Biomaterial mediated simultaneous delivery of spermine and alpha ketoglutarate modulate metabolism and innate immune cell phenotype in sepsis mouse models

Inamdar, Sahil; Tylek, Tina; Thumsi, Abhirami; Suresh, Abhirami P.; Jaggarapu, Madhan Mohan Chandra Sekhar; Halim, Michelle; Mantri, Shivani; Esrafili, Arezoo; Ng, Nathan D.; Schmitzer, Elizabeth; Lintecum, Kelly; Ávila, Camila de; Fryer, John Denis; Xu, Ying; Spiller, Kara L.; Acharya, Abhinav P.

doi:10.1016/j.biomaterials.2022.121973

Cited by 15 publications

(4 citation statements)

References 78 publications

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“…Volcano plots were used to identify differentially expressed genes (DEG) between various treatment groups comparing the log2 fold differences. DEGs were identified as genes with at least 0.5/−0.5 log2 fold differences and an unadjusted p ‐value <0.05 41,42 . p values for NanoString data were obtained from nSolver software using a minimum count of 50 as a cutoff 40 .…”

Section: Resultsmentioning

confidence: 99%

“…DEGs were identified as genes with at least 0.5/−0.5 log2 fold differences and an unadjusted p ‐value <0.05. 41 , 42 p values for NanoString data were obtained from nSolver software using a minimum count of 50 as a cutoff. 40 A total of 134 genes met the inclusion criteria and we identified 92 DEGs for LPS versus no LPS treatment (NT), 7 DEGs for iNP (+LPS) versus LPS, 9 DEGs for iNP‐SAHA (+LPS) versus LPS, and 4 DEG for iNP‐SAHA (+LPS) versus iNP (+LPS).…”

Section: Resultsmentioning

confidence: 99%

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Multimodal nanoparticle‐containing modified suberoylanilide hydroxamic acid polymer conjugates to mitigate immune dysfunction in severe inflammation

Truong,

Cottingham,

Dharmaraj

et al. 2023

Bioengineering & Transla Med

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Excessive immune activation and immunosuppression are opposing factors that contribute to the dysregulated innate and adaptive immune responses seen in severe inflammation and sepsis. Here, a novel analog of the histone deacetylase inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA‐OH), was incorporated into immunomodulatory poly(lactic acid)‐based nanoparticles (iNP‐SAHA) by employing a prodrug approach through the covalent modification of poly(lactic‐co‐glycolic acid) (PLGA) with SAHA‐OH. iNP‐SAHA formulation allowed for controlled incorporation and delivery of SAHA‐OH from iNP‐SAHA and treatment led to multimodal biological responses including significant reductions in proinflammatory cytokine secretions and gene expression, while increasing the survival of primary macrophages under lipopolysaccharide (LPS) challenge. Using a lethal LPS‐induced endotoxemia mouse model of sepsis, iNP‐SAHA administration improved the survival of mice in a dose‐dependent manner and tended to improve survival at the lowest doses compared to iNP control. Further, iNP‐SAHA reduced the levels of plasma proinflammatory cytokines and chemokines associated with sepsis more significantly than iNP and similarly improved inflammation‐induced spleen and liver toxicity as iNP, supporting its potential polypharmacological activity. Collectively, iNP‐SAHA offers a potential drug delivery approach to modulate the multifaceted inflammatory responses observed in diseases such as sepsis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Multimodal nanoparticle‐containing modified suberoylanilide hydroxamic acid polymer conjugates to mitigate immune dysfunction in severe inflammation

Truong,

Cottingham,

Dharmaraj

et al. 2023

Bioengineering & Transla Med

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show abstract

“…As shown in Figure 1 , in the LPS-induced acute inflammation model (see reference [7] for the concentration of LPS), the spleen of the model group was significantly congested with a dark color and blunted rim compared, indicating hyperfunction after LPS treatment. In contrast, the Tube group had less congestion and a relatively lighter color than the model group; however, the overall appearance was similar to that of the control group.…”

Section: Effect Of Tube On the Gross Morphology And Histology In Mous...mentioning

confidence: 99%

Tubeimoside III inhibits lipopolysaccharide-induced inflammatory responses by reprogramming glycolytic metabolism

Li,

Lin,

Yue

et al. 2024

Preprint

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OBJECTIVE To investigate how tubeimoside III inhibits lipopolysaccharide(LPS)-induced inflammatory responses by reprogramming glucose metabolism. METHOD A mouse model of LPS-induced acute inflammation was constructed, and the protective effect of tubeimoside III against LPS-induced injury was investigated using histochemistry and real-time quantitative PCR. Western blotting, Seahorse extracellular flux analyser assays, and pyruvate content assays were used in LPS-induced RAW264.7 cells to explore how tubeimoside III exerts its anti-inflammatory effects. The potential mechanism was also validated using inhibitors. RESULTS Tubeimoside III significantly attenuated the expression of inflammatory cytokines IL-6, IL-1β, and iNOS in lung and liver tissue homogenates and RAW264.7 cells. This agent inhibited inflammatory cell infiltration in alveoli and prevented necrosis in liver lesions in LPS-treated mice. Extracellular flux analyser assays revealed that tubeimoside III regulated glucose metabolism in RAW264.7 cells. Real-time quantitative PCR and western blot revealed that tubeimoside III had similar effects on the downstream effector molecule of itaconic acid. An inhibitor weakened the inhibitory effect of tubeimoside III on the expression of inflammatory factors. CONCLUSIONS Tubeimoside III protects against LPS-induced lung and liver injury by attenuating inflammatory factor secretion and inflammatory cell infiltration, and its mechanism of action involves reprogramming macrophage glucose metabolism and increasing itaconic acid levels.

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“…Trafficking of monocytes from the bloodstream into tissues is mediated by CCR2 signaling 5 , and is crucial to the foreign body response because extravasated monocytes develop into macrophages and dendritic cells, mediating the inflammatory response around implanted biomaterials. Recent advances in understanding metabolic adaptation in the biomaterial microenvironment reveal that changes in immune cell metabolism orchestrate immunological events in complex ways that could be leveraged to enhance regenerative medicine [6][7][8][9][10][11][12][13] . However, how local immunometabolic cues in the biomaterial microenvironment regulate the trafficking of immune cells and organize the relative composition of proinflammatory, transitory and anti-inflammatory or pro-regenerative phenotypes has not been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Immunometabolic cues recompose and reprogram the microenvironment around biomaterials

Maduka,

Schmitter-Sánchez,

Makela

et al. 2023

Preprint

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Circulating monocytes infiltrate and coordinate immune responses in various inflamed tissues, such as those surrounding implanted biomaterials, affecting therapeutic, diagnostic, tissue engineering and regenerative applications. Here, we show that immunometabolic cues in the biomaterial microenvironment govern CCR2- and CX3CR1-dependent trafficking of immune cells, including neutrophils and monocytes; ultimately, this affects the composition and activation states of macrophage and dendritic cell populations. Furthermore, immunometabolic cues around implants orchestrate the relative composition of proinflammatory, transitory and anti-inflammatory CCR2+, CX3CR1+ and CCR2+CX3CR1+ immune cell populations. Consequently, modifying immunometabolism by glycolytic inhibition drives a pro-regenerative microenvironment in part by myeloid cells around amorphous polylactide implants. In addition to, Arginase 1-expressing myeloid cells, T helper 2 cells and γδ+ T-cells producing IL-4 significantly contribute to shaping the metabolically reprogramed, pro-regenerative microenvironment around crystalline polylactide biomaterials. Taken together, we find that local metabolic states regulate inflammatory processes in the biomaterial microenvironment, with implications for translational medicine.

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Biomaterial mediated simultaneous delivery of spermine and alpha ketoglutarate modulate metabolism and innate immune cell phenotype in sepsis mouse models

Cited by 15 publications

References 78 publications

Multimodal nanoparticle‐containing modified suberoylanilide hydroxamic acid polymer conjugates to mitigate immune dysfunction in severe inflammation

Multimodal nanoparticle‐containing modified suberoylanilide hydroxamic acid polymer conjugates to mitigate immune dysfunction in severe inflammation

Tubeimoside III inhibits lipopolysaccharide-induced inflammatory responses by reprogramming glycolytic metabolism

Immunometabolic cues recompose and reprogram the microenvironment around biomaterials

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