Dewei Peng

Background: Heart failure (HF) is one of the major causes of mortality worldwide with high recurrence rate and poor prognosis. Our study aimed to investigate potential mechanisms and drug targets of Shenfu Qiangxin (SFQX), a cardiotonic-diuretic traditional Chinese medicine, in treating HF. Methods: An HF-related and SFQX-targeted gene set was established using disease-gene databases and the Traditional Chinese Medicine Systems Pharmacology database. We performed gene function and pathway enrichment analysis and constructed protein–protein interaction (PPI) network to investigate the potential mechanisms. We also performed molecular docking to analyze the interaction patterns between the active compounds and targeted protein. Results: A gene set with 217 genes was identified. The gene function enrichment indicated that SFQX can regulate apoptotic process, inflammatory response, response to oxidative stress and cellular response to hypoxia. The pathway enrichment indicated that most genes were involved in PI3K–Akt pathway. Eighteen hub target genes were identified in PPI network and subnetworks. mTOR was the key gene among hub genes, which are involved in PI3K–Akt pathway. The molecular docking analysis indicated that 6 active compounds of SFQX can bind to the kinase domain of mTOR, which exerted potential therapeutic mechanisms of SFQX in treating HF. Conclusions: The results of network pharmacology analysis highlight the intervention on PI3K–Akt pathway of SFQX in the treatment of HF. mTOR is a key drug target to help protect myocardium.

Notopterol is a naturally occurring furanocoumarin compound found in the root of Notopterygium incisum. Hyperuricemia involves the activation of chronic inflammation and leads to cardiac damage. Whether notopterol has cardioprotective potential in hyperuricemia mice remains elusive. The hyperuricemic mouse model was constructed by administration of potassium oxonate and adenine every other day for six weeks. Notopterol (20 mg/kg) and allopurinol (10 mg/kg) were given daily as treatment, respectively. The results showed that hyperuricemia dampened heart function and reduced exercise capacity. Notopterol treatment improved exercise capacity and alleviated cardiac dysfunction in hyperuricemic mice. P2X7R and pyroptosis signals were activated both in hyperuricemic mice and in uric acid-stimulated H9c2 cells. Additionally, it was verified that inhibition of P2X7R alleviated pyroptosis and inflammatory signals in uric acid-treated H9c2 cells. Notopterol administration significantly suppressed expression levels of pyroptosis associated proteins and P2X7R in vivo and in vitro. P2X7R overexpression abolished the inhibition effect of notopterol on pyroptosis. Collectively, our findings suggested that P2X7R played a critical role in uric acid-induced NLRP3 inflammatory signals. Notopterol inhibited pyroptosis via inhibiting the P2X7R/NLRP3 signaling pathway under uric acid stimulation. Notopterol might represent a potential therapeutic strategy against pyroptosis and improve cardiac function in hyperuricemic mice.

Cuproptosis resulting from copper (Cu) overload has not yet been investigated in diabetic cardiomyopathy (DCM). Advanced glycosylation end products (AGEs) induced by persistent hyperglycemia play an essential role in cardiotoxicity. To clarify whether cuproptosis was involved in AGEs-induced cardiotoxicity, we analyzed the toxicity of AGEs and copper in AC16 cardiomyocytes and in STZ-induced or db/db-diabetic mouse models. The results showed that copper ionophore elesclomol induced cuproptosis in cardiomyocytes. It was only rescued by copper chelator tetrathiomolybdate rather than by other cell death inhibitors. Intriguingly, AGEs triggered cardiomyocyte death and aggravated it when incubated with CuCl₂ or elesclomol–CuCl2. Moreover, AGEs increased intracellular copper accumulation and exhibited features of cuproptosis, including loss of Fe–S cluster proteins (FDX1, LIAS, NDUFS8 and ACO2) and decreased lipoylation of DLAT and DLST. These effects were accompanied by decreased mitochondrial oxidative respiration, including downregulated mitochondrial respiratory chain complex, decreased ATP production and suppressed mitochondrial complex I and III activity. Additionally, AGEs promoted the upregulation of copper importer SLC31A1. We predicted that ATF3 and/or SPI1 might be transcriptional factors of SLC31A1 by online databases and validated that by ATF3/SPI1 overexpression. In diabetic mice, copper and AGEs increases in the blood and heart were observed and accompanied by cardiac dysfunction. The protein and mRNA profile changes in diabetic hearts were consistent with cuproptosis. Our findings showed, for the first time, that excessive AGEs and copper in diabetes upregulated ATF3/SPI1/SLC31A1 signaling, thereby disturbing copper homeostasis and promoting cuproptosis. Collectively, the novel mechanism might be an alternative potential therapeutic target for DCM.

Cancer survivors suffer a higher risk of coronary artery atherosclerosis (CAA). Whether cancer patients had increased baseline CAA burden prior to cardiotoxic therapy remains unclear. We conducted a case-control study, and 286 consecutive patients were finally included. Among these patients, 181 had newly diagnosed cancer and 105 had nonmalignant diseases. Cancer was confirmed by biopsy. The severity of CAA was determined by coronary angiography and evaluated using the percentage of stenosis or Gensini scoring (GS). Patients with cancer versus cancer-free controls were older (OR = 1.052, 95% CI: 1.021–1.084, ), more commonly male (OR = 0.048, 95% CI: 1.004–2.676, ), and more severely exposed to smoking (OR = 1.020, 95% CI: 1.007–1.033, ). Cancer patients were significantly more commonly complicated by ≥90% coronary stenosis than the gender- and age-matched cancer-free controls (9/93 versus 1/93, OR = 4.875, 95% CI: 1.024–23.213, ). After adjustment for age, gender, hypertension, diabetes, smoking history, blood glucose, and total cholesterol, cancer was significantly associated with high GS (adjusted OR = 2.208, 95% CI: 1.077–4.524, ). Our study demonstrated that cancer patients had increased CAA burden prior to cardiotoxic therapy. Further study is necessary to investigate the link between CAA and cancer.