EP3

Short-chain fatty acids (SCFAs), which are produced by gut bacteria from dietary fiber, regulate our immune system, but the mechanism of their action remains unknown. In a recent study, researchers investigated how SCFAs interact with mast cells, a type of white blood cell that plays a central role in allergic reactions. Their findings and insights could lead to innovative and effective anti-allergy medications, supplements, and diets, paving the way for healthier lives. The intricate relationship that exists between humans and the gut microbiome has become a hot research topic, and scientists are constantly uncovering new reasons why a healthy diet can lead to a healthier life. Dietary fibers are a particularly important aspect of this connection. When we ingest these compounds, which are mainly found in plant-based foods, our gut bacteria break them down into small molecules, called short-chain fatty acids (SCFAs). Over the past few years, studies have revealed various important anti-inflammatory and immunomodulating effects of SCFAs. One of the ways SCFAs interact with our immune system is by mediating the activation of mast cells (MCs). These white blood cells are loaded with small sacs called "granules," which are full of enzymes and signaling molecules like histamine. When an MC detects an antigen (foreign body), it becomes active and undergoes degranulation, releasing these substances to nearby tissue and triggering a fast immune response. Usually, MCs play a central role in allergic diseases, including pollinosis and severe food allergies. While there is considerable evidence that SCFAs have anti-allergic properties, the precise mechanisms by which they regulate the function of MCs remain unclear. In a recent study, a research team led by Professor Chiharu Nishiyama from Tokyo University of Science, Japan, decided to address this knowledge gap through extensive experiments on mouse MCs and SCFAs. Their findings were published in The Journal of Immunologyon January 10, 2024. The researchers initially found that feeding mice with butyric acid and valeric acid, two representative SCFAs, significantly suppressed passive cutaneous anaphylaxis (a type of well-studied allergic reaction induced artificially in laboratory settings). Using MC cultures, the team then showed that treating MCs with various SCFAs suppressed Immunoglobulin E (IgE)-mediated activation, a crucial pathway in allergic reactions. Through subsequent experiments involving genetically modified cells and precise RNA inhibitors, they managed to further piece together the puzzle. The researchers found that SCFAs mediated MC activation in mainly two ways. The first was through the recognition and interaction with the GPR109A receptor. Upon binding with SCFA, a chemical cascade ensues, culminating with the synthesis and secretion of prostaglandins. These substances interact with EP3 receptors in MCs and prevent degranulation, limiting the release of histamine and minimizing allergic response. The second was through epigenetics (or reversibly altering specific genes). The researchers confirmed that SCFAs affected histone deacetylase inhibitory activity, which regulates epigenetic modifications. This led to changes in the expression levels of the IgE-receptor, which ultimately inhibited degranulation in MCs. Additional experiments revealed that non-steroidal anti-inflammatory drugs suppressed the anti-allergic effects of SCFAs, and that vitamin B-3, which interacts with the GPR109A receptor, also inhibited MC degranulation. Together, the findings of this study can help scientists navigate the intricacies of how our bodies regulate our immune system with the help of gut bacteria. However, people with allergies stand to gain from these insights, as Prof. Nishiyama points out: "The activation of mast cell is a common cause of various allergic diseases and not limited to anaphylaxis. In addition, I think that the increasing frequency of allergic patients is associated with changes in diet in these decades. Allergies are so common that one in two Japanese people is said to have some kind of allergic disease, and the results of our study showcase dietary fibers as an effective way of treating them." Considering that about 200,000 visits to the emergency room per year are due to anaphylaxis in the United States alone, this work could not only save lives from by preventing this dangerous condition, but also help ameliorate the burden on healthcare systems. Satisfied with the results, Prof. Nishiyama concludes by noting the importance of eating well. "It is important to demonstrate with scientific evidence how dietary conditions affect health," she says. "This research has revealed part of the complex regulatory mechanisms involving various food-related components, including dietary fiber, SCFAs, polyunsaturated fatty acids, and vitamins." Notably, Prof. Nishiyama and her colleagues now intend to investigate the relationship between the mucosal environment and immunoregulation by focusing on specific SCFAs, which may lead to the uncovering of the health benefits of various foods soon.

Researchers have identified key neurons that regulate body temperature at 37°C in mammals. This finding could pave the way for developing a technology that artificially adjusts body temperature to help treat heat stroke, hypothermia, and even obesity. A research group at Nagoya University in Japan has reported that a group of neurons, called EP3 neurons, in the preoptic area of the brain play a key role in regulating body temperature in mammals. The finding could pave the way for the development of a technology that artificially adjusts body temperature to help treat heat stroke, hypothermia, and even obesity. The new study was published in the journal Science Advances. Body temperature in humans and many other mammals is regulated at around 37°C (98.6°F), which optimizes all regulatory functions. When their body temperature noticeably deviates from the normal range, the functions are impaired, which could lead to heat stroke, hypothermia, and, in the worst case, death. However, these conditions might be treated if body temperature can be artificially adjusted to the normal range. The brain's temperature regulation center resides in the preoptic area, a part of the hypothalamus that controls the body's vital functions. For example, when the preoptic area receives signals from a mediator called prostaglandin E (PGE2) that is produced in response to infections, this area releases a command to raise body temperature to fight against viruses, bacteria, and other disease-causing organisms. However, it is still unclear exactly which neurons in the preoptic area release commands to increase or decrease body temperature. To identify such neurons, Professor Kazuhiro Nakamura, Lecturer Yoshiko Nakamura, and their colleagues at Nagoya University, in collaboration with Professor Hiroyuki Hioki at Juntendo University, conducted a study using rats. They focused on EP3 neurons in the preoptic area, which express EP3 receptors of PGE2, and investigated the function for regulating body temperature. Professor Nakamura and his colleagues first investigated how the activity of EP3 neurons in the preoptic area varies in response to changes in ambient temperature. A comfortable environmental temperature for rats is around 28°C. For two hours, the researchers exposed the rats to cold (4°C), room (24°C) and hot (36°C) temperatures. Results showed that exposure to 36°C activated EP3 neurons, while exposure to 4°C and 24°C did not. The group then observed nerve fibers of EP3 neurons in the preoptic area to identify where the signals from EP3 neurons are transmitted. The observation revealed that nerve fibers are distributed to various brain regions, particularly to the dorsomedial hypothalamus (DMH), which activates the sympathetic nervous system. Their analysis also showed that the substance that EP3 neurons use for the signal transmission to DMH is gamma-aminobutyric acid (GABA), a major inhibitor of neuronal excitation. To further investigate the role of EP3 neurons in temperature regulation, researchers artificially manipulated their activity using a chemogenetic approach. They found that activating the neurons led to a decrease in body temperature, whereas suppressing their activity led to their increase. Taken together, this study showed that EP3 neurons in the preoptic area play a key role in regulating body temperature by releasing GABA to send inhibitory signals to DMH neurons to control sympathetic responses. "Probably, EP3 neurons in the preoptic area can precisely regulate the signal strength to fine-tune body temperature," said Prof. Nakamura, the lead author of the study. "For example, in a hot environment, signals are augmented to suppress sympathetic outputs, resulting in increased blood flows in the skin to facilitate the radiation of the body's heat to prevent heat stroke. However, in a cold environment, signals are reduced to activate sympathetic outputs, which promote heat production in brown adipose tissue and other organs to prevent hypothermia. Furthermore, at the time of infection, PGE2 acts on EP3 neurons to suppress their activity, resulting in activation of sympathetic outputs to develop fever." This study's findings could pave the way for the development of a technology that artificially adjusts body temperature, which can be applied to a wide range of medical fields. Interestingly, this technology may be helpful in the treatment of obesity, by keeping body temperature slightly higher than normal to promote fat burning. "On top of that, this technology could lead to new strategies for survival of people in hotter global environments, which are becoming a serious worldwide problem," said Prof. Nakamura.

Novaliq GmbH, 3E Bioventures Capital and Beijing Whale Technology Corporation Ltd. today announced the establishment of Dermaliq Therapeutics, Inc (Dermaliq), a newly formed Delaware-based pharmaceutical development company, and the signing of a USD 15 million Series A financing round. 3E Bioventures Capital, a leading international life science investor, led the round and was joined by Beijing Whale Technology Corporation Ltd. Dermaliq's existing shareholder Novaliq has transferred, and licensed Intellectual Property (IP) related to the field of dermatology to Dermaliq. Skin diseases are the fourth leading cause of non-fatal disease burden worldwide, underscoring the role of dermatology in the growing field of global health. Skin conditions have significant impact on patients' well-being, mental health, and social participation. Although topical and local delivery of active ingredients to diseased skin is the preferred treatment route for the majority of patients, current therapies often lack satisfactory skin penetration and patient compliance. Dermaliq is developing the next generation of skin care therapies to enhance targeted penetration into skin tissues and to reduce unwanted side effects for millions of patients. The unique and proprietary technology now owned by Dermaliq, called hyliQ™, is designed to allow cutaneous drug delivery with unmatched bioavailability. The technology enables the development of superior, highly effective liquid drug products with exceptional cosmetic properties. The proceeds will be used to conduct three Phase 1/2a clinical dermatology programs with the goal to demonstrate safety and efficacy and to advance this novel skin care drug category to market to improve the lives of millions of patients: DLQ01 is a liquid drug candidate for the topical treatment of female and male androgenetic alopecia, targeting the prostamide E2 (PGE2) receptor in hair bulbs through specific follicular drug delivery. DLQ02 is a novel and liquid topical calcineurin inhibitor drug therapy for plaque psoriasis, particularly in difficult to treat areas. DLQ03 is a broad-spectrum liquid antibiotic drug candidate that targets topical treatment of bacterial skin and soft tissue infections, including the reduction of antibiotic-resistant strains. The Company has demonstrated proof-of-principle for enhanced topical drug delivery using hyliQ™ in nonclinical models for all three applications. "We are excited that 3E Bioventures Capital and Beijing Whale Technology Corporation have committed to support Dermaliq as new investors in the Series A round," said Dr. Frank Löscher, Chief Executive Officer of Dermaliq. "Our spin-off from Novaliq and successful raising of significant funds provides us with the opportunity to build a leading specialty pharmaceutical company and expand the application of Novaliq's transformative drug delivery technology into dermatology." "3E is committed to investing in global leading life sciences and biomedical companies and help them grow with access to globalized resources and capabilities," said Karen Liu, Managing Director 3E Bioventures Capital. "Dermaliq is using a unique, and scientifically sound technology to achieve high efficiency drug delivery across the skin. The technology is already proven in ophthalmology and holds great promise for dermatology. We will be excited to explore additional drug pipelines in China and synergize with Dermaliq on both pre-clinical and clinical development." "Whale Technology values the solid science foundation of Dermaliq's proprietary hyliQ™ technology platform," said Ming Gao, founder and Chief Executive Officer of Whale Technology Co. Ltd. "Dermaliq's founding team demonstrates a great combination of science, clinical experience and commercialization strength. We see great potential of Dermaliq's pipeline in the field of dermatology after Novaliq's proven clinical and commercial success in ophthalmology." "Dermatology is the logical next step into using Novaliq's proprietary technology platform outside eye care," said Dr. Christian Roesky, Chief Executive Officer Novaliq. "The spin-off into an independent company allows Dermaliq to greatly benefit from our experience in ophthalmology while being fully committed to the multiple product development activities in dermatology, and likely to further broaden its pipeline to other skin conditions." To reflect the new shareholder structure, Karen Liu of 3E Bioventures Capital will join Dermaliq's Board of Directors. Dr. Löscher has also transitioned from his role as Chief Technology Officer at Novaliq to lead Dermaliq as its CEO & President. About Dermaliq: Dermaliq Therapeutics, Inc. is a private company founded in 2021 through a spin off from Novaliq to reimagine topical dermatology. The Company is incorporated in Wilmington (DE), USA under Delaware law. The company has signed a USD 15 million series A round to advance three transformative skin care drug therapies through clinical trials. Key shareholders are Novaliq GmbH, 3E Bioventures Capital and Beijing Whale Technology Corporation Ltd. About 3E Bioventures Capital: 3E Bioventures Capital is a healthcare venture capital firm, dedicated to investing in cutting-edge life sciences and biomedical technologies, with a focus on breakthrough first-in-class therapies and disruptive cross-disciplinary innovations in medical devices and diagnostics. 3E Bioventures takes on a science-driven, entrepreneur-friendly investment philosophy by working closely with companies and research institutions to develop drugs or products that have strong unmet medical needs. With offices in Beijing, Shanghai, and the San Francisco Bay Area, 3E Bioventures leverages its experience, capabilities, and network to help companies tap into markets and resources across the Pacific and advance with greater speed and capital efficiency. The motto of 3E Bioventures Capital is captured in its name 3E: Expertise, Efficiency, Execution. About Beijing Whale Technology Corporation Ltd.: Beijing Whale Technology Corporation Ltd. is a China-based pharmaceutical group committed to the long-term sustainable development in the fields of chemistry, pharmaceuticals and aesthetics. With more than 20 years of history, Whale Tech. has developed two core business units. On one hand, Whale Pharmaceutical Co. Ltd., Whale Chemistry Co. Ltd. and Whale Pharmatech Co. Ltd. are grouped as pharmaceutical and chemistry business unit. On the other hand, Whale Biotech is a research stage biotech company with the focus of developing aesthetics products. About Novaliq: Novaliq is a biopharmaceutical company focusing on the development and commercialization of first- and best-in-class ocular therapeutics based on EyeSol®, the worldwide first water-free eyedrop technology. Novaliq offers an industry-leading portfolio addressing today's unmet medical needs of millions of patients with eye diseases. Novaliq GmbH is headquartered in Heidelberg, Germany and Novaliq Inc. has an office in Cambridge, MA, USA. The long-term shareholder is dievini Hopp BioTech holding GmbH & Co. KG, an active investor in Life and Health Sciences companies.