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Results for “Monocrotaline”

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12 recordsLinked to original sources
PubMed1976

Neoplastic transformation in tissues of rats exposed to monocrotaline or dehydroretronecine.

Male Sprague-Dawley rats received sc injections biweekly of either the pyrrolizidine alkaloid monocrotaline or its metabolite dehydroretronecine for 1 year. The animals were then observed for an additional 12 months for the induction of neoplasms. Of 60 rats that received dehydroretronecine, 39 developed rhabdomyosarcomas at the injection site, and 5 of these neoplasms metastasized. In the 60 monocrotaline-treated rats, 31 widely dispersed tumors of various cell types were recorded. The reason suggested for the variation in tissue response was that the metabolite dehydroretronecine is a proximate carcinogen, whereas monocrotaline must first be metabolized before its carcinogenic potential is realized.

Animals↗
PubMed1977

Fibrin thrombosis in monocrotaline pyrrole-induced cor pulmonale in rats.

Investigations were carried out to determine the lung lesions responsible for the development of pulmonary heart disease, cor pulmonale, in rats treated with monocrotaline pyrrole or monocrotaline. Animals with right ventricular hypertrophy showed microscopic lung alterations consisting of alveolar edema; fibrin thrombi with partial to complete occlusion of arteries, arterioles, capillaries, and veins; connective tissue proliferation of alveolar septae; cellular hyperplasia of septae; and medial hypertrophy of arterioles. Due to the high incidence of fibrin thrombi in animals with right ventricular hypertrophy, we believe that formation of fibrin thrombi plays a decisive role in the development of chemically induced cor pulmonale.

Animals↗
PubMed1976

Effects of phenobarbitone, cinnarizine, and zoxazolamine on the development of right ventricular hypertrophy and hypertensive pulmonary vascular disease in rats treated with monocrotaline.

The results of this experiment suggest that the addition of zoxazolamine to the diet may prolong the survival and reduce the incidence of right ventricular hypertrophy and hypertensive pulmonary vascular disease in male rats given a single subcutaneous injection of monocrotaline. Phenobarbitone and cinnarizine were ineffective.

Animals↗
PubMed2026

DNA Methylation-Mediated Regulation of TAGLN2 Expression Promotes Pulmonary Arterial Hypertension.

BACKGROUND: Succinylation, a key post-translational modification, is implicated in the metabolic reprogramming and vascular remodeling of pulmonary arterial hypertension (PAH). While epigenetic regulation, particularly DNA methylation, potentially governs succinylation-related gene expression, its causal links to PAH remain unclear. METHODS: We performed an integrative causal analysis using two-sample Mendelian randomization (MR) and summary-data-based MR (SMR) to identify succinylation-related genes that influence PAH risk. We leveraged PAH GWAS data (FinnGen) and gene expression quantitative trait loci (eQTLGen). Subsequently, methylation-mediated effect decomposition was applied using DNA methylation data (GoDMC) to explore epigenetic regulation. Experimental validation was conducted in lung tissues from a monocrotaline (MCT)-induced PAH rat model via quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Genetic analyses identified a significant causal effect of elevated Transgelin 2 (TAGLN2) expression on increased PAH risk. This effect was mediated by two specific DNA methylation sites, cg13892570 and cg16107628, which influenced PAH pathogenesis by regulating TAGLN2 transcription, with mediation proportions of 86.46 and 97.65%, respectively. Sensitivity analyses supported the robustness of these findings. Consistent with the genetic evidence, TAGLN2 mRNA was significantly upregulated in the lungs of MCT-induced PAH rats. CONCLUSIONS: This study establishes a clear epigenetic causal pathway in which DNA methylation regulates TAGLN2 expression to promote PAH. TAGLN2 is validated as a key disease driver and presents a promising target for diagnostic and therapeutic strategies in PAH.

Animals↗
PubMed1978

Dehydroretronecine-induced skin tumors in mice.

Female Swiss mice susceptible to skin tumors received 6 sc injections and/or topical applications of dehydroretronecine, a metabolite of the pyrrolizidine alkaloid monocrotaline, and were observed for 15 months for tumor development. Of 92 animals examined, 63 had tumors at the site of application or injection; 47 of these had skin tumors, mainly basal cell and squamous cell carcinomas. These data indicate that dehydroretronecine is a proximate carcinogen capable of causing a high incidence of skin tumours in mice at the site of sc injection or topical application.

Administration, Topical↗
PubMed2026

Transcriptomic analysis identifies novel ferroptosis-related biomarkers and therapeutic targets in pulmonary arterial hypertension.

BACKGROUND: Ferroptosis plays a significant role in pulmonary arterial hypertension (PAH), although its underlying mechanisms and key pathogenic genes remain unclear. METHODS: Transcriptomic data from human PAH and control lung tissue were obtained from the Gene Expression Omnibus (GEO) database, whereas ferroptosis-related genes (FRGs) were sourced from the MsigDb and FerrDb databases. Differentially expressed FRGs (DE-FRGs) were identified through the intersection of FRGs with differentially expressed genes (DEGs). Functional enrichment analysis was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Key hub genes were identified through Least Absolute Shrinkage and Selection Operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE), and weighted correlation network analysis (WGCNA). Gene set enrichment analysis (GSEA) was conducted to explore the functional roles and associated pathways of hub genes. The relationship between hub genes and immune infiltration was investigated. Expression levels of potential biomarkers were validated via Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) in two PAH animal models (monocrotaline-induced and Sugen5416 plus hypoxia-induced PAH). Finally, molecular docking was employed to screen potential therapeutic compounds. RESULTS: A total of 133 DE-FRGs were identified, with KEGG and GO analyses highlighting their involvement in intracellular iron homeostasis and ferroptosis. Hub genes, notably FZD7 and NFE2, were identified using LASSO, SVM-RFE, and WGCNA. Immune infiltration analysis suggested that monocytes and neutrophils play key roles in PAH pathogenesis. Validation in PAH animal models showed significant upregulation of Fzd7 and downregulation of Nfe2 in lung tissues of both MCT- and SuHx-induced PAH models. Molecular docking identified tetrachlorodibenzodioxin (TCDD) has good binding affinity. CONCLUSION: In summary, we investigated two ferroptosis-related biomarkers, FZD7 and NFE2, in PAH using transcriptomics, offering new insights into molecular mechanisms and potential targeted therapies for the disease.

Ferroptosis↗
PubMed1979

Haemodynamic studies in veno-occlusive disease of the liver.

Haemodynamic studies in 8 tribal patients from central India with veno-occlusive disease of the liver are reported. The disease was caused by eating cereals contaminated with seeds of a crotalaria species rich in toxic pyrrolizidine alkaloids similar to monocrotaline and fulvine. All patients showed raised hepatic venous wedge pressures and pressure gradients between hepatic venous wedge and free hepatic vein. Significant pressure gradients were also observed in the inferior vena cava. Right and left heart pressures were normal. Cardiac and stroke indices and ventricular work were significantly increased while systemic and pulmonary resistances were reduced. Hepatic blood flow was also reduced. Hepatic venograms were abnormal and the changes correlated well with the pressure gradients between hepatic venous wedge and free hepatic vein and with the histological changes in the liver.

Adolescent↗