PKM2 Inhibitor(University of Shanghai for Science and Technology)

Chronic sympathetic stress contributes significantly to the cardiac hypertrophy (CH) development. Currently, several pharmacological agents and surgical options are available for the treatment of CH. However, available treatment options are associated with side effects and surgical complications. The published reports indicated the PKM2 substantial role in numerous illnesses. Furthermore, the effect of shikonin (SK), a nonselective PKM2 inhibitor, on PKM2/c-Myc/PTBP1/HIF-1α signaling in the CH model has never been explored. Thus, in this study, we explore the effect of SK on the PKM2-mediated c-Myc/PTBP1/HIF-1α signaling pathway in isoproterenol (ISO)-induced CH.

The preclinical rat model of pathological CH was developed by subcutaneous (s.c.) administration of ISO (5 mg/kg/day) over 14 days. ISO-treated rats were orally received SK (2 and 4 mg/kg/day) for a period of 14 days. After all treatment completion, animals were anesthetized for electrocardiogram (ECG), blood pressure, and ventricular function recording. Afterward, animal blood samples were isolated, and then animals were sacrificed for further molecular and histopathology studies.

Fourteen days treatment of SK showed significant improvement in ECG, fibrosis, inflammation, and cardiac function. Moreover, PKM2, PTBP1, c-Myc, and HIF-1α expressions were upregulated, while PKM1 expression was downregulated in ISO-treated rats, which was reversed by SK treatment in ISO-induced CH rats.

Thus, our results demonstrated that SK modulates the PKM2/c-Myc/PTBP1/HIF-1α pathway mediated by PKM2 inhibition, which might be responsible for SK-mediated cardioprotection in ISO-induced CH.

Triclosan (TCS) is an effective broad-spectrum antibacterial agent. TCS possesses a stable structure, can easily accumulate in the environment, and may have numerous negative impacts on human health. One organ particularly susceptible to TCS damage is the liver; however, the molecular mechanisms underlying TCS-induced liver damage remain unclear. A long-term TCS exposure model was established in C57BL/6 mice through maternal administration from gestation to postnatal 8-week-old. The offspring were randomly assigned to three groups (0, 50, and 100 mg/kg TCS) with six animals per group, ensuring an equal gender distribution (3 males and 3 females). The results showed that TCS-exposed mice exhibited serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase enzyme activities increased by 1.5-2 times when compared with vehicle-treated mice, along with features of liver fibrosis. In the LX-2 cell line, used as an in vitro model, TCS promoted proliferation and migration and induced the activation of hepatic stellate cells (HSCs). The level of pyruvate kinase M2 (PKM2) dimer increased by 200 % in LX-2 cells treated with TCS. PKM2 dimer overexpression stimulated HSC activation, whereas treatment with TEPP-46 (a PKM2 dimer inhibitor) significantly decreased the activation process. The expression of heterogeneous ribonucleoprotein particle A1 (hnRNPA1) was upregulated in the TCS treatment group and promoted the PKM2 expression. Moreover, disruption of the hnRNPA1/PKM2 axis reduced HSC proliferation and migration activated by TCS. Overall, our findings highlighted that TCS could cause liver fibrosis by stimulating the proliferation and migration of HSCs activated via the hnRNPA1/PKM2 axis, providing promising treatment options for TCS-related liver damage.