SMAD3

The blood-brain barrier -- a network of blood vessels and tissues that nurtures and protects the brain from harmful substances circulating in the blood -- is disrupted in Alzheimer's disease. Now, researchers have uncovered unique molecular signatures of blood-brain barrier dysfunction that could point to new ways to diagnose and treat the disease. The blood-brain barrier -- a network of blood vessels and tissues that nurtures and protects the brain from harmful substances circulating in the blood -- is disrupted in Alzheimer's disease. Now, researchers at Mayo Clinic and collaborators have uncovered unique molecular signatures of blood-brain barrier dysfunction that could point to new ways to diagnose and treat the disease. Their findings are published in Nature Communications. "These signatures have high potential to become novel biomarkers that capture brain changes in Alzheimer's disease," says senior author Nilüfer Ertekin-Taner, M.D., Ph.D., chair of the Department of Neuroscience at Mayo Clinic and leader of the Genetics of Alzheimer's Disease and Endophenotypes Laboratory at Mayo Clinic in Florida. To conduct the study, the research team analyzed human brain tissue from the Mayo Clinic Brain Bank, as well as published datasets and brain tissue samples from collaborating institutions. The study cohort included brain tissue samples from 12 patients with Alzheimer's disease and 12 healthy patients with no confirmed Alzheimer's disease. All participants had donated their tissue for science. Using these and external datasets, the team analyzed thousands of cells in more than six brain regions, making this one of the most rigorous studies of the blood-brain barrier in Alzheimer's disease to date, according to the researchers. They focused on brain vascular cells, which make up a small portion of cell types in the brain, to examine molecular changes associated with Alzheimer's disease. In particular, they looked at two cell types that play an important role in maintaining the blood-brain barrier: pericytes, the gatekeepers of the brain that maintain the integrity of blood vessels, and their support cells known as astrocytes, to determine if and how they interact. They found Alzheimer's disease patients' samples exhibited altered communication between these cells, mediated by a pair of molecules known as VEGFA, which stimulates the growth of blood vessels, and SMAD3, which plays a key role in cellular responses to the external environment. Using cellular and zebrafish models, the researchers validated their finding that increased levels of VEGFA lead to lower levels of SMAD3 in the brain. The team used stem cells from blood and skin samples of the Alzheimer's disease patient donors and those in the control group. They treated the cells with VEGFA to see how it affected SMAD3 levels and overall vascular health. The VEGFA treatment caused a decline in SMAD3 levels in brain pericytes, indicating interaction between these molecules. Donors with higher blood SMAD3 levels had less vascular damage and better Alzheimer's disease-related outcomes, according to the researchers. The team says more research is needed to determine how SMAD3 levels in the brain impact SMAD3 levels in blood. Researchers plan to further study the SMAD3 molecule and its vascular and neurodegenerative outcomes for Alzheimer's disease and also search for other molecules with potential involvement in maintaining the blood-brain barrier. This research is part of a federal grant supporting projects that identify targets for Alzheimer's disease treatment. The study was supported in part by the National Institutes of Health, National Institute on Aging, the Alzheimer's Association Zenith Fellows Award and Mayo Clinic Center for Regenerative Biotherapeutics.

SOUTH SAN FRANCISCO, Calif., May 20, 2024 /PRNewswire/ -- Rila Therapeutics, Inc., A biotechnology company focused on addressing the burden of chronic fibrotic diseases, today announced that the first cohort of subjects was dosed in a phase 1 trial of RLA-23174 in China in collaboration with our development partner, Yingli Pharmaceutical. RLA-23174 is a first-in-class small molecule allosteric inhibitor of HIPK2 which inhibits TGF-β signaling to address FSGS and other fibrotic diseases. The phase 1 placebo-controlled study for RLA-23174 is designed to assess its safety at multiple dose levels, tolerability, food effect, and pharmacokinetics. The single-center trial is enrolling healthy subjects and consists of staggered single ascending dose and multiple ascending dose cohorts. The trial will enroll up to 80 patients with expected completion by the end of 3Q2024 to support advancement into the Phase 2 clinical program. About RLA-23174 RLA-23174 is a new small molecule allosteric inhibitor of HIPK2 and a potential first-in-class treatment for pan-organ fibrosis. RLA-23174 inhibits the TGF-β/Smad3 signaling pathway by affecting the interaction between HIPK2 and Smad3, without inhibiting the kinase activity of HIPK2 or TGF-β receptor systems. Therefore, RLA-23174 exerts anti-fibrotic effects by reducing TGF-β signaling without serious adverse effects caused by complete HIPK2 or TGF-β signaling blockade. Preclinical studies have shown that RLA-23174 has superior anti-fibrotic effects, significant in vivo activity, excellent pharmacokinetic properties in animals, and a good safety profile. RLA-23174 demonstrates good druggability and excellent development potential. "Dosing of the first cohort in this first human study with RLA-23174 is a meaningful milestone for Rila Therapeutics. It signifies our evolution into a clinical development company bringing us closer to helping patients with kidney disease," stated Robert Drakas, Ph.D., Chief Executive Officer of Rila Therapeutics. "Regardless of several newly approved therapies for chronic kidney disease (CKD), many patients still progress to kidney failure, requiring dialysis or transplantation. Therefore, there is an urgent need to develop more effective drugs to halt disease progression, and we strongly believe that anti-fibrosis drug is one of the most promising drugs for such therapy. We are hopeful that HIPK2 inhibitor molecules/RLA-23174 could provide additional renal protection in conjunction with the current therapies for CKD. The Initiation of the phase 1 clinical trial of RLA-23174 is an important milestone for Rila. RLA-23174 exemplifies Rila's commitment to discovering and developing novel precision medicines for severe chronic kidney diseases," said founder John He, MD, PhD, Chief of Nephrology at Icahn Mount Sinai and key opinion leader at one of the largest medical centers in the US. About Rila Therapeutics Rila Therapeutics is focused on developing first-in-class medicines to treat fibrotic diseases. Rila was founded on exploring novel areas of biology focused on stopping fibrosis progression. Rila's programs target key molecular pathways whose dysfunction are hallmarks of renal fibrosis. Rila is building its pipeline by leveraging insights into the dynamic process of fibrosis progression to discover and develop therapeutics with differentiating mechanisms of action against fibrotic pathways. For more information, please visit SOURCE Rila Therapeutics

KYOTO, Japan, Nov. 27, 2023 /PRNewswire/ -- In a study recently published in the journal Scientific Reports, researchers from Shizuoka University, Noster Inc, and other groups in Japan identify gut-bacteria derived metabolites that can mitigate fatty liver disease. Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition that affects a sizable population of the developed world. Causes of NAFLD are stress, genetic predispositions, and preexisting conditions such as obesity. NAFLD is characterized by fat deposits, inflammation, and gradual death of liver cells. What's more, there is no cure for NAFLD at present. Notably, pioglitazone is a diabetes medication that has shown some signs of improvement in NAFLD. However, the mechanism by which it does so is unclear. In a recent collaboration across institutes in Japan, a team led by Tetsuya Hosooka from Shizuoka University and including researchers from Noster Inc, has shown the pathways pioglitazone modifies in order to achieve this effect. The research team started their study by administering diabetic mice with pioglitazone and examining changes in the adipose (fat) tissue over 4 weeks. It was found that linoleic acid metabolites increased in these mice. Importantly, such metabolites are usually produced by the bacteria residing in the gut. A deeper analysis revealed that pioglitazone in fact increased the Lactobacillus species of bacteria in the gut, which in turn were generating the metabolites. Next, the researchers investigated 10-hydroxy-cis-12-octadecenoic acid (HYA), a metabolite of linoleic acid and its effects on NAFLD directly. Mice were fed a high-fat diet to induce NAFLD, and subsequently the effects of HYA treatment were observed. The group of mice treated with HYA had lower body weights, lower blood insulin levels, and less fatty tissue. At 26 weeks, mice given HYA also had less fibrosis in their livers. HYA thus directly showed beneficial effects in mice with NAFLD. To investigate intricate biological pathways further, a genetic analysis was conducted between the HYA-administered and control mice. The former showed decreased genes related to fibrosis and inflammation. Finally, the team delved even deeper to uncover the effects of TGF-β, a key molecule that drives fibrosis. It was indeed suppressed in liver cells after HYA treatment. This study is the first to uncover the role of linoleic acid metabolites, mainly HYA, in reducing NAFLD by pioglitazone. "[H]YA suppresses fibrosis-related gene expression through inhibition of TGF-β–Smad3 signaling in hepatic stellate cells," elaborates the research team. These results also pave the way for investigating HYA as a therapeutic target for NAFLD. Background Nonalcoholic fatty liver disease (NAFLD) and fibrosis: NAFLD is a chronic form of liver disease that affects 25% of the world's population—most likely people who do not consume much alcohol. The main characteristic of NAFLD is a buildup of fatty tissue in the liver. These fat deposits eventually cause the liver to get inflamed and result in the scarring and death of healthy liver cells, known as fibrosis. NAFLD is more common in patients with preexisting conditions such as type 2 diabetes or obesity. It is hard to diagnose as the damage within the liver is silent, often without major symptoms. What's more, at present the only cure for NAFLD is weight reduction. Thus, there is a dire need for medical interventions that can slow down or cure the condition. Reference Nanaho Kasahara, Yukiko Imi, Reina Amano, Masakazu Shinohara, Kumiko Okada, Yusei Hosokawa, Makoto Imamori, Chiaki Tomimoto, Jun Kunisawa, Shigenobu Kishino, Jun Ogawa, Wataru Ogawa, Tetsuya Hosooka. A gut microbial metabolite of linoleic acid ameliorates liver fibrosis by inhibiting TGF–β signaling in hepatic stellate cells. Scientific Reports, 13, 18983 (2023). About NOSTER Inc "Connecting life & gut microbiome" Noster website By "connecting life and gut microbiome" we will continue to contribute to the improvement of human health and advancement of science. To achieve this vision, the diverse and talented scientists at Noster are working as one team based on mutual trust and respect. Our team is dedicated to advancing scientific research and development on the gut microbiome to find treatments for patients suffering from diseases. We will continue to meet the challenges for the realization of gut microbiome-based drug discovery with passion and confidence that "great things can be achieved by scientific research." For further information: Nanami Akatsuka (Ms) International relations 35-3 Minamibiraki, Kamiueno-cho, Muko-shi, Kyoto, 617-0006, Japan E-Mail: [email protected] Telephone: 81 (0)-75-921-5303 Noster's analytical services NOSTER and Science Microbiome Prize The NOSTER & Science Microbiome Prize has been established to reward innovative research by young investigators working on the functional attributes of the microbiota of any organism that has potential to contribute to our understanding of human or veterinary health and disease or to guide therapeutic interventions. SOURCE Noster Inc