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Nature Metabolism Oct 2022γ-Aminobutyrate (GAB), the biochemical form of (GABA) γ-aminobutyric acid, participates in shaping physiological processes, including the immune response. How GAB...
γ-Aminobutyrate (GAB), the biochemical form of (GABA) γ-aminobutyric acid, participates in shaping physiological processes, including the immune response. How GAB metabolism is controlled to mediate such functions remains elusive. Here we show that GAB is one of the most abundant metabolites in CD4 T helper 17 (T17) and induced T regulatory (iT) cells. GAB functions as a bioenergetic and signalling gatekeeper by reciprocally controlling pro-inflammatory T17 cell and anti-inflammatory iT cell differentiation through distinct mechanisms. 4-Aminobutyrate aminotransferase (ABAT) funnels GAB into the tricarboxylic acid (TCA) cycle to maximize carbon allocation in promoting T17 cell differentiation. By contrast, the absence of ABAT activity in iT cells enables GAB to be exported to the extracellular environment where it acts as an autocrine signalling metabolite that promotes iT cell differentiation. Accordingly, ablation of ABAT activity in T cells protects against experimental autoimmune encephalomyelitis (EAE) progression. Conversely, ablation of GABA receptor in T cells worsens EAE. Our results suggest that the cell-autonomous control of GAB on CD4 T cells is bimodal and consists of the sequential action of two processes, ABAT-dependent mitochondrial anaplerosis and the receptor-dependent signalling response, both of which are required for T cell-mediated inflammation.
Topics: Animals; Th17 Cells; 4-Aminobutyrate Transaminase; Receptors, GABA-A; Encephalomyelitis, Autoimmune, Experimental; Inflammation; Anti-Inflammatory Agents; Energy Metabolism; Aminobutyrates; Carbon; gamma-Aminobutyric Acid; Tricarboxylic Acids
PubMed: 36192601
DOI: 10.1038/s42255-022-00638-1 -
Nature Communications Oct 2020Oncogenic KRAS mutations are the most frequent mutations in human cancer, but most difficult to target. While sustained proliferation caused by oncogenic KRAS-downstream... (Review)
Review
Oncogenic KRAS mutations are the most frequent mutations in human cancer, but most difficult to target. While sustained proliferation caused by oncogenic KRAS-downstream signalling is a main driver of carcinogenesis, there is increasing evidence that it also mediates autocrine effects and crosstalk with the tumour microenvironment (TME). Here, we discuss recent reports connecting KRAS mutations with tumour-promoting inflammation and immune modulation caused by KRAS that leads to immune escape in the TME. We discuss the preclinical work on KRAS-induced inflammation and immune modulation in the context of currently ongoing clinical trials targeting cancer entities that carry KRAS mutations and strategies to overcome the oncogene-induced effects on the immune system.
Topics: Animals; Carcinogenesis; Humans; Immunomodulation; Inflammation; Mice; Models, Immunological; Proto-Oncogene Proteins p21(ras); Signal Transduction; Translational Research, Biomedical
PubMed: 33116132
DOI: 10.1038/s41467-020-19288-6 -
Molecular Biomedicine Jan 2022The purine molecular structure consists of fused pyrimidine and imidazole rings. Purines are main pieces that conform the structure of nucleic acids which rule the... (Review)
Review
The purine molecular structure consists of fused pyrimidine and imidazole rings. Purines are main pieces that conform the structure of nucleic acids which rule the inheritance processes. Purines also work as metabolic intermediates in different cell functions and as messengers in the signaling pathways throughout cellular communication. Purines, mainly ATP and adenosine (ADO), perform their functional and pharmacological properties because of their structural/chemical characteristics that make them either targets of mutagenesis, mother frameworks for designing molecules with controlled effects (e.g. anti-cancer), or chemical donors (e.g., of methyl groups, which represent a potential chemoprotective action against cancer). Purines functions also come from their effect on specific receptors, channel-linked and G-protein coupled for ATP, and exclusively G-coupled receptors for ADO (also known as ADORAs), which are involved in cell signaling pathways, there, purines work as chemical messengers with autocrine, paracrine, and endocrine actions that regulate cell metabolism and immune response in tumor progression which depends on the receptor types involved in these signals. Purines also have antioxidant and anti-inflammatory properties and participate in the cell energy homeostasis. Therefore, purine physiology is important for a variety of functions relevant to cellular health; thus, when these molecules present a homeostatic imbalance, the stability and survival of the cellular systems become compromised.
PubMed: 35079944
DOI: 10.1186/s43556-022-00068-1 -
Journal of Translational Medicine Feb 2020Parkinson's disease (PD) is a neurodegenerative disorder that results in the death of dopaminergic neurons within the substantia nigra pars compacta and the reduction in... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder that results in the death of dopaminergic neurons within the substantia nigra pars compacta and the reduction in dopaminergic control over striatal output neurons, leading to a movement disorder most commonly characterized by akinesia or bradykinesia, rigidity and tremor. Also, PD is less frequently depicted by sensory symptoms (pain and tingling), hyposmia, sleep alterations, depression and anxiety, and abnormal executive and working memory related functions. On the other hand, insulin-like growth factor 1 (IGF-1) is an endocrine, paracrine and autocrine hormone with several functions including tissue growth and development, insulin-like activity, proliferation, pro-survival, anti-aging, antioxidant and neuroprotection, among others. Herein this review tries to summarize all experimental and clinical data to understand the pathophysiology and development of PD, as well as its clear association with IGF-1, supported by several lines of evidence: (1) IGF-1 decreases with age, while aging is the major risk for PD establishment and development; (2) numerous basic and translational data have appointed direct protective and homeostasis IGF-1 roles in all brain cells; (3) estrogens seem to confer women strong protection to PD via IGF-1; and (4) clinical correlations in PD cohorts have confirmed elevated IGF-1 levels at the onset of the disease, suggesting an ongoing compensatory or "fight-to-injury" mechanism.
Topics: Brain; Dopamine; Female; Humans; Insulin-Like Growth Factor I; Neurons; Parkinson Disease
PubMed: 32046737
DOI: 10.1186/s12967-020-02223-0 -
Frontiers in Endocrinology 2021Brown adipose tissue (BAT), consisted of brown adipocytes and stromal vascular fraction, which includes endothelial cells, lymphocytes, fibroblasts and stem cells, plays... (Review)
Review
Brown adipose tissue (BAT), consisted of brown adipocytes and stromal vascular fraction, which includes endothelial cells, lymphocytes, fibroblasts and stem cells, plays a vital role in regulating cardiovascular health and diseases. As a thermogenic organ, BAT can influence body through strengthening energy expenditure by promoting glucose and lipid metabolism. In addition, BAT is also an endocrine organ which is able to secret adipokines in an autocrine and/or paracrine fashion. BAT plays a protective role in cardiovascular system through attenuating cardiac remodeling and suppressing inflammatory response. In this review, we summarize the advances from the discovery of BAT to the present and provide an overview on the role of BAT dysfunction in cardiovascular diseases.
Topics: Adipocytes; Adipokines; Adipose Tissue, Brown; Animals; Anti-Inflammatory Agents; Aortic Aneurysm; Atherosclerosis; Cardiovascular Diseases; Disease Models, Animal; Disease Progression; Endothelial Cells; Energy Metabolism; Glucose; Heart; Humans; Inflammation; Lipid Metabolism; Myocardium; Obesity; Oxidative Stress; Stromal Vascular Fraction; Thermogenesis
PubMed: 34113316
DOI: 10.3389/fendo.2021.652246 -
Cancer Research Apr 2022Wnt signaling driven by genomic alterations in genes including APC and CTNNB, which encodes β-catenin, have been implicated in prostate cancer development and...
UNLABELLED
Wnt signaling driven by genomic alterations in genes including APC and CTNNB, which encodes β-catenin, have been implicated in prostate cancer development and progression to metastatic castration-resistant prostate cancer (mCRPC). However, nongenomic drivers and downstream effectors of Wnt signaling in prostate cancer and the therapeutic potential of targeting this pathway in prostate cancer have not been fully established. Here we analyzed Wnt/β-catenin signaling in prostate cancer and identified effectors distinct from those found in other tissues, including aryl hydrocarbon receptor and RUNX1, which are linked to stem cell maintenance, and ROR1, a noncanonical Wnt5a coreceptor. Wnt/β-catenin signaling-mediated increases in ROR1 enhanced noncanonical responses to Wnt5a. Regarding upstream drivers, APC genomic loss, but not its epigenetic downregulation commonly observed in prostate cancer, was strongly associated with Wnt/β-catenin pathway activation in clinical samples. Tumor cell upregulation of the Wnt transporter Wntless (WLS) was strongly associated with Wnt/β-catenin pathway activity in primary prostate cancer but also associated with both canonical and noncanonical Wnt signaling in mCRPC. IHC confirmed tumor cell WLS expression in primary prostate cancer and mCRPC, and patient-derived prostate cancer xenografts expressing WLS were responsive to treatment with Wnt synthesis inhibitor ETC-1922159. These findings reveal that Wnt/β-catenin signaling in prostate cancer drives stem cell maintenance and invasion and primes for noncanonical Wnt signaling through ROR1. They further show that autocrine Wnt production is a nongenomic driver of canonical and noncanonical Wnt signaling in prostate cancer, which can be targeted with Wnt synthesis inhibitors to suppress tumor growth.
SIGNIFICANCE
This work provides fundamental insights into Wnt signaling and prostate cancer cell biology and indicates that a subset of prostate cancer driven by autocrine Wnt signaling is sensitive to Wnt synthesis inhibitors.
Topics: Autocrine Communication; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Receptor Tyrosine Kinase-like Orphan Receptors; Wnt Signaling Pathway; beta Catenin
PubMed: 35131873
DOI: 10.1158/0008-5472.CAN-21-1807 -
Physiological Reviews Jan 2020The understanding of the nucleotide/P2 receptor system in the regulation of renal hemodynamics and transport function has grown exponentially over the last 20 yr. This... (Review)
Review
The understanding of the nucleotide/P2 receptor system in the regulation of renal hemodynamics and transport function has grown exponentially over the last 20 yr. This review attempts to integrate the available data while also identifying areas of missing information. First, the determinants of nucleotide concentrations in the interstitial and tubular fluids of the kidney are described, including mechanisms of cellular release of nucleotides and their extracellular breakdown. Then the renal cell membrane expression of P2X and P2Y receptors is discussed in the context of their effects on renal vascular and tubular functions. Attention is paid to effects on the cortical vasculature and intraglomerular structures, autoregulation of renal blood flow, tubuloglomerular feedback, and the control of medullary blood flow. The role of the nucleotide/P2 receptor system in the autocrine/paracrine regulation of sodium and fluid transport in the tubular and collecting duct system is outlined together with its role in integrative sodium and fluid homeostasis and blood pressure control. The final section summarizes the rapidly growing evidence indicating a prominent role of the extracellular nucleotide/P2 receptor system in the pathophysiology of the kidney and aims to identify potential therapeutic opportunities, including hypertension, lithium-induced nephropathy, polycystic kidney disease, and kidney inflammation. We are only beginning to unravel the distinct physiological and pathophysiological influences of the extracellular nucleotide/P2 receptor system and the associated therapeutic perspectives.
Topics: Adenosine Triphosphate; Animals; Humans; Kidney; Nucleotides; Receptors, Purinergic P2; Signal Transduction
PubMed: 31437091
DOI: 10.1152/physrev.00038.2018 -
Pathobiology : Journal of... 2020The tumor microenvironment (TME) plays an essential role in the development and progression of neoplasms. TME consists of the extracellular matrix and numerous... (Review)
Review
The tumor microenvironment (TME) plays an essential role in the development and progression of neoplasms. TME consists of the extracellular matrix and numerous specialized cells interacting with cancer cells by paracrine and autocrine mechanisms. Tumor axonogenesis and neoneurogenesis constitute a developing area of investigation. Prostate cancer (PC) is one of the most common malignancies in men worldwide. During the past years, more and more studies have shown that mechanisms leading to the development of PC are not confined only to the epithelial cancer cell, but also involve the tumor stroma. Different nerve types and neurotransmitters present within the TME are thought to be important factors in PC biology. Moreover, perineural invasion, which is a common way of PC spreading, in parallel creates the neural niche for malignant cells. Cancer neurobiology seems to have become a new discipline to explore the contribution of neoplastic cell interactions with the nervous system and the neural TME component, also to search for potential therapeutic targets in malignant tumors such as PC.
Topics: Animals; Disease Progression; Humans; Male; Mice; Nervous System; Prostatic Neoplasms; Signal Transduction; Tumor Microenvironment
PubMed: 32045912
DOI: 10.1159/000505437 -
International Immunopharmacology Apr 2020The "5 International Symposium on Non-neuronal Acetylcholine: from bench to bedside" was held on September 27-29, 2019 in Hyatt Regency, Long Beach, CA, USA....
The "5 International Symposium on Non-neuronal Acetylcholine: from bench to bedside" was held on September 27-29, 2019 in Hyatt Regency, Long Beach, CA, USA. Approximately 50 scientists from 11 countries over 6 continents participated in this meeting. The major topics included an overall biologic significance of non-neuronal acetylcholine (ACh) and the roles of the non-neuronal cholinergic systems in mucocutaneous, respiratory, digestive, immunologic, endocrine, cardiovascular, musculoskeletal and kidney diseases, and cancer. This meeting facilitated continued work to advance the fundamental science and translational aspects of the interdisciplinary studies on non-neuronal ACh. The progress made has opened a new chapter in the field of cholinergic pharmacology, and advanced our knowledge beyond regulation of individual cell- and tissue-types, defining a new paradigm of selective pharmacological regulation of vital function of practically all types of non-neuronal cells. It is now clear that the autocrine and paracrine control of non-neuronal cells by non-neuronal ACh is implemented through synergistic, additive, and reciprocal effects triggered by two different cholinergic receptor classes. Each biologic effect of ACh is determined by a unique combination of cholinergic receptors subtype expressed at each stage of cell development and differentiation. The plasticity of the non-neuronal cholinergic system helps adjust homeostasis to new environmental conditions.
Topics: Acetylcholine; Animals; Homeostasis; Humans; Immune System Diseases; Interdisciplinary Communication; Neoplasms; Neuronal Plasticity; Neurons; Non-Neuronal Cholinergic System
PubMed: 32113128
DOI: 10.1016/j.intimp.2020.106289 -
Journal For Immunotherapy of Cancer May 2023Type I interferons (IFN-Is), secreted by hematopoietic cells, drive immune surveillance of solid tumors. However, the mechanisms of suppression of IFN-I-driven immune...
BACKGROUND
Type I interferons (IFN-Is), secreted by hematopoietic cells, drive immune surveillance of solid tumors. However, the mechanisms of suppression of IFN-I-driven immune responses in hematopoietic malignancies including B-cell acute lymphoblastic leukemia (B-ALL) are unknown.
METHODS
Using high-dimensional cytometry, we delineate the defects in IFN-I production and IFN-I-driven immune responses in high-grade primary human and mouse B-ALLs. We develop natural killer (NK) cells as therapies to counter the intrinsic suppression of IFN-I production in B-ALL.
RESULTS
We find that high expression of IFN-I signaling genes predicts favorable clinical outcome in patients with B-ALL, underscoring the importance of the IFN-I pathway in this malignancy. We show that human and mouse B-ALL microenvironments harbor an intrinsic defect in paracrine (plasmacytoid dendritic cell) and/or autocrine (B-cell) IFN-I production and IFN-I-driven immune responses. Reduced IFN-I production is sufficient for suppressing the immune system and promoting leukemia development in mice prone to MYC-driven B-ALL. Among anti-leukemia immune subsets, suppression of IFN-I production most markedly lowers the transcription of IL-15 and reduces NK-cell number and effector maturation in B-ALL microenvironments. Adoptive transfer of healthy NK cells significantly prolongs survival of overt ALL-bearing transgenic mice. Administration of IFN-Is to B-ALL-prone mice reduces leukemia progression and increases the frequencies of total NK and NK-cell effectors in circulation. Ex vivo treatment of malignant and non-malignant immune cells in primary mouse B-ALL microenvironments with IFN-Is fully restores proximal IFN-I signaling and partially restores IL-15 production. In B-ALL patients, the suppression of IL-15 is the most severe in difficult-to-treat subtypes with MYC overexpression. MYC overexpression promotes sensitivity of B-ALL to NK cell-mediated killing. To counter the suppressed IFN-I-induced IL-15 production in MYC human B-ALL, we CRISPRa-engineered a novel human NK-cell line that secretes IL-15. CRISPRa IL-15-secreting human NK cells kill high-grade human B-ALL in vitro and block leukemia progression in vivo more effectively than NK cells that do not produce IL-15.
CONCLUSION
We find that restoration of the intrinsically suppressed IFN-I production in B-ALL underlies the therapeutic efficacy of IL-15-producing NK cells and that such NK cells represent an attractive therapeutic solution for the problem of drugging MYC in high-grade B-ALL.
Topics: Humans; Mice; Animals; Interferon-gamma; Interleukin-15; Killer Cells, Natural; Burkitt Lymphoma; Mice, Transgenic; Interferon Type I; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tumor Microenvironment
PubMed: 37217248
DOI: 10.1136/jitc-2022-006649