Podcasts about nf kappab

What are the biological mechanisms behind aging? In this special episode of The Thorne Podcast, Dr. Robert Rountree speaks at the Peptide World Congress, in which he reviews cellular signs of aging and different kinds of interventions that can slow down the aging process.  During this episode you'll learn about:  1. Dr. Robert Rountree's background [1:28]  2. What mechanisms drive the aging process? [2:38]  3. Biological age vs. chronological age [7:10]  4. “Inflamm-aging,” blue zones, C-reactive protein (CRP), and NF-KappaB [9:18]  5. How does eating less contribute to longevity? [13:49]  6. Mitochondria's role in aging [16:27]  7. Nutrients that support aging [21:01]  8. What is NAD and how does it affect aging? [24:24]  9. How to extend the health span [28:04]  Resources to topics mentioned in this episode:  What You Should Know About Healthy Aging  6 Steps to Improving The Aging Process  What's Your Actual Age? Chronological vs. Biological Age  This Specific Form of Exercise May Slow Aging  The Deep Dive: An Exploration of Blue Zones and Human Longevity  What is CRP?  Six Ways You Can Benefit From Supplementing with Nicotinamide Riboside (NR)  It's All About NAD  The Connection Between Aging and a Reduced Level of NAD+ in the Body  From the podcast archives: Episode 27: Measures to Support Your Mitochondrial Health  Products mentioned in this episode: Curcumin Phytosome, Berberine, CoQ10, Quercetin Phytosome, Green Tea Phytosome, Nicotinamide Riboside  Subscribe to More Content   Subscribe to the show wherever you listen to podcasts so you never miss an episode. You can also learn more about the topics in the episode by checking out the latest news, videos, and stories on Thorne's Take 5 Daily blog. 

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.14.532132v1?rss=1 Authors: Downton, P., Bagnall, J. S., England, H., Spiller, D. G., Humphreys, N., Jackson, D. A., Paszek, P., White, M. R. H., Adamson, A. D. Abstract: Cells respond to inflammatory stimuli such as cytokines by activation of the nuclear factor-kappaB (NF-kappaB) signalling pathway, resulting in oscillatory translocation of the transcription factor p65 between nucleus and cytoplasm to mediate immune response. We investigate the relationship between p65 and inhibitor-kappa Balpha (IkappaBalpha) protein levels and dynamic properties of the system, and how this interaction impacts on the expression of key inflammatory genes. Using bacterial artificial chromosomes, we developed new cell models of kappaBalpha-eGFP protein overexpression in a native genomic context. We find that cells with high levels of the negative regulator IkappaBalpha remain responsive to inflammatory stimuli and maintain dynamics for both p65 and kappaBalpha. In contrast, canonical target gene expression is dramatically reduced by overexpression of IkappaBalpha, but can be partially rescued by overexpression of p65. Treatment with leptomycin B to promote nuclear accumulation of IkappaBalpha also suppresses canonical target gene expression, suggesting a mechanism in which nuclear IkappaBalpha accumulation prevents productive p65 interaction with promoter binding sites. This causes reduced target promoter binding and gene transcription, which we validate by chromatin immune precipitation and in primary cells. Overall, we show how inflammatory gene transcription is modulated by the expression levels of both IkappaBalpha and p65, and that transcription can be partially decoupled from p65 protein dynamics. This results in an anti-inflammatory effect on transcription, demonstrating a broad mechanism to modulate the strength of inflammatory response. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.03.530727v1?rss=1 Authors: Chauhan, C., Kraemer, A., Knapp, S., Windheim, M., Kotlyarov, A., Menon, M. B., Gaestel, M. Abstract: Receptor-interacting protein kinases (RIPK) -1 and -3 are master regulators of cell fate decisions in response to diverse stimuli and are subjected to multiple checkpoint controls. Earlier studies have established the presence of distinct IKK1/2 and p38/MK2-dependent checkpoints which suppress RIPK1 activation by directly phosphorylating it at different residues. In the present study, we investigated TNF-induced death in MAPK-activated protein kinase 2 (MK2)-deficient cells and show that MK2-deficiency or inactivation predominantly results in necroptotic cell death, even in the absence of caspase inhibition. While MK2-deficient cells can be rescued from necroptosis by RIPK1 inhibitors, RIPK3 inhibition seems to revert the process to apoptosis. To understand the mechanism of this necroptosis switch, we screened a 149-compound kinase inhibitor library for compounds which preferentially sensitize MK2-deficient MEFs to TNF-induced cell death. The most potent inhibitor identified was 5-Iodotubericidin, an adenosine analogue acting as adenosine kinase and protein kinase inhibitor. 5-ITu also potentiated LPS-induced necroptosis when combined with MK2 inhibition in RAW264.7 macrophages. Further mechanistic studies revealed that 5-Iodotubericidin induces RIPK1-dependent necroptosis in the absence of MK2 activity by suppressing IKK signaling. The identification of this role for the multitarget kinase inhibitor 5-ITu in TNF-, LPS- and chemotherapeutics-induced necroptosis will have potential implications in RIPK1-targeted therapies. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.03.530908v1?rss=1 Authors: Prichard, A., Garza, K. M., Shridhar, A., He, C., Bitfaran, S., Wang, Y., Goodson, M. C., Jaeger, D., Wood, L. B., Singer, A. C. Abstract: Microglia, the brain's primary immune cells, transform in response to changes in sensory or neural activity, like sensory deprivation. However, little is known about how specific frequencies of neural activity, or brain rhythms, impact microglia and cytokine signaling. Using visual noninvasive flickering sensory stimulation (flicker) to induce electrical neural activity at different frequencies, 40Hz, within the gamma band and 20Hz, within the beta band, we discovered these brain rhythms differentially affect microglial morphology and cytokine expression in healthy animals. We found that flicker induced expression of certain cytokines, including IL-10 and M-CSF, that was independent of microglia. Because NFkappaB is activated by synaptic activity and regulates cytokines, we hypothesized this pathway plays a causal role in frequency-specific cytokine and microglial responses. Indeed, we found that after flicker, phospho-NFkappaB co-labeled with neurons more than microglia. Furthermore, inhibition of NFkappaB signaling by a small molecule inhibitor down-regulated flicker-induced cytokine expression and attenuated flicker-induced changes in microglia morphology. These results reveal a new mechanism through which brain rhythms affect brain function by altering microglia morphology and cytokines via NFkappaB. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

In this MEGAphone episode we will be shouting out one of the most informative people to follow on social media that I know about, he specializes in power lifting and biomechanics and injury prevention and physical therapy. His Instagram handle is @SquatUniversity and his name is Dr. Aaron Horschig. As a physical therapist & strength coach, Aaron helps athletes move better, decrease their aches & pains associated with training, and find their true athletic potential.Dr. Horschig wrote an extremely informative and also controversial article that I love and want to share. This information addresses a well known injury protocol… A protocol that I used when I was an athlete in high school in college. A protocol that I used with clients and family members of mine when they got injured… A protocol that I believed in whole heartedly and taught every chance I could. A protocol my college courses taught me, straight out of the text books. It was simple… when you get hurt… the solution is RICE. Rest, Ice, Compression, Elevation. We all knew RICE.   And it turns out… we were all wrong. References: Dr. Aaron Horschig IG: @SquatUniversitywww.squatuniversity.com Book: Rebuilding MiloArticle Citations:1.    Mirkin G, Hoffman M. The Sports Medicine Book. 1978. Little Brown & Co2.    Lu H, Huang D, Saederup N, et al. Macrophages recruited via CCR2 produce insulin-like growth factor-1 to repair acute skeletal muscle injury. FASEB J. 2011;25(1):358-69.3.    Summan M, Warren GL, Mercer RR, Chapman R, et al. Macrophages and skeletal muscle regeneration: a clodronate-containing liposome depletion study. Am J Physiol Regul Integr Comp Physiol. 2006;290(6):R1488-954.    Pelosi L, Giacinti C, Nardis C, Borsellino G, et al. (2007) Local expression of IGF-1 accelerates muscle regeneration by rapidly modulating inflammatory cytokines and chemokines. FASEB J. 21, 1393–14025.    Singh DP, Lonbani ZB, Woodruff MA, Parker JP, et al. Effects of topical icing on inflammation, angiogenesis, revascularization, and myofiber regeneration in skeletal muscle following contusion injury. Front Physiol. 2017;8:93.6.    Takagi R., Fujita N., Arakawa T., Kawada S., Ishii N., Miki A. (2011). Influence of icing on muscle regeneration after crush injury to skeletal muscles in rats. J. Appl. Physiol. 110, 382–388.7.    Tiidus PM. Alternative traetments for muscle injury: massage, cryotherapy, and hyperbaric oxygen. Current reviews in musculoskeletal medicine. 2015;8(2):162-78.    Reinl G. Iced! The illusionary treatment option. 2nd Edition. Gary Reinl. 2014.9.    Khoshnevis S, Kraik NK, Diller KR. Cold-induced vasoconstriction may persist long after cooling ends: an evaluation of multiple cryotherapy units. Knee Surg Sports Traumatol Arthrosc. 2015;23(9):2475-238310. Dirks ML, Wall BT, van Loon L CJ. Interventional strategies to combat muscle disuse atrophy in humans: focus on neuromuscular electoral stimulation and dietary protein. J Appl Physiol. 2018;125:850-86111. Raynor MC, Pietrobon R, Guller U, Higgins LD. Cryotherapy after ACL reconstruction: a meta-analysis. J Knee Surg. 2005;18(2):123-912. Spencer JD, Hayes KC, Alexander IJ. Knee joint effusion and quadriceps reflex inhibition in man. Arch Phys Rehabil. 1984;65:171-17713. Buckwalter JA, Grodzinsky AJ. Loading of healing bone, fibrous tissue, and muscle: implications for orthopaedic practice. J Am Acad Orthop Surg. 1999;7(5):291-9.14. Silveria EM, Rodrigues MF, Krause MS, et al. Acute exercise stimulates macrophage function: possible role of NF-kappaB pathways. Cell Biochem Funct. 2007;25(1):63-7315. Teixeira E, Duarte JA. Skeletal muscle loading changes its regenerative capacity. Sports Med.

February 2022 was full of abstracts using unique therapeutic approaches to target Alzheimer's disease. Cassi presents abstracts on both naturally-occurring and pharmaceutical compounds used to treat various neurodegenerative pathology and symptoms.  Sections in this episode:  Microbiome (1:55)  NF-kappaB signaling pathway (6:12)  Sexual dimorphism (11:34)  Naturally-occurring & pharmaceutical treatments (15:37)  -------------------------------------------------------------- To find the numbered bibliography with all the papers covered in this episode, click here, or use the link below:https://drive.google.com/file/d/1kMrWRHBkkRqSrR9XzuEFbfquLGbb26Qe/view?usp=sharingTo access the folder with ALL our bibliographies, follow this link (it will be updated as we publish episodes and process bibliographies), or use the link below:https://drive.google.com/drive/folders/1bzSzkY9ZHzzY8Xhzt0HZfZhRG1Gq_Si-?usp=sharingYou can also find all of our bibliographies on our website: www.amindr.com. --------------------------------------------------------------Follow-up on social media for more updates!Twitter: @AMiNDR_podcastInstagram: @AMiNDR.podcastFacebook:  AMiNDR  Youtube: AMiNDR PodcastLinkedIn: AMiNDR PodcastEmail: amindrpodcast@gmail.com  -------------------------------------------------------------- Please help us spread the word about AMiNDR to your friends, colleagues, and networks! And if you could leave us a rating and/or review on your streaming app of choice (Apple Podcasts, Spotify, or wherever you listen to the podcast), that would be greatly appreciated! It helps us a lot and we thank you in advance for leaving a review! Don't forget to subscribe to hear about new episodes as they come out too. Thank you to our sponsor, the Canadian Consortium of Neurodegeneration in Aging, or CCNA, for their financial support of this podcast. This helps us to stay on the air and bring you high quality episodes. You can find out more about the CCNA on their website: https://ccna-ccnv.ca/. Our team of volunteers works tirelessly each month to bring you every episode of AMiNDR. This episode was scripted and hosted by Cassi Friday, edited by Chihiro Abe, and reviewed by Sarah Louadi and Anusha Kamesh. The bibliography was made by Anjana Rajendrani and the wordcloud was created by Sarah Louadi (www.wordart.com). Big thanks to the sorting team for taking on the enormous task of sorting all of the Alzheimer's Disease papers into episodes each month. For February 2022, the sorters were Sarah Louadi, Christy Yu, Ben Cornish, Eden Dubchak, Vrishali Salian, Kira Tosefsky, and Elyn Rowe. Also, props to our management team, which includes Sarah Louadi, Ellen Koch, Naila Kuhlmann, Elyn Rowe, Anusha Kamesh, and Lara Onbasi for keeping everything running smoothly.Our music is from "Journey of a Neurotransmitter" by musician and fellow neuroscientist Anusha Kamesh; you can find the original piece and her other music on soundcloud under Anusha Kamesh or on her YouTube channel, AKMusic.   https://www.youtube.com/channel/UCMH7chrAdtCUZuGia16FR4w   -------------------------------------------------------------- If you are interested in joining the team, send us your CV by email. We are specifically looking for help with sorting abstracts by topic, abstract summaries and hosting, audio editing, creating bibliographies, and outreach/marketing. However, if you are interested in helping in other ways, don't hesitate to apply anyways.  --------------------------------------------------------------*About AMiNDR: *  Learn more about this project and the team behind it by listening to our first episode: "Welcome to AMiNDR!" 

Here we are 1 year in and we know a lot more than we did from our last official coverage in February. In this episode we cover updates on masks, disinfectants, and lockdowns, as well as new studies demonstrating lack of efficacy and serious concerns. We also unpack the stats on death toll noting this year there has been no increase in total death count when comparing to prior years sharing the work of John Hopins research demonstrating a reclassification of deaths vs. deaths caused by coronavirus. Beyond classification of deaths, we cover the faulty testing being used to drive the case count.   This episode ensures you are empowered with the connection of susceptibility + infection = disease. The infection or exposure alone may not be significant as updated data demonstrates. However, the restrictions continue to tighten and threats loom into 2022?!? We question the narrative and call out medical incongruency with policy as well as cover food-as-medicine and supplement support.   Have you been infected with COVID? We cover the mechanisms of long-haulers and how to support the body in successfully resetting following exposure to rebound energy, reduce inflammation, and regain mental health. Also in this episode we discuss the roles of the medical industrial complex and how facts and clinical information that can serve the public is being blocked and deleted. Learn how you can support your body and be proactive in not just surviving but living your life to the fullest! Also in This Episode: Episode 179: Coronavirus and Immune Support Episode 180: The Stress Immune Connection: Coronavirus updates  Updates on masksThe Denmark study: RCT showing no significant reduction of infection wtih mask wearing  My blog: Safe and Effective disinfectants at work and school  My blog: Why masks don’t work and how to advocate for logic in the time of COVID-19 Wim Hof Breath video to support expanding respiratory function  Infection fatality rate updatesInfection Fatality Ratios for COVID-19 Annals of Internal Medicine September 2, 2020 DOI: 10.7326/M20-5352 Population-level COVID-19 mortality risk for non-elderly individuals overall and for non-elderly individuals without underlying diseases in pandemic epicenters medRxiv May 5, 2020 DOI: 10.1101/2020.04.05.20054361 Updates on how asymptomatic individuals do not spread infectionNature study: Post-lockdown SARS-CoV-2 nucleic acid screening in nearly ten million residents of Wuhan, China  https://www.nature.com/articles/s41467-020-19802-w SkullcapBerberine Boost Sleep Support  HesperidinBio-C Plus Vitamin D and Virus SupportVitamin D Balanced Blend Risk Factors for Coronavirus Vulnerability  Concerns of vaccine Advances in transhumanism or tech impact on humansMIT news from 2019 on tracking vaccines through skin scan and digital record https://news.mit.edu/2019/storing-vaccine-history-skin-1218 Patent on Cryptocurency on humans  Long-haulers and how to regulate and reset bodyDetox packs Inflammazyme Updated Coronavirus Kit SupplementsRebuild Spectrum Probiotic Targeted Strength Probiotic Vitamin D Balanced Blend Multidefense Bio-C Plus Adaptogen Boost Cellular Antiox Naturally Nourished Grassfed Whey Herbal Immune Berberine Boost Additional ProductsColloidal Silver Herbal Throat Spray XClear Nasal Spray Doterra OnGuard Essential Oil Products The Stress-Immune Connection How Stress Impacts the BodyEpisode 56: Rebounding Your Body from Trauma Episode 77: The Stress Connection to Autoimmune Disease The Stress GI ConnectionGI Lining Support Stress Reduction TechniquesWhy You Need SleepSleep Support Relax and Regulate How to Approach Exercise Under Stress Mantra, Meditation and 4-7-8 Breath Stress Supporting Supplements GabaCalm Calm and Clear Adaptogen Boost Other Research Mentioned in This Episode: Wang, L., Ma, Q., 2018. Clinical benefits and pharmacology of scutellarin: A comprehensive review. Pharmacol Ther 190, 105-127. Wang, W., Ma, X., Han, J., Zhou, M., Ren, H., Pan, Q., Zheng, C., Zheng, Q., 2016. Neuroprotective Effect of Scutellarin on Ischemic Cerebral Injury by Down-Regulating the Expression of Angiotensin-Converting Enzyme and AT1 Receptor. PLoS One 11(1), e0146197. Kuhn, J.H., Radoshitzky, S.R., Li, W., Wong, S.K., Choe, H., Farzan, M., 2006. The SARS Coronavirus receptor ACE 2 A potential target for antiviral therapy, New Concepts of Antiviral Therapy. Springer, pp. 397-418. Ding, L., Li, J., 2019. Baicalin ameliorates oxidative stress and apoptosis by restoring mitochondrial dynamics in the spleen of chickens via the opposite modulation of NF-kappaB and Nrf2/HO-1 signaling pathway during Mycoplasma gallisepticum infection. Poult Sci 98(12), 6296-6310. Lingchong Wang† ORCID logoab, Dapeng Zhang† bc, Ning Wangb, Sha Lib, Hor-Yue Tanb and Yibin Feng *b. Polyphenols of Chinese skullcap roots: from chemical profiles to anticancer effects. DOI: 10.1039/C9RA03229K (Review Article) RSC Adv., 2019, 9, 25518-25532 Sponsors For This Episode:   This episode is sponsored by FOND Bone Broth Tonics, Your Sous Chef in a Jar. FOND is slow simmered and lovingly tended from simmer to seal. They partner with organic farms and hand-pick and pair ingredients to optimize absorption and taste. Use code ALIMILLERRD to save at fondbonebroth.com.   This episode is sponsored by the Naturally Nourished supplement line: these pure, potent and effective formulas have been hand selected to deliver profound health benefits. We price our formulas 2-5% below market industry standard and competitors and guarantee that our products will always be third party assessed to ensure they are free of mold, toxins, contaminants, and contain the stated active ingredients in dosages noted.  Use code ALI15 for 15% off your first Naturally Nourished Supplement Order! 

Today I had 30-minutes of Dr. Wahls time to get an update on ways we can improve our resiliency and self defense system. You can learn more from Dr. Wahls website and social media blog posts including this one we review in this episode here   Dr. Terry Wahls is a clinical professor at the University of Iowa where she conducts clinical trials testing the efficacy of therapeutic lifestyle to treat multiple sclerosis related symptoms. In addition, she is the author of The Wahls Protocol: How I Beat Progressive MS Using Paleo Principles and Functional Medicine and the cookbook The Wahls Protocol Cooking for Life: The Revolutionary Modern Paleo Plan to Treat All Chronic Autoimmune Conditions.           The new information scientists are learning and publishing each day is constantly changing how integrative/functional/conventional medical practitioners administer patient care. Information is vital for you—but it has never been harder for the public to access it. Here are the key points about cytokine storm in the C OVID -19 pandemic that I want you to know. When our immune cells are working to kill the virus, the virus activates the NLRP3 inflammasome. If NFKappaB has been excessively activated, the immune cells will then initiate excessive release of inflammation producing cytokines. This leads to a cytokine storm and a massive of fluid into the lungs. This is why people with CV may develop worsening shortness of breath, chest pain, air hunger and steadily declining oxygen. This is when people present to the emergency room with difficulty breathing, needing oxygen and sometimes ventilator support. What can we do to reduce the risk of NLRP3 inflammasomes activation and excessive NFKappaB? The literature I am reading is circling around this question. I actually discuss this in the revised Wahls Protocol® on page 189 and again starting on page 343. Diet and lifestyle choices are key. Targeted supplements may be additionally helpful. There are of conventional experimental drugs that are being tried in our intensive care units all around the world. Even so, once you are on the ventilator, only 17% have survived. There has never been a more critical time for self-care with excellent nutrition, sleep, stress reduction and good sleep. If you have not picked the revised and expanded, The Wahls Protocol A Radical New Way to Treat All Chronic Autoimmune Conditions Using Paleo Principles—now is the time.  Second, If you are attending the Wahls Protocol® Seminar, I am adding a weekly Wahls Protocol® Seminar Family Support call on Sunday afternoons. This first call this Sunday will be devoted to CV19 through what I am learning each day from a conventional, integrative and functional medicine approach and answering attendee questions. Each week I will go through COVID 19 related updates, and how I am addressing prevention, risk reduction and will share the current thinking from the functional/integrative medicine COVID 19 working group I am part of. As I learn new information I have been revising my thinking and recommendations for diet, lifestyle and supplement choices for managing autoimmune and other chronic health problems. To join the Wahls Protocol® Seminar Family and to be a part of this weekly update, visit terrywahls.com/seminar to sign up. Social Media Links  https://www.facebook.com/TerryWahls/ https://www.instagram.com/drterrywahls/ https://twitter.com/terrywahls https://medicine.uiowa.edu/internalmedicine/profile/terry-wahls Debbie Potts Health Coach, Author, Speaker & Podcaster Host of The Low Carb Athlete Podcast The WHOLESTIC Method Coaching Program FNTP, FDN-P, NASM CPT, CHEK HLC, Kion Coach BURN FAT. OPTIMIZE HEALTH. IMPROVE PERFORMANCE.

Learn all that you can about cytokine storm, seeing new patients and more...from Dr. Wahls herself. As everyone in the world seems to be working at home (ideally) and using the internet, as well as ZOOM, we sadly had a poor connection on ZOOM video conference call.  Dr. Wahls shared tons of valuable information that Debbie recorded in the intro as she was cut in/out throughout the entire call (sadly).  We apologize about the quality of recording but it was 7pm in her time zone- when everyone must have been using the WiFi! You can learn more from Dr. Wahls website and social media blog posts:   Dr. Terry Wahls is a clinical professor at the University of Iowa where she conducts clinical trials testing the efficacy of therapeutic lifestyle to treat multiple sclerosis related symptoms. In addition, she is the author of The Wahls Protocol: How I Beat Progressive MS Using Paleo Principles and Functional Medicine and the cookbook The Wahls Protocol Cooking for Life: The Revolutionary Modern Paleo Plan to Treat All Chronic Autoimmune Conditions.           The new information scientists are learning and publishing each day is constantly changing how integrative/functional/conventional medical practitioners administer patient care. Information is vital for you—but it has never been harder for the public to access it. Here are the key points about cytokine storm in the C OVID -19 pandemic that I want you to know. When our immune cells are working to kill the virus, the virus activates the NLRP3 inflammasome. If NFKappaB has been excessively activated, the immune cells will then initiate excessive release of inflammation producing cytokines. This leads to a cytokine storm and a massive of fluid into the lungs. This is why people with C OVID-19 may develop worsening shortness of breath, chest pain, air hunger and steadily declining oxygen. This is when people present to the emergency room with difficulty breathing, needing oxygen and sometimes ventilator support. What can we do to reduce the risk of NLRP3 inflammasomes activation and excessive NFKappaB? The literature I am reading is circling around this question. I actually discuss this in the revised Wahls Protocol® on page 189 and again starting on page 343. Diet and lifestyle choices are key. Targeted supplements may be additionally helpful. There are of conventional experimental drugs that are being tried in our intensive care units all around the world. Even so, once you are on the ventilator, only 17% have survived. There has never been a more critical time for self-care with excellent nutrition, sleep, stress reduction and good sleep. If you have not picked the revised and expanded, The Wahls Protocol A Radical New Way to Treat All Chronic Autoimmune Conditions Using Paleo Principles—now is the time. In response to the COV ID- 19 pandemic, I have made some changes to my annual seminar: First, I am holding the price at $1097 through the end of April. Second, If you are attending the Wahls Protocol® Seminar, I am adding a weekly Wahls Protocol® Seminar Family Support call on Sunday afternoons. This first call this Sunday will be devoted to CO VID 19 through what I am learning each day from a conventional, integrative and functional medicine approach and answering attendee questions. Each week I will go through COVID 19 related updates, and how I am addressing prevention, risk reduction and will share the current thinking from the functional/integrative medicine COVID 19 working group I am part of. As I learn new information I have been revising my thinking and recommendations for diet, lifestyle and supplement choices for managing autoimmune and other chronic health problems. To join the Wahls Protocol® Seminar Family and to be a part of this weekly update, visit terrywahls.com/seminar to sign up. Social Media Links  https://www.facebook.com/TerryWahls/ https://www.instagram.com/drterrywahls/ https://twitter.com/terrywahls https://medicine.uiowa.edu/internalmedicine/profile/terry-wahls Debbie Potts Health Coach, Author, Speaker & Podcaster Host of The Low Carb Athlete Podcast The WHOLESTIC Method Coaching Program FNTP, FDN-P, NASM CPT, CHEK HLC, Kion Coach BURN FAT. OPTIMIZE HEALTH. IMPROVE PERFORMANCE. www.debbiepotts.net Head to my blog page for follow up notes on Dr. Wahls podcast questions since our reception was poor!  

Are you freaking out about the coronavirus? Looking for more food-as-medicine solutions to support your family’s health during this time? Need a little reassurance to reduce the anxiety this pandemic is causing? Tune in to hear Ali and Becki discuss emerging information about the coronavirus, new statistics on infection rates and what this means for you and your family. Learn about the connection of ACE 2 receptors, symptoms of coronavirus vs. cold and flu, and how you can best support your system during this time.   With evolution of the coronavirus pandemic over the past week, we are interrupting our regularly scheduled content to bring you up-to-date information about the mechanism of the virus, how it spreads and factors that put individuals at higher risk. The added stress and anxiety that self-quarantine, 24/7 news coverage and business and school closures is definitely NOT supportive of immune health, in fact stress can actually shut down the immune system! Learn how stress wreaks havoc on your body’s ability to fight, from reduced white blood cell activity to suppressed autophagy to depletion of micronutrients like Vitamin C and what you can do keep your immune system robust to the impact of stress!    Also in This Episode: Episode 179: Coronavirus and Immune Support Symptoms of COVID-19 How COVID-19 Gets Into the Body The ACE-2 Connection and How Herbal Compounds Can Support SkullcapBerberine Boost Sleep Support  HesperidinBio-C Plus Vitamin D and Virus SupportVitamin D Balanced Blend Risk Factors for Coronavirus Vulnerability  Cytokine Storm Why to Skip Elderberry During This Time! Updated Coronavirus Kit SupplementsRebuild Spectrum Probiotic Targeted Strength Probiotic Vitamin D Balanced Blend Multidefense Bio-C Plus Adaptogen Boost Cellular Antiox Naturally Nourished Grassfed Whey Herbal Immune Berberine Boost Additional ProductsColloidal Silver Herbal Throat Spray XClear Nasal Spray Doterra OnGuard Essential Oil Products The Stress-Immune Connection How Stress Impacts the BodyEpisode 56: Rebounding Your Body from Trauma Episode 77: The Stress Connection to Autoimmune Disease The Stress GI ConnectionGI Lining Support Stress Reduction TechniquesWhy You Need SleepSleep Support Relax and Regulate How to Approach Exercise Under Stress Mantra, Meditation and 4-7-8 Breath Stress Supporting Supplements GabaCalm Calm and Clear Adaptogen Boost Research Mentioned in This Episode: Wang, L., Ma, Q., 2018. Clinical benefits and pharmacology of scutellarin: A comprehensive review. Pharmacol Ther 190, 105-127. Wang, W., Ma, X., Han, J., Zhou, M., Ren, H., Pan, Q., Zheng, C., Zheng, Q., 2016. Neuroprotective Effect of Scutellarin on Ischemic Cerebral Injury by Down-Regulating the Expression of Angiotensin-Converting Enzyme and AT1 Receptor. PLoS One 11(1), e0146197. Kuhn, J.H., Radoshitzky, S.R., Li, W., Wong, S.K., Choe, H., Farzan, M., 2006. The SARS Coronavirus receptor ACE 2 A potential target for antiviral therapy, New Concepts of Antiviral Therapy. Springer, pp. 397-418. Ding, L., Li, J., 2019. Baicalin ameliorates oxidative stress and apoptosis by restoring mitochondrial dynamics in the spleen of chickens via the opposite modulation of NF-kappaB and Nrf2/HO-1 signaling pathway during Mycoplasma gallisepticum infection. Poult Sci 98(12), 6296-6310. Cinatl, J., Jr., 2005. Antiviral activity of glycyrrhizic acid derivatives against SARS-coronavirus. J Med Chem 48(4), 1256-1259. Lingchong Wang† ORCID logoab, Dapeng Zhang† bc, Ning Wangb, Sha Lib, Hor-Yue Tanb and Yibin Feng *b. Polyphenols of Chinese skullcap roots: from chemical profiles to anticancer effects. DOI: 10.1039/C9RA03229K (Review Article) RSC Adv., 2019, 9, 25518-25532 Barak V1, Halperin T, Kalickman I. The effect of Sambucol, a black elderberry-based, natural product, on the production of human cytokines: I. Inflammatory cytokines. Eur Cytokine Netw. 2001 Apr-Jun;12(2):290-6. Sponsors For This Episode:   This episode is sponsored by Wild Foods, a company that puts quality, sustainability, and health first in all of their products. They have everything from coffee to turmeric to medicinal mushrooms, and every single product is painstakingly sourced from small farms around the globe. They take their mission seriously to fix the broken food system, and believe real food is medicine. They’ve partnered with us to give you guys an exclusive discount, so use the code ALIMILLERRD for 12% off your order at WildFoods.co!   

Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our feature paper this week tells us more about aortic wall inflammation, and how this predicts abdominal aortic aneurysm expansion, as well as need for surgical repair. Much more, right after these summaries.                                                 Our first original paper sheds light on a novel mechanism for adult cardiac regeneration. This is a paper from first authors Drs. Wang, and Lee, and corresponding authors Dr. Chen, Houser, and Dr. Jeng from Third Military Medical University from Chongqing, China.                                                 In an elegant series of experiments using mouse models, the authors showed that mature adult cardiomyocytes could re-enter the cell cycle and form new cardiomyocytes though a three-step process: of dedifferentiation, proliferation, and redifferentiation. Intercellular calcium signals from neighboring functioning cardiomyocytes through gap junction induce the redifferentiation process. Furthermore, they showed that this mechanism contributed to new cardiomyocyte formation in post MI hearts in mammals. In summary, this study contributes to our understanding of adult cardiac regeneration and could lead to novel strategies to repair the injured heart.                                                 The next paper provides mechanistic data that may explain why thrombotic complications are more prevalent in patients with diabetes, and why some anti-platelet drugs may have limited efficacy in patients with diabetes. In this paper by first author, Dr. Hu, corresponding author Dr. Ding, and colleagues from Fudan University in Shanghai, China, the authors show that platelets of patients with Type 2 diabetes express high levels of activated P2Y12 receptor.                                                 The P2Y12 inverse agonist inhibited P2Y12 activity of platelets from diabetic patients and rats, more than Cangrelore, leading to a stronger in-vivo antithrombotic effect in thrombosis rat models with diabetes. Increased platelets P2Y12 receptor expression in diabetes was mediated by a high-glucose reactive oxygen species, NF-kappaB pathway. In summary, platelet P2Y12 receptor expression was shown to be significantly increased, and the receptor was constitutively activated in Type 2 diabetic patients, which contributed to platelet hyperactivity, and limited anti-platelet drug efficacy in Type 2 diabetes.                                                  The next paper tells us that the majority of cardiovascular disease events are now occurring amongst adults with a systolic and diastolic blood pressure of less than 140 over 90 millimeters mercury. Prior data have shown us that the majority of incident cardiovascular disease events occurred among U.S. adults with higher systolic and diastolic blood pressures of above 140 over 90. However, over the past several decades, blood pressure has declined and hypertension control has improved. Thus, in the current study, Dr. Tajeu and colleagues from Temple University College of Public Health in Philadelphia estimated the percentage of incident cardiovascular disease events that occur at blood pressures below 140-90 in a pooled analysis of three contemporary U.S. cohorts: the Reasons for Geographic and Racial Differences in Stroke, or, REGARDS study, the Multi-Ethnic Study of Atherosclerosis, or MESA study, and the Jackson Heart study.                                                 In these three U.S. cohorts that enrolled after 2000, more than 60% of incident cardiovascular disease events occurred among participants with blood pressures below 140 over 90 millimeters mercury. In the 2001 to 2008 National Health and Nutritional Examination survey mortality follow-up study, 58% of cardiovascular disease stats occurred in U.S. adults with blood pressures below 140 over 90. Among participants taking anti-hypertensive medication, with blood pressures below 140 over 90, only one-third of those who are eligible for starting treatment were taking one, and approximately 20% met the SPRINT eligibility criteria.                                                 In conclusion, while higher blood pressure levels are associated with increased cardiovascular disease risk, in the modern era the majority of incident cardiovascular disease events occur in U.S. adults with blood pressure below 140 over 90. Although absolute risk and cost effectiveness should still be considered, additional cardiovascular disease risk reduction measures for adults with blood pressure less than 140 over 90, and at high risk for cardiovascular disease, may be warranted.                                                 Well, that brings us to the end of our summaries. Now, for our feature discussion. Dr. Carolyn Lam:               On today's podcast discussion, we will be talking about aortic wall inflammation as a possible functional, or biological, imaging bio-marker that may add to the usual structural measurements of size that we use to predict abdominal aortic aneurysm expansion and rupture. Now, to discuss this very important paper, we have the corresponding author, representing the MA3RS study investigators, Professor David Newby from the Center for Cardiovascular Science in Edinburgh, as well as a familiar voice now, Dr. Joshua Beckman, associate editor from Vanderbilt University. Welcome, gentlemen. Professor David Newby: Hi, there. Dr. Joshua Beckman:      So great to be here again, thanks for having me. Dr. Carolyn Lam:               So great that you're back again, Josh! But David, let's start with you. Could you just summarize what this trial was about and your main findings? Professor David Newby: Sure, so this was a major clinical trial that we undertook in the U.K. and Scotland. We approached patients who were in a surveillance program who had an abdominal aortic aneurysm, and we asked the question, "Is there anything we can do better than just serial ultrasound measurements that currently are stunned to this care?" So, in Edinburgh, we developed a technique using ultrasmall, superparamagnetic particles of iron oxide, which is a bit of a powerful ... so we shortened that to USPIOs; these are really small iron particles that are so small they can cross vascular spaces and they get gobbled up by tissue resident macrophages, and then causes a signal that we can detect on magnetic residents' scanning MRI.                                                 So we were really asking the question, "Can we do better than ultrasound by using what we call USPIO-enhanced MRI?" Dr. Carolyn Lam:               So a biological or functional imaging parameter versus just structural. And so, what were your main findings? Professor David Newby: We recruited around 361 patients and ultimately 341 went into the trial because of various exclusions, et cetera. And we followed these patients up for, on average, around three years. And so we were following it up every six months with ultrasound, with other various assessments, and ultimately what we found was that the USPIO-enhanced magnetic residents' scan was positive in around half of patients, and in those patients that took up the USPIOs in their abdominal aortic aneurysm wall, those patients, their aneurysms expanded quicker. So rate of expansion was higher, and they went on the have the primary event of either elective repair, or rupture. And, don't forget, that the clinicians who were looking after these patients, they didn't know the results of the MRI so it didn't influence their clinical minds, when this was completely independent of the clinical team.                                                 So, for the first time, we demonstrated that imaging or tracking macrophages in the abdominal aortic wall could, indeed, predict both disease progression and clinical outcome. Dr. Carolyn Lam:               And Josh, you know, no one can say it better than you: could you just describe what we discussed as the editors about the significance of such a finding? Dr. Joshua Beckman:      I think there's a few things to take home from these three that are really incredible. First, David, were you surprised at the concordance between the USPIO-enhanced imaging and smoking, or was that something that you expected? Professor David Newby: That was a big surprise. That was, actually, as we discussed in the manuscript, quite an interesting finding, and as always with an interesting find, we dig around in the background, and it actually gets more and more exciting and plausible because of the mechanistic work that we'd seen in the pre-clinical science that preceded our trial. So yes, it was a surprise, but actually the more we got into it, the more it made sense. Dr. Joshua Beckman:      One of the other things that I think is really important to talk about is how you get this study done, and one of the things I found incredibly impressive ... I am unaware of any other multi-sensor MRI study like this. How did you organize this amongst the different institutions? Professor David Newby: It can be a bit of a challenge. So I've done quite a few multi-sensor trials in Scotland, and imaging trials, and the community in Scotland actually is very, very supportive and we got a good network of folks. So the three centers are actually two imaging centers: one in Edinburgh one in Glasgow, a further recruitment center in a city just in the center of Scotland, Sterling. And the patients ... we were able to obviously make sure the scanners did the same protocols; fortunately, they were the same scanner, make and model. So that all obviously helped, but we had a lot of inundation, phantom work, to make sure both centers got things right.                                                 But there was a huge motivation to get this done, and I'm indebted to Charles Riditi and Colin Barrie in Glasgow for doing the, and supporting the, imaging work, and also a medical physicist here in Edinburgh, Scott Semple, who'd done a lot of the work to get this to happen. So there's a teamwork in Scotland and the NHS, where the access to patients are in the screening program as well, which made recruitment really well and very efficient. And we started exactly to target, which is pretty unusual in clinical trials, often takes longer to recruit patients, but it was a great team effort. The imaging quality, we checked, verified, centrally read, and it was really good to see it delivered in that way. Dr. Joshua Beckman:      Do you think that agent, the iron oxide particles, is going to be the contrast agent, I guess, of the future, or do you think because it is now so consistent with smoking, it's gonna be more of an investigational tool? Professor David Newby: So there's a couple of things to say here on ferumoxital, which is the USPIO we used. It's currently licensed in the U.S. for the treatment of anemia and chronic renal failure, but it can also be used as an imaging agent and actually this, I think increasingly, might have a role; not just in aneurysms, but elsewhere. So the first thing you can do is actually do angiography with this agent. [Obviously gadolinium is getting a lot of press at the moment, with problems with warnings coming out, of residual brain deposition, and so on. With the USPIOs, you can use this in renal failure patients, so again, another contraindication for us to concern about: NSF in renal failure patients. So actually, for angiography, I think it's going to have an increasing role.                                                 For imaging of inflammation, we've previously demonstrated that you can track inflammation post-myocardial infarction, so you can see air is lighting up following myocardial infarction. We have some papers out on that, and I think, if you are in the business of looking at cellular inflammation, macrophage trafficking, then this technique really can be helpful.                                                 When we come to aneurysm studies, I think it is less clear because ultimately, doing a quick ultrasound, in fact can give you the information together with all of the clinical risk factors, like smoking, and you get to the same end point without doing the MRI. Then, clearly, it's not going to be that impactful. Having said that, I think sometimes we will have patients who've got all this information and we're not sure which way to go. So I think it could be used as an almost umpire test, if you're not sure whether to proceed with surgery or not. And I think, also, if we discover new agents that are anti-inflammatory that may impact on disease progression, with a normal therapy, then clearly this might be a good buyer market to use in future therapeutic trials. Dr. Joshua Beckman:      Yeah, I actually see a huge potential for the testing of new agents, to see whether or not it reduces the inflammation that's associated. I'm gonna ask you a theoretical question, if that's okay with you. Part of the inflammatory process in the aneurysm is based on oxidative stress, but I've always wondered if you provide more oxygen, which may enhance the oxidative stress reaction, are you actually worsening the reaction at the time you're doing the study? Is that possible, or am I just concerned about nothing and making it up? Professor David Newby: Well, obviously your [inaudible 00:13:19] stressors is important in all of cardiovascular disease, and if you increase oxygen supply, maybe you indeed induce more oxidative stress. In the context of an aneurysm, often there's quite an hypoxic state in the aneurysm wall, because obviously the intraluminal thrombus can buffer the wall itself from it, obviously the vasovasorum come in, but they may not be as efficient in doing that. Some of the areas that we're seeing light up probably are quite hypoxic, so they'll be in an oxygen-deprived state. So I think that needs to be put in the balance, too, and there has been some suggestion that iron particles can increase oxidative stress, and it has been suggested maybe harmful; we've not seen that, we've had absolutely no adverse reactions at all in all of our patients. We had one patient whose blood pressure fell a little bit, but we didn't have to medically intervene at all, so it was just observed and it passed; of course it might be due to many things.                                                 We've also studied this in patients with myocardial infarctions, I've said, also bypass surgery, people who've had bypass surgery. We've also published on using these agents there, and again, we've seen absolutely no adverse reactions. And you would've thought, in the context of those situations, if you were going to see an adverse effect you would've seen it behind. Dr. Carolyn Lam:               David, I've got a question for you. I think you mentioned, a little bit earlier, that end of the day this enhanced MRI did not improve the risk stratification beyond the current predictors of clinical outcome in abdominal aortic aneurysms, but what are the next steps for you? Professor David Newby: There's a couple of things, which we've been thinking through. Firstly, I think the primary end point of the trial was mostly driven by repair, and when we looked at the emergent events, so dying, and rupturing, the signal got stronger and very close to statistical significance. And obviously when you've got a population of patients whose elective surgeries mostly dominated by the ultrasound scan decision, therefore makes it difficult to prove, on top of that, the MRI will have value. So it's quite high, and on a difficult bar to cross, so some of the thoughts we've had are thinking about predicting rupture, rather than repair. And there will also be potential for actually doing a trial, where we actually base decisions on the aneurysm, and if you've got an intermediate category of patient, where you're not sure which way to go, those patients you then do use as an arbiter, and that might have, therefore, proof or value for it.                                                 And the final area that we're probably thinking about exploring is, "Okay, paths for macrophages." Is there other pathophysiological processes that we might want to explore with other agents, that might predict aneurysm growth and rupture even stronger, and macrophage inflammation? So those are some of the thoughts that we've had about where the next steps will be. Dr. Joshua Beckman:      This is an incredible amount of work and I always think it's important to make clear to everybody who's listening to this podcast that, even though we may not all do the same kinds of research, it needs to be made clear that having a multi-sensor study in this topic, with this technique, is incredibly impressive. And the physiology that was brought forth, in addition to the clinical stuff that we just heard about, I think is what makes this worthy of a podcast.                                                 Dr. Newby, thanks so much for participating. Professor David Newby: Thank you so much, that's very kind. And just to reiterate, it has been a long journey and a huge effort, but we're reaping the rewards now, and it's nice to see the data being published in circulation. Dr. Carolyn Lam:               Gentlemen, it has been so wonderful having you here to discuss this. Thank you so much for your time.  

Wed, 20 Nov 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/17070/ https://edoc.ub.uni-muenchen.de/17070/1/Stojanovic_Kristina.pdf Stojanovic, Kristina ddc:570, ddc:500, Fakultät für

Vincent and Dickson discuss immune evasion by the cruzain protease of T. cruzi, and novel tetraspanin antigens of S. japonicum.

Antimicrobial peptides (AMPs) are strongly expressed in lesional skin in psoriasis and play an important role as proinflammatory "alarmins" in this chronic skin disease. Vitamin D analogs like calcipotriol have antipsoriatic effects and might mediate this effect by changing AMP expression. In this study, keratinocytes in lesional psoriatic plaques showed decreased expression of the AMPs beta-defensin (HBD) 2 and HBD3 after topical treatment with calcipotriol. At the same time, calcipotriol normalized the proinflammatory cytokine milieu and decreased interleukin (IL)-17A, IL-17F and IL-8 transcript abundance in lesional psoriatic skin. In contrast, cathelicidin antimicrobial peptide expression was increased by calcipotriol while psoriasin expression remained unchanged. In cultured human epidermal keratinocytes the effect of different vitamin D analogs on the expression of AMPs was further analyzed. All vitamin D analogs tested blocked IL-17A induced HBD2 expression by increasing IkappaB-alpha protein and inhibition of NF-kappaB signaling. At the same time vitamin D analogs induced cathelicidin through activation of the vitamin D receptor and MEK/ERK signaling. These studies suggest that vitamin D analogs differentially alter AMP expression in lesional psoriatic skin and cultured keratinocytes. Balancing AMP "alarmin" expression might be a novel goal in treatment of chronic inflammatory skin diseases.

Idiopathic Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimers disease. The specific molecular events that provoke neurodegeneration in PD are still unknown, which is an impediment to the development of neuroprotective drugs. Only recently, genes linked to hereditary forms of PD have been identified. Idiopathic and hereditary variants of PD share important pathological features, most notably the demise of dopaminergic neurons in the substantia nigra. Functional characterization of PD-associated gene products might help to understand the molecular mechanisms underlying the pathogenesis and maybe, in the future, to find preventive and curative treatments for PD. Among the mutated genes is the parkin gene (PARK2), encoding a E3 ubiquitin ligase. Mutations in the parkin gene are responsible for the majority of autosomal recessive parkinsonism. Previous work of our group revealed that misfolding and aggregation of parkin is a major mechanism of parkin inactivation, accounting for the loss-of-function phenotype of various pathogenic parkin mutants, including C-terminal deletion mutants and some missense mutants [1,2]. Remarkably, also wildtype parkin is prone to misfolding under certain cellular conditions, suggesting a more general role of parkin in the pathogenesis of PD. One aim of this thesis was to study the folding characteristics of parkin. To this end, I cloned several parkin mutants and analyzed them in cell-culture based assays to determine their folding properties. Folding analysis of these mutants revealed that pathogenic mutations can lead to aberrant parkin conformers with two distinct phenotypes. One class of mutations destabilized the native conformation of parkin, leading to its proteasomal degradation immediately after synthesis. Another class of mutants first adopted a detergent-soluble conformation, similarly to wildtype parkin. However, within hours these mutants formed relatively stable detergent-insoluble aggregates. A comparative analysis of HHARI, an E3 ubiquitin ligase with a similar modular signature, revealed that folding of parkin is specifically dependent on the integrity of the C-terminal domain, but not on the presence of a putative PDZ binding motif at the extreme C-terminus. This study provided new insight into the propensity of parkin to misfold and suggested that pathogenic mutations can induce the formation of non-native conformers at distinct steps in the folding pathway of parkin. Another focus of this thesis was the functional characterization of parkin. We and others observed that parkin protects neurons against diverse cellular insults in different model systems, indicating that it may play a role in maintaining neuronal integrity. To address the underlying mechanism, we analyzed the effect of parkin on different signaling pathways. Our results revealed that parkin has a permissive effect on NFkappaB signaling by ubiquitylating two components of the signaling cascade in a non-degradative manner. Notably, parkin lost its neuroprotective capacity in the presence of a dominant negative inhibitor of NFkappaB. In addition, we could show that parkin expression is significantly up-regulated in neurons under stress conditions, indicating that parkin is a stress-responsive protein.

Inhibition of NF-kappaB activation in macrophages results in a proinflammatory outcome.

Sepsis patients may die either from an overwhelming systemic immune response and/or from an immunoparalysis-associated lack of anti-bacterial immune defence. We hypothesized that bacterial superantigen-activated T cells may be prevented from contribution into anti-bacterial response due to the inhibition of their effector functions by the hypoxia inducible transcription factor (HIF-1alpha) in inflamed and hypoxic areas. Using the Cre-lox-P-system we generated mice with a T-cell targeted deletion of the HIF-1alpha gene and analysed them in an in vivo model of bacterial sepsis. We show that deletion of the HIF-1alpha gene leads to higher levels of pro-inflammatory cytokines, stronger anti-bacterial effects and much better survival of mice. These effects can be at least partially explained by significantly increased NF-kappaB activation in TCR activated HIF-1 alpha deficient T cells. T cells can be recruited to powerfully contribute to anti-bacterial response if they are relieved from inhibition by HIF-1alpha in inflamed and hypoxic areas. Our experiments uncovered the before unappreciated reserve of anti-bacterial capacity of T cells and suggest novel therapeutic anti-pathogen strategies based on targeted deletion or inhibition of HIF-1 alpha in T cells.

Enhanced Video PodcastAired date: 11/8/2006 3:00:00 PM Eastern Time

Enhanced Audio PodcastAired date: 11/8/2006 3:00:00 PM Eastern Time

Altogether, we have proven that ANP mediated effects are diverse yet similar in different organs derived from endotoxemic mice and in isolated blood leukocytes. These ANP mediated interactions are proceeding at the onset of LPS-induced inflammation and sepsis. Primarily, we can clearly demonstrate that ANP preconditioning in endotoxemic mice yields TNF-alpha m-RNA reduction, determined in the spleen as well as in the liver. As investigated in whole liver tissue, ANP preconditioning mediates its beneficial effects by reducing LPS-induced transcription factor NF-kappaB activation. This reduction is caused by decreased phosphorylation of the NF-kappaB inhibitory factor IkappaBalpha, proximately leading to impaired degradation of IkappaBalpha protein. Thus, enhanced IkappaBalpha protein level in the cytosol prevent NF-kappaB translocation into the nucleus, and subsequently transcription factor activity and gene expression. These effects might be caused by or lead to the reduction in TNF-alpha gene expression, finally preventing liver failure. Secondly, besides the transcriptional regulation of TNF-aplha gene expression determined in spleen and liver tissue, we focused on ANP mediated effects in LPS stimulated murine and human blood derived leukocytes. Following LPS stimulation, we observed reduced total TNF-alpha protein levels as well as decreased TNF-alpha amounts on the cell-surface in ANP preconditioned blood leukocytes, respectively monocytes and neutrophils. These initial investigations indicate that the reduced TNF-alpha protein levels in leukocytes might either be evoked by interference of ANP in transcriptional or posttranscriptional processes. Eventually, due to its effects on key events of cell activation, such as the reduction of LPS-induced TNF-alpha expression, ANP may represent a promising beneficial autocrine substance in modulating early inflammatory signaling pathways.

Trotz wirksamer Antibiotikatherapie, Immunmodulation durch Steroide und spezialisierter intensivmedizinischer Behandlung ist die Prognose der Pneumokokkenmeningitis weiterhin ungünstig. Aufgrund zentralnervöser und systemischer Komplikationen versterben weiterhin 15 bis 35 Prozent der Erkrankten und ein Drittel der überlebenden Patienten leidet an bleibenden neurologischen Schäden. Für die Entwicklung neuer adjuvanter Behandlungsstrategien ist die Kenntnis der Pathophysiologie von zentraler Bedeutung. In der vorliegenden Arbeit wurden Mechanismen der Immuninduktion (am Beispiel der Rolle des Transkriptionsfaktors NF-kappaB, der an der Transkription zahlreicher Entzündungsmediatoren beteiligt ist) und der Immunregulation (am Beispiel der Bedeutung von Mastzellen, deren Bedeutung für die Erregerabwehr im Rahmen der angeborenen Immunantwort man zunehmend erkennt)untersucht. 1. Die Rolle des Transkriptionsfaktors NF-kappaB Die Studie wurden mittels eines Rattenmodell durchgeführt, in dem zahlreiche pathophysiologische Parameter intrakranieller meningitisassoziierter Komplikationen, wie vaskuläres Hirnödem, intrakranieller Druck oder zerebrovaskuläre Autoregulation untersucht werden können. Die Pneumokokkenmeningitis war mit einem Anstieg der NF-kappaB-Aktivität im Gehirn assoziiert, der durch die Behandlung mit NF-kappaB-Inhibitoren gehemmt werden konnte, was zu einem signifikant besseren klinischen Verlauf führte. Dieser günstige Effekt auf die klinische Symptomatik wurde von einer signifikanten Reduktion der Bluthirnschrankenstörung, des Anstiegs des intrakraniellen Druckes, der Störung von zerebrovaskulärer CO2-Reaktivität und Autoregulation sowie von Liquorpleozytose und IL-6-Liquorkonzentration begleitet. Zusammenfassend legen diese Daten nahe, dass die NF-kappaB-Aktivierung eine zentrale Rolle in der Entstehung der meningealen Entzündung und der ZNS-Komplikationen während des Akutstadiums der bakteriellen Meningitis spielt. 2. Die Bedeutung der Mastzelle Die Untersuchungen hierzu wurden an einem Modell mit mastzelldefizienten WBB6F1/J-KitW/KitW-v-Mäusen durchgeführt. Während der Pneumokokkenmeningitis kam es zu einer Aktivierung von Mastzellen im Gehirn. Bei mastzelldefizienten Mäusen verlief die Erkrankung klinisch signifikant milder als bei Wildtypmäusen und mastzellrekonstituierten Tieren. Diese positive Auswirkung der Mastzelldefizienz auf die Klinik wurde von einer Reduktion systemischer und zentralnervöser Komplikationen wie Pneumonie und Anstieg des intrakraniellen Drucks begleitet. Erstaunlicherweise führte die Mastzelldefizienz zu einer massiven Zunahme der Liquorpleozytose, die nicht von relevanten Unterschieden der pneumokokkeninduzierten Entzündungsantwort oder der bakteriellen Vermehrung begleitet war. Zusammenfassend zeigen die Ergebnisse dieser Studie, dass Mastzellen eine signifikante Rolle bei der Pneumokokkenmeningitis im Mausmodell spielen. Sie sind beteiligt an der Entstehung systemischer und zentralnervöser Komplikationen und damit an einem schweren klinischen Krankheitsverlauf. Überraschend ist, dass Mastzellen inhibitorischen Effekt auf die Neutrophilenrekrutierung in das ZNS besitzen.

In der vorliegenden Arbeit wurden Effekte von IL-10 auf monocytäre Lipidrezeptoren und -Transporter untersucht, die zusätzlich zu den anti-inflammatorischen Wirkungen von IL-10 für dessen anti-atherosklerotische Wirkung von Bedeutung sein könnten. Es konnte gezeigt werden, dass IL-10 die Expression des quantitativ wichtigsten Scavenger Rezeptors, CD36, in Monocyten/Makrophagen sowohl auf RNA- als auch auf Proteinebene hemmt. Diese Hemmung ging einher mit einer verringerten zellulären Aufnahme von oxidiertem LDL. Durch PPARgamma-FACS und -Western Blot in Cytosol-Kern-Fraktionen sowie Koinkubationen mit IL-10 und den PPARgamma-Agonisten 15d-PGJ2 (15-deoxy-Δ12,14-Prostaglandin J2) und Indomethacin konnte gezeigt werden, dass die IL-10 Hemmung von CD36 über die Hemmung des Transkriptionsfaktors PPARgamma vermittelt wird. Im Gegensatz dazu stimulierte IL-10 den Cholesterinexporter ABCA1 und dessen wichtigsten Transkriptionsfaktor LXRalpha auf RNA- und Proteinebene. Die Induktion von ABCA1 hatte funktionell einen verstärkten zellulären Cholesterinefflux zur Folge, welcher die Monocyten und Makrophagen vor Lipidakkumulationen schützte und das vermehrte Einschleusen von Cholesterin in den reversen Cholesterintransport ermöglicht. IL-10 stimulierte ABCA1 dabei trotz der Hemmung des Transkriptionsfaktor PPARgamma. Die IL-10 Stimulation von ABCA1 war durch Piceatannol, einem Inhibitor der proximalen, STAT3-vermittelten Signalübertragung des IL-10 Rezeptors, hemmbar. Mittels LXRalpha "knock down" Zellen konnte weiter gezeigt werden, dass für die IL-10-stimulierte ABCA1 Expression ein intakter LXRalpha-Signaltransduktionsweg nötig ist. Koinkubationen mit Fenofibrat, 9-cis RA (9-cis retinoic acid) und 22-OHC (22-Hydroxycholesterol) ergaben, dass IL-10 auch die Induktion von ABCA1 durch die beiden Transkriptionsfaktoren, PPARalpha und LXRalpha, verstärkte. Durch Hemmung der Proteinkinase A (PKA) und Messung der zellulären cAMP-Spiegel konnte des Weiteren ein distaler cross-talk des IL-10-Signalweges mit dem cAMP/PKA-Weg für die ABCA1 Stimulation nachgewiesen werden. Dagegen hatte IL-10 keinen anhaltenden Einfluss auf die Transkription von SR-BI. Der Scavenger Rezeptor BI (SR-BI) kann je nach Konzentrationsgradient sowohl die zelluläre Cholesterinaufnahme wie die Cholesterinabgabe vermitteln. Des Weiteren reduzierte IL-10 die LPS-induzierte ICAM-1 Expression, was auf die Attenuierung der NFkappaB- und PPARgamma-vermittelten ICAM-1 Expression zurückgeführt werden konnte. Insgesamt befördert IL-10 somit den ABCA1-initiierten peripheren Cholesterinabtransport aus Monocyten/Makrophagen durch HDL. Die gezeigten Effekte von IL-10 erklären tierexperimentelle Befunde eines deutlich reduzierten Lipidgehalts in atherosklerotischen Plaques unter IL-10 Behandlung. Sie erklären auch die niedrigen HDL-Spiegel bei IL-10 knock out (IL-10-/-) Mäusen, die durch exogene IL-10 Substitution korrigiert werden können. Demnach sollte IL-10 nicht nur durch seine anti-inflammatorischen Mechanismen, sondern auch durch seine Effekte auf das Cholesterinhandling von Monocyten/Makrophagen in der Gefäßwand die Entstehung und Progression atherosklerotischer Plaques reduzieren.

Background: Hyperoxic exposures are often found in clinical settings of respiratory insufficient patients, although oxygen therapy (>50% O-2) can result in the development of acute hyperoxic lung injury within a few days. Upon hyperoxic exposure, the inducible nitric oxide synthase (iNOS) is activated by a variety of proinflammatory cytokines both in vitro and in vivo. In the present study, we used a murine hyperoxic model to evaluate the effects of iNOS deficiency on the inflammatory response. Methods: Wild-type and iNOS-deficient mice were exposed to normoxia, 60% O-2 or >95% O-2 for 72 h. Results: Exposure to >95% O-2 resulted in an increased iNOS mRNA and protein expression in the lungs from wild-type mice. No significant effects of iNOS deficiency on cell differential in bronchoalveolar lavage fluid were observed. However, hyperoxia induced a significant increase in total cell count, protein concentration, LDH activity, lipid peroxidation, and TNF-alpha concentration in the bronchoalveolar lavage fluid compared to iNOS knockout mice. Moreover, binding activity of NF-kappaB and AP-1 appeared to be higher in wild-type than in iNOS-deficient mice. Conclusion: Taken together, our results provide evidence to suggest that iNOS plays a proinflammatory role in acute hyperoxic lung injury.