL-4 is required for the development of systemic autoimmune diseases SLE, in that it promotes target organ inflammation and pathologies and faciliates production of IgG1 and IgE immunoglobulins [25,69].
A recent report demonstrates the presence of IL-13-producing T cells in salivary gland draining lymph nodes in Id3-deficient mice, a mouse model of primary SjS, but not in wild-type control mice [77]. An increase in IL-17 and IL-23 levels was reported in patients of various autoimmune or inflammatory diseases, including multiple sclerosis, RA, Crohn’s disease and psoriasis, and an essential role of IL-23-IL-17 pathway in the development and onset of these diseases has been demonstrated in the corresponding mouse models [39,78-83]. These findings suggest a potential role of IL-22 in SjS pathogenesis, which remains to be assessed by functional studies using mouse models and human samples. IL-21 also has anti-inflammatory and immunesuppressive effect by promoting the generation of IL-10-producing type 1 regulatory T (Tr1) cells [100,101]. A recent report shows that local suppression of IL-21 in submandibular glands, achieved by lentivirus mediated expression of IL-21 shRNA, reduces target organs inflammation and improves salivary gland secretory function and thus impedes the development of SjS in NOD mice [104]. Die Besserung ist unabhA¤ngig vom AusmaAY der Gewichtsreduktion und tritt bereits kurz nach der Operation auf. Der Konzern kA¶nne die erwA¤hnten Risiken nicht erkennen und habe weiter Vertrauen in die Sicherheit des Medikaments.
The pathogenic processes involved in the development of diabetes include autoimmune destruction of beta cells, secretion of excess insulin to compensate for increased insulin resistance, and increased production of endogenous glucose (5-7).
Body Mass Index (BMI) was calculated as weight in kilograms divided by height in meters squared (27).
Because of the small sample size, categorical data were analyzed by the two-tailed Fisher’s exact test.
Requests for Reprints: United Kingdom Prospective Diabetes Study Group, Diabetes Research Laboratories, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, United Kingdom. Obese patients allocated to metformin gained the least weight and had the fewest hypoglycemic attacks.
Many cytokines have been shown to be elevated in the target organs and serum of SjS patients and mouse models of SjS, as discussed later in this review.
Mechanistically, IFN-γ has been reported to induce death and secretory dysfunction in salivary gland cells as well as enhance the abilities of epithelial cells and antigen presenting cells (APCs) in the salivary glands to present antigens and activate T cells [5,34,35]. Similarly to IL-12, the in vivo pathogenic role of IL-18 in SjS still awaits future determination. Id3-deficient mice demonstrate an increase in mast cells in the salivary glands, which may contribute to the salivary gland dysfunction. Interestingly, overexpression of IL-17 results in the activation of B cell antibody production, the underlying mechanisms for which requires future investigation.
The effect of IL-21 is associated with an impaired TFH response, which might result in subsequent diminished B cell antibody production. IL-10 has certain stimulatory effects on B cells, promoting their survival and proliferation and enhancing plasma cell generation, antibody production and isotype switching [107,111,112]. Patients diagnosed with psoriatic arthritis by a rheumatologist were compared to age- and sex-matched patients without psoriatic arthritis regarding the prevalence of diabetes in a population-based cross-sectional study using logistic multivariate models. Catenarin, the most potent anthraquinone tested in the study, prevented T1D in nonobese diabetic mice.
PVDF membrane and enhanced chemoluminescence detection reagent were purchased from GE healthcare (Piscataway, NJ, USA), and Fura 2-AM was from Molecular Probe (OR, USA).3.
A variable sleeve gastrectomy was performed after the larger curvature from the antrum to the fundus area was devascularized. A significant reduction in postoperative microalbuminuria was observed with a declining trend in lipid parameters.The definition of obesity as it relates to BMI varies in different parts of the world.
Finally, they have a much higher risk of developing B cell lymphoma than the general population and people with other autoimmune disorders [1,3,4]. Functional studies performed with mouse models of SjS that are deficient in specific cytokine genes demonstrate that IFN-γ, IL-4 and IL-17, signature cytokines for Th1, Th2 and Th17 effector cells, are all essential for the full development and onset of SjS by modulating the differentiation, expansion and function of self-reactive T and B cells and by directly affecting the homeostasis and biological activities of the target tissues [14-19]. Furthermore, our own study and another report have shown that IFN-γ induces expression of chemokines CXCL9 and -10, both of which are ligands for CXCR3, in a human salivary gland cell line and in primary salivary gland epithelial cells from SjS patients [36].
However, despite these lines of evidence suggesting a role of TNF-α in SjS pathogenesis, the in vivo functional studies are still lacking. Blockade of IL-13 activity in Id3-KO mice with a neutralizing antibody improves salivary gland secretory function, which is associated with a reduction of mast cells in the target organs [77]. Collectively, these findings define a crucial pathogenic function of IL-17 in SjS and identify it as a potential therapeutic target for this disease.
Thus, IL-21 is a newly characterized pathogenic player in SjS with direct impact on both B and T cells.
The study was performed utilizing the medical database of Clalit, the largest healthcare provider organization in Israel. FA?r dieses vermehrte Gewicht muss die BauchspeicheldrA?se mehr Insulin produzieren - das Hormon, das die Versor- gung der KA¶rperzellen mit Energie in Form von Glukose (Zucker) sicherstellt. Diabetes has been shown to persist in nonobese patients after weight loss had induced complete restoration of normal insulin sensitivity. Relevant biochemistry tests, urinalyses, and imaging studies (chest radiograph and ultrasound of the abdomen) were performed on all patients in a single laboratory that had received approval by the National Accreditation Board for Testing and Calibration Laboratories (NABL). Wright, Cull, Holman, and Turner: United Kingdom Prospective Diabetes Study Group, Diabetes Research Laboratories, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, United Kingdom. SjS is usually chronic, progressive and at times debilitating, thereby greatly affecting the life quality of the patients. In this review, we summarized the recent progress on the expression and functions of cytokines in the pathogenesis of SjS, with specific focus on the cytokines that are either produced by effector T cells or directly affecting T cell responses. Consistent with a potential role of CXCR3 ligands in SjS pathogenesis, CXCL9, -10 and -11 are significantly increased in salivary gland lesions and tears of SjS patients [29,36,37]. Furthermore, a randomized, double-blind and placebocontrolled clinical trial of infliximab, a neutralizing monoclonal antibody against TNF-α that showed promising therapeutic effects on a number of autoimmune or inflammatory disorders including SLE, did not demonstrate any efficacy in treating SjS [62]. This study has presented important evidence that IL-13 facilitates the development of secretory dysfunction, possibly by affecting mast cells. These mechanisms have been demonstrated in the cases of type 1 diabetes and SLE, in which IL-10 exerts pathogenic effects, likely in a fashion that depends on the stage of the disease and the cell types that produce IL-10 [117,118].
It also induces production of matrix metalloproteinases from tissue cells to enhance tissue damage. Und wir wissen, dass sich bei Patienten, die operiert werden, die Balance dieser Hormone A¤ndert", erklA¤rt MA?ller-Wieland.
On the contrary, catenarin inhibited CCR5- and CXCR4-mediated chemotaxis via the reduction of the phosphorylation of mitogen-activated protein kinases (p38 and JNK) and their upstream kinases (MKK6 and MKK7), and calcium mobilization. Catenarin Inhibits CCR5- and CXCR4-Mediated Chemotaxis in Jurkat Cells and SplenocytesLeukocyte migration (insulitis) is associated with β-cell loss in T1D [6] and mediated by chemokines and their receptors [37]. This finding implies that impaired insulin secretion plays an essential role in T2DM (9).Incretins, which include glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), play a major role in insulin secretion. A fully automated clinical chemistry analyzer (Olympus 2700) was used to conduct biochemical analyses. The lumen of the stomach was adjusted using a 32–58 French calibrator (Romsons International, New Delhi, India), which was placed along the smaller curvature.
Therefore, TNF-α may not be an indispensable pathogenic factor for SjS or it may play a more complicated role than simply promoting the disease. Future investigations are warranted to thoroughly delineate the complex function of IL-10 in the pathogenesis of SjS. The study included 549 patients with psoriatic arthritis ≥21 years and 1,098 patients without psoriatic arthritis.
Die Mediziner hA¤tten bis jetzt gelernt, dass das autonome Nervensystem, das die Organe versorgt, eine Rolle spielt. Overall, the data demonstrate the preventive effect and molecular mechanism of action of catenarin on T1D, suggesting its novel use as a prophylactic agent in T1D.1.
In this study, we first evaluated the medicinal effect of catenarin and its 3 derivatives (Figure 1(a)) on chemokine-directed chemotaxis in Jurkat cells and their stable clone, JK-EF1α-CCR5 cells, using transwell migration assays.
Leiter, “The NOD mouse model of type 1 diabetes: as good as it gets?” Nature Medicine, vol. Impaired incretin activity interferes with normal early-phase insulin secretion processes (0–20 min) in T2DM. Fasting and post-meal blood glucose were measured by the hexokinase method; the cholesterol oxidase method was used to estimate the lipid profile.
Postoperatively, improvements were observed in other metabolic parameters like lipids and microalbuminuria; however, only the latter was statistically significant. These findings suggest that induction of CXCR3 ligands is a crucial mechanism by which IFN-γ promotes effector T cell recruitment to target tissues and initiates local autoimmune responses. Von dort wird sie beim gesunden Menschen je nach Bedarf wieder abgegeben, so dass der Blut- zuckerspiegel konstant bleibt. IntroductionT1D is a life-threatening disease arising from the destruction of insulin-producing β cells by leukocytes with a strong inflammatory reaction. CXCR4 and CCR5 chemokines were selected here because both are expressed in naïve and activated T cells, a dominant type of leukocytes in eliciting T1D.
Defective late-phase plasma insulin amplification in response to GIP-induced glucose (20–120 min) has also been observed, whereas GLP-1 has been shown to enhance the late-phase plasma insulin response markedly (10). A Roshe E 601 analyzer was used to assess serum insulin, C-peptide (basal and 1 h post meal), thyroid profile, and microalbuminuria.
Nonobese patients were subjected to fundectomy only, and a sufficient volume of residual stomach remained for normal food intake.
Definitive in vivo studies, especially loss-of-function studies, are required to determine the functions of endogenous IFN-γ in the immunological phase of the SjS development and in the persistence of SjS after disease onset. The loss of early-phase insulin secretion results in insufficient suppression of glucagon secretion, free fatty acid secretion, and hepatic glucose output, all of which trigger continuous delivery of glucose in the circulation (11).
To determine insulin levels, fasting serum samples were subjected to electrochemiluminiscence. Moreover, additional effects of this cytokine in SjS, such as those affecting macrophage and NK cell function and inducing additional chemokines, also await further investigation.
Th2-derived IL-13 facilitates the secretory dysfunction, possibly by enhancing the proliferation and activation of mast cells and histamine release from these cells. Patients with T1D share many similar genetic and immunopathological features with nonobese diabetic (NOD) mice, an established mouse model for T1D study [1, 2].
C-peptide and thyroid profiles (basal and 1 h post meal) were measured by the chemiluminiscence method.
However, how mast cells promote secretory dysfunction requires further characterization. Of note, catenarin, the most potent anthraquinone tested in this study, inhibited CCR5- and CXCR4-implicated chemotaxis in a dose-dependent manner (Figure 1).
Various hypotheses have been proposed to explain glycemic control in 84–97% of diabetic patients who have undergone these surgeries, including exclusion of the duodenum (foregut hypothesis) and early delivery of partially digested chyle to the distal ileum, stimulating the release of GLP-1 (hindgut hypothesis) (15). Significant weight reduction was apparent, compared with baseline, of 21%, 27%, and 30% at the 6-month, 1-year, and 2-year intervals, respectively. Also around this phase or at an even later stage, IL-21 produced by TFH cells or other effector T cell subsets enhances the germinal center (GC) B cell responses to worsen the secretory dysfunction, and further positively reinforce the TFH response.
Denn oft ermA¶glicht erst die enge Zusammenarbeit unterschiedlicher Spezialisten, das komplexe Zusammenspiel der Hormone zu verstehen.
T lymphocytes are main players in T1D though other leukocytes such as B lymphocytes, dendritic cells, macrophages, and NK cells are also implicated [4, 5].
In contrast, two anti-inflammatory compounds, resveratrol and acetylsalicylic acid, had no significant antichemotactic activity in Jurkat cells (Figures 1(b) and 1(c)).
Recent reports have described improved glucose homeostasis after bariatric surgery that was weight loss independent (16, 17).
Glycated hemoglobin (HbA1C) was examined using the high performance liquid chromatography (HPLC) method with Biorad variant D10.
A corresponding, similar decline in BMI also was observed (Table 1) with 23%, 18%, and 23% reduction at 6-month, 1-year, and 2-year intervals, respectively. Leukocyte infiltration into the pancreatic islets, called insulitis, contributes to a gradual loss of pancreatic β cells, leading to insulin insufficiency and deficiency, a hallmark of T1D [6]. Bariatric surgery is an excellent method for controlling diabetes and co-morbid ailments, and has thus led to the concept of metabolic surgery (18).De Paula et al.
Patients with hypothyroidism were prescribed thyroxine replacement and were subjected to surgery after the euthyroid state was achieved. Table 3 compares postoperative glycemic improvements observed in both groups and at all intervals. These data suggest that the suppression of CCR5- and CXCR4-implicated chemotaxis by the anthraquinones is not due to cytotoxicity. The glomerular filtration rate was calculated using the modified Cockgroft-Gault equation (28, 29). Table 4 highlights the diabetes and hypertension remission data in all groups and at all intervals. In such a fashion, the coordinated effects of multiple T cell cytokines mediate distinct pathogenic events, propelling the development of various tissue pathologies and leading to the eventual onset of SjS (Figure 1). Kremers, “Time trends in epidemiology and characteristics of psoriatic arthritis over 3 decades: a population-based study,” Journal of Rheumatology, vol.
Bisher wird vor allem Fettgewebe rund um die Eingeweide, das Bauchfett, als schA¤dlich betrachtet, weil es A?ber Botenstoffe den Stoffwechsel ungA?nstig beeinflusst. Nonresolved inflammation is associated with a broad category of diseases, that is, autoimmune diseases, cancers, and so forth [11]. By combining the II and SG procedures, both the foregut and hindgut hypotheses are addressed.
Insulin resistance (IR) was assessed using the homeostasis model assessment (HOMA) formula (HOMA-IR) with fasting blood glucose and insulin (30). In recent years, molecular studies have identified a variety of proteins and chemical mediators implicated in inflammation. Although sufficient evidence is available in the literature regarding the efficacy of this novel procedure (II + SG) for treating T2DM (19- 24), data from the Indian population is scarce (20, 21). Improvements in postoperative glycemic control were disproportionately greater than weight loss, indicating that weight loss has benefits that are independent of metabolic surgery (Figure 2).
Among them, chemokines and their cognate receptors play an essential role in inflammatory response and therefore, could be potential drug targets for inflammatory diseases [12–15].
This procedure has been performed in obese and nonobese T2DM patients all over the world (22-25). Wenn diese SpeicherkapazitA¤t nicht ausreicht, lagert es sich in Organen wie Leber und Muskeln ab", sagt MA?ller-Wieland. T cells are thought to be important players in T1D [16], although other leukocytes are also involved in the disease [4].
Das AusmaAY der Ablagerungen zeige einen engen Zusammenhang mit einer verminderten Insulinwirksamkeit, einem SchlA?sselmechanismus bei der Entstehung des Diabetes.
Hung, “Emodin down-regulates androgen receptor and inhibits prostate cancer cell growth,” Cancer Research, vol. The key strengths of these studies are that the surgery was safe and efficacious for treating T2DM patients with a lower BMI, and it potentially leads to other benefits beyond glycemic control. These studies showed sustained glycemic improvement with preservation of beta-cell function, and enhanced cardiovascular benefits. Therefore, interference with CXCR4 and CCR5 could be a promising approach for insulitis and T1D prophylaxis and therapy. Chemokine receptors belong to a family of 7-helix transmembrane G-protein-coupled receptors (GPCRs). This activates protein tyrosine kinases, mitogen-activated protein kinases (MAPKs), and phospholipase C.
The beneficial effects on hypertension may be related to weight loss and improved insulin sensitivity. Auf der gemeinsamen Tagung der Deutschen Diabetes-Gesellschaft und der Deutschen Adipositas-Gesellschaft stellte Hauner das Deutsche Gewichtskontrollregister vor, das Forscher des Erlanger Uniklinikums kA?rzlich eingerichtet haben. Secondary messengers, inositol triphospahte and diacylglycerol, which are converted from phosphatidylinositol by phospholipase C, increase calcium mobilization and activation of protein kinase C, respectively. Es soll Erfahrungen bA?ndeln und damit Grundlage fA?r die Entwicklung von wirksamen Therapieprogrammen sein. Interessierte, die mindestens zehn Prozent von ihrem HA¶chstgewicht abgenommen haben und dieses Gewicht seit mindestens einem Jahr halten, kA¶nnen sich auf der Webseite www. Thus, a couple of therapeutic agents such as cyclooxygenase-2 (Cox-2) inhibitors, acetylsalicylic acid and tenidap and immune modulators, FK506, lisofylline and cytopiloyne, were reported to prevent T1D by inhibiting a variety of inflammatory pathways in immune cells [22–25].
Therefore, search for novel anti-inflammatory agent for T1D therapy is practically significant.
Bala, “Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis,” Journal of Rheumatology, vol.
Medicinal plants, used in complementary and alternative medicine worldwide, are a rich source of anti-inflammatory compounds [26].


Moreover, a recent review on traditional Chinese medicines suggests that Chinese herbal formulations with hypoglycemic and anti-inflammatory activities are useful to inhibit diabetes development [27]. Therefore, anti-inflammatory complementary and alternative medicine may be beneficial for T1D. Catenarin, cascarin, emodin, and rhein represent a class of naturally occurring anthraquinone compounds from medicinal herbs.
Neuere Medikamente wie Inkrinmimetika und DPP4-Hemmer, die beide die Wirkung des Darmhormons GLP-1 beeinflussen, bewirken eine InsulinausschA?ttung nur, wenn der Blutzucker erhA¶ht ist. Most of them are best known as active compounds found in laxative herbs, commonly used to treat constipation. So droht keine Gefahr einer Unterzuckerung, die von Schwitzen, Zittern, Seh- und SprachstA¶rungen A?ber unkoordiniertes Handeln bis zur Bewusstlosigkeit und im Extremfall zum Tod fA?hren kann, wenn nicht rechtzeitig reagiert und z.B.
Apart from the laxative activity, emodin, the most studied anthraquinone in the literature, was claimed to possess anti-inflammatory activity as well as anticancer, antimicrobial, diuretic, vasorelaxing and phytoestrogen activities [3, 28–31].
Emodin was shown to inhibit hepatitis [30], pancreatitis [32], and NF-κB activation [33] in cells and animals, suggesting its anti-inflammatory property. Die sogenannten Humaninsuline werden heute gen- technisch hergestellt, sie entsprechen dem menschlichen Insulin. Another anthraquinone, rhein, is an active metabolite of diacerhein, a commercial drug used for osteoarthritis [34]. Hsin et al., “Impairment of NK cell function by NKG2D modulation in NOD mice,” Immunity, vol.
Bornstein et al., “Prevalence and risk factors of atherosclerosis in patients with psoriatic arthritis,” Seminars in Arthritis and Rheumatism, vol. These publications suggest that anthraquinone compounds may have anti-inflammatory activity. We, for the first time, demonstrate that catenarin and its analogs could inhibit CXCR4- and CCR5-implicated cell migration as shown by the two types of migration assays.
Nevertheless, the anti-inflammatory effect and mechanism of the anthraquinones on T1D and other inflammatory diseases are poorly understood.In this study, we examined the effect of catenarin and its derivatives on CCR5- and CXCR4-implicated chemotaxis in T cells.
We then evaluated the in vivo effect of catenarin on leukocyte migration during T1D in NOD mice. Finally, we investigated the likely mechanism by which catenarin inhibited chemotaxis in T cells.2. We first examined the cumulative incidence of diabetes in NOD mice treated with or without catenarin for 30 weeks. All NOD mice (100%) treated with vehicle spontaneously developed T1D from the age of 24 weeks (Figure 2(a)). Drug Administration, Diabetes Measurement, Immunohistochemistry, and Cellularity AnalysisNOD mice were maintained according to the institutional animal care and utilization committee (OMiIBAYW20100043).
In contrast, 83% of 30-week-old NOD mice treated with the anti-inflammatory drug, acetylsalicylic acid [25], developed T1D (Figure 2(a)). Christophers, “Disease concomitance in psoriasis,” Journal of the American Academy of Dermatology, vol.
Die Insulinproduktion ist gestA¶rt, so dass lebenslang Insulin gespritzt werden muss.Beim Diabetes Typ 2 produziert der KA¶rper zunA¤chst zwar noch Insulin, aber es kann nicht mehr richtig wirken. As previously published [24], glycosuria and glycemia in the above mice were monitored every week using a Clinistix strip (Bayer, Pittsburgh, PA, USA) and an Elite glucometer (Bayer), respectively.
The data showed that catenarin prevented T1D in NOD mice to a greater extent than acetylsalicylic acid, a Cox-2 inhibitor. Next, we checked islet architecture and leukocyte migration in the pancreata of these mice (Figure 2(b)).
Ortis, “The role of inflammation in insulitis and beta-cell loss in type 1 diabetes,” Nature Reviews Endocrinology, vol.
Part of the pancreata from the NOD mice was snap-frozen and stained with anti-insulin and anti-CD45 antibodies (Abs) as published [24]. TIB-152), and splenocytes from 7-week-old NOD mice were used to measure CXCR4- and CCR5-mediated chemotaxis as previously described [35].
Bei der Analyse helfen Check- listen, die einen schnellen A?berblick A?ber aufgenommene und verbrauchte Kalorien verschaffen. Brian Wilson, “Fatal attraction: chemokines and type 1 diabetes,” Journal of Clinical Investigation, vol.
Umfangreiche Informationen, viele praktische Tipps sowie Aufgaben und Fragestellungen helfen dabei, neue Gewohnheiten zu entwickeln.a€zAktiv gegen Diabetes! Lindegard, “Diseases associated with psoriasis in a general population of 159,200 middle-aged, urban, native Swedes,” Dermatologica, vol. The number of total cells and leukocyte subsets of pancreatic islets (E) from NOD mice (A) was determined. Briefly, Jurkat cells were loaded in the μ-slide, which was precoated with fibronectin. Anti-CD4 (CD4+ T cells), anti-CD8 (CD8+ T cells), anti-CD11c (DCs, dendritic cells), anti-B220 (B cells), anti-CD68 (macrophages), and anti-CD49 (NK cells) Abs were used to determine leukocyte subsets.The levels of blood glucose and HbA1C represent short-term and long-term glycemic control in diabetic mice.
We found that 4-week-old NOD mice had a normal level of blood glucose and HbA1C (Figures 2(c) and 2(d)).
Our data demonstrate that the maintenance of blood glucose by catenarin is consistent with the islet integrity.Catenarin suppressed leukocyte infiltration into the pancreas in the late-stage diabetes (30-week-old mice) (Figure 2(b)).
Similarly, it reduced leukocyte infiltration and the severity of insulitis in the early-stage diabetes (12-week-old NOD mice) (data not shown). Schioetz et al., “Islet-specific Th1, but not Th2, cells secrete multiple chemokines and promote rapid induction of autoimmune diabetes,” Journal of Immunology, vol. The data suggest that catenarin inhibits the leukocyte migration into pancreas during T1D development.We further analyzed the number and type of leukocytes in pancreatic islets of 30-week-old NOD mice using FACS analysis.
In agreement with the effect of catenarin on leukocyte infiltration as shown in histopathological data (Figure 2(b)), catenarin significantly reduced the number of total leukocytes, CD4+ T cells, macrophages, and B cells in the pancreatic islets of NOD mice in a dose-dependent fashion (Figure 2(e)).
Catenarin also reduced the number of CD8+ T cells and dendritic cells although this decrease was not statistically significant (Figure 2(e)). The cells were subjected to FACS analysis and results were analyzed using FCS Express software. However, acetylsalicylic acid had no significant decrease in the number of leukocytes and their subsets (Figure 2(e)).
Catenarin Does Not Affect Surface Expression of CCR5 and CXCR4 ReceptorsReduction of chemotaxis by catenarin may be due to a decrease in cell surface expression of CCR5 and CXCR4 receptors due to the internalization of these receptors induced by catenarin. Total lysates from the cells were subjected to SDS-PAGE and blotted with Abs against the MAPKs or their phosphorylated forms. To test this possibility, catenarin was used to treat JK-EF1α-CCR5 cells or Jurkat cells.
Gelfand, “Prevalence of cardiovascular risk factors in patients with psoriasis,” Journal of the American Academy of Dermatology, vol. Proteins were visualized using ECL kits and detected using ChemiGenius image analysis system (Syngene, Cambridge, UK).
Grattan et al., “Differential expression of CC chemokines and the CCR5 receptor in the pancreas is associated with progression to type I diabetes,” Journal of Immunology, vol. Statistical AnalysisData from three or more independent experiments are presented as mean ± standard error (SE). The cells were stained with FITC-conjugated anti-CCR5 Ab or isotype Ab plus FITC-conjugated secondary Ab. Catenarin Inhibits Calcium Mobilization in CCR5 and CXCR4 PathwaysCalcium is known to be a secondary messenger downstream of some chemokine receptors in T cells [21]. Interestingly, catenarin dramatically reduced calcium influx triggered by both chemokines in a dose-dependent manner (Figure 4). Higgins, et al., “The comorbid state of psoriasis patients in a university dermatology practice,” Journal of Dermatological Treatment, vol. Delovitch, “Cytokines and chemokines in the pathogenesis of murine type 1 diabetes,” Advances in Experimental Medicine and Biology, vol. Catenarin Inhibits the Activation of MAPK Cascades in CCR5 and CXCR4 PathwaysMAPKs are known to function the downstream of chemokine receptors [21]. Weichenthal, “Increased prevalence of the metabolic syndrome in patients with moderate to severe psoriasis,” Archives of Dermatological Research, vol. Total lysates were immunoblotted with the Abs against MAPKs (p38, JNK, and ERK) or their phosphorylated proteins.
Representative data and the ratio of the signal of the phosphorylated MAPKs to that of total MAPKs are shown.MAPKs can be activated by their upstream regulators, the MAPK kinases (MKKs). MKK3 and MKK6 regulate the activation of p38, whilst MKK4 and MKK7 regulate the activation of JNK [39, 40]. Similarly, catenarin significantly decreased the phosphorylation of MKK7 by either chemokines (lower panels, Figures 6(a) and 6(b)). Williams, “The attraction of chemokines as a target for specific anti-inflammatory therapy,” British Journal of Pharmacology, vol.
JK-EF1α-CCR5 cells (a) and Jurkat cells (b) received the same treatment as described in Figure 5. Abs against MKK6, MKK7, and their phosphorylated proteins were used in immunoblot.To further prove that catenarin inhibited chemotaxis via the signaling cascade of MKKs and MAPKs, we tested the effect of catenarin in Jurkat cells, which were transfected with an active mutant of MKK6 or MKK7.
Accordingly, catenarin significantly abolished Jurkat cell migration mediated by MKK6 and MKK7 (Figure 7(a)).
Similar results were observed in primary CD4+ T cells with the overexpression of MKK6 or MKK7 (data not shown). The cells underwent chemotaxis assay, and the migration index (MI) was determined (upper panel). The expression level of MKK6EE, MKK7EE, and p85, an internal control, was determined by immunoblot using anti-MKK6, anti-MKK7, and anti-p85 Abs (lower panel) (b). Scheme describing the molecular mechanism by which catenarin inhibits leukocyte migration and, thus insulitis in NOD mice. Panzer, “Targeting of Th1-associated chemokine receptors CXCR3 and CCR5 as therapeutic strategy for inflammatory diseases,” Mini-Reviews in Medicinal Chemistry, vol.
Catenarin inhibits leukocyte migration mediated by CCR5 and CXCR4 via the inactivation of MAPKs (p38 and JNK), MKKs (MKK6 and MKK7), and calcium mobilization.4.
Wu et al., “Cardiovascular disease and risk factors among psoriasis patients in two US healthcare databases, 2001-2002,” Dermatology, vol.
We demonstrate that catenarin, the most potent anthraquinone tested in our study, strongly suppresses leukocyte migration in the diabetes. A majority of the literature demonstrate the action of the anthraquinones for constipation [41–43] and cancers [3, 28, 44]. Christen, “Chemokines as drug targets in type 1 diabetes,” Endocrine, Metabolic & Immune Disorders—Drug Targets, vol. Here, CXCR4- and CCR5-implicated chemotaxis in Jurkat T cells was employed as an in vitro system to investigate the anti-inflammatory effect and action of the anthraquinones. With this system, we showed the antichemotactic effect (Figure 1) and mechanism of catenarin and its anthraquinone analogs in T cells (Figures 3–7). Bala, “Psoriasis: cardiovascular risk factors and other disease comorbidities,” Journal of Drugs in Dermatology, vol. In sharp contrast, two anti-inflammatory compounds, resveratrol [45] and acetylsalicylic acid [25] could not inhibit chemotaxis (Figures 1 and 2).
Clearly, not all anti-inflammatory compounds can effectively suppress leukocyte chemotaxis, suggesting the unique anti-chemotactic feature of catenarin and its analogs in leukocytes (Figure 1).
Inhibition of chemotaxis in leukocytes by catenarin was further confirmed by the reduction of insulitis and diabetes in NOD mice (Figure 2 and data not shown). The anti-inflammatory action of catenarin in this study is consistent with the findings showing that emodin, the most extensively studied anthraquinone, inhibited hepatitis [30], pancreatitis [32], and NF-κB [33] in different model systems. Proudfoot, “Chemokine receptors: multifaceted therapeutic targets,” Nature Reviews Immunology, vol. In addition, diacerhein, a drug used for osteoarthritis that has an anthraquinone structure [34], showed beneficial effects on T1D in NOD mice [46]. The data suggest that catenarin and its anthraquinone analogs are prophylactically useful for T1D and, probably, other inflammatory disorders. Interestingly, this activity seems to be related to the number of hydroxyl group at R2 and R3 in anthraquinones (Figure 1).Chemokines and their receptors are potential drug targets in inflammatory diseases such as T1D [14, 47].
Ståhle, “Metabolic disorders in patients with psoriasis and psoriatic arthritis,” Current Rheumatology Reports, vol. CXCR4 is broadly expressed in all the leukocytes and CXCR5 is expressed in macrophages and activated T cells, a pivotal player in autoimmune destruction of pancreatic β cells [17].
Both receptors are known to regulate T1D, although their protective roles in T1D are controversial [7, 18, 19, 48]. Formby, “Contribution of T cells to the development of autoimmune diabetes in the NOD mouse model,” Bioessays, vol.
In view of the importance of CCR5 and CXCR4 in T1D, in this study we explored the anti-inflammatory effect of catenarin based on CCR5- and CXCR4-implicated migration assays. Surprisingly, catenarin and its analogs dose-dependently inhibited CCR5- and CXCR4-mediated chemotaxis in JK-EF1α-CCR5 and Jurkat cells, respectively (Figure 1). This inhibition in human Jurkat T cells was further confirmed in mouse splenocytes and NOD mice (Figures 1 and 2). The data also suggest that the antichemotactic effect of catenarin and its analogs is not limited to T cells and exists in other leukocytes.All chemokine receptors belong to the G-protein-coupled receptor family. In this study, catenarin failed to affect the surface expression level of CCR5 and CXCR4, suggesting that catenarin does not target the receptors themselves (Figure 3). These data suggest that catenarin targets the signaling molecules downstream of CCR5 or CXCR4.
Further, the suppression of MKK6- and MKK7-mediated chemotaxis by catenarin suggests the possibility that catenarin targets the signaling molecule(s) upstream of MKKs (Figure 7). Luster, “Orchestrating the orchestrators: chemokines in control of T cell traffic,” Nature Immunology, vol. Most of the literature suggests that calcium mobilization is located upstream of the activation of MAPKs [52]; however, some studies have suggested that MAPKs control intracellular calcium concentration [53]. We found that P38 and JNK inhibitors suppressed calcium mobilization in CXCR4 and CCR5 pathways (Figure 4), which argues for the possibility that MAPKs control calcium mobilization (Figure 7(b)).In conclusion, we, for the first time, showed that catenarin inhibited CXCR4- and CCR5-implicated leukocyte migration, islet destruction, and diabetes in NOD mice.
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