AIM:To explore the effects of alarmins produced by necrotic human conjunctival fibroblasts on the release of matrix metalloproteinases(MMPs)by human corneal fibroblasts(HCFs).METHODS:A necrotic cell supernatant(NHCS)w...AIM:To explore the effects of alarmins produced by necrotic human conjunctival fibroblasts on the release of matrix metalloproteinases(MMPs)by human corneal fibroblasts(HCFs).METHODS:A necrotic cell supernatant(NHCS)was prepared by subjecting human conjunctival fibroblasts to three cycles of freezing and thawing.The amounts of interleukin(IL)-1βand tumor necrosis factor(TNF)-αin NHCS were determined by enzyme-linked immunosorbent assays.HCFs exposed to NHCS or other agents in culture were assayed for the release of MMPs as well as for intracellular signaling by immunoblot analysis.The abundance of MMP m RNAs in HCFs was examined by reverse transcription and real-time polymerase chain reaction analysis.RESULTS:NHCS increased the release of MMP-1 and MMP-3 by HCFs as well as the amounts of the corresponding m RNAs in the cells.NHCS also induced activation of mitogen-activated protein kinase(MAPK)signaling pathways mediated by extracellular signal-regulated kinase(ERK),p38,and c-Jun NH2-terminal kinase(JNK)as well as elicited that of the nuclear factor(NF)-κB signaling pathway by promoting phosphorylation of the endogenous NF-κB inhibitor IκB-α.Inhibitors of MAPK and NF-κB signaling as well as IL-1 and TNF-αreceptor antagonists attenuated the NHCS-induced release of MMP-1 and MMP-3 by HCFs.Furthermore,IL-1βand TNF-αwere both detected in NHCS,and treatment of HCFs with these cytokines induced the release of MMP-1 and MMP-3 in a concentration-dependent manner.CONCLUSION:Alarmins,including IL-1βand TNF-α,produced by necrotic human conjunctival fibroblasts triggered MMP release in HCFs through activation of MAPK and NF-κB signaling.IL-1βand TNF-αare therefore potential therapeutic targets for the amelioration of corneal stromal degradation in severe ocular burns.展开更多
Neuroinflammation contributes to a wide range of neurodegenerative diseases including Alzheimer's disease,Parkinson's disease,Huntington's disease,and multiple sclerosis.It is driven by non-neuronal glial ...Neuroinflammation contributes to a wide range of neurodegenerative diseases including Alzheimer's disease,Parkinson's disease,Huntington's disease,and multiple sclerosis.It is driven by non-neuronal glial cells,mainly microglia and astrocytes.Microglia are the resident immune cells of the central nervous system,while astrocytes are the main support cells for neuronal functions but can also participate in neuroimmune responses.Both these glial cell types can become reactive upon detection of certain endogenous intracellular molecules that appear in the extracellular space under specific circumstances;these can be pathology-associated abnormal structures,such as amyloidβproteins,or damage-associated molecular patterns released from injured cells,including their mitochondria.Once in the extracellular space,damage-associated molecular patterns act as ligands for specific pattern recognition receptors expressed by glia inducing their reactivity and neuroimmune responses.This review considers the following mitochondrial damage-associated molecular patterns:heme,cytochrome c,cardiolipin,adenosine triphosphate,mitochondrial DNA,mitochondrial transcription factor A,N-formyl peptides,and the tricarboxylic acid cycle metabolites:succinate,fumarate,and itaconate.We describe their well-established functions as damage-associated molecular patterns of the peripheral tissues before summarizing available evidence indicating these molecules may also play significant roles in the neuroimmune processes of the central nervous system.We highlight the pattern recognition receptors that mitochondrial damage-associated molecular patterns interact with and the cellular signaling mechanisms they modulate.Our review demonstrates that some mitochondrial damage-associated molecular patterns,such as cytochrome c,adenosine triphosphate,and mitochondrial transcription factor A,have already demonstrated significant effects on the central nervous system.In contrast,others including cardiolipin,mitochondrial DNA,N-formyl peptides,succinate,fumarate,and itaconate,will require additional studies corroborating their roles as damageassociated molecular patterns in the central nervous system.For all of the reviewed mitochondrial damage-associated molecular patterns,there is a shortage of studies using human cells and tissues,which is identified as a significant knowledge gap.We also assess the need for targeted research on the effects of mitochondrial damage-associated molecular patterns in the central nervous system pathologies where their roles are understudied.Such studies could identify novel treatment strategies for multiple neurodegenerative diseases,which are characterized by chronic neuroinflammation and currently lack effective therapies.展开更多
Background and Aims:Nonalcoholic fatty liver disease(NAFLD)includes a range of progressive disorders generated by excess lipid accumulation in the liver leading to hepatic steatosis and eventually fibrosis.We aimed to...Background and Aims:Nonalcoholic fatty liver disease(NAFLD)includes a range of progressive disorders generated by excess lipid accumulation in the liver leading to hepatic steatosis and eventually fibrosis.We aimed to identify by high performance mass spectrometry-based proteomics the main signaling pathways and liver proteome changes induced by hypercholesterolemia in a rabbit atherosclerotic model that induced high accumulation of lipids in the liver.Methods:The effect of combined lipid-lowering drugs(statins and anti-PCSK9 monoclonal antibody)were used after the interruption of the hypercholesterolemic diet to identify also the potential mediators,such as alarmins,responsible for the irreversible NAFLD build up under the hyperlipidemic sustained stress.Results:Proteomic analysis revealed a number of proteins whose abundance was altered.They were components of metabolic pathways including fatty-acid degradation,glycolysis/gluconeogenesis,and nonalcoholic fatty liver disease.Mitochondrial dysfunction indicated alteration at the mitochondrial respiratory chain level and down-regulation of NADH:ubiquinone oxidoreductase.The expression of a majority of cytochromes(P4502E1,b5,and c)were up-regulated by lipid-lowering treatment.Long-term hyperlipidemic stress,even with a low-fat diet and lipid-lowering treatment,was accompanied by alarmin release(annexins,galectins,HSPs,HMGB1,S100 proteins,calreticulin,and fibronectin)that generated local inflammation and induced liver steatosis and aggressive fibrosis(by high abundance of galectin 3,fibronectin,and calreticulin).Conclusions:The novel findings of this study were related to the residual effects of hyperlipidemic stress with consistent,combined lipid-lowering treatment with statin and inhibitor of PCSK9.展开更多
Our immune system is based on the close collaboration of the innate and adaptive immune systems for the rapid detection of any threats to the host. Recognition of pathogen-derived molecules is entrusted to specific ge...Our immune system is based on the close collaboration of the innate and adaptive immune systems for the rapid detection of any threats to the host. Recognition of pathogen-derived molecules is entrusted to specific germline- encoded signaling receptors. The same receptors have now also emerged as efficient detectors of misplaced or altered self-molecules that signal tissue damage and cell death following, for example, disruption of the blood supply and subsequent hypoxia. Many types of endogenous molecules have been shown to provoke such sterile inflammatory states when released from dying cells. However, a group of proteins referred to as alarmins have both intracellular and extracellular functions which have been the subject of intense research. Indeed, alarmins can either exert beneficial cell housekeeping functions, leading to tissue repair, or provoke deleterious uncontrolled inflammation. This group of proteins includes the high-mobility group box 1 protein （HMGB1）, interleukin （IL）-1α, IL-33 and the Ca^2＋-binding S100 proteins. These dual-function proteins share conserved regulatory mechanisms, such as secretory routes, post-translational modifications and enzymatic processing, that govern their extracellular functions in time and space. Release of alarmins from mesenchymal cells is a highly relevant mechanism by which immune cells can be alerted of tissue damage, and alarmins play a key role in the development of acute or chronic inflammatory diseases and in cancer development.展开更多
Compelling evidence supports the crucial role of the receptor for advanced glycation end-products(RAGE)axis activation in many clinical entities.Since the beginning of the coronavirus disease 2019 pandemic,there is an...Compelling evidence supports the crucial role of the receptor for advanced glycation end-products(RAGE)axis activation in many clinical entities.Since the beginning of the coronavirus disease 2019 pandemic,there is an increasing concern about the risk and handling of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection in inflammatory gastrointestinal disorders,such as inflammatory bowel diseases(IBD).However,clinical data raised during pandemic suggests that IBD patients do not have an increased risk of contracting SARS-CoV-2 infection or develop a more severe course of infection.In the present review,we intend to highlight how two potentially important contributors to the inflammatory response to SARS-CoV-2 infection in IBD patients,the RAGE axis activation as well as the cross-talk with the renin-angiotensin system,are dampened by the high expression of soluble forms of both RAGE and the angiotensin-converting enzyme(ACE)2.The soluble form of RAGE functions as a decoy for its ligands,and soluble ACE2 seems to be an additionally attenuating contributor to RAGE axis activation,particularly by avoiding the transactivation of the RAGE axis that can be produced by the virus-mediated imbalance of the ACE/angiotensin II/angiotensin II receptor type 1 pathway.展开更多
Mesenchymal stromal/stem cells(MSCs)are adult stem cells of stromal origin that possess self-renewal capacity and the ability to differentiate into multiple mesodermal cell lineages.They play a critical role in tissue...Mesenchymal stromal/stem cells(MSCs)are adult stem cells of stromal origin that possess self-renewal capacity and the ability to differentiate into multiple mesodermal cell lineages.They play a critical role in tissue homeostasis and wound healing,as well as in regulating the inammatory microenvironment through interactions with immune cells.Hence,MSCs have garnered great attention as promising candidates for tissue regeneration and cell therapy.Because the inflammatory niche plays a key role in triggering the reparative and immunomodulatory functions of MSCs,priming of MSCs with bioactive molecules has been proposed as a way to foster the therapeutic potential of these cells.In this paper,we review how soluble mediators of the inflammatory niche(cytokines and alarmins)influence the regenerative and immunomodulatory capacity of MSCs,highlighting the major advantages and concerns regarding the therapeutic potential of these inflammatory primed MSCs.The data summarized in this review may provide a significant starting point for future research on priming MSCs and establishing standardized methods for the application of preconditioned MSCs in cell therapy.展开更多
Compelling shreds of evidence derived from both clinical and experimental research have demonstrated the crucial contribution of receptor for advanced glycation end products(RAGE)axis activation in the development of ...Compelling shreds of evidence derived from both clinical and experimental research have demonstrated the crucial contribution of receptor for advanced glycation end products(RAGE)axis activation in the development of neoplasms,including gastric cancer(GC).This new actor in tumor biology plays an important role in the onset of a crucial and long-lasting inflammatory milieu,not only by supporting phenotypic changes favoring growth and dissemination of tumor cells,but also by functioning as a pattern-recognition receptor in the inflammatory response to Helicobacter pylori infection.In the present review,we aim to highlight how the overexpression and activation of the RAGE axis contributes to the proliferation and survival of GC cells as and their acquisition of more invasive phenotypes that promote dissemination and metastasis.Finally,the contribution of some single nucleotide polymorphisms in the RAGE gene as susceptibility or poor prognosis factors is also discussed.展开更多
Prosthetic loosening and periprosthetic osteolysis have been debated for decades,both in terms of the timing and nature of the triggering events.The hypothesis of wear-particle-induced loosening states that wear parti...Prosthetic loosening and periprosthetic osteolysis have been debated for decades,both in terms of the timing and nature of the triggering events.The hypothesis of wear-particle-induced loosening states that wear particles cause a foreign-body response leading to periprosthetic osteolysis and ultimately to late prosthetic loosening,i.e.,that the osteolysis precedes the loosening.The theory of early loosening,on the other hand,postulates that the loosening is already initiated during or shortly after surgery,i.e.,that the osteolysis is secondary to the loosening.This commentary focuses on the causal relationship between prosthetic loosening and periprosthetic osteolysis.展开更多
Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial role of the receptor for advanced-glycation end-products(RAGE)in orchestrating a plethora of proinflammat...Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial role of the receptor for advanced-glycation end-products(RAGE)in orchestrating a plethora of proinflammatory cellular responses leading to many of the complications and end-organ damages reported in patients with diabetes mellitus(DM).During the coronavirus disease 2019(COVID-19)pandemic,many clinical reports have pointed out that DM increases the risk of COVID-19 complications,hospitalization requirements,as well as the overall severe acute respiratory syndrome coronavirus 2 case-fatality rate.In the present review,we intend to focus on how the basal activation state of the RAGE axis in common preexisting conditions in DM patients such as endothelial dysfunction and hyperglycemia-related prothrombotic phenotype,as well as the contribution of RAGE signaling in lung inflammation,may then lead to the increased mortality risk of COVID-19 in these patients.Additionally,the crosstalk between the RAGE axis with either another severe acute respiratory syndrome coronavirus 2 receptor molecule different of angiotensin-converting enzyme 2 or the renin-angiotensin system imbalance produced by viral infection,as well as the role of this multi-ligand receptor on the obesity-associated lowgrade inflammation in the higher risk for severe illness reported in diabetes patients with COVID-19,are also discussed.展开更多
Significant advancements have been made in understanding the cellular and molecular mechanisms of type 2 immunity in allergic diseases such as asthma,allergic rhinitis,chronic rhinosinusitis,eosinophilic esophagitis(E...Significant advancements have been made in understanding the cellular and molecular mechanisms of type 2 immunity in allergic diseases such as asthma,allergic rhinitis,chronic rhinosinusitis,eosinophilic esophagitis(EoE),food and drug allergies,and atopic dermatitis(AD).Type 2 immunity has evolved to protect against parasitic diseases and toxins,plays a role in the expulsion of parasites and larvae from inner tissues to the lumen and outside the body,maintains microbe-rich skin and mucosal epithelial barriers and counterbalances the type 1 immune response and its destructive effects.During the development of a type 2 immune response,an innate immune response initiates starting from epithelial cells and innate lymphoid cells(ILCs),including dendritic cells and macrophages,and translates to adaptive T and B-cell immunity,particularly IgE antibody production.Eosinophils,mast cells and basophils have effects on effector functions.Cytokines from ILC2s and CD4+helper type 2(Th2)cells,CD8+T cells,and NK-T cells,along with myeloid cells,including IL-4,IL-5,IL-9,and IL-13,initiate and sustain allergic inflammation via T cell cells,eosinophils,and ILC2s;promote IgE class switching;and open the epithelial barrier.Epithelial cell activation,alarmin release and barrier dysfunction are key in the development of not only allergic diseases but also many other systemic diseases.Recent biologics targeting the pathways and effector functions of IL4/IL13,IL-5,and IgE have shown promising results for almost all ages,although some patients with severe allergic diseases do not respond to these therapies,highlighting the unmet need for a more detailed and personalized approach.展开更多
基金Supported by the National Natural Science Foundation of China(No.81770889)the Natural Science Foundation of Guangdong Province(No.2018A030313428)。
文摘AIM:To explore the effects of alarmins produced by necrotic human conjunctival fibroblasts on the release of matrix metalloproteinases(MMPs)by human corneal fibroblasts(HCFs).METHODS:A necrotic cell supernatant(NHCS)was prepared by subjecting human conjunctival fibroblasts to three cycles of freezing and thawing.The amounts of interleukin(IL)-1βand tumor necrosis factor(TNF)-αin NHCS were determined by enzyme-linked immunosorbent assays.HCFs exposed to NHCS or other agents in culture were assayed for the release of MMPs as well as for intracellular signaling by immunoblot analysis.The abundance of MMP m RNAs in HCFs was examined by reverse transcription and real-time polymerase chain reaction analysis.RESULTS:NHCS increased the release of MMP-1 and MMP-3 by HCFs as well as the amounts of the corresponding m RNAs in the cells.NHCS also induced activation of mitogen-activated protein kinase(MAPK)signaling pathways mediated by extracellular signal-regulated kinase(ERK),p38,and c-Jun NH2-terminal kinase(JNK)as well as elicited that of the nuclear factor(NF)-κB signaling pathway by promoting phosphorylation of the endogenous NF-κB inhibitor IκB-α.Inhibitors of MAPK and NF-κB signaling as well as IL-1 and TNF-αreceptor antagonists attenuated the NHCS-induced release of MMP-1 and MMP-3 by HCFs.Furthermore,IL-1βand TNF-αwere both detected in NHCS,and treatment of HCFs with these cytokines induced the release of MMP-1 and MMP-3 in a concentration-dependent manner.CONCLUSION:Alarmins,including IL-1βand TNF-α,produced by necrotic human conjunctival fibroblasts triggered MMP release in HCFs through activation of MAPK and NF-κB signaling.IL-1βand TNF-αare therefore potential therapeutic targets for the amelioration of corneal stromal degradation in severe ocular burns.
基金supported by grants from the Jack Brown and Family Alzheimer’s Disease Research Foundationthe Natural Sciences and Engineering Research Council of Canada(No.2020-04407)+1 种基金the University of British Columbia Okanagan CampusThe authors also thank Gentmed SIA for financial assistance。
文摘Neuroinflammation contributes to a wide range of neurodegenerative diseases including Alzheimer's disease,Parkinson's disease,Huntington's disease,and multiple sclerosis.It is driven by non-neuronal glial cells,mainly microglia and astrocytes.Microglia are the resident immune cells of the central nervous system,while astrocytes are the main support cells for neuronal functions but can also participate in neuroimmune responses.Both these glial cell types can become reactive upon detection of certain endogenous intracellular molecules that appear in the extracellular space under specific circumstances;these can be pathology-associated abnormal structures,such as amyloidβproteins,or damage-associated molecular patterns released from injured cells,including their mitochondria.Once in the extracellular space,damage-associated molecular patterns act as ligands for specific pattern recognition receptors expressed by glia inducing their reactivity and neuroimmune responses.This review considers the following mitochondrial damage-associated molecular patterns:heme,cytochrome c,cardiolipin,adenosine triphosphate,mitochondrial DNA,mitochondrial transcription factor A,N-formyl peptides,and the tricarboxylic acid cycle metabolites:succinate,fumarate,and itaconate.We describe their well-established functions as damage-associated molecular patterns of the peripheral tissues before summarizing available evidence indicating these molecules may also play significant roles in the neuroimmune processes of the central nervous system.We highlight the pattern recognition receptors that mitochondrial damage-associated molecular patterns interact with and the cellular signaling mechanisms they modulate.Our review demonstrates that some mitochondrial damage-associated molecular patterns,such as cytochrome c,adenosine triphosphate,and mitochondrial transcription factor A,have already demonstrated significant effects on the central nervous system.In contrast,others including cardiolipin,mitochondrial DNA,N-formyl peptides,succinate,fumarate,and itaconate,will require additional studies corroborating their roles as damageassociated molecular patterns in the central nervous system.For all of the reviewed mitochondrial damage-associated molecular patterns,there is a shortage of studies using human cells and tissues,which is identified as a significant knowledge gap.We also assess the need for targeted research on the effects of mitochondrial damage-associated molecular patterns in the central nervous system pathologies where their roles are understudied.Such studies could identify novel treatment strategies for multiple neurodegenerative diseases,which are characterized by chronic neuroinflammation and currently lack effective therapies.
基金supported by the Romanian Academy and in part by a grant from the Romanian National Authority for Scientific Research and Innovation,CCCDI-UEFISCDI project COFUND-ERA-CVD-XploreCAD,No.41/2018 within PNCDI III.
文摘Background and Aims:Nonalcoholic fatty liver disease(NAFLD)includes a range of progressive disorders generated by excess lipid accumulation in the liver leading to hepatic steatosis and eventually fibrosis.We aimed to identify by high performance mass spectrometry-based proteomics the main signaling pathways and liver proteome changes induced by hypercholesterolemia in a rabbit atherosclerotic model that induced high accumulation of lipids in the liver.Methods:The effect of combined lipid-lowering drugs(statins and anti-PCSK9 monoclonal antibody)were used after the interruption of the hypercholesterolemic diet to identify also the potential mediators,such as alarmins,responsible for the irreversible NAFLD build up under the hyperlipidemic sustained stress.Results:Proteomic analysis revealed a number of proteins whose abundance was altered.They were components of metabolic pathways including fatty-acid degradation,glycolysis/gluconeogenesis,and nonalcoholic fatty liver disease.Mitochondrial dysfunction indicated alteration at the mitochondrial respiratory chain level and down-regulation of NADH:ubiquinone oxidoreductase.The expression of a majority of cytochromes(P4502E1,b5,and c)were up-regulated by lipid-lowering treatment.Long-term hyperlipidemic stress,even with a low-fat diet and lipid-lowering treatment,was accompanied by alarmin release(annexins,galectins,HSPs,HMGB1,S100 proteins,calreticulin,and fibronectin)that generated local inflammation and induced liver steatosis and aggressive fibrosis(by high abundance of galectin 3,fibronectin,and calreticulin).Conclusions:The novel findings of this study were related to the residual effects of hyperlipidemic stress with consistent,combined lipid-lowering treatment with statin and inhibitor of PCSK9.
文摘Our immune system is based on the close collaboration of the innate and adaptive immune systems for the rapid detection of any threats to the host. Recognition of pathogen-derived molecules is entrusted to specific germline- encoded signaling receptors. The same receptors have now also emerged as efficient detectors of misplaced or altered self-molecules that signal tissue damage and cell death following, for example, disruption of the blood supply and subsequent hypoxia. Many types of endogenous molecules have been shown to provoke such sterile inflammatory states when released from dying cells. However, a group of proteins referred to as alarmins have both intracellular and extracellular functions which have been the subject of intense research. Indeed, alarmins can either exert beneficial cell housekeeping functions, leading to tissue repair, or provoke deleterious uncontrolled inflammation. This group of proteins includes the high-mobility group box 1 protein （HMGB1）, interleukin （IL）-1α, IL-33 and the Ca^2＋-binding S100 proteins. These dual-function proteins share conserved regulatory mechanisms, such as secretory routes, post-translational modifications and enzymatic processing, that govern their extracellular functions in time and space. Release of alarmins from mesenchymal cells is a highly relevant mechanism by which immune cells can be alerted of tissue damage, and alarmins play a key role in the development of acute or chronic inflammatory diseases and in cancer development.
文摘Compelling evidence supports the crucial role of the receptor for advanced glycation end-products(RAGE)axis activation in many clinical entities.Since the beginning of the coronavirus disease 2019 pandemic,there is an increasing concern about the risk and handling of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection in inflammatory gastrointestinal disorders,such as inflammatory bowel diseases(IBD).However,clinical data raised during pandemic suggests that IBD patients do not have an increased risk of contracting SARS-CoV-2 infection or develop a more severe course of infection.In the present review,we intend to highlight how two potentially important contributors to the inflammatory response to SARS-CoV-2 infection in IBD patients,the RAGE axis activation as well as the cross-talk with the renin-angiotensin system,are dampened by the high expression of soluble forms of both RAGE and the angiotensin-converting enzyme(ACE)2.The soluble form of RAGE functions as a decoy for its ligands,and soluble ACE2 seems to be an additionally attenuating contributor to RAGE axis activation,particularly by avoiding the transactivation of the RAGE axis that can be produced by the virus-mediated imbalance of the ACE/angiotensin II/angiotensin II receptor type 1 pathway.
基金Supported by the Ministry of Education,Science and Technological Development,Republic of Serbia,No.451-03-68/2020-14/200015.
文摘Mesenchymal stromal/stem cells(MSCs)are adult stem cells of stromal origin that possess self-renewal capacity and the ability to differentiate into multiple mesodermal cell lineages.They play a critical role in tissue homeostasis and wound healing,as well as in regulating the inammatory microenvironment through interactions with immune cells.Hence,MSCs have garnered great attention as promising candidates for tissue regeneration and cell therapy.Because the inflammatory niche plays a key role in triggering the reparative and immunomodulatory functions of MSCs,priming of MSCs with bioactive molecules has been proposed as a way to foster the therapeutic potential of these cells.In this paper,we review how soluble mediators of the inflammatory niche(cytokines and alarmins)influence the regenerative and immunomodulatory capacity of MSCs,highlighting the major advantages and concerns regarding the therapeutic potential of these inflammatory primed MSCs.The data summarized in this review may provide a significant starting point for future research on priming MSCs and establishing standardized methods for the application of preconditioned MSCs in cell therapy.
文摘Compelling shreds of evidence derived from both clinical and experimental research have demonstrated the crucial contribution of receptor for advanced glycation end products(RAGE)axis activation in the development of neoplasms,including gastric cancer(GC).This new actor in tumor biology plays an important role in the onset of a crucial and long-lasting inflammatory milieu,not only by supporting phenotypic changes favoring growth and dissemination of tumor cells,but also by functioning as a pattern-recognition receptor in the inflammatory response to Helicobacter pylori infection.In the present review,we aim to highlight how the overexpression and activation of the RAGE axis contributes to the proliferation and survival of GC cells as and their acquisition of more invasive phenotypes that promote dissemination and metastasis.Finally,the contribution of some single nucleotide polymorphisms in the RAGE gene as susceptibility or poor prognosis factors is also discussed.
文摘Prosthetic loosening and periprosthetic osteolysis have been debated for decades,both in terms of the timing and nature of the triggering events.The hypothesis of wear-particle-induced loosening states that wear particles cause a foreign-body response leading to periprosthetic osteolysis and ultimately to late prosthetic loosening,i.e.,that the osteolysis precedes the loosening.The theory of early loosening,on the other hand,postulates that the loosening is already initiated during or shortly after surgery,i.e.,that the osteolysis is secondary to the loosening.This commentary focuses on the causal relationship between prosthetic loosening and periprosthetic osteolysis.
文摘Compelling pieces of evidence derived from both clinical and experimental research has demonstrated the crucial role of the receptor for advanced-glycation end-products(RAGE)in orchestrating a plethora of proinflammatory cellular responses leading to many of the complications and end-organ damages reported in patients with diabetes mellitus(DM).During the coronavirus disease 2019(COVID-19)pandemic,many clinical reports have pointed out that DM increases the risk of COVID-19 complications,hospitalization requirements,as well as the overall severe acute respiratory syndrome coronavirus 2 case-fatality rate.In the present review,we intend to focus on how the basal activation state of the RAGE axis in common preexisting conditions in DM patients such as endothelial dysfunction and hyperglycemia-related prothrombotic phenotype,as well as the contribution of RAGE signaling in lung inflammation,may then lead to the increased mortality risk of COVID-19 in these patients.Additionally,the crosstalk between the RAGE axis with either another severe acute respiratory syndrome coronavirus 2 receptor molecule different of angiotensin-converting enzyme 2 or the renin-angiotensin system imbalance produced by viral infection,as well as the role of this multi-ligand receptor on the obesity-associated lowgrade inflammation in the higher risk for severe illness reported in diabetes patients with COVID-19,are also discussed.
文摘Significant advancements have been made in understanding the cellular and molecular mechanisms of type 2 immunity in allergic diseases such as asthma,allergic rhinitis,chronic rhinosinusitis,eosinophilic esophagitis(EoE),food and drug allergies,and atopic dermatitis(AD).Type 2 immunity has evolved to protect against parasitic diseases and toxins,plays a role in the expulsion of parasites and larvae from inner tissues to the lumen and outside the body,maintains microbe-rich skin and mucosal epithelial barriers and counterbalances the type 1 immune response and its destructive effects.During the development of a type 2 immune response,an innate immune response initiates starting from epithelial cells and innate lymphoid cells(ILCs),including dendritic cells and macrophages,and translates to adaptive T and B-cell immunity,particularly IgE antibody production.Eosinophils,mast cells and basophils have effects on effector functions.Cytokines from ILC2s and CD4+helper type 2(Th2)cells,CD8+T cells,and NK-T cells,along with myeloid cells,including IL-4,IL-5,IL-9,and IL-13,initiate and sustain allergic inflammation via T cell cells,eosinophils,and ILC2s;promote IgE class switching;and open the epithelial barrier.Epithelial cell activation,alarmin release and barrier dysfunction are key in the development of not only allergic diseases but also many other systemic diseases.Recent biologics targeting the pathways and effector functions of IL4/IL13,IL-5,and IgE have shown promising results for almost all ages,although some patients with severe allergic diseases do not respond to these therapies,highlighting the unmet need for a more detailed and personalized approach.
