Publications
144 results found
Perryman R, Renziehausen A, Shaye H, et al., 2023, Inhibition of the angiotensin II type 2 receptor AT2R is a novel therapeutic strategy for glioblastoma, Proceedings of the National Academy of Sciences of USA, Vol: 119, ISSN: 0027-8424
Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT2R) is a novel therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT2R. We repurposed EMA401, an AT2R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT2R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT2R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G protein or β-arrestin recruitment. The architecture and interactions of EMA401 in AT2R differ drastically from complexes of AT2R with other relevant compounds. To enhance central nervous system (CNS) penetration of EMA401, we exploited the crystal structure to design an angiopep-2 tethered EMA401 derivative, A3E. A3E exhibited enhanced CNS penetration, leading to reduced tumor volume, inhibition of proliferation and increased levels of apoptosis in an orthotopic xenograft model of GBM.
Vaid AK, Batra S, Gupta S, et al., 2023, Pan-cancer analysis of tumor mutation burden and other key ICI biomarkers in the Indian cohort, Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
Limaye SA, Disel U, Plowman N, et al., 2023, Liquid and tissue profiling of somatic mutational landscape of non-small cell lung cancer from an Indian cohort, Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
Schaf J, Shinhmar S, Zeng Q, et al., 2023, Enhanced Sestrin expression through Tanshinone 2A treatment improves PI3K-dependent inhibition of glioma growth, CELL DEATH DISCOVERY, Vol: 9
Renziehausen A, Tsiailanis AD, Perryman R, et al., 2023, Data from Encapsulation of Temozolomide in a Calixarene Nanocapsule Improves Its Stability and Enhances Its Therapeutic Efficacy against Glioblastoma
<jats:p><div>Abstract<p>The alkylating agent temozolomide (TMZ) is the first-line chemotherapeutic for glioblastoma (GBM), a common and aggressive primary brain tumor in adults. However, its poor stability and unfavorable pharmacokinetic profile limit its clinical efficacy. There is an unmet need to tailor the therapeutic window of TMZ, either through complex derivatization or by utilizing pharmaceutical excipients. To enhance stability and aqueous solubility, we encapsulated TMZ in a p-sulphonatocalix[4]arene (Calix) nanocapsule and used <sup>1</sup>H-NMR, LC-MS, and UV–Vis spectroscopy to chart the stability of this novel TMZ@Calix complex according to FDA and European Medicines Agency guidelines. LC-MS/MS plasma stability assays were conducted in mice to further explore the stability profile of TMZ@Calix <i>in vivo</i>. The therapeutic efficacy of TMZ@Calix was compared with that of unbound TMZ in GBM cell lines and patient-derived primary cells with known O6-methylguanine-DNA methyltransferase (<i>MGMT</i>) expression status and <i>in vivo</i> in an intracranial U87 xenograft mouse model. Encapsulation significantly enhanced the stability of TMZ in all conditions tested. TMZ@Calix was more potent than native TMZ at inhibiting the growth of established GBM cell lines and patient-derived primary lines expressing <i>MGMT</i> and highly resistant to TMZ. <i>In vivo,</i> native TMZ was rapidly degraded in mouse plasma, whereas the stability of TMZ@Calix was enhanced threefold with increased therapeutic efficacy in an orthotopic model. In the absence of new effective therapies, this novel formulation is of clinical importance, serving as an inexpensive and highly efficient treatment that could be made readily available to patients with GBM and warrants further pre
Renziehausen A, Tsiailanis AD, Perryman R, et al., 2023, Data from Encapsulation of Temozolomide in a Calixarene Nanocapsule Improves Its Stability and Enhances Its Therapeutic Efficacy against Glioblastoma
<jats:p><div>Abstract<p>The alkylating agent temozolomide (TMZ) is the first-line chemotherapeutic for glioblastoma (GBM), a common and aggressive primary brain tumor in adults. However, its poor stability and unfavorable pharmacokinetic profile limit its clinical efficacy. There is an unmet need to tailor the therapeutic window of TMZ, either through complex derivatization or by utilizing pharmaceutical excipients. To enhance stability and aqueous solubility, we encapsulated TMZ in a p-sulphonatocalix[4]arene (Calix) nanocapsule and used <sup>1</sup>H-NMR, LC-MS, and UV–Vis spectroscopy to chart the stability of this novel TMZ@Calix complex according to FDA and European Medicines Agency guidelines. LC-MS/MS plasma stability assays were conducted in mice to further explore the stability profile of TMZ@Calix <i>in vivo</i>. The therapeutic efficacy of TMZ@Calix was compared with that of unbound TMZ in GBM cell lines and patient-derived primary cells with known O6-methylguanine-DNA methyltransferase (<i>MGMT</i>) expression status and <i>in vivo</i> in an intracranial U87 xenograft mouse model. Encapsulation significantly enhanced the stability of TMZ in all conditions tested. TMZ@Calix was more potent than native TMZ at inhibiting the growth of established GBM cell lines and patient-derived primary lines expressing <i>MGMT</i> and highly resistant to TMZ. <i>In vivo,</i> native TMZ was rapidly degraded in mouse plasma, whereas the stability of TMZ@Calix was enhanced threefold with increased therapeutic efficacy in an orthotopic model. In the absence of new effective therapies, this novel formulation is of clinical importance, serving as an inexpensive and highly efficient treatment that could be made readily available to patients with GBM and warrants further pre
Renziehausen A, Tsiailanis AD, Perryman R, et al., 2023, Supplementary Figure 1 from Encapsulation of Temozolomide in a Calixarene Nanocapsule Improves Its Stability and Enhances Its Therapeutic Efficacy against Glioblastoma
<jats:p><p>Supplementary Figure 1 showing 1H-NMR spectra of Calix, TMZ and TMZ@Calix complex</p></jats:p>
Renziehausen A, Tsiailanis AD, Perryman R, et al., 2023, Supplementary Figure 1 from Encapsulation of Temozolomide in a Calixarene Nanocapsule Improves Its Stability and Enhances Its Therapeutic Efficacy against Glioblastoma
<jats:p><p>Supplementary Figure 1 showing 1H-NMR spectra of Calix, TMZ and TMZ@Calix complex</p></jats:p>
Limaye S, Chowdhury S, Rohatgi N, et al., 2023, Accurate prostate cancer detection based on enrichment and characterization of prostate cancer specific circulating tumor cells, CANCER MEDICINE, ISSN: 2045-7634
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Williams R, Schaf J, Shinhmar S, et al., 2022, Enhanced Sestrin expression through Tanshinone 2A treatment improves PI3K-dependent inhibition of glioma growth
<jats:title>Abstract</jats:title> <jats:p>Glioblastomas are a highly aggressive cancer type which respond poorly to current pharmaceutical treatments, thus novel therapeutic approaches need to be investigated. One such approach involves the use of the bioactive natural product tanshinone IIA (T2A) derived from the Chinese herb Danshen, where mechanistic insight for this anti-cancer agent is needed to validate its use. Here, we employ a tractable model system, <jats:italic>Dictyostelium discoideum</jats:italic>, to provide this insight. T2A potently inhibits cellular proliferation of <jats:italic>Dictyostelium</jats:italic>, suggesting molecular targets in this model. We show that T2A rapidly reduces phosphoinositide 3 kinase (PI3K) and protein kinase B (PKB) activity, but surprisingly, the downstream complex mechanistic target of rapamycin complex 1 (mTORC1) is only inhibited following chronic treatment. Investigating regulators of mTORC1, including PKB, tuberous sclerosis complex (TSC), and AMP-activated protein kinase (AMPK), suggests these enzymes were not responsible for this effect, implicating an additional molecular mechanism of T2A. We identify this mechanism as the increased expression of <jats:italic>sestrin</jats:italic>, a negative regulator of mTORC1. We further show that combinatory treatment using a PI3K inhibitor and T2A gives rise to a synergistic inhibition of cell proliferation. We then translate our findings to human and mouse-derived glioblastoma cell lines, where both a PI3K inhibitor (Paxalisib) and T2A reduces glioblastoma proliferation in monolayer cultures and in spheroid expansion, with combinatory treatment significantly enhancing this effect. Thus, we propose a new approach for cancer treatment, including glioblastomas, through combinatory treatment with PI3K inhibitors and T2A.</jats:p>
Symington J, Perryman R, Morse S, et al., 2022, ADI-PEG20 RESTORES IMMUNITY IN THE TUMOR MICROENVIRONMENT AND ERADICATES GBM TUMORS IN MICE WHEN COMBINED WITH RADIATION, 27th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO), Publisher: OXFORD UNIV PRESS INC, Pages: 278-278, ISSN: 1522-8517
Anichini G, Zepeng H, Leiloglu M, et al., 2022, MULTISPECTRAL ANALYSIS FOR INTRA-OPERATIVE CHARACTERIZATION OF BRAIN TUMOURS, MARGINS OF RESECTION, AND ELOQUENT AREAS ACTIVATION - PRELIMINARY RESULTS, 27th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO), Publisher: OXFORD UNIV PRESS INC, Pages: 147-148, ISSN: 1522-8517
Almekkawi AK, Sheets R, Werner B, et al., 2022, MITOCHONDRIAL AND GENE EXPRESSION CHANGES IN BRAIN TUMOR CELLS GROWN IN.-HYDROXYBUTYRATE, 27th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO), Publisher: OXFORD UNIV PRESS INC, Pages: 266-267, ISSN: 1522-8517
Ghosh A, Perryman R, O'Neill K, et al., 2022, ARGININE DEPRIVATION ALTERS DNA DAMAGE RESPONSE IN ARGINOSUCCINATE SYNTHETASE NEGATIVE GLIOBLASTOMA AND POTENTIATES STANDARD OF CARE, 27th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO), Publisher: OXFORD UNIV PRESS INC, Pages: 280-280, ISSN: 1522-8517
Anichini G, Fulmali P, O'Neill K, et al., 2022, ACCURATE IDENTIFICATION OF GLIAL MALIGNANCIES FROM PERIPHERAL BLOOD, 27th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO), Publisher: OXFORD UNIV PRESS INC, Pages: 155-155, ISSN: 1522-8517
Naseer S, Abelleira Hervas L, Savani D, et al., 2022, Traumatic brain injury leads to alterations in contusional cortical miRNAs involved in dementia, Biomolecules, Vol: 12, ISSN: 2218-273X
There is compelling evidence that head injury is a significant environmental risk factor for Alzheimer's disease (AD) and that a history of traumatic brain injury (TBI) accelerates the onset of AD. Amyloid-β plaques and tau aggregates have been observed in the post-mortem brains of TBI patients; however, the mechanisms leading to AD neuropathology in TBI are still unknown. In this study, we hypothesized that focal TBI induces changes in miRNA expression in and around affected areas, resulting in the altered expression of genes involved in neurodegeneration and AD pathology. For this purpose, we performed a miRNA array in extracts from rats subjected to experimental TBI, using the controlled cortical impact (CCI) model. In and around the contusion, we observed alterations of miRNAs associated with dementia/AD, compared to the contralateral side. Specifically, the expression of miR-9 was significantly upregulated, while miR-29b, miR-34a, miR-106b, miR-181a and miR-107 were downregulated. Via qPCR, we confirmed these results in an additional group of injured rats when compared to naïve animals. Interestingly, the changes in those miRNAs were concomitant with alterations in the gene expression of mRNAs involved in amyloid generation and tau pathology, such as β-APP cleaving enzyme (BACE1) and Glycogen synthase-3-β (GSK3β). In addition increased levels of neuroinflammatory markers (TNF-α), glial activation, neuronal loss, and tau phosphorylation were observed in pericontusional areas. Therefore, our results suggest that the secondary injury cascade in TBI affects miRNAs regulating the expression of genes involved in AD dementia.
kyrkou S, Vrettos E, Gorpas D, et al., 2022, Design principles governing the development of theranostic anticancer agents and their nanoformulations with photoacoustic properties, Pharmaceutics, Vol: 14, ISSN: 1999-4923
The unmet need to develop novel approaches for cancer diagnosis and treatment has led to the evolution of theranostic agents, which usually include, in addition to the anticancer drug, an imaging agent based mostly on fluorescent agents. Over the past few years, a non-invasive photoacoustic imaging modality has been effectively integrated into theranostic agents. Herein, we shed light on the design principles governing the development of theranostic agents with photoacoustic properties, which can be formulated into nanocarriers to enhance their potency. Specifically, we provide an extensive analysis of their individual constituents including the imaging dyes, drugs, linkers, targeting moieties, and their formulation into nanocarriers. Along these lines, we present numerous relevant paradigms. Finally, we discuss the clinical relevance of the specific strategy, as also the limitations and future perspectives, and through this review, we envisage paving the way for the development of theranostic agents endowed with photoacoustic properties as effective anticancer medicines.
Hajji N, Garcia-Revilla J, Sarmiento Soto M, et al., 2022, Arginine deprivation alters microglia polarity and synergises with radiation to eradicate non arginine auxotrophic glioblastoma tumors, Journal of Clinical Investigation, Vol: 132, Pages: 1-19, ISSN: 0021-9738
New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine depleting agent ADI-PEG20 in a non-arginine auxotrophic cellular background (Arginine Succinate Synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response with extended disease-free survival in an orthotopic immune competent model of GBM with no significant toxicity. ADI-PEG20 not only enhances the cellular sensitivity of Arginine succinate synthetase 1 positive GBM to ionising radiation by elevated production of nitric oxide (NO) and hence generation of cytotoxic peroxynitrites, but also promotes glioma-associated macrophages/microglia infiltration into tumors and turns their classical anti-inflammatory (pro-tumor) phenotype into a pro-inflammatory (anti-tumor) phenotype. Our results provide an effective, well-tolerated and simple strategy to improve GBM treatment which merits consideration for early evaluation in clinical trials.
Atkinson A, Syed N, 2021, ARGININE DEPRIVATION THERAPY INDUCES APOPTOTIC CELL DEATH IN MELANOMA BRAIN METASTASIS, Annual Meeting of the British-Neuro-Oncology-Society (BNOS), Publisher: OXFORD UNIV PRESS INC, Pages: 24-24, ISSN: 1522-8517
Zeng Q, Stylianou T, Preston J, et al., 2021, THE KETOGENIC DIET ALTERS THE EXPRESSION OF CHROMATIN MODIFYING ENZYMES IN GBM TO POTENTIATE THE EFFECTS OF CHEMOTHERAPY AND RADIOTHERAPY, Annual Meeting of the British-Neuro-Oncology-Society (BNOS), Publisher: OXFORD UNIV PRESS INC, Pages: 15-16, ISSN: 1522-8517
Diamantis DA, Agalou A, Chatziathanasiadou M, et al., 2021, Biotin-Yellow a biotin guided NIR turn-on fluorescent probe for cancer targeted diagnosis, SENSORS AND ACTUATORS B-CHEMICAL, Vol: 337
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- Citations: 4
Khan S, Anichini G, Mian A, et al., 2021, Tonsillar carcinoma spreading metastases to central nervous system –Case report and literature review, Journal of Neurological Surgery Reports, Vol: 82, Pages: e11-e16, ISSN: 2193-6358
We present a case report of a 51-year-old left-handed gentleman with a background of HPV 16-positive tonsil squamous cell carcinoma presenting with tonic-clonic seizure and a radiological diagnosis of secondary metastatic deposits. These were initially treated with Stereotactic RadioSurgery (SRS), and subsequently with surgery. Surgical resection was performed under general anaesthesia with right-sided temporal and parietal approaches. Both the parietal and temporal deposits were removed, while the intraventricular mass wasintentionally left to avoid post-op deficits. Adjuvant radiotherapy and chemotherapy were administered post-op. The patient experienced a satisfactory recovery post-op and was re-operated for recurrence 4 months later. He maintained a good quality of life and an excellent performance status throughout, but unfortunately passed away in November 2018 due to septic complications. This case history stresses the difficulty in managing SCC with brain metastatic deposits. There are no current guidelines about the management of patients presenting with such a rare condition. More data is thus desirable in order to better definetreatment guidelines and protocols when SCC brain metastases are present.
Hajji N, García-Domínguez DJ, Hontecillas-Prieto L, et al., 2021, The bitter side of epigenetics: variability and resistance to chemotherapy, Epigenomics, Vol: 13, Pages: 397-403, ISSN: 1750-1911
One of the major obstacles to the development of effective new cancer treatments and the main factor for the increasing number of clinical trial failures appears to be the paucity of accurate, reproducible and robust drug resistance testing methods. Most research assessing the resistance of cancers to chemotherapy has concentrated on genetic-based molecular mechanisms, while the role of epigenetics in drug resistance has been generally overlooked. This is rather surprising given that an increasing body of evidence pointing to the fact that epigenetic mechanism alterations appear to play a pivotal role in cancer initiation, progression and development of chemoresistance. This resulted in a series of clinical trials involving epi-drug as single treatment or combined with cancer conventional drugs. In this review, we provided the main mechanisms by which the epigenetic regulators control the resistance to cancer drugs.
Vrettos E, Karampelas T, Sayyad N, et al., 2021, Development of programmable gemcitabine-GnRH pro-drugs bearing linker controllable "click" oxime bond tethers and preclinical evaluation against prostate cancer, EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, Vol: 211, ISSN: 0223-5234
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- Citations: 11
Tsiailanis AD, Renziehausen A, Karakurt S, et al., 2021, Encapsulation of Small Drugs in a Supramolecule Enhances Solubility, Stability, and Therapeutic Efficacy Against Glioblastoma Multiforme, SUPRAMOLECULES IN DRUG DISCOVERY AND DRUG DELIVERY, Vol: 2207, Pages: 175-186, ISSN: 1064-3745
Diamantis DA, Oblukova M, Chatziathanasiadou M, et al., 2020, Bioinspired tailoring of fluorogenic thiol responsive antioxidant precursors to protect cells against H<sub>2</sub>O<sub>2</sub>-induced DNA damage, FREE RADICAL BIOLOGY AND MEDICINE, Vol: 160, Pages: 540-551, ISSN: 0891-5849
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- Citations: 9
Tsiailanis AD, Renziehausen A, Kiriakidi S, et al., 2020, Enhancement of glioblastoma multiforme therapy through a novel Quercetin-Losartan hybrid., Free Radical Biology and Medicine, Vol: 160, Pages: 391-402, ISSN: 0891-5849
Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor. Maximal surgical resection followed by radiotherapy and concomitant chemotherapy with temozolomide remains the first-line therapy, prolonging the survival of patients by an average of only 2.5 months. There is therefore an urgent need for novel therapeutic strategies to improve clinical outcomes. Reactive oxygen species (ROS) are an important contributor to GBM development. Here, we describe the rational design and synthesis of a stable hybrid molecule tethering two ROS regulating moieties, with the aim of constructing a chemopreventive and anticancer chemical entity that retains the properties of the parent compounds. We utilized the selective AT1R antagonist losartan, leading to the inhibition of ROS levels, and the antioxidant flavonoid quercetin. In GBM cells, we show that this hybrid retains the binding potential of losartan to the AT1R through competition-binding experiments and simultaneously exhibits ROS inhibition and antioxidant capacity similar to native quercetin. In addition, we demonstrate that the hybrid is able to alter the cell cycle distribution of GBM cells, leading to cell cycle arrest and to the induction of cytotoxic effects. Last, the hybrid significantly and selectively reduces cancer cell proliferation and angiogenesis in primary GBM cultures with respect to the isolated parent components or their simple combination, further emphasizing the potential utility of the current hybridization approach in GBM.
Perryman R, Zeng Q, Raha O, et al., 2020, THE MICRORNA MIR-138 MAY BE RESPONSIBLE FOR SOME OF THE EFFECTS OF METABOLIC KETOSIS ON MALIGNANT GLIOMA, 25th Virtual Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO), Publisher: OXFORD UNIV PRESS INC, Pages: 96-96, ISSN: 1522-8517
Syed N, Srivastava S, Mukherjee S, et al., 2020, Comprehending meningioma signaling cascades using multipronged proteomics approaches & targeted validation of potential markers, Frontiers in Oncology, Vol: 10, ISSN: 2234-943X
Meningiomas are one of the most prevalent primary brain tumors. Our study aims to obtain mechanistic insights of meningioma pathobiology using mass spectrometry-based label-free quantitative proteome analysis to identifying druggable targets and perturbed pathways for therapeutic intervention. Label-free based proteomics study was done from peptide samples of 21 patients and 8 non-tumor controls which were followed up with Phosphoproteomics to identify the kinases and phosphorylated components of the perturbed pathways. In silico approaches revealed perturbations in extracellular matrix remodeling and associated cascades. To assess the extent of influence of Integrin and PI3K-Akt pathways, we used an Integrin Linked Kinase inhibitor on patient-derived meningioma cell line and performed a transcriptomic analysis of the components. Furthermore, we designed a Targeted proteomics assay which to the best of our knowledge for very first-time enables identification of peptides from 54 meningioma patients via SRM assay to validate the key proteins emerging from our study. This resulted in the identification of peptides from CLIC1, ES8L2, and AHNK many of which are receptors and kinases and are difficult to be characterized using conventional approaches. Furthermore, we were also able to monitor transitions for proteins like NEK9 and CKAP4 which have been reported to be associated with meningioma pathobiology. We believe, this study can aid in designing peptide-based validation assays for meningioma patients as well as IHC studies for clinical applications.
Benito A, Hajji N, O'Neill K, et al., 2020, β-Hydroxybutyrate oxidation promotes the accumulation of immunometabolites in activated microglia cells, Metabolites, Vol: 10, ISSN: 2218-1989
Metabolic regulation of immune cells has arisen as a critical set of processes required for appropriate response to immunological signals. While our knowledge in this area has rapidly expanded in leukocytes, much less is known about the metabolic regulation of brain-resident microglia. In particular, the role of alternative nutrients to glucose remains poorly understood. Here, we use stable-isotope (13C) tracing strategies and metabolomics to characterize the oxidative metabolism of β-hydroxybutyrate (BHB) in human (HMC3) and murine (BV2) microglia cells and the interplay with glucose in resting and LPS-activated BV2 cells. We found that BHB is imported and oxidised in the TCA cycle in both cell lines with a subsequent increase in the cytosolic NADH:NAD+ ratio. In BV2 cells, stimulation with LPS upregulated the glycolytic flux, increased the cytosolic NADH:NAD+ ratio and promoted the accumulation of the glycolytic intermediate dihydroxyacetone phosphate (DHAP). The addition of BHB enhanced LPS-induced accumulation of DHAP and promoted glucose-derived lactate export. BHB also synergistically increased LPS-induced accumulation of succinate and other key immunometabolites, such as α-ketoglutarate and fumarate generated by the TCA cycle. Finally, BHB upregulated the expression of a key pro-inflammatory (M1 polarisation) marker gene, NOS2, in BV2 cells activated with LPS. In conclusion, we identify BHB as a potentially immunomodulatory metabolic substrate for microglia that promotes metabolic reprogramming during pro-inflammatory response.
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