Podcasts about igfs

Professor Chris Elliott is something of a ‘food detective'. A Professor of Food Safety and Microbiology at Queen's University Belfast and a founding director of its Institute for Global Food Security (IGFS), his work is all about developing scientific solutions to protect us from contaminated food, be it accidental or criminal. Following the 2013 horse meat scandal – when prepared foods purporting to be made from beef were found to contain undeclared horse-meat – Chris conducted the independent review of the UK food system that brought to light the growing threat of food crime. Since then, his name's become synonymous with solving cases of food fraud; today he receives regular tip-offs on everything from oregano scams to dodgy potatoes. But as Chris tells Jim Al-Khalili, his team at the IGFS are pioneering new techniques to read the molecular fingerprint of foodstuffs, with technology that they hope will stop the fraudsters in their tracks… Producer: Lucy Taylor

Greater magnesium intake linked with lower risk of liver cancer Mt Sinai Hospital, March 22 2021.    A study of AARP members revealed a protective effect for increased intake of magnesium against the risk of developing liver cancer. The findings were published in the March 2021 issue of The American Journal of Clinical Nutrition.  For the current study, researchers at Vanderbilt University Medical Center in Nashvilleexamined data from 536,359 participants in the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study cohort, which is which is one of the largest and longest prospective cohorts that collected data concerning diet and cancer outcomes in the United States. Food frequency questionnaire responses provided by the participants during 1995 to 1996 were analyzed for total magnesium and total calcium intake from supplements and food. The subjects were followed up to December 31, 2011, during which 1,067 cases of primary liver cancer were diagnosed.  Among those whose total magnesium intake was among the top 25% of participants, there was a 35% lower adjusted risk of developing liver cancer in comparison with participants whose intake was among the lowest 25%. Heavy users of alcohol who had a high magnesium intake experienced an even greater protective effect.  As potential mechanisms for magnesium against liver cancer, authors Shalija C. Shah, MD, and colleagues observed that the mineral is a cofactor for enzymes involved in DNA replication and repair, gene expression, cell proliferation and differentiation, and other factors.  “Based on a prospective cohort analysis, we demonstrated that magnesium intake is associated with a lower risk of primary liver cancer, which was more pronounced among moderate and heavy alcohol users,” they concluded. “These findings add clinical value to the current expansive body of translational literature defining the mechanisms through which this essential micronutrient mediates inflammatory and antineoplastic pathways, particularly within the liver.”     Green leafy vegetables essential for muscle strength Eating just one cup of leafy green vegetables every day could boost muscle function, according to new research. Edith Cowan University (Australia), March 24, 2021   Eating just one cup of leafy green vegetables every day could boost muscle function, according to new Edith Cowan University (ECU) research. The study, published today in the Journal of Nutrition, found that people who consumed a nitrate-rich diet, predominantly from vegetables, had significantly better muscle function of their lower limb. Poor muscle function is linked to greater risk of falls and fractures and is considered a key indicator of general health and wellbeing. Researchers examined data from 3,759 Australians taking part in Melbourne's Baker Heart and Diabetes Institute AusDiab study over a 12-year period. They found those with the highest regular nitrate consumption had 11 per cent stronger lower limb strength than those with the lowest nitrate intake. Up to 4 per cent faster walking speeds were also recorded. Lead researcher Dr Marc Sim from ECU's Institute for Nutrition Research said the findings reveal important evidence for the role diet plays in overall health.  "Our study has shown that diets high in nitrate-rich vegetables may bolster your muscle strength independently of any physical activity," he said. "Nevertheless, to optimise muscle function we propose that a balanced diet rich in green leafy vegetables in combination with regular exercise, including weight training, is ideal." Muscle function is vital for maintaining good overall health, especially bone strength later in life. "With around one in three Australians aged over 65 suffering a fall each year, it's important to find ways of preventing these events and their potentially serious consequences," said Dr Sim. Go for green While leafy greens may be some of our least favourite vegetables, they could be the most important, according to Dr Sim. The research found nitrate-rich vegetables, such as lettuce, spinach, kale and even beetroot, provided the greatest health benefits. "Less than one in ten Australians eat the recommended five to six serves of vegetables per day," Dr Sim said. "We should be eating a variety of vegetables every day, with at least one of those serves being leafy greens to gain a range of positive health benefits for the musculoskeletal and cardiovascular system."  "It's also better to eat nitrate-rich vegetables as part of a healthy diet rather than taking supplements. Green leafy vegetables provide a whole range of essential vitamins and minerals critical for health." Building knowledge The study, a collaboration with Deakin University's Institute of Physical Activity and Nutrition and the Baker Heart and Diabetes Institute, builds on Dr Sim's previous research into nitrate and muscle function in older women.  It also adds to growing evidence linking vegetables with cardiovascular health, including a recent ECU study into cruciferous vegetables and blood vessel health. Dr Sim said the next step of his research will be exploring strategies to increase leafy green vegetable consumption in the general population.  "We are currently recruiting for the MODEL Study, which examines how knowledge of disease can be used to prompt people in making long-term improvements to their diet and exercise," said Dr Sim.     Preservative used in hundreds of popular foods may harm the immune system New science suggests the FDA should test all food chemicals for safety Environmental Working Group, March 25, 2021   A food preservative used to prolong the shelf life of Pop-Tarts, Rice Krispies Treats, Cheez-Its and almost 1,250 other popular processed foods may harm the immune system, according to a new peer-reviewed study by Environmental Working Group. For the study, published this week in the International Journal of Environmental Research and Public Health, EWG researchers used data from the Environmental Protection Agency's Toxicity Forecaster, or ToxCast, to assess the health hazards of the most common chemicals added to food, as well as the "forever chemicals" known as PFAS, which can migrate to food from packaging.  EWG's analysis of ToxCast data showed that the preservative tert-butylhydroquinone, or TBHQ, has been found to harm the immune system both in both animal tests and in non-animal tests known as high-throughput in vitro toxicology testing. This finding is of particular concern during the coronavirus pandemic. "The pandemic has focused public and scientific attention on environmental factors that can impact the immune system," said Olga Naidenko, Ph.D., EWG vice president for science investigations and lead author of the new study. "Before the pandemic, chemicals that may harm the immune system's defense against infection or cancer did not receive sufficient attention from public health agencies. To protect public health, this must change." TBHQ TBHQ is a preservative that is pervasive in processed foods. It has been used in foods for many decades and serves no function besides increasing a product's shelf life. Using new non-animal test results from ToxCast, EWG found that TBHQ affected immune cell proteins at doses similar to those that cause harm in traditional studies. Earlier studies have found that TBHQ might influence how well flu vaccines work and may be linked to a rise in food allergies.  PFAS Using ToxCast, EWG analyzed all publicly available studies that show how PFAS migrate to food from packaging materials or processing equipment. This is the first known compilation of available research on PFAS migration from packaging to food. In 2017, nationwide tests showed that many fast-food chains used food wrappers, bags and boxes coated with highly fluorinated chemicals. Human epidemiological studies show that PFAS suppresses immune function and decreases vaccine efficacy. Recently published research has also found a link between high levels of PFAS in the blood and the severity of Covid-19.  Surprisingly, for most PFAS, the ToxCast results did not match previous animal and human test data. This illustrates the limitations of this new chemical testing method. More research is needed to understand how PFAS harm the immune system. Food Chemicals Regulation The Food and Drug Administration's approach to the regulation of food additives does not consider the latest science on the health harms of additives that may be legally added to processed foods manufactured in the U.S. Last year, EWG published Food Additives State of the Science, which highlighted additives known to increase the risk of cancer, harm the nervous system and disrupt the body's hormonal balance.  Chemicals linked to health harms can be legally added to packaged foods because the FDA frequently allows food manufacturers to determine which chemicals are safe. Additives like TBHQ were approved by the FDA decades ago, and the agency does not consider new science to reassess the safety of food chemicals.  "Food manufacturers have no incentive to change their formulas," said Scott Faber, senior vice president for government affairs at EWG. "Too often, the FDA allows the food and chemical industry to determine which ingredients are safe for consumption. Our research shows how important it is that the FDA take a second look at these ingredients and test all food chemicals for safety." Less Toxic Food Preservatives Processed foods can be made without these potentially harmful ingredients, so shoppers should read labels carefully. TBHQ is often, though not always, listed on the ingredient label. It will be listed if it has been added to the product during manufacturing. But it can also be used in food packaging, particularly plastic packaging, in which case it may migrate to food.  EWG's Food Scores database helps consumers find products made with healthier alternatives, and our Healthy Living app allows shoppers to scan products while in stores to choose a better option.  EWG recommends that immunotoxicity testing be prioritized for chemicals in food and food contact materials in order to protect public health from their potential harm to the immune system.  EWG also calls on the FDA to close the regulatory loophole that allows potentially unsafe food additives to remain on the market. The FDA should also promptly review additives like TBHQ to reflect new science.     Transcendental Meditation effective in reducing PTSD, sleep problems, depression symptoms Maharishi International University, March 19, 2021   Veterans with PTSD who practiced the Transcendental Meditation technique showed significant reductions in PTSD symptom severity, according to a new study published today in Journal of Traumatic Stress. Fifty percent of the meditating veterans no longer met criteria for PTSD after three months compared to only 10 percent of controls. The randomized controlled study also showed significant reductions in veterans' symptoms of depression and anxiety, and sleep difficulties.  "Transcendental Meditation is a non-trauma-focused, easy-to-learn technique that was found in this study to improve PTSD symptoms, likely through the experience of physical rest," said Mayer Bellehsen, Ph.D., director of the Unified Behavioral Health Center for Military Veterans and their Families, Northwell Health, and study principal investigator. "In contrast to commonly administered therapies for PTSD that are trauma-focused and based on a patient's recall of past traumatic experiences, this intervention does not require extensive review of traumatic history, which some individuals find difficult to engage in. This intervention may therefore be more tolerable for some individuals struggling with PTSD." The randomized controlled trial, conducted at Northwell Health in Bay Shore, New York, assigned 40 veterans with documented PTSD to either the Transcendental Meditation (TM) group or treatment as usual control group. The TM treatment provided 16 sessions over 12 weeks, with twice-a-day daily home practice. PTSD symptom severity was assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), and patient self-report with the PTSD Checklist for DSM -5 (PCL-5).  The results showed large effect sizes, indicating a strong TM treatment impact in reducing trauma symptoms for both PTSD measures. Other factors associated with trauma, such as depression and anxiety symptoms and sleep problems, also showed a strong impact of TM treatment. "This trial corroborates the findings of a large clinical trial published in The Lancet Psychiatry," said Sanford Nidich, Ed.D., Director of the Center for Social-Emotional Health at Maharishi International University Research Institute, and study co-investigator. "The current study further supports the effectiveness of Transcendental Meditation as a first-line treatment for PTSD in veterans. The availability of an additional evidence-based therapy will benefit veterans, both by offering them a greater range of options and by serving as an alternative treatment strategy for those who don't want to engage in trauma-focused treatment or who aren't responding to a previous PTSD intervention."  The authors point out in their research paper that TM may positively affect trauma symptom severity through the reduction of hyperarousal symptoms. Previous research has shown that TM practice decreases physiological responses to stressful stimuli. In addition, recent research indicates that TM may improve resilience and positive coping strategies, providing further benefit to both veterans and active military personnel.     Study: Eating White Bread & Bagels Can Be Worse Than Smoking – 49% Increase In Lung Cancer University of Texas, March 17, 2021 An alarming study has found eating foods high on the glycemic index (GI), such as bagels, white bread, and rice, increase the risk of developing lung cancer by 49 percent — particularly for non-smokers. In fact, when researchers studied the diets of 4,320 people, they were shocked to find non-smokers with diets high on the GI had nearly double the risk to develop the disease than those whose eating habits remained on the low end of the GI. Foods with high GI raise blood glucose and insulin, in turn causing increased insulin growth factors (IGFs), which are associated with greater risk for developing lung cancer. University of Texas MD Anderson Cancer Center conducted the study of 1,905 people who had cancer diagnoses and 2,415 healthy people, which was published this month in the journal Cancer, Epidemiology, Biomarkers & Prevention, RTreported. “The results from this study suggest that, besides maintaining healthy lifestyles, such as avoiding tobacco, limiting alcohol consumption, and being physically active, reducing the consumption of foods and beverages with high glycemic index may serve as a means to lower the risk of lung cancer,” explained Dr. Xifeng Wu, study senior author. Lung cancer is the number one cause of cancer deaths in the United States. More the 150,000 people will die from lung cancer in 2016 alone, according to the American Cancer Society. What’s more, a second study revealed Americans consume more than half their calories via “ultra-processed” foods, which directly contribute to health problems like obesity and heart disease. “Ultra-processed foods are products that contain several manufactured ingredients that are not generally used when cooking from scratch, including natural and artificial flavors or colors, artificial sweeteners, preservatives, and other additives,”CBS News explained. Obvious examples of ultra-processed foods include soft drinks; chicken and fish nuggets, as well as other reconstituted meat products; packaged snacks, both sweet and savory; packaged baked goods; and instant noodle products. Lead author of the study, Professor Carlos Augusto Monteiro at the University of São Paulo School of Public Health, Dept. of Nutrition, explained such highly-processed foods are designed to imitate natural foods, but often “disguise undesirable qualities of the final product.” Where a diet of fresh foods and minimally-processed products — like cheeses and simple breads — are healthiest, Monteiro told CBS News, ultra-processed products “are manufactured and marketed to replace those foods, drinks, dishes, and meals.” Such ‘foods’ are generally high in sugars, saturated fat, and sodium and contribute to a wide range of health issues, including diabetes, obesity, heart disease, and many more. Both studies ultimately suggest the need to cut out highly-processed products and return to a natural diet rich in fruits, vegetables, and whole grains. In other words, food — not products.   Move your body for five minutes every hour to counteract lockdown inactivity Kings College London, March 23, 2021 A study which looked at activity levels before and during the COVID-19 pandemic has found lockdown restrictions significantly reduced light activity associated with socialising and work. The study, published recently in BMJ Neurology and led by King's College London, examined how activity levels changed in study participants with muscular dystrophy and other inheritable myopathies. The sample included people with a range of physical abilities, from highly independent to assisted mobility, including 41 wheelchair users, who are often underrepresented in research. However, the authors say the findings are likely to be relevant to adults of various abilities and backgrounds because many people have lost their usual daily routine during lockdown. The study is unique because it used accelerometers to measure physical activity before and during lockdown as part of an ongoing longitudinal physical activity study from 2019 to 2020. The accelerometers measured activity intensity, frequency and time in vigorous, moderate, light and inactive categories. Researchers found there was a significant reduction in daily activity intensity during lockdown. Before lockdown, participants did a mean of 84.5 minutes per day of light activity and had a relatively low frequency of hourly movement. During lockdown, light activity reduced by a mean of 25 minutes per day and frequency of hourly movement reduced by a median of 11%. Moderate and vigorous activity did not change significantly during lockdown, but this might be explained by low baseline levels in this group.  In lockdown, the reduction in light activity time and frequency of movement was explained by restrictions on going to work, leisure pursuits and socialising. This light activity within daily routine is not exercise-focused so it can be difficult for individuals to detect these subtle light activity losses. However, light activity and regular movement throughout the day are associated with improved health outcomes for everyone, regardless of health conditions. Sarah Roberts-Lewis, the study lead and a Neurological Physiotherapist at King's College London, said; "Even people who don't do much exercise have been impacted by lockdown inactivity. During COVID-19 lockdown, our study detected an extra hour per day of inactivity in disabled and independent adults with neuromuscular diseases. Moving less is detrimental to health. Reduced activity can be especially harmful for those with neuromuscular conditions, disabilities or advanced age."  "The reduction in light activity measured in this study is likely to be similar for anybody whose daily routine has been restricted by lockdown. Based on our findings, we suggest people move their bodies for 5 minutes each hour during the day. Additionally, spend 30 minutes each day doing some extra light activity, like yoga or chair exercises. The World Health Organisation activity guidelines state 'every move counts'; they provide suggestions about light activites suitable for all abilities. Simple changes can help with reconditioning during and after lockdown."     Lifestyle program improves fertility for women with obesity, infertility University of Sherbrooke (Quebec) March 19, 2021 A lifestyle intervention targeting women with obesity and infertility is more effective in increasing the pregnancy rate compared with fertility treatments, according to a study presented virtually at ENDO 2021, the Endocrine Society's annual meeting. The lifestyle intervention, called the Fit-For-Fertility (FFF) program, is a cost-effective alternative to the usual standard of care for women with obesity seeking fertility treatments, according to lead researcher Matea Belan, Ph.D., of the University of Sherbrooke and the Research Center of the Centre Hospitalier Universitaire de Sherbrooke (RC-CHUS) in Quebec, Canada. "Our study shows that the FFF program can significantly improve the pregnancy rate, especially the spontaneous pregnancy rate when no fertility treatments are required, as well as the live-birth rate," she said. Obesity is a known risk factor for infertility in women of childbearing age. Lifestyle changes and a moderate weight loss of 5%-10% of a woman's initial weight have been shown to improve the odds of a pregnancy in women with obesity and infertility, Belan noted. "Lifestyle changes are recommended as the first-line treatment for these women," said study author Jean-Patrice Baillargeon, M.D., M.Sc., professor of the University of Sherbrooke and clinician investigator of the RC-CHUS. The new study tested Fit-For-Fertility, a multidisciplinary lifestyle intervention that includes a nutritionist and a kinesiologist, or human movement specialist. The researchers recruited 130 women receiving treatment at a fertility clinic, and randomly divided them into two groups. The first group had access to the Fit-For-Fertility program alone for the first six months of their participation, and in combination with fertility treatments if no pregnancy occurred after six months. The program included individual sessions with a nutritionist and a kinesiologist every six weeks. Women in the FFF group were also asked to follow at least once each one of the 12 group sessions, which included a 45-minute workshop on topics regarding nutrition, lifestyle changes and lifestyle habits, followed by a 45-minute session of initiation to different types of physical activity, including walking, circuit training, step workout and others. In the second group, the control group, women had access to the fertility treatments from the outset but did not take part in the FFF program. Data was collected for 18 months, or until the end of a pregnancy for women who became pregnant during those 18 months of participation. Of the 108 women who completed at least six months of the study, or became pregnant during the first six months, the FFF program generated a difference of 14.2 percentage points in the live-birth rate (51% for the FFF group and 36.8% for the control group). The spontaneous pregnancy rate (pregnancy without any fertility treatments) was 33.3% in the treatment group, compared with 12.3% in the control group. The researchers estimate the cost per additional newborn resulting from the FFF program at $12,633 (in 2019 Canadian dollars), somewhat similar to the willingness-to-pay for a newborn resulting from in vitro fertilization, which can cost up to $15,000. "We hope this research will give women with obesity and infertility affordable access to a tailored lifestyle intervention adapted to their condition and their specific needs in order to improve their chances of having a pregnancy and building a family," Belan said.     Vitamin B3 to stay younger? A global increase in antioxidant defenses of the body may delay aging and its diseases   Centro Nacional de Investigaciones Oncológicas (Spain), March 15, 2021   The gradual accumulation of cell damage plays a very important role in the origin of ageing. There are many sources of cellular damage, however, which ones are really responsible for ageing and which ones are inconsequential for ageing is a question that still lacks an answer. The Oxidative Hypothesis of Ageing -- also known as the Free Radicals Hypothesis -- was put forward in 1956 by Denham Harman. Since then, the large majority of attempts to prove that oxidative damage is relevant for ageing have failed, including multiple clinical trials in humans with antioxidant compounds. For this reason, although the accumulation of oxidative damage with ageing is undisputed, most scientists believe that it is a minor, almost irrelevant, cause of ageing. However, this may change in light of the recently published observations. A group of scientists from the Spanish National Cancer Research Centre (CNIO) headed by Manuel Serrano, in collaboration with a group from the University of Valencia, directed by José Viña, and researchers at IMDEA Food from Madrid, have tried to increase the global antioxidant capacity of the cells, rather than just one or a few antioxidant enzymes. To achieve this global improvement in the total antioxidant capacity, researches have focused on increasing the levels of NADPH, a relatively simple molecule that is of key importance in antioxidant reactions and that, however, had not been studied to date in relation to ageing. The researchers used a genetic approach to increase NADPH levels. In particular, they generated transgenic mice with an increased expression throughout their bodies of one of the most important enzymes for the production of NADPH, namely, glucose-6-phosphate dehydrogenase (or G6PD). The results, published today in the journal Nature Communications, indicate that an increase in G6PD and, therefore, in NADPH, increases the natural antioxidant defences of the organism, protecting it from oxidative damage, reducing ageing-related processes, such as insulin resistance, and increasing longevity. Antioxidants That Delay Ageing "As anticipated, the cells in these transgenic animals are more resistant to highly toxic artificial oxidative treatments, thus proving that an increase in G6PD really improves antioxidant defences," explains Sandrina Nóbrega-Pereira, first author of the study and currently a researcher at the Institute of Molecular Medicine of the University of Lisbon. Furthermore, when researchers analysed long-lived transgenic animals, they noted that their levels of oxidative damage were lower than in non-transgenic animals of the same age. They also studied the propensity of these animals to develop cancer and found no difference, suggesting that enhancing G6PD activity does not have an important effect on the development of cancer. The greatest surprise for the team was when they measured the ageing process in the transgenic mice: the animals with a high G6PD expression and, therefore, high levels of NADPH, delayed their ageing, metabolised sugar better and presented better movement coordination as they aged. In addition, transgenic females lived 14% longer than non-transgenic mice, while no significant effect on the longevity of males was observed. "This increased longevity, although modest, is striking taking into account that until now attempts to increase longevity by manipulating individual antioxidant enzymes had failed," said Pablo Fernández-Marcos, co-first author of the study and researcher at IMDEA Food. Overall Increase in the Antioxidant Capacity of Cells Perhaps the key is that the researchers involved in this paper enhanced all antioxidant enzymes in a comprehensive manner. "Compared to the traditional approach of administering antioxidants that react directly with oxygen, we have stimulated all the cell's natural antioxidant mechanisms by raising G6PD levels, and its by-product, NADPH," emphasizes Mari Carmen Gómez-Cabrera, co-author of the paper and researcher at the University of Valencia. Based on these results, the authors of the study point to the use of pharmacological agents or nutritional supplements that increase NADPH levels as potential tools for delaying the ageing process in humans and age-related diseases, such as diabetes, among others. More specifically, vitamin B3 and its derivatives are responsible for the synthesis of NADPH precursors and are suitable candidates for future studies.

Volume 11, Issue 25 of @Oncotarget reported that the present study was aimed at evaluating the hypothesis that p53 governs the expression and activation of the INSR gene in breast cancer cells. The availability of MCF7 breast cancer-derived cell lines with specific disruption of either the insulin-like growth factor-1 receptor or INSR allowed us to address the impact of the IGF1R and INSR pathways on p53 expression. Wild-type p53 stimulated INSR promoter activity in control cells while disruption of endogenous IGF1R or INSR led to inhibition of promoter activity by p53. Mutant p53 strongly stimulated INSR promoter. Furthermore, p53 directly binds to the INSR promoter in cells with a disrupted IGF1R. Dr. Haim Werner from Tel Aviv University said, "The insulin/insulin-like growth factors (IGFs) create a hormonal network responsible for the regulation of important physiological events throughout life." The classical view that emerged following the cloning and characterization of the INSR and IGF1R genes in the mid-1980s postulated that activation of INSR by insulin leads, predominantly, to metabolic activities. One of the cardinal questions still in need of a biologically plausible rationalization is why the INSR and IGF1R, even though they share the majority of their downstream cytoplasmic targets and signaling pathways, are yet responsible for mediating distinct physiological and pathological activities. Given the emerging evidence of proliferative and potentially anti-apoptotic actions of INSR, the authors investigated in the present paper the regulation of the INSR gene promoter by wild-type and mutant p53 in breast cancer cells. Using cells with specific disruption of the INSR or IGF1R, the authors also assessed the effect of each one of these signaling pathways on p53 expression and activity. The data indicate that: activation of p53 is negatively regulated by IGF1R, as indicated by the augmented phosphorylation of p53 in IGF1R-KD cells; p53 directly binds to the INSR promoter region in cells with a disrupted IGF1R; wild-type p53 represses INSR promoter activity in IGF1R-KD and INSR-KD cells while enhancing promoter activity in control cells; mutant p53 stimulates INSR promoter activity in breast cancer cells. The Werner Research Team concluded in their Oncotarget Research Paper, "we have presented evidence that the INSR gene constitutes a downstream target for p53 action. Whereas wild-type p53 stimulated INSR promoter activity in control MCF7 cells, disruption of endogenous IGF1R or INSR led to inhibition of promoter activity by wild-type p53. Mutant, oncogenic versions of p53, for the most part, strongly stimulated INSR promoter. In addition, p53 exhibits direct binding to the INSR promoter region in cells with a disrupted IGF1R. Taken together, data presented here identifies complex functional and physical interactions between p53 and the INSR pathway. The clinical implications of this interplay in breast cancer needs to be critically assessed." DOI - https://doi.org/10.18632/oncotarget.27645 Full text - https://www.oncotarget.com/article/27645/text/ Correspondence to - Haim Werner - hwerner@post.tau.ac.il Keywords - insulin, insulin-like growth factor-1 (IGF1), insulin receptor, IGF1 receptor, p53 About Oncotarget Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957x105

Wachstum und Differenzierung sind zentrale Prozesse bei der Entstehung und Entwicklung des Lebens. Die Größe eines Zellverbandes wird vor allem durch die Balance zwischen Zellwachstum, Proliferation und die Apoptoserate definiert (Lupu et al. 2001). Unterschiedliche Größen von Organen können durch unterschiedliche Zellzahlen und/oder durch unterschiedliche Zellgrößen bedingt sein. So ist der Mensch beispielsweise größer als eine Maus, vor allem weil er mehr Zellen hat (Raff 1996). Im Vergleich dazu wurden bei verschiedenen Drosophila-Unterarten unterschiedliche Flügelgrößen aufgrund einer Änderung der Zellgröße entdeckt (Prout & Barker 1989). Allerdings ist bis heute nur unzureichend geklärt, wie das Wachstum durch Zellgröße und -zahl koordiniert ist und wie dadurch Struktur und Funktion von Organen bzw. Organismen entstehen. Ein zentrales regulatorisches System für die Kontrolle des Wachstums ist das GH/IGF (Wachstumshormon/Insulin-Like Growth Factor)-System. Ohne die endo- und parakrin wirksamen Komponenten GH und IGF-I ist in der Maus postnatal nahezu kein Wachstum möglich. Mäuse, die weder funktionelles GH noch IGF-I besitzen, erreichen nur 17 % der Größe und des Gewichts einer vergleichbaren adulten Maus. Damit stoßen sie an die kleinste gerade noch für ein Säugetier tolerierbare Größe (Lupu et al. 2001). Wichtige Vermittler der gewebespezifischen Wirkungen von IGF-I und -II sind die IGF-Bindungsproteine (IGFBPs). Bislang sind sechs unterschiedliche IGFBPs bekannt, die durch eine hohe Affinität für die IGFs definiert sind und damit deren biologische Wirkungen beeinflussen. Unter den IGFBPs nimmt IGFBP-2 eine besondere Stellung ein, weil es ein in vivo relevanter Inhibitor für Wachstum ist. Es konnte gezeigt werden, dass IGFBP-2 die Effekte von GH auf die Zellgröße modulieren kann. Während GH in Zona fasciculata Zellen der Nebenniere 11 Wochen alter Mäuse sowohl Zellzahl als auch Zellgröße stimulierte, wirkte sich die Koexpression von IGFBP-2 in einer Normalisierung der GH-induzierten Zellgröße, nicht jedoch der GH-induzierten Zellzahlerhöhung aus (Hoeflich et al. 2002). Dieses Modell eignet sich somit ideal, um die Regulation von Zellgröße und Zellzahl getrennt zu untersuchen. In der vorliegenden Arbeit wurden die molekularen Grundlagen dieser Veränderungen sowohl auf der Ebene des Transkriptoms, als auch der Proteine untersucht. Um Fragen zur Altersabhängigkeit der Wachstumsregulation zu bearbeiten, wurde die Untersuchung an zwei verschiedenen Altersgruppen durchgeführt.

Insulin-like growth factor I (IGF-I) and -II (IGF-II) are single chain peptides produced by many tissues, functioning in an endocrine, autocrine or paracrine fashion to regulate cellular proliferation, survival and differentiation. IGF actions are initiated upon binding to the insulin-like growth factor I receptor (IGF-IR) and are modulated through interactions with a family of six secreted IGF-binding proteins (IGFBP-1 to -6). IGF-I is necessary for normal growth and differentiation during both, embryonic and postnatal development. IGF-II is a stimulator of fetal growth but its functions in the postnatal period are still unclear. Notably, expression of IGF-II is shut down shortly after birth in rodents (but not in humans). Previous studies in phosphoenolpyruvate-carboxykinase (PEPCK)-IGF-II transgenic mice demonstrated that overexpression of IGF-II resulted in disproportionate growth of specific organs but a significant increase in body size was not observed. Homozygous IGF-I deficient mice were shown to be severely retarded in growth. The aim of this study was to test whether elevated levels of circulating IGF-II can rescue the dwarfism in IGF-I deficient mice and thereby function as a stimulator of postnatal growth in the absence of IGF-I. For this purpose, we crossed heterozygous IGF-I deficient mice [I+/- IIwt] with heterozygous IGF-I deficient mice carrying PEPCK-IGF-II transgenes [I+/- IItg]. The resulting offspring comprised six different groups: homozygous IGF-I knockout and PEPCK-IGF-II wildtype mice [I-/- IIwt], homozygous IGF-I knockout and PEPCK-IGF-II transgenic mice [I-/- IItg], animals lacking one IGF-I allele and wildtype for the PEPCK-IGF-II transgene [I+/- IIwt], lacking one IGF-I allele and harbouring the PEPCK-IGF-II transgene [I+/- IItg], wildtype for the IGF-I mutation and carrying the PEPCK-IGF-II transgene [I+/+ IItg], and completely wildtype [I+/+ IIwt]. The genotype of all mice was determined by PCR. Body weight of mice was recorded daily until the age of 8 weeks. The nose-rump length (NRL) and the weights of individual organs and of the carcass were recorded and the femurs and lumbar vertebras prepared for further investigations. At an age of 8 weeks, mean serum concentrations of IGF-I were beyond detection level in [I-/- IIwt] and [I-/- IItg] mice, intermediate in [I+/- IIwt] and [I+/- IItg] animals and highest in [I+/+ IIwt] and [I+/+ IItg] mice. IGF-II levels were significantly increased in animals harbouring the PEPCK-IGF-II transgene ([I-/- IItg], [I+/- IItg], and [I+/+ IItg]) when compared to their wildtype counterparts ([I-/- IIwt], [I+/- IIwt], and [I+/+ IIwt]). This reflected the genotype, demonstrating the appropriateness of our experimental model. Analysis of body weight data from day 3-4 after birth until day 60 revealed that in the absence of IGF-I, elevated levels of IGF-II have no effect on body weight gain. The same was found for the nose-rump length and the carcass. The weight of specific organs, however, was altered. Compared to the wildtype counterparts ([I-/- IIwt]), the relative kidney weight in [I-/- IItg] mice was significantly increased. IGF-I is known to play an important role in bone growth and in cancellous bone homeostasis. Investigations of geometric and structural bone parameters showed that in the presence or absence of IGF-I, an increase in the circulating levels of IGF-II was without effect on the skeleton and could not substitute for the skeletal functions of IGF-I in IGF-I-ablated mice. Homozygous IGF-I deficient mice are known to have elevated levels of growth hormone (GH). To demonstrate that the lack of effect on growth in our [I-/- IItg] animals was not due to a loss of these elevated GH-levels, a GH-Western immunoblot was performed, revealing that, despite elevated levels of IGF-II, increased levels of GH were still present in [I-/- IItg] animals. Evaluation of the serum levels of IGFBPs by Western ligand blot analysis demonstrated that IGFBP-1 and IGFBP-4 levels were similar in all groups, whereas the levels of IGFBP-2 and IGFBP-3 were strongly reduced in [I-/- IIwt] animals. In the presence of IGF-II ([I-/- IItg]), they were partially restored but the amounts were still smaller than in the IGF-I wildtype animals ([I+/+ IIwt] and [I+/+ IItg]). In summary, these results show that under our experimental conditions, IGF-II is not able to rescue the postnatal growth deficit of IGF-I knockout mice and apparently does not exert a negative feedback on the secretion of growth hormone. However, it could be demonstrated, that the IGFs have differentiated effects on the regulation of the expression/stability of individual IGFBPs.

Although the stimulating effect of insulin-like growth factor I (IGF-I) on adrenal steroidogenesis has been well established, the role of IGF-II in the adult adrenal gland remains unknown. We, therefore, investigated the effect of recombinant human IGF-II on cortisol and cAMP synthesis from adult bovine adrenocortical cells. IGF-II, time and dose dependently, stimulated basal cortisol secretion maximally 3-fold. In combination with ACTH, IGF-II (13 nM) synergistically increased cortisol secretion from 1-fold (10(-8) M ACTH) to 28-fold of untreated control levels. In contrast, IGF-I at equimolar concentrations did not show an effect on basal cortisol secretion, and in combination with ACTH elicited a significant weaker stimulatory effect than IGF-II (22-fold increase). The synergistic effect of IGF-II on ACTH-promoted cortisol secretion was paralleled by accumulation of cAMP in the culture medium. Although both IGF receptors are present in adult bovine adrenocortical cells, the effect of IGF-II seems to be mediated through interaction with the IGF-I receptor, as [Arg54,55]IGF-II, which only binds to the IGF-I receptor, was equipotent to native IGF-II, whereas [Leu27]IGF-II, which preferentially binds to the type II IGF receptor, did not show any effect. By Western ligand blotting, four different molecular forms of IGF-binding proteins (IGFBPs) were identified in conditioned medium of bovine adrenocortical cells with apparent molecular masses of 39-44, 34, 29, and 24 kilodaltons. ACTH treatment increased the abundance of all binding proteins, on the average, 2.3-fold, except for the 29-kDa band, which was predominantly induced 6.8-fold. Additionally, [des1-3]IGF-I, a truncated IGF variant that exhibits only minimal binding to IGFBPs, was significant more potent than IGF-I and elicited the same maximum stimulatory effect on cortisol secretion as IGF-II and [des1-6]IGF-II. In conclusion, these results demonstrate that 1) IGF-II stimulates basal as well as ACTH-induced cortisol secretion from bovine adrenocortical cells more potently than IGF-I; 2) this effect is mediated through interaction of IGF-II with the IGF-I receptor; 3) bovine adrenocortical cells synthesize various IGFBPs that are induced differentially by ACTH; and 4) IGFBPs apparently play a modulatory role in IGF-induced stimulation of adrenal steroidogenesis. Therefore, bovine adult adrenocortical cells provide a useful tissue culture model in which the interactions among locally produced IGFs, IGFBPs, and the IGF-I receptor can be evaluated.

The putative effects of diabetes and metabolic control on circulating levels of insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) remain controversial. In the present study, serum levels of IGF-I and IGF-II and IGFBP-1, -2, and -3 were measured in 58 patients (age, 0.8-17 yr) with treated (51 subjects) or untreated (7 subjects) insulin-dependent diabetes mellitus (IDDM) and were compared with the levels in normal subjects. In the untreated patients IGF-I and IGF-II were decreased as compared with the healthy controls. In the treated diabetics IGF-I and IGF-II were reduced; IGFBP-2 (only in prepubertal subjects) and IGFBP-3 were increased. Furthermore, age-adjusted values of IGF-I, IGF-II, and IGFBP-3 were lower in prepubertal than in pubertal patients. Regression analysis revealed a negative correlation between hemoglobin (Hb)A1c and standard deviation scores (SDS) of IGF-I and a positive association between HbA1c and IGFBP-1 SDS or IGFBP-2 SDS. In the treated patients HbA1c was positively related to IGFBP-1 SDS and IGFBP-2 SDS when applying simple regression analysis and to IGFBP-2 SDS when using a multiple regression model. Strong correlations were observed between height SDS and IGF-I SDS, IGF-II SDS, and IGFBP-3 SDS in prepubertal subjects who had had IDDM for at least 2 yr, but not in adolescents. Such correlations have also been found in healthy children and adolescents. In conclusion; 1) IDDM is associated with alterations of the IGF-IGFBP system, which are partially accounted for by differences in metabolic control and pubertal status; 2) the lower plasma concentrations of serum IGF-I may play a role in the pathogenesis of growth impairment of poorly controlled prepubertal, but not pubertal, children and adolescents with IDDM; and 3) in addition, a potential role of the altered IGF-IGFBP system for the development of diabetic late complications is hypothesized.

Cultured cardiac myocytes from adult Sprague-Dawley rats express both insulin-like growth factor-I (IGF-I) receptors and insulin-like growth factor-II/mannose 6-phosphate (IGF-II/Man6P) receptors and respond to IGF-I with a dose-dependent accumulation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and inositol 1,4-bisphosphate [Ins(1,4)P2]. Specific binding of [125I]IGF-I to isolated membranes from cultured cardiac myocytes amounted to 1-1.2%. Binding of [125I]IGF-I was inhibited by unlabeled IGF-I at nanomolar concentrations and insulin at much higher concentrations. These data suggest that IGF-I binds to its own receptor on rat cardiac myocytes. Competitive binding studies using isolated membranes from cardiac myocytes and [125I]IGF-II showed 2-4% specific binding. Binding of [125I]IGF-II was inhibited by IGF-II and much less potently by IGF-I and insulin. Immunoglobulin G (IgG) 3637 (an IgG directed against the IGF-II/Man6P receptor) partially inhibited binding of [125I]IGF-II whereas nonimmune IgG did not. Affinity cross-linking studies with [125I]IGF-II and cardiac myocyte membranes and subsequent analysis of the ligand-receptor complex using SDS-PAGE and autoradiography showed a radiolabeled band of approximately 250 kilodalton (kDa). The formation of the [125I]IGF-II-receptor complex was inhibited by incubation with IGF-II and IgG 3637 but not by insulin or nonimmune IgG. Western blotting of protein extracts from cultured cardiac myocytes was performed using IgG 3637 and an immunoperoxidase technique for the visualization of the IGF-II/Man6P receptor protein. A specific band at 220 kDa under nonreducing conditions was detected on the blots, providing further evidence for the expression of the IGF-II/Man6P receptor by cardiac myocytes. The effect of IGFs on the accumulation of inositol phosphates was measured by HPLC analysis of perchloric acid extracts from myo-[3H]inositol-labeled cultured cardiac myocytes. IGF-I (50 ng/ml) stimulated the accumulation both of Ins(1,4,5)P3 and Ins(1,4)P2 after 30 sec by 43% and 63%. IGF-II (up to 500 ng/ml) had no significant effect on inositol phosphate accumulation under the same conditions. However, in the presence of millimolar concentrations of Man6P, IGF-II (500 ng/ml) also increased Ins(1,4,5)P3 accumulation by 59%. We conclude that cardiac myocytes from adult rats express IGF receptors and respond to IGFs with the accumulation of Ins(1,4,5)P3 and Ins(1,4)P2. This effect seems to be mediated by an IGF-I receptor-specific pathway.