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Biomolecules Apr 2022Fibrosis is often the end result of chronic inflammation. It is characterized by the excessive deposition of extracellular matrix. This leads to structural alterations... (Review)
Review
Fibrosis is often the end result of chronic inflammation. It is characterized by the excessive deposition of extracellular matrix. This leads to structural alterations in the tissue, causing permanent damage and organ dysfunction. Depending on the organ it effects, fibrosis can be a serious threat to human life. The molecular mechanism of fibrosis is still not fully understood, but the NLRP3 (NOD-, LRR- and pyrin-domain-containing protein 3) inflammasome appears to play a significant role in the pathogenesis of fibrotic disease. The NLRP3 inflammasome has been the most extensively studied inflammatory pathway to date. It is a crucial component of the innate immune system, and its activation mediates the secretion of interleukin (IL)-1β and IL-18. NLRP3 activation has been strongly linked with fibrosis and drives the differentiation of fibroblasts into myofibroblasts by the chronic upregulation of IL-1β and IL-18 and subsequent autocrine signaling that maintains an activated inflammasome. Both IL-1β and IL-18 are profibrotic, however IL-1β can have antifibrotic capabilities. NLRP3 responds to a plethora of different signals that have a common but unidentified unifying trigger. Even after 20 years of extensive investigation, regulation of the NLRP3 inflammasome is still not completely understood. However, what is known about NLRP3 is that its regulation and activation is complex and not only driven by various activators but controlled by numerous post-translational modifications. More recently, there has been an intensive attempt to discover NLRP3 inhibitors to treat chronic diseases. This review addresses the role of the NLRP3 inflammasome in fibrotic disorders across many different tissues. It discusses the relationships of various NLRP3 activators to fibrosis and covers different therapeutics that have been developed, or are currently in development, that directly target NLRP3 or its downstream products as treatments for fibrotic disorders.
Topics: Fibrosis; Humans; Inflammasomes; Interleukin-18; Myofibroblasts; NLR Family, Pyrin Domain-Containing 3 Protein
PubMed: 35625564
DOI: 10.3390/biom12050634 -
Cureus Apr 2023Endometriosis, defined as the development of endometrial tissue outside of the uterine cavity, is a common gynecological disorder. The prevalence of pelvic endometriosis... (Review)
Review
Endometriosis, defined as the development of endometrial tissue outside of the uterine cavity, is a common gynecological disorder. The prevalence of pelvic endometriosis approaches 6%-10% in the general female population, and in women with pain, infertility, or both, the frequency is 35%-50%. The gold standard recommended process for diagnosing endometriosis is laparoscopy, an invasive surgical procedure, with or without histologic verification. The currently available nonsurgical treatments include oral contraceptives (estrogen-progestogen preparations), progestogen preparations (containing progesterone derivatives), androgenic hormones (danazol), and gonadotropin-releasing hormone (GnRH) agonists and antagonists. Two GnRH types have been discovered in mammals, GnRH I and GnRH II. In particular, GnRH I is released by the hypothalamus; however, it can be present in various tissues and organs of the body, including neural tissue, where it exerts neuroendocrine, autocrine, and paracrine actions in the peripheral and central nervous system (CNS). Interestingly, another GnRH isoform, GnRH III, has been identified, which has 60% similarity with GnRH I from which it varies by four amino acids. This peptide has been shown to have a significant role in reproduction, specifically in gametogenesis and steroidogenesis. Further research is needed to identify innovative treatment options for endometriosis, such as the therapeutic exogenous administration of GnRH II or antagonists of the GnRH I receptor. In this review, we examined the role of GnRH in endometriosis, outlining the specific actions of GnRH and GnRH receptors (GnRHRs). The innovative use of GnRH analogs and antagonists in the treatment of endometriosis is also discussed.
PubMed: 37122983
DOI: 10.7759/cureus.38136 -
Nature Immunology Jan 2022The molecular mechanisms governing orderly shutdown and retraction of CD4 type 1 helper T (T1) cell responses remain poorly understood. Here we show that complement...
The molecular mechanisms governing orderly shutdown and retraction of CD4 type 1 helper T (T1) cell responses remain poorly understood. Here we show that complement triggers contraction of T1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated the transition from pro-inflammatory interferon-γ T1 cells to suppressive interleukin-10 cells. This process was primed by dynamic changes in the epigenetic landscape of CD4 T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VitD receptor shaped the transcriptional response to VitD. Accordingly, VitD did not induce interleukin-10 expression in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4 T cells of patients with COVID-19 were T1-skewed and showed de-repression of genes downregulated by VitD, from either lack of substrate (VitD deficiency) and/or abnormal regulation of this system.
Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Basic-Leucine Zipper Transcription Factors; Bronchoalveolar Lavage Fluid; COVID-19; Complement C3a; Complement C3b; Humans; Interferon-gamma; Interleukin-10; JNK Mitogen-Activated Protein Kinases; Lymphocyte Activation; Receptors, Calcitriol; Respiratory Distress Syndrome; SARS-CoV-2; STAT3 Transcription Factor; Signal Transduction; Th1 Cells; Transcription, Genetic; Vitamin D
PubMed: 34764490
DOI: 10.1038/s41590-021-01080-3 -
Molecules (Basel, Switzerland) Jan 2022Neuropeptides are autocrine and paracrine signalling factors and mainly bind to G protein-coupled receptors (GPCRs) to trigger intracellular secondary messenger release... (Review)
Review
Neuropeptides are autocrine and paracrine signalling factors and mainly bind to G protein-coupled receptors (GPCRs) to trigger intracellular secondary messenger release including adenosine 3', 5'-cyclic monophosphate (cAMP), thus modulating cancer progress in different kind of tumours. As one of the downstream effectors of cAMP, exchange proteins directly activated by cAMP (EPACs) play dual roles in cancer proliferation and metastasis. More evidence about the relationship between neuropeptides and EPAC pathways have been proposed for their potential role in cancer development; hence, this review focuses on the role of neuropeptide/GPCR system modulation of cAMP/EPACs pathways in cancers. The correlated downstream pathways between neuropeptides and EPACs in cancer cell proliferation, migration, and metastasis is discussed to glimmer the direction of future research.
Topics: Animals; Biomarkers; Cyclic AMP; Disease Susceptibility; Gene Expression Regulation, Neoplastic; Guanine Nucleotide Exchange Factors; Humans; Neoplasms; Neuropeptides; Organ Specificity; Protein Binding; Receptors, Neurotransmitter; Signal Transduction
PubMed: 35011543
DOI: 10.3390/molecules27010311 -
Pharmacology & Therapeutics Jan 2023Extensive injury of endothelial cells in blood vasculature, especially in the microcirculatory system, frequently occurs in hosts suffering from sepsis and the... (Review)
Review
Extensive injury of endothelial cells in blood vasculature, especially in the microcirculatory system, frequently occurs in hosts suffering from sepsis and the accompanied systemic inflammation. Pathological factors, including toxic components derived from invading microbes, oxidative stress associated with tissue ischemia/reperfusion, and vessel active mediators generated during the inflammatory response, are known to play important roles in mediating endothelial injury. Collapse of microcirculation and tissue edema developed from the failure of endothelial barrier function in vital organ systems, including the lung, brain, and kidney, are detrimental, which often predict fatal outcomes. The host body possesses a substantial capacity for maintaining vascular homeostasis and repairing endothelial damage. Bone marrow and vascular wall niches house endothelial progenitor cells (EPCs). In response to septic challenges, EPCs in their niche environment are rapidly activated for proliferation and angiogenic differentiation. In the meantime, release of EPCs from their niches into the blood stream and homing of these vascular precursors to tissue sites of injury are markedly increased. The recruited EPCs actively participate in host defense against endothelial injury and repair of damage in blood vasculature via direct differentiation into endothelial cells for re-endothelialization as well as production of vessel active mediators to exert paracrine and autocrine effects on angiogenesis/vasculogenesis. In recent years, investigations on significance of EPCs in host defense and molecular signaling mechanisms underlying regulation of the EPC response have achieved substantial progress, which promotes exploration of vascular precursor cell-based approaches for effective prevention and treatment of sepsis-induced vascular injury as well as vital organ system failure.
Topics: Humans; Endothelial Progenitor Cells; Microcirculation; Signal Transduction; Cell Differentiation; Sepsis
PubMed: 36436689
DOI: 10.1016/j.pharmthera.2022.108315 -
International Journal of Molecular... Aug 2023Glucagon exerts effects on the mammalian heart. These effects include alterations in the force of contraction, beating rate, and changes in the cardiac conduction system... (Review)
Review
Glucagon exerts effects on the mammalian heart. These effects include alterations in the force of contraction, beating rate, and changes in the cardiac conduction system axis. The cardiac effects of glucagon vary according to species, region, age, and concomitant disease. Depending on the species and region studied, the contractile effects of glucagon can be robust, modest, or even absent. Glucagon is detected in the mammalian heart and might act with an autocrine or paracrine effect on the cardiac glucagon receptors. The glucagon levels in the blood and glucagon receptor levels in the heart can change with disease or simultaneous drug application. Glucagon might signal via the glucagon receptors but, albeit less potently, glucagon might also signal via glucagon-like-peptide-1-receptors (GLP1-receptors). Glucagon receptors signal in a species- and region-dependent fashion. Small molecules or antibodies act as antagonists to glucagon receptors, which may become an additional treatment option for diabetes mellitus. Hence, a novel review of the role of glucagon and the glucagon receptors in the mammalian heart, with an eye on the mouse and human heart, appears relevant. Mouse hearts are addressed here because they can be easily genetically modified to generate mice that may serve as models for better studying the human glucagon receptor.
Topics: Humans; Animals; Mice; Glucagon; Receptors, Glucagon; Heart; Heart Conduction System; Antibodies; Glucagon-Like Peptide-1 Receptor; Mammals
PubMed: 37629010
DOI: 10.3390/ijms241612829 -
Nature Jun 2022T cell development in the thymus is essential for cellular immunity and depends on the organotypic thymic epithelial microenvironment. In comparison with other organs,...
T cell development in the thymus is essential for cellular immunity and depends on the organotypic thymic epithelial microenvironment. In comparison with other organs, the size and cellular composition of the thymus are unusually dynamic, as exemplified by rapid growth and high T cell output during early stages of development, followed by a gradual loss of functional thymic epithelial cells and diminished naive T cell production with age. Single-cell RNA sequencing (scRNA-seq) has uncovered an unexpected heterogeneity of cell types in the thymic epithelium of young and aged adult mice; however, the identities and developmental dynamics of putative pre- and postnatal epithelial progenitors have remained unresolved. Here we combine scRNA-seq and a new CRISPR-Cas9-based cellular barcoding system in mice to determine qualitative and quantitative changes in the thymic epithelium over time. This dual approach enabled us to identify two principal progenitor populations: an early bipotent progenitor type biased towards cortical epithelium and a postnatal bipotent progenitor population biased towards medullary epithelium. We further demonstrate that continuous autocrine provision of Fgf7 leads to sustained expansion of thymic microenvironments without exhausting the epithelial progenitor pools, suggesting a strategy to modulate the extent of thymopoietic activity.
Topics: Aging; Animals; Autocrine Communication; CRISPR-Cas Systems; Cellular Microenvironment; Epithelial Cells; Epithelium; Fibroblast Growth Factor 7; Mice; RNA-Seq; Single-Cell Analysis; Stem Cells; T-Lymphocytes; Thymus Gland
PubMed: 35614226
DOI: 10.1038/s41586-022-04752-8 -
Engineered Tissue Models to Replicate Dynamic Interactions within the Hematopoietic Stem Cell Niche.Advanced Healthcare Materials Apr 2022Hematopoietic stem cells are the progenitors of the blood and immune system and represent the most widely used regenerative therapy. However, their rarity and limited... (Review)
Review
Hematopoietic stem cells are the progenitors of the blood and immune system and represent the most widely used regenerative therapy. However, their rarity and limited donor base necessitate the design of ex vivo systems that support HSC expansion without the loss of long-term stem cell activity. This review describes recent advances in biomaterials systems to replicate features of the hematopoietic niche. Inspired by the native bone marrow, these instructive biomaterials provide stimuli and cues from cocultured niche-associated cells to support HSC encapsulation and expansion. Engineered systems increasingly enable study of the dynamic nature of the matrix and biomolecular environment as well as the role of cell-cell signaling (e.g., autocrine feedback vs paracrine signaling between dissimilar cells). The inherent coupling of material properties, biotransport of cell-secreted factors, and cell-mediated remodeling motivate dynamic biomaterial systems as well as characterization and modeling tools capable of evaluating a temporally evolving tissue microenvironment. Recent advances in HSC identification and tracking, model-based experimental design, and single-cell culture platforms facilitate the study of the effect of constellations of matrix, cell, and soluble factor signals on HSC fate. While inspired by the HSC niche, these tools are amenable to the broader stem cell engineering community.
Topics: Biocompatible Materials; Bone Marrow; Hematopoietic Stem Cells; Stem Cell Niche; Tissue Engineering
PubMed: 34936239
DOI: 10.1002/adhm.202102130 -
Journal of Dental Research Aug 2022Head and neck cancer (HNC) affects over 890,000 people annually worldwide and has a mortality rate of 50%. Aside from poor survival, HNC pain impairs eating, drinking,...
Head and neck cancer (HNC) affects over 890,000 people annually worldwide and has a mortality rate of 50%. Aside from poor survival, HNC pain impairs eating, drinking, and talking in patients, severely reducing quality of life. Different pain phenotype in patients (allodynia, hyperalgesia, and spontaneous pain) results from a combination of anatomical, histopathological, and molecular differences between cancers. Poor pathologic features (e.g., perineural invasion, lymph node metastasis) are associated with increased pain. The use of syngeneic/immunocompetent animal models, as well as a new mouse model of perineural invasion, provides novel insights into the pathobiology of HNC pain. Glial and immune modulation of the tumor microenvironment affect not only cancer progression but also pain signaling. For example, Schwann cells promote cancer cell proliferation, migration, and secretion of nociceptive mediators, whereas neutrophils are implicated in sex differences in pain in animal models of HNC. Emerging evidence supports the existence of a functional loop of cross-activation between the tumor microenvironment and peripheral nerves, mediated by a molecular exchange of bioactive contents (pronociceptive and protumorigenic) via paracrine and autocrine signaling. Brain-derived neurotrophic factor, tumor necrosis factor α, legumain, cathepsin S, and A disintegrin and metalloprotease 17 expressed in the HNC microenvironment have recently been shown to promote HNC pain, further highlighting the importance of proinflammatory cytokines, neurotrophic factors, and proteases in mediating HNC-associated pain. Pronociceptive mediators, together with nerve injury, cause nociceptor hypersensitivity. Oncogenic, pronociceptive mediators packaged in cancer cell-derived exosomes also induce nociception in mice. In addition to increased production of pronociceptive mediators, HNC is accompanied by a dampened endogenous antinociception system (e.g., downregulation of resolvins and µ-opioid receptor expression). Resolvin treatment or gene delivery of µ-opioid receptors provides pain relief in preclinical HNC models. Collectively, recent studies suggest that pain and HNC progression share converging mechanisms that can be targeted for cancer treatment and pain management.
Topics: Animals; Cell Proliferation; Female; Head and Neck Neoplasms; Humans; Hyperalgesia; Male; Mice; Neuroglia; Pain; Quality of Life; Tumor Microenvironment
PubMed: 35416080
DOI: 10.1177/00220345221088527 -
JCI Insight Mar 2024Efficient clearance and degradation of apoptotic cardiomyocytes by macrophages (collectively termed efferocytosis) is critical for inflammation resolution and...
Efficient clearance and degradation of apoptotic cardiomyocytes by macrophages (collectively termed efferocytosis) is critical for inflammation resolution and restoration of cardiac function after myocardial ischemia/reperfusion (I/R). Here, we define secreted and transmembrane protein 1a (Sectm1a), a cardiac macrophage-enriched gene, as a modulator of macrophage efferocytosis in I/R-injured hearts. Upon myocardial I/R, Sectm1a-KO mice exhibited impaired macrophage efferocytosis, leading to massive accumulation of apoptotic cardiomyocytes, cardiac inflammation, fibrosis, and consequently, exaggerated cardiac dysfunction. By contrast, therapeutic administration of recombinant SECTM1A protein significantly enhanced macrophage efferocytosis and improved cardiac function. Mechanistically, SECTM1A could elicit autocrine effects on the activation of glucocorticoid-induced TNF receptor (GITR) at the surface of macrophages, leading to the upregulation of liver X receptor α (LXRα) and its downstream efferocytosis-related genes and lysosomal enzyme genes. Our study suggests that Sectm1a-mediated activation of the Gitr/LXRα axis could be a promising approach to enhance macrophage efferocytosis for the treatment of myocardial I/R injury.
Topics: Mice; Animals; Phagocytosis; Efferocytosis; Apoptosis; Macrophages; Inflammation; Membrane Proteins; Myocardial Reperfusion Injury; Reperfusion
PubMed: 38456501
DOI: 10.1172/jci.insight.173832