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Background: Myocardial infarction (MI) and post-MI-heart failure (pMIHF) are a major cause of death worldwide, however, the underlying mechanisms of pMIHF from MI are not well understood. This study sought to characterize early lipid biomarkers for the development of pMIHF disease. Methods: Serum samples from 18 MI and 24 pMIHF patients were collected from the Affiliated Hospital of Zunyi Medical University and analyzed using lipidomics with Ultra High Performance Liquid Chromatography and Q-Exactive High Resolution Mass Spectrometer. The serum samples were tested by the official partial least squares discriminant analysis (OPLS-DA) to find the differential expression of metabolites between the two groups. Furthermore, the metabolic biomarkers of pMIHF were screened using the subject operating characteristic (ROC) curve and correlation analysis. Results: The average age of the 18 MI and 24 pMIHF participants was 57.83 ± 9.28 and 64.38 ± 10.89 years, respectively. The B-type natriuretic peptide (BNP) level was 328.5 ± 299.842 and 3535.96 ± 3025 pg/mL, total cholesterol(TC) was 5.59 ± 1.51 and 4.69 ± 1.13 mmol/L, and blood urea nitrogen (BUN) was 5.24 ± 2.15 and 7.20 ± 3.49 mmol/L, respectively. In addition, 88 lipids, including 76 (86.36%) down-regulated lipids, were identified between the patients with MI and pMIHF. ROC analysis showed that phosphatidylethanolamine (PE) (12:1e_22:0) (area under the curve [AUC] = 0.9306) and phosphatidylcholine (PC) (22:4_14:1) (AUC = 0.8380) could be potential biomarkers for the development of pMIHF. Correlation analysis showed that PE (12:1e_22:0) was inversely correlated with BNP and BUN, but positively correlated with TC. In contrast, PC (22:4_14:1) was positively associated with both BNP and BUN, and was negatively associated with TC. Conclusions: Several lipid biomarkers were identified that could potentially be used to predict and diagnose patients with pMIHF. PE (12:1e_22:0) and PC (22:4_14:1) could sufficiently differentiate between patients with MI and pMIHF. [ABSTRACT FROM AUTHOR]

Cantharidin (CTD) is a principal bioactive component of traditional Chinese medicine Mylabris used in cancer treatment. However, CTD clinical application is limited due to nephrotoxicity, and the mechanism is unknown. The present study used widely-targeted metabolomics, network pharmacology, and cell experiments to investigate the nephrotoxicity mechanism after CTD exposure. In mice exposed to CTD, serum creatinine and urea nitrogen levels increased with renal injury. Then, 74 differential metabolites were detected, including 51 up-regulated and 23 down-regulated metabolites classified as amino acids, small peptides, fatty acyl, arachidonic acid metabolite, organic acid, and nucleotides. Sixteen metabolic pathways including tyrosine, sulfur, and pyrimidine metabolism were all disrupted in the kidney. Furthermore, network pharmacology revealed that 258 metabolic targets, and pathway enrichment indicated that CTD could activate oxidative phosphorylation and oxidative stress (OS). Subsequently, HK-2 cell experiments demonstrated that CTD could reduce superoxide dismutase while increasing malondialdehyde levels. In conclusion, after CTD exposure, biometabolic processes may be disrupted with renal injury in mice, resulting in oxidative phosphorylation and OS. [ABSTRACT FROM AUTHOR]

Mylabris , as a natural product of traditional Chinese medicine (TCM), exhibiting typical antitumor activity, and cantharidin (CTD) is the major bioactive component. However, drug-induced nephrotoxicity (DIN) extremely limited its clinical application. In this study, we proved that activation of the endoplasmic reticulum (ER) stress-dependent PERK/CHOP pathway exerts a toxic role in rats and HK-2 cells through inducing autophagy and apoptosis. Results showed that CTD could cause renal function damage, cytotoxicity, and apoptosis. The ER dilatation and autolysosomes were observed after CTD treatment. Furthermore, the distribution of LC3, ATF4, and CHOP proteins was observed in the nucleus and cytoplasm. In addition, the mRNA levels of ER stress-regulated genes (PERK , eIF2α , CHOP , and ATF4) were increased, and the expression levels of GRP78, ATF4, CHOP, LC3, Beclin-1, Atg3, Atg7, Caspase 3, and Bax/Bcl-2 proteins were increased both in vitro and in vivo. Consistently, this upregulation could be inhibited by an ER stress inhibitor 4-Phenylbutyric acid (4-PBA), indicating that ER stress is partly responsible for activation of autophagy and apoptosis in CTD-induced DIN. In conclusion, CTD could induce DIN by triggering ER stress, further activating autophagy and apoptosis both in vivo and in vitro. • Cantharidin (CTD) caused renal injury and apoptosis in a dose-time-dependent manner in vivo and in vitro. • CTD could trigger endoplasmic reticulum stress, which in turn activates autophagy and apoptosis in nephrotoxicity. • Apoptosis and autophagy could be mitigated by inhibition of the PERK/CHOP pathway in CTD-induced nephrotoxicity. [ABSTRACT FROM AUTHOR]

Cantharidin (CTD) is the major bioactive compound in Mylabris and has been shown to exhibit antitumor activity. However, its clinical application is relatively limited due to its potential toxic effects, especially nephrotoxicity. In this study, a UHPLC-QE/MS based metabolomics approach combined with network pharmacology was used to investigate the mechanism of CTD-induced nephrotoxicity in HK-2 cells. A total of 76 potential biomarkers and 28 disturbed metabolic pathways were identified in HK-2 cells exposed to CTD. And apoptotic protein expression levels of Caspase 3 and Bax/Bcl-2 ratio were increased in HK-2 cells exposed to CTD. In addition, combined with integrative network pharmacology analysis, the results demonstrated that CTD inhibits the glycerophospholipid and sphingolipid pathways, phosphatidylethanolamine, phosphatidylcholine, MAPK3, and PLD2. These may represent potential diagnostic markers and therapeutic targets, and may also lead to a strategy for reducing CTD-induced toxicity in the clinic. Image 1 • An integrative strategy was proposed for screening putative biomarkers based on metabolomics integrated with network pharmacology. • Potential association between biomarkers and targets was identified through the integrated strategy, for verifying the accuracy of biomarkers. • Cantharidin inhibits the glycerophospholipid, sphingolipid pathways, phosphatidylethanolamine, phosphatidylcholine, MAPK3, and PLD2 in HK-2 cells. [ABSTRACT FROM AUTHOR]

Endemic arsenic (As) poisoning is a severe biogeochemical disease that endangers human health. Epidemiological investigations and animal experiments have confirmed the damaging effects of As on the liver, but there is an urgent need to investigate the underlying mechanisms. This study adopted a metabolomic approach using UHPLC-QE/MS to identify the different metabolites and metabolic mechanisms associated with As-induced hepatotoxicity in mice. A network pharmacology approach was applied to predict the potential target of As-induced hepatotoxicity. The predicted targets of differential metabolites were subjected to a deep matching for elucidating the integration mechanisms. The results demonstrate that the levels of ALT and AST in plasma significantly increased in mice after As exposure. In addition, the liver tissue showed disorganized liver lobules, lax cytoplasm and inflammatory cell infiltration. Metabolomic analysis revealed that As exposure caused disturbance to 40 and 75 potential differential metabolites in plasma and liver, respectively. Further investigation led to discovering five vital metabolic pathways, including phenylalanine, tyrosine, and tryptophan biosynthesis and nicotinate and nicotinamide metabolism pathways. These pathways may responded to As-induced hepatotoxicity primarily through lipid metabolism, apoptosis, and deoxyribonucleic acid damage. The network pharmacology suggested that As could induce hepatotoxicity in mice by acting on targets including Hsp90aa1, Akt2, Egfr, and Tnf, which regulate PI3K Akt, HIF-1, MAPK, and TNF signaling pathways. Finally, the integrated metabolomics and network pharmacology revealed eight key targets associated with As-induced hepatoxicity, namely DNMT1, MAOB, PARP1, MAOA, EPHX2, ANPEP, XDH, and ADA. The results also suggest that nicotinic acid and nicotinamide metabolisms may be involved in As-induced hepatotoxicity. This research identified the metabolites, targets, and mechanisms of As-induced hepatotoxicity, offering meaningful insights and establishing the groundwork for developing antidotes for widespread As poisoning. [ABSTRACT FROM AUTHOR]