Thymol Protects against 5-Fluorouracil-Induced Hepatotoxicity via the Regulation of the Akt/GSK-3ß Pathway in In Vivo and In Silico Experimental Models.

BACKGROUND: 5-fluorouracil (5-FU) is a widely used, highly effective chemotherapeutic agent. However, its therapeutic efficacy is often limited by associated adverse effects, with hepatotoxicity being frequently reported with 5-FU therapy. Thymol is a monoterpene found in thyme (Thymus vulgaris L., Lamiaceae) and is known for its antioxidant, anti-apoptotic, and anticancer activities. This study aimed to explore the hepatoprotective activity of thymol against 5-FU-induced liver injury. METHODS: Rats received two intraperitoneal doses of 5-FU (150 mg/kg) either alone or in combination with thymol at doses of 60 mg/kg or 120 mg/kg. Liver enzymes, oxidative stress, and apoptotic markers, in addition to histopathological changes, were assessed. RESULTS: 5-FU induced marked liver injuries as evidenced by elevated liver enzymes and histopathological changes, in addition to abnormalities of oxidative and apoptotic markers. The administration of thymol ameliorated the 5-FU-induced oxidative damage through increasing hepatic antioxidants and lowering lipid peroxidation. Apoptotic response markers such as Bax, Bcl-2, Bax/Bcl-2 ratio, and PARP were also improved. Furthermore, Western blotting analysis showed that thymol modulated the 5-FU-induced changes in the expression of Akt/GSK-3ß and p44/42 MAPK (ERK1/2) signaling pathways. CONCLUSIONS: Our research is the first to shed light on thymol's potential protective effect against 5-FU- induced hepatotoxicity by inhibiting oxidative and apoptotic pathways and modulating the Akt/ GSK-3ß as well as p44/42 MAPK (ERK1/2) signaling pathways.

Activation of protein kinase R in the manganese-induced apoptosis of PC12 cells.

Manganese neurotoxicity leads to Parkinson-like symptoms associated with the apoptotic cell death of dopaminergic neurons. Protein kinase R (PKR) is a serine/threonine-specific protein kinase that has been implicated in several cellular signal transduction pathways, including the induction of apoptosis. Here, we investigated the role of PKR in the manganese-induced apoptosis of dopamine-producing pheochromocytoma PC12 cells. Manganese (0.5 mM) induced the proteolytic cleavage of PKR and caspase-3, DNA fragmentation, and cell death, which were prevented by the co-treatment of PC12 cells with a PKR specific inhibitor, C16 in a concentration-dependent manner. C16 did not affect the manganese-induced activation of the c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) pathway, indicating that PKR functions downstream of JNK and p38 MAPK. In contrast, C16 triggered the activation of the p44/42 MAPK (ERK1/2) pathway and induced hemoxygenase-1, both in the absence and presence of manganese. PKR is reportedly involved in endoplasmic reticulum (ER) stress-induced apoptosis. Manganese activated all three branches of the unfolded protein response in PC12 cells; however, this effect was very weak compared with the ER stress induced by the well-known ER stress inducers thapsigargin and tunicamycin. Moreover, C16 did not affect manganese-induced ER stress at concentrations that almost prevented caspase-3 activation and DNA fragmentation. These results suggest that PKR is involved in manganese-induced apoptotic cell death and stress response, such as the activation of the p44/42 MAPK pathway and the induction of hemoxygenase-1. Although manganese induced a faint, but typical, ER stress, these events contributed little to manganese-induced apoptosis.

The Fluoro-Thiazolylhydrazone Compound TSC-3C Inhibits Triple Negative Breast Cancer (TNBC) Cell Line Activity by Promoting Apoptosis, Regulating the MAPK Pathway and Inducing Mitochondrial Dysfunction.

Triple negative breast cancer (TNBC) is the most aggressive cancer in women, and despite improved treatments, it remains a major cause of morbidity and mortality. We and others have demonstrated that different hybrid compounds targeting PARP/MAPK or other pathways to inhibit cancer progression may lead to promising therapeutic results. We introduced fluorine to alter the physical properties of the compounds. TSC-3C was one of the generated compounds. Upon treatment with TSC-3C, MDA-MB-231 cell proliferation, invasion, and migration were inhibited. TSC-3C induced MDA-MB-231 cell mitochondrial dysfunction and apoptosis, which may be caused by reducing the level of phosphorylated p44/42 MAPK (ERK1/2) and increasing the level of p-JNK. The present study may help to elucidate the role of the MAPK pathway in the development of breast cancer and may promote further research on halogenated heterocyclic compounds for the treatment of breast cancer.

STAT3-mediated attenuation of CCl4-induced mouse liver fibrosis by the protein kinase inhibitor sorafenib.

There have been major advances in defining the immunological events associated with fibrosis in various chronic liver diseases. We have taken advantage of this data to focus on the mechanisms of action of a unique multi-kinase inhibitor, coined sorafenib, on CCl4-induced murine liver fibrosis, including the effects of this agent in models of both acute and chronic CCl4-mediated pathology. Importantly, sorafenib significantly attenuated chronic liver injury and fibrosis, including reduction in liver inflammation and histopathology as well as decreased expression of liver fibrosis-related genes, including α-smooth muscle actin, collagen, matrix metalloproteinases and the tissue inhibitor of metalloproteinase-1. Furthermore, sorafenib treatment resulted in translocation of cytoplasmic STAT3 to the nucleus in its active form. Based on this observation, we used hepatocyte-specific STAT3 knockout (STAT3(Hep-/-)) mice to demonstrate that hepatic STAT3 was critical for sorafenib-mediated protection against liver fibrosis, and that the upregulation of STAT3 phosphorylation was dependent on Kupffer cell-derived IL-6. In conclusion, these data reflect the clinical potential of the multi-kinase inhibitor sorafenib for the prevention of fibrosis as well as the treatment of established liver fibrosis and illustrate the immunological mechanisms that underlie the protective effects of sorafenib.