A diverse proteome is present and enzymatically active in metabolite extracts DOI Creative Commons
Rachel J. House, Molly T. Soper-Hopper, Michael P. Vincent

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 10, 2024

Abstract Metabolite extraction is the critical first-step in metabolomics experiments, where it generally regarded to inactivate and remove proteins. Here, arising from efforts improve conditions for polar metabolomics, we discover a proteomic landscape of over 1000 proteins within metabolite extracts. This ubiquitous feature across several common sample types. By combining post-resuspension stable isotope addition enzyme inhibitors, demonstrate in-extract interconversions due residual transaminase activity. We extend these findings with untargeted observe extensive protein-mediated changes, including formation glutamate dipeptide depletion total glutathione. Finally, present simple workflow that integrates 3 kDa filtration protein removal as superior method metabolomics. In this work, uncover previously unrecognized, source observer effects experiments broad-reaching implications all research fields using molecular metabolism.

Language: Английский

Ketogenic diet alters the epigenetic and immune landscape of prostate cancer to overcome resistance to immune checkpoint blockade therapy DOI Open Access
Sean Murphy, Sharif Rahmy, Dailin Gan

et al.

Cancer Research, Journal Year: 2024, Volume and Issue: 84(10), P. 1597 - 1612

Published: April 8, 2024

Resistance to immune checkpoint blockade (ICB) therapy represents a formidable clinical challenge limiting the efficacy of immunotherapy. In particular, prostate cancer poses for ICB due its immunosuppressive features. A ketogenic diet (KD) has been reported enhance response in some other models. However, adverse effects associated with continuous KD were also observed, demanding better mechanistic understanding and optimized regimens using as an immunotherapy sensitizer. this study, we established series ICB-resistant cell lines developed highly effective strategy combining anti-PD1 anti-CTLA4 antibodies histone deacetylase inhibitor (HDACi) vorinostat, cyclic (CKD), or dietary supplementation ketone body β-hydroxybutyrate (BHB), which is endogenous HDACi. CKD BHB each delayed tumor growth monotherapy, both adaptive immunity required antitumor activity CKD. Single-cell transcriptomic proteomic profiling revealed that HDACi ketogenesis enhanced through cell-intrinsic mechanisms, including upregulation MHC class I molecules, -extrinsic such CD8+ T-cell chemoattraction, M1/M2 macrophage rebalancing, monocyte differentiation toward antigen-presenting cells, diminished neutrophil infiltration. Overall, these findings illuminate potential path cancer.

Language: Английский

Citations

11
The therapeutic potential of ketones in cardiometabolic disease: impact on heart and skeletal muscle DOI
Shubham Soni, Seyed Amirhossein Tabatabaei Dakhili, John R. Ussher

et al.

AJP Cell Physiology, Journal Year: 2024, Volume and Issue: 326(2), P. C551 - C566

Published: Jan. 9, 2024

β-Hydroxybutyrate (βOHB) is the major ketone in body, and it recognized as a metabolic energy source an important signaling molecule. While oxidation essential brain during prolonged fasting/starvation, other organs such skeletal muscle heart also use ketones substrates. Additionally, βOHB-mediated molecular events occur cells, via metabolism and/or signaling, may contribute to optimal health cardiac function. Of importance, when of for ATP production molecules becomes disturbed presence underlying obesity, type 2 diabetes, cardiovascular diseases, these changes cardiometabolic disease. As result disturbances disease, multiple approaches have been used elevate circulating with goal optimizing either or ketone-mediated signaling. These produced significant improvements disease wide range benefits that include improved metabolism, weight loss, better glycemic control, vascular function, well reduced inflammation oxidative stress. Herein, we present evidence indicates therapy could be approach help treat diseases by targeting muscles.

Language: Английский

Citations

9
Macrophages and T cells in metabolic disorder-associated cancers DOI
Daniel Taranto, Daan J. Kloosterman, Leila Akkari

et al.

Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 1, 2024

Language: Английский

Citations

9
Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation DOI Creative Commons
Eric D. Queathem, Zahra Moazzami, David B. Stagg

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(5)

Published: Jan. 29, 2025

Ketogenesis is a dynamic metabolic conduit supporting hepatic fat oxidation particularly when carbohydrates are in short supply. Ketone bodies may be recycled into anabolic substrates, but physiological role for this process has not been identified. Here, we use mass spectrometry–based 13 C-isotope tracing and shotgun lipidomics to establish link between ketogenesis lipid anabolism. Unexpectedly, mouse liver primary hepatocytes consumed ketone support fatty acid biosynthesis via both de novo lipogenesis (DNL) polyunsaturated (PUFA) elongation. While an acetoacetate intermediate was absolutely required source DNL, PUFA elongation activation of by cytosolic acetoacetyl–coenzyme A synthetase (AACS). Moreover, AACS deficiency diminished free esterified PUFAs hepatocytes, while ketogenic insufficiency depleted increased triacylglycerols. These findings suggest that influences metabolism, representing molecular mechanism through which could influence systemic physiology chronic diseases.

Language: Английский

Citations

1
Targeting the Adenosine‐Mediated Metabolic Immune Checkpoint with Engineered Probiotic for Enhanced Chemo‐Immunotherapy DOI Creative Commons
Jinhui Wang, Jing Wang,

Zhijie Yu

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 22, 2025

Abstract Immunotherapy has revolutionized cancer treatment by leveraging the patient's immune system, yet its efficacy is often hampered immunosuppressive tumor microenvironment (TME). Adenosine, a key player in this milieu, suppresses cell activity via cAMP signaling. Here, an innovative strategy to remodel TME using genetically engineered strain of Escherichia coli Nissle 1917 that expresses adenosine deaminase on surface under hypoxic conditions presented. This probiotic targets tumors, converts inosine, and enhances anti‐tumor responses. In vivo, significantly improved infiltration demonstrated synergistic effects with low‐dose doxorubicin both subcutaneous orthotopic mouse colorectal model. Furthermore, modulated TME, promoting shift from M2‐like M1‐like macrophages increasing effector T populations. These findings highlight potential probiotics for metabolic modulation offering novel approach enhancing immunotherapy.

Language: Английский

Citations

1
ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses DOI Creative Commons
Irem Kaymak, McLane J. Watson, Brandon M. Oswald

et al.

The Journal of Experimental Medicine, Journal Year: 2024, Volume and Issue: 221(9)

Published: July 4, 2024

Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an metabolic node CD8 function in vivo. We show that responses to infection depend on derived from citrate via the enzyme ATP lyase (ACLY). However, ablation ACLY triggers alternative, acetate-dependent pathway mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2). Mechanistically, acetate fuels both TCA cycle and production, impacting effector responses, histone acetylation, chromatin accessibility at gene loci. When functional, ACSS2 not required, suggesting obligate substrate function. loss renders cells dependent (via ACSS2) maintain Together, coordinate

Language: Английский

Citations

8
Spatiotemporal metabolomic approaches to the cancer-immunity panorama: a methodological perspective DOI Creative Commons
Yang Xiao, Yongsheng Li,

Huakan Zhao

et al.

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: Sept. 18, 2024

Language: Английский

Citations

7
The uncharted territory of host-pathogen interaction in tuberculosis DOI Creative Commons

Antara Ghoshal,

Akanksha Verma, Ashima Bhaskar

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Jan. 19, 2024

Mycobacterium tuberculosis ( M.tb ) effectively manipulates the host processes to establish deadly respiratory disease, Tuberculosis (TB). has developed key mechanisms disrupt cell health combat immune responses and replicate efficaciously. antigens such as ESAT-6, 19kDa lipoprotein, Hip1, Hsp70 destroy integrity of organelles (Mitochondria, Endoplasmic Reticulum, Nucleus, Phagosomes) or delay innate/adaptive responses. This is followed by induction cellular stress in host. Such cells can either undergo various death apoptosis necrosis, mount effective clear invading pathogen. Further, infection progression, secretes extracellular vesicles exosomes initiate signaling. The contain well cell-derived peptides that act a double-edged sword signaling event. host-symbiont microbiota produces metabolites are beneficial for maintaining healthy tissue microenvironment. In juxtaposition above-mentioned mechanisms, dysregulates gut microbiome support its replication dissemination process. interconnected Immunometabolism, Cellular stress, Host Microbiome, Extracellular less explored realm exploration novel Host-directed therapies TB. Therefore, this review highlights intertwined control survival showcases important factors be targeted designing efficacious therapy.

Language: Английский

Citations

6
β‐Hydroxybutyrate enhances chondrocyte mitophagy and reduces cartilage degeneration in osteoarthritis via the HCAR2/AMPK/PINK1/Parkin pathway DOI Creative Commons
Huangming Zhuang,

Xunshan Ren,

Yuelong Zhang

et al.

Aging Cell, Journal Year: 2024, Volume and Issue: 23(11)

Published: Aug. 9, 2024

Abstract Osteoarthritis (OA) is widely recognized as the prevailing joint disease associated with aging. The ketogenic diet (KD) has been postulated to impede advancement of various inflammatory ailments. β‐Hydroxybutyrate (βOHB), a prominent constituent ketone bodies, recently proposed possess crucial signaling capabilities. In this study, we propose explore role and mechanism βOHB in OA. Tissue staining factor assay were employed evaluate impacts KD on OA rats. oxidative stress conditions chondrocytes induced using tert‐butyl hydroperoxide (TBHP). mechanisms determined siRNA hydroxycarboxylic acid receptor 2 (HCAR2), antagonist adenosine monophosphate‐activated protein kinase (AMPK), inhibitor mitophagy. administration demonstrated reduction pathological damage cartilage, well decrease plasma levels factors. Furthermore, it resulted an increase concentration blood synovial fluid. vitro experiments showed that facilitated mitophagy triphosphate production. Besides, mitigated chondrocyte senescence, factors secretion, extracellular matrix degradation, apoptosis by TBHP. Subsequent investigations indicated protective effects no longer observed following knockdown HCAR2, AMPK, or Moreover, vivo studies suggested played targeting HCAR2‐AMPK‐PINK1 axis. conclusion, enhanced through HCAR2/AMPK/PINK1/Parkin pathway, offering potential therapeutic approach for treatment

Language: Английский

Citations

6
SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8+ T cell activation DOI
Wenhui Liu,

Danming You,

Jiayang Lin

et al.

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(10), P. 2245 - 2261.e6

Published: Sept. 6, 2024

Language: Английский

Citations

6