Kayothera’s Post

While popular culture has become more aware that certain natural ingredients are harmful in excess (e.g. cholesterol, trace minerals, etc.), there seems to be some cognitive dissonance when it comes to anything labeled as a Vitamin. However, excess intake of Vitamin A (or synthetic #retinoids) comes with a host of issues that we've known about for a long time, including hyperlipidemias (dramatic increases in circulating triglycerides and cholesterol), heart failure, hypothyroidism, and a delayed cancer-promoting effect. Of course, a certain amount of Vitamin A is essential for our health, but this nuclear receptor pathway is often hijacked by diseases like #diabetes, cardiometabolic syndromes and #cancer. In this paper published today at JEM, Yibin Kang, John Amory and I explore the history of Vitamin A in human health and how turning off retinoid nuclear receptor signaling could help to combat #diabetes, #obesity, and #cancer.  https://lnkd.in/gGEntdRh At KayoThera, we've been developing a pipeline of medicines to inhibit retinoid signaling, and we're excited to share that our cancer therapy, KAYO-1609, is expected to show clinical data in 2025. Meanwhile, our candidate therapy for diabetes is already demonstrating tremendous promise in reversing type 2 diabetes in preclinical studies.

🧪 Thursday Antibody! We’re excited to kick off a new series where, every Thursday, we’ll spotlight a unique antibody from our collection and our partners. Our goal? To help researchers like you discover the high-quality tools you need for cutting-edge research! For our first edition, we’re showcasing our ATF3 Polyclonal Antibody. 🎯 What makes ATF3 special? ATF3 (Activating Transcription Factor 3) is a key regulator involved in cellular stress responses, apoptosis, and immune regulation. Our polyclonal antibody is highly sensitive, providing excellent specificity and reliable performance in a variety of applications including Western Blot and IHC. Why choose our ATF3 antibody? • ✅ Research area: Epigenetics and Nuclear Signaling • ✅ Validated for multiple applications • ✅ Ready to support your research Curious to learn more or ready to order? 👉 https://lnkd.in/es84if5A Stay tuned every Thursday for more antibody highlights to enhance your research. #ThursdayAntibody #ResearchTools #LifeSciences #Antibodies #ATF3 #PolyclonalAntibody

A recent study has reported a promising finding in the fight against Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). The study has found that a peptide can prevent the nuclear exit of pathological C9ORF72-repeat RNAs, which in turn prevents the production of DPRs in cellular and animal models of ALS/FTD. This could be a significant breakthrough in the search for a cure for these devastating diseases. To read more about this exciting development, check out the link below. Link: https://lnkd.in/ewyEuuVc

#ferroptosis #hippocampalneuron #autophagy #erastin Inhibition of autophagy rescues HT22 hippocampal neurons from erastin-induced ferroptosis https://lnkd.in/gtPnN7MH Goethe University Frankfurt Ferroptosis is a regulated form of cell death which is considered an oxidative iron-dependent process. The lipid hydroperoxidase glutathione peroxidase 4 prevents the iron (Fe2+)-dependent formation of toxic lipid reactive oxygen species. In this study, we demonstrated by immunofluorescence and western blot analysis, that erastin downregulates dramatically the expression of glutathione peroxidase 4, the sodium-independent cystine-glutamate antiporter and nuclear receptor coactivator 4. The protein levels of ferritin and mitochondrial ferritin in HT22 hippocampal neurons did not remarkably change following erastin treatment. In addition, we demonstrated that not only the ferroptosis inhibitor, ferrostatin1/deferoxamine abrogated the ferroptotic cell death induced by erastin in hippocampal HT22 neurons, but also the potent autophagy inhibitor, 3-methyladenin. We conclude that (1) erastin-induced ferroptosis in hippocampal HT22 neurons, despite reduced nuclear receptor coactivator 4 levels, (2) that either nuclear receptor coactivator 4-mediated ferritinophagy does not occur or is of secondary importance in this model, (3) that ferroptosis seems to share some features of the autophagic cell death process.

#NewAssay #HNF4a #CellBasedAssay #Luciferase We are thrilled to announce the release of a new cell-based reporter assay for the Hepatocyte Nuclear Factor 4 Alpha (HNF4α)! https://lnkd.in/dptCKpdM The Hepatocyte Nuclear Factor 4 Alpha (HNF4α) belongs to the nuclear receptor superfamily, serving as a critical transcription factor involved in the regulation of gene expression in various tissues, particularly the liver, pancreas, kidney, and intestine.  As a master regulator of metabolic pathways, HNF4 plays a pivotal role in maintaining cellular homeostasis and orchestrating physiological processes such as glucose and lipid metabolism, as well as cell differentiation and development. Dysregulation of HNF4α signaling has been implicated in various diseases, including Diabetes Mellitus, liver disease, and intestinal disorders such as Crohn's disease.

Our fluorescent hydroxychloroquine dye HCQFluo was featured in an article about a new Nurr1 agonist for Parkinson's disease models. The article "An optimized Nurr1 agonist provides disease-modifying effects in Parkinson’s disease models" focuses on developing and evaluating an optimized agonist for Nurr1, a nuclear receptor essential for the development and maintenance of midbrain dopamine neurons. Nurr1 represents a promising molecular target for Parkinson's disease (PD) due to its critical role in neuronal health. The study, published in Nature Communications, used HCQFluo in a ligand-binding assay to measure the binding affinity of the optimized agonist 4A7C-301 to the Nurr1 ligand-binding domain (LBD). The findings revealed that 4A7C-301 has a significantly higher binding affinity for Nurr1-LBD, underscoring its potential as a therapeutic option for Parkinson’s disease. Full article here https://lnkd.in/dv63cXDu More info on HCQFluo here https://lnkd.in/dMe-4pQ4 #ParkinsonsDisease #ParkinsonsResearch #NeurodegenerativeDisease #FluorescenceImaging

Source: Talanta A metabolomic analysis using nuclear magnetic resonance (NMR) spectroscopy was conducted in tears to identify biomarkers for the diagnosis of primary open-angle glaucoma (POAG). A classification model based on the metabolomic fingerprint in tears was generated, showing high accuracy in distinguishing between the POAG group and control group. The study identified specific metabolites that were decreased or increased in tear concentration in the POAG group, suggesting the potential of tear metabolomics as a non-invasive approach for early diagnosis and prevention of visual loss in POAG.

Happy to share that my first-author research article on Nuclear respiratory factor-1 (NRF1) overexpression inducing mitochondrial biogenesis and attenuating neurotoxicity is now available online: https://lnkd.in/ggVwvrdn We demonstrate that inducing NRF1—a key regulator of mitochondrial gene expression—through mRNA transfection promotes mitochondrial biogenesis and, crucially, mitigates amyloid beta-associated neurotoxicity. This is achieved by reducing mitochondrial reactive oxygen species (mtROS), enhancing bioenergetic function, and preventing neurite disruption. These findings underscore the pivotal role of mitochondrial homeostasis in Alzheimer's disease and other age-related disorders.

Throughout school, we’re taught that cells are well ‘organized’ machines. Every enzyme/organelle has a job & they seldom overlap. Well…nature & biology really aren’t that neatly ‘organized’. Recently researchers at Center for Genomic Regulation ‘discovered’ that certain metabolic enzymes that are important for energy production or nucleotide synthesis are ‘moonlighting’ within the nucleus. Besides challenging the long-standing & ‘classical’ views of the cell…these findings may also open up new ‘avenues’ for development of new cancer therapies (i.e. new ‘targets’ for drugs & other therapies). What they found: The enzyme MTHFD2 (methylenetrtrahydrogolate dehydrogenase 2) which is ‘normally’ located in the mitochondria & functions within one-carbon metabolic pathways can also be found in the nucleus—when the cell is ready to go through mitosis. It seems that enzyme interacts with other methyl-transferase proteins to ensure proper division of the chromosomes, & when deleted it leads to defects in cell division. In addition, the enzyme IMPDH2 (inosine monophosphate dehydrogenase 2), which is important for the biosynthesis of guanine nucleotides (the Gs), also can be found in the nucleus aiding in DNA repair. This was an important finding because it can help explain why DNA damage doesn’t ‘kill’ triple-negative breast cancer (TNBC) cells, and they also saw that it interacts with PARP1 (an typical cancer target), possibly explaining why at times anti-PARP1 treatments fail. I’m not totally ‘shocked’ that metabolic enzymes are ‘moonlighting’ within the nucleus…I mean there is a ‘limit’ of the number of proteins that our genome encodes for…and why encode for two different proteins, when you can have one protein doing multiple ‘jobs’ at different times in the cell. It will be interesting to see if IMPDH2 becomes a therapeutic target for TNBC…and what other enzymatic enzymes are ‘discovered’ to be moonlighting in other organelles in our cells. #metabolicenzymes #cancerreserach #DNAdamage #enzymes #oneenzymemultipleroles 

A study in The Journal of Nuclear Medicine found that the free-to-total PSA ratio may be an independent predictor of positive 18F-DCFPyL PSMA PET/CT scans in patients experiencing biochemical recurrence of prostate cancer after radical prostatectomy. The research involved 137 patients with a total PSA of less than 1 ng/mL and found an FPSAR of 0.10 or more increased the risk of a positive scan. These findings could help prioritize access to PSMA PET/CT scans in regions where availability is limited.