Podcasts about FOXP3

BUFFALO, NY - April 28, 2025 – A new #research paper was #published in Oncotarget, Volume 16, on April 24, 2025, titled “PD-L1 and FOXP3 expression in high-grade squamous intraepithelial lesions of the anogenital region." Researchers Humberto Carvalho Carneiro, Rodrigo de Andrade Natal, José Vassallo and Fernando Augusto Soares from the Instituto D'Or de Pesquisa e Ensino and Rede D'Or studied early tissue changes caused by human papillomavirus (HPV) in the anal, vulvar, and penile regions. They found that high-grade pre-cancer lesions triggered stronger immune responses and showed higher levels of two immune-related markers, PD-L1 and FOXP3. These findings are important because they help explain how some HPV-related lesions progress to cancer while others heal on their own. High-risk HPV is known to cause several types of anogenital cancers. Before these cancers appear, the virus often leads to abnormal tissue changes known as high-grade squamous intraepithelial lesions. Many of these lesions disappear without treatment, but some become cancer—especially in people with weakened immune systems. This study explored how immune activity may play a role in this progression. The researchers examined tissue from 157 patients—95 males and 55 females—with either high-grade or low-grade HPV-related lesions. They found that T-regulatory cells, marked by the FOXP3 protein, were more common in high-grade lesions. These immune cells are known to suppress immune responses, which can allow infected or abnormal cells to grow. The team also found higher expression of PD-L1, a protein that helps cells evade immune detection, particularly in inflammatory immune cells. "Dense inflammatory infiltrates and high counts of FOXP3+ cells were significantly more frequent in patients with HSILs than in those with LSILsHR (p = 0.04 and 0.02, respectively). HSILs also exhibited higher PD-L1 expression (padj < 0.01 and < 0.01 for the SP142 and 22C3 clones, respectively), based on the Poisson generalized linear model.” These findings suggest that HPV may begin avoiding the immune system early in infection, even before cancer develops. The combination of high FOXP3 and PD-L1 levels may create a protective environment for infected cells, making them harder for the body to eliminate. This immune evasion may allow the lesions to remain and, over time, become cancerous. The study also compared patients with and without HIV to assess whether immune health influenced the results. While those with compromised immune systems had more extensive lesions, PD-L1 and FOXP3 expression was also found in patients with healthy immune systems. This evidence shows that immune evasion by HPV can happen regardless of a person's immune status. Understanding how PD-L1 and FOXP3 function in early HPV-related lesions may help clinicians predict which lesions are more likely to become cancer. These insights could lead to new strategies for monitoring, treating, or preventing HPV-related precancerous lesions and cancer in the anogenital region. The study highlights how early immune system changes can play a key role in the development of HPV-related cancers. DOI - https://doi.org/10.18632/oncotarget.28715 Correspondence to - Humberto Carvalho Carneiro - humberto.carneiro@rededor.com.br Video short - https://www.youtube.com/watch?v=6d8G8TUbgYc Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: 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/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

In this episode, we dive into how short-chain fatty acids (SCFAs), particularly butyrate, and tryptophan metabolites support the gut-immune axis by promoting regulatory T cell differentiation, strengthening the intestinal barrier, and enhancing antimicrobial defenses through IL-22 signaling. We break down how butyrate can improve immune tolerance as well as epithelial integrity, aiding in the prevention of chronic inflammatory responses. We also detail practical ways to support butyrate levels and aid in strengthening both the epithelial barrier and gut-immune axis. Topics: 1. Introduction - Overview of the role of SCFAs and tryptophan metabolites in supporting the gut-immune axis. - Quick review of the location of immune cells in relation to the gut microbiota. 2. The Intestinal Barrier - Structure of the intestinal wall and layers - Focus on the mucosal layer, specifically epithelium and lamina propria. 3. The Lamina Propria - Structural elements: fibroblasts, extracellular matrix (ECM), and myofibroblasts. - Vascular components: endothelial cells, capillaries, and lymphatic vessels. - Importance of the lamina propria as a hub for immune responses. 4. Immune Cells in the Lamina Propria - T cells: Role of regulatory T cells (Tregs) in immune modulation. - B cells: Production of IgA, class switching, and plasma cells. - Dendritic cells: Sampling luminal antigens and initiating immune responses. - Macrophages: Phagocytic activity, pro-inflammatory (M1) vs. anti-inflammatory (M2) states. - Mast cells: Role in allergic responses, chronic inflammatory conditions, and MCAS. 5. Short-Chain Fatty Acids (SCFAs) - Production of SCFAs (acetate, propionate, butyrate) by gut microbiota. - Butyrate's role in supporting regulatory T cell (Treg) differentiation and immune tolerance. -Butyrate as fuel for epithelial cells and the production of tight junction proteins. 6. Mechanisms of Butyrate in Immune Modulation - Impact on Tregs through FoxP3 expression. - SCFA's role in maintaining immune balance. 7. Butyrate and Epithelial Integrity - Support for tight junction protein expression. - Prevention of translocation of harmful microbes and antigens. - Reduced systemic inflammation through a strengthened barrier. 8. Supporting Butyrate Production - Sodium butyrate supplementation and microbiome optimization. - Role of fiber, polyphenols, and probiotics. 9. Tryptophan Metabolites - Overview of tryptophan metabolism by gut bacteria into indoles. - Indoles' role in promoting IL-22 production, contributing to antimicrobial defense and immune tolerance. 10. IL-22 - IL-22's enhancement of antimicrobial peptides (AMPs) and mucin production. - Case Study: Role of Lactobacillus strains in restoring IL-22 and helping to mitigate colitis. 11. Conclusion - Recap of how SCFAs and tryptophan metabolites interact with the gut-immune axis. - Importance of gut microbiome support for maintaining immune balance. Thank you to our episode sponsor: 1. Check out ⁠⁠⁠⁠Daily Nouri⁠⁠⁠⁠ and use code ⁠⁠⁠⁠CHLOE20⁠⁠⁠⁠ for 20% off your order. Thanks for tuning in! Get Chloe's Book Today! "⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠75 Gut-Healing Strategies & Biohacks⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠" Follow Chloe on Instagram ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠@synthesisofwellness⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ Follow Chloe on TikTok @chloe_c_porter Visit ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠synthesisofwellness.com⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ to purchase products, subscribe to our mailing list, and more! --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support

Is the human genome highly functional or mostly junk? This is a question that is not only being asked in the creation-evolution debate; it is a question raging in the ivory tower as well. The 'old guard' is much more likely to resist any claim that large swaths of the genome are useful. The 'young punks' in science is more willing to accept the obvious fact that the genome is highly functional. Who is going to win? In this episode, Dr Carter highlights four new studies that ratchet the argument toward high function. Notes and links:' Carter 2023 What proportion of the human genome is actually functional? And how much variation is tolerable? Zhang et al. 2023 FOXP3 recognizes microsatellites and bridges DNA through multimerization Walter 2024 Are non-protein coding RNAs junk or treasure? Stepankiw et al. 2023 The human genome contains over a million autonomous exons Chen et al. 2023 A genomic mutational constraint map using variation in 76,156 human genomes Moran 2023 What's in your genomes? 90% of your genome is junk  

Reference Nature Immunology 2022. volume 23, pages 1208–1221. --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message

References Front. Immunol. 2015. 6: 493. Prostaglandins Leukot Essent Fatty Acids. 2015 Jul;98:49-55 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

References Front. Immunol., 29 June 2012 J Immunol 2016;197:3762-3770 Front. Immunol., 03 February 2020 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

Nat chats with Allison Creech, mom of twin boys plus an older singleton boy, who is dealing with her son Micah's terminal diagnosis of IPEX Syndrome which will require a bone marrow transplant. Allison shares her feelings around this diagnosis, how she is managing her three boys, and how her faith is helping to get her through this time.IPEX is a genetic disease of immune dysregulation in which patients can present early in life with diarrhea, diabetes, and eczema. It is extremely rare, affecting 1 in every 1.6 million people. Patients with IPEX have abnormalities in the FOXP3 gene, which controls the production of regulatory T cells, a type of immune cell. Without a normal FOXP3 gene, other immune cells attack the body's healthy tissues. You can follow Micah's story here on Facebook.Visit BeTheMatch.org to join the bone marrow registry.For more information on IPEX, click here.PLEASE review our podcast! We'd love to hear what you think!Want to hear about specific podcast topics? Email us!CONTACT USDownload the Twiniversity App: For twin pregnancy tracking and twins baby tracking! Download hereVISIT Twiniversity.com for tons of free twin tips!FOLLOW us on Facebook, Instagram, Pinterest, YouTube, and Twitter.SUBSCRIBE to our email newsletter!Take a class! Twiniversity offers online expecting twins classes (both on-demand and live), a breastfeeding twins class, a twins after singletons class, and a baby safety class including CPR, first aid, car seat safety, and childproofing. Click here to check out our online classes.Twiniversity Memberships: Includes Zoom Twin Club

La Dra. Leticia Vázquez Cortés, oncólogo médico adscrita al Instituto Mexicano del Seguro Social en Morelia, Michoacán, México nos comenta sobre lo más destacado entumores del sistema nervioso central (SNC), presentado en el Congreso Anual de la Sociedad Europea de Oncología Médica, resaltando los siguientes estudios: 343MO: Características clínicas y patrones de metilación del ADN a corto y largo plazo en gliomas de grado II-III afectan a individuos jóvenes, los cuales se caracterizan por un pronóstico de supervivencia que varía de meses a años. El tratamiento postoperatorio prolonga la supervivencia, pero tiene un impacto potencial en la calidad de vida y el funcionamiento cognitivo a largo plazo. Por lo tanto, se necesitan modelos de estratificación pronóstica refinados para guiar los estudios de tratamiento futuros. 344MO: Estudio del grupo español GEINO, el cual investigó el tratamiento del meduloblastoma en adultos (constituye el 1% de los tumores de SNC, es un tumor potencialmente curable con radioterapia al neuroeje y quimioterapia). Se registraron 71 pacientes, el 70.6% se encontraban con resección completa, 23.6% con resección parcial y 5.9% con biopsia. 345MO: El objetivo primario del estudio era observar los cambios en el microambiente inflamatorio después de los tratamientos de radioterapia en pacientes con metástasis cerebrales. Se realizó una división en 5 grupos, en los cuales se investigó los subconjuntos de células T, CD3, CD8, CD45RO, FOXP3, LAG3 y la expresión de PD-L1. Se analizaron 81 muestras, 55 de cáncer de pulmón, 15 de cáncer de mama, 4 cáncer de riñón, 1 de melanoma, 1 de colon y 5 de otros tipos de tumores. 354P: Estudio doble ciego de dos brazos, el objetivo primario fue comparar los beneficios de supervivencia de 12 ciclos vs. 6 ciclos con temozolomida adyuvante en adultos con gliomas de alto grado recién diagnosticados. 1265P: El objetivo primario del estudio fue seleccionar un método más eficaz para el diagnóstico de metástasis leptomeníngeas (ML) comparando varios métodos de detección. El objetivo secundario fue identificar patrones de mutación específicos de genes en el líquido cefalorraquídeo (LCR) con ML y explorar el valor de los marcadores tumorales del LCR y las pruebas de ADN tumoral circulante para guiar el tratamiento clínico. 371P: Bevacizumab en dosis bajas para el tratamiento de la necrosis cerebral focal postradiación. Se investigó un régimen de dosis baja de bevacizumab (dosis de carga de 400 mg seguida de 100 mg cada 4 semanas) en pacientes diagnosticados con necrosis cerebral por radiación focal. Dicho tratamiento es una alternativa eficaz y económica de dosis estándar.

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

Anti-aging compound improves muscle glucose metabolism in people Washington University School of Medicine in St. Louis, April 26, 2021   A natural compound previously demonstrated to counteract aspects of aging and improve metabolic health in mice has clinically relevant effects in people, according to new research at Washington University School of Medicine in St. Louis. A small clinical trial of postmenopausal women with prediabetes shows that the compound NMN (nicotinamide mononucleotide) improved the ability of insulin to increase glucose uptake in skeletal muscle, which often is abnormal in people with obesity, prediabetes or Type 2 diabetes. NMN also improved expression of genes that are involved in muscle structure and remodeling. However, the treatment did not lower blood glucose or blood pressure, improve blood lipid profile, increase insulin sensitivity in the liver, reduce fat in the liver or decrease circulating markers of inflammation as seen in mice. The study, published online April 22 in the journal Science, is the first randomized clinical trial to look at the metabolic effects of NMN administration in people. Among the women in the study, 13 received 250 mg of NMN orally every day for 10 weeks, and 12 were given an inactive placebo every day over the same period. "Although our study shows a beneficial effect of NMN in skeletal muscle, it is premature to make any clinical recommendations based on the results from our study," said senior investigator Samuel Klein, MD, the William H. Danforth Professor of Medicine and Nutritional Science and director of the Center for Human Nutrition. "Normally, when a treatment improves insulin sensitivity in skeletal muscle, as is observed with weight loss or some diabetes medications, there also are related improvements in other markers of metabolic health, which we did not detect in our study participants." The remarkable beneficial effects of NMN in rodents have led several companies in Japan, China and in the U.S. to market the compound as a dietary supplement or a neutraceutical. The U.S. Food and Drug Administration is not authorized to review dietary supplement products for safety and effectiveness before they are marketed, and many people in the U.S. and around the world now take NMN despite the lack of evidence to show clinical benefits in people. The researchers studied 25 postmenopausal women who had prediabetes, meaning they had higher than normal blood sugar levels, but the levels were not high enough to be diagnosed as having diabetes. Women were enrolled in this trial because mouse studies showed NMN had the greatest effects in female mice. NMN is involved in producing an important compound in all cells, called nicotinamide adenine dinucleotide (NAD). NAD plays a vital role in keeping animals healthy. Levels of NAD decline with age in a broad range of animals, including humans, and the compound has been shown to contribute to a variety of aging-associated problems, including insulin resistance in studies conducted in mice. Supplementing animals with NMN slows and ameliorates age-related decline in the function of many tissues in the body.  Co-investigator Shin-ichiro Imai, MD, PhD, a professor of developmental biology and of medicine who has been studying NMN for almost two decades and first reported on its benefits in mice said, "This is one step toward the development of an anti-aging intervention, though more research is needed to fully understand the cellular mechanisms responsible for the effects observed in skeletal muscle in people." Insulin enhances glucose uptake and storage in muscle, so people who are resistant to insulin are at increased risk for developing Type 2 diabetes. But the researchers caution that more studies are needed to determine whether NMN has beneficial effects in the prevention or management of prediabetes or diabetes in people. Klein and Imai are continuing to evaluate NMN in another trial involving men as well as women.     N-acetylcysteine for depression in adolescents and young adults at risk for bipolar disorder University of Cincinnati, April 23, 2021 According to news reporting originating from Cincinnati, Ohio, by NewsRx correspondents, research stated, “To investigate the mechanism of action of N-acetylcysteine (NAC) in depressive symptoms in young individuals at familial risk for bipolar disorder. We conducted an 8-week open label clinical trial of NAC 2400 mg/days in 15-24 years old depressed offspring of a bipolar I disorder parent, with baseline and endpoint proton magnetic resonance spectroscopy acquired within the left ventrolateral prefrontal cortex (VLPFC).” Our news editors obtained a quote from the research from the University of Cincinnati, “Nine participants were enrolled and finished the study. NAC significantly improved depressive and anxiety symptom scores, and clinical global impression (all p< .001). There was a non-significant reduction in glutamate levels in the left VLPFC. Reduction in depressive symptom scores was positively associated with reduction in glutamate levels in the left VLPFC (p = .007).” According to the news editors, the research concluded: “This pilot study suggests that NAC might be efficacious for depressive symptoms in at-risk youth, and that its mechanism of action involves the modulation of glutamate in the left VLPFC.” This research has been peer-reviewed.     Soda consumption linked to accelerated aging and increased mortality risk University of California at San Francisco, April 26, 2021 A recent study by researcher from the University of California, San Francisco says that drinking soda can increase the risk of all-cause mortality and accelerate aging. The findings build on mounting evidence of the adverse effects drinking soda and other sugary beverages have on the body, which include obesity, Type 2 diabetes, heart disease, kidney disease, non-alcoholic fatty liver disease, dental caries and gout. The team collated data from the National Health and Examination Surveys, an annual program for assessing the health and nutrition of American adults and children. They gathered data from over 5,300 participants between 1999 and 2002, all of whom had no history of diabetes or cardiovascular disease.  In particular, they looked at stored DNA data from the participants – measuring telomere length and comparing it with their consumption of sugar-sweetened soda. The researchers found that those who regularly drank sugar-sweetened soda had shorter telomeres than those who didn’t. Research has shown that telomeres have been previously associated with lifespan. Having shorter telomere length, for instance, has been linked to cardiovascular disease, diabetes and even certain types of cancer. The team reported in their study that consuming even just eight ounces of soda every day can accelerate aging by nearly two years. Meanwhile, 20 ounces of soda can accelerate aging by up to 4.6 years when consumed daily. In fact, drinking sugar-sweetened soda can reduce telomere length at a rate similar to smoking. The UCSF study is also the first to link regular consumption of sugar-sweetened soda to telomere shortening. According to study co-author Elissa Epel, drinking sugar-sweetened soda adds strain to the body by metabolizing these sugars and accelerates cellular aging in tissues. “This finding held regardless of age, race, income and education level. Telomere shortening starts long before disease onset,” Epel added. ” Although we only studied adults here, it is possible that soda consumption is associated with telomere shortening in children, as well.” Sugary sodas linked to rising all-cause deaths In another study, European experts revealed that drinking sugary sodas and other sweetened drinks increases the risk of all-cause deaths. The researchers collected data from more than 450,000 individuals enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a large-scale cohort study for biochemical and genetic markers for cancer and other chronic diseases. A follow-up revealed that more than 40,000 participants from the original study had already died. Using their data, the team found a strong link between regular soda consumption and all-cause mortality. Those who regularly drank more than two glasses of sugary drinks increased their risk of dying from circulatory diseases, while those who drank at least one glass of sugary drinks increased their risk of dying from digestive diseases and Parkinson’s disease. “Our results … provide additional support for the possible adverse health effects of sugar-sweetened soft drinks and to replace them with other healthier beverages, preferably water,” explained co-author Neil Murphy. “For artificially-sweetened soft drinks, we now need a better understanding of the mechanisms that may underlie this association and research such as ours will hopefully stimulate these efforts.” The findings appeared in JAMA Internal Medicine.     Curcumin concoction could combat colitis: Study Baylor University, April 25, 2021 A formula that blends curcumin and turmeric oils can prove effective against the activity and inflammatory burden of colitis, a study has determined. Published in Nature Scientific Reports, the study identifies the efficacy of a specific curcumin preparation containing essential turmeric oils (ETO-curcumin) in reducing colitis symptoms. These turmeric oils, aromatic-tumerones (ar-tumerones), alpha-turmerones, beta-turmerones, alpha-santalene and aromatic curcumene, appear to be responsible for an anti-inflammatory and anti-oxidant action, the study suggests. The combination also appeared to exert higher bioactivity than stand-alone curcumin – a feature that could prove valuable in using turmeric for other intestinal conditions. “The therapeutic benefits of turmeric can be attained at its best by combining curcumin with turmerone, an active compound derived from essential oil of turmeric,” said P.J. Kunjachan, chairman and managing director for Arjuna Natural Extracts “This new finding provides our customers an added value for promoting their BCM-95-based formulations in an increasingly crowded curcumin market,” added Dr Benny Antony, joint managing director for Arjuna. BCM-95 often combines curcumin with other turmeric compounds as its poor bioavailability has been cited as a barrier to its use in other disorders. Obstacles are not limited to curcumin's chemical properties. Despite the 17 claims for its anti-inflammatory and digestive health properties, there are currently no approved health claims for curcumin in the EU. These claims are featured on the 2000+ list of on-hold botanical claims yet to be processed by the European Food Safety Authority (EFSA). As well as Arjuna, other manufacturers with an interest in curcumin include herbal manufacturers Sabinsa and Italian botanicals firm Indena. Led by Dr Shusuke Toden, research associate from Baylor University in the US, the trial compared ETO-curcumin preparations  against standard curcumin at three specific doses (0, 5, 25 or 50 milligrams per kilogram (mg/kg)). These doses were administered to an animal model with induced colitis for seven days. The research team found that ETO-curcumin improved disease activity index (DAI) dose-dependently, while the anti-inflammatory efficacy of standard curcumin remained constant. “This suggests that ETO-curcumin may provide superior anti-inflammatory efficacy compared to standard curcumin,” the study explained. “ETO-curcumin associated anti-inflammatory effects were particularly pronounced at higher doses.” Further findings revealed that anti-inflammatory proteins produced included IL-10 and IL-11 as well as FOXP3, which increased in number in the colon by ETO-curcumin.   Study examines association between lifestyle patterns and BMI in early childhood Results support obesity prevention efforts early in life Deakin University (Australia), April 26, 2021   A new Australian study reveals that changes in lifestyle patterns were longitudinally associated with concurrent changes in body mass index (BMI) z scores, and maternal pre-pregnancy BMI, maternal dietary patterns and television viewing time are significant determinants, according to a paper published online in Obesity, The Obesity Society's (TOS) flagship journal. This is the first study that used multi-trajectory modeling to examine the longitudinal relationship between concurrent changes in lifestyle patterns and BMI z scores in early childhood.  "The findings will inform early childhood obesity prevention intervention and policy, and will be of great interest to pediatricians, researchers, policymakers and the general public," said Miaobing Zheng of the Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, in Geelong, Australia. Zheng is the corresponding author of the study.  Experts explain that longitudinal studies investigating the association between lifestyle patterns and obesity in children are scarce. An association between a healthy lifestyle pattern and lower obesity risk has, however, been previously reported in a few cross-sectional studies. In the present study, the co-occurrence of stable healthy lifestyle patterns along with a concurrent normal BMI z score trajectory of one unit from 18 to 60 months in about half of the children provides new longitudinal evidence supporting that children with healthy lifestyles were more likely to concurrently have normal BMI z score development.  Data of 439 children were used from the Melbourne Feeding Activity and Nutrition Trial (InFANT) program. This longitudinal cohort of children commenced in 2008 as a 15-month parent-focused cluster randomized controlled trial aiming to reduce obesity risk behaviors in children until 18 months. Additional follow-ups without interventions occurred for children aged 42 and 60 months. Multi-trajectory modeling identified groups of children following similar lifestyle patterns and BMI z score trajectories and multi-nomial logistic regression assessed the determinants of the trajectory groups.  Three trajectory groups of child lifestyle patterns and BMI z scores were identified and distinguished, showing a mixture of healthy and unhealthy lifestyle behaviors and BMI zscores. Compared to Groups 1 "Unhealthy lifestyle pattern, Low BMI z" and 3 "Unhealthy lifestyle pattern, High BMI z", Group 2 "Healthy lifestyle pattern, Mid BMI z" revealed the most distinctive trajectories across lifestyle patterns and BMI z scores. Group 2 comprised nearly 53 percent of children and followed a stable and low trajectory for an unhealthy lifestyle pattern characterized by energy-dense and nutrient poor discretionary food consumption and television viewing time and a high and rising trajectory for a healthy lifestyle pattern of fruit and vegetable intakes and time outdoors, along with a mean BMI z score of +1 unit over time. Groups 1 and 3 shared similar high trajectories for an unhealthy lifestyle pattern of discretionary food consumption and television viewing time, and low trajectories for a healthy lifestyle pattern of fruit and vegetable intakes and time outdoors. The two groups however differed in BMI z score trajectories, showing stable patterns but at mean scores of 0 and +2 units, respectively. Child sex, breastfeeding duration and maternal physical activity were not associated with the identified trajectory groups. The study's authors note that the co-occurrence of stable lifestyle patterns and BMI z score trajectories in early childhood highlight the importance of initiating lifestyle obesity prevention early in life, and such interventions could target both children and the mother. A multi-behavior approach to simultaneously target healthy diet, physical activity and sedentary behaviors could be adapted. "Young children learn by imitating that which they see daily. There is no doubt that children copy the behaviors observed in the presence of parents: healthy and unhealthy," said Liliana Aguayo, PhD, MPH, a childhood obesity expert, TOS member and research assistant professor from the Hubert Department of Global Health at Emory University in Atlanta, Ga. "Evidence from this study highlights the importance of early childhood as a critical period for development of obesity. More research is needed to identify effective approaches to simultaneously address parent and child health behaviors." Aguayo was not associated with the research.     DDT exposure in grandmothers linked to obesity, earlier periods in granddaughters Young women today may face increased health risks linked to breast cancer due to effects from the banned toxic pesticide lasting over three generations University of California at Davis, April 16, 2021 In the first study to report on the health effects of exposure to a toxic environmental chemical over three human generations, a new study has found that granddaughters whose grandmothers were exposed to the pesticide DDT have higher rates of obesity and earlier first menstrual periods. This may increase the granddaughters' risk for breast cancer as well as high blood pressure, diabetes and other cardiometabolic diseases.  The research by the Public Health Institute's Child Health and Development Studies (CHDS) and the University of California at Davis was published today in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research. It suggests that effects from the pesticide DDT -- despite being banned in the U.S. nearly 50 years ago -- may contribute to the falling age of first periods and increases in obesity rates among young women today. The study found that the risk of obesity in young adult granddaughters was 2 to 3 times greater when their grandmothers (who were not overweight) had higher levels of o,p'-DDT (a contaminant of commercial DDT) in their blood during or just after pregnancy. Granddaughters were twice as likely to have earlier first menstrual periods when their grandmothers had higher o,p'-DDT blood levels. DDT and its related chemicals, including o,p'-DDT, are known to be endocrine disrupting chemicals, compounds that can alter and interfere with natural hormones that are essential for development.  "We already know that it's nearly impossible to avoid exposures to many common environmental chemicals that are endocrine disruptors. Now our study shows for the first time in people that environmental chemicals like DDT may also pose health threats to our grandchildren," said Barbara Cohn, director of CHDS and senior author of the study. "In combination with our on-going studies of DDT effects in the grandmother's and mother's generations, our work suggests we should take precautionary action on the use of other endocrine disrupting chemicals, given their potential to affect generations to come in ways we cannot anticipate today."  The Child Health and Development Studies is a unique project that has followed 20,000 pregnant women and their families for more than 60 years. CHDS enrolled and began following pregnant women in the Bay Area between 1959 and 1967, a time of high pesticide use before DDT was banned in 1972. These "founding grandmothers" in the study gave blood samples at each trimester during pregnancy and one sample shortly after birth. The blood samples were tested for levels of DDT and its related chemicals, including active ingredients, contaminants and their metabolites. The study today focused on o,p'-DDT as it has previously been linked to breast cancer, obesity and other harmful health effects in daughters, and is believed to be the most sensitive biomarker for exposures before and immediately after birth. Since granddaughters' exposure would occur via their mothers' in utero egg cell development, o,p'-DDT levels are a potential predictor of granddaughters' exposure outcomes.  "These data suggest that the disruption of endocrine systems by DDT initiates in immature human eggs, decades before the eggs are fertilized," said Michele La Merrill, associate professor at UCD who was co-lead author of the study. The CHDS study included interviews, home visits and questionnaires from the daughters and granddaughters of the original enrollees. During home visits, blood pressure and height and weight measurements were taken. The study today is based on 365 adult granddaughters who completed questionnaires, participated in a home visit, had available DDT measures from grandmothers' serum, and (for 285 of them) had available information on body mass index (BMI) in all three generations. Information on the age of first period for all three generations was available from 235 granddaughters. Previous CHDS studies have shown that mothers' DDT exposure during pregnancy or immediately after birth correlates with increased daughters' risk of breast cancer and the prevalence of breast cancer risk factors, including obesity, among adult daughters. Other prior studies have linked DDT exposure to birth defects, reduced fertility and an increased risk of diabetes. A commentary in the journal Reproductive Toxicology last year called CHDS "a national treasure that keeps on giving" and noted that "There are no other U.S. studies as well defined, sampled, and followed as the CHDS....The CHDS provides unique and essential value in understanding health effects of environmental exposures as they relate to life-stage sensitivity."       Capsaicin analog could help treatment-resistant lung cancer Small cell lung cancer cells exposed to synthetic analog of chili pepper compound responded better to chemotherapy Marshall University, April 27, 2021 A new study found that non-pungent synthetic analog of capsaicin -- the compound that makes chili peppers hot -- made small cell lung cancer cells more responsive to treatment. Small cell lung cancer is a very aggressive form of cancer with a low survival rate.  Cisplatin-based combination chemotherapy is typically the first-line treatment for small cell lung cancer patients. Although patients initially respond very well to this chemotherapy, the tumor usually comes back within a year in a form that doesn't respond to treatments. Patients with relapsed small cell lung cancer have very few treatment options.  "Irinotecan is the only FDA approved second-line drug for small cell lung cancer, but less than 3% of patients respond to it," said research team leader Piyali Dasgupta, PhD, from Marshall University. "Therefore, agents that improve the anti-cancer activity of irinotecan would be of great value to these patients." Jamie Friedman, a former doctoral student in Dasgupta's lab will present the new findings at the American Society for Investigative Pathology annual meeting during the virtual Experimental Biology (EB) 2021 meeting, to be held April 27-30.  The natural compound capsaicin has been shown to have anti-cancer effects, but its heat can also cause a burning sensation, stomach cramps, gut pain and nausea. In the new work, the researchers studied arvanil, a synthetic capsaicin analog without capsaicin's undesirable side effects.  When the researchers exposed two cisplatin-resistant lung cancer cell lines to a low concentration of arvanil, they saw no growth-inhibitory activity. However, when they treated the cells with varying concentrations of SN38 -- the active ingredient irinotecan -- they observed that the presence of arvanil greatly enhanced the ability of SN38 to slow cancer cell growth. Statistical analysis showed that the interaction between arvanil and SN38 was synergistic in nature.  "Because arvanil enhanced the anti-cancer activity of SN38 in human small cell lung cancer cells, arvanil-based combination therapies may be useful for patients with relapsed small cell lung cancer cells," said Friedman. "We hope that this work will pave the way for novel therapies for relapsed and cisplatin-resistant small cell lung cancer."     Five Therapeutic Properties of Medicinal Mushrooms GreenMedInfo, April 25, 2021   Mushrooms have recently gained popularity in culinary circles, but their far-reaching therapeutic properties should get your attention for a longer and healthier life. Although mushrooms have been part of the healer’s toolbox since ancient times, the medicinal power of mushrooms is gaining momentum in evidence-based journals. Medicinal mushrooms come in a wide variety and shapes such as white button, reishi, maitake, shiitake, oyster, cordyceps, cauliflower, tiger tail and lion’s mane, and most have health benefits that range from fighting cancer and boosting your immunity and memory to preventing diseases like diabetes and arthritis. 1. Anticancer Reishi (in Japanese) or lingzhi (in Chinese) mushrooms are well known in Asia for their anticancer properties. In a meta-analysis by scientists of 23 trials involving 4,246 cancer patients, reishi mushrooms enhanced longevity and quality of life in cancer patients.[i] Therapy with white button mushrooms impacted prostate-specific antigen (PSA) levels and inhibited prostate cancer by decreasing immunosuppressive factors.[ii] Polysaccharides from Cordyceps cicadae mushrooms inhibited the growth of cancer cells and induced cancer cell deaths showing its effectiveness as a low cost and safe treatment for cervical cancer.[iii] A peptide from the shiitake mushroom showed promising results in growth arrest, cell death and cleaning out damaged cells in a breast cancer in vitro study.[iv] In both in vitro and in vivo studies, results showed that mice with induced testicular cancer treated with the Cordyceps sinensis mushroom had significantly smaller and fewer tumors than the control group.[v] Cordyceps cicadae mushroom treatment prevented testicular damage and tumors caused by the chemotherapy drug cisplatin via inhibition of oxidative stress and inflammation in rats.[vi] In a lung cancer-induced study of mice, treatment with reishi mushrooms inhibited cell viability and mobility of lung cancer cells in vitro.[vii] In a cell study of reishi mushroom extract, the treatment offered high antitumor and liver protection with low toxicity on human liver cancer cells.[viii] 2. Immunomodulatory In a meta-analysis of 20 animal disease studies, grifola frondosa, or maitake mushroom, polysaccharide showed strong immune function by enhancing T cells, natural killer cells and macrophages in mice and increasing the secretion of two important immune factors, TNF-α and INF-γ.[ix] In a clinical study of 105 cancer patients undergoing chemotherapy or radiation treatments, a combination of reishi mushroom extract and geraniums improved immunity and fought the cancer and secondary infections that could have compromised treatment and health.[x] In a study of 18 patients diagnosed with low and intermediate myelodysplastic syndrome, which can lead to leukemia if not managed well, maitake mushroom extract treatment of three milligrams (mg) twice a day for 12 weeks increased immunity, positively affecting neutrophil, monocyte and free radical production.[xi] In a clinical study of asymptomatic children from 3 to 5 years old, treatment with beta glucans from reishi mushrooms showed increased immune system cells in the peripheral blood — signaling a strong defense against childhood infections.[xii] Reviewing in vivo and in vitro studies on mice and human cell lines using lion’s mane (Hericium erinaceus) and tiger tail (Trametes versicolor) mushrooms, treatments showed immunomodulatory, anticancer, anti-inflammatory and neuroregenerative effects.[xiii] 3. Antioxidant Polysaccharide beta glucan extracted from reishi mushroom was shown to be a powerful antioxidant in 37 high risk and 34 stable angina patients; those who were treated with 750 mg per day for three months had significantly decreased oxidative radicals and improved progression of atherosclerosis.[xiv] In a study of 42 healthy subjects, another intervention with beta glucan from reishi mushrooms of 225 mg per day for three months demonstrated its antioxidative effects — enhanced total antioxidant capacity and enzyme activities as well as reduced mild fatty liver condition to normal by suppressing oxidative stress were observed.[xv] 4. Anti-inflammatory  Crohn’s disease is a chronic inflammatory disease of the gastrointestinal tract. Treatment with a triterpene compound from reishi mushrooms showed that the inflammatory cytokines were significantly inhibited in a study of children with Crohn’s disease.[xvi] Sixty patients with moderate persistent asthma were studied and those who took the cordyceps sinensis mushroom capsule for two months had reduced airway inflammation caused by their chronic asthma.[xvii] Cordycepin from medicinal mushrooms showed strong effects on many anti-inflammatory diseases.[xviii] In a study of 32 patients with active rheumatoid arthritis, supplementation of medicinal mushroom and Chinese herbs — reishi (4 grams) and San Miao San (2.4 grams) daily — lowered arthritic pain for patients.[xix] The data in a mice study support a model where white button mushrooms regulate immunity in vitro and protect the colon from inflammation-induced injuries in vivo.[xx] The brain is susceptible to inflammation as well. In an Alzheimer’s disease model of rats, treatment with medicinal mushroom extracts delayed disease progression, improved learning and memory functions and stopped neural cell deaths and brain atrophy.[xxi] Chaga mushrooms administered to mice successfully protected against Alzheimer’s disease by modulating oxidative stress, Nrf2 signaling and mitochondrial cell deaths while improving memory and cognition.[xxii] Cordycepin from the Cordyceps sinensis mushroom alleviated Parkinson’s disease motor disorder symptoms by lowering oxidative stress and inflammation in vivo and in vitro.[xxiii] Lion’s mane mushrooms were supplemented for 12 weeks and were effective in preventing dementia and cognitive decline.[xxiv] Lion’s mane supplementation for four weeks in a study of 30 females also reduced depression and anxiety.[xxv] 5. Antidiabetic Dyslipidemia, high blood cholesterol and triglycerides is often a harbinger of future diabetes. In a rat model, white button mushrooms and a probiotic were found to lower dyslipidemia and decrease oxidative stress.[xxvi] In a study of 89 diabetic patients, oyster mushroom consumption significantly reduced blood glucose, blood pressure, triglycerides and cholesterol without ill effects on the liver or kidneys.[xxvii] Polyphenols from Phellinus igniarius, or willow bracket, mushroom extract were used in vitro and in vivo studies of induced Type 2 diabetes mice and showed improved glucose tolerance, reduced hyperglycemia and normalized insulin levels.[xxviii] Diabetic nephropathy, kidney disease caused by Type 2 diabetes, was studied in vitro with disease-induced rats and treatment with Cordyceps cicadae resulted in improved insulin resistance and glucose tolerance, suppressed inflammation and balanced gut microbiome thus stopping the diabetes-related progression of renal disease and tumors.[xxix] In an animal study, maitake mushroom prevented the progression of kidney fibrosis in diabetic nephropathy rats, significantly decreased fasting blood glucose levels, reduced inflammatory cytokines and lowered renal fibrosis indexes indicating its effectiveness in the treatment or prevention of nephropathy.[xxx] In their meta-analysis of 623 articles and 33 randomized controlled experiments using cauliflower mushroom extract (S. Crispa), researchers found statistically significant differences in diabetic symptoms including decreased serum insulin levels and wound rates and an increase in nutrient intake content.[xxxi] Mushrooms and Their Medicinal Powers Medicinal mushrooms are widely researched and used as treatment in the prevention and progression of many diseases from cancer and asthma to diabetes and dementia. Mushrooms protect you due to their anti-inflammatory, antitumor, antidiabetic, immune boosting and antioxidant activities. To learn more, see GreenMedInfo.com’s database on mushrooms.          

Whether it's Multiple Sclerosis, Type 1 Diabetes, Lupus, or Crohn's Disease, autoimmunity is a rapidly growing problem that traditional pharmaceuticals have failed to completely cure. While these diseases have very different symptoms, they all have the same root cause -- the body’s immune system is attacking its own healthy organs. Lurking within ourselves are a group of T cells called regulatory T cells that have the power to suppress immune function. These cells have huge potential to be engineered and utilized as a platform to cure any autoimmune disease. Unfortunately, they easily lose their suppressive abilities and can even exacerbate autoimmunity if handled incorrectly. Looking to stabilize regulatory T cells, Jessica and her colleagues perform a CRISPR screen to map which genes are responsible for maintaining their suppressive function. Using this data, Jessica takes the first step to bring this incredibly powerful cell type to the clinic to help millions of patients suffering from a myriad of diseases.About the AuthorJessica performed this work in the lab of Professor Alex Marson at the University of California, San Francisco. The Marson lab is renowned for their work in building and applying synthetic biology tools to understand and improve the therapeutic value of immune cells.Jessica is driven to understand and cure autoimmune diseases because her mother, her sister, and her have all been diagnosed with autoimmune diseases.Key TakeawaysRegulatory T cells can suppress immune reactions, making them an attractive therapeutic to be used to cure any autoimmune disease.These regulatory T cells do not easily maintain their suppressive function, necessitating some engineering to make sure they maintain their therapeutic value.With CRISPR, Jessica turned every gene off one-by-one in regulatory T cells to find which genes were involved in maintaining its suppressive function.Jessica found a gene, USP22, that when expressed, inhibited regulatory T cell function making it a useful target for both autoimmunity and cancer.TranslationWhile Jessica focused on one of the hits from the screen, there were many more that have massive potential as drug targets or as engineering steps for T cell therapies against autoimmunity.Maintaining a stable regulatory T cell is the vital first step to creating a world where all autoimmune diseases are cured using cells.First Author: Jessica CortezPaper: CRISPR screen in regulatory T cells reveals modulators of Foxp3

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.01.274753v1?rss=1 Authors: Sobolev, V., Soboleva, A., Svitich, O., Dvoriankova, E., Piruzyan, A., Mildzikhova, D., Korsunskaya, I., Nesterova, A. Abstract: Interactions of genes in intersecting signaling pathways, as well as environmental influences, are required for the development of psoriasis. Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) is a nuclear receptor and transcription factor which inhibits the expression of many proinflammatory genes. We tested the hypothesis that low levels of PPAR{gamma} expression promote the development of psoriatic lesions. We combined experimental results and network functional analysis to reconstruct the model of PPAR{gamma} downregulated signaling in psoriasis. We found that the expression of PPAR{gamma} maybe be slightly downregulated in human psoriatic skin and laser treatment may facilitate it. We tested the reconstructed model and found that at least on mRNA level the expression of IL17, STAT3, FOXP3, and RORC and FOSL1 genes in psoriatic skin before and after laser treatment were correlated with the level of PPAR{gamma} mRNA expression suggesting that genes belong to the same signaling pathway that may regulate the development of psoriasis lesion. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.05.238683v1?rss=1 Authors: Zalosnik, M. I., Fabio, M. C., Bertoldi, M. L., Castanares, C. N., Degano, A. L. Abstract: Background: Rett syndrome is a severe and progressive neurological disorder linked to mutations in the MeCP2 gene located on the X chromosome. So far it has not been established how the presence of a mutant form of MeCP2 can maintain essential regulation of immune responses to support the normal homeostasis of individuals. Since MeCP2 is mostly expressed as a "partially functional" protein in humans with RTT, the aim of our work was to evaluate whether a mutation in MeCP2 interferes with the induction of neuroinflammatory responses in real time. Methods: We used MeCP2308/y mouse model (MUT) and exposed it to an autoimmune challenge, experimental autoimmune encephalomyelitis (EAE). WT and MUT mice were immunized with CFA-MOG or CFA alone (control) and clinical scores were evaluated daily. Animals were sacrificed at either 12 days post-induction (dpi, acute stage) or 30 dpi (chronic stage) and spleen and spinal cord were collected from individual mice for further studies. Cellular infiltration and microgliosis was evaluated by IHC. Cytokine production was assessed in spinal cord and in cultured splenocytes after MOG activation ex-vivo by cytometry and real time RT-PCR. Results: Our results showed that MeCP2 deficiency increased the susceptibility to develop EAE, along with a defective induction of anti-inflammatory responses and an exacerbated MOG-specific reactivity with high IFN{gamma} expression in peripheral immune sites. During the chronic stage, an increase in gene expression of pro-inflammatory cytokines (IFN{gamma}, TNF and IL-1{beta}) and downregulation of genes relevant for immune regulation (IL-10, FoxP3 and CX3CR1) was found in MUT-EAE spinal cords. Conclusions: This is the first study performed in a MeCP2 mutant mouse model that explores the pathophysiology and neuroinflammation in the context of an autoimmune challenge. We could establish that an MeCP2 mutation act intrinsically affecting neuroimmune interactions by promoting an inflammatory environment and a deficient immune regulatory setting. These results are relevant for understanding the consequences of MeCP2 mutations on immune homeostasis in MeCP2-related disorders, as well as setting the bases for further therapeutic interventions that consider the immune status in patients. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.28.224709v1?rss=1 Authors: Wang, Z., Wang, L., Zhong, F., Wu, C., Hou, S.-T. Abstract: Although substantial evidence supports smoking as a risk factor for the development of multiple sclerosis (MS) in adulthood, it remains controversial as to whether early-life exposure to environmental tobacco smoke (ETS) increases the risk of MS later in life. Here, using experimental autoimmune encephalomyelitis (EAE) as an animal model for MS, we show that exposing neonatal rats during the 1st week (ETS1-EAE), but not the 2nd week (ETS2-EAE) and the 3rd week (ETS3-EAE) after birth, increased the severity of EAE in adulthood in comparison to pups exposed to filtered compressed air (AIR-EAE). The EST1-EAE rats showed a worse neurological deficit score and a significant increase in CD4+ cell infiltration, demyelination, and axonal injury in the spinal cord compared to AIR-EAE, ETS2-EAE, and ETS3-EAE groups. Flow cytometry analysis showed that the ETS1 group had decreased numbers of regulatory T (Treg) cells and increased effector T (Teff) cells in the brain and spinal cord. The expressions of Treg upstream regulator Foxp3 and downstream cytokines such as IL-10 were also altered accordingly. Together, these findings demonstrate that neonatal ETS exposure suppresses Treg functions and aggravates the severity of EAE, confirming early-life exposure to EST as a potential risk factor for multiple sclerosis in adulthood. Copy rights belong to original authors. Visit the link for more info

Volume 11 Issue 25 of @Oncotarget reported that Indoximod has shaped the understanding of the biology of IDO1 in the control of immune responses, though its mechanism of action has been poorly understood. Indoximod can have a direct effect on T cells, increasing their proliferation as a result of mTOR reactivation. Further, indoximod modulates the differentiation of CD4+ T cells via the aryl hydrocarbon receptor, which controls transcription of several genes in response to different ligands including kynurenine. Indoximod increases the transcription of RORC while inhibiting transcription of FOXP3, thus favoring differentiation to IL-17-producing helper T cells and inhibiting the differentiation of regulatory T cells. Indoximod can also downregulate expression of IDO protein in vivo in murine lymph node dendritic cells and in vitro in human monocyte-derived dendritic cells via a mechanism that involves signaling through the Ah R. Together, these data improve the understanding of how indoximod influences the effects of IDO, beyond and distinct from direct enzymatic inhibition of the enzyme. Dr. Erik L. Brincks from NewLink Genetics Corporation as well as Lumos Pharma, Inc. said "Indoleamine 2,3-dioxygenase (IDO1) plays an important role in the regulation of acquired local and peripheral immune tolerance in normal and pathological scenarios." In cancer, IDO1 can be expressed either directly by the tumor cells or induced indirectly in host antigen presenting cells by the tumor. IDO1 expression by tumor cells has been associated with significantly worse clinical prognosis and reduced survival in malignant melanoma, pancreatic cancer, ovarian cancer, both pediatric and adult acute myelogenous leukemia, colorectal cancer, prostate cancer, endometrial cancer, and others. The cellular pharmacodynamic effects of IDO1 activity include the inhibition of antigen-specific CD8+ T cell proliferation, stimulation of differentiation of na�ve CD4+ T cells to Fox P3+ regulatory T cells, the activation of Tregs, and the recruitment of MDSC to the tumor. Both isomers are capable of restoring T-cell proliferation in an MLR assay with IDO+ dendritic cells as the stimulator cells, or in syngeneic antigen-dependent T-cell proliferation assays using IDO+ dendritic cells isolated from tumor-draining lymph nodes. L1m T is a competitive inhibitor and substrate of IDO1 enzymatic activity in cell-free assays using purified recombinant IDO1 enzyme, and in tumor cells treated with INFγ or in tumor cell lines transfected with expression vectors that encode IDO1 under the control of an heterologous promoter. The Brincks Research Team concluded in their Oncotarget Research Paper that these effects are independent on the Trp metabolizing activity of IDO and/or TDO but happen to oppose the effects of the enzymatic activity of IDO and TDO by multiple mechanisms that act on cell types commonly affected by the IDO and TDO pathways. Indoximod creates a Trp-sufficiency signal which leads to reactivation of MAP4K3 which leads to activation of mTORC1 activity, thus opposing and bypassing the effects of Trp deprivation that lead to GCN2 activation and MAP4K3 and mTOR inactivation. This effect requires a relatively high concentration of indoximod, is observed in both CD4+ and CD8+ T cells and leads to an increase in the proliferative capacity of activated effector and helper T cells. This effect takes place at clinically relevant concentrations of indoximod and is independent of IDO/TDO activity or exogenous Kyn, though it happens to oppose the Kyn/Ah R effects on T cell differentiation. Full text - https://www.oncotarget.com/article/27646/text/

Treg and Th cells are under transcriptional modulation via cytokine mediated control of a Nfil3 protein that serves to block FOXp3 expression.DR Guerra verifies the evidence in the data from a recent paper: Experimental & Molecular Medicine volume 51, Article number: 80 (2019) that demonstrated Inhibition of the TGF-β signaling pathway led to increased Nfil3 expression which blocked Foxp3 transcription via SMAD3. This is an important contribution to the T lymphocyte literature as it points to the proximal and distal modulation of T cell lineage differentiation, thus focusing attention to potential pharmacotherapeutic and immunoepigenetic mechanisms to control inflammation in diseases such as IBD while simultaneously suggesting strategies to reorganize the T cell profile to destroy tumors. Dr Daniel J Guerra, Authentic Biochemistry. 17 August 2019. --- Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

This JCO Podcast provides observations and commentary on the JCO article “PET Score Has Greater Prognostic Significance Than Pre-Treatment Risk Stratification in Early-Stage Hodgkin Lymphoma in the UK NCRI RAPID Study” by Barrington et al. My name is Brue Cheson, and I am at Georgetown University Hospital, Lombardi Comprehensive Cancer Center. My Hematologic-oncologic specialty is Lymphoma.   Hodgkin lymphoma is clearly one of the most dramatic success stories in modern oncology. More than 90% of patients with limited disease and about 85% with advanced disease are cured using conventional chemotherapy regimens.  As a consequence, current clinical trials are focusing on augmenting or modifying treatment for those at higher risk and decreasing the intensity or duration of therapy for those at a lower risk of treatment failure.   One important question has been: how best to distinguish those disparate groups?  Over the years, various prognostic scoring systems have been devised.  The International Prognostic Scoring System (IPSS) differentiated patients into 6 groups using 7 clinical and laboratory factors.  However, only 7% of patients are in both the most and least favorable groups.  The German Hodgkin study Group (GHSG) and the EORTC each published criteria slightly different from each other for treatment selection.  Nevertheless, it is not clear that any of these schemas remains relevant in the context of current Hodgkin regimens.  More importantly, they do not reliably dictate how to treat patients, nor do they offer therapeutic targets.   FDG-PET scanning has revolutionized our management of patients with lymphoma.  In 2005 we first demonstrated that integration of PET into standard response assessment improved the ability to distinguish between residual tumor and fibrosis in patients with diffuse large B-cell lymphoma, leading to a revision of standardized response criteria. More recent studies have confirmed this observation in Hodgkin lymphoma and other histologies. Patients with advanced Hodgkin lymphoma can be distinguished into high and low risk groups based on PET scan results after 2 cycles of standard ABVD chemotherapy, regardless of their pretreatment IPSS score.  In a number of studies, reacting to the positive interim scan by intensifying therapy achieved outcomes markedly improved over expected.   In the paper that accompanies this podcast, Sally Barrington and her colleagues performed a secondary analysis of the RAPID trial to evaluate the role of pre-treatment risk factors and PET results in predicting outcome of patients with early stage Hodgkin lymphoma.  This study accrued 602 patients who were treated with standard ABVD and underwent PET scanning after the third cycle.  Those with a negative scan (a Deauville score of 1-2) were randomized to no further treatment vs involved field radiotherapy.  Despite a failure to demonstrate non-inferiority of progression-free survival in this cohort, the overall survival was the same, thus sparing 90% of patients unnecessary radiotherapy.  Those with a positive scan (defined as a Deauville score of 3-5), the primary focus of the current manuscript, received an additional cycle of ABVD plus radiotherapy.  Only the 21 patients with a Deauville score of 5, defined as an SUV at least 3 times greater than that of the liver, had an inferior time to progression or greater risk of Hodgkin-related death.  Importantly, this finding was independent of pretreatment prognostic factors using either the GHSG or EORTC scores.  Whether this observation can be extrapolated to patients with features not eligible for the RAPID study, such as those with bulky mediastinal disease or B-symptoms, is presently unknown.  Nonetheless, these data support the role of metabolic imaging over standard clinical and laboratory risk factors.   But we are clearly doing this all wrong.  Why do we treat all patients the same and then wait until the disease has demonstrated resistance before we alter therapy?  Several recent papers support the notion that anticipatory, biologically-based, risk-adapted approaches may be feasible. Pre-treatment total metabolic tumor volume (defined as the sum total of all metabolically active lesions) can predict outcome in Hodgkin lymphoma as well as follicular, diffuse large B-cell and primary mediastinal large B-cell lymphoma.  High heterogeneity of intratumoral FDG uptake distribution on PET-CT may be a marker of chemoresistance in solid tumors as well as various lymphoma histologies.  Unfortunately, those tests do not provide a target against which to direct a specific agent.  In contrast, a number of investigators have demonstrated a correlation between bcl-2, p53, FOXP3, CD68, STAT1, pattern of PD-1 expression, mutational patterns derived from next generation sequencing, and other factors in pre-treatment Hodgkin node biopsies and outcome.  Thus, if we are able to predict outcome prior to treatment, why do we expose patients to drugs to which we know they will not benefit? The goal of treatment should be anticipatory, risk-adapted strategies whereby patients with a high likelihood of benefit may receive standard of care, unless there is another clinical question being addressed.  On the other hand, those unlikely to benefit as determined prior to therapy should be spared the waste of time and toxicity and treated with novel regimens directed at specific targets.  Both groups should be monitored during treatment for the emergence of mutations, with treatment altered accordingly.  Yes, we may be a long way from having the appropriate tools for such an approach.  But, to quote the geneticist, molecular engineer and chemist George M. Church, “The best way to predict the future is to change it”.  Anticipatory, risk-adapted strategies could do just that.   This concludes this JCO Podcast. Thank you for listening.

Dr. Jeffrey Bluestone discusses three articles published in 2003 that describe the discovery of FOXP3 as the determinant of Treg cell fate and function.

The TWiPanosomes solve the case about the Young Woman who Went to Belize, and relate how sandfly saliva skews the immune response and increases risk of cutaneous leishmaniasis. Hosts: Vincent Racaniello, Dickson Despommier, and Daniel Griffin   Links for this episode: Sandfly exposure and risk of cutaneous leishmaniasis (J Inf Dis) TWiP 14: Leishmania Image is L. longipalpis (credit) Letters read on TWiP 96 Case study for TWiP 96 Daniel's patient for this week is male patient referred for consultation by OB-GYN: his wife is pregnant, has been admitted and is about the give birth. It is her first pregnancy. There are concerns about the husband's skin problem and whether it is a threat to his pregnant wife. No lesions on woman, husband recently developed itchy skin problem on his hands. Bilateral. Small papules on webs of fingers, brown lines, blood clots at ends, has clearly scratched the lesions. Skin between fingers is involved. Travels, often stays in cheap hotels. Beds not clean. Last trip 1 month before symptoms.  Midwest travel. Family history of heart disease. Sales occupation. No animal exposure. Travels to medium to large cities.  Send your diagnosis to twip@twiv.tv Contact Send your questions and comments (email or mp3 file) to twip@twiv.tv Subscribe Subscribe to TWiP (free) in iTunes, by the RSS feed or by email  

[intro music]   Hello, and welcome to Episode Thirty-One of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Dr. Lloyd Kasper about the gut microbiome and its role in MS. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   Last week our parent organization, the Accelerated Cure Project, launched its latest endeavor called “iConquerMS.” iConquerMS aims to enroll 20,000 people living with MS to play an active role in research, empowering them to securely submit their health data, influence the studies that are carried out by the initiative, and stay informed about the research. Visit iConquerMS.org for more information.   Vision and sensorimotor problems go together in some MS patients. A recent publication in the journal Neurology examined the relationship between MRI measures of the spinal cord and retina in patients with MS. The investigators found some correlation between the two types of metrics, but they also found that damage in each structure had independent relationships with disability. Read the full story in our “news and future directions” section.   And lastly, our previous podcast contained an error. We mentioned a story about a proof-of-concept study of a novel way to monitor lesion repair. However, the story was withheld from publication due to a delay in the release of the research article. The story is now live on our website.   [transition music]   Now to the interview. Dr. Lloyd Kasper is a faculty member of the Geisel School of Medicine at Dartmouth College. He met with MSDF Executive Editor, Bob Finn, to talk about his research on the gut microbiome and MS.   Interviewer – Robert Finn Dr. Kasper, welcome.   Interviewee – Lloyd Kasper Thank you.   MSDF So to start, why on earth would someone interested in a neurological disease such as MS concern himself with bacteria in the intestines; what’s the connection?   Dr. Kasper That’s actually a very valid question. And the answer to that question is pretty straightforward, is that there’s a very clear brain-gut access so that the brain talks to the gut primary modulating the physiology of the gut through secretion of a variety of molecules, vasoactive proteins, etc. That in turn affects the motility of the gut. By affecting the motility of the gut, you also affect everything that’s inside the gut, which is – as you mentioned just previously – the 100 trillion bacteria that each and every one of us in this world has. And those bacteria in response to the changes in motility shift their behavior, because these are living organisms, and they secrete a wide range of metabolites.   For the purposes of simplicity, you can look at those metabolites and the effect of those various metabolites on the immune system, taking into account that the gut is the largest immune system in our body – 80% of our immune cells are in the gut. So you’ll have this clear interaction between the brain, its activity physiologically on the gut, and the gut’s activity on the bacteria, and then the bacteria’s activity back on the immune system which leads to issues related to the brain.   MSDF So you partly answered my next question. There are microbiomes in other places besides the gut – the skin, the urinogenital tract, etc. Do those other microbiomes have any affect or any relationship to multiple sclerosis, do you think?   Dr. Kasper First of all, the association between the gut microbiome and MS has not yet been fully established, there’s experimental data that would suggest that there is a relationship between the two but that’s still at the experimental level. There really has been very little exploration of the other microbiomes within the body. Remember, the microbiome is not just the microflora. What the microbiome is is the genome of the flora in its relationship to the genome of its host. So when you look at the genomics of MS, for example, in the host – which there’s a lot of work that’s being done – you’re only looking at a fraction of the genetic material that’s involved in this relationship between the gut and the body that it’s in OR any of the other sites that we have microflora – our mouth, as you pointed out; our ears – inside of our ears; our lungs. Those are all areas that bacteria in our body exists in balance with us to achieve a homeostasis. The reason for looking at the gut microbiome is that because it’s the largest, probably the most complex as well.   MSDF So you focused much of your attention on a single bacterial species. Let me see if I pronounce this correctly – Bacteroides fragilis– am I close?   Dr. Kasper Correct.   MSDF And a single substance that it produces, polysaccharide A, or PSA – which has no relation to prostate specific antigen. Why are you focusing on that species and that product?   Dr. Kasper Well, there is mounting evidence that there are several phyla that colonize the gut. The two major phyla of interest are Firmicutes, which are gram-positive aerobes, and Bacteroides, which are gram-negative anaerobes. I’m talking about at the phyla level over which there is no kingdom, phylum, class, order, family, genus, species. Under each one of those phyla there are many different species. We’ve focused in on primarily Bacteroides because Bacteroides fragilis is a very common commensal that essentially inhabits in the neighborhood of 80-90% of all mankind in the world. Bacteroides as a phyla has been associated with the induction of regulatory T cells. Regulatory T cells live in the colon, in and around the colon, and that’s where Bacteroides live. And it’s been shown that Bacteroides as a phyla have the capacity to drive regulatory T cells.   The reason it’s important in MS is because there is a known deficit in the regulatory T cell population in patients with MS. And we chose Bacteroides fragilis because of all the Bacteroides species, that’s the one that we actually know most about immunologically. There’s at least 20 or 25 years’ worth of very, very important data that shows how this particular molecule, this polysaccharide A – and it’s a polysaccharide, it’s not a peptide, it’s a polysaccharide – how this polysaccharide can drive the immune system to a regulatory phenotype that’s associated with the induction of regulatory T cells, production of IL10, all those factors which are important in MS which we know are deficient in those with MS.   MSDF When you say drive the immune system, drive T regs, what do you mean by that?   Dr. Kasper Basically, these bacteria have the capacity to convert effector cells, which would be CD4 positive CD25 negative cells to a regulatory phenotype, which would be CD4 CD25 positive associated with sort of the standard-bearer of regulatory cells, which is Foxp3, which is a nuclear antigen that’s been characterized with it. So this molecule has a remarkable capacity to do that both in vivo and our studies show you can do that actually in vitro as well. So you can take cells that are negative that would be considered naïve or effector-type cells, culture them with this PSA molecule, and convert them to regulatory cells which we know are important in controlling the disease.   MSDF So remind me whether you want more or fewer of these regulatory T cells.   Dr. Kasper It depends where you are in life. To give you sort of a circumstantial argument, we know that Firmicutes, which is that other major phyla, has been associated with a number of disease states, including obesity – just to name one – atherosclerosis, but we also know that the Firmicutes have the capacity to drive IL-17. The regulatory T cells are cells that control the IL-17 response, so it’s important to have regulatory T cells to control the IL-17. We know experimentally that IL-17 drives the experimental form of multiple sclerosis EAE, and there is mounting data – and pretty conclusive, I think – MS is probably at least in part driven by IL-17 cells. So you need these regulatory T cells to control that IL-17 response which is probably being driven by the Firmicutes population. And I’m oversimplifying this, because you remember, you’ve got a hundred trillion cells downstairs making god knows how many different metabolites with over a million genes. So what I’m presenting to you is a very simplified version of this remarkably complex organ.   MSDF So is this leading toward clinical utility for polysaccharide A?   Dr. Kasper We hope so.   MSDF Can you tell me more about that?   Dr. Kasper Well, again, our experimental data – at least in EAE – demonstrates that animals that have been induced with EAE are protected by this polysaccharide. Animals that have EAE, we can therapeutically treat them with this. So this is the first demonstration that a commensal-derived bacterial product that’s within essentially pretty much all of mankind has the capacity to induce regulatory T cells. We don’t know if MS patients are deficient in this or they have the genetic makeup that they can’t respond to it, or whatever it may be. As I said, there’s a real complexity. But the simple observation as we know is that if we take animals that are susceptible to EAE and we treat the prophylactically or therapeutically, we’re able to protect them very, very nicely against the disease process.   And now we have preliminary data in humans that we can take human cells in vitro out of a person and we can drive those human cells from an effector CD4-positive CD25-negative phenotype to a regulatory phenotype by this molecule; just five days of exposure and you see this very nice conversion that’s associated with increased IL10 protection, etc.   MSDF Do you imagine that the PSA molecule itself, if drug development goes on, is there any chemistry that needs to be done before it might possibly be therapeutic?   Dr. Kasper A lot of the chemistry has been done. We have a pretty good idea of what the molecule looks like, it’s a repeating polysaccharide chain. And we know what the conditions are at least in animals as far as innate response molecules – TLRs, toll-like receptors, etc. So as far as the molecule itself, I think we have a pretty good understanding. As I said, there’s about 20 years’ worth of very solid biology behind this molecule. So how far we are away from the clinic at this point is a matter of time, resources, and money to be able to move it from the experimental stage that we’re in into the clinic.   MSDF So you’re not the only research group working on the connection between the gut microbiome and multiple sclerosis. I wonder if you can talk a little bit about how your research fits in with the various other approaches that are going on.   Dr. Kasper Our research has been focused primarily on immune regulation – how to get the disease under control, at least experimentally and hopefully in MS patients. Most of the other labs are looking primarily at what bacteria or bacteria populations are responsible for affecting the disease; what’s driving the disease. We’ve sort of kept away from that because we were fortunate in being able to find this one molecule derived from a bacteria, as I said, that much of mankind is colonized with, so we’ve been focused mostly on how to regulate the disease rather than what’s driving the disease.   MSDF Now, as you know, there’s been a lot of talk and controversy about the role of diet in multiple sclerosis. Do you think that gut bacteria and the substances they product may provide that missing link connecting diet with MS.   Dr. Kasper I think that diet’s going to turn out to be one of the more critical environmental factors that’s associated with the disease process.   MSDF Can you say a little bit more about that?   Dr. Kasper Well, if you look at all the risk factors that we know for MS, that being genetics, obesity, smoking, gender – just to name a few – there’s about six or seven of them. Every one of those risk factors is associated with the microbiome. The common denominator for all the risk factors we know so far in MS is the microbiome, and that includes genetics. As I said, the microbiome is a two-way street; it induces things in us and we do things in turn to it, so it’s a binary system. So our speculations – and we just had a paper published in FEBs – Federation of Experimental Biology – is we’re speculating that the gut microbiome is the major environmental risk factor for MS because it includes all of the known risk factors.   So how can you adjust that? Well, the most logical way is diet, right, because it’s the change in the human diet over the last hundred years that may be accountable for the rise in the disease process. It may also be the change in the diet in Africa as well as Asia which were relatively unknown for MS, but now the incidents in Asia as well as in Africa is approaching about the same as it is in the United States and Europe. So as diet has changed, so has the incidence of the disease gone up. So I’m speculating that diet will turn out to be a very important factor in controlling the microflora, which in turn allows for the balance, the homeostasis, in individuals.   MSDF Well, very interesting. We’ve come to the end of our time, but is there anything you’d like to add, any important questions that I haven’t asked that I should have asked?   Dr. Kasper No. I think the question about the diet, you know, where do you go from here? Because it’s going to take years and years for scientists and clinicians to sort out what’s actually going on in the microbiome. We’re at the tip of the iceberg in this really, because not only is it the immunology that’s important but it’s the physiology and the physiologic changes that the gut microbiome may be creating in people. So as we get better definition of what activities are going on in the microbiome, the greater the likelihood we’ll have of understanding a whole range of human diseases. And not just MS, but that’s all other autoimmune diseases, cancer, obesity, you know, it’s a long list.   And it may ultimately turn out that it’s a clue to our understanding of cancer, for example, because as the microflora shifts as we grow older – which it does – perhaps what we’re seeing is that early on we have bacteria that induce inflammatory processes – which is why MS is a disease of young people – that tends to peter out as you get older. It’s a well-known thing. It doesn’t go away but it tends to peter out. But that may be parallel to the shift in the microflora that’s going on. So early on in the western diet you’re having mostly Firmicutes. As we get older that shifts to more of Bacteroides, which has more regulation. What does more regulation equal? Well, you’re down-regulating the immune system, and as we get older what do we become susceptible? Cancer. So there’s a real balance that’s going on here. And I think a lot of the clues to human biology as far as disease state are going to ultimately be related to the microbiome.   MSDF Dr. Kasper, thank you very much.   Dr. Kasper Thank you.   [transition music]   Thank you for listening to Episode Thirty-One of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.    [outro music]  

Thu, 21 Nov 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16356/ https://edoc.ub.uni-muenchen.de/16356/1/Hermans_Cecilia.pdf Hermans, Cecilia ddc:610, ddc:600, Medi

Penelope Morel and James Faeder discuss their finding that the duration of T cell receptor signaling determines the fate of regulatory versus helper T cells.

Regulatory T-cells (Tregs), characterized as CD4+CD25(hi) T-cells expressing FOXP3, play a crucial role in controlling healthy immune development during early immune maturation. Recently, FOXP3 demethylation was suggested to be a novel marker for natural Tregs in adults. In cord blood, the role and function of Tregs and its demethylation is poorly understood. We assessed FOXP3 demethylation in cord blood in relation to previously used Treg markers such as CD4+CD25(hi), FOXP3 mRNA, protein expression, and suppressive Treg function.

Há as T CD4 reguladoras FOXP3, há as células Tr1, há as células Th3 e ... Num artigo publicado no volume 182 do Journal of Immunology, Han et al da República Popular da China, descreve uma nova subpopulação CD4 com fenótipo imunosupressivo. Estas células sobrerepresentadas em esplenócitos de ratinhos com tumores epiteliais implantados, expressa CD69. Estas células defínidas pelos autores como CD4+ CD69+ e CD25-, não expressam FOXP3 (associado com o fenótipo regulador das células CD4+ CD25+), não produzem citocinas de maneira relevante em repouso ou após activação não específica, não respondem a um estímulo proliferativo alogénico e sobretudo impedem a proliferação de outros linfócitos CD4 específicos de um antigénio. A acção imunosupressiva é transmitida por contacto via TGF-Beta1 presente na membrana celular e modulada pela activação de CD69 e ERK. A ler se tiverem curiosidade... PS: no podcast eu refiro o volume como 189. Peço desculpa pelo erro.

Background: Maternal atopic background and stimulation of the adaptive immune system with allergen interact in the development of allergic disease. Stimulation of the innate immune system through microbial exposure, such as activation of the innate Toll-like- receptor 2 (TLR2), may reduce the development of allergy in childhood. However, little is known about the immunological effects of microbial stimulation on early immune responses and in association with maternal atopy. Methods: We analyzed immune responses of cord blood mononuclear cells ( CBMC) from 50 healthy neonates ( 31 non-atopic and 19 atopic mothers). Cells were stimulated with the TLR2 agonist peptidoglycan (Ppg) or the allergen house dust mite Dermatophagoides farinae (Derf1), and results compared to unstimulated cells. We analyzed lymphocyte proliferation and cytokine secretion of CBMC. In addition, we assessed gene expression associated with T regulatory cells including the transcription factor Foxp3, the glucocorticoid-induced TNF receptor ( GITR), and the cytotoxic lymphocyte antigen 4 (CTLA4). Lymphocyte proliferation was measured by H-3-Thymidine uptake, cytokine concentrations determined by ELISA, mRNA expression of T cell markers by real-time RT-PCR. Results: Ppg stimulation induced primarily IL-10 cytokine production, in addition to IFN-gamma, IL-13 and TNF-alpha secretion. GITR was increased following Ppg stimulation ( p = 0.07). Ppg- induced IL-10 production and induction of Foxp3 were higher in CBMC without, than with maternal atopy ( p = 0.04, p = 0.049). IL-10 production was highly correlated with increased expression of Foxp3 ( r = 0.53, p = 0.001), GITR ( r = 0.47, p = 0.004) and CTLA4 ( r = 0.49, p = 0.003), independent of maternal atopy. Conclusion: TLR2 stimulation with Ppg induces IL-10 and genes associated with T regulatory cells, influenced by maternal atopy. Increased IL-10 and Foxp3 induction in CBMC of non-atopic compared to atopic mothers, may indicate an increased capacity to respond to microbial stimuli.

Das Nierenzellkarzinom ist die häufigste neoplastische Erkrankung der Niere und stellt das siebthäufigste Malignom beim Mann dar, an der in Deutschland jedes Jahr mehr als 11 000 Menschen erkranken. Bei Erstdiagnose sind etwa 13 % der Karzinome bereits metastasiert. Die 1-Jahres-Überlebensrate dieser Patienten beträgt bei rein operativer Behandlung lediglich 15 %. Da das Nierenzellkarzinom keine Strahlensensitivität zeigt und gegenüber gängigen Chemotherapeutika refraktär ist, wird seit langem nach alternativen Behandlungsmöglichkeiten gesucht. Hierbei wird berücksichtigt, dass das Karzinom zu der relativ kleinen Gruppe immunogener Tumoren gezählt wird, da es möglich ist in vitro eine Immunantwort gegen den Tumor zu induzieren. Zudem zeigen einige Patienten Remissionen von Primärtumoren oder Metastasen nach systemischer Gabe von IL-2, so dass scheinbar auch in vivo eine Immunantwort gegen den Tumor ausgelöst werden kann. Die Tumorgewebe weisen in den meisten Fällen außerdem eine sehr starke Infiltration von Lymphozyten auf, unter denen beispielsweise bereits Tumor-spezifische T-Zellen identifiziert werden konnten. Die Lymphozyten scheinen im Tumorgewebe allerdings inaktiv zu sein, da sie das Wachstum des Tumors in vivo nicht verhindern können. Die Erkennung und Bekämpfung der Ursachen für diese funktionelle Inaktivität der Lymphozyten könnte zu einer Entwicklung neuer immuntherapeutischer Ansätze führen. In der vorliegenden Arbeit konnte gezeigt werden, dass die NK-Zellen innerhalb der infiltrierenden Lymphozyten tatsächlich in einem funktionell inaktivierten Zustand vorliegen. Sie sind nicht in der Lage Zellen zu lysieren, selbst wenn diese keine MHC-Klasse-I-Moleküle exprimieren und deshalb von allen NK-Zellen erkannt werden sollten. Durch die direkte ex vivo-Isolierung der Lymphozyten konnte allerdings gezeigt werden, dass die infiltrierenden NK-Zellen durchaus eine maßgebliche Effektorpopulation bei der Eliminierung der Tumorzellen darstellen können. Ihre Zytotoxizität gegen Tumorzellen konnte bereits über eine Kurzzeitkultivierung der Zellen mit IL-2 induziert werden. Die infiltrierenden NK-Zellen waren in der Vergangenheit wenig untersucht worden, da viele Eigenschaften dieser Zellpopulation erst in den letzten Jahren charakterisiert wurden und sowohl Techniken als auch Reagenzien für ihre Beschreibung fehlten. In der vorliegenden Arbeit konnte gezeigt werden, dass eine NK-Zell-Subpopulation, die durch die Expression des inhibitorischen Rezeptorkomplexes CD94/NKG2A charakterisiert ist, verglichen mit autologen peripheren Lymphozyten im Tumorgewebe überrepräsentiert ist. Die Charakterisierung weiterer phänotypischer und funktioneller Merkmale der infiltrierenden NK-Zellen ließ vermuten, dass sie sowohl durch das Expressionsmuster der inhibitorischen Rezeptoren, als auch durch die Expression bestimmter Zytokine wie IL-10 sowie durch ihre geringe zytotoxische Aktivität in situ eine Herabregulierung der Immunantwort im Tumorgewebe verursachen. Dass die NK-Zellen jedoch bereits über eine Kurzzeitstimulierung mit IL-2 aktivierbar waren, könnte erklären, warum die Immuntherapie an Patienten mit metastasiertem Nierenzellkarzinom über IL-2 auch in vivo Wirkung gegen die Tumoren zeigen kann. Die Aktivität der NK-Zellen nach dieser Stimulierung konnte allerdings nur dann festgestellt werden, wenn der Anteil der NK-Zellen innerhalb der TIL hoch lag. Somit konnte ein Zusammenhang zwischen der zytotoxischen Aktivität der NK-Zellen und ihrer Anzahl im Tumor festgestellt werden. Allerdings lag keine Korrelation mit der Größe und Ausbreitung des Primärtumors vor. Dies scheint nicht verwunderlich, da die NK-Zellen im Tumor funktionell inaktiv sind und den primären Tumor somit nicht bekämpfen können. Es wäre allerdings möglich, dass die Anzahl der NK-Zellen nicht nur mit ihrer Aktivierbarkeit im Tumor selbst in Zusammenhang steht, sondern bei diesen Patienten gleichzeitig eine generell bessere Aktivierbarkeit des Immunsystems gegen den Tumor wiederspiegelt. Bei verschiedenen anderen Tumortypen konnte bereits gezeigt werden, dass sowohl die Anzahl als auch die Aktivität der NK-Zellen für die klinische Prognose der Patienten entscheidend sein kann. Somit wäre möglich, dass ein hoher Anteil an NK-Zellen im Tumor einen prognostischen Faktor für das Ansprechen der Patienten auf die systemische Immuntherapie mit IL-2 darstellt und könnte helfen solche Patienten zu selektieren, die somit für diese Therapie mit den zum Teil schwerwiegenden Nebenwirkungen in Frage kommen. Eine Untersuchung dieses Zusammenhangs ist nun retrospektiv auf einfache Weise möglich, da in dieser Arbeit eine Methode dargestellt werden konnte, die es erlaubt die NK-Zellen erstmals über eine einfarbige immunhistochemische Färbung in asservierten Gewebeproben bereits vor längerer Zeit operierter Patienten spezifisch zu identifizieren und die Korrelation mit deren klinischem Krankheitsverlauf zu untersuchen. Bisher ist nicht geklärt, warum verschiedene Tumoren unterschiedliche Anteile infiltrierender NK-Zellen aufweisen. Neben einer verstärkten Einwanderung von NK-Zellen wäre es möglich, dass NK-Zellen in verschiedenen Tumoren unterschiedlich stark proliferieren können. Diese Tumoren weisen dann möglicherweise eine verminderte Fähigkeit auf, das Immunsystem zu unterdrücken und könnten auch aus diesem Grund eine bessere klinische Prognose für die Patienten darstellen. Die Ursachen für die unterschiedliche Aktivierbarkeit der NK-Zellpopulationen konnten bisher ebenso nicht geklärt werden. Hierfür würde sich anbieten, Unterschiede in der Genexpression zwischen verschiedenen NK-Zellpopulationen zu suchen, was beispielsweise mithilfe der Array-Technolgie bewerkstelligt werden könnte. Ein Zusammenhang zwischen der Anzahl der NK-Zellen im Tumor und der Prognose für die Tumorpatienten könnte bestätigen, dass die Population der NK-Zellen in vivo eine ausschlaggebende Effektorpopulation bei der Bekämpfung der Tumoren darstellen. Weiterhin wurden in der vorliegenden Arbeit Untersuchungen an infiltrierenden T-Zellen durchgeführt, die vermuten lassen, dass sowohl aktivierte T-Zell-Populationen als auch regulatorische T-Zellen im Tumorgewebe vorhanden sind. Dies konnte durch die Expression verschiedener Oberflächenmarker und Proteine wie beispielsweise Foxp3, das spezifisch von regulatorischen T-Zellen exprimiert wird, gezeigt werden. Die Anwesenheit verschiedener regulatorischer Zellen könnte einen entscheidenden Beitrag zu einer funktionellen Inaktivierung der Lymphozyten im Tumor und der damit verbundenen Toleranz gegenüber Tumorzellen leisten, da bereits gezeigt wurde, dass regulatorische Zellen beispielsweise die Immunantwort gegen Selbst-Antigene, die auch von Tumorzellen exprimiert werden, unterdrücken können. Erkenntnisse über die Eigenschaften infiltrierender Lymphozyten tragen entscheidend zu einem besseren Verständnis der immunologischen Vorgänge im Nierenzellkarzinom bei. Die in dieser Arbeit aufgezeigten Charakteristika der TIL und die Etablierung einer Methode für die spezifische Identifizierung der NK-Zellen im Gewebe könnten in Zukunft eine Grundlage für die Entwicklung neuer Immuntherapien darstellen, die eine gezielte Aktivierung des Immunsystems gegen den Tumor bewirken könnten.