Molecular immunology最新文献

Fructus arctii mitigates diabetic nephropathy via the Apoh/PPAR-γ pathway

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-03-07 DOI: 10.1016/j.molimm.2025.02.017

Na Zhang , Anhui Chen , Yuwei Dong , Deqiang Dou

Background

Diabetic nephropathy (DN) is characterized by renal fibrosis and functional decline. Apolipoprotein H (Apoh) and Fructus arctii, a traditional medicinal plant, have demonstrated potential in treating metabolic and fibrotic disorders. This study Focused on revealing the roles of Apoh and Fructus arctii in mitigating DN.

Methods

Db/db mice served as an in vivo DN model, and mouse glomerular mesangial cells (mMCs) and renal tubular epithelial cells (mTECs) were treated with high glucose (HG) to simulate DN in vitro. Apoh silencing and overexpression were performed using shRNA and pcDNA3.1 vectors. Fructus arctii was administered to both cellular and animal models to assess its therapeutic potential. Cellular proliferation was measured using CCK-8 and EdU assays, while fibrosis markers were analyzed by Western blot, IHC and RT-qPCR. PPAR-γ pathway involvement was confirmed through treatment with the antagonist GW9662. Renal structural changes were evaluated with histological staining including H&E, PAS, Masson’s trichrome, and picrosirius red staining.

Results

Apoh expression was markedly reduced in HG-treated cells and the kidneys of db/db mice. Overexpression of Apoh suppressed HG-induced proliferation in mMCs and mTECs by downregulating cyclin D1 and PCNA. Additionally, Apoh overexpression alleviated fibrosis by reducing Fibronectin, Collagen I, and α-SMA levels, effects mediated through the PPAR-γ pathway. Treatment with the PPAR-γ antagonist GW9662 reversed these protective effects. In db/db mice, Fructus arctii administration improved renal function by reducing blood glucose, proteinuria, and renal collagen deposition. It also alleviated fibrosis and enhanced Apoh and PPAR-γ expression. Silencing Apoh nullified the protective effects of Fructus arctii on cell proliferation and fibrosis, confirming its reliance on the Apoh/PPAR-γ pathway.

Conclusion

Fructus arctii alleviated DN progression by modulating cell proliferation and renal fibrosis via the Apoh/PPAR-γ pathway.

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引用次数: 0

Cigarette smoke-exposed microparticles released from T lymphocytes contribute to autophagy and apoptosis dysfunction in pulmonary microvascular endothelial cells

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-03-05 DOI: 10.1016/j.molimm.2025.02.020

Gang Chen , Zhaoji Meng , Pei Wang

Cigarette smoke can cause dysfunction of the vascular endothelium; however, the underlying mechanisms have not been fully elucidated. We hypothesized that T lymphocyte-derived microparticles (TLMPs) are involved in cigarette-related diseases, especially those involving the vascular endothelium. The effect of cigarette smoke on the release of microparticles from human lymphocytes was investigated. The contributions of TLMPs induced by cigarette smoke to endothelial proliferation/apoptosis, autophagy and cytokine levels were also measured. Notably, the potential mechanism of autophagy and apoptosis dysfunction in endothelial cells was further examined. Cigarette smoke promoted the release of microparticles from T lymphocytes. TLMPs attenuated endothelial proliferation but promoted endothelial apoptosis/autophagy and the expression of proinflammatory cytokines, especially when T lymphocytes were preexposed to cigarette smoke. The potential mechanism may involve disorders of oxidative stress and STAT3 phosphorylation. In conclusion, cigarette smoke-exposed microparticles released from T lymphocytes contribute to autophagy and apoptosis dysfunction in pulmonary microvascular endothelial cells.

{"title":"Cigarette smoke-exposed microparticles released from T lymphocytes contribute to autophagy and apoptosis dysfunction in pulmonary microvascular endothelial cells","authors":"Gang Chen , Zhaoji Meng , Pei Wang","doi":"10.1016/j.molimm.2025.02.020","DOIUrl":"10.1016/j.molimm.2025.02.020","url":null,"abstract":"<div><div>Cigarette smoke can cause dysfunction of the vascular endothelium; however, the underlying mechanisms have not been fully elucidated. We hypothesized that T lymphocyte-derived microparticles (TLMPs) are involved in cigarette-related diseases, especially those involving the vascular endothelium. The effect of cigarette smoke on the release of microparticles from human lymphocytes was investigated. The contributions of TLMPs induced by cigarette smoke to endothelial proliferation/apoptosis, autophagy and cytokine levels were also measured. Notably, the potential mechanism of autophagy and apoptosis dysfunction in endothelial cells was further examined. Cigarette smoke promoted the release of microparticles from T lymphocytes. TLMPs attenuated endothelial proliferation but promoted endothelial apoptosis/autophagy and the expression of proinflammatory cytokines, especially when T lymphocytes were preexposed to cigarette smoke. The potential mechanism may involve disorders of oxidative stress and STAT3 phosphorylation. In conclusion, cigarette smoke-exposed microparticles released from T lymphocytes contribute to autophagy and apoptosis dysfunction in pulmonary microvascular endothelial cells.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"181 ","pages":"Pages 9-17"},"PeriodicalIF":3.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143549964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The superantigen SEA binds to human γδ T cell receptor and activates γδ T cells with moderate MHC class II dependence

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-03-03 DOI: 10.1016/j.molimm.2025.02.019

Sibel Uzunçayır , Ganna Petruk , Manuel Mata Forsberg , Claudia Arasa , Eva Sverremark-Ekström , Karin Lindkvist-Petersson

Bacterial toxins, called superantigens, are produced by Staphylococcus aureus and are known to activate γδ T cells. γδ T cells contribute to long-lasting immunity against bacterial skin infections caused by S. aureus. γδ T cells are a distinct subgroup of T cells containing the T cell receptor (TCR) γ and δ chains. The γδ TCR harbouring the variable chains TRGV9/TRDV2 is the most common TCR in human peripheral blood and is known to be activated by superantigens and are also promising candidates for tumor immunotherapy. However, detailed analyses of antigen binding to γδ TCR have been severely hampered by difficulties in producing large amounts of γδ TCR. In this study, we report a protocol to produce recombinant γδ TCR (TRGV9/TRDV2) by fusing the variable domains γδ TCR with the constant domains of αβ TCR. Subsequently, binding analyses were executed applying microscale thermophoresis showing a clear binding between superantigen and the γδ TCR in the micro molar range. In addition, the superantigen SEA was shown to induce cytokine expression in γδ T cells with moderate MHC dependence, suggesting that other receptors can act as antigen presenting molecules upon γδ T cell activation. These results pave the way towards a better understanding of superantigen recognition by the γδ T cells and facilitates the future use of γδ TCR in cellular tumor immunotherapy.

{"title":"The superantigen SEA binds to human γδ T cell receptor and activates γδ T cells with moderate MHC class II dependence","authors":"Sibel Uzunçayır , Ganna Petruk , Manuel Mata Forsberg , Claudia Arasa , Eva Sverremark-Ekström , Karin Lindkvist-Petersson","doi":"10.1016/j.molimm.2025.02.019","DOIUrl":"10.1016/j.molimm.2025.02.019","url":null,"abstract":"<div><div>Bacterial toxins, called superantigens, are produced by <em>Staphylococcus aureus</em> and are known to activate γδ T cells. γδ T cells contribute to long-lasting immunity against bacterial skin infections caused by <em>S. aureus</em>. γδ T cells are a distinct subgroup of T cells containing the T cell receptor (TCR) γ and δ chains. The γδ TCR harbouring the variable chains TRGV9/TRDV2 is the most common TCR in human peripheral blood and is known to be activated by superantigens and are also promising candidates for tumor immunotherapy. However, detailed analyses of antigen binding to γδ TCR have been severely hampered by difficulties in producing large amounts of γδ TCR. In this study, we report a protocol to produce recombinant γδ TCR (TRGV9/TRDV2) by fusing the variable domains γδ TCR with the constant domains of αβ TCR. Subsequently, binding analyses were executed applying microscale thermophoresis showing a clear binding between superantigen and the γδ TCR in the micro molar range. In addition, the superantigen SEA was shown to induce cytokine expression in γδ T cells with moderate MHC dependence, suggesting that other receptors can act as antigen presenting molecules upon γδ T cell activation. These results pave the way towards a better understanding of superantigen recognition by the γδ T cells and facilitates the future use of γδ TCR in cellular tumor immunotherapy.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"181 ","pages":"Pages 1-8"},"PeriodicalIF":3.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143549963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

circSTIL mediates pirarubicin inhibiting the malignant phenotype of triple-negative breast cancer and acts as a biomarker in plasma exosomes

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-02-28 DOI: 10.1016/j.molimm.2025.02.014

Jiahua Ji , Min Li , Kaixu Yan , Jiulong Ma , Dexian Wei , Fan Zhang , Sennan Qiao , Peng Huang , Wenqing Zhang , Lu Li , Wentao Zheng , Liqun Ren

In clinical practice, pirarubicin (THP) is a widely used triple-negative breast cancer (TNBC) agent. It has been found that circular RNAs (circRNAs) are involved in cancer treatment and progression. However, the biological function of circRNAs in TNBC and the relationship between THP and circRNAs remain poorly studied. circSTIL (hsa_circ_0000069) was screened and validated by bioinformatics analysis, demonstrating that it was highly expressed in TNBC cell lines and plasma exosomes, and correlated with a poor prognosis of patients. The expression level of circSTIL in patients’ plasma exosomes has potential diagnostic value in distinguishing TNBC from non-TNBC. In vitro studies confirmed that overexpression of circSTIL promotes the proliferation, migration, and invasion of MDA-MB-231 cells whereas silicification of circSTIL shows the reverse effect. Also, circSTIL mediates THP inhibiting the malignant phenotype of MDA-MB-231 cells. The above results suggested that circSTIL is a possible biomarker for the diagnosis, treatment, and prognosis of TNBC.

{"title":"circSTIL mediates pirarubicin inhibiting the malignant phenotype of triple-negative breast cancer and acts as a biomarker in plasma exosomes","authors":"Jiahua Ji , Min Li , Kaixu Yan , Jiulong Ma , Dexian Wei , Fan Zhang , Sennan Qiao , Peng Huang , Wenqing Zhang , Lu Li , Wentao Zheng , Liqun Ren","doi":"10.1016/j.molimm.2025.02.014","DOIUrl":"10.1016/j.molimm.2025.02.014","url":null,"abstract":"<div><div>In clinical practice, pirarubicin (THP) is a widely used triple-negative breast cancer (TNBC) agent. It has been found that circular RNAs (circRNAs) are involved in cancer treatment and progression. However, the biological function of circRNAs in TNBC and the relationship between THP and circRNAs remain poorly studied. circSTIL (hsa_circ_0000069) was screened and validated by bioinformatics analysis, demonstrating that it was highly expressed in TNBC cell lines and plasma exosomes, and correlated with a poor prognosis of patients. The expression level of circSTIL in patients’ plasma exosomes has potential diagnostic value in distinguishing TNBC from non-TNBC. In vitro studies confirmed that overexpression of circSTIL promotes the proliferation, migration, and invasion of MDA-MB-231 cells whereas silicification of circSTIL shows the reverse effect. Also, circSTIL mediates THP inhibiting the malignant phenotype of MDA-MB-231 cells. The above results suggested that circSTIL is a possible biomarker for the diagnosis, treatment, and prognosis of TNBC.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"180 ","pages":"Pages 86-95"},"PeriodicalIF":3.2,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel mechanistic insights into the comorbidity of anemia and rheumatoid arthritis: Identification of therapeutic targets

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-02-27 DOI: 10.1016/j.molimm.2025.02.011

Cun Li , Xiongzhi Shi, Shou Chen , Xiaoming Peng , Shaohui Zong

Objectives

To investigate the mechanisms underlying the comorbidity of anemia and rheumatoid arthritis (RA) and identify promising therapeutic targets.

Methods

We assessed the phenotypic linkage between anemia and RA. Using the largest genome-wide association studies (GWAS) summary statistics of European populations, we scrutinized the causal association and shared genetic architecture between the two conditions using multiple complementary approaches.

Results

Logistic regression analysis confirmed a strong clinical association between anemia and RA. Using GWAS data, we identified a significant causal effect of RA on anemia and positive global genetic correlations between the two conditions (r_g (genotype) = 0.28, P = 9.6 × 10⁻⁷; r_g (gene expression) = 0.45, P = 2 × 10⁻³). After dividing the genome into 2495 independent regions, we identified 15 significant regions associated with both conditions, with 14 showing concordant effects. Fine-mapping at the SNP level revealed 72 % of RA-associated SNPs overlapped with anemia, most with concordant effects. Stratified Q-Q plots visualized the shared genetic enrichment, showing a 12-fold enrichment for RA conditional on anemia and 100-fold enrichment for anemia conditional on RA. Further analysis using conjFDR method pinpointed 14 pleiotropic loci, including several novel loci. Gene mapping identified 33 shared genes, with BLK and FAM167A further prioritized as the top two genes by SMR analysis. Enrichment analysis highlighted pathways related to inflammation, immune response, and iron metabolism. Blood and T cells showed significant tissue- and cell-type-specific enrichment.

Conclusions

This study provides novel insights into anemia-RA comorbidity mechanisms and identifies new drug targets for RA.

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引用次数: 0

C-reactive protein attenuates CCl4-induced acute liver injury by regulating complement system activation

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-02-26 DOI: 10.1016/j.molimm.2025.02.008

Zhao-Ming Tang , Ping Yuan , Ning Gao , Jia-Geng Lei , Mustafa Ahmed , Yu-Xin Hua , Ze-Rui Yang , Qiu-Yu Li , Hai-Yun Li

Acute liver injury is liver dysfunction caused by multiple factors without any pre-existing liver disease. C-reactive protein (CRP) is an acute-phase protein produced by hepatocytes, serving as a marker of inflammation and tissue damage. However, its role in CCl₄-induced acute liver injury has not been elucidated. Here, we report that CRP protects against CCl₄-induced acute liver injury by regulating complement activation. CRP knockout exacerbates CCl₄-induced acute liver injury in mice and rats, markedly enhances tissue damage, and reduces survival. Administration of exogenous CRP to CRP-knockout mice rescues the CCl₄-induced liver injury phenotype. The protective effect of CRP is independent of its cellular receptor FcγR2b and early metabolic pathways. Instead, CRP suppresses the late-phase amplification of inflammation by inhibiting terminal complement pathway overactivation in injured hepatocytes via factor H recruitment. In complement C3 knockout (C3^-/-) mice, the protective effect of CRP against CCl₄-induced acute liver injury is lost. These results suggest that CRP can alleviate CCl₄-induced acute liver injury by regulating the complement pathway, providing a theoretical basis for CRP's potential involvement and regulation of disease severity.

{"title":"C-reactive protein attenuates CCl4-induced acute liver injury by regulating complement system activation","authors":"Zhao-Ming Tang , Ping Yuan , Ning Gao , Jia-Geng Lei , Mustafa Ahmed , Yu-Xin Hua , Ze-Rui Yang , Qiu-Yu Li , Hai-Yun Li","doi":"10.1016/j.molimm.2025.02.008","DOIUrl":"10.1016/j.molimm.2025.02.008","url":null,"abstract":"<div><div>Acute liver injury is liver dysfunction caused by multiple factors without any pre-existing liver disease. C-reactive protein (CRP) is an acute-phase protein produced by hepatocytes, serving as a marker of inflammation and tissue damage. However, its role in CCl<sub>4</sub>-induced acute liver injury has not been elucidated. Here, we report that CRP protects against CCl<sub>4</sub>-induced acute liver injury by regulating complement activation. CRP knockout exacerbates CCl<sub>4</sub>-induced acute liver injury in mice and rats, markedly enhances tissue damage, and reduces survival. Administration of exogenous CRP to CRP-knockout mice rescues the CCl<sub>4</sub>-induced liver injury phenotype. The protective effect of CRP is independent of its cellular receptor <em>FcγR2b</em> and early metabolic pathways. Instead, CRP suppresses the late-phase amplification of inflammation by inhibiting terminal complement pathway overactivation in injured hepatocytes via factor H recruitment. In complement C3 knockout (C3<sup>-/-</sup>) mice, the protective effect of CRP against CCl<sub>4</sub>-induced acute liver injury is lost. These results suggest that CRP can alleviate CCl<sub>4</sub>-induced acute liver injury by regulating the complement pathway, providing a theoretical basis for CRP's potential involvement and regulation of disease severity.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"180 ","pages":"Pages 44-54"},"PeriodicalIF":3.2,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

KRT14 is a promising prognostic biomarker of breast cancer related to immune inﬁltration

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-02-26 DOI: 10.1016/j.molimm.2025.02.016

Siqi Liao , Xin Zhang , Lanhui Chen , Jianning Zhang , Weiyu Lu , Mengou Rao , Yifan Zhang , Zijian Ye , Deyana Ivanova , Fangfang Li , Xuemei Chen , Yingxiong Wang , Anchao Song , Biao Xie , Meijiao Wang

Background

Breast cancer (BC) is the leading cancer among women globally, which has the highest incidence and mortality rate in over a hundred countries. This study was intended to discover a new prognostic biomarker, facilitating personalized treatment approaches.

Methods

RNA sequencing data from The Cancer Genome Atlas database and Gene Expression Omnibus database were utilized to download to evaluate expression levels and prognostic significance of Keratin 14 (KRT14). Methylation of KRT14 was also assessed. The CIBERSORT and single-sample gene set enrichment analysis algorithms were applied to explore the connection between KRT14 and the tumor microenvironment. Primary drugs' sensitivity and potential small molecule therapeutic compounds were analyzed through the "pRRophetic" R package and the Connectivity Map. The prognostic value of KRT14 was additionally corroborated through a comparison of protein levels in peritumoral and cancerous tissues via immunohistochemistry. Moreover, an immune-related prognostic model based on KRT14 was designed to enhance the prediction accuracy for the prognosis of BC patients.

Results

The study found that KRT14 expression was generally downregulated in BC, correlating strongly with poor prognosis. Compared to normal tissues, the methylation level of KRT14 was higher in BC tissues. Lower expression of KRT14 was linked to decreased anti-tumoral immune cells infiltration and increased immunosuppressive cells infiltration. Sensitivity to various key therapeutic drugs was lower in groups with diminished KRT14 expression. In addition, several potential anti-BC small molecule compounds were identified. The model designed in this study significantly enhanced the predictive capability for BC patients compared to predictions based solely on KRT14 expression levels.

Conclusion

Overall, KRT14 was closely correlated with the prognosis in BC, making it a reliable biomarker.

{"title":"KRT14 is a promising prognostic biomarker of breast cancer related to immune inﬁltration","authors":"Siqi Liao , Xin Zhang , Lanhui Chen , Jianning Zhang , Weiyu Lu , Mengou Rao , Yifan Zhang , Zijian Ye , Deyana Ivanova , Fangfang Li , Xuemei Chen , Yingxiong Wang , Anchao Song , Biao Xie , Meijiao Wang","doi":"10.1016/j.molimm.2025.02.016","DOIUrl":"10.1016/j.molimm.2025.02.016","url":null,"abstract":"<div><h3>Background</h3><div>Breast cancer (BC) is the leading cancer among women globally, which has the highest incidence and mortality rate in over a hundred countries. This study was intended to discover a new prognostic biomarker, facilitating personalized treatment approaches.</div></div><div><h3>Methods</h3><div>RNA sequencing data from The Cancer Genome Atlas database and Gene Expression Omnibus database were utilized to download to evaluate expression levels and prognostic significance of Keratin 14 (KRT14). Methylation of KRT14 was also assessed. The CIBERSORT and single-sample gene set enrichment analysis algorithms were applied to explore the connection between KRT14 and the tumor microenvironment. Primary drugs' sensitivity and potential small molecule therapeutic compounds were analyzed through the \"pRRophetic\" R package and the Connectivity Map. The prognostic value of KRT14 was additionally corroborated through a comparison of protein levels in peritumoral and cancerous tissues via immunohistochemistry. Moreover, an immune-related prognostic model based on KRT14 was designed to enhance the prediction accuracy for the prognosis of BC patients.</div></div><div><h3>Results</h3><div>The study found that KRT14 expression was generally downregulated in BC, correlating strongly with poor prognosis. Compared to normal tissues, the methylation level of KRT14 was higher in BC tissues. Lower expression of KRT14 was linked to decreased anti-tumoral immune cells infiltration and increased immunosuppressive cells infiltration. Sensitivity to various key therapeutic drugs was lower in groups with diminished KRT14 expression. In addition, several potential anti-BC small molecule compounds were identified. The model designed in this study significantly enhanced the predictive capability for BC patients compared to predictions based solely on KRT14 expression levels.</div></div><div><h3>Conclusion</h3><div>Overall, KRT14 was closely correlated with the prognosis in BC, making it a reliable biomarker.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"180 ","pages":"Pages 55-73"},"PeriodicalIF":3.2,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neem leaf extract alleviates LPS/D-GalN induced acute hepatitis in mice through its anti-inflammatory effects and activation of autophagy

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-02-24 DOI: 10.1016/j.molimm.2025.02.015

Meiyu Jin , LV Mengfan , Hao Yu , Jiaqi Cheng , Yibo Zhang , Yaxin Zhai , Haihua Feng

Acute hepatitis, characterized by rapid onset and high mortality, can result from infections, toxins, and other factors. However, current treatment options have significant side effects, necessitating further research into alternative therapies. This study investigated the extraction method of neem extract and found that its ethanolic extract effectively reduced mortality and decreased ALT and AST levels in mice serum, improving liver pathology. HPLC analysis identified azadirachtin and nimbolide in the extract. It also downregulated NF-κB, NLRP3, and p62 levels, while upregulating Lc3B and Atg5 levels. Experiments in Atg5 knockout mice showed that the absence of Atg5 weakened the extract's efficacy in reducing liver damage and inflammation and affected the extent of NLRP3 protein downregulation. However, it did not affect the extract's ability to reduce NF-κB. Overall, the ethanolic extract of neem leaves primarily modulates the inflammatory response through the NF-κB signaling pathway. The extract's efficacy in reducing NLRP3 is associated with autophagy. These discoveries offer a new theoretical basis for the role of neem in treating acute hepatitis.

{"title":"Neem leaf extract alleviates LPS/D-GalN induced acute hepatitis in mice through its anti-inflammatory effects and activation of autophagy","authors":"Meiyu Jin , LV Mengfan , Hao Yu , Jiaqi Cheng , Yibo Zhang , Yaxin Zhai , Haihua Feng","doi":"10.1016/j.molimm.2025.02.015","DOIUrl":"10.1016/j.molimm.2025.02.015","url":null,"abstract":"<div><div>Acute hepatitis, characterized by rapid onset and high mortality, can result from infections, toxins, and other factors. However, current treatment options have significant side effects, necessitating further research into alternative therapies. This study investigated the extraction method of neem extract and found that its ethanolic extract effectively reduced mortality and decreased ALT and AST levels in mice serum, improving liver pathology. HPLC analysis identified azadirachtin and nimbolide in the extract. It also downregulated NF-κB, NLRP3, and p62 levels, while upregulating Lc3B and Atg5 levels. Experiments in Atg5 knockout mice showed that the absence of Atg5 weakened the extract's efficacy in reducing liver damage and inflammation and affected the extent of NLRP3 protein downregulation. However, it did not affect the extract's ability to reduce NF-κB. Overall, the ethanolic extract of neem leaves primarily modulates the inflammatory response through the NF-κB signaling pathway. The extract's efficacy in reducing NLRP3 is associated with autophagy. These discoveries offer a new theoretical basis for the role of neem in treating acute hepatitis.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"180 ","pages":"Pages 33-43"},"PeriodicalIF":3.2,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Artemisinin analogues are effective in the treatment of psoriasis by targeting RORγt

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-02-22 DOI: 10.1016/j.molimm.2025.02.006

Xuyan Tian , Fanrong Peng , xiaoxiao xiong , Xiaoting Xu , Yu Zan , Xinran Wang , Bolan Yu , Zhonghua Liu , Xixin He , Zhaofeng Huang

Psoriasis is a chronic inflammatory skin autoimmune disease. Th17 cells, when pathologically activated, significantly contribute to the progression of psoriasis. The symptoms of this skin condition could be notably alleviated by targeting and suppressing the activity of these cells. Retinoic acid receptor-associated orphan nuclear hormone receptor γ-t (RORγt), a critical transcription factor in Th17 cells, emerges as a promising therapeutic target for autoimmune conditions which are mediated by the dysregulation of these cells. In this study, we designed and synthesised a series of artemisinin analogues based on the chemical structure of artemisinin, and screened 3 compounds, QHS-1, QHS-2, and QHS-3, with better inhibition efficiency of RORγt activity. We found that each of the three artemisinin analogues were demonstrated efficacy in curbing IMQ-induced skin inflammation and the abnormal proliferation of keratinocytes within the BALB/c mouse model of psoriasis. Our findings indicate that the three artemisinin analogues not only effectively mitigated skin inflammation and the abnormal proliferation of keratinocytes in the IMQ-induced psoriasis model of BALB/c mice but also curtailed the infiltration of immune cells and the production of pro-inflammatory cytokines in the dermis. Furthermore, these compounds modulated the cytokine expression profiles within Th17 cells. They exerted a suppressive effect on the activity of Th17 cells by targeting RORγt, thereby dampening the inflammatory response in the dorsal skin of the mice. This inhibition led to a reduction in the pathological proliferation of keratinocytes. In conclusion, our research underscores the promising therapeutic potential of artemisinin analogues in the treatment of psoriasis, offering a slate of candidate compounds which could pave the way for novel drug development in this field.

{"title":"Artemisinin analogues are effective in the treatment of psoriasis by targeting RORγt","authors":"Xuyan Tian , Fanrong Peng , xiaoxiao xiong , Xiaoting Xu , Yu Zan , Xinran Wang , Bolan Yu , Zhonghua Liu , Xixin He , Zhaofeng Huang","doi":"10.1016/j.molimm.2025.02.006","DOIUrl":"10.1016/j.molimm.2025.02.006","url":null,"abstract":"<div><div>Psoriasis is a chronic inflammatory skin autoimmune disease. Th17 cells, when pathologically activated, significantly contribute to the progression of psoriasis. The symptoms of this skin condition could be notably alleviated by targeting and suppressing the activity of these cells. Retinoic acid receptor-associated orphan nuclear hormone receptor γ-t (RORγt), a critical transcription factor in Th17 cells, emerges as a promising therapeutic target for autoimmune conditions which are mediated by the dysregulation of these cells. In this study, we designed and synthesised a series of artemisinin analogues based on the chemical structure of artemisinin, and screened 3 compounds, QHS-1, QHS-2, and QHS-3, with better inhibition efficiency of RORγt activity. We found that each of the three artemisinin analogues were demonstrated efficacy in curbing IMQ-induced skin inflammation and the abnormal proliferation of keratinocytes within the <em>BALB/c</em> mouse model of psoriasis. Our findings indicate that the three artemisinin analogues not only effectively mitigated skin inflammation and the abnormal proliferation of keratinocytes in the IMQ-induced psoriasis model of <em>BALB/c</em> mice but also curtailed the infiltration of immune cells and the production of pro-inflammatory cytokines in the dermis. Furthermore, these compounds modulated the cytokine expression profiles within Th17 cells. They exerted a suppressive effect on the activity of Th17 cells by targeting RORγt, thereby dampening the inflammatory response in the dorsal skin of the mice. This inhibition led to a reduction in the pathological proliferation of keratinocytes. In conclusion, our research underscores the promising therapeutic potential of artemisinin analogues in the treatment of psoriasis, offering a slate of candidate compounds which could pave the way for novel drug development in this field.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"180 ","pages":"Pages 11-22"},"PeriodicalIF":3.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Andrographolide represses HIF-1α and VEGFA expression, thus inhibiting hypoxia-induced proliferation, oxidative stress, and inflammatory cytokine secretion in human keratinocytes

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology

Pub Date : 2025-02-22 DOI: 10.1016/j.molimm.2025.02.013

Hui Ma , Fu Liu , Youhua Fang

Epidermal hypoxia, hyperproliferation of keratinocytes, and inflammation in skin lesions are relevant to the pathogenesis of inflammatory skin diseases, including psoriasis. Andrographolide (Andro) is a natural labdane diterpene with diverse biofunctions. Andro has been reported to alleviate psoriasis in mice. However, the exact mechanisms need further study. Our results demonstrated that Andro inhibited hypoxia-induced proliferation of human keratinocytes. Andro also protected the keratinocytes from hypoxia-induced oxidative stress and inflammatory response. Furthermore, we found that Andro suppressed the expression of HIF-1α and VEGFA expression in hypoxia-exposed keratinocytes. Overexpression of either HIF-1α or VEGFA attenuated the inhibitory effects of Andro on hypoxia-induced proliferation, oxidative stress, and inflammatory cytokine secretion. In summary, our results demonstrated that Andro protected keratinocytes from hypoxia-induced proliferation, oxidative stress, and inflammatory cytokine secretion by suppressing HIF-1α and VEGFA expression. Our findings provide an unreported insight into the potential use of Andro as an effective agent for the treatment of inflammatory skin diseases such as psoriasis in the future.

{"title":"Andrographolide represses HIF-1α and VEGFA expression, thus inhibiting hypoxia-induced proliferation, oxidative stress, and inflammatory cytokine secretion in human keratinocytes","authors":"Hui Ma , Fu Liu , Youhua Fang","doi":"10.1016/j.molimm.2025.02.013","DOIUrl":"10.1016/j.molimm.2025.02.013","url":null,"abstract":"<div><div>Epidermal hypoxia, hyperproliferation of keratinocytes, and inflammation in skin lesions are relevant to the pathogenesis of inflammatory skin diseases, including psoriasis. Andrographolide (Andro) is a natural labdane diterpene with diverse biofunctions. Andro has been reported to alleviate psoriasis in mice. However, the exact mechanisms need further study. Our results demonstrated that Andro inhibited hypoxia-induced proliferation of human keratinocytes. Andro also protected the keratinocytes from hypoxia-induced oxidative stress and inflammatory response. Furthermore, we found that Andro suppressed the expression of HIF-1α and VEGFA expression in hypoxia-exposed keratinocytes. Overexpression of either HIF-1α or VEGFA attenuated the inhibitory effects of Andro on hypoxia-induced proliferation, oxidative stress, and inflammatory cytokine secretion. In summary, our results demonstrated that Andro protected keratinocytes from hypoxia-induced proliferation, oxidative stress, and inflammatory cytokine secretion by suppressing HIF-1α and VEGFA expression. Our findings provide an unreported insight into the potential use of Andro as an effective agent for the treatment of inflammatory skin diseases such as psoriasis in the future.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"180 ","pages":"Pages 23-32"},"PeriodicalIF":3.2,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0