Podcasts about tnfr2

Video: Scientist Carl Sagan testifying to the U.S. Senate in 1985 on the greenhouse effect: (2:00) WEF: The Most Evil Business in the World – Samuel Leeds (10:49) Israel caught hiding BOMBSHELL Pfizer   Frequent nut consumption associated with less inflammation Brigham and Women's Hospital, September 1, 2022 In a study of more than 5,000 people, investigators from Brigham and Women's Hospital have found that greater intake of nuts was associated with lower levels of biomarkers of inflammation, a finding that may help explain the healthbenefits of nuts. The results of the study appear in the American Journal of Clinical Nutrition. “Population studies have consistently supported a protective role of nuts against cardiometabolic disorders such as cardiovascular disease and type 2 diabetes, and we know that inflammation is a key process in the development of these diseases,” said corresponding author Ying Bao, MD, ScD, an epidemiologist in BWH's Channing Division of Network Medicine. “Our new work suggests that nuts may exert their beneficial effects in part by reducing systemic inflammation.” Previously Bao and her colleagues observed an association between increased nut consumption and reduced risk of major chronic diseases and even death, but few prospective cohort studies had examined the link between nut intake and inflammation. In the current study, the research team performed a cross-sectional analysis of data from the Nurses' Health Study, which includes more than 120,000 female registered nurses, and from the Health Professionals Follow-Up Study, which includes more than 50,000 male health professionals. The team assessed diet using questionnaires and looked at the levels of certain telltale proteins known as biomarkers in blood samples collected from the study participants. They measured three well-established biomarkers of inflammation: C-reactive protein (CRP), interleukin 6 (IL6) and tumor necrosis factor receptor 2 (TNFR2). After adjusting for age, medical history, lifestyle and other variables, they found that participants who had consumed five or more servings of nuts per week had lower levels of CRP and IL6 than those who never or almost never ate nuts. In addition, people who substituted three servings per week of nuts in place of red meat, processed meat, eggs or refined grains had significantly lower levels of CRP and IL6. Peanuts and tree nuts contain a number of healthful components including magnesium, fiber, L-arginine, antioxidants and unsaturated fatty acids such as α-linolenic acid. Researchers have not yet determined which of these components, or if the combination of all of them, may offer protection against inflammation, but Bao and her colleagues are interested in exploring this further through clinical trials that would regulate and monitor diet. “Much remains unknown about how our diet influences inflammation and, in turn, our risk of disease,” said Bao. “But our study supports an overall healthful role for nuts in the diet and suggests reducing inflammation as a potential mechanism that may help explain the benefits of nuts on cardiometabolic diseases.” Blueberry extract could help fight gum disease and reduce antibiotic use Laval University (Quebec), September 2, 2022 Gum disease is a common condition among adults that occurs when bacteria form biofilms or plaques on teeth, and consequently the gums become inflamed. Some severe cases, called periodontitis, call for antibiotics. But now scientists have discovered that wild blueberry extract could help prevent dental plaque formation. Their report in ACS' Journal of Agricultural and Food Chemistry could lead to a new therapy for periodontitis and a reduced need for antibiotics. Many people have had some degree of gum inflammation, or gingivitis, caused by dental plaque. The gums get red and swollen, and they bleed easily. If left unchecked, the condition can progress to periodontitis. The plaque hardens into tartar, and the infection can spread below the gum line and destroy the tissue supporting the teeth. To treat this condition, dentists scrape off the tartar and sometimes have to resort to conventional antibiotics. But recently, researchers have started looking at natural antibacterial compounds to treat gum disease. Daniel Grenier and colleagues wanted to see if blueberry polyphenols, which work against foodborne pathogens, could also help fight Fusobacterium nucleatum, one of the main species of bacteria associated with periodontitis. In the lab, the researchers tested extracts from the wild lowbush blueberry, Vaccinium angustifolium Ait., against F. nucleatum. The polyphenol-rich extracts successfully inhibited the growth of F. nucleatum, as well as its ability to form biofilms. It also blocked a molecular pathway involved in inflammation, a key part of gum disease. The researchers say they're developing an oral device that could slowly release the extract after deep cleaning to help treat periodontitis. Meat consumption contributing to global obesity University of Adelaide, August 11, 2022 Should we be warning consumers about over-consumption of meat as well as sugar? That's the question being raised by a team of researchers from the University of Adelaide, who say meat in the modern diet offers surplus energy, and is contributing to the prevalence of global obesity. “Our findings are likely to be controversial because they suggest that meat contributes to obesity prevalence worldwide at the same extent as sugar,” says Professor Maciej Henneberg. “In the analysis of obesity prevalence across 170 countries, we have found that sugar availability in a nation explains 50% of obesity variation while meat availability another 50%. After correcting for differences in nations' wealth (Gross Domestic Product), calorie consumption, levels of urbanization and of physical inactivity, which are all major contributors to obesity, sugar availability remained an important factor, contributing independently 13%, while meat contributed another 13% to obesity. “While we believe it's important that the public should be alert to the over-consumption of sugar and some fats in their diets, based on our findings we believe meat protein in the human diet is also making a significant contribution to obesity,” Professor Henneberg says. “There is a dogma that fats and carbohydrates, especially fats, are the major factors contributing to obesity,” Mr You says. “Whether we like it or not, fats and carbohydrates in modern diets are supplying enough energy to meet our daily needs. Because meat protein is digested later than fats and carbohydrates, this makes the energy we receive from protein a surplus, which is then converted and stored as fat in the human body.” “Nevertheless, it is important that we show the contribution meat protein is making to obesity so that we can better understand what is happening. In the modern world in which we live, in order to curb obesity it may make sense for dietary guidelines to advise eating less meat, as well as eating less sugar,” he says. Study suggests possible link between artificial sweeteners and heart disease French National Institute for Health and Medical Research, September 7, 2022 A large study of French adults published by The BMJ today suggests a potential direct association between higher artificial sweetener consumption and increased cardiovascular disease risk, including heart attack and stroke. The findings indicate that these food additives, consumed daily by millions of people and present in thousands of foods and drinks, should not be considered a healthy and safe alternative to sugar, in line with the current position of several health agencies. Artificial sweeteners are widely used as no- or low-calorie alternatives to sugar. They represent a $7.2 billion (£5900m; €7000m) global market and are found in thousands of products worldwide, particularly ultra-processed foods such as artificially sweetened drinks, some snacks, and low calorie ready meals. Several studies have linked consumption of artificial sweeteners or artificially sweetened beverages (ASB) to weight gain, high blood pressure, and inflammation. To investigate this further, a team of researchers at the French National Institute for Health and Medical Research (Inserm) and colleagues drew on data for 103,388 participants (average age 42 years; 80% female) of the web-based NutriNet-Santé study, launched in France in 2009 to investigate relations between nutrition and health. Dietary intakes and consumption of artificial sweeteners were assessed by repeated 24-hour dietary records and a range of potentially influential health, lifestyle, and sociodemographic factors were taken into account. A total of 37% of participants consumed artificial sweeteners, with an average intake of 42.46 mg/day, which corresponds to approximately one individual packet of table top sweetener or 100 mL of diet soda. The researchers found that total artificial sweetener intake was associated with an increased risk of cardiovascular disease (absolute rate 346 per 100,000 person years in higher consumers and 314 per 100,000 person years in non-consumers). Artificial sweeteners were more particularly associated with cerebrovascular disease risk (absolute rates 195 and 150 per 100,000 person-years in higher and non-consumers, respectively). Aspartame intake was associated with increased risk of cerebrovascular events (186 and 151 per 100,000 person-years in higher and non-consumers, respectively), while acesulfame potassium and sucralose were associated with increased coronary heart disease risk (acesulfame potassium: 167 and 164 per 100,000 person-years; sucralose: 271 and 161 per 100,000 person-years in higher and non-consumers, respectively). Your soap and toothpaste could be messing with your microbiome University of Chicago, September 2, 2022 Antimicrobial chemicals found in common household products could be wreaking havoc with people's guts, according to a research paper out this week in the journal Science. Triclosan is an antibacterial compound used in soaps, detergent and toothpaste, as well as toys and plastics. It was originally only used in hospitals, but it found its way into homes as Americans became more germ-phobic. (However, recent studies have found it no more effective at killing bacteria than plain soap. ) Now, there are growing concerns about the possible negative effects of the chemical on human health and the environment. According to the US Food and Drug Administration (FDA), animal studies have shown that the chemical can act as a hormone disruptor. A 2008 study found traces of triclosan in the urine of 75% of the participants – some as young as six. The chemical has also been found in more than half of freshwater streams in the US. Disturbing the human microbiome has been “linked to a wide array of diseases and metabolic disorders, including obesity, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and behavioral and metabolic disorders,” wrote the paper's authors, Alyson L Yee and Jack A Gilbert. Yee and Gilbert also suggested that exposure to triclosan could be even more detrimental to the health of developing fetuses and newborns than to adults. A 2014 New York University study found that gut disruptions in early infancy could have lasting negative effects on immune and brain development. Triclosan could also be contributing to antibiotic resistance, which scientists believe is caused by the overuse of antimicrobials in humans and animals. There are partial bans of the chemical in the European Union and in Minnesota, and the FDA says it will continue reviewing the chemical for its safety. Exposure to phthalates could be linked to pregnancy loss Peking University, September 2, 2022 A new study of more than 300 women suggests that exposure to certain phthalates — substances commonly used in food packaging, personal-care and other everyday products — could be associated with miscarriage, mostly between 5 and 13 weeks of pregnancy. The research, appearing in the ACS journal Environmental Science & Technology, is the first epidemiological study on non-work-related exposure to phthalates to provide evidence for the possible link among a general population. Out of concern over the potential health effects of phthalates, the U.S. has banned six of these substances from use in certain products made for young children. But many are still included as ingredients in paints, medical tubes, vinyl flooring, soaps, shampoos and other items. Research on phthalates has shown that long-term exposure to low levels of some of these compounds harms lab animals' health and can increase their risk for pregnancy loss. Additionally, at least one study found that female factory workers exposed to high levels of phthalates through their work were at a higher risk for miscarriage. But there is little epidemiological evidence of phthalates' effects on pregnancy among women with non-occupational exposure. Jianying Hu, Huan Shen and colleagues wanted to find out if there might be a link. The researchers tested urine samples from 132 women who had miscarriages and 172 healthy pregnant women in China. They found pregnancy loss was associated with higher levels of urinary phthalate metabolites from diethyl phthalate (DEP), di-isobutyl phthalate (DiBP) and di-n-butyl phthalate (DnBP). Although this doesn't prove that phthalates cause pregnancy loss, the study suggests an association exists that the researchers say should be studied further.

VIDEOS: 1. The Anti-Smartphone Revolution – (13:23) ColdFusion 2. Gravitas Plus: Explained: The China-Taiwan conflict (9:11)   HEALTH NEWS Astonishing effects of grapes, remarkable potential for health benefits Frequent nut consumption associated with less inflammation Body posture affects how oral drugs absorbed by stomach [why not supplements too?]  Lifting Weights Beats Out Cycling, Swimming For Vegans Wanting Stronger Bones Perfectionism Linked To Burnout At Work, School And Sports, Research Finds  Mindfulness Therapy Better Than Antidepressants Astonishing effects of grapes, remarkable potential for health benefits Western New England University, August 8, 2022 Recent studies released by Dr. John Pezzuto and his team from Western New England University show “astonishing” effects of grape consumption and “remarkable” impacts on health and on lifespans. Published in the journal Foods, one study showed that adding grapes in an amount equal to just under two cups of grapes per day to a high-fat diet, typically consumed in western countries, yielded reductions in fatty liver and extended lifespans.  Noting that these studies add an entirely new dimension to the old saying ‘you are what you eat,' Pezzuto, who has authored over 600 scientific studies, said that the work with grapes showed actual changes in genetic expression. “That is truly remarkable.” Adding grapes to a high-fat diet also increased levels of antioxidant genes and delayed natural death.  Acknowledging that it is not an exact science to translate years of lifespan from a mouse to a human, Pezzuto said that his best estimate is the change observed in the study would correspond to an additional 4-5 years in the life of a human. Another study by Dr. Pezzuto and his team published in the journal Antioxidants, reported that grape consumption altered gene expression in the brain and had positive effects on behavior and cognition that were impaired by a high-fat diet.  Frequent nut consumption associated with less inflammation Brigham and Women's Hospital, August 1, 2022 In a study of more than 5,000 people, investigators from Brigham and Women's Hospital have found that greater intake of nuts was associated with lower levels of biomarkers of inflammation, a finding that may help explain the health benefits of nuts. The results of the study appear in the American Journal of Clinical Nutrition. “Population studies have consistently supported a protective role of nuts against cardiometabolic disorders such as cardiovascular disease and type 2 diabetes, and we know that inflammation is a key process in the development of these diseases,” said corresponding author Ying Bao, MD, ScD, an epidemiologist in BWH's Channing Division of Network Medicine. “Our new work suggests that nuts may exert their beneficial effects in part by reducing systemic inflammation.” In the current study, the research team performed a cross-sectional analysis of data from the Nurses' Health Study, which includes more than 120,000 female registered nurses, and from the Health Professionals Follow-Up Study, which includes more than 50,000 male health professionals. The team assessed diet using questionnaires and looked at the levels of certain telltale proteins known as biomarkers in blood samples collected from the study participants. They measured three well-established biomarkers of inflammation: C-reactive protein (CRP), interleukin 6 (IL6) and tumor necrosis factor receptor 2 (TNFR2). After adjusting for age, medical history, lifestyle and other variables, they found that participants who had consumed five or more servings of nuts per week had lower levels of CRP and IL6 than those who never or almost never ate nuts. In addition, people who substituted three servings per week of nuts in place of red meat, processed meat, eggs or refined grains had significantly lower levels of CRP and IL6. Peanuts and tree nuts contain a number of healthful components including magnesium, fiber, L-arginine, antioxidants and unsaturated fatty acids such as α-linolenic acid.  Body posture affects how oral drugs absorbed by stomach [why not supplements too?]  Johns Hopkins School of Medicine, August 8, 2022 A common, economic, and easy method of administering drugs is orally, by swallowing a pill or capsule. But oral administration is the most complex way for the human body to absorb an active pharmaceutical ingredient, because the bioavailability of the drug in the gastrointestinal tract depends on the medication's ingredients and the stomach's dynamic physiological environment. In Physics of Fluids, researchers from Johns Hopkins School of Medicine employ a biomimetic in-silico simulator based on the realistic anatomy and morphology of the stomach—a “StomachSim”—to investigate and quantify the effect of body posture and stomach motility on drug bioavailability. “”When the pill reaches the stomach, the motion of the stomach walls and the flow of contents inside determine the rate at which it dissolves. The properties of the pill and the stomach contents also play a major role. Stomach contents, motility, and gastric fluid dynamics all play a role in a drug's bioavailability, and stomach contractions can induce pressure and generate complex pill trajectories. This results in varying rates of pill dissolution and nonuniform emptying of the drug into the duodenum and, sometimes, gastric dumping in the case of modified-release dosage. The modeling appears to be the first of its kind to couple gastric biomechanics of posture with pill movement and drug dissolution to quantify an active pharmaceutical ingredientpassing through the pylorus into the duodenum. The model enabled the researchers to calculate and compare the emptying rate and the release of a dissolved active pharmaceutical ingredient into the duodenum for a variety of physiological situations. Lifting Weights Beats Out Cycling, Swimming For Vegans Wanting Stronger Bones Medical University of Vienna (Austria), August 2, 2022 When it comes to bone health, a new study finds people on a plant-based diet should grab the dumbbells. Researchers in Austria have found that lifting weights is the best form of exercise for vegans – trumping cycling and swimming. The team found that vegans who do resistance training once a week – such as machine-work, free weights, or bodyweight resistance – have stronger bones than plant-based eaters who do other forms of exercise. The new study, published in the Journal of Clinical Endocrinology & Metabolism, found vegans who did resistance training had similar bone structure to omnivores — people who eat both meat and vegetables. For at least five years, authors followed 43 men and women on a plant-based diet and 45 men and women who eat meat as well. “Our study showed resistance training offsets diminished bone structure in vegan people when compared to omnivores.” Perfectionism linked to burnout at work, school and sports, research finds  York St. John University (UK), July 31, 2022 Concerns about perfectionism can sabotage success at work, school or on the playing field, leading to stress, burnout and potential health problems, according to new research published by the Society for Personality and Social Psychology.  In the first meta-analysis of the relationship between perfectionism and burnout, researchers analyzed the findings from 43 previous studies conducted over the past 20 years. It turns out perfectionism isn't all bad. One aspect of perfectionism called “perfectionistic strivings” involves the setting of high personal standards and working toward those goals in a pro-active manner. These efforts may help maintain a sense of accomplishment and delay the debilitating effects of burnout, the study found.  The dark side of perfectionism, called “perfectionistic concerns,” can be more detrimental when people constantly worry about making mistakes, letting others down, or not measuring up to their own impossibly high standards, said lead researcher Andrew Hill, an associate professor of sport psychology at York St. John University in England. Previous research has shown that perfectionistic concerns and the stress they generate can contribute to serious healthproblems, including depression, anxiety, eating disorders, fatigue and even early mortality. The study was published online in the Personality and Social Psychology Review. The study found that perfectionistic concerns had the strongest negative effects in contributing to burnout in the workplace, possibly because people have more social support and clearly defined objectives in education and sports. A student can be rewarded for hard work with a high grade, or a tennis player can win the big match, but a stellar performance in the workplace may not be recognized or rewarded, which may contribute to cynicism and burnout.  “People need to learn to challenge the irrational beliefs that underlie perfectionistic concerns by setting realistic goals, accepting failure as a learning opportunity, and forgiving themselves when they fail,” Hill said. “Creating environments where creativity, effort and perseverance are valued also would help.”  Mindfulness Therapy Better Than Antidepressants University of Exeter (UK), July 31, 2022  Antidepressants are big business.  But for the same money, and without the side effects, a little mindfulness can do the same job.  A new study from the University of Exeter in the UK suggests that mindfulness-based cognitive therapy (MBCT) is just as good as drugs – and maybe even better   MBCT is a structured training program for the mind and body.  It was developed to help people deal with repeated bouts of depression.  It teaches them skills to recognize and respond constructively to the thoughts and feelings associated with relapse.  In other words, it helps patients re-focus their thoughts as a way to avoid falling back into depression. Prior studies have shown that MBCT reduces the risk of relapse or recurrence of depression by about 34% compared to usual care or placebo.  B The research published in The Lancet  followed a group of 424 depressed patients for two years. The patients had all suffered three or more previous major depressive episodes.  And they were all taking a maintenance course of antidepressants. The MBCT group attended eight group therapy sessions in which they learned mindfulness practices and cognitive-behavioral skills, and participated in group discussions.   After two years, relapse rates were worse in the drug group.  The drug group relapsed at the rate of 47% compared to only 44% for the mindfulness group.  The researchers concluded that MBCT may be an effective alternative to antidepressants for prevention of depressive relapse with no significant difference in cost. And it may be a good alternative for people who choose not to use drugs.  But they also suggested MBCT was more beneficial than drugs in preventing relapses in patients who were at highest risk of relapse especially those who reported severe childhood abuse.

CoQ10 supplementation associated with improved trauma patient outcomes Urmia University of Medical Sciences (Iran) July 23 2021.    Findings from a trial reported on July 12, 2021 in the Journal of Nutritional Science revealed benefits for hospitalized traumapatients who were given supplements that contained coenzyme Q10.  The trial enrolled 40 men and women with traumatic injury and low plasma levels of CoQ10. Participants received a placebo or 400 milligrams CoQ10 daily for seven days. Blood samples collected at the beginning and end of the trial were analyzed for interleukin 6 (IL-6), which may be elevated during inflammation, and the oxidative stress markers malondialdehyde (MDA) and thiobarbituric acid reactive substances (TBARS). Body composition was also assessed at these time points, as well secondary outcomes that included Sequential Organ Failure Assessment (SOFA) and the Glasgow Coma Scale (GCS).  While interleukin-6 levels at the beginning of the study were similar between the CoQ10 and placebo groups at an average of 175.05 pg/mL and 177.82 pg/mL, they were reduced by 76.99 pg/mL in the CoQ10 group and 17.35 pg/mL in the placebo group. MDA values averaged 232.37 picograms per milliliter (pg/mL) and 239.96 pg/mL and were lowered by 88.84 pg/ml among participants who received CoQ10 and by 26.23 pg/mL among those who received a placebo. In comparison with the placebo group, fat free mass, skeletal muscle mass and body cell mass increased among those who received CoQ10. GCS and SOFA scores, and duration of hospital stay, ICU stay and ventilator use also improved among treated patients.  “To date, no randomized clinical trial study has been conducted to evaluate the effect of CoQ10 supplementation in traumatic mechanical ventilated patients and we hypothesized that CoQ10 administration in these patients could have beneficial effects on biochemical and clinical factors,” the authors wrote. “We have shown that CoQ10 could improve some of the clinical and anthropometric parameters in patients with a traumatic injury.”     Nigella sativa (black seed) prevents covid-induced vascular damage, scientists conclude   Oriental Institute of Science and Technology (India), July 27, 2021 New research published in the journal Vascular Pharmacology shows that Nigella sativa, also known as black seed or black cumin, binds to ACE2 in the lungs, effectively stopping the Wuhan coronavirus (Covid-19) from inducing inflammation and vascular damage. Researchers out of India investigated the effects of nigellidine, an indazole alkaloid of black seed, using molecular docking for binding to different angiotensin-binding proteins, as well as the Chinese Virus spike glycoprotein. They found that nigellidine “strongly binds” to the Chinese Virus spike protein at what is known as the hinge region or active site opening, which may in turn hamper its binding to the nCoV2-ACE2 surface. “Nigellidine effectively binds in the Angiotensin-II binding site / entry pocket,” the study explains. “Nigellidine showed strong binding to mono / multi-meric ACE1.” This process of ACE blocking could, the study goes on to suggest, restore angiotensin levels and restrict vasoturbulence in Chinese Virus patients, while the receptor blocking could help to stop resulting inflammation and vascular impairment. “Nigellidine may slow down the vaso-fluctuations due to Angiotensin deregulations in Covid patients,” the paper further explains. “Angiotensin II-ACE2 binding (ACE-value -294.81) is more favorable than nigellidine-ACE2. Conversely, nigellidine-ACE1 binding-energy / Ki is lower than nigellidine-ACE2 values indicating a balanced-state between constriction-dilatation.” Nigellidine also binds to the viral spike proteins, which when taken by Chinese Virus patients, and especially those who fall in the elderly category, could greatly reduce their risk of suffering complications or death. Nigellidine impairs SARS-CoV-2 infection, “cytokine storm” through numerous mechanisms In a related study that was published last year in the journal Europe PMC, researchers learned that nigellidine inhibits the Chinese Virus infection in several other ways. It was discovered early on in the “pandemic” that many of those who tested “positive” for the virus were suffering associated “cytokine storms,” in which their immune systems were over-responding and causing more damage, or even death. Nigellidine was then studied and discovered to possess certain properties that inhibit cytokine storms, as well as impede the SARS CoV-2 virus from causing infection. It is also hepato- and reno-protective, meaning it protects against liver damage. Beyond this, nigellidine was determined to possess unique immunomodulatory and anti-inflammatory characteristics, as well as antioxidant potential strong enough to inhibit important proteins associated with the Chinese Virus. In their quest to uncover possible “drug” candidates to protect patients against hyper-inflammation and other associated problems, the researchers learned that nigellidine – and more than likely other black seed constituents – helps tremendously with preventing negative side effects. Along with nigellicine, nigellidine is found in the seed coat of Nigella sativa. Both of these constituents in their sulfated forms are extremely bioavailable, and along with thymoquinone and dithymoquinone, two other black seed components, they show strong antioxidant, antibacterial, anti-hypertensive, anti-inflammatory and immunomodulatory effects. Black seed extracts have been shown in other experiments to decrease oxidative stress, effectively lowering the risk of inflammation-related diseases. We now know that this includes the Wuhan coronavirus (Covid-19). Black seed is also recognized as a metabolic protector, helping to improve lipid and blood sugar levels. “Most importantly, in SARS CoV-2 infection ACE-2 mediated impairment of aldosterone system may be repaired by,” the study further explains, providing relevant information to the current “pandemic.” “Vasorelaxant and anti-hypertensive function of [black seed] helps in the modulation of renin angiotensin system (RAS) or the diuretic activity, which is one of the major targets of COVID. It might have great protective role during post infective secondary disorder of the peripheral vasculature namely cardiac and renal systems. In most of the instances patients die due to this organ dysfunction/failure in COVID-19 infection.” By quelling inflammation, black seed could save lives from covid Laboratory studies have found that intake of Nigella sativa significantly improves the parameters for hyperglycemia and diabetes control, as well as glycated hemoglobin and insulin resistance. Based on this, experts believe that nigellidine specifically could play an important role in fighting the Chinese Virus by “docking” to the proteins and inflammatory molecules that can cause a cytokine storm – mainly TNF-? receptors such as TNFR1, TNFR2 and IL1R. “In the experimental rat model the source of this drug Nigella sativa; black cumin seed extracts were tested for its role on antioxidant, hepatic and renal status,” the paper states. “This work will help in the urgent therapeutic intervention against COVID-19 global pandemic.” “In the current study, we have decisively shown by molecular modeling that nigellidine can bind in the active sites of several important proteins of SARS CoV 2, several host receptors specific for SARS CoV-2 induced inflammatory markers IL1, IL6, TNF-?. Moreover, the extract from black cumin seed has been shown in experimental rat to be highly antioxidative, hepato- and reno-protective. Further studies are necessary to verify the potential effects of nigellidine in in vivo laboratory experimental animal model.”   Vitamin D supplementation improves recovery time of children with pneumonia at pediatric hospital Cairo University (Egypt), July 20, 2021 According to news reporting originating from Cairo, Egypt, by NewsRx correspondents, research stated, “Despite the well-recognized effect of vitamin D in metabolism and homeostasis, there is now growing interest in its probable association with pneumonia. This study aims to supply vitamin D3 (Cholecalciferol) (100,000 IU) to pneumonic children to minimize the duration of illness and improve their outcome.” Our news editors obtained a quote from the research from Cairo University, “A double-blinded, randomized, placebo-controlled trial was conducted in a Pediatric Cairo University affiliated hospital. An intervention arm (93 children) and a control arm (98 children), who had pneumonia with an insufficient or deficient level of vitamin D and whose parental permission was obtained, were enrolled in the trial. All children were treated with antibiotics according to WHO guidelines. Children were given a single injection of 1 mL of 100,000 IU of vitamin D3 or placebo. Clinical data were recorded every eight hours for all children. Outcomes were assessed 7 days after vitamin D injection. The primary outcome variable was the change in serum level of 25(OH)D, while the secondary outcomes were the medical state of the assigned cases (improvement or death) and duration between enrollment and hospital discharge for improved cases. In the supplementation group, the percentage of patients who suffered either deficient (38.7%) or insufficient levels (61.3%) of 25 (OH)D at day one had significantly decreased in the seventh day to (11.8%) and (52.7%), respectively. Kaplan--Meier plots highlighted that the median time to recover of the placebo group was significantly longer than that of the supplementation group (Log Rank P value < .001). VDD was detected in pediatric critical care children.” According to the news editors, the research concluded: “In pneumonic children with high VDD, it is illustrated that Vitamin D supplementation is accompanied by lowered mortality risk and pSOFA scores, reduced time to recover, and improved PaO2/FiO(2).”   Physical activity could combat fatigue, cognitive decline in cancer survivors University of Illinois, July 26, 2021 A new study indicates that cancer patients and survivors have a ready weapon against fatigue and "chemo brain": a brisk walk. Researchers at the University of Illinois, along with collaborators at Digital Artefacts in Iowa City, Iowa, and Northeastern University in Boston, looked at the association between physical activity, fatigue and performance on cognitive tasks in nearly 300 breast cancer survivors. "The data suggest that being more physically active could reduce two of the more commonly reported symptoms in breast cancer survivors: fatigue and cognitive impairment," said study leader Edward McAuley, a professor of kinesiology and community health at Illinois. "Most people think, 'If I exercise, I'll become tired.' In our study, exercise actually was associated with reduced fatigue, which in turn was associated with better cognitive function." Cognitive impairment, such as memory problems or shortened attention spans, is a common complaint among cancer patients and survivors, and is thought to be similar to decline due to aging. Past Illinois research has explored the effect of physical fitness on age-related cognitive decline, so the researchers wondered whether cancer survivors would respond similarly to exercise. "Other studies of cancer survivors have relied on small samples of cancer survivors, and used self-reporting measures of physical activity and cognitive function, which can be very biased," said postdoctoral researcher Diane Ehlers, the first author of the study, which is published in the journal Breast Cancer Research and Treatment. "What makes our study novel is that we had objective measures for both physical activity and cognitive performance, and a nationwide sample of breast cancer survivors." The researchers worked with Digital Artefacts -- developer of the commercial neuroscience app BrainBaseline - to create an iPad app tailored to this study. The app included questionnaires and activities designed to measure attention, memory and multitasking skills. The researchers also sent each participant an accelerometer to track daily physical activity. "We found that higher levels of daily moderate-to-vigorous physical activity were associated with better performance on the cognitive tasks measuring attention, memory and multitasking," Ehlers said. "What was notable was that physical activity's effect on cognitive performance was mediated by fatigue. This provides evidence that physical activity interventions targeting fatigue in cancer patients and survivors might provide promising models for improving cognitive function as well." Next, the researchers plan to conduct further studies to establish causation and further explore the pathways of how physical exercise improves cognitive performance. They are working with Digital Artefacts to conduct an iPhone-based study and focusing on diverse populations of breast cancer survivors. "The message for cancer patients and survivors is, get active!" Ehlers said. "Even if it's 10-minute bouts of brisk walking. It's not a magical cure-all, but we've seen many benefits of physical activity for cancer patients and survivors."   Cannabidiol promotes oral ulcer healing by inactivating CMPK2-mediated NLRP3 inflammasome Sichuan University (China), July 26, 2021 Xingying Qi, West China Hospital of Stomatology, Sichuan University, Chengdu, China, presented the oral session "Cannabidiol Promotes Oral Ulcer Healing by Inactivating CMPK2-Mediated NLRP3 Inflammasome" at the virtual 99th General Session & Exhibition of the International Association for Dental Research (IADR), held in conjunction with the 50th Annual Meeting of the American Association for Dental Research (AADR) and the 45th Annual Meeting of the Canadian Association for Dental Research (CADR), on July 21-24, 2021. The oral ulcer is a common oral inflammatory lesion with severe pain but little effective treatment is currently available. Cannabidiol (CBD) is recently emerging as a therapeutic agent for inflammatory diseases. However, the underlying mechanisms are not fully elucidated. Qi and colleagues sought to investigate whether and how CBD could play a therapeutic role in the oral ulcer. Oral ulcer models were performed in the tongue of C57BL/6 mice by acid etching or mechanical trauma, followed by CBD local administration. Samples were harvested for macroscopic and histological evaluation. CBD oral spray on acid- or trauma-induced oral ulcers on mice tongues inhibited inflammation, relieved pain and accelerated lesions closure in a dose-dependent manner. The results show that CBD accelerates oral ulcer healing by inhibiting CMPK2-mediated NLRP3 inflammasome activation and pyroptosis, which is mediated mostly by PPARγ in nucleus and partially by CB1 in plasma membrane. This data may shed light on the development of new therapeutic strategies for oral ulcers.   Algal solution: Could Spirulina modify the microbiome to protect against age-related damage? Louvain Drug Research Institute (Belgium), July 25 2021 Spirulina might help protect against age-related liver inflammation by modifying pathways in the microbiome, say researchers. Consumption of spirulina could help protect against hepatic inflammation in the elderly, according to the new animal research published in Nutrients. Belgian researchers carried out tests on mice, which suggest that the algae Spirulina has an impact on the gut microbiota, which in turn activates the immune system in the gut and improves inflammation in the liver that is associated with ageing. Led by senior author Professor Nathalie Delzenne from the Louvain Drug Research Institute in Belgium, the team said oral feeding of Spirulina was found to modulates several immunological functions involving, among others, the TLR4 pathway in old mice. “The fact that its oral consumption can influence both gut immunity and systemic sites, such as the liver, suggests that its immune action is not confined to the gut immune system,” wrote the team – who said the findings open the way to new therapeutic tools “in the management of immune alterations in aging, based on gut microbe-host interactions.” Furthermore, they suggested that improvement of the homeostasis in the gut ecosystem ‘could be essential' during the aging process, “and, in this perspective, dietary manipulation of the gut microbiota of the elderly with Spirulina, may represent a tool for preserving a healthy gastrointestinal microbial community in addition to its beneficial effects on immune function.” Study details Delzenne and colleagues noted that while the possible cardiovascular and immune support benefits of Spirulina have been fairly widely reported, the new study brings a fresh approach by testing whether the effects could be related to a modulation of gut micrbiota. In the trial, young mice aged three months were fed a standard diet, while older mice aged 24 months were fed a standard diet either with or without 5% Spirulina for six weeks. Upton supplementation with Spirulina, the team reported several changes to gut microbiota composition, including an increase in Roseburia and Lactobacillus populations. “Interestingly, parameters related to the innate immunity are upregulated in the small intestine of Spirulina-treated mice,” said the team. “Furthermore, the supplementation with Spirulina reduces several hepatic inflammatory and oxidative stress markers that are upregulated in old mice versus young mice.” Expression of several genetic and biochemical markers of inflammation and immunity were altered by supplementation with Spirulina, said the team. In particular, the transcription factor Foxp3 – involved in the differentiation of T cells into regulatory T cells (Tregs) – and MCP1 were increased due to Spirulina supplementation in old mice. Old mice that consumed Spirulina also showed activation of several immune parameters including Foxp3 in the ileum – suggesting an improvement of the gut immune function upon Spirulina treatment in this segment, said the Belgian researchers. Furthermore, Spirulina supplementation upregulated both TLR2 and TLR4 expression in the ileum of aged mice. “In accordance with these results, a solution of Spirulina (5%) exhibited a TLR4 agonist activity similar to the one reached in old-SP mice, suggesting a direct effect of the Spirulina, itself, on the TLR4 pathway,” they added. Microbiome mechanisms While the positive effect of Spirulina on the microbiome and liver inflammation is clear, the team noted that the mechanism by which the algae could change the composition of the intestinal microbiota remains unanswered. One possible mechanism could be the presence of antimicrobial substances produced by Spirulina, they said. “On the other hand, antimicrobial peptides (AMPs) could be mediators of the nutritional modulation of the gut microbiota.” “In the present study, RegIIIγ and Pla2g2 were increased by the supplementation with Spirulina, suggesting that the host contributes to the reduction and modification of the microbial community by modulating the production of specific AMPs,” they added.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.16.341644v1?rss=1 Authors: Lantoine, J., Proces, A., Villers, A., Halliez, S., Buee, L., Ris, L., Gabriele, S. Abstract: Traumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide. Despite its high prevalence and extensive efforts to develop neuroprotective therapies, effective treatments for TBI are still limited. Among important neuronal damages, TBI induces structural and functional alterations of astrocytes, the most abundant cell type in the brain. Injured astrocytes respond in diverse mechanisms that result in reactive astrogliosis and are involved in the physiopathological mechanisms of TBI in an extensive and sophisticated manner. The establishment of effective neuroprotective treatments for TBI requires to better understand the complex biochemical interactions between activated astrocytes and neurons that contribute to the secondary injury. To address this challenge, we studied in vitro the role of mechanically injured astrocytes on the growth and synaptic connections of cortical neuronal networks of controlled architectures grown on well-defined protein micropatterns. Astrocytes were cultivated on elastic membranes and mechanically activated by stretching cycles. The culture media of healthy or activated astrocytes was then introduced on neuronal networks. We analyzed the neuronal viability, the neurite growth and the synaptic density of neuronal networks to understand the role of the inflammatory molecules secreted by mechanically activated astrocytes. Furthermore, we cultivated neuronal networks during 13 days with different doses of TNF- in order to decipher its individual contribution among the other cytokines. Here we show that the ratio of tubulin to synapsin area was significantly higher in neuronal networks treated with either 4 or 2 doses of TNF-, suggesting that TNF- can promote the tubulin polymerization process. Assuming that TNF- can bind to either TNFR1 or TNFR2 receptors, which lead respectively to the cell survival or the cell apoptosis, we studied the modulation of the both TNF- receptors in response to the medium of mechanically activated astrocytes and different doses of TNF-. Our findings indicate that the amount of both receptors increases with the maturation of the network. In addition, we observed a significant modulation of the amount of TNFR1 and TNFR2 in response to the media of injured astrocytes that leads to a large imbalance between both receptors, suggesting an important role for TNF-signaling in the physiopathological mechanisms of TBI. Copy rights belong to original authors. Visit the link for more info

Die von intrinsichen renalen Zellen und infiltrierenden Leukozyten exprimierten Zytokine sind zentrale Vermittler entzündlicher Nierenerkrankungen. Tumor Nekrose Faktor-α (TNF) ist ein solches proinflamatorisches Zytokin, das in der glomerulären Entzündungsreaktion involviert ist. Die funktionelle Rolle von TNF wurde in Tiermodellen der Glomerulonephritis belegt. Die biologischen Effekte von TNF werden durch die beiden funktionell eigenständigen TNF-Rezeptoren TNFR1 (CD120a) und TNFR2 (CD120b) vermittelt. Neuere Daten zeigen, dass in Modellen einer Immunkomplex-Glomerulonephritis wie der nephrotoxische Serumnephritis die beiden TNF-Rezeptoren in vivo unterschiedliche Funktionen bei der glomerulären Entzündung vermitteln können. Der vorliegenden Arbeit liegt die Hypothese zugrunde, dass Tnfr1 und Tnfr2 unterschiedliche inflammatorische TNF-Effekte in Glomeruli vermitteln. Daher war das Ziel dieser Arbeit, Expression und Funktion der beiden TNF-Rezeptoren in Maus-Glomeruli zu charakterisieren und die Tnfr-abhängig exprimierten Entzündungsmediatoren in Maus-Glomeruli zu identifizieren. Aufbauend auf den Ergebnissen dieser Arbeit könnten selektive, Tnfr-spezifische Therapien zur Hemmung der glomerulären Entzündungsreaktion entwickelt werden. Zudem wurde in dieser Arbeit die funktionelle Rolle der beiden TNF-Rezeptoren im MRL/lpr-Mausmodell der Lupusnephritis untersucht, um eine selektive Tnfr-Blockade als mögliche Therapiestrategie zu charakterisieren. Hierfür war eine Rückkreuzung von Tnfr1- und Tnfr2-defizienten C57BL/6J-Mäusen in den MRL/lpr-Hintergrund erforderlich. Um TNF-Rezeptor-1- und 2-vermittelte inflammatorische Signalwege in Glomeruli zu identifizieren wurde die Expression und die Funktion der beiden TNF-Rezeptoren in Mausnieren, in isolierten Glomeruli ex vivo und murinen glomerulären Endothel- und Mesangialzellen in vitro untersucht. In normaler Mausniere konnte eine Tnfr1- und Tnfr2-mRNA- und Protein-Expressionen präferentiell in Glomeruli im Vergleich zum Tubulointerstitium nachgewiesen werden. Die Expression von beiden TNF-Rezeptoren und die TNF-induzierte Induktion von Tnfr2-mRNA-Expression wurde auch in vitro sowohl in murinen glomerulären Endothel- als auch Mesangialzelllinien bestätigt. Die prominente glomeruläre TNF-Rezeptor-Expression korrelierte mit einer konstitutiven glomerulären mRNA-Expression von Adhäsionsmolekülen wie Icam-1, Vcam-1, E- und P-Selektin und Chemokinen wie Ccl2, Ccl3 und Ccl5. Eine intraperitoneale TNF-Injektion induzierte die Expression dieser Mediatoren präferentiell in Glomeruli. Diese in vivo TNF-Exposition führte zu einer raschen glomerulären Akkumulation von Leukozyten einschließlich Neutrophilen und mononukleären Phagozyten, die mittels einer kompartimentspezifischer Durchflußzytometrie analysiert wurden. Um Tnfr-abhängige inflammatorische Effekte in intrinsischen glomerulären Zellen unabhängig von infiltrierenden Leukozyten zu untersuchen, wurde eine Microarray-Gene-Expressionsanalyse an intakten Glomeruli durchgeführt, die aus Wildtyp und Tnfr-defizienten Mäusen isoliert und anschließend mit TNF ex vivo stimuliert wurden. Die meisten TNF-Effekte wurden ausschließlich durch Tnfr1 vermittelt, unter anderem die induzierte mRNA-Expression von Adhäsionsmolekülen, proinflammatorischen Chemokinen, Komplement-Faktoren und proapoptotischen Molekülen. Im Gegensatz dazu fanden wir nur vier Tnfr2-abhängig exprimierte Gene, einschließlich einer kleinen GTPase der Rab-Familie (Rab6b). Diese Ergebnisse wurden durch quantitative RT-PCR-Analysen von TNF-stimulierten Glomeruli und primären Mesangialzellen bestätigt. Weitere Untersuchungen zeigten allerdings auch einen Beitrag von Tnfr2 bei der gesteigerten glomerulären Expression von Adhäsionsmolekülen und Chemokine nach Stimulation mit niedrigen TNF-Konzentrationen auf. Im Gegensatz zur Wildtyp-Kontrolle fehlte in TNF-stimulierten Tnfr1-defizienten Glomeruli die Sekretion verschiedener proinflammatorischer Chemokine beinahe vollständig. Interessanterweise war die Proteinexpression auch in Tnfr2-defizienten Glomeruli signifikant herunterreguliert. Folglich sind die meisten inflammatorischen TNF-Effekte in Glomeruli via Tnfr1 durch die induzierte Expression von proinfammatorischen Mediatoren wie Adhäsionsmolekülen und Chemokinen vermittelt. Darüber hinaus dürfte Tnfr2 zu dieser inflammatorischen Antwort beitragen, wenn Glomeruli niedrigen TNF-Konzentrationen ausgesetzt sind. Ferner scheint Tnfr2 posttranskriptionell die Chemokinsekretion in Glomeruli nach einer TNF-Exposition zu beeinflussen, möglicherweise durch die Tnfr2-abhängig exprimierte Rab GTPase Rab6b, die am intrazellulären Transport und der Sekretion von inflammatorischen Molekulen beteiligt sein könnte. In Bezug auf Tnfr-spezifische, anti-inflammatorische Therapien weisen die hier präsentierten Ergebnisse somit darauf hin, dass eine selektive Tnfr1-Blockade eine glomeruläre, insbesondere durch Granulozyten und Makrophagen vermittelte Entzündung verbessern könnte, möglicherweise bei geringer Hemmung immunregulatorischer und antimikrobieller Funktionen von TNF, die redundant durch Tnfr2 vermittelt werden könnten. Dagegen erscheint aufgrund der erhobenen Daten im MRL/lpr-Mausmodell eine Blockade von TNF oder beider Rezeptoren bei der Lupusnephritis, in der glomeruläre Neutrophileninfiltrate keine entzündliche Rolle spielen, weniger erfolgversprechend. Gleichzeitig weisen die vorliegenden Ergebnisse auf eine immunsuppressive, die systemische Immunreaktivität beim SLE begrenzende Funktion von Tnfr2 hin.

Introduction: Elevated serum levels of the proinflammatory cytokine tumor necrosis factor alpha (TNF alpha) correlate with an increased risk for atherothrombotic events and TNF alpha is known to induce prothrombotic molecules in endothelial cells. Based on the preexisting evidence for the impact of TNF alpha in the pathogenesis of autoimmune disorders and their known association with an acquired hypercoagulability, we investigated the effects of TNF alpha and the role of the TNF receptor subtypes TNFR1 and TNFR2 for arteriolar thrombosis in vivo. Methods: Arteriolar thrombosis and platelet-rolling in vivo were investigated in wildtype, TNFR1-/-, TNFR2-/- and TNFR1-/R2-/-C57BL/6 mice using intravital microscopy in the dorsal skinfold chamber microcirculation model. In vitro, expression of prothrombotic molecules was assessed in human endothelial cells by real-time PCR and flow cytometry. Results: In wildtype mice, stimulation with TNF alpha significantly accelerated thrombotic vessel occlusion in vivo upon ferric chloride injury. Arteriolar thrombosis was much more pronounced in TNFR1-/- animals, where TNF alpha additionally led to increased platelet-endothelium-interaction. TNF alpha dependent prothrombotic effects were not observed in TNFR2-/- and TNFR1-/R2- mice. In vitro, stimulation of human platelet rich plasma with TNF alpha did not influence aggregation properties. In human endothelial cells, TNF alpha induced superoxide production, p-selectin, tissue factor and PAI-1, and suppressed thrombomodulin, resulting in an accelerated endothelial dependent blood clotting in vitro. Additionally, TNF alpha caused the release of soluble mediators by endothelial cells which induced prothrombotic and suppressed anticoagulant genes comparable to direct TNF alpha effects. Conclusions: TNF alpha accelerates thrombus formation in an in vivo model of arteriolar thrombosis. Its prothrombotic effects in vivo require TNFR2 and are partly compensated by TNFR1. In vitro studies indicate endothelial mechanisms to be responsible for prothrombotic TNF alpha effects. Our results support a more selective therapeutic approach in anticytokine therapy favouring TNFR2 specific antagonists.

Die Familie der Sorting Nexine (SNX) umfasst 33 bekannte Mitglieder, jedoch ist der Funktionsmechanismus vieler Sorting Nexine bislang nicht aufgeklärt. Auf der Suche neuer Modulatoren der βAPP-Proteolyse konnte im Rahmen eines Expressionsklonierungs-Screens (Schobel et al., 2006) ein bislang nicht beschriebenes Protein, Sorting Nexin 33 (SNX33), als Aktivator der βAPP-Proteolyse identifiziert werden. SNX33 ist ein phosphoryliertes Protein, das ubiquitär exprimiert wird und zudem eine hohe Homologie zu den Proteinen SNX9 und SNX18 aufweist. SNX33 ist im Zytosol lokalisiert, kann jedoch auch Membran-assoziiert vorliegen. Es konnte gezeigt werden, dass Überexpression von SNX33 zu einer Inhibition Dynamin-abhängiger Endozytose und in Folge dessen zu einer etwa 50% -igen Reduktion der βAPP-Endozytose führt. Die von SNX33 induzierte Endozytosehemmung wird durch die SH3-Domäne des Proteins vermittelt. Im Rahmen dieser Doktorarbeit durchgeführte Koimmunpräzipitationsstudien zeigten, dass SNX33 mittels seiner SH3-Domäne mit Dynamin interagiert und auf diese Weise möglicherweise dessen Funktion moduliert. In Übereinstimmung mit den durchgeführten Zellkultur-Experimenten führte eine Überexpression von SNX33 im Modellorganismus Caenorhabditis elegans ebenfalls zu einem Dynamin-Funktionsverlust. Da SNX33 Expression zu einer generellen Inhibition Dynamin-abhängiger Endozytose führt, handelt es sich dabei nicht um einen spezifischen βAPP-Modulator. Konsequenz einer reduzierten βAPP-Internalisierung ist eine starke Zunahme der neurotrophen sAPPα-Bildung sowie - je nach verwendeter Zelllinie - ein leichter Anstieg bzw. eine geringe Reduktion der pathogenen sAPPβ-Generierung. Es konnte gezeigt werden, dass Überexpression der homologen Proteine SNX9 und SNX18 ebenfalls zu einer Zunahme der βAPP-Spaltung führt. Es handelt sich also um einen Effekt, der von der ganzen Sorting Nexin-Subgruppe (SNX33/SNX9/SNX18) vermittelt wird. Diese Beobachtung legt die Vermutung nahe, dass diese Funktion innerhalb dieser Subgruppe konserviert ist. Transfektion von SNX1 führte zu keiner Änderung der βAPP-Proteolyse, was bedeutet, dass dieser Effekt nicht von der gesamten Sorting Nexin-Familie vermittelt wird. Interessanterweise ist die Spaltung von βAPP besonders sensitiv bezüglich einer veränderten Endozytose-Rate, da die Proteolyse der Transmembranproteine L-Selektin und des Tumornekrosisfaktor-Rezeptors 2 (TNFR2) unter SNX33 Überexpressionsbedingungen nicht signifikant verändert war. Ein siRNA-vermittelter Knock-Down von SNX33 führte zu keiner generellen Endozytoseinhibition in HEK293 Zellen, es konnte keine veränderte βAPP-Endozytoserate beobachtet werden. Die Bildung von sAPPα- und sAPPβ war in Folge dessen unverändert. Auch ein lst-4/SNX33-Knock-Down in C. elegans führte überraschenderweise zu keiner Inhibition der Dynamin-Funktion, äußerte sich jedoch in einer Fehlfunktion der Insulin-Signaltransduktion. SNX33-Knock-Down in humanen Zellen brachte keine nachweisbare Beeinträchtigung des Insulinsignalweges mit sich, jedoch besteht die Möglichkeit, dass die Homologen SNX9 und SNX18 einen Verlust von SNX33 kompensieren können. Dabei gilt zu beachten, dass eine Funktionsübernahme durch homologe Proteine in C. elegans nicht möglich ist, da dieser Organismus nur ein einziges homologes Protein der SNX33/SNX9/SNX18-Subgruppe besitzt. Im Rahmen dieser Doktorarbeit präsentierten sowie diskutierten Daten zeigen, dass SNX33 in unterschiedliche zellulärer Prozesse involviert ist. SNX33 ist ein neu identifizierter Modulator der Zelle, der für zentrale Signalwege und Vorgänge, wie zum Beispiel der Insulinrezeptor-Signaltransduktion und Endozytose, von Bedeutung ist. Im Gegensatz zum Modellorganismus C. elegans kann im humanen Zellkultursystem ein durch siRNA induzierter Funktionsverlust von SNX33 durch die homologen Proteine SNX9 und SNX18 kompensiert werden.

The study is subdivided into two different parts: the first part deals with the development of a method to gain uterus milk in vivo during the preimplantation periode in cattle for the investigation of regulatory factors. The second part investigates different proteases in bovine follicles 20 hours after GnRH (Gonadotropin releasing hormone) injection (shortly bevor ovulation) for comparable as well as in the corpus luteum (CL) during oestrous cycle and induced luteolysis. In addition apoptotic as well as anti-apoptotic factors were evaluated in the CL during oestrous cycle and induced luteolysis. For the development of a method for gaining uterus milk in vivo during the first 24 days of gravidity in cattle, nine heifers were cycle synchronised using the Ovsynch method and artificially inseminated. Before flushing an epiduralanaesthesia was given and both uterus horns were flushed with 13ml 0.9% NaCl using a balloon embryo transfer catheter at day 5, 7, 12, 17 and 24 of gravidity. The catheter was placed 1cm cranial to the bifurcatio uteri in both horns. It was possible to retrive between 3ml and 13ml of the used flushing fluid. The uterus milk from the ipsilateral horn was inspected for an embryo and an EDTA-stabilisator was given to the uterus milk of both horns. An infection of the uterus occured in three heifers after the second and in five heifers after the third flushing. In one heifer no infection was found. Between day 17 and day 24 all heifers showed clear signs of oestrus. It was possible to detect progesterone, oestradiol-17-beta, PGF2alpha and VEGF via enzyme immunoassay (EIA) and radio immunoassay (RIA), respectively. Because of the occurred infection no statistic analysis was made. But it could be seen that the level of progesterone ranged between

Zelllinienentscheidungen in der Hämatopoese werden eingeleitet und sind abhängig von der Aktivierung von Transkriptionsfaktoren. Es ist allerdings bisher nicht geklärt, ob die initiale Aktivierung früher hämatopoetischer Transkriptionsfaktoren durch bisher unbekannte extrinsische Signale oder durch ein zellinternes autonomes Programm erfolgt. Notch Rezeptoren sind evolutionär hoch konservierte Transmembranrezeptoren, die an der Regulation von Zelllinienentscheidungen, Differenzierung und Proliferation in verschiedenen embryonalen und adulten Geweben beteiligt sind. Die Expression von Notch Rezeptoren auf hämatopoetischen Zellen und der dazugehörigen Liganden wie Jagged1 auf Knochenmarksstromazellen deutet auf eine Bedeutung von Notch in der Regulation der Hämatopoese. Vor Kurzem konnte die Induktion der myeloischen Differenzierung von hämatopoetischen Stamm- und Vorläuferzellen durch Notch nachgewiesen werden. Die molekularen Mechanismen dieses Prozesses sind dabei noch völlig unklar. Darin Einblick zu gewinnen wurde im Rahmen dieser Doktorarbeit durch die Suche nach Zielgenen von Notch in der Myelopoese versucht. Dazu wurden die multipotente myeloische Stammzelllinie FDCP-mix und die granulozytäre Vorläuferzelllinie 32D mit einem durch Tamoxifen aktivierbarem Notch als Zellsysteme gewählt. In dieser Arbeit durchgeführte zytokingesteuerte Differenzierungskinetiken konnten bestätigen, dass die verwendeten FDCP-mix Zellen während ihrer Differenzierung in reife Granulozyten, Makrophagen und Erythrozyten auf RNA-Ebene charakteristische Regulationen von wichtigen myeloischen Transkriptionsfaktoren, Zytokinrezeptoren sowie differenzierungsabhängigen Funktionsproteinen durchlaufen. Sie stellen somit ein optimales Zellsystem zur Analyse von Notch-Zielgenen in der Myelopoese dar. Mit dem Tamoxifen induzierbaren System der Notchaktivierung wurden zuerst bekannte, zentrale Regulationsfaktoren der Myelopoese auf eine Induktion durch Notch im Northern Blot untersucht. Dabei stellte sich als entscheidendes Ergebnis sowohl in 32D als auch FDCP-mix Zellen die direkte, spezifische Induktion des frühen myeloischen Transkriptionsfaktors PU.1 heraus, von dem bekannt ist, dass er myeloische Differenzierung initiiert. Außerdem kam es zu einer indirekten Hochregulation des M-CSF-Rezeptors, der als wichtiges Zielgen von PU.1 bekannt ist. Diese Ergebnisse zeigen, dass ein extrinsisches Signal, im Organismus durch den Jagged / Notch Signalweg vermittelt, zu einer Aktivierung eines frühen hämatopoetischen Transkriptionsfaktors führt, welcher Zelllinienentscheidungen in der Hämatopoese bestimmt. In Zusammenschau mit den biologischen Wirkungen von Notch in der Hämatopoese weist dies darauf hin, dass extrinsische Mechanismen eine wichtige Rolle in der Regulation der Hämatopoese spielen dürften. Durch ein neu zu etablierendes cDNA-Filter (cDNA-Microarray) Screening-Verfahren konnten dann als weitere wichtige Zielgene von Notch in der Hämatopoese u.a. der Interferon Regulatory Factor-1 (IRF-1), der Interleukin1-Rezeptor-Antagonist (IL1RA), der Tumornekrosefaktor-Rezeptor 2 (TNFR2), sowie c-myc und myb identifiziert werden.