Podcasts about apoptotic

CME credits: 0.25 Valid until: 22-12-2024 Claim your CME credit at https://reachmd.com/programs/cme/how-modulation-of-apoptotic-pathways-can-fill-important-unmet-needs-in-la-scchn/16195/ The treatment of LA SCCHN has remained largely unchanged for >2 decades and the standard of care, concurrent chemoradiotherapy (CRT) with high-dose cisplatin, is associated with substantial toxicity and limited efficacy. SMAC mimetic modulation of apoptosis and tumor cell death may well change that dynamic. Join Drs. Jonathan Schoenfeld and Robert Ferris as they focus attention on this unmet need and critically evaluate how therapeutic modulation of the apoptotic pathway may improve patient outcomes.=

Hair follicles are dynamic structures that undergo cyclic phases of growth, regression and quiescence. The growth phase, known as anagen, lasts for several years, followed by a short regression phase called catagen. During catagen, most cells within the follicle undergo programmed cell death, but a small population of stem cells remains viable to replenish the follicle during the subsequent growth phase. Understanding the mechanisms involved in hair follicle regression is not only important for elucidating normal tissue homeostasis but also for studying pathological conditions such as cancer and aging. In a recent study, researchers Bradley D. Keister, Kailin R. Mesa and Krastan B. Blagoev from the National Science Foundation, The Jane Coffin Childs Memorial Fund for Medical Research, Yale School of Medicine, Johns Hopkins University, Bulgarian Academy of Sciences, and Sorbonne Université shed light on the role of apoptotic cells in hair follicle regression and cell death. Their research paper was published in Oncotarget on October 19, 2023, entitled, “Apoptotic cells may drive cell death in hair follicles during their regression cycle.” “Here, we use a quantitative analysis of the length of hair follicles during their regression cycle.” Full blog - https://www.oncotarget.org/2023/11/29/can-mechanisms-of-hair-loss-shed-light-on-cancer-and-aging/ Paper DOI - https://doi.org/10.18632/oncotarget.28529 Correspondence to - Krastan B. Blagoev - kblagoev@nsf.gov Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28529 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, hair follicle, stem cells, regression cycle, mathematical model, analysis About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

BUFFALO, NY- October 23, 2023 – A new research paper was published in Oncotarget's Volume 14 on October 19, 2023, entitled, “Apoptotic cells may drive cell death in hair follicles during their regression cycle.” Intravital microscopy in live mice has shown that the elimination of epithelial cells during hair follicle regression involves supra-basal cell differentiation and basal cell apoptosis through synergistic action of TGF-β (transforming growth factor) and mesenchymal-epithelial interactions. In this process the basal epithelial cells are not internally committed to death and the mesenchymal dermal papilla (DP) plays an essential role in death induction. Given that DP cells are not necessary for completion of the cycle, only for its initiation, it is still an open question as to the mechanism that leads to the propagation of apoptosis towards the regenerative stem cell population. In their new study, researchers Bradley D. Keister, Kailin R. Mesa and Krastan B. Blagoev from the National Science Foundation, The Jane Coffin Childs Memorial Fund for Medical Research, Yale School of Medicine, Johns Hopkins University, Bulgarian Academy of Sciences, and Sorbonne Université performed a quantitative analysis of the length of hair follicles to investigate their regression cycle. “In this paper we introduced a mathematical model of the hair follicle regression cycle that postulates that the regression is initiated by the dermal papilla, but that this signal affects only the cells adjacent to it.” The data are consistent with a propagation mechanism driven by apoptotic cells inducing apoptosis in their neighboring cells. The observation that the apoptosis slows down as the apoptotic front approaches the stem cells at the end of the follicle is consistent with a gradient of a pro-survival signal sent by these stem cells. An experiment that can falsify this mechanism is proposed. “In conclusion, hair follicle regression may be governed by cell-cell induced programmed cell death, which slows down as the stem cell compartment is approached and does not affect the stem cell compartment from which the growth phase is initiated. The class of models introduced here can be used to describe the renewal kinetics of other stem cell niches like the intestinal stem cell niche [18].” DOI - https://doi.org/10.18632/oncotarget.28529 Correspondence to - Krastan B. Blagoev - kblagoev@nsf.gov Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28529 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, hair follicle, stem cells, regression cycle, mathematical model, analysis About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.20.549931v1?rss=1 Authors: Scordino, M., Urone, G., Frinchi, M., Valenza, C., Bonura, A., Cipollina, C., Ciriminna, R., Meneguzzo, F., Pagliaro, M., Mudo, G., Di Liberto, V. Abstract: Despite the intense research, most therapeutic strategies failed in preventing or treating neurodegenerative diseases, characterized by a combination of chronic neurodegeneration, oxidative stress and neuroinflammation. The broad protective activity of IntegroPectin derived from industrial waste grapefruit peel via hydrodynamic cavitation has been recently characterized. In this study, we investigated the beneficial effects of grapefruit IntegroPectin treatment in microglia cells exposed to oxidative stress conditions. Human microglial HMC3 cells were challenged with tert-butyl hydroperoxide (TBH), a powerful hydroperoxide, in the presence of grapefruit IntegroPectin. The apoptotic process, the oxidative stress and the neuroinflammatory responses with the relative intracellular cascades were evaluated. Grapefruit IntegroPectin fully counteracted the apoptotic process induced by cell exposure to TBH. The protective effects of grapefruit IntegroPectin were accompanied with a decrease in the amount of ROS, and were strictly dependent on the activation of the PI3K/Akt cascade. Finally, IntegroPectin treatment inhibited basal microglia activation and the neuroinflammatory response by down-regulating the PI3K-NF-kB- iNOS cascade. These findings reveal that the innovative IntegroPectin exerts a potent protective activity on microglia cells and strongly support further investigations aimed at exploring its therapeutic role in in vivo models of neurodegenerative disorders. 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/2023.04.02.535249v1?rss=1 Authors: Pemberton, J. M., Osterlund, E. J., Schoormann, W., Pogmore, J., Nguyen, D., Leber, B., Andrews, D. Abstract: Anti-apoptotic proteins such as BCL-XL promote cell survival by sequestering pro-apoptotic BCL-2 family members, an activity that frequently contributes to tumorigenesis. Thus, the development of small-molecule inhibitors for anti-apoptotic proteins, termed BH3-mimetics, is revolutionizing how we treat cancer. BH3 mimetics kill cells by displacing sequestered pro-apoptotic proteins to initiate tumor-cell death. Recent evidence has demonstrated that in live cells the BH3-only proteins PUMA and BIM resist displacement by BH3-mimetics, while others like tBID do not. Analysis of the molecular mechanism by which PUMA resists BH3-mimetic mediated displacement from full-length anti-apoptotic proteins (BCL-XL, BCL-2, BCL-W and MCL-1) reveals that both the BH3-motif and a novel binding site within the carboxyl-terminal sequence (CTS) of PUMA contribute to binding. Together these sequences bind to anti-apoptotic proteins, which effectively "double-bolt locks" the proteins to resist BH3-mimetic displacement. The pro-apoptotic protein BIM has also been shown to double-bolt lock to anti-apoptotic proteins however, the novel binding sequence in PUMA is unrelated to that in the CTS of BIM and functions independent of PUMA binding to membranes. Moreover, contrary to previous reports, we find that when exogenously expressed, the CTS of PUMA directs the protein primarily to the endoplasmic reticulum (ER) rather than mitochondria and that residues I175 and P180 within the CTS are required for both ER localization and BH3-mimetic resistance. Understanding how PUMA resists BH3-mimetic displacement will be useful in designing more efficacious small-molecule inhibitors of anti-apoptotic BCL-2 proteins. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

References Authentic Biochemistry Podcast Immunoepigenetics lectures XXIX-XXX1 Dr. Guerra's intermediary metabolism and bioenergetics lectures Nature. 2019 Jul; 571(7765): 403–407 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

References Cancers (Basel). 2020 Aug; 12(8): 2137. Cell Death Dis. 2020 Jan 2;11(1):5 Cell. 2022. 185. 9. :521-1538.e18 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.17.528998v1?rss=1 Authors: Scholz, N., Siebzehnrubl, F. A., Licchesi, J. D. F. Abstract: Programmed cell death is a complex and tightly regulated sequence of events that determines cell fate during tissue homeostasis, development, and pathogenesis. The small protein modifier ubiquitin mediates important regulatory functions during cell death by regulating the stability and activity of checkpoint proteins and the assembly of cell death signalling complexes. The caspase family of cysteine aspartases are essential effectors of apoptotic cell death. Components of the ubiquitin system including RING ubiquitin ligases XIAP, MDM2, RBX1; RBR E3 ubiquitin ligases Parkin and LUBAC; and HECT E3 ubiquitin ligases NEDD4 and Itch are also substrates of caspase-mediated cleavage. In the case of NEDD4 and Itch, the single cleavage event occurs outside of the catalytic HECT domain and it remains unclear whether such cleavage events impact on ubiquitin ligase activity and/or function. Here, we identified the E3 ubiquitin ligase HECTD1 as the third HECT E3 cleaved by caspase-mediated cleavage during apoptotic cell death, in a manner which does not affect the integrity of the catalytic C-ter HECT domain. We mapped the single cleavage event to DFLD1664{downarrow}S and showed that the cleaved C-ter product, which contains the HECT ligase domain, is as stable as the endogenous full length protein. We also found that HECTD1 transient depletion led to reduced caspase-3 activity, but not caspase 8 nor 9. Furthermore, we also identified caspase-3 as the protease responsible for HECTD1 cleavage at Asp1664 suggesting that HECTD1 and caspase-3 might be part of a novel feedback loop mechanism during apoptotic cell death. This study highlight novel crosstalk between cell death mechanisms and the ubiquitin system and raises important questions on whether proteolytic cleavage of E3 ubiquitin ligases might represent an underappreciated mode of regulation during cell death mechanisms. 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/2023.02.10.527989v1?rss=1 Authors: Carvalho, N. D., Rofatto, H. K., Villar, K. S., Magnelli, R. F., Mendonca, R. Z. Abstract: Brazil has a very large biological variety, which is an almost inexhaustible source of substances of pharmacological and biotechnological interest. Several studies have demonstrated the presence of bioactive peptides in insect hemolymph and their potential use as therapeutic agents. However, few data are available regarding molecules extracted from insects with anti-apoptotic action. The objective of this work was to identify and isolate proteins from the hemolymph of caterpillars of the Megalopygidae family with pharmacological and biotechnological interest. Two species of this family were studied, Podalia sp and Megalopyge albicolis. Cytotoxicity tests on Vero and Sf-9 cells revealed that the hemolymph of both caterpillars were cytotoxic only at concentrations greater than 5%v/v. In the anti-apoptotic activity assays, it was verified that the supplementation of cell cultures with only 1% of hemolymph v/v is sufficient to inhibit cell death by apoptosis induced by different inducers such as terbutyl, actinomycin D, hydrogen peroxide or even by nutrient depletion. For this study, cells were staining with trypan blue, crystal violet and fluorescent markers to cytoskeleton (actin and tubulin), mitochondria membrane electric potential (JC-1) and apoptosis marker (acridine orange and ethidium). The protein responsible for anti-apoptotic action was isolated through gel filtration chromatography, using an AKTA purifier high-resolution liquid chromatography system. The hemolymph was fractionated into 3 pools for Podalia sp and 6 pools for M. abicolis. In the antiapoptotic tests, semi purified hemolymph from both caterpillars showed anti-apoptotic effect in VERO and SF-9 cells, pre-treated with only 1% v/v of hemolymph and induced to death by different and apoptotic inductors. Was observed that the molecule with anti-apoptotic effect are present in pool 3 in both hemolymphs. This protector effect blocked and attenuated the disruption of the cytoskeleton (actin filaments), being that the protective effect also was observed on the integrity of the mitochondrial membrane of SF-9 cells pre-treated with both hemolymphs and treated with the apoptosis inducer Terbutil at concentrations of 25 to 100uM. 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/2022.10.05.511004v1?rss=1 Authors: Haorei, Y., Vidyadhara, D., Nambisan, A. K., Raju, T. R., Sagar, B. K. C., Alladi, P. A. Abstract: Identification of genetic mutations in Parkinson's disease (PD) promulgates the genetic nature of disease susceptibility. Resilience-associated genes being unknown till date, the normal genetic makeup of an individual may be determinative too. Our earlier studies comparing the substantia nigra (SN) and striatum of C57BL/6J, CD-1 mice and their F1- crossbreds demonstrated neuroprotective role of admixing, against the neurotoxin MPTP. Further, the differences in levels of mitochondrial fission/fusion proteins in the SN of parent strains, imply effect on mitochondrial biogenesis. Our present investigations suggest that the baseline levels of apoptotic factors Bcl-2, Bax and AIF differ across the three strains and, are differentially altered in SN following MPTP-administration. The reduction in complex-I levels exclusively in MPTP-injected C57BL/6J, reiterate mitochondrial involvement in PD pathogenesis. The MPTP induced increase in complex-IV, in the nigra of both parent strains may be compensatory in nature. Ultrastructural evaluation showed fairly preserved mitochondria in the dopaminergic neurons of CD-1 and F1-crossbreds. However, in CD-1, the endoplasmic reticulum demonstrated distinct luminal enlargement, bordering onto ballooning, suggesting proteinopathy as a possible initial trigger. The increase in -synuclein in the pars reticulata of crossbreds suggests a supportive role for this output nucleus in compensating for the lost function of pars compacta. Alternatively, since -synuclein over-expression occurs in different brain regions in PD, the -synuclein increase here may suggest similar pathogenic outcome. Further understanding is required to resolve this biological contraption. Nevertheless, admixing reduces the risk to MPTP by favouring anti-apoptotic consequences. Similar neuroprotection may be envisaged in the admixed populace of Anglo-Indians. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

References Dr. Guerra's notes The Journal of Nutrition, Volume 137, Issue 3, March 2007, Pages 548–553 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

This week we dive into one of our top ten lists, the 10 important health benefits of iodine. This critically important nutrient is used by the thyroid gland to make thyroid hormones that control many functions in the body including growth and development. Because your body does not produce iodine, it needs to be supplied in the diet. When iodine intake is poor, the body cannot produce enough thyroid hormones. Tune in to learn more…   Iodine The fact is that iodine is utilized for just about every function in your body. Yet many people are unaware of their body's need for iodine, and that iodine deficiency has reached epidemic proportions worldwide. 10 Important Health Benefits of Iodine Here are 10 reasons why maintaining sufficient iodine levels is an absolute MUST for your health: #10. Iodine Helps Stabilize Your Mood It is well known that low iodine levels can have an impact on the brain, as mentioned above. More recent research has also linked iodine deficiency to depression and anxiety. A 2004 study conducted by German researchers and published in the Journal of Psychiatry and Neuroscience [1] found a link between “alterations of thyroid-stimulating hormone (TSH) and mild cases of depression and anxiety.” TSH is produced by the pituitary gland to signal the thyroid to produce more thyroid hormones. Fluctuations in TSH are often an indication that the thyroid is not getting enough iodine to do its job [2].   #9. Iodine Maintains Strong Teeth and Bones Iodine assists in the production of strong teeth and bones by being a key player in calcium absorption. In fact, the connection between low iodine, low calcium absorption, and hypothyroidism has been known by researchers for at least the last hundred years [3] One of the functions of the thyroid is the production of calcitonin, a hormone which helps balance blood calcium levels. This mechanism not only leads to maintain strong bones; it also plays a role in healthy functioning of the nervous system, heart and muscles. #8. Iodine Helps Prevents Hair Loss Besides protecting the skin and eyes from UV radiation, adequate levels of iodine can give your skin and hair a healthy glow. This is because iodine is involved in cellular rejuvenation [4]. Healthy iodine levels also prevent hair loss because of the nutrients supplied to the thyroid gland [5]. Iodine in combination with other essential minerals such as iron, magnesium, and zinc can be a powerful internal tonic for thinning hair. #7. Iodine Ensures Reproductive Health Did you know that Japanese women have the lowest rates of breast cancer in the world? A 2003 report published in the journal Breast Cancer Research postulated that this could be a direct result of eating iodine- and selenium-rich seaweed, which is a staple in the Japanese diet [6 ]. Iodine is fuel for reproductive glands as well as the thyroid. Studies suggest that getting enough iodine can help prevent fibrocystic breast disease, preeclampsia, ovarian cancer, ovarian cysts, vaginitis, polycystic ovary syndrome, and even breast cancer. Enough iodine in the body is also one aspect of a healthy pregnancy [7]. #6. Iodine Is a Powerful Antioxidant According to some experts, iodine may be as powerful in this regard as vitamin C! [8] It can help reduce free radical damage that may lead to gene mutation and disease. It is a great boon for the immune system as it helps clean the blood of harmful pathogens. A 2013 meta-analysis [9] published by the National Autonomous University of Mexico (UNAM) in the journal Thyroid found that iodine is “an antioxidant as well as an antiproliferative and differentiation agent” which can help clear up free radical damage in many organs of the body. It is also a powerful anti-inflammatory. #5. Iodine Is a Natural Antiseptic Maybe you remember that brownish-red solution your mom used to apply when you had a cut? For everything from cleaning wounds to purifying water, iodine is a sterilizing substance that can kill unhealthy organisms, bacteria and viruses. A 2015 Iranian study found that a low-concentration iodine antiseptic used after oral surgery helped instigate first-stage wound healing in the surgery area, leading to faster recovery and less chance of infection [10]. #4. Iodine Protects You From Radiation It is a natural protectant from UV radiation for the eyes, according to a 2004 Austrian study [11]. Iodine supplementation can also be used to help individuals suffering from long-term radiation exposure. The effects of too much radiation can happen because of accidents, medical devices, and the radiation emitted by TSA scanners at airports. A 2008 study [12] published in Radiation Research discovered that “terahertz radiation” like that found in airport x-ray scanners is linked to genetic mutation. Adequate amounts of iodine in the body is a must for anyone who travels a lot. #3. Iodine Protects the Body From Toxins Fluoride, chlorine, and bromine are dangerous chemicals found in everything from new car interiors to tap water. They can also severely hinder thyroid function. Maintaining healthy iodine levels can block these “halide” chemicals from accumulating [13]. Iodine can also protect against xenoestrogens – “chemical mimics” – that can lead to reproductive conditions like ovarian cysts and uterine fibroids [14]. Some experts, such as author and natural health advocate Dr. Mark Sircus [15], point to the possibility that iodine may also help with mercury detoxification. #2. Iodine Helps Your Brain Stay Sharp Iodine deficiency has been linked to cognitive decline in countless studies and is one of the “world's most prevalent, yet easily preventable, cause[s] of brain damage,” according to the World Health Organization [16]. Iodine deficiency during pregnancy has been linked to autism in a recent University of Arizona study [17]. Furthermore, a 2013 Australian investigation published in the journal Frontiers in Neuroscience found that iodine supplementation improved the perceptual reasoning of slightly deficient children considerably [18]. #1. Iodine Is Necessary for Metabolism and Thyroid Function Metabolism is the act of converting food into substances your body can use. It helps the body break down food into nutrients via the thyroid gland and other mechanisms. Iodine is the literal “fuel” for the thyroid. Triiodothyronine (T3) and thyroxine (T4) are the main hormones that the thyroid produces. For these hormones to be created, they need iodine. Good thyroid health also helps your body keep a steady heart rate, regulate temperature, improve digestion, and maintain a healthy weight.  [19]    Nascent Iodine –  is also known as atomic iodine, monatomic iodine, Atomidine, or colloidal iodine. The term “nascent” refers to iodine that has an incomplete number of electrons. This gives it an electrical charge, according to a report conducted by the non-profit Weston Price Foundation and others. Many forms of dietary iodine break down into iodide in the digestive tract. In this state, iodine-dependent organs like the thyroid and reproductive organs cannot use it. The charge of nascent iodine helps it stay intact and absorb quickly and thoroughly into the organs that need it most.   Resources: [1] Testing the association between thyroid dysfunction and psychiatric diagnostic group in an iodine-deficient area [2] How Your Thyroid Works [3] CALCIUM AND IODINE METABOLISM IN THYROID DISEASE [4] A Comparison Study of Growth Factor Expression following Treatment with Transcutaneous Electrical Nerve Stimulation, Saline Solution, Povidone-Iodine, and Lavender Oil in Wounds Healing [5] Vitamin deficiencies are a lot more obvious than you might think [6] The thyroid, iodine and breast cancer [7] Iodine supplementation for women during the preconception, pregnancy and postpartum period [8] Thyroid Hormones Directly Alter Human Hair Follicle Functions: Anagen Prolongation and Stimulation of Both Hair Matrix Keratinocyte Proliferation and Hair Pigmentation [9] The Extrathyronine Actions of Iodine as Antioxidant, Apoptotic, and Differentiation Factor in Various Tissues [10] Effect of low-concentration povidone iodine on postoperative complications after third molar surgery: a pilot split-mouth study [11] Iodide protection from UVB irradiation-induced degradation of hyaluronate and against UVB-damage of human conjunctival fibroblasts [12] Terahertz Radiation Increases Genomic Instability in Human Lymphocytes [13] Interaction of bromine with iodine in the rat thyroid gland at enhanced bromide intake [14] Endocrine disrupting chemicals and uterine fibroids [15] Iodine and Detoxification [16] Micronutrient deficiencies [17] Analyses of toxic metals and essential minerals in the hair of Arizona children with autism and associated conditions, and their mothers [18] The role of nutrition in children's neurocognitive development, from pregnancy through childhood [19] Endocrinology: An Integrated Approach Organixx Iodine History of U.S. Iodine Fortification and Supplementation NIH Fact Sheet for Professionals Iodine Deficiency - American Thyroid Association The Great Iodine Debate - Weston Price Foundation Organixx Nascent Iodine What You Need to Know About Iodine & Iodine Deficiency Symptoms What Is Povidone Iodine and How Is It Different From Nascent Iodine? Are You Eating Enough of These Foods With Iodine? Iodine Articles in Organixx's INSPIRED Health Library

This week we dive into one of our top ten lists, the 10 important health benefits of iodine. This critically important nutrient is used by the thyroid gland to make thyroid hormones that control many functions in the body including growth and development. Because your body does not produce iodine, it needs to be supplied in the diet. When iodine intake is poor, the body cannot produce enough thyroid hormones. Tune in to learn more…   Iodine The fact is that iodine is utilized for just about every function in your body. Yet many people are unaware of their body's need for iodine, and that iodine deficiency has reached epidemic proportions worldwide. 10 Important Health Benefits of Iodine Here are 10 reasons why maintaining sufficient iodine levels is an absolute MUST for your health: #10. Iodine Helps Stabilize Your Mood It is well known that low iodine levels can have an impact on the brain, as mentioned above. More recent research has also linked iodine deficiency to depression and anxiety. A 2004 study conducted by German researchers and published in the Journal of Psychiatry and Neuroscience [1] found a link between “alterations of thyroid-stimulating hormone (TSH) and mild cases of depression and anxiety.” TSH is produced by the pituitary gland to signal the thyroid to produce more thyroid hormones. Fluctuations in TSH are often an indication that the thyroid is not getting enough iodine to do its job [2].   #9. Iodine Maintains Strong Teeth and Bones Iodine assists in the production of strong teeth and bones by being a key player in calcium absorption. In fact, the connection between low iodine, low calcium absorption, and hypothyroidism has been known by researchers for at least the last hundred years [3] One of the functions of the thyroid is the production of calcitonin, a hormone which helps balance blood calcium levels. This mechanism not only leads to maintain strong bones; it also plays a role in healthy functioning of the nervous system, heart and muscles. #8. Iodine Helps Prevents Hair Loss Besides protecting the skin and eyes from UV radiation, adequate levels of iodine can give your skin and hair a healthy glow. This is because iodine is involved in cellular rejuvenation [4]. Healthy iodine levels also prevent hair loss because of the nutrients supplied to the thyroid gland [5]. Iodine in combination with other essential minerals such as iron, magnesium, and zinc can be a powerful internal tonic for thinning hair. #7. Iodine Ensures Reproductive Health Did you know that Japanese women have the lowest rates of breast cancer in the world? A 2003 report published in the journal Breast Cancer Research postulated that this could be a direct result of eating iodine- and selenium-rich seaweed, which is a staple in the Japanese diet [6 ]. Iodine is fuel for reproductive glands as well as the thyroid. Studies suggest that getting enough iodine can help prevent fibrocystic breast disease, preeclampsia, ovarian cancer, ovarian cysts, vaginitis, polycystic ovary syndrome, and even breast cancer. Enough iodine in the body is also one aspect of a healthy pregnancy [7]. #6. Iodine Is a Powerful Antioxidant According to some experts, iodine may be as powerful in this regard as vitamin C! [8] It can help reduce free radical damage that may lead to gene mutation and disease. It is a great boon for the immune system as it helps clean the blood of harmful pathogens. A 2013 meta-analysis [9] published by the National Autonomous University of Mexico (UNAM) in the journal Thyroid found that iodine is “an antioxidant as well as an antiproliferative and differentiation agent” which can help clear up free radical damage in many organs of the body. It is also a powerful anti-inflammatory. #5. Iodine Is a Natural Antiseptic Maybe you remember that brownish-red solution your mom used to apply when you had a cut? For everything from cleaning wounds to purifying water, iodine is a sterilizing substance that can kill unhealthy organisms, bacteria and viruses. A 2015 Iranian study found that a low-concentration iodine antiseptic used after oral surgery helped instigate first-stage wound healing in the surgery area, leading to faster recovery and less chance of infection [10]. #4. Iodine Protects You From Radiation It is a natural protectant from UV radiation for the eyes, according to a 2004 Austrian study [11]. Iodine supplementation can also be used to help individuals suffering from long-term radiation exposure. The effects of too much radiation can happen because of accidents, medical devices, and the radiation emitted by TSA scanners at airports. A 2008 study [12] published in Radiation Research discovered that “terahertz radiation” like that found in airport x-ray scanners is linked to genetic mutation. Adequate amounts of iodine in the body is a must for anyone who travels a lot. #3. Iodine Protects the Body From Toxins Fluoride, chlorine, and bromine are dangerous chemicals found in everything from new car interiors to tap water. They can also severely hinder thyroid function. Maintaining healthy iodine levels can block these “halide” chemicals from accumulating [13]. Iodine can also protect against xenoestrogens – “chemical mimics” – that can lead to reproductive conditions like ovarian cysts and uterine fibroids [14]. Some experts, such as author and natural health advocate Dr. Mark Sircus [15], point to the possibility that iodine may also help with mercury detoxification. #2. Iodine Helps Your Brain Stay Sharp Iodine deficiency has been linked to cognitive decline in countless studies and is one of the “world's most prevalent, yet easily preventable, cause[s] of brain damage,” according to the World Health Organization [16]. Iodine deficiency during pregnancy has been linked to autism in a recent University of Arizona study [17]. Furthermore, a 2013 Australian investigation published in the journal Frontiers in Neuroscience found that iodine supplementation improved the perceptual reasoning of slightly deficient children considerably [18]. #1. Iodine Is Necessary for Metabolism and Thyroid Function Metabolism is the act of converting food into substances your body can use. It helps the body break down food into nutrients via the thyroid gland and other mechanisms. Iodine is the literal “fuel” for the thyroid. Triiodothyronine (T3) and thyroxine (T4) are the main hormones that the thyroid produces. For these hormones to be created, they need iodine. Good thyroid health also helps your body keep a steady heart rate, regulate temperature, improve digestion, and maintain a healthy weight.  [19]    Nascent Iodine –  is also known as atomic iodine, monatomic iodine, Atomidine, or colloidal iodine. The term “nascent” refers to iodine that has an incomplete number of electrons. This gives it an electrical charge, according to a report conducted by the non-profit Weston Price Foundation and others. Many forms of dietary iodine break down into iodide in the digestive tract. In this state, iodine-dependent organs like the thyroid and reproductive organs cannot use it. The charge of nascent iodine helps it stay intact and absorb quickly and thoroughly into the organs that need it most.   Resources: [1] Testing the association between thyroid dysfunction and psychiatric diagnostic group in an iodine-deficient area [2] How Your Thyroid Works [3] CALCIUM AND IODINE METABOLISM IN THYROID DISEASE [4] A Comparison Study of Growth Factor Expression following Treatment with Transcutaneous Electrical Nerve Stimulation, Saline Solution, Povidone-Iodine, and Lavender Oil in Wounds Healing [5] Vitamin deficiencies are a lot more obvious than you might think [6] The thyroid, iodine and breast cancer [7] Iodine supplementation for women during the preconception, pregnancy and postpartum period [8] Thyroid Hormones Directly Alter Human Hair Follicle Functions: Anagen Prolongation and Stimulation of Both Hair Matrix Keratinocyte Proliferation and Hair Pigmentation [9] The Extrathyronine Actions of Iodine as Antioxidant, Apoptotic, and Differentiation Factor in Various Tissues [10] Effect of low-concentration povidone iodine on postoperative complications after third molar surgery: a pilot split-mouth study [11] Iodide protection from UVB irradiation-induced degradation of hyaluronate and against UVB-damage of human conjunctival fibroblasts [12] Terahertz Radiation Increases Genomic Instability in Human Lymphocytes [13] Interaction of bromine with iodine in the rat thyroid gland at enhanced bromide intake [14] Endocrine disrupting chemicals and uterine fibroids [15] Iodine and Detoxification [16] Micronutrient deficiencies [17] Analyses of toxic metals and essential minerals in the hair of Arizona children with autism and associated conditions, and their mothers [18] The role of nutrition in children's neurocognitive development, from pregnancy through childhood [19] Endocrinology: An Integrated Approach Organixx Iodine History of U.S. Iodine Fortification and Supplementation NIH Fact Sheet for Professionals Iodine Deficiency - American Thyroid Association The Great Iodine Debate - Weston Price Foundation Organixx Nascent Iodine What You Need to Know About Iodine & Iodine Deficiency Symptoms What Is Povidone Iodine and How Is It Different From Nascent Iodine? Are You Eating Enough of These Foods With Iodine? Iodine Articles in Organixx's INSPIRED Health Library

Oncotarget published "TRAIL receptor agonists convert the response of breast cancer cells to ONC201 from anti-proliferative to apoptotic" which reported normal fibroblasts do not undergo apoptosis following rhTRAIL plus ONC201. In vivo, MDA-MB-361 tumor growth rate is significantly reduced following treatment with a combination of ONC201 and rhTRAIL as compared to control tumors. Natural killer cells which use TRAIL to kill DR5-expressing cancer cells, exhibit greater cytotoxicity against ONC201-treated breast cancer cells compared to controls. rhTRAIL also converts the response of cells from other tumor types to ONC201 from anti-proliferative to apoptotic. A monoclonal DR5-agonistic antibody converts the response of non-TNBC cells to ONC201 from anti-proliferative to apoptotic. These Oncotarget findings describe a novel therapeutic strategy that potently converts the response of a cancer cell to ONC201 from anti-proliferative to apoptotic. Dr. Wafik S. El-Deiry Founding Editorial Board Member of Oncotarget said, "Breast cancer is the most commonly diagnosed cancer and is the number three cause of cancer-related death in United States women." The potential of TRAIL to kill cancerous cells while leaving normal cells unharmed led to the development and clinical testing of TRAIL-based therapies such as recombinant human TRAIL and death receptor agonistic antibodies. ONC201 potently induced cell death through the extrinsic pathway in cancer cells from a variety of tumor types. The compound is unique in that it is a dual activator of the TRAIL pathway, able not only to upregulate pro-death ligand TRAIL, but also its receptor DR5. Early studies of the mechanism of action of ONC201 showed that the compound inhibited pro-survival kinases Akt and ERK, leading to the dephosphorylation and activation of transcription factor FOXO3a. Previous work has shown that ONC201 is a potent dual inducer of the TRAIL pathway at the level of both the ligand and the receptor, and that breast cancers show decreased sensitivity to TRAIL . The authors hypothesized that profiling the effects of the compound on the TRAIL pathway in breast cancer and identifying blocks in signal transduction would allow us to identify therapeutic strategies with the potential to induce apoptosis and that could potentially translate to tumor regressions in patients who do not respond to treatment with ONC201 alone. The El-Deiry Research Team concluded in their Oncotarget Research Output that this team's previous data showed that in breast cancer, the anti-proliferative effects of ONC201 are more common than the apoptotic effects. While the apoptotic effects of ONC201 led to in vivo efficacy of the compound, the anti-proliferative effects did not. In the present study, they investigated mechanisms as well as strategies to convert the response of breast cancer cells to ONC201 from anti-proliferative to pro-apoptotic. TRAIL receptor agonists such as rhTRAIL or a DR5-agonistic antibody convert the response of these cells to ONC201 from anti-proliferative to apoptotic. These findings may have clinical relevance as ONC201 is currently being tested in patients with breast cancer, and the authors believe that this newly identified combinatorial strategy has the potential to induce tumor regressions in patients with limited response to ONC201 monotherapy. DOI - https://doi.org/10.18632/oncotarget.27773 Full text - https://www.oncotarget.com/article/27773/text/ Correspondence to - Wafik S. El-Deiry - wafik@brown.edu Keywords - ONC201, TRAIL, breast cancer, death receptors, apoptosis

This episode is also available as a blog post: http://biopatrika.com/2021/06/24/interview-gut-pathogens-deploy-anti-apoptotic-pathway-to-maintain-infectious-foothold-in-their-host/

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.08.288043v1?rss=1 Authors: Cosker, K., Mallach, A., Limaye, J., Piers, T. M., Staddon, J., Neame, S. J., Hardy, J., Pocock, J. M. Abstract: The R47H variant of the microglial membrane receptor TREM2 is linked to increased risk of late onset Alzheimers disease. Human induced pluripotent stem cell derived microglia, iPS-Mg, from patient iPSC lines expressing the AD-linked R47Hhet TREM2 variant, common variant, Cv, or an R47Hhom CRISPR edited line and its isogeneic control, demonstrated that R47H-expressing iPS-Mg expressed a deficit in signal transduction in response to the TREM2 endogenous ligand phosphatidylserine with reduced pSYK-pERK1/2 signalling and a reduced NLRP3 inflammasome response, including ASC speck formation, Caspase-1 activation and IL-1beta secretion. Apoptotic cell phagocytosis and soluble TREM2 shedding were unaltered, suggesting a disjoint between these pathways and the signalling cascades downstream of TREM2 in R47H-expressing iPS-Mg, whilst metabolic deficits in glycolytic capacity and maximum respiration were reversed when R47H expressing iPS-Mg were exposed to PS+ expressing cells. These findings suggest that R47H-expressing microglia are unable to respond fully to cell damage signals such as phosphatidylserine, which may contribute to the progression of neurodegeneration in late-onset AD. Copy rights belong to original authors. Visit the link for more info

11 February 2014: In this Skinpod episode Dr. Jean Krutmann, from the IUF Leibniz Research Institute for Environmental Medicine, discusses the transcription factor AHR and its anti-apoptotic role in UVB-irradiated keratinocytes.

ATLANTA—Adding anti-BCL-2 therapy with the small-molecule drug venetoclax (VEN) to standard low-dose cytarabine (LDAC) chemotherapy tripled response rates over historical comparators and extended survival in older patients with acute myeloid leukemia (AML) who were ineligible for intensification of their chemotherapy …Andrew Wei INTEVIEW PRODUCTION MASTER

Fri, 2 Aug 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16044/ https://edoc.ub.uni-muenchen.de/16044/1/Motamedi_Mina.pdf Motamedi, Mina

Stephen D. Miller, Ph.D., Judy Gugenheim Research Professor, Director-Interdepartmental Immunobiology Center,Northwestern University Medical School “Antigen-Specific Tolerance Strategies Using Apoptotic Cells and PLG Nanoparticles for the Treatment of Type 1 Diabetes and Islet Transplantation” 9:00 AM Russell Berrie Pavilion, 1st Floor Conference Room

Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and antiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more antiinflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair. Copyright (C) 2012 S. Karger AG, Basel

Introduction Loss of corneal endothelial cells (CECs) is one major factor limiting transplant clarity and survival after keratoplasty. Amongst other factors, apoptosis due to cellular stress is responsible for these problems. This study investigates the possible anti-apoptotic and cytoprotective effects of minocycline on a human corneal endothelial cell line (HCEC-SV40) cultured under oxidative stress and with transforming growth factor beta (TGF-beta). Methods CECs were treated with 1-150 mM minocycline. Cell viability and the median inhibitory concentration (IC(50)) were evaluated after 48 h and after H(2)O(2) treatment (tetrazolium dye reduction assay and liveedead assay). Expression of B-cell CLL/lymphoma 2 (Bcl-2) and X-linked inhibitor of apoptosis (XIAP) and their mRNA were assessed by reverse transcriptase (RT)-PCR and western blot analysis after treatment with minocycline alone and consecutive incubation with 200 mM H(2)O(2) and TGF-beta 2. A quantitative detection of histone-associated DNA fragmentation by ELISA was performed. Results Minocycline concentrations from 1-50 mM showed no toxic effects on CECs. Pre-treatment with 10-40 mM minocycline led to an increase in viability after H(2)O(2) treatment. In addition, minocycline pretreatment attenuated the increase of histone-associated DNA fragmentation after treatment with H(2)O(2) and TGF-beta 2 significantly. When CECs were treated with minocycline and then consecutively with H(2)O(2) or TGF-beta 2, RT-PCR and western blot analysis yielded an overexpression of Bcl-2 and XIAP. Conclusion In this study minocycline prevented apoptotic cell death in cultured CECs in vitro. Our results suggest that minocycline might offer cytoprotective properties that might help to prevent loss of corneal endothelial cells in vivo.

The pleiotropic cytokine interleukin-6 (IL-6) is one of the major growth factors for multiple myeloma cells. It was previously shown that IL-6 induces the activation of Src family kinases Hck, Lyn and Fyn and that Hck is associated with the IL-6-receptor beta chain (gp130) via an acidic domain in gp130. In the first part of this thesis the acidic domain is narrowed down from 41 to 18 amino acids by a peptide-based functional screening assay. A derivative of the acidic domain, an 18mer lipopeptide, peptide 18AD, is characterised on the cellular and molecular level. IL-6-dependent growth of human and murine myeloma cells is inhibited with an IC50 of 25-30 µM by the addition of peptide 18AD to the growth medium. These cells remain unaffected by treatment with a control peptide with scrambled sequence (18sc). Furthermore, growth of IL-6-independent myeloma cells is not inhibited by peptide 18AD. In IL-6-dependent cells, peptide 18AD causes the same degree of apoptosis induction as IL-6 deprivation. On the molecular level it is shown by peptide competition assays that the association of Hck and gp130 is inhibited by peptide 18AD in a concentration dependent way. Peptide 18AD blocked the IL-6-induced activity of the Src family kinases Hck, Lyn and Fyn. Results from different factor-dependent cell lines demonstrate a common mechanism of the molecular peptide effects on Src family kinase activity, but the involved pathways downstream of the kinases appear to differ among species and cell lines tested. Treatment of human IL-6-dependent myeloma cells with peptide 18AD reduced the activating tyrosine phosphorylation of the signal transducer and activator of transcription 3 (STAT3), while STAT3 activation remains unaffected in murine cells. The Co-immunoprecipitations from different overexpressed receptor-deletionmutants and Hck confirms that the association is mainly due to the interaction between the kinase and a 9 amino acids spanning region within the acidic domain which carries the highest accumulation of acidic residues. Apparently, a sequence of 8-9 amino acids within gp130 with the prevalence of acidic side chains resembles a potential pseudosubstrate domain of tyrosine kinases and is responsible for localisation and activation of Src family kinases in response to receptor stimulation. The identification of sequence motives similar to the acidic domain of gp130 in other cytokine receptors, receptor tyrosine kinases and adapter proteins by an in silicio motive scan might suggest a general role of such motives. This could be the efficient recruitment of cytoplasmic kinases to signalling complexes at the time of ligand stimulation. Here, the importance of the acidic domain-kinase interaction for the IL-6-signaling pathway is shown by the growth-inhibiting effect of peptide 18AD on myeloma cells. In the second part, a novel sequence and celltype-specific anti-myeloma agent, peptide 1A, is characterised. It was initially designed as the negative control for a "reverse alanine scan" to define the role of the acidic residues within the sequence of peptide 18AD. Unexpectedly it turned out to be at least a 25-fold more potent growth inhibitor of myeloma cells than peptide 18AD. Similar molecular bases of the observed effects of peptide 18AD and peptide 1A are very unlikely, because in contrast to peptide 18AD, peptide 1A efficiently kills IL-6-independent myeloma cells as well. Moreover, an excess of IL-6 fails to rescue the cells from peptide 1A-induced cell death. Peptide 1A shows, as tested so far, no effects on cells derived from non-tumor tissue or tumor cells of various origins other than multiple myeloma. Peptide 1A specifically kills myeloma cells by the induction of apoptosis and severely disturbs cell cycle progression. Apoptotic cell death induction by peptide 1A is shown by peptide 1A-induced caspase-3 activation and the cleavage of PARP, a substrate of effector caspases. Peptide-induced cell death can partly be inhibited by co-treatment with the pan-caspase inhibitor ZVAD-fmk. Major survival pathways like the STAT3, PI3K/Akt and the MAPK pathway are inhibited in peptide 1A treated cells. If a biotinylated version of the peptide is added to the growth medium, it is incorporated into human myeloma cells and localised in defined regions of the cytoplasm of myeloma cells. Here some of the molecular mechanisms of peptide 1A-induced cell death are elucidated. However, the direct molecular target(s) are still unknown. Despite the potential difference in the molecular mechanisms, both peptides 18AD and 1A are expected to prove useful for developing derivatives with possible applications for the treatment of multiple myeloma.

Learn about an unexpected pro-apoptotic role for the retinoblastoma tumor suppressor (start 1:22), a cytoplasmic filter in neurons (start 9:35) and an intricate molecular interaction that underpins the oxidative stress response in yeast (start 17:13).

Tue, 27 Mar 2007 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/7317/ https://edoc.ub.uni-muenchen.de/7317/1/Rudy_Anita.pdf Rudy, Anita ddc:540, ddc:500, Fakultät für Chemie und Pha

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

Apoptotic markers and tumor-associated antigens might be suitable to indicate the response to radiochemotherapy early. We analyzed the courses of nucleosomes, CEA, CA 19-9 and CYFRA 21-1 in 25 colorectal cancer patients during radiochemotherapy (4 postoperative, 13 preoperative, 8 local relapse therapy). Blood was taken before therapy, daily during the first week, once weekly during the following weeks, and at the end of the radiochemotherapy. After a temporary decline 6 h after the first irradiation, nucleosomes rose in most patients rapidly reaching a maximum during the first days which was followed by a subsequent decrease. In patients receiving postoperative therapy after complete resection of tumor, nucleosome levels generally were lower than in patients with preoperative or relapse therapy. Correspondingly, CEA, CA 19-9 and CYFRA 21-1 levels of postoperatively treated patients were the lowest whereas those with tumor relapse had the highest ones. During preoperative therapy, lower nucleosome concentrations were found in patients with response to therapy resulting in a smaller area under the curve of days 1-3 (AUC) than in those with progressive disease (p = 0.028). The other parameters did not indicate the response to therapy at the initial treatment phase. In conclusion, the course of nucleosomes (AUC) might be valuable for the early prediction of therapy response in preoperatively treated colorectal cancer patients. Copyright (c) 2006 S. Karger AG, Basel.

Aim of the study: I. Salicylate and heme oxygenase-1: The adhesion molecule P-selectin has been shown to be a major determinant of inflammatory responses. Different pharmacological agents including salicylate have been shown to inhibit IL-4-induced P-selectin expression in endothelial cells. Mechanisms responsible for P-selectin inhibition, however, are as yet not very well known. In the present work we confirmed this finding and aimed to elucidate the events leading to this inhibition. II. Metalloporphyrins and caspases: Apart from the beneficial effects of HO-1 on inflammatory processes, HO-1 is known to provoke anti-apoptotic effects. Metalloporphyrins are heme-analogous and are thus able to inhibit the activity of the heme-converting enzyme HO-1. Therefore, they are widely used and accepted tools in research investigating functional aspects of HO-1. In studies concerning the anti-apoptotic features of HO-1, different metalloporphyrins are often employed to either stimulate HO-1-expression or inhibit its activity. Apoptotic cell death is then quantified with various assay methods, such as the measurement of caspase-3-like activity. In an approach to determine potential anti-apoptotic features of ASA-induced HO-1 we observed contradictory results in a respective experimental setting. This led to the hypothesis that metalloporphyrins exert actions other than their well-known HO-1-dependent effects. Therefore, the second part of this work deals with the specificity of metalloporphyrins. Aim of the study was to find the cause for these contradictory results and further investigate a potential effect of the metalloporphyrins on caspase activity.

Both, the R-enantiomer of the antioxidant alpha-lipoic acid (R-LA) and the hormone atrial natriuretic peptide (ANP) are known to exert potent hepatoprotective action. The present work characterises alpha-lipoic acid- and ANP-mediated signal transduction pathways involved in the regulation of apoptotic cell death in two different models: primary hepatocytes and ischemic isolated perfused rat livers. alpha-lipoic acid was shown to protect isolated hepatocytes from TNF-alpha-/ActinomycinD-induced apoptosis. Astonishingly, this effect did not seem to be governed neither by its well described antioxidative nor its Fe-chelating properties. In fact, the LA-mediated activation of the PI3-K/Akt survival pathway seemed to be responsible for the antiapoptotic properties of alpha-lipoic acid. Consequently, incubation with a specific PI3-K-inhibitor significantly reduced both, R-LA-mediated decrease in caspase activity and R-LA-induced BAD phosphorylation. Thus, PI3-K-mediated Akt activation and subsequent phosphorylation of the proapoptotic protein BAD at Ser136 are causally involved in the antiapoptotic signalling mediated by R-LA. Perfusion with ANP 20 min prior to the ischemic period is known to reduce apoptotic cell death occurring at the end of the ischemic period. We could previously show that this preconditioning of rat livers leads to a marked activation of p38 MAPK. Since ANP reduces apoptotic cell death, the potential connection between this ANP-induced p38 MAPK activation and apoptosis reduction was investigated. Astonishingly, liver perfusion with an p38 MAPK inhibitor even decreased apoptotic cell death, supporting a detrimental role of this kinase. PKA-specific inhibitors demonstrated the involvement of PKA in this ANP-mediated protection. Interestingly, it also turned out that PKA phosphorylates the proapoptotic protein BAD at Ser112, an effect known to contribute to the inhibition of apoptosis. In summary, the present data show for the first time that phosphorylation of BAD at either Ser136 or Ser112 turns out to be a central protective mechanism to defend from hepatocyte apoptosis.

This work characterizes the protective effects of ANP preconditioning in ischemia-reperfusion injury of the isolated perfused rat liver. It was of particular interest to evaluate the influence of ANP on the mode of cell death occurring during cold ischemia and reperfusion and to elucidate the involved signal transduction pathways. Apoptotic cell death was mainly seen after cold liver storage, whereas necrosis was predominant in the reperfusion period. It could be demonstrated for the first time that preconditioning with ANP was able to reduce both apoptotic as well as necrotic cell death. After cold ischemia, in particular hepatocytes were protected against apoptosis. After reperfusion, protection against necrosis comprised hepatocytes and sinusendothelial cells predominantly in the periportal liver areas. As target molecules for ANP action, the cGMP-dependent protein kinases did not seem to be responsible for the conferred cytoprotection. In the liver, no expression of these kinases could be detected and a functional connection could not be derived. In contrast, the cAMP-dependent protein kinases were identified to promote survival. This was further supported by the ability of ANP to directly activate cAMP-dependent protein kinases in livers and hepatocytes. An early transcriptional induction of HO-1 by ANP independent of cGMP could be demonstrated. The induction of heme oxygenase-1 by ANP might not be responsible for the observed hepatoprotection, since inhibition of HO-1 activity did not abrogate the ANP effect. Interestingly, cell-type specific evaluation detected that induction of HO-1 in livers by ANP is exclusively restricted to Kupffer cells. In summary, this thesis gives new insights into the actions of the cardiovascular hormone ANP in IRI of the rat liver. This data helps to understand the mechanisms of how ANP mediates cytoprotection by illuminating effects and potential pathways, an important prerequisite for a rational application in therapy. This work was supported by the Deutsche Forschungsgemeinschaft (DFG: Ge 576/14-2 and FOR 440/1, TP2).