Podcasts about pi3k akt

BUFFALO, NY- April 10, 2024 – A new #researchpaper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 6, entitled, “Geraniol attenuates oxidative stress and neuroinflammation-mediated cognitive impairment in D galactose-induced mouse aging model.” D-galactose (D-gal) administration was proven to induce cognitive impairment and aging in rodents' models. Geraniol (GNL) belongs to the acyclic isoprenoid monoterpenes. GNL reduces inflammation by changing important signaling pathways and cytokines, and thus it is plausible to be used as a medicine for treating disorders linked to inflammation. In this new study, researchers Peramaiyan Rajendran, Fatma J. Al-Saeedi, Rebai Ben Ammar, Basem M. Abdallah, Enas M. Ali, Najla Khaled Al Abdulsalam, Sujatha Tejavat, Duaa Althumairy, Vishnu Priya Veeraraghavan, Sarah Abdulaziz Alamer, Gamal M. Bekhet, and Emad A. Ahmed from King Faisal University, Kuwait University, Center of Biotechnology of Borj-Cedria, Saveetha University, Alexandria University, and Assiut University examined the therapeutic effects of GNL on D-gal-induced oxidative stress and neuroinflammation-mediated memory loss in mice. “Life expectancy in the 21st century is rising, resulting in more age-related illnesses, such as memory impairment and Alzheimer's disease. In this study, GNL was studied for its protective effect on D-gal-induced aging in mice.” The study was conducted using six groups of mice (6 mice per group). The first group received normal saline, then D-gal (150 mg/wt) dissolved in normal saline solution (0.9%, w/v) was given orally for 9 weeks to the second group. In the III group, from the second week until the 10th week, mice were treated orally (without anesthesia) with D-gal (150 mg/kg body wt) and GNL weekly twice (40 mg/kg body wt) four hours later. Mice in Group IV were treated with GNL from the second week up until the end of the experiment. For comparison of young versus elderly mice, 4 month old (Group V) and 16-month-old (Group VI) control mice were used. “We evaluated the changes in antioxidant levels, PI3K/Akt levels, and Nrf2 levels. We also examined how D-gal and GNL treated pathological aging changes.” Administration of GNL induced a significant increase in spatial learning and memory with spontaneously altered behavior. Enhancing anti-oxidant and anti-inflammatory effects and activating PI3K/Akt were the mechanisms that mediated this effect. Further, GNL treatment upregulated Nrf2 and HO-1 to reduce oxidative stress and apoptosis. This was confirmed using 99mTc-HMPAO brain flow gamma bioassays. “Thus, our data suggested GNL as a promising agent for treating neuroinflammation-induced cognitive impairment.” DOI - https://doi.org/10.18632/aging.205677 Corresponding authors - Peramaiyan Rajendran - prajendran@kfu.edu.sa, and Fatma J. Al-Saeedi - fatma.alsaeedi@ku.edu.kw About Aging-US Aging publishes research papers in all fields of aging research including but not limited, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer's diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan. The journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases. Please visit our website at https://www.Aging-US.com​​ and connect with us on social media. MEDIA@IMPACTJOURNALS.COM

A new paper entitled “Isorhamnetin protects porcine oocytes from zearalenone-induced reproductive toxicity through the PI3K/Akt signaling pathway” investigated the effects of a natural flavonoid called isorhamnetin on the damage caused by a toxin called Zearalenone (ZEA) to pig oocytes (immature egg cells). Zearalenone (ZEA) is a harmful mycotoxin found in moldy grain like corn, oats, and millet that can cause irreversible damage to the reproductive system of animals and humans. It can cause reproductive disorders by binding to estrogen receptors and has been shown to impair the development of sperm and oocytes in humans and animals. ZEA can cause oxidative stress that leads to the production of reactive oxygen species (ROS), which can be harmful and contribute to cell death. ZEA can also disrupt pregnancy, inhibit the meiosis of oocytes, and induce mitochondrial damage and stress in the maturation of oocytes. Since ZEA is heat-stable and cannot be completely eliminated from the food chain, it is important to explore potential compounds that can protect against ZEA-induced damage to oocytes. In recent years, natural substances called flavonoids, which have antioxidant properties, have gained attention for their ability to support the development of oocytes. For example, quercetin has been found to increase the proportion of porcine oocytes developing into blastocysts, while kaempferol has shown potential in reducing the negative effects of aging on the development of porcine oocytes by improving mitochondrial function and reducing oxidative stress. Isorhamnetin is a compound found in the herb ginkgo biloba and in foods like pears, onions, and peanuts. It has various pharmacological activities, such as being an antioxidant, anti-inflammatory, and antiviral.     Isorhamnetin acts as an antioxidant by decreasing the production of reactive oxygen species (ROS) and increasing the expression of SOD2 protein, which helps protect against oxidative stress. This study found that isorhamnetin can protect the oocytes from ZEA-induced damage by improving their development, reducing oxidative stress, preventing mitochondrial dysfunction, and inhibiting apoptosis. This research provides a potential solution for reproductive toxicity caused by ZEA and treating female infertility. Mold Toxicity and Ginkgo Biloba Clinical Applications Ginkgo biloba is rich in isorhamnetin as well as other powerful flavonoids like quercetin, kaempferol, and luteolin which makes it the perfect herb for patients with mold toxicity. Ginkgo biloba has many benefits including anti-inflammatory, antioxidant, antiviral, anticoagulant, anti-obesity, hypolipidemic, hypotensive, anti-diabetic, anti-cancer, adaptogenic, and it protects the brain, eye, inner ear, heart, liver, cardiovascular system, reproductive system, lungs, and kidneys. Patients with mold toxicity tend to have reactivated herpes viruses like EBV, CMV, and HHV-6 and ginkgo biloba is effective against these types of viruses as explained in this article. I use VascuSelect from Moss Nutrition which contains 120 mg of standardized ginkgo biloba extract along with grape seed extract and mango extract to further support microcirculation. 120 mg of ginkgo biloba twice a day is the usual dose for this versatile herbal medicine. If you're a practitioner who sees patients with mold toxicity and/or infertility, then VascuSelect should be considered an important part of your protocol. Click here to learn more about the Hedberg Institute Membership to take your functional medicine practice to the next level.

BUFFALO, NY- October 11, 2023 – A new research paper was published in Oncotarget's Volume 14 on October 4, 2023, entitled, “Inhibiting BRAF/EGFR/MEK suppresses cancer stemness and drug resistance of primary colorectal cancer cells.” Drug resistance is a major barrier against successful treatments of cancer patients. Gain of stemness under drug pressure is a major mechanism that renders treatments ineffective. Identifying approaches to target cancer stem cells (CSCs) is expected to improve treatment outcomes for patients. In their new study, researchers Astha Lamichhane, Gary D. Luker, Seema Agarwal, and Hossein Tavana from The University of Akron, University of Michigan and Georgetown University aimed to elucidate the role of cancer stemness in resistance of colorectal cancer cells to targeted therapies. “[...] we developed spheroid cultures of patient-derived BRAFmut and KRASmut tumor cells and studied resistance mechanisms to inhibition of MAPK pathway through phenotypic and gene and protein expression analysis.” They found that treatments enriched the expression of CSC markers CD166, ALDH1A3, CD133, and LGR5 and activated PI3K/Akt pathway in cancer cells. The team examined various combination treatments to block these activities and found that a triple combination against BRAF, EGFR, and MEK significantly reduced stemness and activities of oncogenic signaling pathways. This study demonstrates the feasibility of blocking stemness-mediated drug resistance and tumorigenic activities in colorectal cancer. “Our approach to identify mechanisms of drug resistance of patient-derived cancer cells to targeted therapies and develop effective treatments is promising toward cancer precision medicine.” DOI - https://doi.org/10.18632/oncotarget.28517 Correspondence to - Hossein Tavana - tavana@uakron.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28517 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, drug resistance, cancer stem cells, patient-derived tumor model, colorectal cancer, combination treatment 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- September 25, 2023 – A new research paper was published in Oncotarget's Volume 14 on September 22, 2023, entitled, “Transcriptomic analysis identifies four novel receptors potentially linking endometrial cancer with polycystic ovary syndrome and generates a transcriptomic atlas.” Polycystic Ovary Syndrome (PCOS) is associated with a 3 to 4-fold increased risk of endometrial cancer (EC), but molecular mechanisms are unclear. Upregulation of the IGF1 gene in PCOS endometrium may increase EC risk, but this is uncertain. In this new study, researchers Fatma Alqutami, Mahmood Hachim, Charlie Hodgman, and William Atiomo from the Mohammed Bin Rashid University of Medicine and Health Sciences and the University of Nottingham aimed to investigate links between EC and PCOS, by analyzing publicly available transcriptomic data. “The original aim of this study was to investigate the links between EC and PCOS, by analysing publicly available transcriptomic data and investigate IGF-1 and IGFBP gene expression in the endometrium of women with PCOS and EC compared with normal endometrium.” The NCBI Gene Expression Omnibus was used to identify relevant studies. Differentially expressed genes (DEGs) were identified and analyzed using Metascape to identify pathways of interest. PCOS DEGs that encode proteins secreted into blood were identified using the Human Protein Atlas blood protein database. EC DEGs that are cellular receptors were identified using EcoTyper. These were intersected to identify which EC receptors interact with PCOS secreted proteins. Seven receptors were identified in EC but only PTPRF, ITGA2, ITGA3, and ITGB4 genes were expressed on epithelial cells. Pathway enrichment of these genes showed that the major and common pathway involved was that of the PI3K-AKT signaling pathway which was consistent with a link between PCOS and EC. However, IGF1 was down regulated in PCOS and EC. “Our conclusions at this stage do not support a link between IGF-1 and IGFBP genes in PCOS and EC. However, we have identified four novel receptors which may underpin the risk of EC in PCOS, and we believe our findings provide sufficient evidence to form the basis for a transcriptomic atlas to underpin future research into the links between PCOS and EC and the molecular mechanisms underpinning both diseases.” DOI - https://doi.org/10.18632/oncotarget.28513 Correspondence to - William Atiomo - william.atiomo@mbru.ac.ae Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28513 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, polycystic ovary syndrome, endometrial cancer, transcriptomics, IGF1, in-silico 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/ Twitter - 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

This week's podcast is sponsored by Vetter.On this week's episode, we have a conversation with Steve Worland, CEO of eFFECTOR Therapeutics.eFFECTOR is a clinical-stage biopharmaceutical company pioneering the development of a new class of oncology drugs referred to as STRIs (selective translation regulation inhibitors). eFFECTOR's STRI product candidates target the eIF4F complex and its activating kinase, mitogen-activated protein kinase interacting kinase (MNK). The eIF4F complex is a central node where two of the most frequently mutated signaling pathways in cancer, the PI3K-AKT and RAS-MEK pathways, converge to activate the translation of select mRNA into proteins that are frequent culprits in key disease-driving processes. The company's product candidates are designed to act on a single protein that drives the expression of a network of functionally related proteins, including oncoproteins and immunosuppressive proteins in T cells, that together control tumor growth, survival and immune evasion. The lead product candidate, tomivosertib, is an MNK inhibitor currently being evaluated in KICKSTART, a randomized, double-blind, placebo-controlled phase 2b trial of tomivosertib in combination with pembrolizumab in patients with metastatic non-small cell lung cancer (NSCLC). Zotatifin, eFFECTOR's inhibitor of eIF4A, is currently being evaluated in phase 2a expansion cohorts in certain biomarker-positive solid tumors, including ER+ breast cancer and KRAS-mutant NSCLC. eFFECTOR has a global collaboration with Pfizer to develop inhibitors of a third target, eIF4E.

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

A new research paper was published in Oncotarget's Volume 14 on April 10, 2023, entitled, “A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850.” Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in the pathogenesis of multiple cancers. Riluzole, an inhibitor of glutamate release, showed synergistic antitumor activity in combination with the multi-kinase inhibitor sorafenib in preclinical models. In a new phase I trial, researchers Kristen R. Spencer, Daniella E. Portal, Joseph Aisner, Mark N. Stein, Jyoti Malhotra, Weichung Shih, Nancy Chan, Ann W. Silk, Shridar Ganesan, Susan Goodin, Murugesan Gounder, Hongxia Lin, Jiadong Li, Robert Cerchio, Christina Marinaro, Suzie Chen, and Janice M. Mehnert from Rutgers University, Dana-Farber Cancer Institute, and the Perlmutter Cancer Center of NYU Langone Health identified the toxicity profile, dose-limiting toxicities, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of riluzole combined with sorafenib in patients with advanced cancers. “Riluzole functions as an inhibitor of GRM1 signaling through antagonism of glutamate release, and sorafenib is a multi-kinase inhibitor targeting both the MAPK and PI3K/AKT pathways through the inhibition of RAF1, ARAF and, to a lesser extent BRAF, as well as a set of tyrosine kinases including VEGFR. Our phase I study determined the tolerable dose of this combination and investigated its biologic effects.” Patients with refractory solid tumors were enrolled utilizing a 3+3 dose-escalation design. Riluzole was given at 100 mg PO BID in combination with sorafenib, beginning at 200 mg PO daily and escalating in 200 mg increments per level in 28-day cycles. Restaging evaluations were performed every 2 cycles. In total, 35 patients were enrolled over 4 dose levels. The MTD was declared at dose level 3 (riluzole: 100 mg PO BID; sorafenib: 400 mg AM/200 mg PM). Pharmacokinetic analyses did not reveal definitive evidence of drug-drug interactions. Consistent decreases in phospho-forms of ERK and AKT in tumor tissue analyses with accompanying decrease in GRM1 expression and increase in pro-apoptotic BIM suggest target engagement by the combination. Best responses included a partial response in 1 (2.9%) patient with pancreatic acinar cell carcinoma with a KANK4-RAF1 fusion, and stable disease in 11 (36%) patients. “Combination therapy with riluzole and sorafenib was safe and tolerable in patients with advanced solid tumors. The partial response in a patient with a RAF1 fusion suggests that further exploration in a genomically selected cohort may be warranted.” DOI: https://doi.org/10.18632/oncotarget.28403 Correspondence to: Janice M. Mehnert - Janice.Mehnert@nyulangone.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28403 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - GRM1, riluzole, sorafenib, phase I, clinical trial About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. 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/ Twitter - 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@IMPACTJOURNALS.COM

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.06.535850v1?rss=1 Authors: Giunti, S., Blanco, M. G., De Rosa, M. J., Rayes, D. Abstract: Increased Excitation/Inhibition (E/I) ratio in the brain is a hallmark of neurological disorders, such as Autism Spectrum Disorders (ASD). Mutations in PTEN, the main PI3K/Akt pathway negative regulator, are strongly associated with ASD. It is unclear how PTEN deficiencies lead to E/I disequilibrium. Using C. elegans neuromuscular system as a model for studying E/I balance, we find that daf-18/PTEN mutations affect GABAergic (but not cholinergic) neurodevelopment, leading to behavioral phenotypes typical of an increased E/I ratio. The specific defects in GABAergic development in daf-18 mutants are due to the reduced activity of DAF-16/FOXO3A. Ketogenic diets (KGDs) are effective approaches for disorders associated with E/I imbalances. However, their mechanisms of action are not understood. We show, in daf-18 mutants, that a diet enriched with the ketone body hydroxybutyrate during early development improves GABAergic neurodevelopment and rescued behavioral defects in a DAF-16/FOXO-dependent manner. Our study offers universal insights into the proven link between PTEN mutations and neurodevelopmental defects and provides new insights into the mechanisms underlying KGDs' positive effects on neuronal disorders characterized by E/I imbalance. 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/2023.04.04.535604v1?rss=1 Authors: Rong, Z., Mai, H., Kapoor, S., Puelles, V., Czogalla, J., Schaedler, J., Vering, J., Delbridge, C., Steinke, H., Frenzel, H., Schmidt, K., Caliskan, O. S., Wettengel, J. M., Cherif, F., Ali, M., Kolabas, Z. I., Ulukaya, S., Horvath, I., Zhao, S., Krahmer, N., Tahirovic, S., Yildirim, A. O., Huber, T., Ondruschka, B., Bechmann, I., Ebert, G., Protzer, U., Bhatia, H. S., Hellal, F., Erturk, A. Abstract: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has been associated mainly with a range of neurological symptoms, including brain fog and brain tissue loss, raising concerns about the virus's acute and potential chronic impact on the central nervous system. In this study, we utilized mouse models and human post-mortem tissues to investigate the presence and distribution of the SARS-CoV-2 spike protein in the skull-meninges-brain axis. Our results revealed the accumulation of the spike protein in the skull marrow, brain meninges, and brain parenchyma. The injection of the spike protein alone caused cell death in the brain, highlighting a direct effect on brain tissue. Furthermore, we observed the presence of spike protein in the skull of deceased long after their COVID-19 infection, suggesting that the spike's persistence may contribute to long-term neurological symptoms. The spike protein was associated with neutrophil-related pathways and dysregulation of the proteins involved in the PI3K-AKT as well as complement and coagulation pathway. Overall, our findings suggest that SARS-CoV-2 spike protein trafficking from CNS borders into the brain parenchyma and identified differentially regulated pathways may present insights into mechanisms underlying immediate and long-term consequences of SARS-CoV-2 and present diagnostic and therapeutic opportunities. 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/2023.02.13.528249v1?rss=1 Authors: Jing, J., Chen, S., Wu, X., Yang, J., Liu, X., Wang, J., Wang, J., Li, Y., Zhang, P., Tang, Z. Abstract: Intracerebral hemorrhage (ICH) is an acute cerebrovascular disease with high disability and mortality rates. Recombinant tissue plasminogen activator (rtPA) is commonly applied for hematoma evacuation in minimally invasive surgery (MIS) after ICH. However, rtPA may contact directly with brain tissue during MIS procedure, which makes it necessary to discuss the safety of rtPA. We found that, in the in vivo ICH model induced by VII-type collagenase, rtPA treatment improved the neurological function of ICH mice, alleviated the pathological damage and decreased the apoptosis and autophagy level of the peri-hematoma tissue. In the in-vitro model of ICH induced by hemin, the administration of rtPA down-regulated neuronal apoptosis, autophagy, and endoplasmic reticulum stress of neurons. Transcriptome sequencing analysis showed that rtPA treatment upregulated the PI3K/AKT/mTOR pathway in neurons, and PI3K inhibitor (LY294002) can reverse the protective effects of rtPA in inhibiting excessive apoptosis, autophagy and ER-stress. Epidermal growth factor receptor inhibitor (AG-1487) reversed the effect of rtPA on PI3K/AKT/mTOR pathway, which might indicate that the EGF domain played an important role in the activation of PI3K/AKT/mTOR pathway. 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/2023.02.02.526751v1?rss=1 Authors: Zhang, H., Xie, Z., Zhao, Y., Chen, Y., Xu, X., Ye, Y., Yang, Y., Zhong, W., Zhao, B., Ma, X. Abstract: Vascular aging, characterized by brain endothelial cells (ECs) senescence and dysfunction, has been known to lead to various age-related cerebrovascular and neurodegenerative diseases. However, its underlying mechanisms remain elusive. ECs derived microvesicles (EMVs) and exosomes (EEXs) carry the characteristics of parent cells and transfer their contents to modulate the functions of recipient cells, holding the potential to evaluate or regulate vascular aging. Here, we found that young or aged ECs released EMVs were more effective than their released EEXs on alleviating or aggravating mice cerebrovascular and brain aging as indicated by SA-{beta}-gal staining, cerebral blood flow, blood brain barrier function, aging related markers and cognitive ability test. We further identified that these EMVs regulated cerebrovascular and brain aging by transferring miR-17-5p and could modulate ECs senescence and functions via miR-17-5p/PI3K/Akt pathway. Plasma EMVs and their contained miR-17-5p (EMV-miR-17-5p) were significantly increased or decreased in the elderly, and were closely correlated with vascular aging. Receiver Operating Characteristic (ROC) analysis showed that the area under the curve was 0.724 for EMVs, 0.77 for EMV-miR-17-5p and 0.815 for their combination for distinguishing vascular aging. Our results revealed the novel roles for EMVs that could more effectively modulate vascular and brain aging than EEXs by regulating ECs functions through miR-17-5p/PI3K/Akt pathway, and also suggested that EMVs and EMV-miR-17-5p represent promising biomarkers and therapeutic targets for vascular aging. 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/2022.11.21.517445v1?rss=1 Authors: sukumaran, s., M, S., Iyer, S., Banerjee, A., Purushottam, M., Jain, S., Viswanath, B., Sud, R. Abstract: Adults with bipolar disorder or epileptic seizures are commonly prescribed sodium valproate. In utero exposure to this drug is linked to a multitude of defects in normal brain development, from neural tube defects to autism spectrum disorders. During the course of brain development, neural precursor cells (NPCs) give rise to neurons and glia, and therefore to understand the valproate-induced defects, it is crucial to understand its effect on NPCs. Two NPC lines, both derived from healthy individuals, were used for all experiments. Cells were treated with 0.7mM valproate for one week. Fresh media (+/- drug) was replenished every alternate day. RNA was extracted on day 7 of drug treatment, and transcriptomics performed. All experiments were performed in biological replicates. Genes that showed greater than 1-fold difference (with FDR adjusted q-value less than or equal to 0.05) were considered differentially expressed. We further investigated the interacting partners of the differentially expressed genes using PINOT, as well as cellular pathways using DAVID. Our primary endpoint of analysis were genes that were differentially expressed (DEGs) with valproate treatment in both the NPC lines used. We found 21 such genes that were common in the two lines. PINOT revealed 504 interacting partners of the DEGs. Functional annotation analysis showed significant enrichment of four signaling pathways - Wnt, Notch, Rho-GTPase and PI3K-AKT. While the role of Rho-GTPase is a novel finding, we have replicated previously reported findings on Wnt, Notch and PI3K-Akt pathways, which further strengthens their role in mediating neurodevelopmental anomalies. 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/2022.11.02.514847v1?rss=1 Authors: Bea-Mascato, B., Gomez-Castaneda, E., Sanchez-Corrales, Y. E., Castellano, S., Valverde, D. Abstract: Background: Alstrom syndrome (ALMS) is a rare autosomal recessive disease that is associated with mutations in ALMS1 gene. The main clinical manifestations of ALMS are retinal dystrophy, obesity, type 2 diabetes mellitus, dilated cardiomyopathy and multi-organ fibrosis, characteristic in kidneys and liver. Depletion of the protein encoded by ALMS1 has been associated with the alteration of different processes regulated via the primary cilium, such as the NOTCH or TGF-{beta} signalling pathways. However, the cellular impact of these deregulated pathways in the absence of ALMS1 remains unknown. Methods: In this study, we integrated RNA-seq and proteomic analysis to determine the gene expression profile of hTERT-BJ-5ta ALMS1 knockout fibroblasts after TGF-{beta} stimulation. In addition, we studied alterations in cross-signalling between the TGF-{beta} pathway and the AKT pathway in this cell line. Results: We found that ALMS1 depletion affects the TGF-{beta} pathway and its cross-signalling with other pathways such as PI3K/AKT, EGFR1 or p53. In addition, alterations associated with ALMS1 depletion clustered around the processes of extracellular matrix regulation and lipid metabolism in both the transcriptome and proteome. By studying the enriched pathways of common genes differentially expressed in the transcriptome and proteome, collagen fibril organisation, {beta}-oxidation of fatty acids and eicosanoid metabolism emerged as key processes altered by the absence of ALMS1. Finally, an overactivation of the AKT pathway was determined in the absence of ALMS1 that could be explained by a decrease in PTEN gene expression. Conclusion: ALMS1 deficiency disrupts cross-signalling between the TGF-{beta} pathway and other dependent pathways in hTERT-BJ-5ta cells. Furthermore, altered cross-signalling impacts the regulation of extracellular matrix-related processes and fatty acid metabolism, and leads to over-activation of the AKT pathway. Keywords: ALMS1, TGF-{beta}, AKT, primary cilia, ciliopathy, ECM, lipid metabolism, Alstrom syndrome. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Dr. Ya-Jen Chiu from the Department of Life Science at National Taiwan Normal University in Taipei, discusses a research paper she co-authored that was published by Aging (Aging-US) in Volume 14, Issue 18, entitled, “Novel TRKB agonists activate TRKB and downstream ERK and AKT signaling to protect Aβ-GFP SH-SY5Y cells against Aβ toxicity.” DOI - https://doi.org/10.18632/aging.204306 Corresponding authors - Chiung-Mei Chen - cmchen@cgmh.org.tw, Ying-Chieh Sun - sun@ntnu.edu.tw, Guey-Jen Lee-Chen - t43019@ntnu.edu.tw Video - https://www.youtube.com/watch?v=1rT96K9VeZw Transcript - https://aging-us.net/2022/11/01/behind-the-study-novel-trkb-agonists-activate-trkb-and-downstream-erk-and-akt-signaling/ Abstract Decreased BDNF and impaired TRKB signaling contribute to neurodegeneration in Alzheimer's disease (AD). We have shown previously that coumarin derivative LM-031 enhanced CREB/BDNF/BCL2 pathway. In this study we explored if LM-031 analogs LMDS-1 to -4 may act as TRKB agonists to protect SH-SY5Y cells against Aβ toxicity. By docking computation for binding with TRKB using 7,8-DHF as a control, all four LMDS compounds displayed potential of binding to domain d5 of TRKB. In addition, all four LMDS compounds exhibited anti-aggregation and neuroprotective efficacy on SH-SY5Y cells with induced Aβ-GFP expression. Knock-down of TRKB significantly attenuated TRKB downstream signaling and the neurite outgrowth-promoting effects of these LMDS compounds. Among them, LMDS-1 and -2 were further examined for TRKB signaling. Treatment of ERK inhibitor U0126 or PI3K inhibitor wortmannin decreased p-CREB, BDNF and BCL2 in Aβ-GFP cells, implicating the neuroprotective effects are via activating TRKB downstream ERK, PI3K-AKT and CREB signaling. LMDS-1 and -2 are blood-brain barrier permeable as shown by parallel artificial membrane permeability assay. Our results demonstrate how LMDS-1 and -2 are likely to work as TRKB agonists to exert neuroprotection in Aβ cells, which may shed light on the potential application in therapeutics of AD. Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204306 Keywords - aging, Alzheimer's disease, TRKB agonists, Aβ, neuroprotection, therapeutics About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/agingus​ LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.26.513928v1?rss=1 Authors: chattopadhyay, c., Bhattacharya, R., Roszik, J., Khan, F., Wells, G. A., Villanueva, H., Qin, Y., Bhattacharya, R., Patel, S., Grimm, E. A. Abstract: Uveal melanoma (UM) originating in the eye and metastasizing to the liver is associated with poor prognosis. Here, we investigated whether the IGF-1/IGF-1R signaling axis is involved in UM growth and metastasis. TCGA dataset analysis reveals that UM has high IRS-1 expression, which is the first substrate of IGF-1R. Furthermore, IRS-1 is over-expressed in all UM cell lines tested (relative to non -cancer/normal cells) and in matched eye and liver UM tumors. Therefore, we targeted IRS-1/2 in UM cells as well as UM tumors developed on a chicken egg chorioallantoic membrane (CAM) model, and subcutaneous (subQ) UM tumors grown in mice using NT157, a small molecule inhibitor of IRS-1/2. NT157 treatment in UM cells resulted in reduced cell survival and cell migration, and increased apoptosis. NT157 treatment also significantly inhibited UM tumor growth in the in vivo chicken egg CAM and subQ mouse models, validating the in vitro effect. Moreover, NT157 appears more effective than a monoclonal antibody-based approach to block IGF-1R signaling. Mechanistically, through reverse phase protein array (RPPA) analysis, we identified significant proteomic changes in the PI3K/AKT pathway with NT157 treatment. Together, these results suggest that NT157 inhibits cell survival, migration in vitro and tumor growth in vivo via inhibiting IGF-1 signaling in UM cells. 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/2022.10.23.513322v1?rss=1 Authors: Chen, X., Rong, K., Han, W., Pang, Y., Chai, G. Abstract: In previous research, miR-148a-3p deficiency was observed in bone malformation in hemifacial microsomia. Herein, in this article, we probed into the role of miR-148a-3p in bone physiology by utilizing miR-148a knock-out (KO) mice. Compared with wild-type (WT) or heterozygotic (HE) littermates, miR-148a knock-out mice manifested lower body weight, bone dysplasia with increased bone mass. Through in-vitro experiments, in terms of miR-148a-3p overexpression (miRNA mimic transfection) and knockout (primary cells from WT and KO littermates), we found that miR-148a-3p can suppress osteogenesis, either in the ALP activity or bone nodules formation. Afterward, by means of proteomics, combined with RNA-sequencing and prediction databases of microRNA targets (miRDB and TargetScan), nine candidate genes targeted by miR-148a-3p were identified. Among them, only Itga11 was regulated by mRNA degradation, while the others were modulated via post-transcriptional inhibition. Based on several online databases (GenePaint, BioGPS, STRING), Integrin Subunit Alpha 11 (Itga11) was suggested to play an essential role in osteogenesis and it was confirmed as one direct target of miR-148a-3p by dual-luciferase reporter assay. Meanwhile, gene set enrichment analysis (GSEA) indicated activation of PI3K-Akt signaling pathway and WNT signaling pathway in miR-148a KO mice. The thereafter western blot confirmed that PI3K/Akt/GSK3/{beta}-catenin signaling pathway was involved. Taken together, we demonstrated that miR-148a-3p can inhibit osteogenesis by targeting Itga11 via PI3K/Akt/GSK3/{beta}-catenin pathway. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

The mammalian target of rapamycin (mTOR) operates within two distinct protein complexes—mTOR complex 1 (mTORC1) and complex 2 (mTORC2). These protein complexes are not yet fully understood, as they were only recently identified in humans in 1994. What researchers do know is that mTORC1 is involved in the regulation of many cellular processes and is a key mediator of cell growth and proliferation. mTORC1 is activated by growth factor receptor signals through the PI3K–AKT and RAS–ERK mitogen-activated protein kinase (MAPK) pathways. The PI3K/AKT/mTOR pathway may be an efficacious target in the treatment of patients with non-small cell lung cancer (NSCLC). This theory is based on the identification of particular gene mutations in NSCLC that are associated with the PI3K/AKT/mTOR pathway. However, previous studies have not yet succeeded in defining an effective monotherapy or combination of therapies that targets this pathway while improving NSCLC patient outcome. Researchers from Institut Curie, PSL University, Xentech, BioPôle Alfort, Hôpital Foch, and Centre Léon Bérard designed a study using a new methodology to test treatment combinations based on specific targets identified as biomarkers of resistance to PI3K-targeting treatments, and not based on the NSCLC mutations themselves. Their trending research paper was published by Oncotarget in 2021 and entitled, “High in vitro and in vivo synergistic activity between mTORC1 and PLK1 inhibition in adenocarcinoma NSCLC.” Full blog - https://www.oncotarget.org/2021/09/30/trending-with-impact-unconventional-method-effectively-targets-nsclc/ Press release - https://www.oncotarget.com/news/pr/mtorc1-and-plk1-inhibition-in-adenocarcinoma-nsclc/ Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.27930 DOI - https://doi.org/10.18632/oncotarget.27930 Full text - https://www.oncotarget.com/article/27930/text/ Correspondence to - Didier Decaudin - Didier.decaudin@curie.fr Keywords - NSCLC, Pi3K signalling pathway, mTORC1, RAD001 (everolimus), PLK1 About Oncotarget Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget YouTube - https://www.youtube.com/c/OncotargetYouTube/ LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit https://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Traditional Japanese food may hold building blocks of COVID-19 treatments Tokyo University of Agriculture and Technology, July 21, 2021 Natto, a fermented soybean dish often served for breakfast in Japan, originated at the turn of the last millennium but may hold an answer to a modern problem: COVID-19, according to a new study based on cell cultures.  Long thought to contribute to longer, healthier lives across Japan -- the country with the longest life expectancy on Earth and home to more than a quarter of the world's population aged 65 years or older -- natto was previously found to be a diet staple in those who were least likely to die from stroke or cardiac disease. Now, researchers have found that extract made from the sticky, strong smelling natto may inhibit the ability of the virus that causes COVID-19 to infect cells.  The team published its results on July 13th in Biochemical and Biophysical Research Communications.  "Traditionally, Japanese people have assumed that natto is beneficial for their health," said paper author Tetsuya Mizutani, director of the Center for Infectious Disease Epidemiology and Prevention Research at the Tokyo University of Agriculture and Technology (CEPiR-TUAT). "In recent years, research studies have revealed scientific evidence for this belief. In this study, we investigated natto's antiviral effects on SARS-CoV-2, the virus that causes COVID-19, and bovine herpesvirus 1 (BHV-1), which causes respiratory disease in cattle." Natto is made by fermenting soybeans with Bacillus subtilis, a bacteria found in plant and in soil. The researchers prepared two natto extracts from the food, one with heat and one without. They applied the extracts to sets of lab-cultured cells from cattle and from humans. One set was infected with SARS-CoV-2, while the other set was infected with BHV-1.  When treated with the natto extract made without heat, both SARS-CoV-2 and BHV-1 lost the ability to infect cells. However, neither virus appeared to be affected by the heat-treated natto extract.  "We found what appears to be a protease or proteases -- proteins that metabolize other proteins -- in the natto extract directly digests the receptor binding domain on the spike protein in SARS-CoV-2," Mizutani said, noting that the protease appears to break down in heat, losing the ability to digest proteins and letting the virus remain infectious.  The spike protein sits on the virus's surface and binds to a receptor on host cells. With an inactive spike protein, SARS-CoV-2 cannot infect healthy cells. The researchers found a similar effect on BHV-1.  "We also confirmed that the natto extract has the same digestive effects on the receptor binding domain proteins of the SARS-CoV-2 mutated strains, such as the Alpha variant," Mizutani said.  While the results are promising, Mizutani said, he also cautioned that further studies are needed to identify the exact molecular mechanisms at work. He also stressed that the research does not provide any evidence of reduced viral infection simply by eating natto. Once the components are identified and their functions verified, the researchers plan to advance their work to clinical studies in animal models.  "Although there are vaccines for COVID-19, we do not know how they effective they may be against every variant," Mizutani said. "It will also take time to vaccinate everyone, and there are still reports of breakthrough cases, so we need to make treatments for those who develop COVID-19. This work may offer a big hint for such pharmaceutical design."       Excess caffeine intake may be linked to an increased risk of osteoporosis   University of South Australia, July 19, 2021 University of South Australia researchers have a bone to pick when it comes to drinking too much coffee as new research finds that excess caffeine may be linked to an increased risk of osteoporosis. Investigating the effects of coffee on how the kidneys regulate calcium in the body, researchers found that high doses of caffeine (800 mg) consumed over a six-hour period almost doubled the amount of calcium lost in the urine. This is the first study to report the impact of high-dose, short-term caffeine intake on renal clearance of calcium, sodium, and creatinine in healthy adults. UniSA's Dr. Hayley Schultz says with the emergence of an increasing "coffee culture" it's important for people to understand the impacts of what they are putting into their bodies. "Caffeine is one of the most widely used recreational drugs in the world, with 80 percent of adults consuming at least one caffeinated beverage per day," Dr. Schultz says. "It's a common stimulant, consumed by professionals, parents, shift workers, and teenagers alike to start their day and stay alert—even the military use caffeine to help combat sleepiness.  "But while coffee has its perks, it's also important to acknowledge its fallbacks—one of them being how our kidneys handle calcium. "Our research found that people who consume 800 mg of caffeine over a typical working day will have a 77 percent increase in calcium in their urine, creating a potential deficiency that could impact their bones." Osteoporosis is a chronic, painful, and debilitating disease which makes your bones less dense and more susceptible to fracture. More common in women, it occurs when bones lose calcium and other minerals faster than the body can replace them. In Australia, an estimated 924,000 people have osteoporosis. The double-blind clinical study saw participants chew caffeine or a placebo gum for five minutes at two-hour intervals over a six-hour treatment period (total caffeine 800 mg). While the primary research objective was to examine the impact of caffeine consumption on wakefulness and other factors, this sub-study aimed to evaluate the impact of caffeine consumption on the renal clearance of calcium. Co-researcher, UniSA's Dr. Stephanie Reuter Lange says understanding the long-term impacts of high caffeine consumption is especially important for higher risk groups. "The average daily intake of caffeine is about 200 mg—roughly two cups of coffee. While drinking eight cups of coffee may seem a lot (800 mg of caffeine), there are groups who would fall into this category," Dr. Reuter Lange says. "People at risk could include teenagers who binge-consume energy drinks are at are at risk because their bones are still developing; professional athletes who use caffeine for performance enhancement; as well as post-menopausal women who often have low blood calcium levels due to hormonal changes and lack sufficient daily dietary calcium intake. "Increasingly, we are also seeing high levels of caffeine among shiftworkers who need to stay alert over the night-time hours, as well as those in the military who use caffeine to combat sleep deprivation in operational settings. "Caffeine in moderation certainly has its pros. But understanding how excess consumption could increase the risks of a highly preventable disease such as osteoporosis, is important." From here, researchers will explore and predict the impact of different levels of caffeine intake on short- and long-term bone health, with the aim to inform dietary guidelines in Australia.     From heart to diabetes, these are the health benefits of strawberries University of Nevada, July 16, 2021 Dietary berries, such as strawberries, are rich in bioactive compounds and have been shown to lower cardiometabolic risk. We examined the effects of two dietary achievable doses of strawberries on glycemic control and lipid profiles in obese adults with elevated serum LDL cholesterol (LDL-C).  Methods: In this 14-week randomized controlled crossover study, participants were assigned to one of the three arms for four weeks separated by a one-week washout period: control powder, one serving (low dose: 13 g strawberry powder/day), or two-and-a -half servings (high dose: 32 g strawberry powder/day). Participants were instructed to follow their usual diet and lifestyle while refraining from consuming other berries and related products throughout the study interval. Blood samples, anthropometric measures, blood pressure, and dietary and physical activity data were collected at baseline and at the end of each four-week phase of intervention.  Results: In total, 33 participants completed all three phases of the trial [(mean ± SD): Age: 53 ± 13 y; BMI: 33 ± 3.0 kg/m2). Findings revealed significant reductions in fasting insulin (p = 0.0002) and homeostatic model of assessment of insulin resistance (p = 0.0003) following the high dose strawberry phase when compared to the low dose strawberry and control phases. Glucose and conventional lipid profiles did not differ among the phases. Nuclear magnetic resonance-determined particle concentrations of total VLDL and chylomicrons, small VLDL, and total and small LDL were significantly decreased after the high dose strawberry phase, compared to control and low dose phases (all p < 0.0001). Among the biomarkers of inflammation and adipokines measured, only serum PAI-1 showed a decrease after the high dose strawberry phase (p = 0.002). Conclusions: These data suggest that consuming strawberries at two-and-a-half servings for four weeks significantly improves insulin resistance, lipid particle profiles, and serum PAI-1 in obese adults with elevated serum LDL-C.     Omega 3 has beneficial effects on reducing relapse rate, inflammatory markers in MS patients Imam Abdulrahman Bin Faisal University (Saudi Arabia), July 14, 2021 According to news originating from Dammam, Saudi Arabia, research stated, “Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system, resulting in the degradation of the myelin sheath. Diet especially fish oils and omega-3 has been found to play an important role in MS.” Our news journalists obtained a quote from the research from Imam Abdulrahman Bin Faisal University, “This work aimed to review the literature systematically for evidence on the effect of omega-3 fatty acids (EPA, DPA and DHA) on MS progression in adults. The literature search was conducted in PubMed, Oxford, Cochrane, Embase, International pharmaceutical abstract, PsychINFO, and clinical trials government. The inclusions were studies performed on humans both male and female, aged 18 years at minimum, diagnosed with MS according to McDonald 2010 criteria. Otherwise, all studies were excluded. A total of 5554 studies were screened and seven were thoroughly focused on as they typically met the inclusion criteria. These studies showed the beneficial roles of fish oil supplementation and omega-3 fatty acids in improving the quality of life of MS patients. These roles were attributed to their beneficial effects on inflammatory markers, glutathione reductase, reducing the relapsing rate, and achieving balanced omega-6 to omega-3 ratios.” According to the news editors, the research concluded: “Omega-3 and fish oils supplementations have beneficial effects on reducing the relapsing rate, inflammatory markers, and improving the quality of life for MS patients.” This research has been peer-reviewed.           Championing chrononutrition with protein, the morning elixir for muscle growth Waseda University (Japan), July 20, 2021 Proteins constitute an essential dietary component that help in the growth and repair of the body. Composed of long chains of amino acids, proteins promote the growth of skeletal muscles, the group of muscles that help us move. Humans have been aware of the benefits of proteins for long. However, recent studies have shown that having the right amount of protein at the right time of the day is essential for proper growth. This is called 'Chrononutrition,' in which when you eat is as important as what and how you eat. The reason behind this is the body's internal biological clock, called the 'circadian rhythm'. This rhythm is followed by all cells and controls life functions like metabolism and growth. Interestingly, protein digestion and absorption have been found to fluctuate across day and night according to this clock. Moreover, earlier studies have reported that intake of protein at breakfast and lunch promotes skeletal muscle growth in adults. However, details on the effect of the time of protein intake on muscle growth and function have remained elusive till date. Fortunately, researchers from Waseda University, led by Professor Shigenobu Shibata, recently endeavored to understand the effect of the distribution of protein intake through the day on muscles. They fed laboratory mice two meals per day containing either high (11.5% by proportion) or low (8.5% by proportion) protein concentrations. The researchers noted that protein intake at breakfast induced an increase in muscle growth, determined by assessing induced hypertrophy of the plantaris muscle in the leg, when compared with the effects of protein intake at dinner. Specifically, the ratio of muscle hypertrophy determined against the growth of the control muscle was 17% higher in mice fed 8.5% protein at breakfast, than that in mice fed 11.5% protein at dinner, despite the former group consuming a low proportion of protein overall. They also found that intake of a type of protein called the BCCA, short for branched-chain amino acids, early in the day increased the size of skeletal muscles specifically. To confirm the association of these effects with the workings of the circadian rhythm, the researchers next engineered whole-body mutant ClockΔ19 or muscle-specific Bmal1 knockout mice lacking the genes that control the biological clock. They repeated diet distribution experiments on these mice but did not observe similar muscle change, which confirmed the involvement of the circadian rhythm in muscle growth in the context of protein intake. Excited about the findings of their study published in a recent issue of the Cell Reports, Prof. Shibata emphasizes, "Protein-rich diet at an early phase of the daily active period, that is at breakfast, is important to maintain skeletal muscle health and enhance muscle volume and grip strength." To check if their findings were applicable to humans, the team recruited women in their study and tested if their muscle function, determined by measuring skeletal muscle index (SMI) and grip strength, varied with the timing of the protein-rich diet consumed. Sixty women aged 65 years and above who took protein at breakfast rather than at dinner showed better muscle functions, suggesting the possibility of the findings to be true across species. Additionally, the researchers also found a strong association between SMI and the proportion of protein intake at breakfast relative to total protein intake through the day. Prof. Shibata is hopeful that the findings of their study will lead to a widespread modification in the current diet regime of most people across the Western and Asian countries, who traditionally consume low amounts of protein at breakfast. He therefore stresses, "For humans, in general, the protein intake at breakfast averages about 15 grams, which is less than what we consume at dinner, which is roughly 28 grams. Our findings strongly support changing this norm and consuming more protein at breakfast or morning snacking time."   Ginseng compound exerts neuroprotective effects Gachon University (South Korea), July 16, 2021 According to news reporting from Gyeonggi Do, South Korea, research stated, “Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of b-amyloid plaques and hyperphosphorylated tau proteins in the brain.” The news correspondents obtained a quote from the research from Gachon University: “Cell signaling pathways such as PI3K/Akt are known to play an essential role in regulating cell survival, motility, transcription, metabolism, and progression of the cell cycle. Recent studies demonstrated that the disruption of these signaling pathways in neurodegenerative disorders leads to oxidative stress and cell death. Targeting these altered signaling pathways could be considered as the therapeutic approach for neurodegenerative disorders. Ginsenoside Rh1 is known to provide beneficial effects in various diseases such as cancer, diabetes, and inflammation. In this study, human neuroblastoma SH-SY5Y cells were treated with the b-amyloid oligomers alone or in combination with ginsenoside Rh1. We observed that ginsenoside Rh1 was able to attenuate b-amyloid induced oxidative stress and cell death by activating the PI3K/Akt signaling pathway.” According to the news reporters, the research concluded: “Based on these findings, we suggest that ginsenoside Rh1 might be an efficacious therapeutic agent for AD.”     Many kinds of happiness promote better health, study finds Weill Cornell University of Medicine, July 21, 2021  A new study links the capacity to feel a variety of upbeat emotions to better health. The research suggests people who experience a range of positive emotions in their daily lives – from enthusiasm to cheerfulness and calm – have lower levels of inflammation, compared to those who experience a narrower range of emotions. Lower levels of inflammation are linked to a lower risk of premature death and chronic diseases like diabetes. The researchers drew on analytic approaches used to measure the biodiversity of ecosystems. Their study was published June 22 in the journal Emotion. "There are many kinds of happiness, and experiencing a diversity of emotional states might reduce a person's vulnerability to psychopathology by preventing any one emotion from dominating their emotional life," said lead author Anthony Ong, professor of human development in the College of Human Ecology and professor of geriatrics and palliative medicine at Weill Cornell Medicine. Little is known about the biological processes through which emotional experiences influence health outcomes. This study sought to fill a bit of that gap. Specifically, the study sheds light on one potential biological pathway – systemic inflammation – through which diversity in everyday positive emotional experiences might "get under the skin" to influence long-term health. Ong and his colleagues analyzed the connection between "emodiversity" – the breadth and abundance of different emotions people experience – and markers of inflammation in the body. A person with low emodiversity feels about the same through most of the day, with emotions concentrated in just a few categories. In contrast, a person with high emodiversity feels a range of emotions throughout the day, distributed evenly across the spectrum of feelings. The researchers analyzed data from 175 people ages 40 to 65 who reported on their negative and positive emotions for 30 days. Each evening, they rated the extent to which they had experienced 16 positive emotions that day, from interested and determined to happy, excited, amused, inspired, alert, active and strong. They were also asked to rate their experience of 16 negative emotions, including scared, afraid, upset, distressed, jittery, nervous and ashamed. Their blood was drawn six months later and was tested for three inflammation markers that circulate in the blood. Their range of negative emotions – regardless of whether it was narrow or wide – had no effect on inflammation. But people in the study who reported a wide range of positive emotions had lower levels of inflammation than those who said they felt a narrower range. "Emotions serve functional roles for individuals, helping them prioritize and regulate behavior in ways that optimize adjustment to situational demands," Ong said. "Our findings suggest that depletion or overabundance of positive emotions, in particular, has consequences for the functioning and health of one's emotional ecosystem." Growing evidence from other research has linked emotional processes with systemic inflammation, which has been shown to contribute to poor health, such as atherosclerosis, diabetes, rheumatoid disease and osteoporosis, and leads to a number of processes that play a major role in premature death. How can these findings help one achieve better health? Label your good feelings as you experience them, Ong said. "The simple daily practice of labeling and categorizing good feelings in specific terms may help us experience more differentiated emotions in different contexts," Ong said.

Growing evidence fruit may lower type 2 diabetes risk Research has found eating at least two serves of fruit daily has been linked with 36% lower odds of developing type 2 diabetes Edith Cowan University (Australia), June 2, 2021 Eating at least two serves of fruit daily has been linked with 36 percent lower odds of developing type 2 diabetes, a new Edith Cowan University (ECU) study has found.  The study, published today in the Journal of Clinical Endocrinology and Metabolism, revealed that people who ate at least two serves of fruit per day had higher measures of insulin sensitivity than those who ate less than half a serve.  Type 2 diabetes is a growing public health concern with an estimated 451 million people worldwide living with the condition. A further 374 million people are at increased risk of developing type 2 diabetes. The study's lead author, Dr Nicola Bondonno from ECU's Institute for Nutrition Research, said the findings offer fresh evidence for the health benefits of fruit.  "We found an association between fruit intake and markers of insulin sensitivity, suggesting that people who consumed more fruit had to produce less insulin to lower their blood glucose levels," said Dr Bondonno.  "This is important because high levels of circulating insulin (hyperinsulinemia) can damage blood vessels and are related not only to diabetes, but also to high blood pressure, obesity, and heart disease. "A healthy diet and lifestyle, which includes the consumption of whole fruits, is a great strategy to lower your risk of developing type 2 diabetes." Fresh is best The study examined data from 7,675 Australians participating in the Baker Heart and Diabetes Institute's AusDiab Study and assessed fruit and fruit juice intake and the prevalence of diabetes after five years. Dr Bondonno said they did not observe the same beneficial relationship for fruit juice.  "Higher insulin sensitivity and a lower risk of diabetes was only observed for people who consumed whole fruit, not fruit juice," she said.  "This is likely because juice tends to be much higher in sugar and lower in fibre."  Dr Bondonno said that it's still unclear exactly how fruit contributes to insulin sensitivity, but it is likely to be multifaceted.  "As well as being high in vitamins and minerals, fruits are a great source of phytochemicals which may increase insulin sensitivity, and fibre which helps regulate the release of sugar into the blood and also helps people feel fuller for longer," she said. "Furthermore, most fruits typically have a low glycaemic index, which means the fruit's sugar is digested and absorbed into the body more slowly."  The study builds on Dr Bondonno's research into the health benefits of fruit and vegetables, particularly those that contain a key nutrient known as flavonoids. The research is part of ECU's Institute of Nutrition Research.     Ginkgo biloba leaves have multicomponent and multitarget synergistic effects on treatment of neurodegenerative diseases Jiangsu Kanion Pharmaceutical Co (China), June 1, 2021 According to news reporting out of Jiangsu, People's Republic of China, research stated, “Ginkgo biloba L. leaves (GBLs), as widely used plant extract sources, significantly improve cognitive, learning and memory function in patients with dementia. However, few studies have been conducted on the specific mechanism of Neurodegenerative diseases (NDs).” Our news journalists obtained a quote from the research from Jiangsu Kanion Pharmaceutical Co. Ltd., “In this study, network pharmacology was employed to elucidate potential mechanism of GBLs in the treatment of NDs. Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) was used to obtain the chemical components in accordance with the screening principles of oral availability and drug-like property. Potential targets of GBLs were integrated with disease targets, and intersection targets were exactly the potential action targets of GBLs for treating NDs; these key targets were enriched and analyzed by the protein protein interaction (PPI) analysis and molecular docking verification. Key genes were ultimately used to find the biological pathway and explain the therapeutic mechanism by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Twenty-seven active components of GBLs may affect biological processes such as oxidative reactions and activate transcription factor activities. These components may also affect 120 metabolic pathways, such as the PI3K/AKT pathway, by regulating 147 targets, including AKT1, ALB, HSP90AA1, PTGS2, MMP9, EGFR and APP. By using the software iGEMDOCK, the main target proteins were found to bind well to the main active components of GBLs.” According to the news editors, the research concluded: “GBLs have the characteristics of multi-component and multi-target synergistic effect on the treatment of NDs, which preliminarily predicted its possible molecular mechanism of action, and provided the basis for the follow-up study.” This research has been peer-reviewed.     Diets that promote inflammation could increase breast cancer risk Analysis of dietary patterns for over 350,000 women suggests eating more anti-inflammatory foods helps lower risk Catalan Institute of Oncology and Biomedical Research Institute (Spain) June 7, 2021  A new study of more than 350,000 women found that women with diets incorporating more foods that increase inflammation in the body had a 12% increase in their risk of breast cancer compared to women who consume more anti-inflammatory diets. The new findings are being presented at NUTRITION 2021 LIVE ONLINE.  The study authors found that moving from a more anti-inflammatory diet toward one that increases inflammation upped breast cancer risk in an almost linear manner. Foods that increase inflammation include red and processed meat; high-fat foods such as butter, margarines and frying fats; and sweets including sugar, honey and foods high in sugar. Fruits, vegetables, legumes, tea and coffee all have potentially anti-inflammatory properties. "Most studies examining diet and breast cancer risk have focused on single nutrients or foods rather than the whole diet," said the study's first author Carlota Castro-Espin, a predoctoral fellow at the Catalan Institute of Oncology and Bellvitge Biomedical Research Institute in Barcelona, Spain. "People consume food not nutrients, thus examining overall dietary patterns, rather than single components of diets can lead to more accurate conclusions when analysing associations with a health outcome such as breast cancer."  The new results are based on data from the European Investigation into Cancer and Nutrition (EPIC) study, a prospective study that recruited more than 500,000 participants across 10 European countries starting in the mid-1990s. The study included more than 13,000 breast cancer diagnoses during approximately 15 years of follow-up.  The typical diet for EPIC participants was measured for a year using food frequency or diet history questionnaires. The researchers used this information to calculate an inflammatory score for each study participant based on their intake of 27 foods.  The researchers examined dietary patterns linked with inflammation because long-term, low grade inflammation has been linked with the development of breast cancer. The large number of women in the study allowed the researchers to take a more nuanced look at the relationship between dietary patterns and breast cancer risk.  Their analysis showed that the increase in breast cancer risk due to pro-inflammatory diets appears to be more pronounced among premenopausal women. They also found that the association did not vary by breast cancer hormone receptor subtypes.  "Our results add more evidence of the role that dietary patterns play in the prevention of breast cancer," said Castro-Espin. "With further confirmation, these findings could help inform dietary recommendations aimed at lowering cancer risk."  As a next step, the researchers plan to evaluate the association of the inflammatory potential of diet and other dietary patterns with breast cancer survival using participants in the EPIC study.      Emerging impact of quercetin in the treatment of prostate cancer Shahid Beheshti University of Medical Sciences (Iran), June 3, 2021   According to news originating from Tehran, Iran, research stated, “Quercetin is a flavonoid agent detected in fruits and vegetables with anti-inflammatory, antioxidant, and anticancer effects. This flavonoid can suppress cell cycle transition and induce apoptosis in neoplastic cells.” Our news reporters obtained a quote from the research from Shahid Beheshti University of Medical Sciences: “Therapeutic effects of quercetin have been assessed in diverse cancers including prostate cancer through the establishment of in vitro and in vivo experiments. Moreover, this agent might prevent the initiation of this type of cancer as it indirectly blocks the activity of promoters of two important genes in the pathogenesis of prostate cancer i.e. androgen receptor (AR) and prostate specific antigen (PSA). Several in vitro investigations have identified the differential influence of quercetin on normal prostate cells versus neoplastic cells, emphasizing its specific cytotoxic effects on cancerous cells. The most appreciated route of quercetin effect on prostate cancer cells is the detachment of Bax from Bcl-xL and the stimulation of caspase families. Besides, quercetin might enhance the effects of other therapeutic options against prostate cancer. For instance, a combination of TNF-related apoptosis-inducing ligand (TRAIL) and quercetin has been recommended as a novel modality for the treatment of prostate cancer.” According to the news editors, the research concluded: “These kinds of strategies might overcome resistance to apoptosis in cancer cells. In the current paper, we summarize the recent data about the preventive and therapeutic influences of quercetin in prostate cancer.”     Breast microbiome modified by diet, fish oil Wake Forest School of Medicine, June 4 2021.    Findings reported on June 3, 2021 in Cancer Research add evidence to the effects of diet on the breast's microbiome, the community of microorganisms that exists in breast tissue.  “We have recently demonstrated that dietary patterns modulate mammary microbiota populations,” wrote David R. Soto-Pantoja and colleagues. “An important and largely open question is whether the microbiome of the gut and mammary gland mediates the dietary effects on breast cancer.” To help answer this question, the researchers fed a high fat or a control diet to mice that are susceptible to developing breast cancer. Animals that received the high fat diet had a greater number of tumors, more rapid tumor growth and larger tumor size than those that received the control diet.  Next, mice that were given high fat diets received fecal transplants from mice that received control diets, and control diet-fed animals received transplants from high fat diet-fed animals. The team found that animals that received the control diet developed as many tumors as mice that received the high fat diet.   In a double-blind trial, breast cancer patients were given fish oil supplements or a placebo for two to four weeks prior to surgical removal of their tumors. The researchers observed a change in the microbiota of tumor and normal breast tissue in participants who received fish oil, including an increase in Lactobacilli (which has been associated with reduce breast cancer tumor growth in animals) in normal tumor-adjacent breast tissue of participants who received fish oil for four weeks.  "Obesity, typically associated with a high-fat diet consumption, is a well-known risk factor in postmenopausal breast cancer," commented coauthor Katherine L. Cook, PhD, of Wake Forest University. "This study provides additional evidence that diet plays a critical role in shaping the gut and breast microbiome."     Self-administered aroma foot massage may reduce symptoms of anxiety   Okayama University (Japan), June 8, 2021  Researchers at Okayama University conduct the first community-based study on the effects of self-administered aromatherapy foot massage on stress and anxiety symptoms. The results suggest aromatherapy massages might provide an inexpensive, simple way of managing anxiety.   The continuing popularity of complementary therapies, such as aromatherapy and massage, has prompted scientists to investigate the effects of such therapies on the body in more detail. Complementary therapies are said to reduce the symptoms associated with stress and anxiety, and therefore may reduce the chances of severe illness, such as hypertension and heart disease. The precise effects on the body following such therapies is unclear, however.   Previous studies have focused on the effects of massage and aromatherapy treatments on blood pressure and mental state in hospitalized patients in Japan, but none have been conducted on individuals living in the community. Now, Eri Eguchi and co-workers at Okayama University, together with researchers across Japan, have conducted the first study into the effect of aromatherapy-based foot massage on blood pressure, anxiety and health-related quality of life in people living in the community.   57 participants took part in the study; 52 women and 5 men. Baseline blood pressure and heart rate values were taken at the start and end of the four-week trial period, as well as at a follow-up session 8 weeks later. Participants also completed questionnaires on anxiety status and health-related quality of life at each stage of the trial. The participants were divided into two groups, and one group were taught to perform a 45-minute aromatherapy-based foot massage on themselves three times a week for four weeks.   The results suggest that aroma foot massage decreased the participants' average blood pressure readings, and state of anxiety, and tended to increased mental health-related quality of life score. However the effect of massages was not significant with changes in other factors such as physical health-related quality of life scores and heart rate.   In their paper published in March 2016 in PLOS One, Eguchi's team are cautiously optimistic about the potential for self-administered massage to reduce anxiety in the population: "[although] it was difficult to differentiate the effects of the aromatherapy from the effects of the massage therapy... [the combination] may be an effective way to increase mental health and improve blood pressure."     Aromatherapy and massage Aromatherapy has long been used to relieve stress and anxiety in populations across the globe. Different aroma essential oils are said to have different properties, and are used to induce relaxation and promote well-being. Trials have indicated that certain essential oils, when inhaled, can reduce blood pressure levels and alleviate depression by stimulating the olfactory system. Massage (in its many forms) also has a long history in therapeutic medicine, and the practice of manipulating key pressure points in the body to induce relaxation has been shown to improve mental and physical health. However, detailed scientific studies of the effects of aromatherapy foot massage – an increasingly popular treatment in Japan – on blood pressure and perceived quality of life are limited.   Significance and further work While the trial carried out by Eguchi and her team is limited in some respects, their results provide an initial starting point from which to extend studies into the benefits of aroma foot massage for the general population. Their findings that massage, or the aromatherapy, or a combination of both, reduce blood pressurereadings (at least in the short term) warrants further investigation. Eguchi and her team acknowledge that their decision to advertise for participants may have encouraged more health-conscious and pro-active people to apply. They also received far more applications from women than men, although their age-range (from 27 to 72) was diverse. Further work is needed to determine the effect of aroma foot massage on specific age and sex categories, for example, before such interventions are encouraged in the wider population.     Proteomics reveals how exercise increases the efficiency of muscle energy production University of Copenhagen (Denmark), May 27, 2021 Mitochondria are the cell's power plants and produce the majority of a cell's energy needs through an electrochemical process called electron transport chain coupled to another process known as oxidative phosphorylation. A number of different proteins in mitochondria facilitate these processes, but it's not fully understood how these proteins are arranged inside mitochondria and the factors that can influence their arrangement. Now, scientists at the University of Copenhagen have used state-of-the-art proteomics technology to shine new light on how mitochondrial proteins gather into electron transport chain complexes, and further into so-called supercomplexes. The research, which is published in Cell Reports, also examined how this process is influenced by exercise training.  "This study has allowed for a comprehensive quantification of electron transport chain proteins within supercomplexes and how they respond to exercise training. These data have implications for how exercise improves the efficiency of energy production in muscle," says Associate Professor Atul S. Deshmukh from the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen.  Traditional methods provide too little detail It is already well established that exercise training stimulates mitochondrial mass and affects the formation of supercomplexes, which allows mitochondria in skeletal muscle to produce energy more efficiently. But questions remain about which complexes cluster into supercomplexes and how. To better understand supercomplex formation, particularly in response to exercise, the team of scientists studied two groups of mice. One group was active, and given an exercise wheel for 25 days, and the second group was sedentary, and was not provided the exercise wheel. After 25 days, they measured the mitochondrial proteins in skeletal muscle from both groups to see how the supercomplexes had changed over time.  When scientists typically analyze how supercomplexes form, they use antibodies to measure one or two proteins per electron transport chain complex. But as there can be up to 44 proteins in a complex, this method is both time consuming and provides limited information about what happens to the remainder of the proteins in each complex.  As a result, there is a lack of detailed knowledge in the field. Proteomics helps supercomplexes give up their secrets To generate much more detailed data, the team applied a proteomic technology called mass spectrometry to measure the mitochondrial proteins. By applying proteomics instead of antibodies, the scientists were able to measure nearly all of the proteins in each complex. This provided unprecedented detail of mitochondrial supercomplexes in skeletal muscle and how exercise training influences their formation. Their approach demonstrated that not all of the proteins in each complex or a supercomplex respond to exercise in the same manner.  "Mitochondrial protein content is known to increase with exercise, thus understanding how these proteins assemble into supercomplexes is crucial to decipher how they work. Our research represents a valuable and precious resource for the scientific community, especially for those studying how the mitochondrial proteins organize to be better at what they do best: produce energy under demand,", explains Postdoc Alba Gonzalez-Franquesa. The interdisciplinary project was a collaboration between the Deshmukh, Treebak and Zierath Groups at CBMR, and the Mann Group at the Novo Nordisk Foundation Center for Protein Research.

Study presents evidence supporting the use of curcumin as alternative treatment for kidney fibrosis Zhejiang University (China), May 7, 2021 In a recent study, Chinese researchers explored the anti-fibrotic effects of curcumin, the active component of turmeric. Specifically, they looked at how curcumin affects epithelial-mesenchymal transition (EMT) and the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. EMT refers to epithelial cells undergoing molecular changes and gaining new characteristics, such as an enhanced ability to produce ECM components. Meanwhile, the PI3K/Akt pathway is one of the major cell signaling pathways that regulate fibrosis. The researchers reported their findings in an article published in the journal Biological and Pharmaceutical Bulletin. Curcumin is an effective alternative treatment for renal fibrosis According to several animal studies, curcumin can protect the kidneys by preventing the development of renal fibrosis. However, the mechanisms underlying this activity are still unknown. To explore these mechanisms and the anti-fibrotic activities of curcumin, the researchers treated human kidney tubular epithelial cells (HKCs) with transforming growth factor-B1 (TGF-B1), curcumin and a combination of both. TGF-B1 is a protein that’s involved in many cellular functions, including cell growth, proliferation, differentiation and death, as well as the induction of EMT. The researchers used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to assess the effect of curcumin on cell proliferation. They also used immunocytochemistry, real-time PCR and Western blot to analyze the expression of epithelial cell markers (E-cadherin and cytokeratin), mesenchymal cell markers (vimentin, alpha smooth muscle actin (a-SMA) and fibroblast-specific protein 1 (FSP1)) and key proteins involved in the Akt/mammalian target of rapamycin (mTOR) pathway. The researchers found that low-dose curcumin (3.125 and 25?micromol/L) effectively promoted HKC proliferation. After 72 hours of incubating HKCs with TGF-B1 and curcumin, curcumin caused the cells to maintain epithelial morphology in a dose-dependent manner. It also decreased the expression of EMT-related proteins, such as vimentin, a-SMA and FSP1, and increased the expression of E-cadherin and cytokeratin. In addition, the researchers noted that curcumin reduced Akt, mTOR and P70S6K phosphorylation, which effectively suppressed the activation of the Akt/mTOR pathway in HKCs. Based on these findings, the researchers concluded that curcumin is an effective alternative treatment for renal fibrosis because it can promote HKC proliferation and stop EMT by inhibiting the activation of the Akt/mTOR pathway activity.     Research reveals new approach to understanding our wellbeing Swansea University, May 12, 2021 The ability to connect and feel a sense of belonging are basic human needs but new Swansea University research has examined how these are determined by more than just our personal relationships. Research led by psychologist Professor Andrew Kemp, of the College of Human and Health Sciences, highlights the importance of taking a wider approach to wellbeing and how it can be influenced by issues such as inequality and anthropogenic climate change. Professor Kemp worked with Ph.D. student Jess Mead and consultant clinical psychologist Dr. Zoe Fisher, of the University's Health and Wellbeing Academy, on the study which presents a transdisciplinary framework to help understand and improve wellbeing. Professor Kemp said: "We define wellbeing as positive psychological experience, promoted by connections to self, community and environment, supported by healthy vagal function, all of which are impacted by socio-contextual factors that lie beyond the control of the individual." The researchers say their latest findings, which have just been published in Frontiers in Psychology, are particularly topical as society looks to recover and learn from COVID-19. He said: "Our framework has already contributed to a better understanding of how to protect wellbeing during the pandemic and has led to the development of an innovative wellbeing science intervention, targeting university students and people living with acquired brain injury." Professor Kemp added: "We feel our invited paper is timely as it not only aligns with a post-pandemic future that requires societal transformation, but it also picks up on global efforts to promote planetary wellbeing. "Globalization, urbanization and technological advancements have meant that humans have become increasingly disconnected from nature. This continues despite research showing that contact with nature improves wellbeing." The research reveals the advantages to health and wellbeing derived from connecting to oneself, others and nature and emphasizes a need for focused efforts to tackle major societal issues that affect our capacity for connection. He added: "The poorest are disproportionally impacted by major societal challenges including increasing burden of chronic disease, societal loneliness and anthropogenic climate change. "Economic inequality has adverse impacts on the entire population, not just the poor, so improving economic inequality is fundamental to improving population wellbeing." Taking a transdisciplinary approach to the topic of wellbeing is something currently reflected across Swansea University, particularly since the opening of the Morgan Advanced Studies Institute (MASI) which is dedicated to supporting transformative interdisciplinary research.   Taurine’s neuroprotective effect on cells under oxidative stress   University of Vale do Paraiba (Brazil), May 10, 2021 According to news reporting based on a preprint abstract, our journalists obtained the following quote sourced from biorxiv.org: “Alzheimer’s disease (AD) is a type of dementia that affects millions of people. Although there is no cure, several study strategies seek to elucidate the mechanisms of the disease. Recent studies address the benefits of taurine. Thus, the present study aims to analyze the neuroprotective effect of taurine on human neuroblastoma, using an in vitro experimental model of oxidative stress induced by hydrocortisone in the SH-SY5Y cell line as a characteristic model of AD. “The violet crystal assay was used for cell viability and the evaluation of cell morphology was performed by scanning electron microscopy (SEM). After pretreatment with taurine, the SH-SY5Y cell showed an improvement in cell viability in the face of oxidative stress and improved cell morphology. Thus, the treatment presented a neuroprotective effect.” This preprint has not been peer-reviewed.     Efficacy of magnesium oxide and sodium valproate in prevention of migraine headache: a randomized, controlled, double-blind, crossover study Mazandaran University of Medical Sciences (Iran), May 4, 2021 According to news originating from Sari, Iran, by NewsRx correspondents, research stated, “Migraine is a disabling disorder that affects the quality of life of patients. Different medications have been used in prevention of migraine headache.” Our news journalists obtained a quote from the research from the Mazandaran University of Medical Sciences, “In this study, we evaluated the effectiveness of magnesium oxide in comparison with valproate sodium in preventing migraine headache attacks. This is a single-center, randomized, controlled, crossover trial which is double-blind, 24-week, 2-sequence, 2-period, 2-treatment. After patient randomization into two sequences, the intervention group received magnesium oxide 500 mg and the control group received valproate sodium 400 mg two tablets each day (every 12 h) for 8 weeks. The primary efficacy variable was reduction in the number of migraine attacks and number of days with moderate or severe headache and hours with headache (duration) per month in the final of 8 weeks in comparison with baseline. Seventy patients were randomized and seven dropped out, leaving 63 for analysis. In an intention-to-treat analysis, 31 patients were in group 1 (magnesium oxide-valproate) and 32 patients were in group 2 (valproate-magnesium oxide). The mean number of migraine attacks and days per month was 1.72 +/- 1.18 and 2.09 +/- 1.70, with a mean duration of 15.50 +/- 21.80 h in magnesium group and 1.27 +/- 1.27 and 2.22 +/- 1.96, with a mean duration 13.38 +/- 14.10 in valproate group.” According to the news editors, the research concluded: “This study has shown that 500 mg magnesium oxide appears to be effective in migraine prophylaxis similar to valproate sodium without significant adverse effect.” This research has been peer-reviewed       Vitamin D and calcium from food is associated with lower risk of early menopause University of Massachusetts, May 10, 2021 A new study led by epidemiologists at the University of Massachusetts Amherst's School of Public Health and Health Sciences suggests that high intake of dietary vitamin D and calcium may be modestly associated with lower risk of early menopause, the cessation of ovarian function before age 45. Early menopause affects about 10 percent of women and is associated with higher risk of cardiovascular disease, osteoporosis and early cognitive decline. Epidemiology doctoral candidate Alexandra Purdue-Smithe and her advisor Elizabeth Bertone-Johnson, with colleagues at Brigham and Women's Hospital, Boston, and Harvard Medical School, evaluated how vitamin D and calcium intake is associated with incidence of early menopause in the prospective Nurses' Health Study II. The study population includes 116,430 female U.S. registered nurses who were 25-42 years old when they responded to a baseline questionnaire. Diet was assessed five times over the 20-year study, allowing the researchers to capture changes in food and nutrient intake over time, Purdue-Smithe notes. Participants in the study contributed more than 1 million person-years of follow-up, during which 2,041 women experienced early menopause. The authors report the hazard ratio for early menopause comparing the highest vs. lowest dietary vitamin D intake groups was 0.83 (95% confidence interval = 0.72-0.95) and for dietary calcium 0.87 (95% CI=0.76-1.00). Details of the study, supported by the National Institutes of Health, appear in the current early online edition of the American Journal of Clinical Nutrition. Purdue-Smithe says, "Laboratory evidence relating vitamin D to some of the hormonal mechanisms involved in ovarian aging provided the foundation for our hypothesis. However, to our knowledge, no prior epidemiologic studies have explicitly evaluated how vitamin D and calcium intake may be related to risk of early menopause. We found that after adjusting for a variety of different factors, vitamin D from food sources, such as fortified dairy and fatty fish, was associated with a 17 percent lower risk of early menopause when comparing the highest intake group to the lowest intake group." Because higher intake of vitamin D and calcium from foods may simply act as a marker for better nutrition and overall health, Purdue-Smithe says, the researchers took into account other factors such as intake of vegetable protein and alcohol, as well as body mass index and smoking. She adds, "The large size of this study allowed us to consider a variety of potential correlates of a healthy lifestyle that might explain our findings; however, adjusting for these factors made almost no difference in our estimates." The nutritional and reproductive epidemiologist notes that "in addition to placing women at higher risk of adverse future health outcomes, early menopause is also problematic as women are increasingly delaying childbearing into their later reproductive years. Fertility declines drastically during the 10 years leading up to menopause, so early menopause can have profound psychological and financial implications for couples who are unable to conceive as they wish. As such, it is important to identify modifiable risk factors for early menopause, such as diet." Because associations were stronger for vitamin D and calcium from dairy sources than from non-dairy food sources in the study, and Purdue-Smithe plans further analyses investigating individual dairy foods and other components of dairy and how they may be associated with early menopause.     High levels of exercise linked to 9 years of less aging at the cellular level Brigham Young University, May 10, 2021 Despite their best efforts, no scientist has ever come close to stopping humans from aging. Even anti-aging creams can't stop Old Father Time. But new research from Brigham Young University reveals you may be able to slow one type of aging--the kind that happens inside your cells. As long as you're willing to sweat. "Just because you're 40, doesn't mean you're 40 years old biologically," Tucker said. "We all know people that seem younger than their actual age. The more physically active we are, the less biological aging takes place in our bodies." The study, published in the medical journal Preventive Medicine, finds that people who have consistently high levels of physical activity have significantly longer telomeres than those who have sedentary lifestyles, as well as those who are moderately active. Telomeres are the protein endcaps of our chromosomes. They're like our biological clock and they're extremely correlated with age; each time a cell replicates, we lose a tiny bit of the endcaps. Therefore, the older we get, the shorter our telomeres. Exercise science professor Larry Tucker found adults with high physical activity levels have telomeres with a biological aging advantage of nine years over those who are sedentary, and a seven-year advantage compared to those who are moderately active. To be highly active, women had to engage in 30 minutes of jogging per day (40 minutes for men), five days a week. "If you want to see a real difference in slowing your biological aging, it appears that a little exercise won't cut it," Tucker said. "You have to work out regularly at high levels." Tucker analyzed data from 5,823 adults who participated in the CDC's National Health and Nutrition Examination Survey, one of the few indexes that includes telomere length values for study subjects. The index also includes data for 62 activities participants might have engaged in over a 30-day window, which Tucker analyzed to calculate levels of physical activity. His study found the shortest telomeres came from sedentary people--they had 140 base pairs of DNA less at the end of their telomeres than highly active folks. Surprisingly, he also found there was no significant difference in telomere length between those with low or moderate physical activity and the sedentary people. Although the exact mechanism for how exercise preserves telomeres is unknown, Tucker said it may be tied to inflammation and oxidative stress. Previous studies have shown telomere length is closely related to those two factors and it is known that exercise can suppress inflammation and oxidative stress over time. "We know that regular physical activity helps to reduce mortality and prolong life, and now we know part of that advantage may be due to the preservation of telomeres," Tucker said.       How isolation affects memory and thinking skills Harvard University, May 2021 We've all been isolated from many family members and friends during the pandemic. If you've been having a harder time remembering things or processing information since the pandemic began, it could be an isolation side effect. "It's something I'm seeing clinically. Some people were okay before the pandemic and now they're having faster cognitive decline," says Dr. Joel Salinas, a behavioral neurologist and faculty member of the Harvard Center for Population and Development Studies. Dr. Salinas says we don't have a lot of evidence yet to back up a clear association between pandemic lockdowns and a change in memory or thinking skills. One small 2020 study found that 60% of people with mild cognitive impairment or Alzheimer's disease experienced worsening cognition and delirium during the lockdown. But the link between isolation and cognitive decline is more than speculation. Isolation risks Isolation (being cut off from social contact) was a problem for older adults long before the pandemic began. Life circumstances — such as living far from friends and family, losing a partner, or being unable to drive — often create unanticipated situations in which we find ourselves isolated. That sometimes puts health in jeopardy. "In studies of people, isolation is associated with an increased risk for dementia, although it's unclear how high the risk is," Dr. Salinas says. "In lab animals, isolation has been shown to cause brain shrinkage and the kind of brain changes you'd see in Alzheimer's disease — reduced brain cell connections and reduced levels of brain-derived neurotrophic factor, which is important for the formation, connection, and repair of brain cells." Isolation is also associated with elevated risks for heart attack, stroke, chronic inflammation, depression, anxiety, perceived stress, and loneliness. People who feel lonely (disconnected from others) have been shown to have faster rates of cognitive decline than people who don't feel lonely. Loneliness is also tied to risks of losing the ability to take care of yourself and early death. What's the link? We don't exactly know why being isolated sometimes leads to cognitive decline. Possibilities include a lack of access to crucial resources or help with daily needs a decrease in stimulating mental activity that can come from social interaction a reduction in social support. "Having access to others for emotional support or listening to you seems to have a protective brain health effect — increased levels of brain-derived neurotrophic factor, and reduced risks for dementia or stroke," Dr. Salinas says. In the pandemic, you may also be experiencing high stress levels, which can affect your brain's processing skills. "We're not good at being focused when there's danger," Dr. Salinas says. "It's the 'fight or flight' mode all the time." If family members are noticing that you seem to be experiencing cognitive changes, Dr. Salinas says it could be a new problem — or it could be that you're spending more time together and they're picking up on changes that were already occurring before the pandemic.

Authentic Biochemistry Podcast 29 December 2020 Daniel J. Guerra Ph.D. •All scientific inquiry should start with dialectical method that uses the current knowledge base to generate various specific Theses and then follow each with the counter-argument by employing the Square of Opposition thus producing Anti-theses and then, making the third movement, which allows for a Synthesis that has the flavor of rejection, acceptance or indifference. *Downstream of co-stimulation and PI3K-AKT, the mammalian target of Rapamycin (mTOR) kinase pathway integrates multiple signals and regulates anabolic metabolic reprogramming in T cells exiting quiescence. mTOR complex 1 (mTORC1) is required for cell cycle entry and coordination of early metabolic changes that occur upon T cell activation. *T cells deficient in Raptor, an essential component of mTORC1, fail to upregulate the expression of Glut1 and other glycolytic enzymes when activated. *Raptor-deficient T cells also exhibit defects in de novo lipid synthesis and oxidative phosphorylation, suggesting the mTOR pathway is a global regulator of T cell metabolic programs. *mTORC1-mediated signaling is also required for proteomic remodeling of pathways including one-carbon metabolism(SAM and Folic acid), FAO, and the electron transport chain (ETC) that occurs early in activating T cells. --- 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/2020.10.15.341115v1?rss=1 Authors: Tan, Y., Zhao, X., Zhao, J., Ji, Q., Xiao, L., Hao, D. Abstract: The polyphagous pest Apolygus lucorumhas become the dominant insect in Bacillus thuringiensis (Bt) cotton fields. The hormone 20-hydroxyecdysone (20E) regulates multiple events in insect development and physiology. 20E responses are controlled by pathways triggered by phospholipase C (PLC)-associated proteins. However, 20E-modulated genes whose expression is affected by PLC remain unknown. Here, isobaric tag for relative and absolute quantitation (iTRAQ) and immunoblot were carried out for comparing differentially expressed proteins (DEPs) in A. lucorumin response to 20E and the PLC inhibitor U73122, respectively. Totally 1624 DEPs were, respectively, found in the 20E/control, U73122/control, and 20E+U73122/control groups. Venn diagram analysis further revealed 8 DEPs that were shared among the three groups. Immunoblot validated these findings, which corroborated and highlighted the reliability of proteomics. KEGG enrichment analysis showed that the DEPs were included in diverse signaling pathways. The largest portion of DEPs among the three groups were categorized in metabolic pathways. In addition, DEPs among the three groups were also found to regulate the Ras-MAPK and PI3K-AKT pathways. This is the first time that iTRAQ was carried out to assess proteome alteration in A. lucorum nymphs in response to 20E and a PLC inhibitor. These findings provide novel insights into protein expression in A. lucorumin response to 20E, and a more comprehensive understanding of the function of PLC in 20E signal transduction. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.14.340067v1?rss=1 Authors: Okerman, T., Jurgenson, T., Moore, M., Klein, A. H. Abstract: Background: Opioid management of chronic pain can cause opioid-induced analgesic tolerance and hyperalgesia, complicating clinical pain-management treatments. Research presented here sought to determine if opioid induced tolerance is linked to activity changes within the PI3K{gamma}-AKT-cGMP-JNK intracellular signaling pathway in spinal cord or peripheral nervous systems. Methods: Morphine or saline injections were given subcutaneously twice a day for five days (15 mg/kg) to male C57Bl6 mice. A separate cohort of mice received spinal nerve ligation (SNL) one week prior to the start of morphine tolerance. Afterwards, spinal cord, dorsal root ganglia, and sciatic nerves were isolated for quantifying total and phosphorylated- JNK levels, cGMP, and gene expression analysis. Results: Gene expression for the PI3K{gamma}-AKT-cGMP-JNK signaling pathway including, Akt1, Akt2, Akt3, Pik3cg, Pten, Jnk3, and nNos1 were decreased in the spinal cord with varied expression changes in the dorsal root ganglia and sciatic nerve of morphine tolerant and morphine tolerant mice after SNL. We observed significant increases in total and phosphorylated- JNK levels in the spinal cord, total JNK in dorsal root ganglia, and cGMP in the sciatic nerve of morphine tolerant mice with SNL. Pharmacological inhibition of PI3K, nNOS, or JNK, using thalidomide, quercetin, or SP600125, attenuated the development of morphine tolerance in mice with SNL as measured by thermal paw withdrawal. Conclusions: Overall, the PI3K/AKT intracellular signaling pathway is a potential target for reducing the development of morphine tolerance. Continued research into this pathway will contribute to the development of new analgesic drug therapies. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.31.230763v1?rss=1 Authors: Zhao, Y., Zheng, K., Guan, B., Guo, M., Song, L., Gao, J., Qu, H., Wang, Y., Zhang, Y., Shi, D. Abstract: To elucidate novel molecular mechanism of known drugs, efficient and feasible computational methods for predicting potential drug-target interactions (DTI) would be of great importance. A novel calculation model called DLDTI was generated, for predicting DTI based on network representation learning and convolutional neural networks. The proposed approach simultaneously fuses the topology of complex networks and diverse information from heterogeneous data sources, and copes with the noisy, incomplete, and high-dimensional nature of large-scale biological data by learning low-dimensional and rich depth features of drugs and proteins. Low-dimensional feature vectors were used to train DLDTI to obtain optimal mapping space and infer new DTIs by ranking DTI candidates based on their proximity to optimal mapping space. DLDTI achieves promising performance under 5-fold cross-validation with AUC values of 0.9172, which was higher than that of the method based on different classifiers or different feature combination technique. Moreover, biomedical experiments were also completed to validate the performance of DLDTI. Consistent with the predicted result, tetramethylpyrazine, an amide analogous monomer, ameliorated atherosclerosis progression and inhibited signal transduction in platelets, via PI3K/Akt, cAMP and calcium signaling pathways. The source code and datasets explored in this work are available at https://github.com/CUMTzackGit/DLDTI Copy rights belong to original authors. Visit the link for more info

The cover for issue 6 of Oncotarget features Figure 3, "The effect of NCs treatments on routine lab results during disease and recovery progress," by Ben-Nun-Shaul, et al. Numerous previous attempts to develop therapeutic treatments, directed at discreet targets of the sepsis cascade, could not cope with the complex pathophysiology of sepsis and failed. Studies in a severe rat sepsis model showed that pre-treatment by NCs led to a dramatic increase in survival, from zero to 75%. Further studies are needed to determine whether when applied after sepsis onset, the NCs still improve outcomes. Dr. Arieh Eden from the Department of Anesthesiology, Critical Care and Pain Medicine at the Lady Davis Carmel Medical Center in Haifa, Israel said in their Oncotarget Research Paper, "Sepsis affects millions of individuals annually worldwide, with a mortality of greater than 25%" and according to the Cancer | Sepsis Alliance "Having cancer and undergoing certain treatments for cancer, such as chemotherapy, can result in a weakened immune system, putting you at higher risk for developing an infection that could lead to sepsis. Sometimes incorrectly called blood poisoning, sepsis is the body's often deadly response to infection." https://www.sepsis.org/sepsisand/cancer/ It accounts for more than 50% of hospital deaths, with mortality rates of 10 20% for sepsis, 20 40% for severe sepsis, and 40 80% for septic shock. In the present study, the authors tested the hypothesis, based on their earlier unpublished research, that empty SV40 capsids would improve the outcome of sepsis. Twenty years ago we established a procedure for the production of empty SV40 capsid, in order to develop a safe gene delivery vector, to be assembled in vitro from empty capsids and plasmid DNA of choice. The underlying mechanism was up-regulation of Hsp/c70 and induction of the PI3K/Akt survival pathway, both seen exclusively in kidney tissue of NCs treated mice. That study revealed that SV40 and/or its NCs elicit concurrently opposing pathways: cellular stress response, pro-apoptotic host defense, and Akt-1 survival pathway. The Eden Research Team concluded in their Oncotarget paper, that these findings, and the dynamic adjustment of the therapeutic pathways to the recovery course, lead them to suggest that the effect of the NCs is tailored both to the type and to the temporal course of the injury, implying a general homeostatic activity. The homeostatic nature of the NC activity is also manifested in their negligible effect on the normal control rats. Full text - https://doi.org/10.18632/oncotarget.27448 Correspondence to - Ariella Oppenheim - ariellao@mail.huji.ac.il and Arieh Eden - ganyneden@gmail.com Keywords - sepsis, empty SV40 capsids, RNAseq, signaling, cellular functions About Oncotarget Oncotarget is a weekly, peer-reviewed, open-access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit http://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/onco... Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact media@impactjournals.com 18009220957x105

Maurizio Scaltriti explains why a combination therapy that targets the PI3K-Akt pathway and signaling through the growth factor receptors EGFR and HER3 may be effective against triple-negative breast cancer.

Dr Loibl talks to ecancertv at SABCS 2013 about her study "PIK3CA mutation predicts resistance to anti-HER2/chemotherapy in primary HER2-positive/hormone-receptor-positive breast cancer". Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in breast cancer, PIK3CA mutations being the most common. Mutations are frequently found in hot-spots located in the helical and kinase domains (exons 9 and 20). Reported data is discrepant with regard to prognostic or predictive value of PIK3CA mutations especially in HER2 positive breast cancer. The team investigated the frequency and prognostic associations of PIK3CA mutations in HER2 positive and triple negative primary breast cancer treated with neoadjuvant therapy. Patients with PIK3CA mutant HER2 positive / HR negative breast cancer are resistant to chemotherapy and dual anti-HER2 treatment. Other treatment options are needed to be tested in this group.

ecancer reporter Peter Goodwin talks to Dr Yanina Dockx at the 2013 IMPAKT meeting in Brussels. Aberrant activation of the PI3K-Akt-mTOR pathway is an important driver of resistance to HER2 targeted therapies and is involved in glucose homeostasis. 18F-FDG-PET has been proposed for early response assessment for targeted therapies, but knowledge on the effects of blocking this pathway on FDG uptake dynamics is limited. The study investigated the effect of pharmacological PI3K-Akt-mTOR blockade on in vitro FDG uptake in HER2 breast cancer cells resistant to trastuzumab. Blockade of PI3K-Akt-mTOR in trastuzumab resistant HER2 breast cancer was found to affect in vitro 18F-FDG uptake in transient and opposite ways, depending on the pharmacological target and duration of treatment. Therefore, further validation is necessary to elucidate the cellular mechanisms involved in tracer uptake prior to routine clinical use for early response assessment.

ecancer reporter Peter Goodwin talks to Dr Sara Hurvitz at IMPAKT 2013 in Brussels. What does the future hold for PI3K/AKT/mTOR inhibitors in breast cancer?

ecancer reporter Peter Goodwin talks to Dr Ana Vivancos at the 2013 IMPAKT meeting in Brussels about her research in to enrolement strategies in Phase I clinical trials. Dr Vivancos offers advice on the assessment of different mutations and what biomarkers are currently being looked at. Being able to more properly profile the molecular characetirstics of a tumour can lead to improvement of clinical trials and the best therapy for the patient. Dr Vivancos encourages clinicians to integrate genomics in to their every day practice.

Background: Recently it has been shown that radiation induces migration of glioma cells and facilitates a further spread of tumor cells locally and systemically. The aim of this study was to evaluate whether radiotherapy induces migration in head and neck squamous cell carcinoma (HNSCC). A further aim was to investigate the effects of blocking the epidermal growth factor receptor (EGFR) and its downstream pathways (Raf/MEK/ERK, PI3K/Akt) on tumor cell migration in vitro. Methods: Migration of tumor cells was assessed via a wound healing assay and proliferation by a MTT colorimeritric assay using 3 HNSCC cell lines (BHY, CAL-27, HN). The cells were treated with increasing doses of irradiation (2 Gy, 5 Gy, 8 Gy) in the presence or absence of EGF, EGFR- antagonist (AG1478) or inhibitors of the downstream pathways PI3K (LY294002), mTOR (rapamycin) and MEK1 (PD98059). Biochemical activation of EGFR and the downstream markers Akt and ERK were examined by Western blot analysis. Results: In absence of stimulation or inhibition, increasing doses of irradiation induced a dose-dependent enhancement of migrating cells (p < 0.05 for the 3 HNSCC cell lines) and a decrease of cell proliferation (p < 0.05 for the 3 HNSCC cell lines). The inhibition of EGFR or the downstream pathways reduced cell migration significantly (almost all p < 0.05 for the 3 HNSCC cell lines). Stimulation of HNSCC cells with EGF caused a significant increase in migration (p < 0.05 for the 3 HNSCC cell lines). After irradiation alone a pronounced activation of EGFR was observed by Western blot analysis. Conclusion: Our results demonstrate that the EGFR is involved in radiation induced migration of HNSCC cells. Therefore EGFR or the downstream pathways might be a target for the treatment of HNSCC to improve the efficacy of radiotherapy.

Pathological changes in the dopaminergic system account for a number of devastating illnesses including schizophrenia, psychosis, depression, addiction, obsessive compulsive disorder or the most well known Parkinson’s disease (PD). The nigrostriatal pathway is an important component of the dopaminergic (DA) system mediating voluntary movement and originates in the ventral midbrain from where substantia nigra pars compacta (SN) neurons send their axons to the dorsal striatum. Massive loss of SN neurons as seen in PD leads to postural imbalance, rigidity, tremor and bradykinesia, however, the precise mechanisms involved in the maintenance and the demise of SN neurons are poorly understood. Endogenous neurotrophic factors such as the Glial cell line-derived neurotrophic factor (GDNF; signaling via the Ret receptor tyrosine kinase) and Brain-derived neurotrophic factor (BDNF; signaling via the TrkB receptor tyrosine kinase) were reported to have protective and rescuing properties on DA neurons; however, their physiological roles in SN neurons remained unknown. Inactivation of the oxidative stress suppressor DJ-1 causes PD; remarkably, mice lacking DJ-1 function do not display overt SN degeneration, suggesting that additional DJ-1 interactors compensate for loss of DJ-1 function. To begin characterizing the cellular and molecular networks mediating SN neuron survival, I used mouse genetics to investigate the roles and the interaction between GDNF/BDNF-mediated trophic signaling and the DJ-1-mediated stress response in SN neurons. While mice lacking TrkB function specifically in SN neurons display a normal complement of SN neurons up to 24-months, loss of Ret function in DA neurons causes adult-onset and progressive SN degeneration, suggesting that GDNF/Ret signaling is required for long-term maintenance of SN neurons. I then generated and aged mice lacking Ret and DJ-1 and found remarkably that they display an enhanced SN degeneration relative to mice lacking Ret. Thus, DJ-1 promotes survival of Ret-deprived SN neurons. Interestingly, the survival requirement for Ret and DJ-1 is restricted to those SN neurons which express the ion channel GIRK2, project exclusively to the striatum and specifically degenerate in PD. This is the first in vivo evidence for a pro-survival role of DJ-1. To understand how DJ-1 interacts molecularly with Ret signaling, I performed epistasis analysis in Drosophila melanogaster. Although DJ-1 orthologs DJ-1A and DJ-1B are dispensable for fly development, the developmental defects induced by targeting constitutively active Ret to the retina were suppressed in a background of reduced DJ-1A/B function. Moreover, DJ-1A/B interacted genetically with Ras/ERK, but not PI3K/Akt signaling to regulate photoreceptor neuron development. Flies with reduced ERK activity and lacking DJ-1B function had more severe defects in photoreceptor neuron and wing development than flies with reduced ERK function. These observations establish, for the first time, a physiological role for DJ-1B in the intact Drosophila. Our findings suggest that the triple interaction between aging, trophic insufficiency and cellular stress may cause Parkinsonism. Because Ret and DJ-1 show convergence of their pro-survival activities, we predict that striatal delivery of GDNF might be most effective in PD patients carrying DJ-1 mutations. A better understanding of the molecular connections between trophic signaling, cellular stress and aging will accelerate the process of drug development in PD.

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.