ReferenceID 2204
A molecular phenotypic screen reveals that lobetyolin alleviates cardiac dysfunction in 5/6 nephrectomized mice by inhibiting osteopontin
Phytomedicine
Background: Cardiovascular diseases are the major cause of mortality in patients with advanced chronic kidney diseases. The predominant abnormality observed among this population is cardiac dysfunction secondary to myoca
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- Reference Id
- 2204
- Evidence Id
- 18794
- Core Evidence Id
- 18794
- Source Reference Id
- 4451
- Herb2 Reference Id
- HBREF005248
- Subject Paper Key
- HBIN033455_36191549
- Pubmed Id
- 36191549
- Doi
- 10.1016/j.phymed.2022.154412
- Paper Title
- A molecular phenotypic screen reveals that lobetyolin alleviates cardiac dysfunction in 5/6 nephrectomized mice by inhibiting osteopontin
- Paper Abstract
- Background: Cardiovascular diseases are the major cause of mortality in patients with advanced chronic kidney diseases. The predominant abnormality observed among this population is cardiac dysfunction secondary to myocardial remodelings, such as hypertrophy and fibrosis, emphasizing the need to develop potent therapies that maintain cardiac function in patients with end-stage renal disease. Aims: To identify potential compounds and their targets as treatments for cardiorenal syndrome type 4 (CRS) using molecular phenotyping and in vivo/in vitro experiments. Methods: Gene expression was assessed using bioinformatics and verified in animal experiments using 5/6 nephrectomized mice (NPM). Based on this information, a molecular phenotyping strategy was pursued to screen potential compounds. Picrosirius red staining, wheat germ agglutinin staining, Echocardiography, immunofluorescence staining, and real-time quantitative PCR (qPCR) were utilized to evaluate the effects of compounds on CRS in vivo. Furthermore, qPCR, immunofluorescence staining and flow cytometry were applied to assess the effects of these compounds on macrophages/cardiac fibroblasts/cardiomyocytes. RNA-Seq analysis was performed to locate the targets of the selected compounds. Western blotting was performed to validate the targets and mechanisms. The reversibility of these effects was tested by overexpressing Osteopontin (OPN). Results: OPN expression increased more remarkably in individuals with uremia-induced cardiac dysfunction than in other cardiomyopathies. Lobetyolin (LBT) was identified in the compound screen, and it improved cardiac dysfunction and suppressed remodeling in NPM mice. Additionally, OPN modulated the effect of LBT on cardiac dysfunction in vivo and in vitro. Further experiments revealed that LBT suppressed OPN expression via the phosphorylation of c-Jun N-terminal protein kinase (JNK) signaling pathway. Conclusions: LBT improved CRS by inhibiting OPN expression through the JNK pathway. This study is the first to describe a cardioprotective effect of LBT and provides new insights into CRS drug discovery.
- Journal
- Phytomedicine
- Publish Year
- 2022
- Experiment Subject
- mouse; patient; wheat
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Cardiorenal Syndrome Type 4; Uremia-induced Cardiac Dysfunction; End-stage Renal Disease; Myocardial Remodelings; Cardiac Dysfunction; Fibrosis; Cardiomyopathies; Advanced Chronic Kidney Diseases; Cardiovascular Diseases; Hypertrophy
- Paper Title Cn
- Paper Title En
- A molecular phenotypic screen reveals that lobetyolin alleviates cardiac dysfunction in 5/6 nephrectomized mice by inhibiting osteopontin
- Bilingual Status
- semi_complete