Title : HDAC6 inhibition and CitH3-mAb: Advancements in sepsis treatment
Abstract:
Sepsis, a severe and often fatal condition, has long evaded effective treatment strategies. For over 16 years, our research has been at the forefront of investigating histone deacetylase (HDAC) inhibitors (HDACIs) as a novel approach in sepsis management. We are excited to share our groundbreaking discoveries, focusing on HDACIs, at the 7th WCID.
Histone lysine-acetylation, a key post-translational modification, is dynamically regulated by histone/lysine acetyltransferase enzymes (HATs) and reversed by histone deacetylases (HDACs). Human HDAC enzymes are classified into four classes: Class-I (Rpd3-like), Class-II (Hda1-like), Class-III (Sir2-like), and Class-IV. Our keynote presentation will showcase the culmination of our extensive research on HDACIs, particularly emphasizing the role of histone deacetylase-6 (HDAC6) inhibitor, and the novel citrullinated histone H3 monoclonal antibody (CitH3-mAb). Through our prolific scientific contributions, including over 23 articles in leading journals such as Science, Shock, Surgery, and Frontiers in Immunology, we have illuminated the path towards significant advancements in the field of sepsis therapy (click for our HDAC-Sepsis related articles).
We have focused on the HDAC6 inhibitor Tubastatin-A (Tub-A) after screening all inhibitors of four classes of HDACs, uncovering a variety of Tub-A's mechanisms, as documented in our studies below:
- Tub-A enhances monocyte count, reduces granulocyte percentage, restores lymphocyte populations, and lowers the granulocyte-to-lymphocyte ratio (Zhao, et al. J Surg Res).
- Tub-A mitigates thymic and bone marrow atrophy, as well as reduces splenic apoptosis (Zhao et al. Surgery).
- Tub-A diminishes the "cytokine storm," alleviates acute liver injury, enhances bacteria clearance and immune cell phagocytosis, and inhibits macrophage apoptosis (Li, et al. J Trauma Acute Care Surg).
- Tub-A reinstates innate immune cell and macrophage populations while increasing neutrophil composition in the bone marrow (Zhao, et al. J Trauma Acute Care Surg).
- Tub-A significantly improves survival, attenuates inflammation, and downregulates TNF-α and IL-6 gene expression in a rodent model of haemorrhagic shock followed by septic shock (Cheng et al. J Surg Res).
- Tub-A restores B lymphocyte percentages, significantly raises innate immune cell and macrophage percentages, decreases bacterial load in the spleen, and enhances macrophage phagocytic ability (Deng, et al. Inflammation).
- Furthermore, Tub-A's inhibition of NLRP3- and pyrin-mediated inflammasome assembly underscores
its crucial role in modulating sepsis-related inflammatory pathways (Magupalli, et al. Science).
Beyond Tub-A, our innovative development of a CitH3-mAb represents a parallel breakthrough. CitH3-mAb targets the N-terminal histone H3, where it influences the balance between lysine-acetylation and arginine-citrullination, thus offering a synergistic effect used in conjunction with HDACIs. This dual approach presents a novel strategy in modulating the complex epigenetic and inflammatory pathways involved in sepsis, paving the way for more effective treatment options.
In conclusion, our research signifies a paradigm shift in sepsis therapeutics. By elucidating the roles of HDACIs and CitH3-mAb, we offer new hope in the battle against sepsis, promising to improve outcomes for countless patients worldwide.
Our HDACIs-Sepsis Publications
Audience Take Away:
- From the presentation on HDAC inhibitors, and CitH3-mAb in sepsis treatment, the audience will gain comprehensive insights applicable in research, education, and policy-making:
- Expanding Research: Our presentation provides a solid foundation for ongoing and future research in molecular biology, pharmacology, and infectious diseases. We'll delve into the mechanisms of HDAC6 inhibitors, highlighting Tubastatin-A.
- Enhancing Teaching and Education: This presentation will be a valuable resource for medical and biological sciences educators. It offers an opportunity to integrate the latest developments in sepsis treatment into academic curricula, including the role of epigenetics, the therapeutic potential of HDAC inhibitors like Tub-A, and the process of drug discovery and development.
- Informing Healthcare Policy and Planning: Healthcare professionals can stay informed about promising developments in sepsis therapy, even if these therapies are not yet clinically available. This knowledge can encourage them to collaborate with researchers, explore potential clinical trials, or keep these therapies in mind for future patient care.
- Opportunities for Medical Device Design in Sepsis Treatment: Designers and engineers attending the presentation can gain inspiration from our research to develop medical devices or technologies related to sepsis treatment. For example, they could explore innovative ways to deliver HDAC inhibitors or Citrullinated Histone H3-targeted therapies in clinical settings, potentially simplifying treatment protocols and making the job of healthcare providers more efficient.
- In summary, the presentation will be instrumental in advancing academic research and education, providing attendees with novel perspectives and up-to-date information on sepsis treatment, particularly highlighting the role of Tub-A as an emerging HDAC6 inhibitor.
