Biology subjects

Acharya, A. P.

Publications and source records attributed to Acharya, A. P..

3 recordsLinked to original sources

bioRxiv2026

Polymer of methyl malonic acid suppress inflammation by downregulating IL-2 through ROS overproduction

Metabolites belonging to the propionate metabolism pathway can regulate immune cell responses in the context of autoimmunity and chronic inflammation. Methyl malonic acid (MMA), a metabolite in this pathway is known to cause dysregulation of T cell oxidative phosphorylation (OXPHOS) and downregulating pro inflammatory T cell effector functions. However, the effects of MMA on T cell signaling and T cell activation is not clearly known. Furthermore, since MMA is a small molecule, using it in the context of therapy remains a problem. It gets metabolized in a short time and millimolar concentrations are required to get effective results. This work describes a novel polymer, 1,6 MMA, synthesized using 1,6 Hexane-diol and MMA, which helps in slow, steady and continuous release of the small molecule. Doses in micromolar ranges generate long lasting and robust immunosuppression of activated T cells via an IL2 dependent mechanism in both human and mice T cells without causing non-specific toxicity. This causes a dysregulated expression of pSTAT5 which eventually enhances BLIMP1 mediated T cell apoptosis. Finally, 1,6 MMA mediated T cell suppression is caused due to increase in mitochondrial ROS production. Extrapolation of our findings in-vivo showed the polymer inhibited autoreactive T cell responses in mice with collagen induced arthritis (CIA). Overall, 1,6 MMA, a novel metabolite polymer, has major therapeutic potential in combating inflammatory disorders.

bioengineering↗

bioRxiv2025

Development of itaconate polymer microparticles for intracellular regulation of pro-inflammatory macrophage activation

Itaconate (IA) is an endogenous metabolite and a potent regulator of the innate immune system. Its use in immunomodulatory therapies has faced limitations due to inherent challenges in achieving controlled delivery and requirements for high extracellular concentrations to achieve internalization of the highly polar small molecule to achieve its intracellular therapeutic activity. Microparticle (MP)-based delivery strategies are a promising approach for intracellular delivery of small molecule metabolites through macrophage phagocytosis and subsequent intracellular polymer degradation-based delivery. Toward the goal of intracellular delivery of IA, degradable polyester polymer-(poly(itaconate-co-dodecanediol)) based IA polymer microparticles (IA-MPs) were generated using an emulsion method, forming micron-scale ([~] 1.5 {micro}m) degradable microspheres. IA-MPs were characterized with respect to their material properties and IA release kinetics to inform particle fabrication. Treatment of murine bone marrow-derived macrophages with an optimized particle concentration of 0.1 mg/million cells enabled phagocytosis-mediated internalization and low levels of cytotoxicity. Flow cytometry demonstrated IA-MP-specific regulation of IA-sensitive inflammatory targets. Metabolic analyses demonstrated that IA-MP internalization inhibited oxidative metabolism and induced glycolytic reliance, consistent with the established mechanism of IA-associated inhibition of succinate dehydrogenase. This development of IA-based polymer microparticles provides a basis for additional innovative metabolite-based microparticle drug delivery systems for the treatment of inflammatory disease.

bioengineering↗

bioRxiv2024

Vaccines for immunological defense against traumatic brain injury

Traumatic brain injury (TBI) and subsequent neurodegeneration is partially driven by chronic inflammation both locally and systemically. Yet, current clinical intervention strategies do not mitigate inflammation sequalae necessitating the development of innovative approaches to reduce inflammation and minimize deleterious effects of TBI. Herein, a subcutaneous formulation based on polymer of alpha-ketoglutarate (paKG) delivering glycolytic inhibitor PFK15 (PFKFB3 inhibitor, a rate limiting step in glycolysis), alpha-ketoglutarate (to fuel Krebs cycle) and peptide antigen from myelin proteolipid protein (PLP139-151) was utilized as the prophylactic immunosuppressive formulation in a mouse model of TBI. In vitro, the paKG(PFK15+PLP) vaccine formulation stimulated proliferation of immunosuppressive regulatory T cells and induced generation of T helper-2 cells. When given subcutaneously in the periphery to two weeks prior to mice sustaining a TBI, the active vaccine formulation increased frequency of immunosuppressive macrophages and dendritic cells in the periphery and the brain at day 7 post- TBI and by 28 days post-TBI enhanced PLP-specific immunosuppressive cells infiltrated the brain. While immunohistology measurements of neuroinflammation were not altered 28 days post-TBI, the vaccine formulation improved motor function and enhanced autophagy mediated genes in a spatial manner in the brain. Overall, these data suggest that the TBI vaccine formulation successfully induced an anti-inflammatory profile and decreased TBI-associated inflammation. TeaserIn this study, a vaccine formulation was generated to develop central nervous specific immunosuppressive responses for TBI.

bioengineering↗