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Nature Nov 2023Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapies. Inflammatory and immunomodulatory signals co-exist in the pancreatic...
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapies. Inflammatory and immunomodulatory signals co-exist in the pancreatic tumour microenvironment, leading to dysregulated repair and cytotoxic responses. Tumour-associated macrophages (TAMs) have key roles in PDAC, but their diversity has prevented therapeutic exploitation. Here we combined single-cell and spatial genomics with functional experiments to unravel macrophage functions in pancreatic cancer. We uncovered an inflammatory loop between tumour cells and interleukin-1β (IL-1β)-expressing TAMs, a subset of macrophages elicited by a local synergy between prostaglandin E (PGE) and tumour necrosis factor (TNF). Physical proximity with IL-1β TAMs was associated with inflammatory reprogramming and acquisition of pathogenic properties by a subset of PDAC cells. This occurrence was an early event in pancreatic tumorigenesis and led to persistent transcriptional changes associated with disease progression and poor outcomes for patients. Blocking PGE or IL-1β activity elicited TAM reprogramming and antagonized tumour cell-intrinsic and -extrinsic inflammation, leading to PDAC control in vivo. Targeting the PGE-IL-1β axis may enable preventive or therapeutic strategies for reprogramming of immune dynamics in pancreatic cancer.
Topics: Humans; Carcinogenesis; Carcinoma, Pancreatic Ductal; Dinoprostone; Disease Progression; Gene Expression Regulation, Neoplastic; Inflammation; Interleukin-1beta; Pancreatic Neoplasms; Tumor Microenvironment; Tumor Necrosis Factors; Tumor-Associated Macrophages
PubMed: 37914939
DOI: 10.1038/s41586-023-06685-2 -
Redox Biology Sep 2023Chemotherapeutic agents, such as doxorubicin (DOX), may cause cardiomyopathy, even life-threatening arrhythmias in cancer patients. Ferroptosis-an iron-dependent...
Chemotherapeutic agents, such as doxorubicin (DOX), may cause cardiomyopathy, even life-threatening arrhythmias in cancer patients. Ferroptosis-an iron-dependent oxidative form of programmed necrosis, plays a pivotal role in DOX-induced cardiomyopathy (DIC). Prostaglandins (PGs) are bioactive signaling molecules that profoundly modulate cardiac performance in both physiologic and pathologic conditions. Here, we found that PGE production and its E-prostanoid 1 receptor (EP1) expression were upregulated in erastin (a ferroptosis inducer) or DOX-treated cardiomyocytes. EP1 inhibition markedly aggravated erastin or DOX-induced cardiomyocyte ferroptosis, whereas EP1 activation exerted opposite effect. Genetic depletion of EP1 in cardiomyocytes worsens DOX-induced cardiac injury in mice, which was efficiently rescued by the ferroptosis inhibitor Ferrostatin-1 (Fer-1). Mechanistically, EP1 activation protected cardiomyocytes from DOX-induced ferroptosis by promoting nuclear factor erythroid 2-related factor 2 (Nrf2)-driven anti-oxidative gene expression, such as glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). EP1 was coupled with G to elicit intracellular Ca flux and activate the PKC/Nrf2 cascade in ferroptotic cardiomyocytes. EP1 activation also prevents DOX-induced ferroptosis in human cardiomyocytes. Thus, PGE/EP1 axis protects cardiomyocytes from DOX-induced ferroptosis by activating PKC/Nrf2 signaling and activation of EP1 may represent an attractive strategy for DIC prevention and treatment.
Topics: Animals; Humans; Mice; Apoptosis; Dinoprostone; Doxorubicin; Ferroptosis; Myocytes, Cardiac; NF-E2-Related Factor 2
PubMed: 37531930
DOI: 10.1016/j.redox.2023.102825 -
Immunity Jun 2023Type 1 conventional dendritic cells (cDC1s) are critical for anti-cancer immunity. Protective anti-cancer immunity is thought to require cDC1s to sustain T cell...
Type 1 conventional dendritic cells (cDC1s) are critical for anti-cancer immunity. Protective anti-cancer immunity is thought to require cDC1s to sustain T cell responses within tumors, but it is poorly understood how this function is regulated and whether its subversion contributes to immune evasion. Here, we show that tumor-derived prostaglandin E2 (PGE) programmed a dysfunctional state in intratumoral cDC1s, disabling their ability to locally orchestrate anti-cancer CD8 T cell responses. Mechanistically, cAMP signaling downstream of the PGE-receptors EP2 and EP4 was responsible for the programming of cDC1 dysfunction, which depended on the loss of the transcription factor IRF8. Blockade of the PGE-EP2/EP4-cDC1 axis prevented cDC1 dysfunction in tumors, locally reinvigorated anti-cancer CD8 T cell responses, and achieved cancer immune control. In human cDC1s, PGE-induced dysfunction is conserved and associated with poor cancer patient prognosis. Our findings reveal a cDC1-dependent intratumoral checkpoint for anti-cancer immunity that is targeted by PGE for immune evasion.
Topics: Humans; Dinoprostone; Neoplasms; Antibodies; CD8-Positive T-Lymphocytes; Dendritic Cells; Receptors, Prostaglandin E
PubMed: 37315536
DOI: 10.1016/j.immuni.2023.05.011 -
International Journal of Molecular... Jun 2023Vitiligo is an acquired chronic depigmenting disorder of skin. It is mostly asymptomatic and characterized by amelanotic macules and patches that affects 0.5% to 2% of... (Review)
Review
Vitiligo is an acquired chronic depigmenting disorder of skin. It is mostly asymptomatic and characterized by amelanotic macules and patches that affects 0.5% to 2% of the world's population. The etiology of vitiligo has not been clearly elucidated and multiple theories have been proposed regarding the causes of the disorder. Among the most prevalent theories, the genetic predisposition, oxidative stress theory, promotion of cellular stress and pathologic influence of lymphocytes T have been highlighted. As a result of increases in in-depth knowledge concerning the pathogenetic processes in vitiligo, we review the most recent information concerning its etiopathogenesis and treatment methods including topical and oral Janus kinase inhibitors, prostaglandins and their analogues, namely afamelanotide, Wnt/β-catenin-signaling agonists and cell-based therapies. Topical ruxolitinib has been registered for vitiligo treatment, whereas other agents as oral ritlecitinib, afamelanotide and latanoprost have been studied in ongoing clinical trials. New highly effective therapeutic strategies may be developed thanks to molecular and genetic studies.
Topics: Humans; Vitiligo; Janus Kinase Inhibitors; Protein Kinase Inhibitors; Skin; Prostaglandins
PubMed: 37298700
DOI: 10.3390/ijms24119749 -
The Journal of Clinical Investigation Sep 2023Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with poor survival. The incidence and mortality of IPF are rising, but treatment... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with poor survival. The incidence and mortality of IPF are rising, but treatment remains limited. Currently, two drugs can slow the scarring process but often at the expense of intolerable side effects, and without substantially changing overall survival. A better understanding of mechanisms underlying IPF is likely to lead to improved therapies. The current paradigm proposes that repetitive alveolar epithelial injury from noxious stimuli in a genetically primed individual is followed by abnormal wound healing, including aberrant activity of extracellular matrix-secreting cells, with resultant tissue fibrosis and parenchymal damage. However, this may underplay the importance of the vascular contribution to fibrogenesis. The lungs receive 100% of the cardiac output, and vascular abnormalities in IPF include (a) heterogeneous vessel formation throughout fibrotic lung, including the development of abnormal dilated vessels and anastomoses; (b) abnormal spatially distributed populations of endothelial cells (ECs); (c) dysregulation of endothelial protective pathways such as prostacyclin signaling; and (d) an increased frequency of common vascular and metabolic comorbidities. Here, we propose that vascular and EC abnormalities are both causal and consequential in the pathobiology of IPF and that fuller evaluation of dysregulated pathways may lead to effective therapies and a cure for this devastating disease.
Topics: Humans; Endothelial Cells; Cicatrix; Idiopathic Pulmonary Fibrosis; Drug-Related Side Effects and Adverse Reactions; Epoprostenol
PubMed: 37712420
DOI: 10.1172/JCI172058 -
Marine Drugs Oct 2023Reef-building corals, recognized as cornerstone species in marine ecosystems, captivate with their unique duality as both symbiotic partners and autotrophic entities.... (Review)
Review
Reef-building corals, recognized as cornerstone species in marine ecosystems, captivate with their unique duality as both symbiotic partners and autotrophic entities. Beyond their ecological prominence, these corals produce a diverse array of secondary metabolites, many of which are poised to revolutionize the domains of pharmacology and medicine. This exhaustive review delves deeply into the multifaceted world of coral-derived lipids, highlighting both ubiquitous and rare forms. Within this spectrum, we navigate through a myriad of fatty acids and their acyl derivatives, encompassing waxes, sterol esters, triacylglycerols, mono-akyl-diacylglycerols, and an array of polar lipids such as betaine lipids, glycolipids, sphingolipids, phospholipids, and phosphonolipids. We offer a comprehensive exploration of the intricate biochemical variety of these lipids, related fatty acids, prostaglandins, and both cyclic and acyclic oxilipins. Additionally, the review provides insights into the chemotaxonomy of these compounds, illuminating the fatty acid synthesis routes inherent in corals. Of particular interest is the symbiotic bond many coral species nurture with dinoflagellates from the Symbiodinium group; their lipid and fatty acid profiles are also detailed in this discourse. This exploration accentuates the vast potential and intricacy of coral lipids and underscores their profound relevance in scientific endeavors.
Topics: Animals; Anthozoa; Ecosystem; Fatty Acids; Prostaglandins; Coral Reefs; Dinoflagellida; Symbiosis
PubMed: 37888474
DOI: 10.3390/md21100539