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Researchers have found a protein that is responsible for turning off brown fat activity. This new discovery could lead to a promising strategy for safely activating brown fat and tackling obesity and related health problems. Brown fat, also known as brown adipose tissue (BAT), is a type of fat in our bodies that's different from the white fat around our belly and thighs that we are more familiar with. Brown fat has a special job -- it helps to burn calories from the foods that we eat into heat, which can be helpful, especially when we're exposed to cold temperatures like during winter swimming or cryotherapy. For a long time, scientists thought that only small animals like mice and newborns had brown fat. But new research shows that a certain number of adults maintain their brown fat throughout life. Because brown fat is so good at burning calories, scientists are trying to find ways to activate it safely using drugs that boost its heat-producing abilities. A new study from the research groups of Prof. Jan-Wilhelm Kornfeld from the University of Southern Denmark/the Novo Nordisk Center for Adipocyte Signaling (Adiposign) and Dagmar Wachten from the University Hospital Bonn and the University of Bonn (Germany) has found that brown fat has a previously unknown built-in mechanism that switches it off shortly after being activated. This limits its effectiveness as treatment against obesity. According to first author of the study, Hande Topel, who is a Senior Postdoc at the University of Southern Denmark and the Novo Nordisk Center for Adipocyte Signaling (Adiposign), the team has now discovered a protein responsible for this switching-off process. It is called 'AC3-AT'. Blocking the "off switch" opens up a new strategy "Looking ahead, we think that finding ways to block AC3-AT could be a promising strategy for safely activating brown fat and tackling obesity and related health problems," Hande Topel says. The research team found the switch-off protein using advanced technology predicting unknown proteins. Hande Topel explains: "When we investigated mice that genetically didn't have AC3-AT, we found that they were protected from becoming obese, partly because their bodies were simply better at burning off calories and were able to increase their metabolic rates through activating brown fat." Two groups of mice were fed a high-fat diet for 15 weeks, which rendered them obese. The group that had their AC3-AT protein removed, gained less weight than the control group and were metabolically healthier. "The mice that have no AC3-AT protein, also accumulated less fat in their body and increased their lean mass when compared to the control mice," says co-author, Ronja Kardinal, who is a PhD student at the University of Bonn in the lab of Dagmar Wachten at UKB, continuing: "As AC3-AT is found not only in mice but also in humans and other species, there are direct therapeutic implications for humans." Hope for strategies that support weight loss Although the prevalence of brown fat decreases as humans age, and despite grown-ups not having as much brown fat as newborns, it can still be activated, for instance by cold exposure. When it gets activated, it enhances the rate of metabolism of these individuals, which again may help to stabilize weight loss in conditions where calorie intake is (too) high. Intriguingly, this study not only identified AC3-AT, which is a shorter, previously unknown form of the AC3protein. The researchers also identified other unknown protein/gene versions, that respond to cold exposure, similar to AC3-AT. "However, further research is needed to elucidate the therapeutic impact of these alternative gene products and their regulatory mechanisms during BAT activation," says co-corresponding author Prof. Dagmar Wachten, Co-Director of the Institute of Innate Immunity at the UKB and member of the Cluster of Excellence ImmunoSensation2 and the Transdisciplinary Research Areas (TRA) "Modelling" and "Life & Health" at the University of Bonn. "Understanding these kinds of molecular mechanisms not only sheds light on the regulation of brown fat but also holds promise for unraveling similar mechanisms in other cellular pathways. This knowledge can be instrumental in advancing our understanding of various diseases and in the development of novel treatments," says co-corresponding author Prof. Jan-Wilhelm Kornfeld, University of Southern Denmark. This study was conducted in the context of the DFG Collaborative Research Center Transregio-SFB 333 "Brown and Beige Fat -- Organ Interactions, Signaling Pathways and Energy Balance (BATenergy)," which is pursuing a better understanding of the different types of adipose tissue and their role in metabolic diseases and the Novo Nordisk Foundation Center for Adipocyte Signaling (Adiposign) at University of Southern Denmark that aims to understand fat cell dysfunction in model organisms and obese patients.

Researchers identify promising treatment candidates for morphine tolerance and cancer, as well as a biomarker for kidney injury. XI'AN, China, Dec. 15, 2023 /PRNewswire/ -- Long-term use of analgesics such as morphine leads to "tolerance" that reduces drug efficacy. In such cases, dose escalation may be required to achieve the same analgesic effects. The key molecular mechanism of morphine tolerance is its inefficiency in inducing mu-opioid receptor (MOR) endocytosis. None of the currently available strategies to counter morphine tolerance address this underlying molecular mechanism. Moreover, understanding how drugs work is crucial to determine their efficacy. There is also an unmet need for new diagnostic biomarkers that can help identify diseases at an early stage. The October issue of JPA features three articles that address these issues and systematically lay a foundation for future studies and treatment strategies. Continue Reading Opioids, including morphine, are frequently used for managing chronic pain. However, long-term use of morphine leads to tolerance, resulting in reduced analgesic efficacy. The first study aimed to address the issue of morphine tolerance by developing a monoclonal antibody (mAb) named 3A5C7 that precisely targets MOR. The therapeutic efficacy of 3A5C7 and its underlying molecular mechanisms were also evaluated as part of the study. The article was available online in June 2023 and published in Volume 13, Issue 10 in October 2023. The results showed that cell lines HEK293T and SH-SY5Y treated with 3A5C7 exhibited enhanced morphine-induced MOR endocytosis and recycling from cytoplasm to plasma membrane. Further, 3A5C7 diminished hyperactivation of adenylate cyclase, an in vitro biomarker of morphine tolerance. Finally, chronic intrathecal 3A5C7 administration significantly alleviated morphine tolerance in mice, while both chronic and acute 3A5C7 intrathecal administration attenuated morphine dependence. Corresponding author Prof. Zhi-Nan Chen states, "Our newly developed mAb targets MOR with high affinity and specificity, and alleviates morphine tolerance and physical dependence, offering a new therapeutic strategy in the management of chronic pain." In the second study, researchers dug deeper into the anticancer mechanisms of the drug 'pracinostat,' which is a histone deacetylase inhibitor (HDACi). Findings revealed that pracinostat exerts its antitumor effects by inducing excessive asymmetric mitochondrial fission in tumor cells. It switches the scission position from the mitochondrial midzone to the periphery and leads to the selective cell death of tumor cells with high cyclin-dependent kinase 5 (CDK5) levels, representing a promising strategy for anticancer therapy. "Our results revealed the anticancer mechanism of the HDACi pracinostat in colorectal cancer (CRC) via the activation of CDK5-Drp1 signaling to cause selective mitofission-associated cell death (MFAD) of CDK5-high tumor cells, which implicates a new paradigm to develop potential therapeutic strategies for CRC treatment," explains the corresponding author Dr. Yang Wang. In the third study, kynurenic acid was identified as a potential biomarker of renal tubular 'organic anion transporter (OAT)' channels for predicting kidney injury. Serum kynurenic acid concentrations were dramatically increased in rats treated with an OAT1/3 inhibitor and in OAT1/3 double knockout rats. Further, renal kynurenic acid levels were significantly raised in response to a multidrug resistance-associated protein 4 (MRP4), which is key to drug and toxin excretion. Corresponding author Prof. Xinan Wu speculates by saying, "Our findings could aid in adjusting drug dosage or predicting renal injury via OAT channels." Together, these articles offer hope for improved treatment strategies in the future. Reference Title of original paper: Monoclonal antibody targeting mu-opioid receptor attenuates morphine tolerance via enhancing morphine-induced receptor endocytosis Journal: Journal of Pharmaceutical Analysis DOI: Media Contact: Mengjie Wang +86-(0)29-88960092 [email protected] SOURCE Journal of Pharmaceutical Analysis

MONTREAL, Sept. 13, 2023 (GLOBE NEWSWIRE) -- DalCor Pharmaceuticals today announced the closing of the company’s Series D financing round of $80m USD to conduct the Dal-GenE-2 confirmatory trial in North America under a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA). Dal-GenE-2 (Dal-302), a phase III, double-blind, randomized placebo-controlled study, will evaluate the potential of dalcetrapib to reduce the occurrence of fatal and non-fatal myocardial infarction (MI) in approximately 2,000 patients with a documented recent acute coronary syndrome (ACS) and the AA genotype at variant rs1967309 in the ADCY9 gene. “Following the dal-GenE trial results showing a potential benefit in a genetically defined patient population, we are pleased to have reached agreement with the FDA to conduct the Dal-GenE-2 confirmatory trial to support a potential new drug application (NDA) filing,” said Dr. Fouzia Laghrissi Thode, CEO of DalCor Pharmaceuticals. This confirmatory trial follows the results of the dal-GenE trial which showed a 21% relative risk reduction (RRR) in fatal and non-fatal MI in 6,149 patients across 34 countries, and a 45% RRR in 1,200 patients in North America and confirmed the safety profile of dalcetrapib. “The AA genotype frequency is up to 20% in European populations and is higher than 40% in populations of African ancestery,” said Dr Eldrin F. Lewis, Chief of the Division of Cardiovascular Medicine at Stanford University, Professor of Cardiovascular Medicine, and Chair of the Dal-GenE-2 diversity committee. “With the relative risk reduction seen in North American patients in the dal-GenE study and the continued commitment to investigating the first potential pharmacogenetic precision medicine for patients with cardiovascular disease, we are pleased to partner with DalCor Pharmaceuticals in this confirmatory trial.” The Series D financing includes the participation of Fonds de Developpement Économique from the Québec government managed by Investissement Québec and Fonds Propres d’ Investissement Québec as well as current investors including Andes Growth, TB Pharma, Fonds de Solidarité FTQ, and CTI Life Sciences. “Québec’s life-sciences expertise is recognized worldwide. Our government is keen to support projects with the potential to generate meaningful spinoffs, like DalCor’s work on cardiovascular health,” said Pierre Fitzgibbon, Minister of Economy, Innovation and Energy, Minister Responsible for Regional Economic Development and Minister Responsible for the Montréal Region. “We are pleased to support DalCor in this round of financing so they can carry on development in precision medicine for cardiovascular disease,” said Guy LeBlanc, President, and CEO of Investissement Québec. “Their research can ultimately revolutionize their industry and reduce the number of cardiovascular events. Investissement Québec will keep supporting emerging young businesses to position Québec in key sectors of our economy, such as life sciences.”- - Notes: Dal-GenE-2: The primary objective of Dal-GenE-2 is to evaluate the potential of dalcetrapib to reduce the occurrence of fatal and non-fatal myocardial infarction in 2,000 patients with a documented recent ACS and the AA genotype at variant rs1967309 in the ADCY9 gene. The trial is expected to start in Q3 2023 with an interim efficacy analysis in 2026, and completion anticipated in 2027. Dal-GenE: While the trial missed the primary endpoint, most likely due to the impact of the COVID-19 pandemic, the results show a 21% relative risk reduction (RRR) in fatal and non-fatal MI in 6,149 patients across 34 countries, and 45% RRR in 1,200 patients in North America. These data support the further development of dalcetrapib. DalCor Pharmaceuticals: DalCor Pharmaceuticals is pioneering precision medicine for patients with cardiovascular disease. By combining genetic and clinical insights, the company’s development program, dalcetrapib, is intended to reduce fatal and non-fatal myocardial infarction (MI) following a recent acute coronary syndrome and deliver superior cardiovascular outcome in a specific genetic subset of patients. DalCor Pharmaceuticals holds the worldwide exclusive license to develop, manufacture and commercialise dalcetrapib, and holds the right to the genetic marker for use with dalcetrapib in patients with the AA genotype at variant rs1967309 in the ADCY9 gene. A companion diagnostic test, developed in conjunction with Roche Diagnostics, identifies patients with the ADCY9 AA genotype who may potentially benefit from dalcetrapib treatment. For more information, visit www.dalcorpharma.com.