Resolvin D1 Induces mTOR-independent and ATG5-dependent Autophagy in BV-2 Microglial Cells.
作者: Shang-Wen Pan ; Li-Sha Hu ; Han Wang ; Rui-Ting Li ; Ya-Jun He ; You Shang ; Zhong-Liang Dai ; Li-Xin Chen ; Wei Xiong
The activation state of microglia is known to occupy a central position in the pathophysiological process of cerebral inflammation. Autophagy is a catabolic process responsible for maintaining cellular homeostasis. In recent years, autophagy has been demonstrated to play an important role in neuroinflammation. Resolvin D1 (RvD1) is a promising therapeutic mediator that has been shown to exert substantial anti-inflammatory and proresolving activities. However, whether RvD1-mediated resolution of inflammation in microglia is related to autophagy regulation needs further investigation. The present study aimed to explore the effect of RvD1 on microglial autophagy and its corresponding pathways.
Mouse microglial cells (BV-2) were cultured, treated with RvD1, and examined by Western blotting, confocal immunofluorescence microscopy, transmission electron microscopy, and flow cytometry.
RvD1 promoted autophagy in both BV-2 cells and mouse primary microglia by favoring the maturation of autophagosomes and their fusion with lysosomes. Importantly, RvD1 had no significant effect on the activation of mammalian target of rapamycin (mTOR) signaling. Furthermore, RvD1-induced mTOR-independent autophagy was confirmed by observing reduced cytoplasmic calcium levels and suppressed calcium/calmodulin-dependent protein kinase II (CaMK II) activation. Moreover, by downregulating ATG5, the increased phagocytic activity induced by RvD1 was demonstrated to be tightly controlled by ATG5-dependent autophagy.
The present work identified a previously unreported mechanism responsible for the role of RvD1 in microglial autophagy, highlighting its therapeutic potential against neuroinflammation.
2023-11-01·FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Resolvin D1 improves airway inflammation and exercise capacity in cystic fibrosis lung disease.
作者: Giulia Ferri ; Matteo Serano ; Elisa Isopi ; Matteo Mucci ; Domenico Mattoscio ; Romina Pecce ; Feliciano Protasi ; Marcus A Mall ; Mario Romano ; Antonio Recchiuti
Mucus plugging and non-resolving inflammation are inherent features of cystic fibrosis (CF) that may lead to progressive lung disease and exercise intolerance, which are the main causes of morbidity and mortality for people with CF. Therefore, understanding the influence of mucus on basic mechanisms underlying the inflammatory response and identifying strategies to resolve mucus-driven airway inflammation and consequent morbidity in CF are of wide interest. Here, we investigated the effects of the proresolving lipid mediator resolvin (Rv) D1 on mucus-related inflammation as a proof-of-concept to alleviate the burden of lung disease and restore exercise intolerance in CF. We tested the effects of RvD1 on inflammatory responses of human organotypic airways and leukocytes to CF mucus and of humanized mice expressing the epithelial Na + channel (βENaC-Tg) having CF-like mucus obstruction, lung disease, and physical exercise intolerance. RvD1 reduced pathogenic phenotypes of CF-airway supernatant (ASN)-stimulated human neutrophils, including loss of L-selectin shedding and CD16. RNASeq analysis identified select transcripts and pathways regulated by RvD1 in ASN-stimulated CF bronchial epithelial cells that are involved in sugar metabolism, NF-κB activation and inflammation, and response to stress. In in vivo inflammation using βENaC TG mice, RvD1 reduced total leukocytes, PMN, and interstitial Siglec-MΦ when given at 6-8 weeks of age, and in older mice at 10-12 weeks of age, along with the decrease of pro-inflammatory chemokines and increase of anti-inflammatory IL-10. Furthermore, RvD1 treatment promoted the resolution of pulmonary exacerbation caused by Pseudomonas aeruginosa infection and significantly enhanced physical activity and energy expenditure associated with mucus obstruction, which was impaired in βENaC-Tg mice compared with wild-type. These results demonstrate that RvD1 can rectify features of CF and offer proof-of-concept for its therapeutic application in this and other muco-obstructive lung diseases.
2023-11-01·Neural regeneration research
High-intensity swimming alleviates nociception and neuroinflammation in a mouse model of chronic post-ischemia pain by activating the resolvin E1-chemerin receptor 23 axis in the spinal cord.
作者: Xin Jia ; Ziyang Li ; Xiafeng Shen ; Yu Zhang ; Li Zhang ; Ling Zhang
Physical exercise effectively alleviates chronic pain associated with complex regional pain syndrome type-I. However, the mechanism of exercise-induced analgesia has not been clarified. Recent studies have shown that the specialized pro-resolving lipid mediator resolvin E1 promotes relief of pathologic pain by binding to chemerin receptor 23 in the nervous system. However, whether the resolvin E1-chemerin receptor 23 axis is involved in exercise-induced analgesia in complex regional pain syndrome type-I has not been demonstrated. In the present study, a mouse model of chronic post-ischemia pain was established to mimic complex regional pain syndrome type-I and subjected to an intervention involving swimming at different intensities. Chronic pain was reduced only in mice that engaged in high-intensity swimming. The resolvin E1-chemerin receptor 23 axis was clearly downregulated in the spinal cord of mice with chronic pain, while high-intensity swimming restored expression of resolvin E1 and chemerin receptor 23. Finally, shRNA-mediated silencing of chemerin receptor 23 in the spinal cord reversed the analgesic effect of high-intensity swimming exercise on chronic post-ischemic pain and the anti-inflammatory polarization of microglia in the dorsal horn of the spinal cord. These findings suggest that high-intensity swimming can decrease chronic pain via the endogenous resolvin E1-chemerin receptor 23 axis in the spinal cord.
Dr. Sznol to guide clinical investigation of Resolvin-based therapies in metastatic melanoma
ESSEX, CT., November 7, 2023. Thetis Pharmaceuticals LLC (“Thetis”), a biopharmaceutical company developing a first-in-class small molecule ChemR23 agonist to treat cancer and autoimmune diseases small molecule (TP-317) to treat cancer and autoimmune diseases, announced today that Dr. Mario Sznol has joined its Scientific Advisory Board (SAB). Dr. Sznol is Professor of Medicine, Clinical Research Team Leader (Melanoma-Renal Cancer Program), and Co-Leader of Cancer Immunology Program at the Yale Cancer Center.
Gary Mathias, Chief Executive Officer of Thetis, commented, “Dr. Sznol has an international reputation with unique expertise and experience in cancer immunotherapy, drug development for cancer, and treatment of patients with melanoma and renal cell carcinoma, which makes him a perfect choice to help Thetis in the development of TP-317 to treat metastatic melanoma. Dr. Sznol is an expert in clinical application of immune checkpoint inhibitors and brings an important perspective to our clinical strategy for TP-317, which in preclinical studies has shown single agent efficacy comparable to standard-of-care immunotherapy and chemotherapy and enhanced efficacy when combined with these other agents.”
Dr. Sznol noted that “TP-317 offers a highly differentiated strategy to address resistance to immunotherapy in the tumor microenvironment (TME), which is an important target in cancer drug development. I am delighted to join the Thetis SAB to help develop this promising small molecule drug for metastatic melanoma.”
Dr. Sznol joins the Thetis SAB with 35 years of experience in cancer research and development. He graduated from Baylor College of Medicine where he subsequently trained in internal medicine, and then completed a medical oncology fellowship in the Department of Neoplastic Diseases at Mount Sinai Hospital. He spent the next twelve years in the Cancer Therapy Evaluation Program of the National Cancer Institute. From 1999-2004, he served as Vice President of Clinical Development and Executive Officer of Vion Pharmaceuticals in New Haven, Connecticut. In 2004, he joined the medical oncology faculty of the Yale University School of Medicine as co-leader of the Melanoma Program and is currently Professor of Internal Medicine, Leader of the Melanoma-Renal Cancer Clinical Research Team, and Co-Director of Cancer Immunology Program.
About TP-317 and Disease Programs
TP-317 is a patent-protected small molecule drug that delivers Resolvin E1 (RvE1), an endogenous lipid mediator that restores immune homeostasis. Unlike anti-inflammatory drugs and anti-cancer agents that are immuno-suppressive, TP-317 activates innate and adaptive immune pathways to treat disease without compromising host-protective immunity.
Cancer Program: In cancer, TP-317 is being developed as an adjunct to immune checkpoint inhibitors in refractory metastatic melanoma and advanced non-small cell lung cancer (NSCLC), and as adjunct to chemotherapy in pancreatic cancer. TP-317 has demonstrated potent single agent activity in melanoma, lung cancer and pancreatic cancer tumor models, and enhanced efficacy when combined with immune checkpoint inhibitors or chemotherapy in “immune cold” and immune-responsive tumors. In the same studies, TP-317 has been shown to promote myeloid directed antigen presentation and increased IFN-y response in the tumor microenvironment, which may contribute to TP-317’s robust anti-tumoral effects.
IBD Program: In inflammatory bowel disease, TP-317 is being developed as a first-line oral therapy for mild-to-moderate Crohn’s disease and as second-line oral therapy for mild-to-moderate ulcerative colitis patients who are not well controlled on 5-ASA or corticosteroids. In colitis models, oral TP-317 dosed once daily has shown efficacy in DSS, TNBS, TNFΔARE and T-cell transfer colitis models. In DSS-induced colitis, TP-317 has shown comparable efficacy to 5-ASA and the JAK inhibitor filgotinib and enhanced efficacy when combined with 5-ASA. Mechanistically, RvE1 has demonstrated a unique ability to shift the inflamed mucosa towards immune homeostasis and promote intestinal barrier repair, a key driver and measure of efficacy in human IBD.
About Thetis Pharmaceuticals
Thetis is a biopharmaceutical company dedicated to improving the lives of patients suffering from cancer and inflammatory bowel disease. Thetis’ proprietary HEALER™ technology enables the pharmaceutical development of Resolvins, overcoming the stability, manufacturing, and formulation hurdles that have limited their commercial development. Thetis is supported by venture capital investors, NIH, and leading private philanthropies, including the Helmsley Charitable Trust, the Crohn’s & Colitis Foundation, and the Kenneth Rainin Foundation.
TP-317 is an investigational drug product that has not been approved by the U.S. Food and Drug Administration.
For more information, please visit Thetis Pharmaceuticals’ website ( ).
Gary Mathias, CEO
BEDFORD, Mass.--(BUSINESS WIRE)--Resolvyx Pharmaceuticals, Inc., the leading resolvin therapeutics company, today announced that it has raised $25 million in a Series B financing led by funds managed by QVT Financial LP. Proceeds from the financing will be used to accelerate the development of Resolvyx’s preclinical pipeline and to advance multiple resolvin drug candidates into clinical trials in 2008. Resolvins are a recently discovered family of naturally-occurring, small molecule lipid mediators that actively resolve inflammation and can be targeted to treat a wide range of diseases, including asthma, cardiovascular disease and multiple eye diseases.
New investors QVT Financial LP, Radius Ventures, and Biogen Idec New Ventures joined existing venture investors Atlas Venture, CHL Medical Partners, and Flagship Ventures in the round. Resolvyx previously closed a $17 million Series A financing in December of 2005.
“We are excited about the growing recognition of the value of our unique resolvin platform. Attracting investors of this caliber underscores the significant progress we have made toward breakthrough drug products,” said Paul Rubin, M.D., President and Chief Executive Officer of Resolvyx. “This funding allows us to continue to advance our resolvin therapeutic candidates, RvE1 and RX-10045, and to further evaluate additional resolvin and protectin compounds.”
“Resolvins clearly provide a novel approach to creating a new class of therapeutics for a range of important and underserved diseases,” said Keith Manchester, M.D., Portfolio Manager at QVT Financial LP. “We believe that resolvin therapeutics have blockbuster potential to dramatically improve the way diseases are treated and that Resolvyx has a world-class drug discovery and development platform and strong management team in place to rapidly develop a portfolio of next generation therapeutics.”
As part of the closing of this financing transaction, Keith Manchester will join the Resolvyx board of directors.
“Resolvyx combines high quality science with powerful biology to create a unique approach to treating a broad range of diseases,” said David Stoffel, M.D., partner at Radius Ventures and new observer to the Resolvyx board of directors. “We are pleased to partner with such a talented management team and quality investment syndicate to further the exciting potential of the company.”
“We are encouraged by the positive response in the scientific community for resolvin-based therapeutics and their potential to address diseases through a new mechanism,” said Per Gjorstrup, M.D., Ph.D., co-founder and Chief Medical Officer of Resolvyx. “We look forward to validating our exciting results in pre-clinical models of asthma, atherosclerosis, inflammatory bowel disease, dry eye and other diseases as we progress into clinical trials later this year.”
Resolvins are a recently discovered family of naturally-occurring, small molecule lipid mediators that can be targeted to treat a wide range of diseases. In particular, resolvins act to protect healthy tissue during an immuno-inflammatory response to infection, injury or other environmental challenge, and then act to resolve inflammation and promote healing after the environmental insult has passed. Resolvins have shown highly potent efficacy in pre-clinical models of asthma, atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, dry eye and retinal disease, among others.
Resolvins are attractive drug candidates to treat a broad range of acute and chronic diseases caused by a failure to resolve the inflammatory response and restore immune homeostasis. Such diseases include auto-immune diseases (like Crohn’s disease, psoriasis and rheumatoid arthritis), allergic diseases (like asthma) and chronic inflammatory disease (like atherosclerosis, degenerative retinal diseases, chronic dry eye and Alzheimer’s disease). Resolvins offer an entirely novel biological approach to treating significant inflammatory diseases, with a decreased potential for immuno-suppression.
About Resolvyx Pharmaceuticals
Resolvyx Pharmaceuticals is a privately-held biopharmaceutical company dedicated to the discovery, development and commercialization of resolvins, a novel class of therapies to treat inflammatory diseases and their complications. Resolvyx's drug R&D programs are focused on characterizing and developing resolvin-based compounds. With its experienced management team, world-class scientists and leading investors, Resolvyx is well-positioned to capitalize on its extensive portfolio of more than 55 patents and applications. The company's headquarters are in Bedford, Massachusetts.
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Source: Resolvyx Pharmaceuticals