Complexity of TNF-α Signaling in Heart Disease

Rolski, Filip; Błyszczuk, Przemysław

doi:10.3390/jcm9103267

Cited by 94 publications

(81 citation statements)

References 158 publications

(188 reference statements)

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“…Similarly, in our analyses, TNF-α signaling via NF-kB was found to be shared between COVID-19 and its comorbid conditions—cancers, CVDs, and CKDs. TNF-α signaling via NF-kB is a target as it is associated with the inflammation-triggered CVDs [ 59 , 60 ], cancer cell migration and invasion [ 61 , 62 , 63 ], the pathogenesis of CKDs [ 64 , 65 , 66 ], and severity of COVID-19 [ 67 , 68 , 69 ]. In the case of a shared pathway between hypertension and COVID-19, we found that the renin-angiotensin system is the key pathway that links these two diseases.…”

Section: Discussionmentioning

confidence: 99%

Predicting COVID-19—Comorbidity Pathway Crosstalk-Based Targets and Drugs: Towards Personalized COVID-19 Management

et al. 2021

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It is well established that pre-existing comorbid conditions such as hypertension, diabetes, obesity, cardiovascular diseases (CVDs), chronic kidney diseases (CKDs), cancers, and chronic obstructive pulmonary disease (COPD) are associated with increased severity and fatality of COVID-19. The increased death from COVID-19 is due to the unavailability of a gold standard therapeutic and, more importantly, the lack of understanding of how the comorbid conditions and COVID-19 interact at the molecular level, so that personalized management strategies can be adopted. Here, using multi-omics data sets and bioinformatics strategy, we identified the pathway crosstalk between COVID-19 and diabetes, hypertension, CVDs, CKDs, and cancers. Further, shared pathways and hub gene-based targets for COVID-19 and its associated specific and combination of comorbid conditions are also predicted towards developing personalized management strategies. The approved drugs for most of these identified targets are also provided towards drug repurposing. Literature supports the involvement of our identified shared pathways in pathogenesis of COVID-19 and development of the specific comorbid condition of interest. Similarly, shared pathways- and hub gene-based targets are also found to have potential implementations in managing COVID-19 patients. However, the identified targets and drugs need further careful evaluation for their repurposing towards personalized treatment of COVID-19 cases having pre-existing specific comorbid conditions we have considered in this analysis. The method applied here may also be helpful in identifying common pathway components and targets in other disease-disease interactions too.

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Section: Discussionmentioning

confidence: 99%

Predicting COVID-19—Comorbidity Pathway Crosstalk-Based Targets and Drugs: Towards Personalized COVID-19 Management

et al. 2021

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“… 36 These results suggest that TNF-α-induced COX-2/PGE 2 elevation in cardiac fibroblasts is initiated via TNFR1 activity and its downstream signaling cascades and possibly involved in the development of cardiovascular disorders. 37 …”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that p38 MAPK and JNK1/2 signaling cascades mediate TNFR1 responses elicited by TNF-α in heart diseases. 37 TNF-α has been demonstrated to induce COX-2 expression mediated through p38 MAPK activity in various types of cells. 24 , 25 Consistently, we revealed that TNF-α-induced COX-2 and PGE 2 upregulation were mediated by p38 MAPK signaling pathway, which was attenuated by pretreatment with p38i VIII or transfection with p38 siRNA.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of COX-2 and PGE2 Induced by TNF-α Mediated Through TNFR1/MitoROS/PKCα/P38 MAPK, JNK1/2/FoxO1 Cascade in Human Cardiac Fibroblasts

Yang¹,

Hsiao²,

Yu³

et al. 2021

JIR

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Purpose Tumor necrosis factor-α (TNF-α) has been shown to exert as a pathogenic factor in cardiac fibrosis and heart failure which were associated with the up-regulation of cyclooxygenase (COX)-2/prostaglandin E 2 (PGE 2 ) axis. However, whether TNF-α-induced COX-2/PGE 2 upregulation mediated through ROS-dependent cascade remains elusive in human cardiac fibroblasts (HCFs). This study aims to address the underlying mechanisms of TNF-α-induced COX-2/PGE 2 expression. Methods Here, we used TNF receptor neutralizing antibody (TNFR nAb), pharmacologic inhibitors, and siRNAs to dissect the involvement of signaling components examined by Western blot and ELISA in TNF-α-mediated responses in HCFs. MitoSOX Red was used to measure mitoROS generation. Isolation of subcellular fractions was performed to determine membrane translocation of PKCα. Promoter luciferase assay and chromatin immunoprecipitation (ChIP) assay were used to determine the role of transcription factor. Results We found that TNF-α time- and concentration-dependently upregulated COX-2 protein and mRNA expression as well as PGE 2 synthesis which was attenuated by TNFR1 nAb, the inhibitor of mitochondrial ROS scavenger (MitoTEMPO), protein kinase C [(PKC)α, Gö6976], p38 MAPK [p38 inhibitor VIII, (p38i VIII)], JNK1/2 (SP600125), or forkhead box protein O1 [(FoxO1), AS1842856], and transfection with their respective siRNAs in HCFs. TNF-α-stimulated PKCα phosphorylation was inhibited by TNFR1 nAb, MitoTEMPO, or Gö6976. TNF-α stimulated phosphorylation of p38 MAPK and JNK1/2 was attenuated by TNFR1 nAb, MitoTEMPO, Gö6976, and their inhibitors p38i VIII and SP600125. Moreover, TNF-α-triggered FoxO1 phosphorylation was abolished by AS1842856, TNFR1 nAb, and its upstream inhibitors MitoTEMPO, Gö6976, p38i VIII, and SP600125. Phosphorylation of FoxO1 could enhance its interaction with the COX-2 promoter element revealed by ChIP assay, which was attenuated by AS1842856. Conclusion Our results suggested that TNF-α-induced COX-2/PGE 2 upregulation is mediated through TNFR1-dependent MitoROS/PKCα/p38 MAPK and JNK1/2 cascade to activate FoxO1 binding with the COX-2 promoter in HCFs.

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“…TNF- α increasing ROS levels and decreasing nitric oxide production in blood vessels leads to endothelial dysfunction. It contributes also to the development of atherosclerotic plaques [ 56 ]. Dysregulation of these Ca 2+ fluxes will lead to different heart and vascular pathologies [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Research on Effect and Mechanism of Xuefu Zhuyu Decoction on CHD Based on Meta-Analysis and Network Pharmacology

Kui

Gao

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Xuefu Zhuyu Decoction (XFZY) is an ancient compound widely used in the treatment of coronary heart disease. However, its efficacy evaluation is not complete and its mechanism of action is not clear enough. In an attempt to address these problems, the efficacy was evaluated by meta-analysis and the mechanism was elucidated by the network pharmacology method. We systematically searched relevant studies in PubMed, Chinese National Knowledge Infrastructure Database (CNKI), Cochrane Library, Wanfang Data, and other databases from 2007 to 2019. The association between XFZY treatment and CHD was estimated by risk ratio (RR) and corresponding 95% confidence intervals (95% CIs). The compounds and the potential protein targets of XFZY were obtained from TCMSP, and active compounds were selected according to their oral bioavailability and drug similarity. The potential genes of coronary heart disease were obtained from TTD, OMIM, and GeneCards. The potential pathways related to genes were determined by GO and KEGG pathway enrichment analyses. The compound-target and compound-target-pathway networks were constructed. Molecular docking validates the component and the target. A total of 21 studies including 1844 patients were enrolled in the present meta-analysis, indicating that XFZY has a greater beneficial on total effect (fixed effect RR = 1.30; 95% Cl: 1.24–1.36; P = 0.82 ; I2 = 0.0%) and electrocardiogram efficacy (fixed effect RR = 1.40; 95% Cl: 1.26–1.56; P = 0.96 ; I2 = 0.0%) compared with the control group. A total of 1342 components in XFZY were obtained, among which, 241 were chosen as bioactive components. GO and KEGG analyses got top 10 significantly enriched terms and 10 enriched pathways. The C-T network included 192 compounds and 3085 targets, whereas the C-T-P network included 10 compounds, 109 targets, and 5 pathways. There was a good binding activity between the components and the targets. XFZY has the curative effect on coronary heart disease, and its mechanism is related to 10 compounds, 10 core targets, and 5 pathways.

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Complexity of TNF-α Signaling in Heart Disease

Cited by 94 publications

References 158 publications

Predicting COVID-19—Comorbidity Pathway Crosstalk-Based Targets and Drugs: Towards Personalized COVID-19 Management

Predicting COVID-19—Comorbidity Pathway Crosstalk-Based Targets and Drugs: Towards Personalized COVID-19 Management

Upregulation of COX-2 and PGE2 Induced by TNF-α Mediated Through TNFR1/MitoROS/PKCα/P38 MAPK, JNK1/2/FoxO1 Cascade in Human Cardiac Fibroblasts

Research on Effect and Mechanism of Xuefu Zhuyu Decoction on CHD Based on Meta-Analysis and Network Pharmacology

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