-
Frontiers in Endocrinology 2023Primary hypertrophic osteoarthropathy (PHO) is a genetic disorder mainly characterized by clubbing fingers, pachydermia and periostosis. Mutations in the or gene lead... (Review)
Review
Primary hypertrophic osteoarthropathy (PHO) is a genetic disorder mainly characterized by clubbing fingers, pachydermia and periostosis. Mutations in the or gene lead to impaired prostaglandin E2 (PGE2) degradation, thus elevating PGE2 levels. The identification of the causative genes has provided a better understanding of the underlying mechanisms. PHO can be divided into three subtypes according to its pathogenic gene and inheritance patterns. The onset age, sex ratio and clinical features differ among subtypes. The synthesis and signaling pathways of PGE2 are outlined in this review. Cyclooxygenase-2 (COX-2) is the key enzyme that acts as the rate-limiting step for prostaglandin production, thus COX-2 inhibitors have been used to treat this disease. Although this treatment showed effective results, it has side effects that restrain its use. Here, we reviewed the genetics, clinical features, differential diagnosis and current treatment options of PHO according to our many years of clinical research on the disease. We also discussed probable treatment that may be an option in the future.
Topics: Humans; Dinoprostone; Osteoarthropathy, Primary Hypertrophic; Cyclooxygenase 2; Diagnosis, Differential; Drug-Related Side Effects and Adverse Reactions; Organic Anion Transporters
PubMed: 37705574
DOI: 10.3389/fendo.2023.1235040 -
Current Osteoporosis Reports Dec 2023Orthodontic tooth movement is characterized by periodontal tissue responses to mechanical loading, leading to clinically relevant functional adaptation of jaw bone.... (Review)
Review
PURPOSE OF REVIEW
Orthodontic tooth movement is characterized by periodontal tissue responses to mechanical loading, leading to clinically relevant functional adaptation of jaw bone. Since osteocytes are significant in mechanotransduction and orchestrate osteoclast and osteoblast activity, they likely play a central role in orthodontic tooth movement. In this review, we attempt to shed light on the impact and role of osteocyte mechanotransduction during orthodontic tooth movement.
RECENT FINDINGS
Mechanically loaded osteocytes produce signaling molecules, e.g., bone morphogenetic proteins, Wnts, prostaglandins, osteopontin, nitric oxide, sclerostin, and RANKL, which modulate the recruitment, differentiation, and activity of osteoblasts and osteoclasts. The major signaling pathways activated by mechanical loading in osteocytes are the wingless-related integration site (Wnt)/β-catenin and RANKL pathways, which are key regulators of bone metabolism. Moreover, osteocytes are capable of orchestrating bone adaptation during orthodontic tooth movement. A better understanding of the role of osteocyte mechanotransduction is crucial to advance orthodontic treatment. The optimal force level on the periodontal tissues for orthodontic tooth movement producing an adequate biological response, is debated. This review emphasizes that both mechanoresponses and inflammation are essential for achieving tooth movement clinically. To fully comprehend the role of osteocyte mechanotransduction in orthodontic tooth movement, more knowledge is needed of the biological pathways involved. This will contribute to optimization of orthodontic treatment and enhance patient outcomes.
Topics: Humans; Osteocytes; Mechanotransduction, Cellular; Tooth Movement Techniques; Osteoclasts; Osteoblasts; Bone Remodeling
PubMed: 37792246
DOI: 10.1007/s11914-023-00826-2 -
Cell Reports Feb 2024Elevated interleukin (IL)-1β levels, NLRP3 inflammasome activity, and systemic inflammation are hallmarks of chronic metabolic inflammatory syndromes, but the...
Elevated interleukin (IL)-1β levels, NLRP3 inflammasome activity, and systemic inflammation are hallmarks of chronic metabolic inflammatory syndromes, but the mechanistic basis for this is unclear. Here, we show that levels of plasma IL-1β are lower in fasting compared to fed subjects, while the lipid arachidonic acid (AA) is elevated. Lipid profiling of NLRP3-stimulated mouse macrophages shows enhanced AA production and an NLRP3-dependent eicosanoid signature. Inhibition of cyclooxygenase by nonsteroidal anti-inflammatory drugs decreases eicosanoid, but not AA, production. It also reduces both IL-1β and IL-18 production in response to NLRP3 activation. AA inhibits NLRP3 inflammasome activity in human and mouse macrophages. Mechanistically, AA inhibits phospholipase C activity to reduce JNK1 stimulation and hence NLRP3 activity. These data show that AA is an important physiological regulator of the NLRP3 inflammasome and explains why fasting reduces systemic inflammation and also suggests a mechanism to explain how nonsteroidal anti-inflammatory drugs work.
Topics: Animals; Mice; Humans; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Arachidonic Acid; Inflammation; Interleukin-1beta; Anti-Inflammatory Agents, Non-Steroidal; Eicosanoids; Fasting
PubMed: 38265935
DOI: 10.1016/j.celrep.2024.113700 -
Journal of Ovarian Research Aug 2023Bi-directional communication between cumulus cells and the surrounded oocytes is important for the development and functions of both compartments. However, the metabolic...
Bi-directional communication between cumulus cells and the surrounded oocytes is important for the development and functions of both compartments. However, the metabolic framework in cumulus cells has not been systematically described. In the present study, cumulus cells from cumulus-oocyte complexes (COCs) at three key time points were isolated (arrested GV stage, post-hCG 0h; meiotic resumption GVBD stage, post-hCG 3h; and metaphase II stage, post-hCG 12h), and the temporal metabolomic and proteomic profiling were performed. Integrated multi-omics analysis reveals the global metabolic patterns in cumulus cells during mouse oocyte maturation. In particular, we found the active hyaluronic acid metabolism, steroid hormone synthesis, and prostaglandin E2 (PGE2) production in cumulus cells. Meanwhile, accompanying the oocyte maturation, a progressive increase in nucleotide and amino acid metabolism was detected in the surrounding cumulus cells. In sum, the data serve as a valuable resource for probing metabolism during terminal differentiation of ovarian granulosa cells, and provide the potential biomarkers for improving and predicting oocyte quality.
Topics: Female; Mice; Animals; Cumulus Cells; Multiomics; Proteomics; Oocytes; Oogenesis; Meiosis
PubMed: 37550748
DOI: 10.1186/s13048-023-01237-8 -
Cancers Jan 2024GBM accounts for most of the fatal brain cancer cases, making it one of the deadliest tumor types. GBM is characterized by severe progression and poor prognosis with a... (Review)
Review
GBM accounts for most of the fatal brain cancer cases, making it one of the deadliest tumor types. GBM is characterized by severe progression and poor prognosis with a short survival upon conventional chemo- and radiotherapy. In order to improve therapeutic efficiency, considerable efforts have been made to target various features of GBM. One of the targetable features of GBM is the rewired lipid metabolism that contributes to the tumor's aggressive growth and penetration into the surrounding brain tissue. Lipid reprogramming allows GBM to acquire survival, proliferation, and invasion benefits as well as supportive modulation of the tumor microenvironment. Several attempts have been made to find novel therapeutic approaches by exploiting the lipid metabolic reprogramming in GBM. In recent studies, various components of lipogenesis, fatty acid oxidation, lipid uptake, and prostaglandin synthesis have been considered promising targets in GBM. Emerging data also suggest a significant role hence therapeutic potential of the endocannabinoid metabolic pathway in GBM. Here we review the lipid-related GBM characteristics in detail and highlight specific targets with their potential therapeutic use in novel antitumor approaches.
PubMed: 38254886
DOI: 10.3390/cancers16020397 -
Biomedicine & Pharmacotherapy =... Dec 2023Inflammation is a protective response of the body potentially caused by microbial, viral, or fungal infections, tissue damage, or even autoimmune reactions. The cardinal... (Review)
Review
Inflammation is a protective response of the body potentially caused by microbial, viral, or fungal infections, tissue damage, or even autoimmune reactions. The cardinal signs of inflammation are consequences of immunological, biochemical, and physiological changes that trigger the release of pro-inflammatory chemical mediators at the local of the injured site thus, increasing blood flow, vascular permeability, and leukocyte recruitment. The aim of this study is to give an overview of the inflammatory process, focusing on chemical mediators. The literature review was based on a search of journals published between the years 2009 and 2023, regarding the role of major chemical mediators in the inflammatory process and current studies in pathogenesis, diagnosis, and therapy. Some of the recent contributions in the study of inflammatory pathologies and their mediators, including cytokines and chemokines, the kinin system, free radicals, nitric oxide, histamine, cell adhesion molecules, leukotrienes, prostaglandins and the complement system and their role in human health and chronic diseases.
Topics: Humans; Inflammation; Leukocytes; Cytokines; Prostaglandins; Histamine; Inflammation Mediators
PubMed: 37897973
DOI: 10.1016/j.biopha.2023.115764 -
Nature May 2024Expansion of antigen-experienced CD8 T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer....
Expansion of antigen-experienced CD8 T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer. Interleukin-2 (IL-2) acts as a key regulator of CD8 cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE), a known negative regulator of immune response in the tumour microenvironment, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8 TILs via the PGE receptors EP2 and EP4. Mechanistically, PGE inhibits IL-2 sensing in TILs by downregulating the IL-2Rγ chain, resulting in defective assembly of IL-2Rβ-IL2Rγ membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.
Topics: Animals; Humans; Mice; CD8-Positive T-Lymphocytes; Cell Proliferation; Dinoprostone; Down-Regulation; Ferroptosis; Interleukin Receptor Common gamma Subunit; Interleukin-2; Interleukin-2 Receptor beta Subunit; Lymphocytes, Tumor-Infiltrating; Mitochondria; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Microenvironment
PubMed: 38658764
DOI: 10.1038/s41586-024-07352-w -
JCI Insight Dec 2023Idiopathic pulmonary fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive...
Idiopathic pulmonary fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2α, and its cognate receptor FPr (Ptgfr) are implicated as a TGF-β1-independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER-SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen-treated IER-SftpcI73T mice developed an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. IER-SftpcI73T mice crossed to a Ptgfr-null (FPr-/-) line showed attenuated weight loss and gene dosage-dependent rescue of mortality compared with FPr+/+ cohorts. IER-SftpcI73T/FPr-/- mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single-cell RNA-Seq, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts, which were reprogrammed to an "inflammatory/transitional" cell state in a PGF2α /FPr-dependent manner. Collectively, the findings provide evidence for a role for PGF2α signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.
Topics: Mice; Animals; Dinoprost; Fibroblasts; Idiopathic Pulmonary Fibrosis; Fibrosis; Population Dynamics
PubMed: 37934604
DOI: 10.1172/jci.insight.172977 -
Cell Death & Disease Oct 2023Acute kidney injury (AKI) is a clinical syndrome with high morbidity and mortality but no specific therapy. Microsomal prostaglandin E synthase-2 (mPGES-2) is a PGE...
Acute kidney injury (AKI) is a clinical syndrome with high morbidity and mortality but no specific therapy. Microsomal prostaglandin E synthase-2 (mPGES-2) is a PGE synthase but can metabolize PGH to malondialdehyde by forming a complex with heme. However, the role and mechanism of action of mPGES-2 in AKI remain unclear. To examine the role of mPGES-2, both global and tubule-specific mPGES-2-deficient mice were treated with cisplatin to induce AKI. mPGES-2 knockdown or overexpressing HK-2 cells were exposed to cisplatin to cause acute renal tubular cell injury. The mPGES-2 inhibitor SZ0232 was used to test the translational potential of targeting mPGES-2 in treating AKI. Additionally, mice were subjected to unilateral renal ischemia/reperfusion to further validate the effect of mPGES-2 on AKI. Interestingly, both genetic and pharmacological blockage of mPGES-2 led to decreased renal dysfunction and morphological damage induced by cisplatin and unilateral renal ischemia/reperfusion. Mechanistic exploration indicated that mPGES-2 deficiency inhibited ferroptosis via the heme-dependent regulation of the p53/SLC7A11/GPX4 axis. The present study indicates that mPGES-2 blockage may be a promising therapeutic strategy for AKI.
Topics: Animals; Mice; Acute Kidney Injury; Cisplatin; Ferroptosis; Heme; Ischemia; Prostaglandin-E Synthases; Tumor Suppressor Protein p53
PubMed: 37907523
DOI: 10.1038/s41419-023-06236-7 -
The Journal of Clinical Investigation Sep 2023Recognition of pathogen-associated molecular patterns can trigger the inositol-requiring enzyme 1 α (IRE1α) arm of the endoplasmic reticulum (ER) stress response in...
Recognition of pathogen-associated molecular patterns can trigger the inositol-requiring enzyme 1 α (IRE1α) arm of the endoplasmic reticulum (ER) stress response in innate immune cells. This process maintains ER homeostasis and also coordinates diverse immunomodulatory programs during bacterial and viral infections. However, the role of innate IRE1α signaling in response to fungal pathogens remains elusive. Here, we report that systemic infection with the human opportunistic fungal pathogen Candida albicans induced proinflammatory IRE1α hyperactivation in myeloid cells that led to fatal kidney immunopathology. Mechanistically, simultaneous activation of the TLR/IL-1R adaptor protein MyD88 and the C-type lectin receptor dectin-1 by C. albicans induced NADPH oxidase-driven generation of ROS, which caused ER stress and IRE1α-dependent overexpression of key inflammatory mediators such as IL-1β, IL-6, chemokine (C-C motif) ligand 5 (CCL5), prostaglandin E2 (PGE2), and TNF-α. Selective ablation of IRE1α in leukocytes, or treatment with an IRE1α pharmacological inhibitor, mitigated kidney inflammation and prolonged the survival of mice with systemic C. albicans infection. Therefore, controlling IRE1α hyperactivation may be useful for impeding the immunopathogenic progression of disseminated candidiasis.
Topics: Humans; Animals; Mice; Protein Serine-Threonine Kinases; Endoribonucleases; Candidiasis; Endoplasmic Reticulum Stress; Candida albicans; Toll-Like Receptors; Adaptor Proteins, Signal Transducing
PubMed: 37432737
DOI: 10.1172/JCI167359