Pub Date : 2024-08-31DOI: 10.1016/j.intimp.2024.112983
Diabetic foot ulcers (DFUs) are serious skin injuries whereby the wound healing process is frequently stalled in the inflammatory phase. Currently, there is a lack of effective therapeutic strategies. MCC950, a highly selective nod-like receptor family pyrin domain containing 3 (NLRP3) inhibitor, has been reported to show strong anti-inflammation effects in many diseases. In this study, we unveiled the role of MCC950 in DFU mice model and its underlying molecular mechanisms. MCC950 could significantly accelerate diabetic wound healing, as shown by shortened healing time and better healing quality. Moreover, increased M2 phenotype macrophages and decreased pro-inflammatory genes were observed in MCC950-treated DFU mice. Additionally, myeloid-derived suppressor cells (MDSCs) were significantly increased in blood, spleen and wound tissues at different time courses. Specifically, MCC950 could recruit more MDSCs in an early phase in DFU mice, exerting an anti-inflammation effect. We identified the cell crosstalk between macrophages and MDSCs with MCC950 treatment process. Depleting MDSCs in vivo could eliminate the therapeutic effect of MCC950 on diabetic wound healing through inhibiting M2 macrophage polarization. Besides, MDSCs isolated from the wounds of MCC950 or saline treated mice were cocultured with bone marrow derived macrophage (BMDM) in a transwell system. Results confirmed that MDSCs sorted from MCC950 treated mice caused a significant increased percentage of M2 macrophages. Collectively, our findings suggest that the administration of MCC950 has the potential to accelerate diabetic wound healing by promoting M2 macrophage polarization in an MDSC-dependent manner. This study provides valuable insights into the utilization of pharmacological agents for DFU treatment.
{"title":"MCC950 promotes diabetic wound healing through modulating macrophage polarization in an MDSC-dependent manner","authors":"","doi":"10.1016/j.intimp.2024.112983","DOIUrl":"10.1016/j.intimp.2024.112983","url":null,"abstract":"<div><p>Diabetic foot ulcers (DFUs) are serious skin injuries whereby the wound healing process is frequently stalled in the inflammatory phase. Currently, there is a lack of effective therapeutic strategies. MCC950, a highly selective nod-like receptor family pyrin domain containing 3 (NLRP3) inhibitor, has been reported to show strong anti-inflammation effects in many diseases. In this study, we unveiled the role of MCC950 in DFU mice model and its underlying molecular mechanisms. MCC950 could significantly accelerate diabetic wound healing, as shown by shortened healing time and better healing quality. Moreover, increased M2 phenotype macrophages and decreased pro-inflammatory genes were observed in MCC950-treated DFU mice. Additionally, myeloid-derived suppressor cells (MDSCs) were significantly increased in blood, spleen and wound tissues at different time courses. Specifically, MCC950 could recruit more MDSCs in an early phase in DFU mice, exerting an anti-inflammation effect. We identified the cell crosstalk between macrophages and MDSCs with MCC950 treatment process. Depleting MDSCs in vivo could eliminate the therapeutic effect of MCC950 on diabetic wound healing through inhibiting M2 macrophage polarization. Besides, MDSCs isolated from the wounds of MCC950 or saline treated mice were cocultured with bone marrow derived macrophage (BMDM) in a transwell system. Results confirmed that MDSCs sorted from MCC950 treated mice caused a significant increased percentage of M2 macrophages. Collectively, our findings suggest that the administration of MCC950 has the potential to accelerate diabetic wound healing by promoting M2 macrophage polarization in an MDSC-dependent manner. This study provides valuable insights into the utilization of pharmacological agents for DFU treatment.</p></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1567576924015042/pdfft?md5=abbae5a8cf8cd4e946ca0ef5561879ce&pid=1-s2.0-S1567576924015042-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142098720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1016/j.intimp.2024.113011
Depression is a serious mental disorder that threatens patients’ physical and mental health worldwide. The activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome is essential for microglia-mediated neuroinflammation and neuronal damage in depression. Numerous pathophysiological factors, such as mitochondrial dysfunction and impaired mitophagy, have an essential role in activating the NLRP3 inflammasome. AdipoRon is a potent adiponectin receptor agonist; however, its antidepressant effects have not been thoroughly investigated. In this study, we found that AdipoRon ameliorated depression-like behavior and neuronal damage induced by chronic unpredictable mild stress (CUMS). Further research demonstrated that AdipoRon inhibited the activation of the NLRP3 inflammasome and protected hippocampal neurons from microglial cytotoxicity by promoting mitophagy, increasing the clearance of damaged mitochondria, and reducing mtROS accumulation. Importantly, inhibition of mitophagy attenuated the antidepressant and neuroprotective effects of AdipoRon. Overall, these findings indicate that AdipoRon alleviates depression by inhibiting NLRP3 inflammasome activation in microglia via improving mitophagy.
{"title":"AdipoRon exerts an antidepressant effect by inhibiting NLRP3 inflammasome activation in microglia via promoting mitophagy","authors":"","doi":"10.1016/j.intimp.2024.113011","DOIUrl":"10.1016/j.intimp.2024.113011","url":null,"abstract":"<div><p>Depression is a serious mental disorder that threatens patients’ physical and mental health worldwide. The activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome is essential for microglia-mediated neuroinflammation and neuronal damage in depression. Numerous pathophysiological factors, such as mitochondrial dysfunction and impaired mitophagy, have an essential role in activating the NLRP3 inflammasome. AdipoRon is a potent adiponectin receptor agonist; however, its antidepressant effects have not been thoroughly investigated. In this study, we found that AdipoRon ameliorated depression-like behavior and neuronal damage induced by chronic unpredictable mild stress (CUMS). Further research demonstrated that AdipoRon inhibited the activation of the NLRP3 inflammasome and protected hippocampal neurons from microglial cytotoxicity by promoting mitophagy, increasing the clearance of damaged mitochondria, and reducing mtROS accumulation. Importantly, inhibition of mitophagy attenuated the antidepressant and neuroprotective effects of AdipoRon. Overall, these findings indicate that AdipoRon alleviates depression by inhibiting NLRP3 inflammasome activation in microglia via improving mitophagy.</p></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142097186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1016/j.intimp.2024.113043
Objective
Limited research has focused on the role of dihydrouridine synthases (DUS) family members in human tumors. Our previous findings indicated an impact of dihydrouridine synthase 4 like (DUS4L) on cell proliferation and apoptosis in lung adenocarcinoma (LUAD) A549 cell, yet its broader functions and regulatory mechanisms in LUAD remain elusive.
Methods
Using a LUAD tissue microarray and immunohistochemical (IHC) staining, we validated variations in DUS4L protein expression levels among LUAD patients and assessed its clinical significance. Additional experiments using short hairpin RNA (shRNA) against DUS4L (sh-DUS4L-2), LUAD cell lines, cell function assays (including wound healing, transwell migration and invasion, colony formation, and apoptosis assays), and mouse tumor xenografts were performed to examine the biological roles of DUS4L in LUAD progression. RNA sequencing, proteomic analyses, mass spectrometry, and co-immunoprecipitation experiments were conducted to identify and validate DUS4L-regulated downstream target genes and signaling pathways.
Results
We identified a consistent upregulation of DUS4L in LUAD tissues. In vitro and in vivo experiments underscored the inhibitory effect of DUS4L downregulation on LUAD progression, including migration, invasion, and proliferation. Mechanistically, DUS4L was found to interact with the signaling molecule GRB2, promoting LUAD progression and metastasis by inducing epithelial-mesenchymal transition (EMT) via the PI3K/AKT and ERK/MAPK pathways.
Conclusion
Our results establish the functional role of DUS4L in driving the progression and metastasis of LUAD, implicating its potential as a candidate therapeutic target for LUAD.
{"title":"DUS4L suppresses invasion and metastasis in LUAD via modulation of PI3K/AKT and ERK/MAPK signaling through GRB2","authors":"","doi":"10.1016/j.intimp.2024.113043","DOIUrl":"10.1016/j.intimp.2024.113043","url":null,"abstract":"<div><h3>Objective</h3><p>Limited research has focused on the role of dihydrouridine synthases (DUS) family members in human tumors. Our previous findings indicated an impact of dihydrouridine synthase 4 like (DUS4L) on cell proliferation and apoptosis in lung adenocarcinoma (LUAD) A549 cell, yet its broader functions and regulatory mechanisms in LUAD remain elusive.</p></div><div><h3>Methods</h3><p>Using a LUAD tissue microarray and immunohistochemical (IHC) staining, we validated variations in DUS4L protein expression levels among LUAD patients and assessed its clinical significance. Additional experiments using short hairpin RNA (shRNA) against DUS4L (sh-DUS4L-2), LUAD cell lines, cell function assays (including wound healing, transwell migration and invasion, colony formation, and apoptosis assays), and mouse tumor xenografts were performed to examine the biological roles of DUS4L in LUAD progression. RNA sequencing, proteomic analyses, mass spectrometry, and co-immunoprecipitation experiments were conducted to identify and validate DUS4L-regulated downstream target genes and signaling pathways.</p></div><div><h3>Results</h3><p>We identified a consistent upregulation of DUS4L in LUAD tissues. In vitro and in vivo experiments underscored the inhibitory effect of DUS4L downregulation on LUAD progression, including migration, invasion, and proliferation. Mechanistically, DUS4L was found to interact with the signaling molecule GRB2, promoting LUAD progression and metastasis by inducing epithelial-mesenchymal transition (EMT) via the PI3K/AKT and ERK/MAPK pathways.</p></div><div><h3>Conclusion</h3><p>Our results establish the functional role of DUS4L in driving the progression and metastasis of LUAD, implicating its potential as a candidate therapeutic target for LUAD.</p></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1567576924015649/pdfft?md5=aa638c11e91724a24f2aad8c4b51d1c5&pid=1-s2.0-S1567576924015649-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142098709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1016/j.intimp.2024.113039
Ulcerative colitis (UC) poses a threat to human health. The present study attempts to unravel the efficacy and potential mechanisms of paeoniflorin (PF), a naturally sourced active ingredient, for the management of UC. By establishing a DSS (dextran sulphate sodium)-induced experimental rat model of UC, this study found that PF was effective in ameliorating UC symptoms, inhibiting oxidative stress, inflammation and apoptosis, and repairing colonic epithelial damage. In addition, metabolomics revealed that PF may alleviate UC by primarily improving linoleic acid metabolism. Mechanistically, PF inhibited the CDC42/JNK signaling pathway by targeting CDC42. In particular, HuProtTM20K proteomics, molecular docking and MST revealed that PF is a novel CDC42 inhibitor. In LPS-treated Caco-2 cells, PF similarly inhibited oxidative stress, inflammation, and apoptosis and down-regulated the CDC42/JNK signaling pathway. Overall, PF inhibits oxidative stress, inflammation and apoptosis and repairs colonic epithelial damage through modulation of serum metabolites and inhibition of the CDC42/JNK signaling pathway, leading to alleviation of UC.
{"title":"Paeoniflorin alleviates DSS-induced ulcerative colitis by suppressing inflammation, oxidative stress, and apoptosis via regulating serum metabolites and inhibiting CDC42/JNK signaling pathway","authors":"","doi":"10.1016/j.intimp.2024.113039","DOIUrl":"10.1016/j.intimp.2024.113039","url":null,"abstract":"<div><p>Ulcerative colitis (UC) poses a threat to human health. The present study attempts to unravel the efficacy and potential mechanisms of paeoniflorin (PF), a naturally sourced active ingredient, for the management of UC. By establishing a DSS (dextran sulphate sodium)-induced experimental rat model of UC, this study found that PF was effective in ameliorating UC symptoms, inhibiting oxidative stress, inflammation and apoptosis, and repairing colonic epithelial damage. In addition, metabolomics revealed that PF may alleviate UC by primarily improving linoleic acid metabolism. Mechanistically, PF inhibited the CDC42/JNK signaling pathway by targeting CDC42. In particular, HuProtTM20K proteomics, molecular docking and MST revealed that PF is a novel CDC42 inhibitor. In LPS-treated Caco-2 cells, PF similarly inhibited oxidative stress, inflammation, and apoptosis and down-regulated the CDC42/JNK signaling pathway. Overall, PF inhibits oxidative stress, inflammation and apoptosis and repairs colonic epithelial damage through modulation of serum metabolites and inhibition of the CDC42/JNK signaling pathway, leading to alleviation of UC.</p></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142098710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1016/j.intimp.2024.113027
Objective
This study aimed to elucidate the causal relationships between antibodies and autoimmune diseases using Mendelian randomization (MR).
Methods
Data on 46 antibodies were obtained from genome-wide association studies (GWAS). Autoimmune disease data were sourced from the FinnGen consortium and the IEU OpenGWAS project. Inverse-variance weighted (IVW) analysis was the primary method, supplemented by heterogeneity and sensitivity analyses. We also examined gene expression near significant SNPs and conducted drug sensitivity analyses.
Results
Antibodies and autoimmune diseases exhibit diverse interactions. Antibodies produced after Polyomavirus infection tend to increase the risk of several autoimmune diseases, while those following Human herpesvirus 6 infection generally reduce it. The impact of Helicobacter pylori infection varies, with different antibodies affecting autoimmune diseases in distinct ways. Overall, antibodies significantly influence the risk of developing autoimmune diseases, whereas autoimmune diseases have a lesser impact on antibody levels. Gene expression and drug sensitivity analyses identified multiple genes and drugs as potential treatment options for ankylosing spondylitis (AS), with the AIF1 gene being particularly promising.
Conclusions
Bidirectional MR analysis confirms complex causal relationships between various antibodies and autoimmune diseases, revealing intricate patterns of post-infection antibody interactions. Several drugs and genes, notably AIF1, show potential as candidates for AS treatment, offering new avenues for research. Further exploration of the underlying mechanisms is necessary.
方法 46种抗体的数据来自全基因组关联研究(GWAS)。46种抗体的数据来自全基因组关联研究(GWAS),自身免疫性疾病的数据来自FinnGen联盟和IEU OpenGWAS项目。反方差加权(IVW)分析是主要方法,并辅以异质性和敏感性分析。我们还检测了重要 SNP 附近的基因表达,并进行了药物敏感性分析。感染多瘤病毒后产生的抗体往往会增加罹患多种自身免疫性疾病的风险,而感染人类疱疹病毒 6 后产生的抗体通常会降低罹患风险。幽门螺旋杆菌感染的影响也各不相同,不同的抗体对自身免疫性疾病的影响方式也不同。总体而言,抗体对自身免疫性疾病的发病风险影响很大,而自身免疫性疾病对抗体水平的影响较小。结论双向磁共振分析证实了各种抗体与自身免疫性疾病之间复杂的因果关系,揭示了感染后抗体相互作用的复杂模式。一些药物和基因,特别是 AIF1,显示出治疗强直性脊柱炎的潜力,为研究提供了新的途径。有必要进一步探索其潜在机制。
{"title":"Elucidating the causal nexus between antibody-mediated immunity and autoimmune diseases: Insights from bidirectional mendelian randomization, gene expression profiling, and drug sensitivity analysis","authors":"","doi":"10.1016/j.intimp.2024.113027","DOIUrl":"10.1016/j.intimp.2024.113027","url":null,"abstract":"<div><h3>Objective</h3><p>This study aimed to elucidate the causal relationships between antibodies and autoimmune diseases using Mendelian randomization (MR).</p></div><div><h3>Methods</h3><p>Data on 46 antibodies were obtained from genome-wide association studies (GWAS). Autoimmune disease data were sourced from the FinnGen consortium and the IEU OpenGWAS project. Inverse-variance weighted (IVW) analysis was the primary method, supplemented by heterogeneity and sensitivity analyses. We also examined gene expression near significant SNPs and conducted drug sensitivity analyses.</p></div><div><h3>Results</h3><p>Antibodies and autoimmune diseases exhibit diverse interactions. Antibodies produced after Polyomavirus infection tend to increase the risk of several autoimmune diseases, while those following Human herpesvirus 6 infection generally reduce it. The impact of Helicobacter pylori infection varies, with different antibodies affecting autoimmune diseases in distinct ways. Overall, antibodies significantly influence the risk of developing autoimmune diseases, whereas autoimmune diseases have a lesser impact on antibody levels. Gene expression and drug sensitivity analyses identified multiple genes and drugs as potential treatment options for ankylosing spondylitis (AS), with the AIF1 gene being particularly promising.</p></div><div><h3>Conclusions</h3><p>Bidirectional MR analysis confirms complex causal relationships between various antibodies and autoimmune diseases, revealing intricate patterns of post-infection antibody interactions. Several drugs and genes, notably AIF1, show potential as candidates for AS treatment, offering new avenues for research. Further exploration of the underlying mechanisms is necessary.</p></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142098711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1016/j.intimp.2024.113022
Cholinergic circuit defects have been linked to various neurological abnormalities, yet the precise mechanisms underlying the impact of cholinergic signaling on cognitive functions, particularly in the context of neuroinflammation-associated, remain poorly understood. Similarly, while the dopamine receptor (D2R) has been implicated in the pausing of cholinergic interneurons (CIN), its relationship with behavior remains inadequately elucidated. In this study, we aimed to investigate whether D2R plays a role in the regulation of fear and memory in the Hsp60 knockout condition, given the non-canonical involvement of Hsp60 in inflammation. Using a CRE-floxed system, we selectively generated cholinergic neurons specific to Hsp60 knockout mice and subjected them to memory tests. Our results revealed a significant increase in freezing levels during recall and contextual tests in Hsp60-deprived mice. We also observed dysregulation of neurotransmitters and D2R in the hippocampus of Hsp60 knockout mice, along with enhanced impairments in cytokine levels and synaptic protein dysregulations. These changes were accompanied by alterations in PI3K/eIF4E/Jak/ERK/CREB signaling pathways. Notably, D2R agonism via Quinpirole led to a decrease in freezing levels during recall and contextual tests, alongside an increase in IBA-1 expression and improvements in inflammatory response-linked signaling pathways, including JAK/STAT/P38/JNK impairments. Given that these pathways are well-known downstream signaling cascades of D2R, our findings suggest that D2R signaling may contribute to the neuroinflammation induced by Hsp60 deprivation, potentially exacerbating memory impairments.
{"title":"Hsp60 deletion in cholinergic neurons: Impact on neuroinflammation and memory","authors":"","doi":"10.1016/j.intimp.2024.113022","DOIUrl":"10.1016/j.intimp.2024.113022","url":null,"abstract":"<div><p>Cholinergic circuit defects have been linked to various neurological abnormalities, yet the precise mechanisms underlying the impact of cholinergic signaling on cognitive functions, particularly in the context of neuroinflammation-associated, remain poorly understood. Similarly, while the dopamine receptor (D2R) has been implicated in the pausing of cholinergic interneurons (CIN), its relationship with behavior remains inadequately elucidated. In this study, we aimed to investigate whether D2R plays a role in the regulation of fear and memory in the Hsp60 knockout condition, given the non-canonical involvement of Hsp60 in inflammation. Using a CRE-floxed system, we selectively generated cholinergic neurons specific to Hsp60 knockout mice and subjected them to memory tests. Our results revealed a significant increase in freezing levels during recall and contextual tests in Hsp60-deprived mice. We also observed dysregulation of neurotransmitters and D2R in the hippocampus of Hsp60 knockout mice, along with enhanced impairments in cytokine levels and synaptic protein dysregulations. These changes were accompanied by alterations in PI3K/eIF4E/Jak/ERK/CREB signaling pathways. Notably, D2R agonism via Quinpirole led to a decrease in freezing levels during recall and contextual tests, alongside an increase in IBA-1 expression and improvements in inflammatory response-linked signaling pathways, including JAK/STAT/P38/JNK impairments. Given that these pathways are well-known downstream signaling cascades of D2R, our findings suggest that D2R signaling may contribute to the neuroinflammation induced by Hsp60 deprivation, potentially exacerbating memory impairments.</p></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142097189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1016/j.intimp.2024.113018
Jeong-Won Kim, Ji-Soo Jeong, Jin-Hwa Kim, Chang-Yeop Kim, Eun-Hye Chung, Je-Won Ko, Tae-Won Kim
Turmeric (Curcuma longa L.) extract (CLE) has been shown to elicit several pharmacological properties and is widely used in Asian traditional medicine. Herein, we assessed the impact of CLE on airway inflammation in BALB/c mice and A549 cells to clarify the underlying mechanism. An asthmatic mouse model was established by administering ovalbumin (OVA). CLE (100 or 300 mg/kg/day) was orally administered daily from days 18 to 23, with dexamethasone (3 mg/kg/day) used as the positive control. Human airway epithelial cells, A549, were stimulated using recombinant tumor necrosis factor-α. The CLE100 and CLE400 groups exhibited a significant downregulation in eosinophil counts, cytokine levels, and immunoglobulin-E levels. Moreover, CLE administration dose-dependently suppressed oxidative stress and airway inflammation in the lung tissue. CLE administration inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs) and the expression and activity of matrix metalloproteinase (MMP)-9. In vitro, CLE treatment reduced mRNA levels of proinflammatory cytokines, MAPK phosphorylation, and the expression and activity of MMP-2 and MMP-9. Additionally, 50 µg/mL CLE and 2.5 µg/mL curcumin showed similar anti-inflammatory effects. Collectively, our findings revealed that CLE could suppress airway inflammation in asthmatic mice and A549 cells via oxidative stress-driven MAPK/MMPs signaling, suggesting that CLE could be developed as a potential treatment option for patients with asthma.
{"title":"Turmeric extract alleviates airway inflammation via oxidative stress-driven MAPKs/MMPs pathway.","authors":"Jeong-Won Kim, Ji-Soo Jeong, Jin-Hwa Kim, Chang-Yeop Kim, Eun-Hye Chung, Je-Won Ko, Tae-Won Kim","doi":"10.1016/j.intimp.2024.113018","DOIUrl":"https://doi.org/10.1016/j.intimp.2024.113018","url":null,"abstract":"<p><p>Turmeric (Curcuma longa L.) extract (CLE) has been shown to elicit several pharmacological properties and is widely used in Asian traditional medicine. Herein, we assessed the impact of CLE on airway inflammation in BALB/c mice and A549 cells to clarify the underlying mechanism. An asthmatic mouse model was established by administering ovalbumin (OVA). CLE (100 or 300 mg/kg/day) was orally administered daily from days 18 to 23, with dexamethasone (3 mg/kg/day) used as the positive control. Human airway epithelial cells, A549, were stimulated using recombinant tumor necrosis factor-α. The CLE100 and CLE400 groups exhibited a significant downregulation in eosinophil counts, cytokine levels, and immunoglobulin-E levels. Moreover, CLE administration dose-dependently suppressed oxidative stress and airway inflammation in the lung tissue. CLE administration inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs) and the expression and activity of matrix metalloproteinase (MMP)-9. In vitro, CLE treatment reduced mRNA levels of proinflammatory cytokines, MAPK phosphorylation, and the expression and activity of MMP-2 and MMP-9. Additionally, 50 µg/mL CLE and 2.5 µg/mL curcumin showed similar anti-inflammatory effects. Collectively, our findings revealed that CLE could suppress airway inflammation in asthmatic mice and A549 cells via oxidative stress-driven MAPK/MMPs signaling, suggesting that CLE could be developed as a potential treatment option for patients with asthma.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1016/j.intimp.2024.113029
Autoimmune hemolytic anemia (AIHA) is a heterogeneous group of diseases mediated by autoantibody directed against RBCs causing hemolysis and anemia. AIHA develops rapidly or over time, depending on the triggering factor. Desidustat is a prolyl hydroxylase inhibitor clinically used for the treatment of chronic kidney disease (CKD)-induced anemia. In this study, we investigated the effect of desidustat in preclinical model of AIHA. We used rat RBC for induction of AIHA in mice. These mice were then treated with desidustat (15 mg/kg, PO, once a day) for eight weeks. Desidustat treatment increased hemoglobin, RBC and hematocrit and decreased WBC and lymphocytes. This treatment suppressed serum LDH, oxidative stress in RBCs, antibody titer and antibody deposition on RBC surface, and increased RBC lifespan. Serum and spleen iron along with spleen mass and oxidative stress were decreased by desidustat. Bone marrow iron was increased and expression of CD71 (cell surface marker for early erythroid progenitor) and TER-119 (cell surface marker for late erythroid progenitor) in bone marrow were found to be elevated by desidustat by treatment. This treatment also suppressed deposition of membrane-bound antibody in late erythroid cells. The treatment showed reduction in total splenic cells, CD71 and TER-119 positive cells in the spleen. Thus, desidustat treatment increased erythropoiesis, early maturation of bone marrow erythroid cells having longer RBC life span due to decrease in the antibody-mediated lysis of RBCs and its progenitors leading to reduced oxidative stress. Thus, desidustat can be a good therapeutic option for treatment of AIHA.
{"title":"Prolyl hydroxylase inhibitor desidustat attenuates autoimmune hemolytic anemia in mice","authors":"","doi":"10.1016/j.intimp.2024.113029","DOIUrl":"10.1016/j.intimp.2024.113029","url":null,"abstract":"<div><p>Autoimmune hemolytic anemia (AIHA) is a heterogeneous group of diseases mediated by autoantibody directed against RBCs causing hemolysis and anemia. AIHA develops rapidly or over time, depending on the triggering factor. Desidustat is a prolyl hydroxylase inhibitor clinically used for the treatment of chronic kidney disease (CKD)-induced anemia. In this study, we investigated the effect of desidustat in preclinical model of AIHA. We used rat RBC for induction of AIHA in mice. These mice were then treated with desidustat (15 mg/kg, PO, once a day) for eight weeks. Desidustat treatment increased hemoglobin, RBC and hematocrit and decreased WBC and lymphocytes. This treatment suppressed serum LDH, oxidative stress in RBCs, antibody titer and antibody deposition on RBC surface, and increased RBC lifespan. Serum and spleen iron along with spleen mass and oxidative stress were decreased by desidustat. Bone marrow iron was increased and expression of CD71 (cell surface marker for early erythroid progenitor) and TER-119 (cell surface marker for late erythroid progenitor) in bone marrow were found to be elevated by desidustat by treatment. This treatment also suppressed deposition of membrane-bound antibody in late erythroid cells. The treatment showed reduction in total splenic cells, CD71 and TER-119 positive cells in the spleen. Thus, desidustat treatment increased erythropoiesis, early maturation of bone marrow erythroid cells having longer RBC life span due to decrease in the antibody-mediated lysis of RBCs and its progenitors leading to reduced oxidative stress. Thus, desidustat can be a good therapeutic option for treatment of AIHA.</p></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142097888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1016/j.intimp.2024.112845
Objective
To evaluate the safety and efficacy of neoadjuvant immunotherapy in patients with esophageal squamous cell carcinoma (ESCC) and construct a prognostic model.
Methods
Clinical data were retrospectively collected from patients with locally advanced ESCC who received neoadjuvant immunotherapy and chemotherapy. The primary endpoints were major pathologic remission rate and disease-free survival, and secondary endpoints were treatment-related adverse events and perioperative complications. Correlates affecting pathological response were analyzed using univariate and multivariate logistic regression, survival-related variables were screened by Boruta and least absolute shrinkage and selection operator Cox regression analysis. A nomogram was constructed and utilized to test the predictive efficacy of the treatment with receiver operating characteristic curve and decision curve analysis.
Results
A total of 181 patients were enrolled, of whom 119 (66 %) patients received 3–4 cycles of treatment. Treatment-related adverse events occurred in 65.2 % of the patients, with 13.3 % experiencing severe complications. Major pathological remission rate was achieved in 68 (37.6 %) patients, with no significant difference between the treatment cycle groups (P=0.925). The nomogram included pathologic TNM stage, lymphovascular invasion, post-treatment and post-surgery albumin levels, and post-treatment systemic immune-inflammation index. One-year disease-free survival area under the curve was 0.86 (95 %CI, 0.75–0.97) in the derivation cohort and 0.75 (95 %CI, 0.50–0.99) in the validation cohort, with good calibration performance.
Conclusions
Pathological staging combined with albumin level and systemic immune-inflammation index could be a superior predictor of survival prognosis in ESCC patients receiving neoadjuvant immunotherapy. The findings of this study yield new evidence regarding the efficacy and safety of neoadjuvant immunotherapy in ESCC and provide a tool for identifying patients at risk of recurrence.
{"title":"Efficacy, safety, and prognostic modeling in neoadjuvant immunotherapy for esophageal squamous cell carcinoma","authors":"","doi":"10.1016/j.intimp.2024.112845","DOIUrl":"10.1016/j.intimp.2024.112845","url":null,"abstract":"<div><h3>Objective</h3><p>To evaluate the safety and efficacy of neoadjuvant immunotherapy in patients with esophageal squamous cell carcinoma (ESCC) and construct a prognostic model.</p></div><div><h3>Methods</h3><p>Clinical data were retrospectively collected from patients with locally advanced ESCC who received neoadjuvant immunotherapy and chemotherapy. The primary endpoints were major pathologic remission rate and disease-free survival, and secondary endpoints were treatment-related adverse events and perioperative complications. Correlates affecting pathological response were analyzed using univariate and multivariate logistic regression, survival-related variables were screened by Boruta and least absolute shrinkage and selection operator Cox regression analysis. A nomogram was constructed and utilized to test the predictive efficacy of the treatment with receiver operating characteristic curve and decision curve analysis.</p></div><div><h3>Results</h3><p>A total of 181 patients were enrolled, of whom 119 (66 %) patients received 3–4 cycles of treatment. Treatment-related adverse events occurred in 65.2 % of the patients, with 13.3 % experiencing severe complications. Major pathological remission rate was achieved in 68 (37.6 %) patients, with no significant difference between the treatment cycle groups (<em>P</em>=0.925). The nomogram included pathologic TNM stage, lymphovascular invasion, post-treatment and post-surgery albumin levels, and post-treatment systemic immune-inflammation index. One-year disease-free survival area under the curve was 0.86 (95 %CI, 0.75–0.97) in the derivation cohort and 0.75 (95 %CI, 0.50–0.99) in the validation cohort, with good calibration performance.</p></div><div><h3>Conclusions</h3><p>Pathological staging combined with albumin level and systemic immune-inflammation index could be a superior predictor of survival prognosis in ESCC patients receiving neoadjuvant immunotherapy. The findings of this study yield new evidence regarding the efficacy and safety of neoadjuvant immunotherapy in ESCC and provide a tool for identifying patients at risk of recurrence.</p></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1567576924013663/pdfft?md5=3ecad8dc2717305bb8402fb5170e0622&pid=1-s2.0-S1567576924013663-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142098810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1016/j.intimp.2024.113036
Macrophage polarization is a key process involved in wound healing. The continuous release of proinflammatory cytokines by macrophages inhibits the healing process of chronic wounds, such as diabetic wounds. To promote wound healing, it is important to change the phenotype of resident macrophages to prevent inflammation. We previously reported that dried tangerine peel polysaccharide (DTPP) binds to and inhibits the TLR4/MD-2 complex, which is crucial for the inflammatory activation of macrophages, suggesting the potential of DTPP in wound healing applications. Both zebrafish and mouse models were used to evaluate the therapeutic efficacy of DTPP. Moreover, we found that DTPP recruited macrophages to the wound area and promoted their M2 repolarization. Using hyperglycaemic zebrafish and db/db mouse models, we discovered that DTPP accelerated wound healing in vivo in metabolic disorders. Our results suggest that DTPP promotes the recruitment of macrophages, shifts macrophages towards the anti-inflammatory M2 phenotype, and ultimately accelerates the wound healing process.
{"title":"Dried tangerine peel polysaccharide accelerates wound healing by recruiting anti-inflammatory macrophages","authors":"","doi":"10.1016/j.intimp.2024.113036","DOIUrl":"10.1016/j.intimp.2024.113036","url":null,"abstract":"<div><p>Macrophage polarization is a key process involved in wound healing. The continuous release of proinflammatory cytokines by macrophages inhibits the healing process of chronic wounds, such as diabetic wounds. To promote wound healing, it is important to change the phenotype of resident macrophages to prevent inflammation. We previously reported that dried tangerine peel polysaccharide (DTPP) binds to and inhibits the TLR4/MD-2 complex, which is crucial for the inflammatory activation of macrophages, suggesting the potential of DTPP in wound healing applications. Both zebrafish and mouse models were used to evaluate the therapeutic efficacy of DTPP. Moreover, we found that DTPP recruited macrophages to the wound area and promoted their M2 repolarization. Using hyperglycaemic zebrafish and db/db mouse models, we discovered that DTPP accelerated wound healing in vivo in metabolic disorders. Our results suggest that DTPP promotes the recruitment of macrophages, shifts macrophages towards the anti-inflammatory M2 phenotype, and ultimately accelerates the wound healing process.</p></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142098721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}