-
International Journal of Molecular... Jun 2021Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the... (Review)
Review
Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the stability of iron concentration in plasma and extracellular fluid, and the total body iron content are maintained by the interaction of the iron-regulatory peptide hormone hepcidin with its receptor and cellular iron exporter ferroportin (SLC40a1). Ferroportin exports iron from duodenal enterocytes that absorb dietary iron, from iron-recycling macrophages in the spleen and the liver, and from iron-storing hepatocytes. Hepcidin blocks iron export through ferroportin, causing hypoferremia. During iron deficiency or after hemorrhage, hepcidin decreases to allow iron delivery to plasma through ferroportin, thus promoting compensatory erythropoiesis. As a host defense mediator, hepcidin increases in response to infection and inflammation, blocking iron delivery through ferroportin to blood plasma, thus limiting iron availability to invading microbes. Genetic diseases that decrease hepcidin synthesis or disrupt hepcidin binding to ferroportin cause the iron overload disorder hereditary hemochromatosis. The opposite phenotype, iron restriction or iron deficiency, can result from genetic or inflammatory overproduction of hepcidin.
Topics: Animals; Autocrine Communication; Biological Transport; Cation Transport Proteins; Disease Susceptibility; Hepcidins; Homeostasis; Humans; Iron; Ligands; Metabolic Networks and Pathways; Paracrine Communication; Protein Binding; Signal Transduction; Tissue Distribution
PubMed: 34204327
DOI: 10.3390/ijms22126493 -
Osteoarthritis and Cartilage May 2020OA is now well accepted as a low-grade inflammatory disease affecting the whole joint. In addition to mechanical loading, inflammation (particularly synovitis),... (Review)
Review
OA is now well accepted as a low-grade inflammatory disease affecting the whole joint. In addition to mechanical loading, inflammation (particularly synovitis), contributes significantly to OA. Synovial macrophages act as immune cells and are of critical importance in the symptomology and structural progression of OA. Activated macrophages are regulated by mTOR, NF-κB, JNK, PI3K/Akt and other signaling pathways, and are polarized into either M1 or M2 subtypes in OA synovial tissues, synovial fluid, and peripheral blood. The activation state and the M1/M2 ratio is highly associated with OA severity. Aside from autocrine interactions, paracrine interactions between macrophages and chondrocytes play a vital role in the initiation and development of OA by secreting inflammatory cytokines, growth factors, matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs), which lead to subsequent cartilage degradation and destruction. Treatments targeting synovial macrophages relieve pain, and protect from synovitis, cartilage damage, and osteophyte formation during OA development. Macrophage reprogramming of transformation from the M1 to M2 subtype, more than a decrease in the quantity of activated macrophages, appears to be an effective treatment option for OA. This review provides a broad understanding of the contributions of polarized macrophages to joint health and disease. Multifunctional agents with immunomodulatory effects on macrophage reprogramming can skew the inflammatory microenvironment towards a pro-chondrogenic atmosphere, and are thus, potential therapeutic options for the treatment of OA and other immune diseases.
Topics: Chondrocytes; Disease Progression; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Macrophage Activation; Macrophages; Matrix Metalloproteinases; Osteoarthritis; Paracrine Communication; Phenotype; Synovial Membrane; Synovitis; Tissue Inhibitor of Metalloproteinases
PubMed: 31982565
DOI: 10.1016/j.joca.2020.01.007 -
Critical Care (London, England) Apr 2020Early detection of cardiovascular dysfunctions directly caused by acute ischemic stroke (AIS) has become paramount. Researchers now generally agree on the existence of a... (Review)
Review
Early detection of cardiovascular dysfunctions directly caused by acute ischemic stroke (AIS) has become paramount. Researchers now generally agree on the existence of a bidirectional interaction between the brain and the heart. In support of this theory, AIS patients are extremely vulnerable to severe cardiac complications. Sympathetic hyperactivity, hypothalamic-pituitary-adrenal axis, the immune and inflammatory responses, and gut dysbiosis have been identified as the main pathological mechanisms involved in brain-heart axis dysregulation after AIS. Moreover, evidence has confirmed that the main causes of mortality after AIS include heart attack, congestive heart failure, hemodynamic instability, left ventricular systolic dysfunction, diastolic dysfunction, arrhythmias, electrocardiographic anomalies, and cardiac arrest, all of which are more or less associated with poor outcomes and death. Therefore, intensive care unit admission with continuous hemodynamic monitoring has been proposed as the standard of care for AIS patients at high risk for developing cardiovascular complications. Recent trials have also investigated possible therapies to prevent secondary cardiovascular accidents after AIS. Labetalol, nicardipine, and nitroprusside have been recommended for the control of hypertension during AIS, while beta blockers have been suggested both for preventing chronic remodeling and for treating arrhythmias. Additionally, electrolytic imbalances should be considered, and abnormal rhythms must be treated. Nevertheless, therapeutic targets remain challenging, and further investigations might be essential to complete this complex multi-disciplinary puzzle. This review aims to highlight the pathophysiological mechanisms implicated in the interaction between the brain and the heart and their clinical consequences in AIS patients, as well as to provide specific recommendations for cardiovascular management after AIS.
Topics: Brain; Heart; Humans; Ischemia; Paracrine Communication; Stroke
PubMed: 32317013
DOI: 10.1186/s13054-020-02885-8 -
Cancer Letters Feb 2021The endocrine FGF21 was discovered as a novel metabolic regulator in 2005 with new functions bifurcating from the canonic heparin-binding FGFs that directly promote cell... (Review)
Review
The endocrine FGF21 was discovered as a novel metabolic regulator in 2005 with new functions bifurcating from the canonic heparin-binding FGFs that directly promote cell proliferation and growth independent of a co-receptor. Early studies have demonstrated that FGF21 is a stress sensor in the liver and possibly, several other endocrine and metabolic tissues. Hepatic FGF21 signals via endocrine routes to quench episodes of metabolic derangements, promoting metabolic homeostasis. The convergence of mouse and human studies shows that FGF21 promotes lipid catabolism, including lipolysis, fatty acid oxidation, mitochondrial oxidative activity, and thermogenic energy dissipation, rather than directly regulating insulin and appetite. The white and brown adipose tissues and, to some extent, the hypothalamus, all of which host a transmembrane receptor binary complex of FGFR1 and co-receptor KLB, are considered the essential tissue and molecular targets of hepatic or pharmacological FGF21. On the other hand, a growing body of work has revealed that pancreatic acinar cells form a constitutive high-production site for FGF21, which then acts in an autocrine or paracrine mode. Beyond regulation of macronutrient metabolism and physiological energy expenditure, FGF21 appears to function in forestalling the development of fatty pancreas, steato-pancreatitis, fatty liver, and steato-hepatitis, thereby preventing the development of advanced pathologies such as pancreatic ductal adenocarcinoma or hepatocellular carcinoma. This review is intended to provide updates on these new discoveries that illuminate the protective roles of FGF21-FGFR1-KLB signal pathway in metabolic anomalies-associated severe tissue damage and malignancy, and to inform potential new preventive or therapeutic strategies for obesity-inflicted cancer patients via reducing metabolic risks and inflammation.
Topics: Adipose Tissue; Animals; Autocrine Communication; Carcinoma, Hepatocellular; Carcinoma, Pancreatic Ductal; Cell Proliferation; Disease Models, Animal; Energy Metabolism; Fatty Liver; Fibroblast Growth Factors; Humans; Hypothalamus; Klotho Proteins; Lipid Metabolism; Liver; Liver Neoplasms; Membrane Proteins; Mice; Mice, Transgenic; Obesity; Pancreas; Pancreatic Neoplasms; Paracrine Communication; Protective Factors; Receptor, Fibroblast Growth Factor, Type 1; Signal Transduction
PubMed: 33264641
DOI: 10.1016/j.canlet.2020.11.026 -
Nature Jul 2021Obesity is a worldwide epidemic that predisposes individuals to many age-associated diseases, but its exact effects on organ dysfunction are largely unknown. Hair...
Obesity is a worldwide epidemic that predisposes individuals to many age-associated diseases, but its exact effects on organ dysfunction are largely unknown. Hair follicles-mini-epithelial organs that grow hair-are miniaturized by ageing to cause hair loss through the depletion of hair follicle stem cells (HFSCs). Here we report that obesity-induced stress, such as that induced by a high-fat diet (HFD), targets HFSCs to accelerate hair thinning. Chronological gene expression analysis revealed that HFD feeding for four consecutive days in young mice directed activated HFSCs towards epidermal keratinization by generating excess reactive oxygen species, but did not reduce the pool of HFSCs. Integrative analysis using stem cell fate tracing, epigenetics and reverse genetics showed that further feeding with an HFD subsequently induced lipid droplets and NF-κB activation within HFSCs via autocrine and/or paracrine IL-1R signalling. These integrated factors converge on the marked inhibition of Sonic hedgehog (SHH) signal transduction in HFSCs, thereby further depleting lipid-laden HFSCs through their aberrant differentiation and inducing hair follicle miniaturization and eventual hair loss. Conversely, transgenic or pharmacological activation of SHH rescued HFD-induced hair loss. These data collectively demonstrate that stem cell inflammatory signals induced by obesity robustly represses organ regeneration signals to accelerate the miniaturization of mini-organs, and suggests the importance of daily prevention of organ dysfunction.
Topics: Alopecia; Animals; Autocrine Communication; Cell Count; Cell Differentiation; Cell Lineage; Cellular Senescence; Diet, High-Fat; Disease Models, Animal; Hair Follicle; Hedgehog Proteins; Inflammation; Male; Mice; Mice, Inbred C57BL; Obesity; Oxidative Stress; Paracrine Communication; Receptors, Interleukin-1; Stem Cells
PubMed: 34163066
DOI: 10.1038/s41586-021-03624-x -
International Journal of Molecular... Jun 2020Interventions to prevent pregnancy complications have been largely unsuccessful. We suggest this is because the foundation for a healthy pregnancy is laid prior to the... (Review)
Review
Interventions to prevent pregnancy complications have been largely unsuccessful. We suggest this is because the foundation for a healthy pregnancy is laid prior to the establishment of the pregnancy at the time of endometrial decidualization. Humans are one of only a few mammalian viviparous species in which decidualization begins during the latter half of each menstrual cycle and is therefore independent of the conceptus. Failure to adequately prepare (decidualize) the endometrium hormonally, biochemically, and immunologically in anticipation of the approaching blastocyst-including the downregulation of genes involved in the pro- inflammatory response and resisting tissue invasion along with the increased expression of genes that promote angiogenesis, foster immune tolerance, and facilitate tissue invasion-leads to abnormal implantation/placentation and ultimately to adverse pregnancy outcome. We hypothesize, therefore, that the primary driver of pregnancy health is the quality of the soil, not the seed.
Topics: Animals; Autocrine Communication; Biomarkers; Decidua; Embryo Implantation; Endometrium; Female; Gene Expression Regulation; Humans; Paracrine Communication; Placentation; Pregnancy; Pregnancy Complications; Pregnancy Outcome
PubMed: 32521725
DOI: 10.3390/ijms21114092 -
Nature Reviews. Cardiology Nov 2020Extracellular vesicles (EVs) are a heterogeneous group of natural particles that are relevant to the treatment of cardiovascular diseases. These endogenous vesicles have... (Review)
Review
Extracellular vesicles (EVs) are a heterogeneous group of natural particles that are relevant to the treatment of cardiovascular diseases. These endogenous vesicles have certain properties that allow them to survive in the extracellular space, bypass biological barriers and deliver their biologically active molecular cargo to recipient cells. Moreover, EVs can be bioengineered to increase their stability, bioactivity, presentation to acceptor cells and capacity for on-target binding at both cell-type-specific and tissue-specific levels. Bioengineering of EVs involves the modification of the donor cell before EV isolation or direct modification of the EV properties after isolation. The therapeutic potential of native EVs and bioengineered EVs has been only minimally explored in the context of cardiovascular diseases. Efforts to harness the therapeutic potential of EVs will require innovative approaches and a comprehensive integration of knowledge gathered from decades of research into molecular-compound delivery. In this Review, we outline the endogenous properties of EVs that make them natural delivery agents as well as the features that can be improved by bioengineering. We also discuss the therapeutic applications of native and bioengineered EVs to cardiovascular diseases and examine the opportunities and challenges that need to be addressed to advance this research area, with an emphasis on clinical translation.
Topics: Bioengineering; Brain; Cardiovascular Diseases; Cell Survival; Extracellular Vesicles; Extremities; Heart; Humans; Ischemia; MicroRNAs; Myocardial Infarction; Myocytes, Cardiac; Paracrine Communication; Regeneration; Stem Cells; Stroke
PubMed: 32483304
DOI: 10.1038/s41569-020-0389-5 -
Nature Jun 2022During infection, animals exhibit adaptive changes in physiology and behaviour aimed at increasing survival. Although many causes of infection exist, they trigger...
During infection, animals exhibit adaptive changes in physiology and behaviour aimed at increasing survival. Although many causes of infection exist, they trigger similar stereotyped symptoms such as fever, warmth-seeking, loss of appetite and fatigue. Yet exactly how the nervous system alters body temperature and triggers sickness behaviours to coordinate responses to infection remains unknown. Here we identify a previously uncharacterized population of neurons in the ventral medial preoptic area (VMPO) of the hypothalamus that are activated after sickness induced by lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid. These neurons are crucial for generating a fever response and other sickness symptoms such as warmth-seeking and loss of appetite. Single-nucleus RNA-sequencing and multiplexed error-robust fluorescence in situ hybridization uncovered the identity and distribution of LPS-activated VMPO (VMPO) neurons and non-neuronal cells. Gene expression and electrophysiological measurements implicate a paracrine mechanism in which the release of immune signals by non-neuronal cells during infection activates nearby VMPO neurons. Finally, we show that VMPO neurons exert a broad influence on the activity of brain areas associated with behavioural and homeostatic functions and are synaptically and functionally connected to circuit nodes controlling body temperature and appetite. Together, these results uncover VMPO neurons as a control hub that integrates immune signals to orchestrate multiple sickness symptoms in response to infection.
Topics: Animals; Appetite; Appetite Depressants; Fever; In Situ Hybridization, Fluorescence; Infections; Lipopolysaccharides; Neurons; Paracrine Communication; Poly I-C; Preoptic Area
PubMed: 35676482
DOI: 10.1038/s41586-022-04793-z -
The EMBO Journal May 2021Cellular senescence is characterized by an irreversible cell cycle arrest as well as a pro-inflammatory phenotype, thought to contribute to aging and age-related...
Cellular senescence is characterized by an irreversible cell cycle arrest as well as a pro-inflammatory phenotype, thought to contribute to aging and age-related diseases. Neutrophils have essential roles in inflammatory responses; however, in certain contexts their abundance is associated with a number of age-related diseases, including liver disease. The relationship between neutrophils and cellular senescence is not well understood. Here, we show that telomeres in non-immune cells are highly susceptible to oxidative damage caused by neighboring neutrophils. Neutrophils cause telomere dysfunction both in vitro and ex vivo in a ROS-dependent manner. In a mouse model of acute liver injury, depletion of neutrophils reduces telomere dysfunction and senescence. Finally, we show that senescent cells mediate the recruitment of neutrophils to the aged liver and propose that this may be a mechanism by which senescence spreads to surrounding cells. Our results suggest that interventions that counteract neutrophil-induced senescence may be beneficial during aging and age-related disease.
Topics: Acute Lung Injury; Animals; Carbon Tetrachloride; Cell Line; Cellular Senescence; Coculture Techniques; Disease Models, Animal; Female; Fibroblasts; Humans; Male; Mice; Neutrophils; Oxidative Stress; Paracrine Communication; Reactive Oxygen Species; Telomere Shortening
PubMed: 33764576
DOI: 10.15252/embj.2020106048 -
Cellular and Molecular Life Sciences :... Mar 2022There is a steadily growing interest in the use of mitochondria as therapeutic agents. The use of mitochondria derived from mesenchymal stem/stromal cells (MSCs) for... (Review)
Review
There is a steadily growing interest in the use of mitochondria as therapeutic agents. The use of mitochondria derived from mesenchymal stem/stromal cells (MSCs) for therapeutic purposes represents an innovative approach to treat many diseases (immune deregulation, inflammation-related disorders, wound healing, ischemic events, and aging) with an increasing amount of promising evidence, ranging from preclinical to clinical research. Furthermore, the eventual reversal, induced by the intercellular mitochondrial transfer, of the metabolic and pro-inflammatory profile, opens new avenues to the understanding of diseases' etiology, their relation to both systemic and local risk factors, and also leads to new therapeutic tools for the control of inflammatory and degenerative diseases. To this end, we illustrate in this review, the triggers and mechanisms behind the transfer of mitochondria employed by MSCs and the underlying benefits as well as the possible adverse effects of MSCs mitochondrial exchange. We relay the rationale and opportunities for the use of these organelles in the clinic as cell-based product.
Topics: Cell- and Tissue-Based Therapy; Humans; Lung Diseases; Macrophages; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mitochondria; Mitochondrial Dynamics; Paracrine Communication
PubMed: 35247083
DOI: 10.1007/s00018-022-04207-3