Doxorubicin induced immune abnormalities and inflammatory responses via HMGB1, HIF1-α and VEGF pathway in progressive of cardiovascular damage

Syukri, Ahmad; Budu,; Hatta, Mochammad; Amir, Muzakkir; Rohman, Mohammad Saifur; Mappangara, Idar; Kaelan, Cahyono; Wahyuni, Sitti; Bukhari, Agussalim; Junita, Ade Rifka; Primaguna, Muhammad Reza; Dwiyanti, Ressy; Febrianti, Andini

doi:10.1016/j.amsu.2022.103501

Cited by 27 publications

(20 citation statements)

References 90 publications

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“…HMGB1 is a nuclear protein with pro-inflammatory effects, participating in the progress of autophagy, apoptosis, ferroptosis, inflammation etc. [204][205][206][207]. HMGB1, acted as a damage-associated molecular pattern (DAMP) protein, is secreted in response to ROS, RNS, Ca2 + and other stimuli, and is released extracellular by activated macrophages to mediate inflammatory response [208,209].…”

Section: Hmgb1/tlr4/mapks/nf-κb Signaling Pathwaymentioning

confidence: 99%

Role of oxidative stress and inflammation-related signaling pathways in doxorubicin-induced cardiomyopathy

et al. 2023

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Doxorubicin (DOX) is a powerful and commonly used chemotherapeutic drug, used alone or in combination in a variety of cancers, while it has been found to cause serious cardiac side effects in clinical application. More and more researchers are trying to explore the molecular mechanisms of DOX-induced cardiomyopathy (DIC), in which oxidative stress and inflammation are considered to play a significant role. This review summarizes signaling pathways related to oxidative stress and inflammation in DIC and compounds that exert cardioprotective effects by acting on relevant signaling pathways, including the role of Nrf2/Keap1/ARE, Sirt1/p66Shc, Sirt1/PPAR/PGC-1α signaling pathways and NOS, NOX, Fe2+ signaling in oxidative stress, as well as the role of NLRP3/caspase-1/GSDMD, HMGB1/TLR4/MAPKs/NF-κB, mTOR/TFEB/NF-κB pathways in DOX-induced inflammation. Hence, we attempt to explain the mechanisms of DIC in terms of oxidative stress and inflammation, and to provide a theoretical basis or new idea for further drug research on reducing DIC.

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Section: Hmgb1/tlr4/mapks/nf-κb Signaling Pathwaymentioning

confidence: 99%

Role of oxidative stress and inflammation-related signaling pathways in doxorubicin-induced cardiomyopathy

et al. 2023

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“…We noted VEGF (Vascular endothelial growth factor) signaling pathway is a major regulator of vascular development and lymphatic function, which also plays an important role in tumor growth, retinopathy, tissue inflammation and immunity ( 34 , 35 ). In this pathway, HIF1A acts as a central link and transmits signals to the downstream PIGF ( 36 – 39 ). PIGF (placental growth factor), is a member of the VEGF family, which can bind VEGFR1 with high affinity, plays a key role in pathological angiogenesis, especially in cancer, cardiovascular, autoimmune and inflammatory diseases ( 40 , 41 ).…”

Section: Resultsmentioning

confidence: 99%

Cd248a and Cd248b in zebrafish participate in innate immune responses

Guo

Yang

et al. 2022

Front. Immunol.

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CD248, also known as endosialin or tumor endothelial marker 1, is a type I single transmembrane glycoprotein. CD248 has been demonstrated to be upregulated in cancers, tumors and many fibrotic diseases in human and mice, such as liver damage, pulmonary fibrosis, renal fibrosis, arthritis and tumor neovascularization. However, no definite CD248 orthologs in fish have been documented so far. In this study, we report the identification of cd248a and cd248b in the zebrafish. Both the phylogenetic analysis and the conserved synteny strongly suggested that zebrafish cd248a and cd248b are orthologs of the human CD248. Both cd248a and cd248b exhibited similar and dynamic expression pattern in early development, both genes had weak maternal expression, the zygotic transcripts were first seen in anterior somites and head mesenchyme, then shifted to eyes and head mesenchyme, later expanded to branchial arches, and gradually declined with development. The expression profiles of cd248a and cd248b were upregulated upon LPS (Lipopolysaccharide) challenge. Both Cd248a protein and Cd248b protein were localized on the cell membrane and cytoplasm, and overexpression of cd248a and cd248b induced the expression of pro-inflammatory cytokines, in vitro and in vivo. Moreover, deficiency of cd248a or cd248b both downregulated the expression of pro-inflammatory cytokines and upregulated anti-inflammatory cytokine. Additionally, loss of cd248a or cd248b both downregulated the expression of pro-inflammatory cytokines after LPS treatment. Taken together, these results indicated that cd248a and cd248b in zebrafish were involved in immune response and would provide further information to understand functions of Cd248 protein in innate immunity of fish.

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“…The DOX-induced immune abnormalities had significant effects on the progression of cardiovascular damage, particularly in the acute phase ( 31 , 32 ). In the acute model, a seemingly contradictory result showed the coexistence of inflammation and immunosuppression.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel biomarkers involved in doxorubicin-induced acute and chronic cardiotoxicity, respectively, by integrated bioinformatics

Qian

Liu

et al. 2023

Front. Cardiovasc. Med.

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BackgroundThe mechanisms of doxorubicin (DOX) cardiotoxicity were complex and controversial, with various contradictions between experimental and clinical data. Understanding the differences in the molecular mechanism between DOX-induced acute and chronic cardiotoxicity may be an ideal entry point to solve this dilemma.MethodsMice were injected intraperitoneally with DOX [(20 mg/kg, once) or (5 mg/kg/week, three times)] to construct acute and chronic cardiotoxicity models, respectively. Survival record and ultrasound monitored the cardiac function. The corresponding left ventricular (LV) myocardium tissues were analyzed by RNA-seq to identify differentially expressed genes (DEGs). Gene Ontology (GO), Kyoto Encyclopedia of Gene and Genome (KEGG), and Gene Set Enrichment Analysis (GSEA) found the key biological processes and signaling pathways. DOX cardiotoxicity datasets from the Gene expression omnibus (GEO) database were combined with RNA-seq to identify the common genes. Cytoscape analyzed the hub genes, which were validated by quantitative real-time PCR. ImmuCo and ImmGen databases analyzed the correlations between hub genes and immunity-relative markers in immune cells. Cibersort analyzed the immune infiltration and correlations between the hub genes and the immune cells. Logistic regression, receiver operator characteristic curve, and artificial neural network analysis evaluated the diagnosis ability of hub genes for clinical data in the GEO dataset.ResultsThe survival curves and ultrasound monitoring demonstrated that cardiotoxicity models were constructed successfully. In the acute model, 788 DEGs were enriched in the activated metabolism and the suppressed immunity-associated signaling pathways. Three hub genes (Alas1, Atp5g1, and Ptgds) were upregulated and were negatively correlated with a colony of immune-activating cells. However, in the chronic model, 281 DEGs showed that G protein-coupled receptor (GPCR)-related signaling pathways were the critical events. Three hub genes (Hsph1, Abcb1a, and Vegfa) were increased in the chronic model. Furthermore, Hsph1 combined with Vegfa was positively correlated with dilated cardiomyopathy (DCM)-induced heart failure (HF) and had high accuracy in the diagnosis of DCM-induced HF (AUC = 0.898, P = 0.000).ConclusionAlas1, Atp5g1, and Ptgds were ideal biomarkers in DOX acute cardiotoxicity. However, Hsph1 and Vegfa were potential biomarkers in the myocardium in the chronic model. Our research, first, provided bioinformatics and clinical evidence for the discovery of the differences in mechanism and potential biomarkers of DOX-induced acute and chronic cardiotoxicity to find a therapeutic strategy precisely.

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Doxorubicin induced immune abnormalities and inflammatory responses via HMGB1, HIF1-α and VEGF pathway in progressive of cardiovascular damage

Cited by 27 publications

References 90 publications

Role of oxidative stress and inflammation-related signaling pathways in doxorubicin-induced cardiomyopathy

Role of oxidative stress and inflammation-related signaling pathways in doxorubicin-induced cardiomyopathy

Cd248a and Cd248b in zebrafish participate in innate immune responses

Identification of novel biomarkers involved in doxorubicin-induced acute and chronic cardiotoxicity, respectively, by integrated bioinformatics

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