Romilly Wilde’s Post

New research reveals that deleting the S6K1 gene in mice reduces inflammation and extends lifespan, highlighting a promising new approach for treating age-related diseases. - 🌱 Deleting S6K1 gene suppresses inflammatory proteins that contribute to aging - 🧬 S6K1 protein is a key target in the mTOR pathway, which regulates growth and metabolism - 🩺 The findings show how inflammation, metabolism, and senescence are interconnected in aging - 🧠 The study offers insights into replicating the benefits of calorie restriction, like lower body fat and stronger bones - 🔬 Research shows potential for new therapies to treat aging-related conditions like diabetes and cardiovascular diseases #LongevityResearch #Inflammation #AgeRelatedDiseases - 📊 S6K1 inhibition has been linked to lifespan extension in mice by reducing inflammatory responses - 🍎 Mice showed resistance to diabetes, lower body fat, and increased bone strength, mimicking effects seen in calorie restriction - 🧪 The protein’s inhibition could be a critical step toward designing treatments targeting aging and metabolic disorders - 🧬 Studies highlight the broader role of senescent cells, which accumulate with age and release inflammatory proteins - 🧘 Targeting S6K1 could reduce the age-related inflammatory processes known as SASP, which is a driver of aging - 🔄 This research aligns with other studies showing that inflammation plays a key role in aging and many age-related diseases - 🧫 Future research will explore if S6K1 inhibition can provide similar benefits in other tissues, beyond the liver By exploring the complex relationship between aging, inflammation, and metabolism, scientists are uncovering new ways to potentially slow down the aging process and improve health span. https://lnkd.in/gCT3cuAF

https://lnkd.in/ghveXQHC Notably, the absence of injury in the distal colon of germ-free (GF) Hsp60Δ/ΔIEC mice underscores the pivotal influence of microbiota on metabolic injury. Introducing a synthetic microbial community (OMM12) and the specific colonization by Bacteroides caecimuris recapitulating the injury suggest that microbial composition and metabolic flexibility are key factors in disease manifestation. The transcriptional profiling data revealing oxidative stress-related gene signatures (Ido1, Nos2, Duox2) align with those found in Crohn’s disease patients, providing a translational link between the model and human pathology. This study sheds light on the microbiota-dependent mechanisms of mitochondrial dysfunction-induced injury and the potential for targeting these pathways in IBD treatment strategies. Identifying specific gene signatures associated with active inflammation could also serve as valuable biomarkers for disease activity and therapeutic response in IBD patients.

Recent research has unveiled the critical role of 𝐔𝐁𝐗𝐍6, a cofactor of the p97 protein, in regulating inflammation and autophagy in monocytes/macrophages during sepsis. Patients with sepsis exhibited significantly elevated 𝐔𝐁𝐗𝐍6 levels in peripheral blood mononuclear cells (PBMCs), negatively correlating with inflammatory gene expression. In myeloid-specific UBXN6-deficient mice, increased susceptibility to systemic inflammation highlighted 𝐔𝐁𝐗𝐍6's importance in controlling inflammatory responses through autophagy and ER-associated degradation pathways. This deficiency also led to a metabolic shift towards aerobic glycolysis and the accumulation of branched-chain amino acids (BCAAs), further promoting inflammatory responses. These findings suggest that targeting 𝐔𝐁𝐗𝐍6 could provide novel therapeutic strategies for managing sepsis and related inflammatory diseases, emphasizing the need to understand the balance between innate immunity and inflammation for potential advancements in therapeutic interventions. #Immunology #Inflammation #Autophagy 𝘒𝘪𝘮, 𝘠.𝘑., 𝘓𝘦𝘦, 𝘚𝘎., 𝘗𝘢𝘳𝘬, 𝘚.𝘠. 𝘦𝘵 𝘢𝘭. 𝘜𝘣𝘪𝘲𝘶𝘪𝘵𝘪𝘯 𝘳𝘦𝘨𝘶𝘭𝘢𝘵𝘰𝘳𝘺 𝘟 (𝘜𝘉𝘟) 𝘥𝘰𝘮𝘢𝘪𝘯-𝘤𝘰𝘯𝘵𝘢𝘪𝘯𝘪𝘯𝘨 𝘱𝘳𝘰𝘵𝘦𝘪𝘯 6 𝘪𝘴 𝘦𝘴𝘴𝘦𝘯𝘵𝘪𝘢𝘭 𝘧𝘰𝘳 𝘢𝘶𝘵𝘰𝘱𝘩𝘢𝘨𝘺 𝘪𝘯𝘥𝘶𝘤𝘵𝘪𝘰𝘯 𝘢𝘯𝘥 𝘪𝘯𝘧𝘭𝘢𝘮𝘮𝘢𝘵𝘪𝘰𝘯 𝘤𝘰𝘯𝘵𝘳𝘰𝘭 𝘪𝘯 𝘮𝘢𝘤𝘳𝘰𝘱𝘩𝘢𝘨𝘦𝘴. 𝘊𝘦𝘭𝘭 𝘔𝘰𝘭 𝘐𝘮𝘮𝘶𝘯𝘰𝘭 (2024).

Genome-wide association studies have linked a gene called CARD9 to immunity against fungal infections and, through work done several years ago at Broad, to inflammatory bowel disease. In Cell Reports, Marta Brandt, Zhifang Cao, Ramnik Xavier, and colleagues report that a specific variant of the gene, R101C, disrupts inflammatory signaling by the CARD9 protein in myeloid cells, which is important for immune responses against fungal infection. Mice carrying the human CARD9 variant failed to fend off fungal skin infection and showed minimal inflammation. The findings suggest the variant disables a phosphorylation-dependent signaling switch that activates immune defenses. #BroadInstitute #Science #ScienceNews #Research #ScientificResearch

I am delighted to share our recent research article, published in Genes MDPI “Extracellular Vesicles from NSC-34 MN-like Cells Transfected with Mutant SOD1 Modulate Inflammatory Status of Raw 264.7 Macrophages”. Our study focuses on #extracellular #vesicles (EVS)-mediated cell-to-cell communication and, in particular, we analyze the response of macrophages. NSC-34 cells transfected with mutant #SOD1 (G93A, A4V, G85R, G37R) and differentiated towards MN-like cells, and Raw 264.7 macrophages are the cellular models of the study. #mSOD1 NSC-34 cells release a high number of vesicles, both large-#lEVs  (300 nm diameter) and small-#sEVs (90 nm diameter), containing #inflammation-modulating molecules, and are efficiently taken up by macrophages. RT-PCR analysis of inflammation mediators demonstrated that the conditioned medium of mSOD1 NSC-34 cells polarizes Raw 264.7 macrophages towards both pro-inflammatory and anti-inflammatory phenotypes. sEVs act on macrophages in a time-dependent manner: an anti-inflammatory response mediated by TGFβ firstly starts (12 h); successively, the response shifts towards a pro-inflammation IL-1β-mediated (48 h). The response of macrophages is strictly dependent on the SOD1 mutation type. The results suggest that EVs impact physiological and behavioral macrophage processes and are of potential relevance to MN #degeneration. MDPI I am grateful to my colleagues for the opportunity to take part in this work. 🔗 Link to the publication:

Excited to share this paper from my lab. We identified a potential new target for VCP Disease (emphasize potential). TL;DR - Mutations in the VCP gene can lead to diseases of the bone, brain, and muscle. The cluster of diseases is known as Multisystem Proteinopathy (MSP). Patients with the same mutation, even within the same family, can have any combination of these diseases. Others may also develop amyotrophic lateral sclerosis (ALS). The difficulty in understanding VCP Diseases is the many mutations and the varied effects. So, how do we target a disease with so many variables? We found that all cells die when we overexpress a protein called Small VCP-interacting Protein (SVIP) with mutant VCP. We could reverse this by targeting a lipid modification of SVIP. We think that blocking this lipid modification might provide a target in VCP Diseases. Firyal Ramzan, Ph.D. Ashish Kumar Fatima Abrar Zurie Campbell Anthony Dang Timi Akanni Colm Guyn and more. https://lnkd.in/ga8U4QFg

Recent research has identified a protein, MED12, as a key regulator in the immune system's balance between rest and activation. This discovery, published in Nature, highlights MED12's role in orchestrating T cell functions by controlling gene expression through chromatin structure. The study reveals that MED12 influences both conventional and regulatory T cells, affecting their response to environmental signals. This understanding could lead to advancements in treatments for diseases like cancer and autoimmune disorders, as manipulating MED12 may enhance the effectiveness of immunotherapies by maintaining T cell functionality under various conditions.

APOE4: no longer just a risk factor for Alzheimer’s, it's a genetically distinct form of the disease! Alzheimer’s disease (AD) is the cause of ~ 70% of the cases of dementia in the US. It's also the seventh leading cause of death. The cause of AD is still largely unknown although there are genetic and environmental factors that contribute to the disease. It is typified by the development of plaques in the brain that lead to the progressive loss of brain function. The plaques are caused by the abnormal accumulation of the proteins amyloid beta (Aβ) and Tau. Deficiencies in clearing these proteins are thought to result in inflammation of the brain that interferes with the connections between neurons and, ultimately, their death. The best evidence we have for this mechanism is that the gene that leads to the creation of Aβ, Amyloid Precursor Protein (APP), is found on chromosome 21 and people with Down Syndrome (three copies of 21) generally show symptoms of AD by the age of 40. This is further supported by Autosomal Dominant AD which is caused by mutations in APP and the proteolytic proteins PSEN1 and PSEN2. These result in the abnormal overproduction of Aβ. But, greater than 90% of cases of AD are sporadic (no family history or obvious genetic cause), although there are a number of genes that are risk factors for the disease. One of those is Apolipoprotein E (APOE) which is involved in transporting lipids. Genetic studies have identified 3 variants of APOE in humans: ε2, ε3, and ε4. APOEε4 (or just APOE4) is associated with problems in regulating lipid metabolism and is often seen in people with hypercholesterolemia (too much cholesterol) and hyperlipidemia (too much fat in the blood). It has also been associated with up to 80% of sporadic cases of AD and people who carry two copies of APOE4 have a 60% lifetime risk of developing disease. While a lot of questions still remain about how APOE4 can cause AD, the author’s of today’s paper make a very compelling argument that APOE4 represents a genetically distinct form of AD showing “near-full penetrance, symptom onset predictability and a predictable sequence of biomarker and clinical changes” that lead to disease. They looked at the brains of >3,000 deceased AD patients and the clinical presentation of >10,000 individuals living with AD. What they found (see the figure below) is that APOE4/4 AD patients a) have intermediate to high levels of neuropathology, b) >90% show biological hallmarks of the disease by age 65, c and d) have earlier disease onset, comparable to the other genetically distinct forms of AD. This genetic distinction is important because it allows us to better inform patients of their risk, and gives us new tools to predict onset and track disease progression. ### Fortea J, et al. 2024. APOE4 homozygozity represents a distinct genetic form of AD. Nature Medicine. DOI: 10.1038/s41591-024-02931-w --- Want this in your inbox? Visit my website ⬆️

🔍 New Study Uncovers Genetic Links to Juvenile Arthritis! 🧬 Researchers at the Children’s Medical Center Hospital have made significant strides in understanding juvenile idiopathic arthritis (JIA) by investigating variations in the NLRP3 gene. Key Findings: - NLRP3 Gene Variations: May influence susceptibility to JIA, despite similar SNP frequencies. - SNP Interactions: A notable interaction between specific SNPs could alter genetic risk profiles. - Haplotype Analysis: Identified markers that may increase or decrease JIA risk. This groundbreaking research emphasizes the complex genetic relationships that could inform targeted therapies and personalized treatments for affected children. As we expand our knowledge of autoimmune diseases, these insights pave the way for improved patient care and outcomes. 👉 Click on the link to learn more about how these findings could transform our approach to juvenile arthritis! #AutoimmuneDiseases #ClinicalResearches #GeneticResearch #HealthcareInnovation #JuvenileArthritis #NLRP3 #MarketAccess #MarketAccessToday

Recent research has identified a protein, MED12, as a key regulator in the immune system's balance between rest and activation. This discovery, published in Nature, highlights MED12's role in managing T cell functions, crucial for immune response. The study reveals that MED12 influences chromatin structure, affecting gene activation in T cells. This understanding could lead to advancements in therapies for diseases like cancer and autoimmune disorders, where T cell activity is pivotal. By manipulating MED12, scientists may enhance the effectiveness of immunotherapies, offering new avenues for treatment development.