Podcasts about stat5

Multiple Sclerosis News Today's multimedia associate, Price Wooldridge, explains how a four-protein complex of the protein STAT5 could be involved in the development of MS-like autoimmune disease in mice. He also reads “One Month of MS Awareness Isn't Enough”, from Ed Tobias' column, "The MS Wire". =================================== Are you interested in learning more about multiple sclerosis? If so, please visit: https://multiplesclerosisnewstoday.com/ ===================================== To join in on conversations regarding multiple sclerosis, please visit: https://multiplesclerosisnewstoday.com/forums/

That there are senescence-associated decreases in the JAK-STAT signaling transduction cascade has been observed in human lymphocyte lineages. This phenomena, as associated with a decreased JAK- tyrosine phosphorylation of STAT5, is linked to plasma membrane cholesterol content. Therefore, plasma membrane cholesterol content is involved in T cells modulation and proliferation. Acid sphingomyelinase- mediated ceramide lipid raft mobilization and aggregation of membrane receptors plays a crucial role in this pathobiochemical dynamic leading to multiple disease and comorbidity states in the elderly. Classical Papers Examined: Mech Ageing Dev. 2001 Sep 15;122(13):1413-30 Cytometry A. 2006 Mar;69(3):189-91 J Lipid Res. 2007 Jan;48(1):19-29. doi: 10.1194 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

Red and processed meat linked to increased risk of heart disease, study shows Oxford University, July 21, 2021 Globally, coronary heart diseases (caused by narrowed arteries that supply the heart with blood) claim nearly nine million lives each year1, the largest of any disease, and present a huge burden to health systems. Until now, it has been unclear whether eating meat increases the risk of heart disease, and if this varies for different kinds of meat. Researchers at the University of Oxford's Nuffield Department of Population Health have conducted the largest systematic review of the prospective evidence to date, including thirteen cohort studies involving over 1.4 million people. The study participants completed detailed dietary assessments, and their health was tracked for up to 30 years. The results are published today in Critical Reviews in Food Science and Nutrition. Overall, the evidence from the analysis indicated that: Each 50 g/day higher intake of processed meat (e.g. bacon, ham, and sausages) increased the risk of coronary heart disease by 18%. Each 50 g/day higher intake of unprocessed red meat (such as beef, lamb and pork) increased the risk of coronary heart disease by 9%. There was no clear link between eating poultry (such as chicken and turkey) and an increased risk of coronary heart disease. The findings may be because of the high content of saturated fat in red meat, and of sodium (salt) in processed meat. High intakes of saturated fat increase levels of harmful low-density lipoprotein (LDL) cholesterol, whilst excess salt consumption raises blood pressure. Both LDL cholesterol and high blood pressure are well-established risk factors for coronary heart disease. Previous work from the same research team has also indicated that even moderate intakes of red and processed meat are associated with increased risk of bowel cancer2. Dr. Keren Papier (Nuffield Department of Population Health), co-lead author of the study, said: "Red and processed meat have been consistently linked with bowel cancer and our findings suggest an additional role in heart disease. Therefore, current recommendations to limit red and processed meat consumption may also assist with the prevention of coronary heart disease." Dr. Anika Knüppel, from the Nuffield Department of Population Health and the other co-lead author of the study, added: "We know that meat production is a major contributor to greenhouse gas emissions and we need to reduce meat production and thereby consumption to benefit the environment. Our study shows that a reduction in red and processed meat intake would bring personal health benefits too." Currently in the UK, about 10 in 100 people would be expected to eventually die from coronary heart disease. Based on the findings from the present study and current red and processed meat intakes in the UK,4 if all these 100 people reduced their unprocessed red meat intake by three-quarters (for example from four times a week to one time a week), or if they stopped consuming processed meat altogether, deaths from coronary heart disease would decrease from 10 in 100 down to 9 in 100. The studies involved in this analysis were mostly based on white adults living in Europe or the U.S.. The research team say more data are needed to examine these associations in other populations, including East Asia and Africa.   C is for Vitamin C -- a key ingredient for immune cell function Harnessing the combined power of Vitamin C and TET proteins may give scientists a leg up in treating autoimmune diseases   La Jolla Institute for Immunology and Emory University, July 22, 2021 You can't make a banana split without bananas. And you can't generate stable regulatory T cells without Vitamin C or enzymes called TET proteins, it appears.  Regulatory T cells (Tregs) help control inflammation and autoimmunity in the body. Tregs are so important, in fact, that scientists are working to generate stable induced Tregs (iTregs) in vitro for use as treatments for autoimmune diseases as well as rejection to transplanted organs. Unfortunately, it has proven difficult to find the right molecular ingredients to induce stable iTregs. Now scientists at La Jolla Institute for Immunology and Emory University School of Medicine report that Vitamin C and TET proteins can work together to give Tregs their life-saving power.  "Vitamin C can be used to stabilize iTregs generated in vitro," says LJI Instructor Xiaojing Yue, Ph.D., who served as co-first author for the EMBO Reports study. "We hope that these kinds of induced Tregs can be used in the future for treatment of autoimmune diseases and organ transplantation." The recent study, led by LJI Professor Anjana Rao, Ph.D., and Emory Instructor Benjamin G Barwick, Ph.D., builds on the previous discovery that Vitamin C can enhance the enzymatic activity of TET proteins and prompt the generation of stable iTregs under lab conditions. This finding was encouraging, but the scientists did not want to work toward new autoimmune therapies without first analyzing the gene expression patterns and other key epigenetic features of the induced Tregs.  "We wanted to study the entire system at a whole genome level using next generation sequencing technology to better understand the molecular features of these cells," says Yue. Study co-first author Daniela Samaniego-Castruita, a graduate student at LJI, spearheaded the analysis of gene expression and epigenetic changes in the iTregs. A major type of epigenetic modification involves the DNA itself through the addition or removal of molecules called methyl groups from cytosines, one of the four DNA bases. The methyl groups can be further oxidized by TET enzymes. All of these interactions can eventually change how cells "read" the DNA code.  Another type of epigenetic change involves the alteration of DNA accessibility: whether DNA is loosely or tightly coiled. As the DNA coils unwind, regulatory regions become exposed which subsequently influence gene expression. In their analysis, the researchers found TET proteins are absolutely required for maintaining the gene expression and epigenetic features that make Tregs as what they are; and adding Vitamin C led to iTregs with similar similar gene expression and epigenetic features as normal "wild type" Tregs found in the body. The study also reveals an intriguing connection between TET enzymatic activity, Vitamin C and IL-2/STAT5 signaling. "In mice that are deficient for components of IL-2/STAT5 signaling, such as IL-2, IL-2 receptors or STAT5, the Tregs cannot develop properly or they can have impaired function," Yue says. The researchers demonstrate that on one hand, TET-deficiency in Treg cells leads to impaired IL-2/STAT5 signaling; on the other hand, Vitamin C confers iTregs enhanced IL-2/STAT5 signaling by increasing the expression level of IL-2 receptor and the functional form of STAT5, and STAT5 binding to essential regions in the genome, rendering these cells survive better in tough environments with low IL-2 supplementation. "We are looking for more small molecules to stabilize TET activity and generate induced Tregs that are even more stable," says Yue. "These induced Tregs could eventually be used to treat patients." "This research gives us a new way to think about treating autoimmune diseases," says Samaniego-Castruita.       Resveratrol ameliorates high-fat-diet-induced abnormalities in liver glucose metabolism in mice via the AMPK pathway Hebei Medical Institute (China), July 19, 2021 A new study on high fat diet is now available. According to news originating from the Department of Internal Medicine by NewsRx correspondents, research stated, “Diabetes mellitus is highly prevalent worldwide.” Our news reporters obtained a quote from the research from Department of Internal Medicine: “High-fat-diet (HFD) consumption can lead to liver fat accumulation, impair hepatic glycometabolism, and cause insulin resistance and the development of diabetes. Resveratrol has been shown to improve the blood glucose concentration of diabetic mice, but its effect on the abnormal hepatic glycometabolism induced by HFD-feeding and the mechanism involved are unknown. In this study, we determined the effects of resveratrol on the insulin resistance of high-fat-diet-fed mice and a hepatocyte model by measuring serum biochemical indexes, key indicators of glycometabolism, glucose uptake, and glycogen synthesis in hepatocytes. We found that resveratrol treatment significantly ameliorated the HFD-induced abnormalities in glucose metabolism in mice, increased glucose absorption and glycogen synthesis, downregulated protein phosphatase 2A (PP2A) and activated Ca2+/CaM-dependent protein kinase kinase b (CaMKKb), and increased the phosphorylation of AMP-activated protein kinase (AMPK). In insulin-resistant HepG2 cells, the administration of a PP2A activator or CaMKKb inhibitor attenuated the effects of resveratrol, but the administration of an AMPK inhibitor abolished the effects of resveratrol. Resveratrol significantly ameliorates abnormalities in glycometabolism induced by HFD-feeding and increases glucose uptake and glycogen synthesis in hepatocytes.” According to the news editors, the research concluded: “These effects are mediated through the activation of AMPK by PP2A and CaMKKb.”     Hundreds of chemicals, many in consumer products, could increase breast cancer risk List includes potential carcinogens that act by stimulating production of hormones that fuel breast tumors Silent Spring Institute, July 22, 2021 Every day, people are exposed to a variety of synthetic chemicals through the products they use or the food they eat. For many of these chemicals, the health effects are unknown. Now a new study shows that several hundred common chemicals, including pesticides, ingredients in consumer products, food additives, and drinking water contaminants, could increase the risk of breast cancer by causing cells in breast tissue to produce more of the hormones estrogen or progesterone. "The connection between estrogen and progesterone and breast cancer is well established," says co-author Ruthann Rudel, a toxicologist and research director at Silent Spring Institute. "So, we should be extremely cautious about chemicals in products that increase levels of these hormones in the body." For instance, in 2002, when the Women's Health Initiative study found combination hormone replacement therapy to be associated with an increased risk of breast cancer, women stopped taking the drugs and incidence rates went down. "Not surprisingly, one of the most common therapies for treating breast cancer is a class of drugs called aromatase inhibitors that lower levels of estrogen in the body, depriving breast cancer cells of the hormones they need to grow," adds Rudel. To identify these chemical risk factors, Rudel and Silent Spring scientist Bethsaida Cardona combed through data on more than 2000 chemicals generated by the U.S. Environmental Protection Agency (EPA)'s ToxCast program. The goal of ToxCast is to improve the ability of scientists to predict whether a chemical will be harmful or not. The program uses automated chemical screening technologies to expose living cells to chemicals and then examine the different biological changes they cause. Reporting in the journal Environmental Health Perspectives, Rudel and Cardona identified 296 chemicals that were found to increase estradiol (a form of estrogen) or progesterone in cells in the laboratory. Seventy-one chemicals were found to increase levels of both hormones. The chemicals included ingredients in personal care products such as hair dye, chemical flame retardants in building materials and furnishings, and a number of pesticides. The researchers don't yet know how these chemicals are causing cells to produce more hormones. It could be the chemicals are acting as aromatase activators, for instance, which would lead to higher levels of estrogen, says Cardona. "What we do know is that women are exposed to multiple chemicals from multiple sources on a daily basis, and that these exposures add up." The Silent Spring researchers hope this study will be a wakeup call for regulators and manufacturers in how they test chemicals for safety. For instance, current safety tests in animals fail to look at changes in hormone levels in the animal's mammary glands in response to a chemical exposure. And, although high throughput testing in cells has been used to identify chemicals that activate the estrogen receptor, mimicking estrogen, the testing has not been used to identify chemicals that increase estrogen or progesterone synthesis. "This study shows that a number of chemicals currently in use have the ability to manipulate hormones known to adversely affect breast cancer risk," says Dr. Sue Fenton, associate editor for the study and an expert in mammary gland development at the National Institute of Environmental Health Sciences. "Especially concerning is the number of chemicals that alter progesterone, the potential bad actor in hormone replacement therapy. Chemicals that elevate progesterone levels in the breast should be minimized." The researchers outlined a number of recommendations in their study for improving chemical safety testing to help identify potential breast carcinogens before they end up in products, and suggest finding ways to reduce people's exposures, particularly during critical periods of development, such as during puberty or pregnancy when the breast undergoes important changes. The project is part of Silent Spring Institute's Safer Chemicals Program which is developing new cost-effective ways of screening chemicals for their effects on the breast. Knowledge generated by this effort will help government agencies regulate chemicals more effectively and assist companies in developing safer products.     Antioxidant activity of limonene counteracts neurotoxicity triggered by amyloid beta 1-42 oligomers in cortical neurons University of Naples (Italy), July 19, 2021 According to news reporting from Naples, Italy, by NewsRx journalists, research stated, “Many natural-derived compounds, including the essential oils from plants, are investigated to find new potential protective agents in several neurodegenerative disorders such as Alzheimer's disease (AD).” The news editors obtained a quote from the research from School of Medicine: “In the present study, we tested the neuroprotective effect of limonene, one of the main components of the genus * * Citrus* * , against the neurotoxicity elicited by Ab [ [1-42] ] oligomers, currently considered a triggering factor in AD. To this aim, we assessed the acetylcholinesterase activity by Ellman's colorimetric method, the mitochondrial dehydrogenase activity by MTT assay, the nuclear morphology by Hoechst 33258, the generation of reactive oxygen species (ROS) by DCFH-DA fluorescent dye, and the electrophysiological activity of K [ [V] ] 3.4 potassium channel subunits by patch-clamp electrophysiology. Interestingly, the monoterpene limonene showed a specific activity against acetylcholinesterase with an IC [ [50] ] almost comparable to that of galantamine, used as positive control. Moreover, at the concentration of 10 g/mL, limonene counteracted the increase of ROS production triggered by Ab [ [1-42] ] oligomers, thus preventing the upregulation of K [ [V] ] 3.4 activity. This, in turn, prevented cell death in primary cortical neurons, showing an interesting neuroprotective profile against Ab [ [1-42] ] -induced toxicity.” According to the news editors, the research concluded: “Collectively, the present results showed that the antioxidant properties of the main component of the genus * * Citrus* * , limonene, may be useful to prevent neuronal suffering induced by Ab [ [1-42] ] oligomers preventing the hyperactivity of K [ [V] ] 3.4.”     Meditation And Yoga Change Your DNA To Reverse Effects Of Stress, Study Shows Coventry University (UK), July 22, 2021 Many people participate in practices such as meditation and yoga because they help us relax. At least those are the immediate effects we feel. But much more is happening on a molecular level, reveal researchers out of Coventry University in England. Published in the journal Frontiers in Immunology, this new research examined 18 studies on mind-body interventions (MBIs). These include practices such as mindfulness meditation and yoga. Comprehensively, these studies encompassed 846 participants over 11 years. The new analysis reveals that MBIs result in molecular changes in the human body. Furthermore, researchers claim that these changes are beneficial to our mental and physical health. Body's Response to Stress Causes Damage To elaborate, consider the effect that stress has on the body. When we are under stress, the body increases the production of proteins that cause cell inflammation. This is the natural effect of the body's fight-or-flight response. It is widely believed that inflammation in the body leads to numerous illnesses, including cancer. Moreover, scientists also deduct that a persistent inflammation is more likely to cause psychiatric problems. Unfortunately, many people suffer from persistent stress, therefore they suffer from pro-inflammatory gene expression. But there is good news! According to this new analysis out of Coventry, people that practice MBIs such as meditation and yoga can reverse pro-inflammatory gene expression. This results in a reduced risk of inflammation-related diseases and mental conditions. Lead investigator Ivana Buric from Coventry University's Centre for Psychology, Behaviour and Achievement stated: Millions of people around the world already enjoy the health benefits of mind-body interventions like yoga or meditation, but what they perhaps don't realise is that these benefits begin at a molecular level and can change the way our genetic code goes about its business. These activities are leaving what we call a molecular signature in our cells, which reverses the effect that stress or anxiety would have on the body by changing how our genes are expressed. Put simply, MBIs cause the brain to steer our DNA processes along a path which improves our wellbeing. More needs to be done to understand these effects in greater depth, for example how they compare with other healthy interventions like exercise or nutrition. But this is an important foundation to build on to help future researchers explore the benefits of increasingly popular mind-body activities.               Large-scale study finds greater sedentary hours increases risk of obstructive sleep apnea Study finds that maintaining an active lifestyle can reduce the risk of OSA, encourages physicians to recommend exercise-based interventions for those at risk Brigham and Women's Hospital, July 22, 2021 A new study by investigators from Brigham and Women's Hospital examined the relationship between active lifestyles and the risk of obstructive sleep apnea (OSA). The study followed around 130,000 men and women in the United States over a follow-up period of 10-to-18 years and found that higher levels of physical activity and lower levels of sedentary behavior were associated with a lower risk of OSA. Their results are published in the European Respiratory Journal.  "In our study, higher levels of physical activity and fewer hours of TV watching, and sitting either at work or away from home were associated with lower OSA incidence after accounting for potential confounders," said Tianyi Huang, MSc, ScD, an Associate Epidemiologist at the Brigham. "Our results suggest that promoting an active lifestyle may have substantial benefits for both prevention and treatment of OSA."  OSA is a type of sleep apnea in which some muscles relax during sleep, causing an airflow blockage. Severe OSA increases the risk of various heart issues, including abnormal heart rhythms and heart failure.  Using the Nurses' Health Study (NHS), Nurses' Health Study II (NHSII) and Health Professionals Follow-Up Study (HPFS), the research team used statistical modeling to compare physical activity and sedentary hours with diagnoses of OSA. Both moderate and vigorous physical activity were examined separately and both were strongly correlated with lower risk of OSA, showing no appreciable differences in the intensity of activity. Moreover, stronger associations were found for women, adults over the age of 65 and those with a BMI greater than or equal to 25 kg/m2.  "Most prior observational studies on the associations of physical activity and sedentary behavior with OSA were cross-sectional, with incomplete exposure assessment and inadequate control for confounding," said Huang. "This is the first prospective study that simultaneously evaluates physical activity and sedentary behavior in relation to OSA risk."  This study also differs from others because of its large sample size and detailed assessment pf physical activity and sedentary behaviors. The research team was able to take many associated factors into account, making the findings more credible.  The authors note that all collected data, both of OSA diagnosis and physical activity or sedentary behavior, were self-reported. While all study participants were health professionals, mild OSA is often difficult to detect and can remain clinically unrecognized. Furthermore, only recreational physical activity was taken into consideration, leaving out any physical activity in occupational settings. Sedentary behavior was only counted as sitting while watching TV and sitting away from home or at work.  According to Huang, the next research steps would be to collect data using actigraphy, home sleep apnea tests and polysomnography, rather than self-reports.  In light of the findings, investigators encourage physicians to highlight the benefits of physical activity to lower OSA risk.  "We found that physical activity and sedentary behavior are independently associated with OSA risk," said Huang. "That is, for people who spend long hours sitting every day, increasing physical activity in their leisure time can equally lower OSA risk. Similarly, for those who are not able to participate in a lot of physical activity due to physical restrictions, reducing sedentary hours by standing or doing some mild activities could also lower OSA risk. However, those who can lower sedentary time and increase physical activity would have the lowest risk."

Episode 347 is an updated guide to somatropic hormone and GOD did I go crazy on this one! I honestly want to know more about growth hormone than anyone alive and thus, begins this string of GH based guides! I DID finally discuss the MoA for how GH causes localized fat loss which really had me excited since no one in our industry has EVER talked about this so that definitely was an interesting avenue to go down! Below I am going to reference a lot of the literature for this hormone that I was read through over the past few years on this topic so please DO NOT TAKE MY WORD FOR THIS - READ THESE YOURSELF! Keep in mind this is a brief snippet of every bit of literature on the topic however. REFERENCES   Daughaday WH, Rotwein P. Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev. 1989;10:68–91. [PubMed] [Google Scholar] Jones JI, Clemmons DR. 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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.15.285551v1?rss=1 Authors: Ali, A., Shehwana, H., Hanif, A., Fatima, A., Shabbir, M., Rafiq, M. Abstract: Sepsis is a serious health situation caused by uncontrolled infection and septic shock is a severe condition of sepsis. RHBDD2 is a member of the rhomboid superfamily which is overexpressed in different types of cancer and associated with ER stress and estrogen receptor. Using microarray gene expression data and using different computational techniques this study investigated the role of RHBDD2 in sepsis and septic shock. Finds functional annotation of RHBDD2 using co-expression analysis and identified the deregulation of RHBDD2 in sepsis using differential expression analysis. Results show that RHBDD2 is overexpressed in sepsis and septic shock. The GO enrichment analysis, KEGG pathways, and biological functions of the RHBDD2 co-expressed genes module show that it is involved in most of the sepsis-related biological functions and also plays a role in most of the infection-related pathways which lead to sepsis and septic shock. RHBDD2 is regulated by STAT5 and SP1 transcriptional factors in sepsis and septic shock. The identification of the RHBDD2 as a biomarker may facilitate in septic shock diagnosis, treatment, and prognosis. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.10.087650v1?rss=1 Authors: Georgescu, T., Ladyman, S. R., Brown, R. S. E., Grattan, D. R. Abstract: The anterior pituitary hormone, prolactin, is a fundamental regulator of lactation, and also plays a role in many other physiological processes including maternal behaviour, reproduction, immune response and even energy balance. Indeed, prolactin receptors (Prlr) are widely distributed throughout the body, including a number of different brain regions, further attesting to its pleiotropic nature. Within the brain, previous research has identified key areas upon which prolactin exerts effects on gene transcription through the canonical JAK2/STAT5 pathway downstream of the Prlr. In some neurones, however, such as the tuberoinfundibular dopamine neurones that control prolactin secretion, prolactin can also exert rapid actions to stimulate neuronal activity. While prolactin-induced activation of STAT5 has been described in a wide variety of brain regions, its capacity for acute modulation of electrical properties of many Prlr-expressing neurones remains to be elucidated. To investigate how widespread these rapid actions of prolactin are in various Prlr-expressing neurones, we utilised a transgenic mouse line in which Cre recombinase is specifically expressed in the coding region of the prolactin long form receptor gene (Prlr-iCre). This mouse line was crossed with a Cre-dependent calcium indicator (GCaMP6f) transgenic mouse, allowing us to visually monitor the electrical activity of Prlr-expressing neurones in ex vivo brain slice preparations. Here, we survey hypothalamic regions implicated in prolactin's diverse physiological functions such as: the arcuate (ARC) and paraventricular nuclei of the hypothalamus (PVN), and the medial preoptic area (MPOA). We observe that in both males and virgin and lactating females, bath application of prolactin is able to induce electrical changes in a subset of Prlr-expressing cells in all of these brain regions. The effects we detected ranged from rapid or sustained increases in intracellular calcium to inhibitory effects, indicating a heterogeneous nature of these Prlr-expressing populations. These results enhance our understanding of mechanisms by which prolactin acts on hypothalamic neurones and provide insights into how prolactin might influence neuronal circuits in the mouse brain. Copy rights belong to original authors. Visit the link for more info

¡Gracias por escuchar! Los medicamentos antimaláricos, hidroxicloroquina y cloroquina, son fármacos moduladores de las enfermedades reumáticas introducidos por serendipia y empíricamente para el tratamiento de diversas enfermedades reumáticas. Ni la cloroquina ni la hidroxicloroquina se sometieron al proceso de desarrollo de fármacos convencional, pero su uso se ha convertido en parte importante de los tratamiento actuales para la artritis reumatoide, lupus eritematoso sistémico, síndrome de anticuerpos antifosfolípido y síndrome de Sjögren primario. En este episodio exploraremos sus principales características desde la perspectiva farmacológica.Les pido amablemente dejen sus comentarios en tukua.podbean.com y la calificación a este y otros episodios en iTunes.Estas son algunas referencias de utilidad:Ruiz-Irastorza, G. et al. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann. Rheum. Dis. 69, 20–28 (2010).Ostensen, M. et al. 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Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 6, and interferon-gamma production by peripheral blood mononuclear cellFasano, S. et al. Longterm hydroxychloroquine therapy and low-dose aspirin may have an additive effectiveness in the primary prevention of cardiovascular events in patients with systemic lupus erythematosus. J. Rheumatol. 44, 1032–1038 (2017).Towers, C. G. & Thorburn, A. Therapeutic targeting of autophagy. EBioMedicine 14, 15–23 (2016).Rand, J. H. et al. Hydroxychloroquine directly reduces the binding of antiphospholipid antibodyβ2-glycoprotein I complexes to phospholipid bilayers. Blood 112, 1687–1695 (2008).Jancinova, V., Nosal, R. & Petrikova, M. On the inhibitory effect of chloroquine on blood platelet aggregation. Thromb. Res. 74, 495–504 (1994).Bertrand, E. et al. Antiaggregation action of chloroquine. Med. Trop. 50, 143–146 (1990).Nosal, R., Jancinova, V. & Petrikova, M. 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Increased incidence of gastrointestinal side effects in patients taking hydroxychloroquine: a brand-related issue? J. Rheumatol. 44, 398 (2017).Abdel-Hamid, H., Oddis, C. V. & Lacomis, D. Severe hydroxychloroquine myopathy. Muscle Nerve 38, 1206–1210 (2008).Jafri, K. et al. Antimalarial myopathy in a systemic lupus erythematosus patient with quadriparesis and seizures: a case-based review. Clin. Rheumatol. 36, 1437–1444 (2017).Khosa, S. et al. Hydroxychloroquine-induced autophagic vacuolar myopathy with mitochondrial abnormalities. Neuropathology 38, 646–652 (2018).Stein, M., Bell, M. J. & Ang, L. C. Hydroxychloroquine neuromyotoxicity. J. Rheumatol. 27, 2927–2931 (2000). Int. J. Cardiol. 157, 117–119 (2012).Sundelin, S. P. & Terman, A. Different effects of chloroquine and hydroxychloroquine on lysosomal function in cultured retinal pigment epithelial cells. APMIS 110, 481–489 (2002).Jorge, A. et al. Hydroxychloroquine retinopathy implications of research advances for rheumatology care. Nat. Rev. Rheumatol. 14, 693–703 (2018).Marmor, M. F. et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 Revision). Ophthalmology 123, 1386–1394 (2016).Yusuf, I. H. et al. The Royal College of Ophthalmologists recommendations on screening for hydroxychloroquine and chloroquine users in the United Kingdom: executive summary. Eye 32, 1168–1173 (2018). J. Rheumatol. 44 1841–1849 (2017).Padol, I. T. & Hunt, R. H. Association of myocardial infarctions with COX-2 inhibition may be related to immunomodulation towards a Th1 response resulting in atheromatous plaque instability: an evidencebased interpretation. Rheumatology 49, 837–843 (2010).Hage, M. P., Al-Badri, M. R. & Azar, S. T. A favorable effect of hydroxychloroquine on glucose and lipid metabolism beyond its anti-inflammatory role. Ther. Adv. Endocrinol. Metab. 5, 77–85 (2014).Costedoat-Chalumeau, N. et al. Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum. 54, 3284–3290 (2006).Costedoat-Chalumeau, N. et al. A prospective international study on adherence to treatment in 305 patients with flaring SLE: assessment by drug levels and self-administered questionnaires. Clin. Pharmacol. Ther. 103, 1074–1082 (2018).Bethel, M. et al. Hydroxychloroquine in patients with systemic lupus erythematosus with end-stage renal disease. J. Investig. Med. 64, 908–910 (2016).Sperati, C. J. & Rosenberg, A. Z. Hydroxychloroquineinduced mimic of renal Fabry disease. Kidney Int. 94, 634 (2018).Yusuf, I. H., Lotery, A. J. & Ardern-Jones, M. R. Joint recommendations for retinal screening in longterm users of hydroxychloroquine and chloroquine in the United Kingdom, 2018. Br. J. Dermatol. 179, 995–996 (2018).Melles, R. B. & Marmor, M. F. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol. 132, 1453–1460 (2014).Costedoat-Chalumeau, N., Isenberg, D. & Petri, M. Letter in response to the 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus by Fanouriakis et al. Ann. Rheum. Dis. https://doi.org/10.1136/annrheumdis-2019215573 (2019).

Dr Jimena Ferraris of the Karolinska Institute and the University of Buenos Aires talks with NEN about her recently published work in Neuroendocrinology on the identification of signal transduction pathways that may play a role in the pathogenesis of prolactinomas. Interview by Dr. Julie Ann Lough de Dios, N., Orrillo, S.J., Irizarri, M., Theas, M., Boutillon, F., Candolfi, M., Seilicovic, A., Goffin, V., Pisera, D., Ferraris, J. (2018). JAK2/STAT5 pathway mediates prolactin-induced apoptosis of lactotropes. Neuroendocrinology, doi: 10.1159/000494975.

Haiyan Li

Haiyan Li

Top News aus der Medizinischen Forschung Wien vom 2010-05-05

Bei etwa 30 % der Patienten mit akuter myeloischer Leukämie (AML) können aktivierende Mutationen der Rezeptortyrosinkinase FLT3 gefunden werden. Damit ist FLT3 eines der am häufigsten mutierten Gene in der AML. Die Mutationen treten in zwei Regionen des FLT3-Rezeptors auf: Längenmutationen (FLT3-LM) in der juxtamembranösen Region (24 %) und Punktmutationen der Aktivationsschleife der zweiten Tyrosinkinasedomäne (FLT3-TKD-Mutationen; 7 %). FLT3-Mutationen verleihen Ba/F3-Zellen Unabhängigkeit von Interleukin-3. In einem Knochenmarktransplantationsmodell der Maus erzeugen FLT3-LM ein myeloproliferatives Syndrom und in Zusammenwirken mit PML-RARα eine akute Promyelozytenleukämie. Darüber hinaus scheint das Auftreten von FLT3-LM bei Patienten mit einer schlechteren Prognose assoziiert zu sein. In dieser Arbeit wurden AML-Zelllinien und durch FLT3-Mutationen transformierte Ba/F3-Zellen mit dem kleinmolekularen PTK-Inhibitor SU5614 behandelt. SU5614 induziert selektiv Wachstumsarrest, Zellzyklusarrest und Apoptose in Ba/F3-Zellen und leukämischen Zelllinien, die FLT3-Mutationen tragen. Darüber hinaus hebt SU5614 die antiapoptotische und wachstumsfördernde Wirkung von FLT3-Ligand (FL) in FL-abhängigen Zellen auf. In Zelllinien, die keinen aktivierten FLT3-Rezeptor tragen, zeigte die Substanz keine zytotoxische Wirkung. Auf biochemischer Ebene hemmt SU5614 die Hyperphosphorylierung des FLT3-Rezeptors und seiner Downstream-Targets STAT3, STAT5 und MAPK, sowie die Expression der STAT5-Zielgene BCL-XL und p21. Es konnte somit demonstriert werden, dass das Indolinonderivat SU5614 ein potenter Hemmstoff von mutiertem FLT3 und Wildtyp-FLT3 ist. Des Weiteren konnte gezeigt werden, dass Zelllinien leukämischen Ursprungs, die endogen FLT3-Mutationen exprimieren, selektiv empfindlich gegenüber SU5614 sind. Diese selektive und potente Zytotoxizität von FLT3-Inhibitoren impliziert den klinischen Einsatz solcher Inhibitoren als zusätzliche molekulare Therapiemöglichkeit bei Patienten mit akuter myeloischer Leukämie und FLT3-Mutationen.

Activating mutations in the juxtamembrane domain of FLT3 (FLT3-internal tandem duplications, FLT3-ITDs) represent the most frequent genetic alterations in acute myeloid leukemia (AML). FLT3-internal tandem duplications (FLT3-ITDs) are a heterogenous group of mutations in patients with acute leukemias that are prognostically important. To characterize the mechanism of transformation by FLT3-ITDs, we sequenced the juxtamembrane region (JM) of FLT3 from 284 patients with acute leukemias. The length of FLT3-ITDs varied from 2 to 42 amino acids (AA) with a median of 17 AA. The analysis of duplicated AAs showed that in the majority of patients, the duplications localize between AA 591 to 599 (YVDFREYEY). Arginine 595 (R595) within this region is duplicated in 77% of patients. Single duplication of R595 in FLT3 conferred factor-independent growth to Ba/F3 cells and activated STAT5. Moreover, deletion or substitution of the duplicated R595 in two FLT3-ITD constructs as well as the deletion of wildtype-R595 in FLT3-ITD substantially reduced the transforming potential, pointing to a critical role of the positive charge of R595 in stabilizing the active confirmation of FLT3-ITDs. Deletion of R595 in the FLT3-WT inhibited the growth of cells upon FL stimulation and the STAT5 activation. In this study we could also show that the tyrosine residues 589 and 591 of the FLT3-ITDs could be important phosphorylation sites and are very crucial for the activation of FLT3- ITDs. Simultaneous substitution of these two tyrosine residues with phenyalanine showed complete inhibition of the transforming potential of FLT3-ITDs and STAT5 activation. The substitution of tyrosine residues 597 and 599 did not show any effect on the transforming potential of FLT3-ITDs, supporting the previous hypothesis that these tyrosines may be only important to maintain the integrity of FLT3-WT in its inactive state. Our data provide important insights into the role of the juxtamembrane domain in the mechanism of transformation by FLT3-ITDs.

FLT3 (fms-like tyrosine kinase 3) ist bei ca. 30% aller Patienten mit akuter myeloischer Leukämie konstitutiv aktiviert und repräsentiert einen krankheitsspezifischen molekularen Marker. Zwei verschiedene Arten von Mutationen sind hierbei vorherrschend: ITD (internal tandem duplications) im Bereich der juxtamembranösen Region sind bei ungefähr 20-25% der Patienten nachweisbar sowie Mutationen im Bereich der Tyrosinkinasedomäne (TKD), die bei bis zu 8% der AML-Fälle auftreten. Es wurde bisher davon ausgegangen, dass die beiden Mutationstypen nicht im gleichen Patienten auftreten, da sie eine funktionelle Redundanz aufweisen. Neuere Daten zeigen jedoch, dass 1-2% aller AML-Patienten beide Mutationen (FLT3-ITD-TKD, duale Mutanten) tragen. Die Signifikanz dieser Beobachtung ist noch unklar, erste Studien haben jedoch gezeigt, dass diese dualen Mutationen mit einer besonders schlechten Prognose assoziiert sind. In dieser Arbeit konnte gezeigt werden, dass FLT3 duale Mutanten in in vitro Modellsystemen nicht nur Resistenzen gegenüber PTK Inhibitoren, sondern auch gegenüber dem Zytostatikum Daunorubicin induzieren können. Als molekularer Mechanismus hierfür konnte eine verstärkte Aktivierung von STAT5 (signal transducer and activator of transcription 5) sowie eine erhöhte Expression der STAT5-Zielproteine Bcl-x(L) und RAD51 identifiziert werden. Darüber hinaus konnte ein Arrest in der G2/M Phase des Zellzyklus beobachtet werden. Dieser Zellzyklusarrest erlaubt, DNA-Schäden zu reparieren und eine Apoptose zu vermeiden. Dass die Überexpression von Bcl-x(L) den wohl kritischen Punkt bei der Resistenzentstehung von FLT3-ITD-TKD Mutationen ausmacht, konnte dadurch bewiesen werden, dass Bcl-x(L)- und ITD- koexprimierende Zellen das Resistenzbild der dualen Mutanten imitieren können. Interessanterweise konnte der selektive mTOR-Inhibitor Rapamycin in Kombination mit PTK Inhibitoren die Sensitivität der dualen Mutanten wiederherstellen. Diese Arbeit beschreibt die molekularen Grundlagen von Resistenzbildungen gegenüber FLT3 PTK Inhibitoren und zeigt gleichzeitig therapeutische Ansätze auf, um Resistenzen zu verhindern oder zu überkommen.

In der akuten myeloischen Leukämie (AML) sind zwei Cluster aktivierender Mutationen im ´FMS-like tyrosine kinase-3´ (FLT3)-Gen bekannt: FLT3-´internal tandem duplications´ (FLT3-ITD) in der juxtamembranösen (JM)-Domäne in 20 - 25 % der Patienten und FLT3-Punktmutationen in der Tyrosinkinasedomäne (FLT3-TKD) in 7 – 10 % der Patienten. In dieser Studie haben wir eine neue Klasse aktivierender Punktmutationen (PM) charakterisiert, die in einem 16-Aminosäuren-Abschnitt der JM-Domäne von FLT3 (FLT3-JM-PM) lokalisiert sind. Die Expression von vier FLT3-JM-PM in IL-3-abhängigen Ba/F3-Zellen führte zu wachstumsfaktor-unabhängigem Wachstum, Hyperproliferation in Gegenwart von FL und Resistenz gegenüber apoptotischem Zelltod. FLT3-JM-PM-Rezeptoren waren autophosphoryliert und zeigten verglichen mit FLT3-WT-Rezeptoren eine höhere konstitutive Dimerisierungsrate. Als einen molekularen Mechanismus konnten wir die Aktivierung von STAT5 und eine erhöhte Expression von Bcl-x(L) in allen FLT3-JM-PM-exprimierenden Zellen im Vergleich zu FLT3-WT-Zellen zeigen. Der FLT3-Inhibitor PKC412 inhibierte das wachstumsfaktor-unabhängige Wachstum der FLT3-JM-PM-Zellen. Verglichen mit FLT3-ITD- und FLT3-TKD-Zellen, zeigten die FLT3-JM-PM-Zellen ein schwächeres Transformationspotential, verbunden mit geringerer Autophosphorylierung des Rezeptors und dessen nachgeordneten Ziel-Protein STAT5. Die Kartierung der FLT3-JM-PM auf die Kristallstruktur des FLT3-Proteins zeigte, dass diese Punktmutationen wahrscheinlich die Stabilität der autoinhibitorischen JM-Domäne reduzieren. Dies liefert eine strukturelle Erklärung für das transformierende Potential dieser neuen Klasse aktivierender Mutationen von FLT3. Die defekte Negativ-Regulation aktivierter Rezeptortyrosinkinasen (RTKs) ist ein bekannter Mechanismus der Onkogenese. Die RTK FLT3 wird in frühen myeloischen und lymphoiden Progenitorzellen exprimiert und ist an der Pathogenese der AML beteiligt. Das ´Casitas B-lineage lymphoma´ (CBL)-Protein ist in der Evolution stark konserviert und übernimmt wichtige Funktionen in der Negativ-Regulation der Signalübertragung verschiedener Zelloberflächenrezeptoren. Zwei CBL-Deletionsmutanten, die in vitro Fibroblasten transformieren, wurden aus murinen Retroviren isoliert, die Vorläufer-B-Zelllymphome induzieren. In dieser Arbeit konnte gezeigt werden, dass CBL nach FL-Stimulierung von FLT3-WT-exprimierenden Ba/F3-Zellen phosphoryliert wird und damit in die FLT3-nachgeordnete Signaltransduktion involviert ist. Die Koexpression der CBL-Deletionsmutanten CBL-70Z oder v-CBL mit FLT3 führt zur Transformation von Ba/F3-Zellen. Das transformierende Potential wird durch den FLT3-Rezeptor vermittelt, da die selektiven FLT3-PTK-Inhibitoren SU5614 und PKC412 die Proliferation der FLT3-WT/CBL-mutanten-Zellen vollständig aufheben. Die Aktivierung des PI3K/mTOR/AKT-Signalweges, jedoch nicht der SRC-Kinasen und MAPK, trägt wesentlich zum hyperproliferierenden Phänotyp der FLT3-WT/CBL-mutanten Zellen nach Ligandenstimulierung bei. Die Koexpression von CBL-70Z oder v-CBL mit FLT3 führt zur konstitutiven Aktivierung der FLT3-Rezeptoren sowie STAT5 und AKT. Nach FL-Stimulierung konnten wir eine Hyperaktivierung von STAT5 und AKT in FLT3-WT/CBL-70Z und FLT3-WT/v-CBL-Zellen beobachten. An der Interaktion von CBL und FLT3 sind die TKB-Domäne des CBL-Proteins und die JM-Tyrosine Y589 und Y599 des FLT3-Rezeptors beteiligt. Die Internalisierung der FLT3-Rezeptoren wird durch die Koexpression von CBL-70Z nicht verändert. Allerdings ist CBL an der Ubiquitinierung und Degradierung von Rezeptoren beteiligt und wir konnten zeigen, dass CBL-WT die Dephosphorylierung und Degradierung des FLT3-Rezeptors fördert. Es wurde vorgeschlagen, dass die CBL-Deletionsmutanten in dominant-negativer Weise agieren und die negativ-regulatorische Funktion von CBL-WT blockieren. Wir haben eine CBL-Deletionsmutante in den AML Zelllinie MOLM-13 und MOLM-14 identifiziert. Dieser CBL-Mutante fehlt Exon 8, das für Teile der Linker- und RING-Finger-Domäne kodiert, und erinnert an CBL-70Z. Die Entdeckung einer möglicherweise transformierenden CBL-Mutante in AML-Zellen unterstützt die Hypothese, dass CBL zum malignen Phänotyp der AML beiträgt. Zusammenfassend haben wir gezeigt, dass die strukturelle oder funktionelle Inaktivierung negativ-regulatorischer Mechanismen das transformierende Potential von FLT3 aktivieren kann: 1. Der Verlust der Autoinhibition durch Punktmutationen, die die geordnete Konformation der autoinhibitorischen JM-Domäne stören. 2. Die funktionelle Inaktivierung eines negativ-regulatorischen Proteins durch ´loss-of-function´-Mutationen. Diese Daten unterstreichen die zentrale Rolle von FLT3 in der Leukämogenese und als ein Zielprotein für therapeutische Ansätze.

Die akute Pankreatitis beginnt in den Azinuszellen, allerdings bestimmen die sich anschließenden außerazinären, immunologischen Geschehnisse den Schweregrad der Erkrankung. Diese immunologische Reaktion wird über Zytokine vermittelt, die hauptsächlich von Immunzellen, zusätzlich aber auch von Pankreasazinuszellen selbst sezerniert werden. In dieser Arbeit wurde untersucht, ob Pankreasazinuszellen in der Lage sind, auf autokrin oder parakrin freigesetzte Zytokine zu reagieren. Der JAK/STAT-Signaltransduktionsweg, eine Phosphorylierungskaskade, die von Oberflächenrezeptoren initiierte Signale in den Zellkern weiterleitet, stellt den Haupteffektor der meisten Zytokine dar. Wir konnten mittels Immunopräzipitation und Western-Blot die meisten JAK und STAT Proteine in Pankreasazinuszellen nachweisen (JAK1, JAK2 und TYK2 sowie STAT1, STAT2, STAT3, STAT5 und STAT6). Darüber hinaus konnten wir zeigen, dass einige dieser Proteine in Pankreasazinustellen durch physiologische (Zytokine), aber auch unphysiologische (Stress) Stimuli phosphoryliert und damit aktiviert werden. Dies belegt neben der Expression zusätzlich eine Regulation dieser Proteine und damit eine funktionelle Rolle des JAK/STATSignaltransduktionsweges im Pankreas. Exemplarisch wurde mitttels Immunhistochemie gezeigt, dass IFN-

Thu, 7 Oct 2004 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/2709/ https://edoc.ub.uni-muenchen.de/2709/1/Pau_Michael.pdf P